Serotonin and psychostimulant addiction: Focus on 5-HT1A-receptors

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Progress in Neurobiology 81 (2007) 133–178

Serotonin and psychostimulant addiction: Focus on 5-HT1A-receptors

Christian P. Muller a,*, Robert J. Carey b, Joseph P. Huston a, Maria A. De Souza Silva a

a Institute of Physiological Psychology I, University of Dusseldorf, Universitatsstr. 1, 40225 Dusseldorf, Germanyb Research and Development (151), VA Medical Center and SUNY Upstate Medical University, 800 Irving Avenue, Syracuse, NY 13210, USA

Received 6 September 2006; received in revised form 4 December 2006; accepted 3 January 2007

Abstract

Serotonin1A-receptors (5-HT1A-Rs) are important components of the 5-HT system in the brain. As somatodendritic autoreceptors they control

the activity of 5-HT neurons, and, as postsynaptic receptors, the activity in terminal areas. Cocaine (COC), amphetamine (AMPH),

methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (‘‘Ecstasy’’, MDMA) are psychostimulant drugs that can lead to

addiction-related behavior in humans and in animals. At the neurochemical level, these psychostimulant drugs interact with monoamine

transporters and increase extracellular 5-HT, dopamine and noradrenalin activity in the brain. The increase in 5-HT, which, in addition to

dopamine, is a core mechanism of action for drug addiction, hyperactivates 5-HT1A-Rs. Here, we first review the role of the various 5-HT1A-R

populations in spontaneous behavior to provide a background to elucidate the contribution of the 5-HT1A-Rs to the organization of

psychostimulant-induced addiction behavior. The progress achieved in this field shows the fundamental contribution of brain 5-HT1A-Rs to

virtually all behaviors associated with psychostimulant addiction. Importantly, the contribution of pre- and postsynaptic 5-HT1A-Rs can be

dissociated and frequently act in opposite directions. We conclude that 5-HT1A-autoreceptors mainly facilitate psychostimulant addiction-related

behaviors by a limitation of the 5-HT response in terminal areas. Postsynaptic 5-HT1A-Rs, in contrast, predominantly inhibit the expression of

various addiction-related behaviors directly. In addition, they may also influence the local 5-HT response by feedback mechanisms. The reviewed

findings do not only show a crucial role of 5-HT1A-Rs in the control of brain 5-HT activity and spontaneous behavior, but also their complex role in

the regulation of the psychostimulant-induced 5-HT response and subsequent addiction-related behaviors.

# 2007 Elsevier Ltd. All rights reserved.

Keywords: Psychostimulants; 5-HT1A-receptor; Cocaine; Amphetamine; Methamphetamine; MDMA; Behavior; Addiction; Serotonin

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

2. The neurochemical effects of psychostimulants in the 5-HT system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

2.1. Acute effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

2.2. Chronic effects and withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

3. The 5-HT1A-receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

3.1. 5-HT1A-receptor ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

3.2. Brain distribution of 5-HT1A-receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

3.2.1. 5-HT1A-autoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

3.2.2. Postsynaptic 5-HT1A-receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Abbreviations: 5,7-DHT, 5,7-dihydroxytryptamine; 5-HT, 5-hydroxytryptamine (serotonin); 5-HT-R, serotonin receptor; 5-HT1A-R, serotonin1A-receptor; ACh,

acetylcholine; ACTH, adrenocorticotrophin; AMPH, amphetamine; COC, cocaine; CPA, conditioned place avoidance; CPP, conditioned place preference; DA,

dopamine; DAT, dopamine transporter; DRN, dorsal raphe nucleus; FC, frontal cortex; GABA, g-aminobutyric acid; i.c.v., intracerebroventricular; i.p.,

intraperitoneal; i.v., intravenous; PFC, prefrontal cortex; LC, locus coeruleus; METH, methamphetamine; MDMA, 3,4-methylenedioxymethamphetamine; mPFC,

medial prefrontal cortex; MRN, median raphe nucleus; mRNA, messenger ribonucleic acid; NA, noradrenaline; Nac, nucleus accumbens; NAT, noradrenaline

transporter; PCA, p-chloroamphetamine; PCP, p-chlorophenylalanine; PET, positron emission tomography; R, receptor; s.c., subcutaneous; SERT, serotonin

transporter; SSRI, selective serotonin reuptake inhibitors; SN, substantia nigra; VTA, ventral tegmental area

* Corresponding author. Tel.: +49 211 81 13491; fax: +49 211 81 12024.

E-mail address: [email protected] (C.P. Muller).

0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pneurobio.2007.01.001

mailto:[email protected]

http://dx.doi.org/10.1016/j.pneurobio.2007.01.001

C.P. Muller et al. / Progress in Neurobiology 81 (2007) 133–178134

4. The 5-HT1A-receptors and psychostimulant-induced behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

4.1. Locomotor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

4.1.1. Role of the 5-HT1A-receptors in spontaneous locomotor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

4.1.2. Psychostimulant-induced locomotor activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

4.1.3. 5-HT1A-receptors in psychostimulant-induced hyperlocomotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

4.2. Behavioral stereotypies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

4.2.1. The 5-HT1A-receptors and the serotonin syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

4.2.2. Psychostimulant-induced behavioral stereotypies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

4.2.3. 5-HT1A-receptors in psychostimulant-induced stereotypies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.3. Grooming behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.3.1. Role of the 5-HT1A-receptors in grooming behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.3.2. Psychostimulant effects on grooming behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.3.3. 5-HT1A-receptors in suppression of grooming behavior by psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.4. Feeding behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.4.1. Role of the 5-HT1A-receptors in feeding behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

4.4.2. Psychostimulant-induced suppression of feeding behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

4.4.3. 5-HT1A-receptors in psychostimulant-induced suppression of feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

4.5. Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

4.5.1. The 5-HT1A-receptors and anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

4.5.2. Psychostimulant effects on anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

4.5.3. 5-HT1A-receptors in psychostimulant effects on anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

4.6. Discriminative stimulus properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

4.6.1. 5-HT1A-receptor stimulation and inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

4.6.2. Psychostimulant discriminative stimulus properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

4.6.3. 5-HT1A-receptors and psychostimulant discriminative stimulus properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

4.7. Learning, memory and reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

4.7.1. The role of the 5-HT1A-receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

4.7.2. Psychostimulant effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

4.7.3. 5-HT1A-receptors in psychostimulant memory and reinforcing effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

5. 5-HT1A-receptor modulation of the neurochemical effects of psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

6. The effects of psychostimulants on 5-HT1A-receptor binding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

1. Introduction

Drug abuse is a serious and complex health problem, which

not only affects the individual user but all aspects of social and

economic life. The quest to understand the development of

abuse habits and drug addiction is, therefore, a major challenge

for behavioral neuroscience. Commonly abused drugs are the

so-called ‘‘psychostimulants’’, which comprise a class of drugs

that do not share a common chemical structure, but have

common behavioral and subjective effects. These drugs

increase behavioral activity and arousal, and can also induce

euphoria in humans. Drugs that share these effects include

cocaine (COC), a major alkaloid of the South American shrub

Erythroxylum coca, and the synthetic substance amphetamine

(AMPH) together with its derivates methamphetamine

(METH) and 3,4-methylenedioxymethamphetamine (MDMA,

also known as ecstasy). The amphetamines occur as stereo-

isomers d-AMPH and l-AMPH, (+)METH and (�)METH, and

(+)MDMA and (�)MDMA, or as the respective racemic

mixture. Notably, the d- or (+) isomer is usually more potent at

the behavioral and neurochemical level, and is more often used

for scientific investigation (e.g. Steele et al., 1987; Callaway

et al., 1990; Rothman et al., 2001; Fantegrossi et al., 2002).

The classification of these substances as ‘‘psychostimulant

drugs’’ reflects their commonality in the ability to evoke

increases in locomotor activity, arousal and euphoria. However,

the consumption of these compounds has many more

behavioral and subjective consequences, of which some

contribute to what is commonly recognized as ‘‘addiction

behavior’’, whereas other additional effects, like suppression of

grooming and eating behavior, do not directly constitute

addictive behaviors. The acute behavioral and subjective effects

of the psychostimulants are related to the tissue concentration

of the active substance as well as to the less active metabolites

(e.g. Bedford et al., 1980; Risner and Jones, 1980). However,

due to the brain’s function to maintain homeostasis, counter-

regulatory processes are evoked by the strong neurochemical

impact of the psychostimulant drugs. Immediately after the

intake of a psychostimulant drug, temporally limited functional

changes in the brain occur, that may endure beyond the

presence of the actual drug/metabolites in the brain (Ungless

et al., 2001). These functional changes and corresponding

homeostatic responses may be responsible for behavioral and

subjective effects of the drug intake that outlast the presence of

the drug in the brain (Koob and Le Moal, 1997). When the

consumption of a psychostimulant is repeated, the frequency of

C.P. Muller et al. / Progress in Neurobiology 81 (2007) 133–178 135

intake may increase, and eventually a transition to a binge-

taking pattern can take place. At the same time, the route of

application may become more ‘‘aggressive’’, i.e. it can change

from sniffing to smoking or to i.v. injection (Kramer et al.,

1967; Gawin and Kleber, 1986; Gawin, 1991). This transition

occurs because the euphoric effects of the psychostimulants

develop tolerance, i.e. the same dose of a drug induces less

euphoria with repeated administration. This effect is usually

counteracted by increasing the dose or/and changing the rout of

administration in the way that the bioavailability of the

administered drug increases and the time it arrives in the brain

decreases. At this point, not only the acute effects of the intake

change, but also new behaviors may appear. These new

behaviors are related to the ‘‘mental’’ occupation with the drug,

with drug-seeking, and, finally, with the self-administration of

the drug. This behavioral pattern occurs despite the possible

development of severe negative consequences (Deroche-

Gamonet et al., 2004; Vanderschuren and Everitt, 2004). The

occurrence and frequency of such newly developed behaviors is

usually considered when drug use, abuse or addiction is

diagnosed. Usually, the development of these behaviors

correlates with the changes in the acute effects of a

psychostimulant drug. This observation allows investigation

of the change in the acute effects, such as the development of

sensitization for the hyperlocomotor action, as an indicator for

the long-term effects of a psychostimulant drug. Hereby,

sensitization refers to an increase of the locomotor effects of the

drug with repeated application of the same dose. Chronic

stimulant use induces neuroadaptive changes, the behavioral

manifestations of which can often be observed in the absence of

the drug. In this case, behaviors are initiated in a drug-free state.

The mechanism behind these effects are not neurochemical

rebound responses, but are based on morphological and

functional long-term changes in the brain (Robinson and Kolb,

1997, 1999, 2004; Robinson et al., 2001; Li et al., 2003).

Accordingly, brain substrates mediating the acute pharmaco-

logical drug effects on behavior are not necessarily the same as

those underlying addiction-related behaviors in a drug-free

state. As the addiction-related behaviors promote continued

drug taking, the resulting long-term neurophysiological

alterations in brain function continue to be reinforced by the

acute neuropharmacological effects of the psychostimulant

drug.

Intensive research directed to understand the brain

mechanisms by which psychostimulants exert their strong

influence on behavior, have revealed that the mesolimbic

dopamine (DA) system plays a crucial role (Koob et al., 1998;

Wise, 2002). However, several lines of evidence have clearly

demonstrated that DA is not the sole mediator of the behavioral

effects of psychostimulant drugs. It was found that the

occupation of the dopamine transporter (DAT) by selective

DA reuptake blockers does not correlate with their locomotor

stimulant effects (Rothman et al., 1992; Newman et al., 1994).

Also the expression of psychostimulant-induced locomotor

sensitization can be dissociated from the expression of the

sensitization of the DA response in the nucleus accumbens

(Nac) (Szumlinski et al., 2000a,b). Furthermore, the effects of

psychostimulants on transcription factor gene expression seem

to be mediated by a synergistic action of DA and serotonin (5-

HT). The COC- and AMPH-induced increase in striatal zif268

mRNA expression could be only partially mimicked by the

selective DAT blocker, mazindol. This effect could be

potentiated with the selective serotonin reuptake inhibitors

(SSRI), fluoxetine or citalopram, but not with the noradrenalin

transporter (NAT) blocker, desipramine (Bhat and Baraban,

1993). A lesion of the 5-HT system with p-chloroamphetamine

(PCA) significantly attenuated the zif268 response to COC and

AMPH in the striatum (Bhat and Baraban, 1993), underscoring

an essential role for 5-HT in this psychostimulant effect. The

crucial role of the DAT for the reinforcing effects of COC has

been further questioned in experiments with transgenic mice.

Rocha et al. (1998a) found that COC is still self-administered in

knock-out mice that lack the DAT. Also, the ability of COC to

induce conditioned place preference (CPP) was preserved in

DAT knock-out mice. However, when DAT and serotonin

transporter (SERT) genes were both knocked out concurrently,

COC-induced CPP was eliminated (Sora et al., 2001; Hall et al.,

2004).

It has long been known that psychostimulants do not only

interact with the DA reuptake site, but also with 5-HT reuptake,

which results in an acute increase of extracellular 5-HT levels.

This increase in 5-HT levels hyperactivates the 5-HT-receptors

(5-HT-R) in the respective brain areas. At least 14 different 5-

HT-Rs have been characterized (Barnes and Sharp, 1999;

Hoyer et al., 2002). One of the most important is the 5-HT1A-R.

The 5-HT1A-R, which occurs pre- and postsynaptically,

displays a high affinity to 5-HT (Van Wijngaarden et al.,

1990) and is found in many brain areas. Therefore, it may not be

surprising, that this receptor is involved in virtually all 5-HT

mediated behaviors, and, as such, is also an important target for

pharmacological interventions. In the last two decades,

knowledge about its role in the various behavioral changes

induced by psychostimulants has accumulated together with

insights into the neurochemical mechanisms of how 5-HT1A-Rs

interact with the neurochemical effects of psychostimulant

drugs. This review attempts to summarize these findings and

provides an overview about the different psychostimulant-

related behaviors and the respective experimental approaches

(for a review on the functions of other 5-HT-Rs in

psychostimulant-induced behavior see: Walsh and Cunning-

ham, 1997; Muller et al., 2003a; Filip et al., 2005; Muller and

Huston, 2006; Muller and Carey, 2006).

After a short update on 5-HT1A-R anatomy and pharmacol-

ogy, we discuss the contribution of the 5-HT1A-R to the

behavioral effects of the four psychostimulant drugs COC,

AMPH, METH and MDMA. Although other amphetamine

derivates are also psychostimulants, 5-HT1A-R research has

focused primarily on the investigation of these four drugs. In

order to understand the contribution of the 5-HT1A-R to each

drug-related behavior, it appears essential to know which role

the 5-HT1A-R plays in this behavior in an undrugged state, i.e.

under natural conditions. Therefore, each behavioral discussion

consists of three parts: (1) the role of the 5-HT1A-R alone, (2)

the effects of psychostimulants on this behavior and (3) how


5-HT1A-Rs contribute to the psychostimulant effects. In the

second part, we outline in detail what is known about the effects

of psychostimulant drugs on extracellular 5-HT activity after

acute and chronic psychostimulant consumption, and how 5-

HT1A-Rs modulate these effects. Since, 5-HT1A-R density and

affinity are affected by environmental stimuli, behavior and

pharmacological intervention, we also discuss the effects of

prolonged psychostimulant consumption on 5-HT1A-R binding

density and affinity.

2. The neurochemical effects of psychostimulants in the

5-HT system

2.1. Acute effects

Psychostimulant drugs interfere with the function of

monoamine transporters for 5-HT, DA and NA (Ross and

Renyi, 1967, 1969; Koe, 1976). Thereby, they lead to an increase

of extracellular 5-HT, DA and NA levels in the brain, which can

be seen as the ‘‘primary neurochemical effects’’. The increase of

these three transmitters results in a number of subsequent

neurochemical responses, such as an increase of glutamatergic,

acetylcholinergic or peptidergic activity (Reid et al., 1997;

Consolo et al., 1999; Beinfeld et al., 2002), which can be seen as

‘‘secondary neurochemical responses’’. Modulating the primary

neurochemical responses has, therefore, significant conse-

quences on subsequent secondary neurochemical responses

(Cameron and Williams, 1994). Although all psychostimulants

interact with all three monoamine transporters, their relative

impacts are different. While COC shows a relative potency on

monoaminergic systems 5-HT > DA > NA, the potency of

AMPH and METH is NA > DA� 5-HT, and that of MDMA is

5-HT = NA� DA (Battaglia et al., 1988; Ritz and Kuhar, 1989;

Crespi et al., 1997; Rothman et al., 2001; Wee et al., 2005).

Psychostimulants can be further divided into two principal

classes according to their mechanism of action: in reuptake

blockers or transmitter releasers. COC acts by blocking the

reuptake of 5-HT, DA and NA from the synaptic cleft (Johanson

and Fischman, 1989). In contrast, AMPH and its derivates are

substrates of the monoamine transporters and compete with the

transmitters for the binding. By diffusion exchange, the drug is

transported into the cell. At the same time, transmitter is

actively transported out of the cytoplasma into extracellular

space. Amphetamines may also get into the nerve terminal by

passive diffusion. Within the nerve terminal amphetamines are

a substrate for vesicular monoamine transporters. Ampheta-

mines compete with the transmitters for these binding sites and

are actively transported into the vesicle. At the same time, the

transmitter is removed from the vesicle into the cytoplasma

(Berger et al., 1992; Schmidt, 1987a; Schmidt et al., 1987;

Seiden et al., 1993). The impact that each psychostimulant drug

has on extracellular 5-HT differs considerably, and, in relation

to the effects on DA activity, may be the primary source for

differences in the expression of the various addiction-related

behaviors between the psychostimulant drugs. We next discuss

the primary neurochemical effects of psychostimulant drugs

within the 5-HT system.

In the rat, acute COC administration at doses of

approximately 10 mg/kg (i.p.) or more leads to a temporally

limited increase in extracellular 5-HT levels in various

subcortical structures in rodents (Table 1), such as the Nac

(Parsons and Justice, 1993; Broderick et al., 1993; Teneud et al.,

1996; Andrews and Lucki, 2001; Muller et al., 2003b), the

dorsal striatum (Bradberry et al., 1993), ventral pallidum

(Sizemore et al., 2000), hippocampus (Muller et al., 2003a,

2004a), thalamus (Rutter et al., 1998), hypothalamus (Shimizu

et al., 1992), ventral tegmental area (VTA; Parsons and Justice,

1993; Chen and Reith, 1994; Reith et al., 1997) and dorsal

raphe nucleus (DRN; Parsons and Justice, 1993). COC also has

profound effects on extracellular 5-HT levels in various

neocortical areas, such as the prefrontal cortex (PFC;

Mangiavacchi et al., 2001; Pum et al., submitted for

publication), the occipital and temporal cortices (Muller

et al., 2007) and the entorhinal and perirhinal cortices (Pum

et al., submitted for publication). Small doses of COC or

d-AMPH lead to a much more intense and prolonged increase

in 5-HT than sensory stimulation (Muller et al., 2007; Pum

et al., submitted for publication) or behavioral activity (Rueter

et al., 1997). When animals are allowed to self-administer COC

with an unlimited access, 5-HT levels initially increase in the

Nac and ventral pallidum, and remain at a plateau level

(Parsons et al., 1995; Sizemore et al., 2000), possibly self-

titrated by the self-administration behavior (for a detailed

review on COC pharmacology see: Johanson and Fischman,

1989).

AMPH increases extracellular 5-HT levels in the Nac and

the striatum at doses of 2–9 mg/kg (s.c. or i.p.), parallel to the

expression of hyperlocomotion and behavioral stereotypies

(Table 1) (Hernandez et al., 1987; Kuczenski and Segal, 1989,

1997; Kuczenski et al., 1995; Segal and Kuczenski, 1997a,c;

Kankaanpaa et al., 1998; Millan et al., 1999). An AMPH-

induced 5-HT increase was also observed with 2.5 mg/kg (i.p.)

in the FC (Millan et al., 1999) and with 1–2.5 mg/kg (i.p.) in the

mPFC (Kuroki et al., 1996; Pum et al., submitted for

publication), and the entorhinal and perirhinal cortices parallel

to locomotor activation (Pum et al., submitted for publication),

which might suggest a higher 5-HT sensitivity in cortical

compared to limbic areas. An increase in extracellular 5-HT

levels was also reported in the DRN during local AMPH

application (Ferre et al., 1994), but not in the striatum (Dawson

et al., 2003). Local application of AMPH by reverse dialysis

into the infralimbic and anterior cingular subregions of the

prefrontal cortex also increases extracellular 5-HT levels in the

respective regions (Hedou et al., 2000). Also at the

neurochemical level, d-AMPH appears to be more potent than

l-AMPH (Kuczenski et al., 1995; for a detailed review see:

Seiden et al., 1993).

An increase of extracellular 5-HT activity in the Nac and

dorsal striatum was reported after METH application (2 and

4.42 mg/kg, s.c.) (Table 1) (Kuczenski et al., 1995; Segal and

Kuczenski, 1997b), with the METH d-isomer being neuro-

chemically more active than the l-isomer (Kuczenski et al.,

1995). d-METH (7.5 mg/kg, i.p.) increased 5-HT levels in the

ventral hippocampus of freely moving rats (Rocher and

Table 1

The effects of cocaine, amphetamine, methamphetamine and MDMA on extracellular levels of serotonin in discrete brain regions as determined by in vivo

microdialysis ("/# significant increase or decrease; – no significant change; SA, determined during drug self-administration)

Drug Brain area Species Dose Effect Reference

Cocaine Ncl. Accumbens Rat 10 mg/kg, i.p. – Andrews and Lucki (2001)

Rat 10 mg/kg, i.p. " Parsons and Justice (1993)

Rat 10 mg/kg, i.p. " Teneud et al. (1996)

Rat 10 mg/kg, i.p. " Muller et al. (2002b, 2003b)

Rat 10 mg/kg, i.p. " Muller et al. (2004a,b)

Rat 18 mg/kg, i.p. " Andrews and Lucki (2001)


Rat 20 mg/kg, i.p. " Reith et al. (1997)

Rat 25 mg/kg, i.p. " Andrews and Lucki (2001)


Rat 0.1 mM local " Andrews and Lucki (2001)

Rat 3 mM local – Andrews and Lucki (2001)

Rat 3.6 mM local " Teneud et al. (1996)


Rat 10 mM local " Andrews and Lucki (2001)


Rat SA: 0.25 mg/inf. " Parsons et al. (1995)

Ventral pallidum Rat SA: 0.17–0.33 mg/inf. " Sizemore et al. (2000)

Striatum Rat 3 mmol/kg, i.v. " Bradberry et al. (1993)

44 mmol/kg, i.p. " Bradberry et al. (1993)

Hippocampus Rat 10 mg/kg, i.p. " Muller et al. (2002b, 2003b, 2004a)

Thalamus Rat 0.75 mg/kg, i.v. " Rutter et al. (1998)

Hypothalamus Rat 30 mM (local) " Shimizu et al. (1992)

VTA Rat 10 mg/kg, i.p. " Parsons and Justice (1993)

Rat 20 mg/kg, i.p. " Reith et al. (1997)

Rat 20 mg/kg, i.p. " Chen and Reith (1994)

Rat 40 mg/kg, i.p. " Chen and Reith (1994)

DRN Rat 10 mg/kg, i.p. " Parsons and Justice (1993)

Prefrontal cortex Rat 5 mg/kg, i.p. – Pum et al. (submitted for publication)

Rat 5 mg/kg, i.p. " Mangiavacchi et al. (2001)

Rat 10 mg/kg, i.p. " Pum et al. (submitted for publication)


Occipital cortex Rat 5 mg/kg, i.p. – Muller et al. (2007)

Rat 10 mg/kg, i.p. " Muller et al. (2007)


Temporal cortex Rat 5 mg/kg, i.p. – Muller et al. (2007)



Perirhinal cortex Rat 5 mg/kg, i.p. – Pum et al. (submitted for publication)



Entorhinal cortex Rat 5 mg/kg, i.p. – Pum et al. (submitted for publication)



Amphetamine Ncl. Accumbens Rat 0.16 mg/kg, i.p. d-AMPH – Millan et al. (1999)

Rat 0.63 mg/kg, i.p. d-AMPH – Millan et al. (1999)

Rat 1 mg/kg, s.c. – Kankaanpaa et al. (1998)

Rat 2 mg/kg, i.p. d-AMPH " Hernandez et al. (1987)

Rat 2.5 mg/kg, i.p. d-AMPH " Millan et al. (1999)

Rat 3 mg/kg, s.c. – Kankaanpaa et al. (1998)

Rat 4 mg/kg, s.c. – Segal and Kuczenski (1997b)

Rat 9 mg/kg, s.c. " Kankaanpaa et al. (1998)

Rat 4 mg local d-AMPH " Hernandez et al. (1987)

Striatum Rat 0.16 mg/kg, i.p. d-AMPH – Millan et al. (1999)

Rat 0.3 mg/kg, s.c. d,l-AMPH – Dawson et al. (2003)

Rat 0.5 mg/kg, s.c. – Kuczenski and Segal (1989)



Table 1 (Continued )

Drug Brain area Species Dose Effect Reference

Rat 1 mg/kg, s.c. – Kuczenski and Segal (1989)

Rat 2 mg/kg, s.c. " Kuczenski and Segal (1989)

Rat 2 mg/kg, i.p. d-AMPH " Hernandez et al. (1987)

Rat 2 mg/kg, s.c. d-AMPH " Kuczenski et al. (1995)

Rat 2.5 mg/kg, s.c. " Kuczenski and Segal (1989)

Rat 2.5 mg/kg, s.c. " Kuczenski and Segal (1997)


Rat 4 mg/kg, s.c. – Segal and Kuczenski (1997b)

Rat 5 mg/kg, s.c. " Kuczenski and Segal (1989)

Rat 6 mg/kg, s.c. l-AMPH " Kuczenski et al. (1995)

Rat 8 mg/kg, i.p. d-AMPH " Segal and Kuczenski (1997c)

Rat 100 nM local d,l-AMPH – Dawson et al. (2003)

Rat 4 mg local d-AMPH " Hernandez et al. (1987)

Substantia nigra Rat 5 mg/kg, i.p. d-AMPH – Yamamoto et al. (1995)

DRN Rat 10 mM local d-AMPH " Ferre et al. (1994)

Frontal cortex Rat 0.16 mg/kg, i.p. d-AMPH – Millan et al. (1999)



PFC Rat 0.5 mg/kg, i.p. d-AMPH – Pum et al. (submitted for publication)

Rat 1 mg/kg, s.c. d-AMPH " Kuroki et al. (1996)

Rat 1 mg/kg, i.p. d-AMPH " Pum et al. (submitted for publication)

Rat 2.5 mg/kg, i.p. d-AMPH " Pum et al. (submitted for publication)

Infralimbic cortex Rat 1 mM local d-AMPH – Hedou et al. (2000)

Rat 10 mM local d-AMPH – Hedou et al. (2000)

Rat 100 mM local d-AMPH " Hedou et al. (2000)



Anterior cingulate cortex Rat 1 mM local d-AMPH – Hedou et al. (2000)

Rat 10 mM local d-AMPH – Hedou et al. (2000)




Perirhinal cortex Rat 0.5 mg/kg, i.p. d-AMPH – Pum et al. (submitted for publication)

Rat 1 mg/kg, i.p. d-AMPH " Pum et al. (submitted for publication)

Rat 2.5 mg/kg, i.p. d-AMPH – Pum et al. (submitted for publication)

Entorhinal cortex Rat 0.5 mg/kg, i.p. d-AMPH – Pum et al. (submitted for publication)

Rat 1 mg/kg, i.p. d-AMPH – Pum et al. (submitted for publication)

Rat 2.5 mg/kg, i.p. d-AMPH " Pum et al. (submitted for publication)

Methamphetamine Ncl. Accumbens Rat 4.42 mg/kg, s.c. " Segal and Kuczenski (1997b)

Striatum Rat 2 mg/kg, s.c. d-METH " Kuczenski et al. (1995)

Rat 3 mg/kg, s.c. l-METH – Kuczenski et al. (1995)

Rat 4.42 mg/kg, s.c. " Segal and Kuczenski (1997b)

Rat 6 mg/kg, s.c. l-METH " Kuczenski et al. (1995)



Hippocampus Rat 7.5 mg/kg, i.p. d-METH " Rocher and Gardier (2001)

PFC Mouse 1 mg/kg, i.p. " Ago et al. (2006)

MDMA Ncl. Accumbens Rat 1 mg/kg, s.c. " Kankaanpaa et al. (1998)



Striatum Rat 10 mg/kg, i.p. " Gough et al. (1991)

Rat 10 mg/kg, i.p. " Sabol and Seiden (1998)

Hippocampus Rat 1 mg/kg, i.v. " Gartside et al. (1997)

Rat 3 mg/kg, i.v. " Gartside et al. (1997)

Rat 15 mg/kg, i.p. " Mechan et al. (2002)

Substantia nigra Rat 20 mg/kg, i.p. (�) MDMA " Yamamoto et al. (1995)

Frontal cortex Rat 1 mg/kg, i.v. " Gartside et al. (1997)

Rat 3 mg/kg, i.v. " Gartside et al. (1997)



Gardier, 2001). In mice a 5-HT increase was reported in the

PFC after 1 mg/kg (i.p.) METH (Ago et al., 2006a).

MDMA (1–9 mg/kg, s.c.) increases extracellular 5-HT

activity in the Nac (Kankaanpaa et al., 1998), the striatum

(Gough et al., 1991; Sabol and Seiden, 1998), the substantia

nigra (SN; Yamamoto et al., 1995), the hippocampus (Gartside

et al., 1997; Mechan et al., 2002) and the FC (Gartside et al.,

1997), as measured by in vivo microdialysis studies in rats

(Table 1), or in superfused rat brain slices (Schmidt, 1987a).

Microdialysis measurements in slice preparations also revealed

an increase of extracellular 5-HT levels in the striatum (Koch

and Galloway, 1997), and in the DRN (Sprouse et al., 1989,

1990; for a detailed review on MDMA pharmacology see:

Green et al., 2003).

2.2. Chronic effects and withdrawal

The usual way of psychostimulant use is a repeated single

dose application over prolonged periods of time, which may

eventually develop to a binge-taking pattern with escalating

doses (Kramer et al., 1967; Gawin and Kleber, 1986; Gawin,

1991). The neurochemical effects of this intake pattern have

been investigated in systematic studies in rats. The results show

that AMPH and METH increase extracellular 5-HT levels in the

Nac and dorsal striatum after each single dose during a binge

phase. However, the amplitude of the increase in 5-HT is

diminished in the course of the repeated drug application

(Kuczenski et al., 1995; Segal and Kuczenski, 1997a,b), which

might be one reason for an escalation of the dose during a binge

in humans.

The termination of unrestricted self-administration is

followed by a withdrawal syndrome, which is characterized

by dysphoria, anhedonia, depression and anxiety in humans

(Kramer et al., 1967; Gawin and Kleber, 1986; Gawin, 1991).

These behavioral effects appear to be associated with profound

changes in 5-HT activity in rodents. It was reported that

extracellular 5-HT levels in the Nac and ventral pallidum,

which were increased during COC self-administration, drop

below pre-drug baseline levels within 2 h (Parsons et al., 1995;

Sizemore et al., 2000). This reduction in 5-HT (and also DA)

activity in the Nac could be observed for at least 12 h (Parsons

et al., 1995). When COC (20 mg/kg/day) was administered by

the experimenter on 10 consecutive days, no change in basal 5-

HT levels was found in the Nac, the VTA or the DRN 1 day after

this treatment regimen in rats (Parsons and Justice, 1993).

However, the chronic treatment led to a significantly higher

percentage 5-HT increase after an acute COC (10 mg/kg, i.p.)

challenge in all three areas, suggesting an augmented

responsiveness of the 5-HT system after chronic COC

treatment (Parsons and Justice, 1993). Given the similarities

in the behavioral state between psychostimulant withdrawal

and depression, it was argued that a reduced 5-HTactivity in the

limbic system may be a common neurochemical mechanism

(Parsons et al., 1995; Baumann and Rothman, 1998; Markou

et al., 1998).

Interestingly, basal extracellular 5-HT levels in the FC and

hippocampus, and 5-HT neuronal firing pattern were not

changed after repeated MDMA treatment (20 mg/kg, s.c. twice

daily for 4 days) in rats, when measured 10–12 days after the

end of the treatment. However, 5-HT release induced by D-

fenfluramine in the FC (Series et al., 1994), and stimulation-

evoked 5-HT release in the FC, but not in the ventral

hippocampus, were markedly decreased after MDMA treat-

ment (Gartside et al., 1996).

3. The 5-HT1A-receptors

The 5-HT1A-R is member of the 5-HT1-R family which also

comprises the 5-HT1B-R and the 5-HT1D-R. These receptors

show a high amino acid sequence homology and a high affinity

for 5-HT (Van Wijngaarden et al., 1990). The 5-HT1A-R is coded

by an intronless gene. In rats it contains 422 amino acids with a

tertiary structure containing 7 transmembrane spanning

domains, with sites for glycosylation within the extracellular

N-terminal region of the receptor protein, and sites for

phosphorylation within the third intracellular loop. Rat and

human 5-HT1A-Rs show a sequence homology of 89%, with the

rat receptor being only one amino acid longer than the human

receptor (Kobilka et al., 1987; Fargin et al., 1988; Albert et al.,

1990; Albert, 1992). 5-HT1A-Rs in the brain couple via Gi/Go-

proteins (Innis and Aghajanian, 1987) to the inhibition of

adenylate cyclase and to the direct activation of an inwardly

rectifying K+ conductance (De Vivo and Maayani, 1985, 1986;

Weiss et al., 1986; Innis et al., 1988; Schoeffter and Hoyer, 1988;

Hamon et al., 1990; Haj-Dahmane et al., 1991; Blier et al., 1993b;

Chamberlain et al., 1993; Hartig, 1999). The opening of these K+

channels leads to a hyperpolarization and a decrease in

membrane resistance. In the DRN 5-HT1A-Rs also reduce a

Ca2+ conductance, which contributes to the negative effects of 5-

HT1A-R stimulation on cell firing of 5-HT neurons (Andrade and

Nicoll, 1987a; Ropert, 1988; Sprouse and Aghajanian, 1987,

1988). Binding studies with [3H]-8-OH-DPAT suggest that 5-

HT1A-Rs can occur in two functional states characterized by a

high and low agonist binding affinity (Mongeau et al., 1992;

Chamberlain et al., 1993; Nenonene et al., 1994). These two

states possibly reflect the binding to the G-protein associated

receptor protein (high affinity) and the binding to the receptor

protein without G-protein association (low affinity) (Harrington

and Peroutka, 1990; Mongeau et al., 1992).

3.1. 5-HT1A-receptor ligands

In order to identify 5-HT1A-Rs in the brain and to study their

functions, several ligands have been developed and success-

fully applied. These compounds differ considerably in their

affinity, selectivity and potency for pre- and postsynaptic 5-

HT1A-Rs. In order to allow an interpretation of the action of

these compounds on psychostimulant effects on behavior and

neurochemistry, the properties of the compounds used in

psychostimulant research will be briefly outlined here. For a

detailed discussion of these and other 5-HT1A-R ligands,

several reviews provide an overview and critical discussion (De

Vry, 1995; Routledge, 1996; Barnes and Sharp, 1999; Hoyer

et al., 2002).


A selective agonist for the 5-HT1A-R was available earlier

than a selective antagonist. 8-Hydroxy-2-(di-n-propylamino)-

tetralin (8-OH-DPAT) was the first selective 5-HT1A-R ligand

(Arvidsson et al., 1981; Hjorth et al., 1982), which was able to

discriminate between different 5-HT1-Rs (Middlemiss and

Fozard, 1983; Marcinkiewicz et al., 1984; Peroutka, 1985). 8-

OH-DPAT shows a high affinity for the 5-HT1A-R

(Ki = 0.5 nM), and a low affinity for the D2 DA-R (Ki = 86 nM)

and the a2 adrenoceptor (Ki = 116 nM) (Piercey et al., 1994).

Furthermore, 8-OH-DPAT displays a low affinity for 5-HT

uptake sites (Schoemaker and Langer, 1986; Van Wijngaarden

et al., 1990; Assie and Koek, 1996a). Although, 8-OH-DPAT

was widely used for more than two decades as the 5-HT1A-R

agonist of choice to explore 5-HT1A-R function in the brain, it

became apparent that it may also be an agonist for the 5-HT7-R

(Assie and Koek, 2000a; Bonaventure et al., 2002). It should be

noted, that several studies found a stimulation of adenylate

cyclase activity in the hippocampus in vitro and in vivo after

application of 8-OH-DPAT (Markstein et al., 1986, 1999;

Sijbesma et al., 1991; Cadogan et al., 1994). It seems very

likely that this effect is mediated by stimulation of hippocampal

5-HT7-Rs, which are positively coupled to adenylate cyclase

activity (Lovenberg et al., 1993; Thomas et al., 1999;

Vanhoenacker et al., 2000). This property of 8-OH-DPAT in

particular may account for many 8-OH-DPAT effects on

psychostimulant-induced behavior and neurochemistry, show-

ing an inverted-U-shaped dose–response curve with high

concentrations of 8-OH-DPAT (e.g. Muller et al., 2004a,b).

Another potent and selective 5-HT1A-R agonist is 5-{3-[((2S)-

1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodiox-

ole HCl (MKC-242 = osemozotan) (Matsuda et al., 1995). In

vitro, the compound showed a high affinity for the 5-HT1A-R

(Ki = 0.35 nM), but also a moderate affinity for the a1-

adrenoceptors (Ki = 21 nM). Osemozotan acts as a full agonist

at presynaptic 5-HT1A-Rs and as a partial agonist at

postsynaptic 5-HT1A-Rs (Matsuda et al., 1995). The 5-HT1A-

R agonist, flesinoxan, shows also a high affinity for the 5-HT1A-

R (pKi = 8.82), but also an affinity for other 5-HT-Rs, as well as

the D2 DA-R and adrenoceptors of two orders of magnitude

less (Van Wijngaarden et al., 1990). Buspirone, ipsapirone and

gepirone are piperazine derivatives developed as axiolytics,

which appeared to have 5-HT1A-R agonist properties (Bockaert

et al., 1987; Traber and Glaser, 1987). Ipsapirone and gepirone

display a higher affinity for the 5-HT1A-R (Ki = 1.8 and 13 nM)

than for the D2 DA-R (Ki = 110 and 58 nM). Ipsapirone also

shows affinity for the a1-adrenoceptor (Ki = 43 nM) (Piercey

et al., 1994). Buspirone has an approximately equal affinity for

the 5-HT1A-R (Ki = 9.2 nM) and the D2 DA-R (Ki = 13 nM),

but little affinity for a1- and a2-adrenoceptors (Ki > 1 mM)

(Piercey et al., 1994).

The development of potent and selective 5-HT1A-R

antagonists was delayed compared to the 5-HT1A-R agonists

and had to face the problem of the ligands showing partial 5-

HT1A-R agonist properties at the 5-HT1A-autoreceptor (Rou-

tledge, 1996). A selective 5-HT1A-R antagonist is 1-(2-

methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-

190), which binds with high affinity to hippocampal 5-HT1A-Rs

(Ki = 0.58 nM). It has only a low affinity for other 5-HT and DA

receptors, but a high affinity for a1-adrenergic sites

(Ki = 0.8 nM) (Glennon et al., 1988). With N-tert-butyl-

3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide

(WAY 100135) another selective 5-HT1A-R antagonist was

developed, that displayed a high affinity for the 5-HT1A-R

(pKi = 8.35), but only a moderate affinity for the a1-

adrenoceptor (pKi = 6.64) (Fletcher et al., 1993a; Assie and

Koek, 1996b). The 5-HT1A-R antagonists, NAN-190 and WAY

100135, however, also behave as partial agonists at the

somatodendritic 5-HT1A-autoreceptor (Fornal et al., 1994,

1996; Assie and Koek, 1996b), which restricts its use today. The

highly selective 5-HT1A-R antagonist, N-{2-[4-2-methoxyphe-

nyl)-1-piperazinyl}ethyl}-N-(2-pyridinyl) cyclohexane car-

boxamide trihydrochloride (WAY 100635) (Fletcher et al.,

1994, 1996; Forster et al., 1995), in contrast, is devoid of

agonist properties at pre- and postsynaptic 5-HT1A-R sites

(Fornal et al., 1996; Assie and Koek, 1996b). WAY 100635

shows a high affinity for the 5-HT1A-R (pKi = 9.02), but only a

moderate affinity for the a1-adrenoceptor (pKi = 7.24) (Assie

and Koek, 1996b, 2000b). In order to differentiate antagonists

with partial agonist properties, the notation ‘‘silent antagonist’’

was introduced (Fletcher et al., 1993a), which can be applied to

the widely used potent and highly selective 5-HT1A-R

antagonist WAY 100635 (Fletcher et al., 1996). WAY

100635 is >100-fold more selective for the 5-HT1A-R than

for other 5-HT-Rs, DA receptors, adrenoceptors and NA-, DA-

or 5-HT reuptake sites. Saturation studies showed an

approximately six times higher affinity for [3H]-WAY

100635 (Kd = 0.1–0.12 nM) than for [3H]-8-OH-DPAT

(Fletcher et al., 1996). In the investigation of the role of 5-

HT1A-Rs in psychostimulant effects on behavior and neuro-

chemistry using 8-OH-DPAT, a canceling out group with a

WAY 100635 pretreatment is often used to prove 5-HT1A-R

involvement in the effects of 8-OH-DPAT, given the affinity of

8-OH-DPAT for the 5-HT7-R (Assie and Koek, 2000a;

Bonaventure et al., 2002). Two other compounds with selective

5-HT1A-R antagonist properties are 4-(20-methoxyphenyl)-1-

[20-[N-(200-pyridinyl)-p-iodo-benzamido]ethyl] piperazine ( p-

MPPI) and 4-(20-methoxyphenyl)-1-[20-[N-(200-pyridinyl)-p-

fluorobenzamido] ethyl]piperazine (p-MPPF) (Zhuang et al.,

1994). Both display a high 5-HT1A-R affinity (p-MPPI:

Kd = 0.32 nM; p-MPPF: Kd = 0.34 nM) and selectivity (Zhuang

et al., 1994; Kung et al., 1996). In vivo physiological and

behavioral models of hypothermia and forepaw treading

induced by 8-OH-DPAT revealed that p-MPPI and p-MPPF

behave as competitive 5-HT1A-R antagonists with no signs of

partial agonist properties (Thielen et al., 1996).

3.2. Brain distribution of 5-HT1A-receptors

In the brain, the distribution of the 5-HT1A-R has been

characterized by receptor autoradiography, in situ hybridiza-

tion, immunocytochemistry and by PET studies in rodents, non-

human primates and in humans. Thereby, a high correlation

between receptor binding with [H3]-8-OH-DPATand 5-HT1A-R

mRNA distribution has been shown (Pompeiano et al., 1992),


which suggests that the receptor protein is not transported

over long distances from its synthesis site. A high 5-HT1A-R

density has been found in the DRN and median raphe nucleus

(MRN), in limbic brain areas, such as the hippocampus, the

lateral septum and the amygdala, and in limbic cortical areas,

such as the entorhinal and cingular cortices. Medium binding

was detected in the olfactory bulb, the thalamus, hypotha-

lamus, several brain stem nuclei and in the neocortex. In the

basal ganglia and cerebellum low levels, or no binding, were

detected (Gozlan et al., 1983; Marcinkiewicz et al., 1984;

Hall et al., 1985; Verge et al., 1986; Albert et al., 1990;

Palacios et al., 1990; Pompeiano et al., 1992; Khawaja, 1995;

Kia et al., 1996a,b; Farde et al., 1997; Mengod et al., 1999;

Hume et al., 2001; Maeda et al., 2001; Palchaudhuri and

Flugge, 2005). Within the brain 5-HT1A-Rs, two principal

types of 5-HT1A-Rs can be distinguished: the 5-HT1A-

autoreceptors and postsynaptic 5-HT1A-Rs. It was shown that

the 5-HT1A-R is the inhibitory autoreceptor at the soma and

dendrites of the 5-HT neurons in the raphe nuclei (Gozlan

et al., 1983; Riad et al., 2000). Postsynaptic 5-HT1A-Rs and

5-HT1A-autoreceptors were shown to possess different

properties despite a similar radioligand binding profile (Blier

et al., 1993a,b). 5-HT1A-Rs were not reported in glia cells

(Kia et al., 1996a,b).

3.2.1. 5-HT1A-autoreceptors

In the raphe nuclei, 5-HT1A-Rs are localized somatoden-

dritically at 5-HT neurons (Gozlan et al., 1983; Verge et al.,

1985; Riad et al., 2000). Their localization is mostly

extrasynaptic at the plasma membrane, supporting the idea

of a volume transmission activation of these receptors (Agnati

et al., 1995; Zoli et al., 1998; Bunin and Wightman, 1999). Riad

et al. (2000) reported in the DRN a ratio of 40:1 of the

membrane-associated to cytoplasmatic 5-HT1A-Rs. The source

of 5-HT1A-autoreceptor activation is 5-HT, which is released

from 5-HT neurons within one raphe nucleus, or from 5-HT

neurons projecting from other raphe nuclei. Thereby, 5-HT is

released by exocytosis, or, alternatively, approximately 10–

30% from a non-vesicular pool (Adell et al., 2002). Several

studies found a high 5-HT1A-R reserve for the inhibition of

DRN cell firing and 5-HT synthesis activity (Meller et al., 1990;

Cox et al., 1993), thus, allowing a short term increase in 5-

HT1A-R activation without new protein synthesis at the

somatodendritic level of 5-HT neurons. Stimulation of the

tonically activated 5-HT1A-autoreceptors (Haddjeri et al.,

2004) was consistently found to inhibit 5-HT cell firing in

the raphe nuclei and to reduce 5-HT synthesis and 5-HT release

in the raphe nuclei and in terminal areas of the DRN and MRN

projections (Van der Maelen et al., 1986; Sprouse and

Aghajanian, 1987, 1988; Hjorth and Magnusson, 1988; Hutson

et al., 1989; Blier et al., 1990; Invernizzi et al., 1991; Bonvento

et al., 1992; Yoshimoto and McBride, 1992; Kreiss and Lucki,

1994; Casanovas and Artigas, 1996; Ago et al., 2003). These

effects can be blocked by various 5-HT1A-R antagonists

(Martin et al., 1999). Activation of 5-HT1A-autoreceptors

mimics the effects of systemic 5-HT1A-R agonist application on

extracellular 5-HT levels, causing a 5-HT decrease in a

regionally specific manner (Sharp et al., 1989; Sharp and

Hjorth, 1990; Chen and Reith, 1995; Casanovas et al., 1997).

Importantly, the ability of 8-OH-DPAT to suppress DRN cell

firing, and the ability of spiperone and WAY 100635 to increase

DRN cell firing, varies considerably with the behavioral states

and the baseline firing activity of the 5-HT cells in a behaving

animal (Fornal et al., 1994, 1996). 8-OH-DPAT was most

effective in blocking DRN cell firing during low levels of

arousal, when spontaneous cell firing was low (drowsiness). In

contrast, the 5-HT1A-R antagonist-induced increase in 5-HT

cell firing was most pronounced during the awake state, when

basal cell firing was at a high level. This effect was blunted

when animals became drowsy or were asleep (Fornal et al.,

1994, 1996). Long-term stimulation (for 14 days) of DRN 5-

HT1A-Rs led to a desensitization and internalization of the

autoreceptors, which resulted in an attenuated suppression of 5-

HT neuron firing frequency (Blier and de Montigny, 1987; Blier

et al., 1998; Riad et al., 2001). Notably, the efficacy of 5-HT1A-

R stimulation in blocking 5-HT neuronal activity is different

between the raphe nuclei. As such, the 5-HT1A-R agonists, 8-

OH-DPAT and ipsapirone, appeared to be more effective in

blocking 5-HT cell firing, terminal 5-HT synthesis and 5-HT

release after DRN compared to MRN stimulation (Sinton and

Fallon, 1988; Blier et al., 1990; Casanovas and Artigas, 1996).

Overall, 5-HT1A-autoreceptors in the raphe nuclei appear to be

in a crucial position to regulate the 5-HT activity in the terminal

regions of the 5-HT projections by modulating the activity of 5-

HT neurons (Stamford et al., 2000).

3.2.2. Postsynaptic 5-HT1A-receptors

In several forebrain terminal regions of the ascending 5-HT

projections, which arise form the DRN and MRN, 5-HT1A-Rs

were found as postsynaptic receptors (Hall et al., 1985; Verge

et al., 1985). Terminal autoreceptors at the serotonergic synapse

are, however, of the 5-HT1B-R type (Hjorth and Magnusson,

1988; Riad et al., 2000). 5-HT1A-Rs were found either at the

dendrites or soma of postsynaptic neurons, or at non-

serotonergic synapses, were they serve as heteroreceptors

(Riad et al., 2000). In the hippocampus and in the cortex, 5-

HT1A-Rs are located in principal cells and pyramidal neurons,

respectively, which are mostly glutamatergic (Riad et al., 2000;

Palchaudhuri and Flugge, 2005). Postsynaptic 5-HT1A-Rs in

the hippocampus were detected in the cell membrane within

and outside synaptic specializations (Kia et al., 1996a,b; Riad

et al., 2000). A lack of an apparent 5-HT1A-R reserve was

observed in the hippocampus (Yocca et al., 1992). In contrast to

the DRN, in the hippocampus (CA3) no 5-HT1A-R internaliza-

tion was observed after agonist stimulation (Riad et al., 2001).

Pharmacological stimulation of 5-HT1A-Rs in the hippo-

campus mimics the hyperpolarization of CA1 cells induced by

5-HT, and reduces neuronal activity (Andrade and Nicoll,

1987b; Rowan and Anwyl, 1987; Ropert, 1988; Sprouse and

Aghajanian, 1988; Segal et al., 1989; Schmitz et al., 1995a,b).

Stimulation-induced field potentials and excitatory synaptic

transmission in the entorhinal cortex were also inhibited by 5-

HT, which could by mimicked by 5-HT1A-R agonism with 8-

OH-DPAT (Schmitz et al., 1998a, 1999). Furthermore, also the


polysynaptic inhibition in the projection neurons of the

entorhinal cortex was suppressed by 5-HT1A-R activation,

which depressed the excitatory postsynaptic potentials on

inhibitory interneurons (Schmitz et al., 1998b). Interestingly,

the effects of various 5-HT1A-R agonists on hippocampal

neuronal activity are considerably weaker than on DRN cell

firing (Sprouse and Aghajanian, 1988) and do not undergo a

desensitization with repeated stimulation (for 14 days) (Blier

and de Montigny, 1987). Less straightforward are the effects of

5-HT1A-R stimulation with 8-OH-DPAT on cell firing in the

ventral pallidum. Enhancing and suppressory effects were

reported with a comparable incidence. Both effects could be

blocked by the 5-HT1A-R antagonist (+)WAY 100135

(Heidenreich and Napier, 2000). Postsynaptic 5-HT1A-Rs in

the medial prefrontal cortex (mPFC) were shown to be involved

in the regulation of the DRN firing rate (Hajos et al., 1999) and

5-HT release in the mPFC (Casanovas et al., 1999). Application

of 8-OH-DPAT into the mPFC significantly attenuated DRN

cell firing and the extracellular 5-HT level in the mPFC

(Casanovas et al., 1999), possibly by blocking the direct

glutamatergic projection from the mPFC to different neurons in

the DRN (Celada et al., 2001). In contrast, local 5-HT1A-Rs in

the hippocampus, the ventral and dorsal striatum, and the

hypothalamus were not found to be involved in the control of

the basal 5-HT activity in the respective regions (Kreiss and

Lucki, 1994; Casanovas et al., 1999; Celada et al., 2002; Muller

et al., 2004a,b).

5-HT1A-Rs were shown to have an important influence on

the release of other neurotransmitters from non-serotonergic

synapses. Systemic application of 8-OH-DPAT increased

extracellular acetylcholine (ACh) levels in the hippocampus

(Fujii et al., 1997; Nakai et al., 1998), possibly by an interaction

with the 5-HT1A-Rs expressed in ACh neurons of the medial

septum (Kia et al., 1996c). However, the local application of 8-

OH-DPAT into the hippocampus was shown to increase

extracellular ACh levels. This effect was also evident in p-

chlorophenylalanine (PCP) treated rats with a reduced 5-HT

content in the hippocampus, and could be blocked by

pretreatment with the 5-HT1A-R antagonists NAN-190 and

WAY 100135 (Izumi et al., 1994; Fujii et al., 1997; Nakai et al.,

1998).

Postsynaptic 5-HT1A-Rs, located in structures of the

mesocorticolimbic DA system and in the ascending noradre-

nergic (NA) system are of special importance with respect to

psychostimulant effects in the brain. Serotonergic projections

from the DRN synapse on dopaminergic and GABAergic

neurons of the VTA, which send projections to the Nac (Herve

et al., 1987; Van Bockstaele et al., 1994; Van Bockstaele and

Pickel, 1995), a brain structure associated with major

behavioral effects of psychostimulant drugs (Koob et al.,

1998; McBride et al., 1999). Complementarily, a strong

influence of the dopaminergic afferents on 5-HT projections

was shown (Ferre et al., 1994; Adell et al., 2002). The 5-HT

innervation of the VTA controls cell firing of dopaminergic

and non-dopaminergic neurons via 5-HT1A-Rs. In contrast to

the hippocampus, a high 5-HT1A-R reserve has been detected in

the cytoplasma of VTA cells. The local application of 5-HT or

the 5-HT1A-R agonist 8-OH-DPAT into the VTA, and the

systemic application of the 5-HT1A-R agonist, flesinoxan, was

shown to increase firing rate and burst firing of the VTA DA

cells (Arborelius et al., 1993; Pessia et al., 1994; Lejeune and

Millan, 1998) and to increase DA release in the Nac (Guan and

McBride, 1989). The effect of flesinoxan was abolished by the

selective 5-HT1A-R antagonist WAY 100635, which, by itself,

had no effect on basal firing patterns (Lejeune and Millan,

1998). The local application of the 5-HT1A-R agonists, 8-OH-

DPAT and ipsapirone, increased DA release in the striatum, the

Nac and the FC, terminal areas of the nigrostriatal, mesolimbic

and mesocortical DA projections (Benloucif and Galloway,

1991; Benloucif et al., 1993; Golembiowska and Wedzony,

1993; Nomikos et al., 1996; Ago et al., 2003). These effects are

interesting, given the anatomical evidence showing only a very

low density of 5-HT1A-Rs in these brain regions. It suggests that

also in regions with low 5-HT1A-R density, 5-HT1A-R

stimulation may, nevertheless, have a profound modulatory

influence on DA activity.

In the VTA at least three different types of neurons have been

described, namely dopaminergic projection neurons (hyperpo-

larized by DA, but not by Met-enkephaline), GABAergic

interneurons (hyperpolarized by Met-enkephaline, but not by

DA) and GABAergic projection neurons (hyperpolarized by

DA and Met-enkephaline; Cameron et al., 1997). 5-HT1A-Rs in

the VTA were not exclusively localized on dopaminergic

neurons, but were also found on non-dopaminergic neurons and

glia (Doherty and Pickel, 2001). While the DA neurons and

GABAergic interneurons are depolarized by 5-HT, putative

GABAergic projection neurons are hyperpolarized. These

effects could be blocked by the 5-HT1A-R antagonist NAN-190,

indicating a 5-HT1A-R mediated mechanism (Cameron et al.,

1997). Accordingly, an attenuation of the 5-HT innervation of

the VTA DA neurons by local application of 8-OH-DPAT into

the DRN may explain the resulting decline of extracellular DA

levels in the Nac (Yoshimoto and McBride, 1992). These

findings are generally in line with the effects of systemic 8-OH-

DPAT or MKC-242 administration, which increase extracel-

lular DA levels in the mPFC and hippocampus, but not in the

striatum and nucleus accumbens. These effects could be

reversed by pre-treatment with the 5-HT1A-R antagonist WAY

100635, which by itself had no effect on DA levels (Sakaue

et al., 2000; Ichikawa et al., 2001; Ago et al., 2003). Altogether,

these data suggest a facilitatory role of 5-HT1A-Rs on DA

activity at the somatodendritic level and at the terminal level of

the DA projections in reward-related brain structures. The

activity of ascending GABAergic projections arising from the

VTA is attenuated by 5-HT1A-R activation.

Serotonergic projections to the locus coeruleus (LC) (Beart

and McDonald, 1982; Jacobs and Azmitia, 1992) control the

cell firing of NA neurons via inhibitory 5-HT1A-R activation.

Complementarily, a strong influence of noradrenergic afferents

on DRN 5-HT cell firing has been shown (Baraban and

Aghajanian, 1980, 1981; Adell et al., 2002). Furthermore, the 5-

HT1A-R agonist, 8-OH-DPAT, enhanced cell firing of NA

neurons in the LC, an effect that was reversed by WAY 100635

after systemic application (Piercey et al., 1994; Szabo and


Blier, 2001). However, the effects of 8-OH-DPAT as well as

WAY 100635 were dependent on intact serotonergic projec-

tions to the LC, suggesting that this effect is not mediated by 5-

HT1A-Rs at NA neurons in the LC (Szabo and Blier, 2001).

Postsynaptic 5-HT1A-Rs also influence NA activity in the

terminal regions of the noradrenergic projections. It was shown

that stimulation of postsynaptic 5-HT1A-Rs in the hippocampus

increases local NA release (Hajos-Korcsok et al., 1999). These

findings are in line with the augmenting effects of systemic

application of 8-OH-DPAT and other 5-HT1A-R agonists on

extracellular NA levels in the hippocampus of awake, but not

anesthetized animals (Done and Sharp, 1994). Altogether, 5-

HT1A-Rs appear to facilitate noradrenergic activity at the

somatodendritic as well as at the terminal level.

4. The 5-HT1A-receptors and psychostimulant-induced

behaviors

Given the high affinity for 5-HT and the localization as

somatodendritic autoreceptors and postsynaptic receptors in

terminal regions of the 5-HT projections, it may not be surprising

that 5-HT1A-Rs appear to be involved in spontaneous behavior,

emotion, memory and reinforcement processes. This is also the

basis for the contribution of 5-HT1A-Rs to various pathologies,

such as anxiety disorders, depression, schizophrenia and drug

addiction. Psychostimulant drugs exert a strong influence on 5-

HT activity in the brain, which leads to a hyperactivation of 5-

HT1A-Rs. This interaction may then contribute to the acute

behavioral effects of such drugs. In addition, long-term exposure

to psychostimulant drugs may alter 5-HT1A-R density and

function, which may contribute to the development and

maintenance of addiction-related behaviors. As such, an

overview of the involvement of 5-HT1A-Rs in ‘‘normal’’

behavior provides clues as to what kinds of functions may be

impacted by psychostimulants via an interaction with the 5-HT

system of the brain (Lucki and Wieland, 1990; Lucki, 1992).

4.1. Locomotor activity

4.1.1. Role of the 5-HT1A-receptors in spontaneous

locomotor activity

Basal behavioral activity can be measured as locomotor

activity in a habituated environment. Many studies provide

evidence for an essential contribution of the 5-HT1A-R to basal

locomotor activity. The 5-HT1A-R agonist, 8-OH-DPAT, can

lead to either locomotor activation (Tricklebank et al., 1986;

Dourish et al., 1985a,b; Lucki et al., 1989; Jackson et al., 1998;

Muller et al., 2003b) or inhibition (Carli et al., 1989; Hillegaart

et al., 1989; Mittman and Geyer, 1989; Dekeyne et al., 2000). A

considerable variation in the size of the test arena and pretest

habituation to the arena may be two of the reasons for the

different findings (Evenden and Angeby-Moller, 1990). In fact,

8-OH-DPAT tends to inhibit locomotor activity in larger test

environments or/and in non-habituated animals, whereas an

increase in locomotor activity was found preferentially in

smaller arenas and/or with well habituated animals (Evenden

and Angeby-Moller, 1990). In well habituated animals, when

novelty interacts little with the drug, the effects are also dose

dependent. Low doses of 8-OH-DPAT (�0.05 mg/kg, i.p.),

which preferentially activate 5-HT1A-autoreceotors, were

shown to reduce locomotor activity (Dekeyne et al., 2000;

Carey et al., 2004a,b, 2005d), while higher doses (�0.1 mg/kg),

that stimulate pre- and postsynaptic 5-HT1A-Rs, were shown to

enhance locomotor activity (Tricklebank et al., 1986; Dourish

et al., 1985b; Lucki et al., 1989; Jackson et al., 1998; Muller

et al., 2003b). In addition, several intracerebral application

studies have shown a different contribution of 5-HT1A-

autoreceptors in the DRN and MRN to the generation of

locomotor activity. While stimulation of the more sensitive 5-

HT1A-autoreceptors in the DRN induced hypoactivity (Elliott

et al., 1990; Higgins and Elliott, 1991), the stimulation of the

MRN 5-HT1A-autoreceptors elicited hyperactivity (Hillegaart

and Hjorth, 1989; Elliott et al., 1990; Higgins and Elliott, 1991;

Shim et al., 1997). These findings may support the view that

DRN and MRN serotonergic activity may exert opposite

influences on certain behaviors (Lechin et al., 2006). The

results are further supported by the finding that stimulation of

postsynaptic 5-HT1A-Rs with 8-OH-DPAT in monoamine-

depleted rats increased locomotor activity (Mignon and Wolf,

2002). However, several studies targeting postsynaptic 5-HT1A-

Rs with local application of 8-OH-DPAT failed to show a

facilitatory effect on locomotion for either dorsal or ventral

hippocampus or for Nac 5-HT1A-Rs (Andrews et al., 1994;

Muller et al., 2004a,b). In contrast, mice that overexpress 5-

HT1A-Rs selectively in the outer cortical layers (I–III) and in

the dentate gyrus, displayed a lower level of spontaneous

locomotor activity in the openfield test and stronger inhibitory

effects of 8-OH-DPAT (Bert et al., 2006). These findings rather

suggest an inhibitory effect of postsynaptic 5-HT1A-Rs in the

cortex and dentate gyrus in the generation of locomotor activity.

Overall, the evidence suggests that 5-HT1A-Rs in the DRN

attenuate locomotor activity, possibly by reducing the

serotonergic tone in terminal areas (Jacobs et al., 1990; Jacobs

and Fornal, 1993), while locomotor activity is preferentially

stimulated by 5-HT1A-autoreceptors within the MRN and by

postsynaptic 5-HT1A-Rs.

4.1.2. Psychostimulant-induced locomotor activity

4.1.2.1. Acute effects. The most prominent acute behavioral

effect of psychostimulants is an increase in locomotor activity.

Acute systemic administration of COC, AMPH, METH and

MDMA increases locomotor activity in rodents (van Rossum

and Simons, 1969; Segal, 1975; Scheel-Kruger et al., 1977;

Shuster et al., 1977; Tyler and Tessel, 1979; Gold et al., 1988;

Camp et al., 1994) and monkeys (Tatum and Seevers, 1929;

Miczek and Yoshimura, 1982). The dose–response curves for

this behavioral effect are not linear, and may be inverted U-

shaped or even multiphasic. In a very low dose range, for

example, COC (0.1–0.75 mg/kg, i.p.) was reported to decrease

locomotor activity in rats and mice (George, 1989, 1990).

Within a dose range of 1–5 mg/kg (i.p.) COC no or only slight

facilitating effects on locomotor activity were reported in rats

and mice (Tyler and Tessel, 1979; George, 1989; Ruth et al.,

1988; Paulus et al., 1993). The commonly reported increase in


locomotor activity and rearing behavior was found in a medium

to high dose range of 5–30 mg/kg (i.p.) of COC in rats and mice

(Scheel-Kruger et al., 1977; Pradhan et al., 1978; Kelly and

Iversen, 1976; Tyler and Tessel, 1979; Hemby et al., 1995). d-

AMPH can increase locomotor activity at doses of �0.5 mg/kg

(s.c.) with a fivefold higher potency than l-AMPH. At the same

time, AMPH reduces rearing and exploratory behavior (Segal,

1975; Geyer et al., 1987; Paulus et al., 1993; Kuczenski and

Segal, 1999). METH increases locomotor activity and rearing

in a dose range of 0.1–3 mg/kg (s.c. and i.p.) in mice, with an

inverted U-shaped dose–response curve (Witkin et al., 1999).

An increase in locomotor activity was observed for (+)MDMA

in a dose range of 1.25–20 mg/kg (s.c.). MDMA, however, also

reduced rearing and exploratory behavior at the same dose

range (Gold et al., 1988; Callaway et al., 1990; Bankson and

Cunningham, 2001). As for AMPH, the behavioral effects of

MDMA are stereoselective, showing a much higher potency for

the (+)MDMA than for the (�)MDMA isomer or the racemic

(�)MDMA (Callaway et al., 1990).

4.1.2.2. Sensitization of the hyperlocomotor response. When

psychostimulants are administered chronically, the acute

behavioral and subjective effects of an acute drug application

undergo changes compared to the first application. The acute

effects are then modulated by the expression of sensitization as

Table 2

The effects of 5-HT1A-receptor agonist and antagonist on locomotor activity, the sens

cocaine, amphetamine, methamphetamine and MDMA

Behaviour Drug 5-HT1A-receptor ligand Dose

Locomotion Cocaine

Agonist: S 16924 0.9

Agonist: Osemozotan 0.1

1

Agonist: 8-OH-DPAT 0.01

0.02

0.05

0.05

0.1

0.12

0.2

0.2

0.2

0.25

0.3

0.4

0.5

Antagonist: NAN-190 0.5

1

2

Antagonist: WAY 100135 10

Antagonist: WAY 100635 0.05

0.1

0.1

0.4

0.4

0.8

1

1.5

well as tolerance effects. For the sensitization of the hyperlo-

comotor effects induction and expression can be distinguished

and independently modulated by pharmacological treatments.

When 5-HT1A-R ligandsareapplied beforeeach psychostimulant

on the consecutive sensitization days, they modulate the

induction of sensitization, whereas administration before the

psychostimulant only on the testing day modulates its expression.

Sensitization of the acute hyperlocomotor effects of COC,

AMPH, METH andMDMA can beobserved afteronly a few days

of repeated or escalating treatment in rats (Post and Rose, 1976;

Kalivas et al., 1988; Spanos and Yamamoto, 1989; Yeh and

Haertzen, 1991; Camp et al., 1994; Kuczenski and Segal, 1997),

mice (Shuster et al., 1977) and dogs (Tatum and Seevers, 1929).

4.1.3. 5-HT1A-receptors in psychostimulant-induced

hyperlocomotion

4.1.3.1. Acute effects. A considerable number of studies have

investigated the contribution of 5-HT1A-Rs in the brain to the

hyperlocomotor effects of psychostimulant drugs (Table 2).

The involvement of 5-HT1A-Rs in COC-induced hyperlocomo-

tion was investigated in rats in a study by Przegalinski and Filip

(1997) using the selective 5-HT1A-R agonist 8-OH-DPAT. The

hyperlocomotor effects of a rather low dose of COC (5 mg/kg)

were blocked by pretreatment with 0.125–0.5 mg/kg 8-OH-

DPAT. Also the partial 5-HT1A-R agonist S 16924 blocked

itization of the hyperlocomotor response and behavioral stereotypies induced by

(mg/kg) Species Effect Reference

Increase See text

Rat # Millan et al. (1998)

Mouse – Nakamura et al. (2006)

Mouse # Nakamura et al. (2006)

Rat – Carey et al. (2004a)

5 Rat – Carey et al. (2004a)

Rat – Carey et al. (2004a)

Rat # Carey et al. (2004b, 2005a)

Rat – De La Garza and Cunningham (2000)

5 Rat – Przegalinski and Filip (1997)

Rat " De La Garza and Cunningham (2000)

Rat " Carey et al. (2001, 2002b, 2004a)

Rat " Muller et al. (2003b)

Rat – Przegalinski and Filip (1997)

Rat " Carey et al. (2004a)

Rat " Carey et al. (2002a)

Rat # Przegalinski and Filip (1997)

Rat # King et al. (1993a)



Rat – Przegalinski and Filip (1997)

Rat # Carey et al. (2005a)

Rat – Herges and Taylor (1998)

Mouse " Nakamura et al. (2006)

Rat # Carey et al. (2000, 2001)

Rat # Muller et al. (2002a,b)

Rat # Carey et al. (2002a)

Mouse " Nakamura et al. (2006)

Rat – Herges and Taylor (1998)


Behaviour Drug 5-HT1A-receptor ligand Dose (mg/kg) Species Effect Reference

Amphetamine Increase See text

Agonist: S 16924 2.4 Rat # Millan et al. (1998)

Agonist: Buspirone 5.7 Rat # Jackson et al. (1994)

Agonist: Ipsapirone 35 Rat # Maj et al. (1987)

2.5 Mouse # Maj et al. (1987)

Agonist: 8-OH-DPAT 0.1 Rat – Jackson et al. (1994)

0.125 Rat – Przegalinski and Filip (1997)


0.5 Rat # Przegalinski and Filip (1997)

1.0 Rat " Jackson et al. (1994)

Antagonist: NAN-190 8 Rat # Layer et al. (1992)

Antagonist: WAY 100135 10 Rat – Przegalinski and Filip (1997)

METH Increase See text

Agonist: Osemozotan 0.3 Mouse # Ago et al. (2006a)

1 Mouse # Ago et al. (2006a)

MDMA Increase See text

Antagonist: Propranolol 20 Rat # Callaway et al. (1992)

20 Rat # Kehne et al. (1996)

Antagonist: Pindolol 20 Rat # Callaway et al. (1992)

Antagonist: WAY 100635 0.5 Rat – McCreary et al. (1999)

1 Rat – McCreary et al. (1999)

2 Rat – McCreary et al. (1999)

Sensitization Cocaine Increase See text

Agonist: Osemozotan 0.1 Mouse – Ago et al. (2006b)

0.3 Mouse #a Ago et al. (2006b)

1 Mouse #a Ago et al. (2006b)

0.1 Mouse #b Ago et al. (2006b)

0.3 Mouse #b Ago et al. (2006b)

1 Mouse #b Ago et al. (2006b)

0.1 Mouse –c Ago et al. (2006b)

0.3 Mouse –c Ago et al. (2006b)

1 Mouse –c Ago et al. (2006b)

Agonist: 8-OH-DPAT 0.1 Rat –a De La Garza and Cunningham (2000)

0.2 Rat "a De La Garza and Cunningham (2000)

0.2 Rat "a Carey et al. (2001)

Antagonist: NAN-190 0.5 Rat #b King et al. (1993a)

1 Rat #b King et al. (1993a)

2 Rat #b King et al. (1993a)

Antagonist: WAY 100635 0.4 Rat #a Carey et al. (2001)

Amphetamine Increase See text

Agonist: 8-OH-DPAT 0.25 Mouse –b Przegalinski et al. (2000)

0.5 Mouse #a Przegalinski et al. (2000)

0.5 Mouse #b Przegalinski et al. (2000)

1 Mouse #b Przegalinski et al. (2000)

Antagonist: WAY 100135 5 Mouse –a Przegalinski et al. (2000)

5 Mouse –b Przegalinski et al. (2000)

METH Increase See text

Agonist: Osemozotan 0.1 Mouse –c Ago et al. (2006a)

0.3 Mouse #c Ago et al. (2006a)

Behavioral stereotypies Cocaine Increase See text

Antagonist: WAY 100635 0.1 Rat " Herges and Taylor (1998)

1.5 Rat " Herges and Taylor (1998)

If not indicated otherwise, drug doses refer to systemic administration ("/# significant increase or decrease; – no significant change).a Induction of sensitization.b Expression of sensitization.c Maintainance of sensitization.



COC (20 mg/kg)-induced hyperlocomotion in rats (Millan

et al., 1998). In mice, also an inhibition of the hyperlocomotor

effects of COC (15 mg/kg) by a high dose of the 5-HT1A-R full

agonist, osemozotan, was reported (Nakamura et al., 2006). A

study by De La Garza and Cunningham (2000), in contrast,

found that stimulation of the 5-HT1A-R with 8-OH-DPAT (0.1–

0.2 mg/kg) potentiated COC-induced hyperlocomotion. A

behavioral fine analysis revealed that this effect was only

observed in the periphery, but not in the center of a

40 cm � 40 cm � 40 cm arena. The authors noted that the

peripheral effect may have been masked when the whole size of

the arena was considered, as was the case, e.g., in the study by

Przegalinski and Filip (1997). The COC-induced increase in

vertical activity was attenuated by 8-OH-DPAT pre-treatment

in this study (De La Garza and Cunningham, 2000). Subsequent

studies also found potentiating effects of 0.2–0.4 mg/kg 8-OH-

DPAT on hyperlocomotion induced by COC in large and small

test arenas in well habituated animals (Carey et al., 2001,

2002a,b, 2004a; Muller et al., 2003b). An attenuation of the

COC-induced increase in rearing behavior was also evident in

these studies. Since the effects of 8-OH-DPAT alone on

locomotor activity depend on experimental parameters, such as

the size of the arena, pretest handling and habituation

procedures, which interfere with the emotional status of the

animals, it may not be surprising that also 5-HT1A-R effects on

COC-induced hyperlocomotion depend on these factors. The

effects in non-habituated animals may interact with aversive

components of the test procedure, such as a large open area of a

testing arena (Thiel et al., 1998, 2000). A similar interaction

was also reported for COC, for which the degree of behavioral

activation, but not the degree of suppression of grooming,

essentially depends on pre-test maze experience (Carey et al.,

2005c). Differences in the test procedure may, therefore, be a

crucial factor regarding the different findings on the effects of

5-HT1A-R agonists on the acute hyperlocomotor effects of

COC.

The 5-HT1A-R antagonist, NAN-190 (0.5–2.0 mg/kg),

blocked COC (15 mg/kg)-induced behavioral activity in rats

(King et al., 1993a). The selective 5-HT1A-R antagonist, WAY

100135 (10 mg/kg), failed to affect COC (5 mg/kg)-induced

hyperlocomotion (Przegalinski and Filip, 1997), while the

selective and silent 5-HT1A-R antagonist, WAY 100635 (0.4–

0.8 mg/kg), clearly attenuated the acute hyperlocomotor and

rearing effects of COC (10 and 15 mg/kg), when administered

20 min before COC treatment (Carey et al., 2000, 2001, 2002a;

Muller et al., 2002a,b). In mice, however, pretreatment with

WAY 100635 (0.1 and 1 mg/kg) potentiated COC (15 mg/kg)-

induced hyperlocomotion (Nakamura et al., 2006). Herges and

Taylor (1998), however, failed to find an influence of 0.1 and

1.5 mg/kg WAY 100635 administered 1 h before COC (15 mg/

kg). Considering the attenuating effects of 5-HT1A-R antagon-

ism, it is important to note that, although pretreatment with

WAY 100635 significantly attenuated the COC effects, the

resulting behavior was not equivalent to an undrugged

condition. The rats, instead, showed an increase in a behavior

which was classified as ‘‘active immobility’’, characterized by

the absence of locomotor activity, freezing or behavioral

stereotypies, but a high level of body tension and arousal

(Muller et al., 2004c). The expression of COC-induced ‘‘active

immobility’’ in well habituated animals decreased when COC-

induced hyperlocomotion was potentiated by 8-OH-DPAT, and

increased when COC-induced hyperlocomotion was blocked

by WAY 100635 (Muller et al., 2004c).

The partial 5-HT1A-R agonists, ipsapirone (Maj et al., 1987)

and S 16924 (Millan et al., 1998), blocked the hyperlocomotion

induced by d-AMPH in mice and rats. The hyperlocomotor

effects of 0.5 mg/kg AMPH were also blocked by pretreatment

with 0.125–0.5 mg/kg 8-OH-DPAT in rats (Przegalinski and

Filip, 1997). In contrast to that is the finding that, while the non-

selective 5-HT1A-R agonist buspirone blocked the hyperloco-

motor effects of AMPH with an ED50 = 5.7 mmol/kg, the

application of the selective agonist, 8-OH-DPAT (1.0 but not

0.1 mg/kg), significantly potentiated the hyperlocomotor

effects of AMPH (Jackson et al., 1994). The selective 5-

HT1AR antagonist, WAY 100135 (10 mg/kg), failed to

influence hyperlocomotion induced by AMPH (0.5 mg/kg)

(Przegalinski and Filip, 1997). Layer et al. (1992), in contrast,

reported a marked inhibition of d-AMPH-stimulated locomotor

activity by the 5-HT1A-R antagonist, NAN-190 (8 mg/kg, s.c.),

in rats. Also, a study in marmoset monkeys reported inhibitory

effects of 5-HT1A-R antagonism on psychostimulant-induced

hyperlocomotion. It was shown that the selective 5-HT1A-R

antagonist WAY 100635 (0.4 and 0.8, but not 0.2 mg/kg)

attenuates the hyperlocomotor effects of the low potency

psychostimulant, diethylpropion, in response-sensitive mar-

moset monkeys (Mello et al., 2005).

Few studies are available on the acute behavioral effects of

METH and MDMA, in conjunction with selective 5-HT1A-R

ligands. A recent study in mice reported an inhibitory effect of

the 5-HT1A-R agonist, osemozotan (0.3 and 1 mg/kg), on

METH (1 mg/kg)-induced hyperlocomotion (Ago et al.,

2006a). Early evidence suggested an inhibitory role of 5-

HT1A-R antagonist pretreatment with propranolol and pindolol

on (+)MDMA-induced hyperlocomotion (Callaway et al.,

1992; Kehne et al., 1996). However, propranolol and pindolol

also display a b-adrenoceptor antagonist profile, which restricts

the interpretation of these studies. When the effects of the

selective 5-HT1A-R antagonist, WAY 100635 (0.5–2 mg/kg),

on (+)MDMA (3 mg/kg)-induced hyperlocomotion were

investigated in rats, however, no effect could be found

(McCreary et al., 1999). Accordingly, authors concluded that

the 5-HT1A-R is not involved in (+)MDMA-induced locomotor

activation (Bankson and Cunningham, 2001).

Several studies aimed to determine the brain areas where the

5-HT1A-Rs interact with psychostimulant-induced behavior

(Muller and Huston, 2006). In order to determine the contribution

of different 5-HT1A-R populations to the behavioral effects of

psychostimulants two different approaches have been used,

including (A) local application studies targeting 5-HT1A-Rs in

restricted brain areas and (B) systemic application studies with

very low doses of 5-HT1A-R agonists or antagonists, which

preferentially target the more sensitive 5-HT1A-autoreceptors in

the raphe nuclei. Both approaches were usually combined with

the systemic application of a psychostimulant drug. In the


systemic approach with low doses, it was shown that doses of

0.025 and 0.05 mg/kg 8-OH-DPAT, which preferentially

stimulate 5-HT1A-autoreceptors, blocked the acute hyperloco-

motor effects of COC (Carey et al., 2004a, 2005a). Interestingly,

the acute inhibitory effect of a low dose 8-OH-DPAT was

reversed by repeated treatment over 9 days (Carey et al., 2005a).

Another study suggested that the disappearance of this effect by

repeated autoreceptor stimulation is not caused by a COC-

sensitization or altered neurochemical effects, but, most likely by

a transformation of the 8-OH-DPAT drug cue into a COC-

conditioned stimulus, which, by itself, elicits hyperlocomotor

activity (Carey et al., 2005b,c). Furthermore, pre-treatment with

the 5-HT1A-R antagonist, WAY 100635, at a low dose (0.05 mg/

kg) blocked the acute hyperlocomotor effects of COC (Carey

et al., 2004a). The studies using local application also mainly

support an inhibitory role of 5-HT1A-autoreceptors in COC-

induced hyperlocomotion, but, also showed that there are

differences in the contribution of several 5-HT1A-autoreceptor

populations. Activating 5-HT1A-autoreceptors in the MRN by

local application of 8-OH-DPAT or blocking them with WAY

100635 did not affect COC-induced hyperlocomotion or rearing

(Szumlinski et al., 2004; Herges and Taylor, 1999). In contrast,

the activation of 5-HT1A-autoreceptors in the DRN by 8-OH-

DPAT potentiated the COC-induced hyperlocomotion (Szum-

linski et al., 2004), suggesting a facilitatory role for these

receptors. The application of WAY 100635 into the DRN

potentiated COC-induced hyperlocomotion, but not rearing

behavior (Herges and Taylor, 1999). This effect may, however,

have been caused by a diffusion to the LC noradrenergic neurons.

WAY 100635 was shown to attenuate the firing frequency of NA

neurons, which tonically activate 5-HT neurons in the raphe

nuclei. The WAY 100635 effects on the DRN neurons may,

therefore, be masked by effects on the NA neurons (Haddjeri

et al., 2004). Local application studies have also revealed

multiple dissociations in the contribution of the several

postsynaptic 5-HT1A-R subpopulations to the hyperlocomotor

effects of COC. Application of 8-OH-DPAT into the ventral

hippocampus of rats showed that 5-HT1A-Rs in the ventral

hippocampus suppress COC-induced hyperlocomotion and

rearing behavior (Muller et al., 2004a), while application of 8-

OH-DPAT into the ventral striatal region potentiated COC-

induced hyperlocomotion, but not rearing behavior (Muller et al.,

2004b). A facilitatory role of the 5-HT1A-R in the Nac in

psychostimulant-induced hyperlocomotion was also found with

d-AMPH, as intra-Nac application of 8-OH-DPAT tended to

facilitate hyperlocomotion induced by d-AMPH (0.5 mg/kg,

s.c.) (Layer et al., 1992).

Overall, the available studies support the view that 5-

HT1A-Rs are essentially involved in acute psychostimulant-

induced hyperlocomotion, which was mainly demonstrated

for COC and AMPH. However, it appears that 5-HT1A-

autoreceptors and postsynaptic 5-HT1A-Rs contribute differ-

ently. Activation of the 5-HT1A-autoreceptors, in particular in

the DRN, can facilitate acute psychostimulant-induced

hyperlocomotion, while MRN 5-HT1A-autoreceptor activa-

tion is ineffective. This is in contrast to the role of the 5-

HT1A-autoreceptors in spontaneous locomotor activity, which

was facilitated by MRN autoreceptor activation and reduced

by DRN autoreceptor activation. Accordingly, the psychos-

timulant-induced increase in local 5-HT activity does not

simply potentiate the normal 5-HT1A-autoreceptor contribu-

tion to the generation of locomotor activity, but acts in a more

complex way. Nevertheless, the findings support the view that

DRN 5-HT1A-autoreceptors attenuate spontaneous locomotor

activity by a reduction of the serotonergic tone in terminal

areas. During psychostimulant application, however, the

increase in 5-HT appears to limit expression of the acute

psychostimulant behavioral effects (Muller et al., 2002b,

2003b). Reducing the 5-HT overshoot by DRN 5-HT1A-

autoreceptor activation, may, therefore, reduce the inhibitory

role of 5-HT in terminal areas, and consequently facilitate the

expression of the acute hyperlocomotor response. At the

postsynaptic level 5-HT1A-Rs were shown to facilitate

spontaneous locomotor activity, possibly contributing to

the 5-HT-mediated increase in behavioral activity. The

psychostimulant-induced increase of 5-HT in some, but not

all investigated brain areas, appears to potentiate this effect,

as it was shown for the Nac, but not for the hippocampus.

However, if the psychostimulant-induced increase of 5-HT in

terminal areas has a net attenuating effect on hyperlocomo-

tion, it appears very likely that other 5-HT-Rs in these regions

exert a strong inhibition, thus, ‘‘overwriting’’ the contribution

of the 5-HT1A-R (Higgins and Fletcher, 2003; Muller and

Huston, 2006; Muller and Carey, 2006).

4.1.3.2. Sensitization of the hyperlocomotor response. The

induction of sensitization for the hyperlocomotor effects of

COC was potentiated by agonism of the 5-HT1A-R with 0.2 mg/

kg 8-OH-DPT in rats (De La Garza and Cunningham, 2000;

Carey et al., 2001), while it was attenuated by antagonism of the

5-HT1A-R with WAY 100635 (Carey et al., 2001) (Table 2).

Furthermore, the expression of COC-induced locomotor

sensitization was attenuated by the 5-HT1A-R antagonist,

NAN-190 (King et al., 1993a). In mice, however, the 5-HT1A-R

agonist, osemozotan, blocked the establishment and expres-

sion, but not the maintenance of COC-induced sensitization of

the hyperlocomotor action (Ago et al., 2006b). The majority of

the findings suggest a facilitatory role of 5-HT1A-Rs in the

induction and expression of COC-induced sensitization, but no

role in its maintenance. In contrast to these findings is a study in

mice on the induction and expression of sensitization induced

by repeated AMPH treatment (Przegalinski et al., 2000). In this

study, 8-OH-DPAT (0.5 and 1 mg/kg, s.c.) blocked the

induction as well as the expression of AMPH-induced

sensitization. While these effects were reversed by WAY

100135, the antagonist alone did not have an influence

(Przegalinski et al., 2000). A study by Ago et al. (2006a)

investigated the effect of the 5-HT1A-R agonist, osemozotan, on

the maintenance of METH-induced sensitization in mice.

Repeated METH (1 mg/kg) application for 7 days induced a

profound sensitization of the hyperlocomotor response. The

maintenance of the sensitized response was blocked by twice

daily treatment with 0.3 but not 0.1 mg/kg osemozotan for 7

days, as revealed by a challenge injection with METH 8 days


later. The osemozotan effect was antagonized by WAY 100635

(Ago et al., 2006a).

Stimulating preferentially 5-HT1A-autoreceptors with the

systemic application of low doses of 8-OH-DPAT (0.05 mg/kg,

i.p.) initially blocked the acute hyperlocomotor effects of COC,

but facilitated the induction of locomotor sensitization during

repeated COC treatment (Carey et al., 2005a). This effect,

however, appeared to be not a true sensitization effect, but a 8-

OH-DPAT drug-cue conditioned stimulus effect (Carey et al.,

2005b). An essential facilitation of the associative process

during the induction of a sensitized hyperlocomotor COC

response by 5-HT1A-autoreceptor stimulation was shown by

Carey et al. (2005d). In well habituated animals the 5-HT1A-

autorecpetor stimulation initially blocked the hyperlocomotor

effects of COC. After 10 treatment combinations with 8-OH-

DPAT and COC, however, a clear hyperlocomotor response was

observed. A drug challenge revealed that neither the respon-

siveness to saline, nor to an autoreceptor preferring dose of 8-

OH-DPAT (0.05 mg/kg, i.p), nor to COC had been changed by

the sensitization procedure compared to an unpaired control.

However, a potentiated response to a combined 8-OH-DPAT

(0.05 mg/kg, i.p)-COC challenge revealed a pronounced

hyperlocomotor response in the paired compared to the

unpaired control group. These findings support the view of a

highly selective 5-HT1A-autoreceptor gating of the behavioral

expression of COC sensitization (Carey et al., 2005d). This

view is also supported by a local application study that targeted

5-HT1A-autoreceptors in the DRN and MRN with 8-OH-DPAT.

5-HT1A-Rs were found to have a facilitatory role in the MRN,

but not in the DRN in the induction of COC-induced locomotor

sensitization (Szumlinski et al., 2004). This finding supports the

view that there are not only dissociable contributions of 5-

HT1A-autoreceptors and postsynaptic receptors, but also

dissociations within the population of the 5-HT1A-autorecep-

tors, with a dominant role for the MRN (Muller and Huston,

2006).

4.2. Behavioral stereotypies

4.2.1. The 5-HT1A-receptors and the serotonin syndrome

Hyperstimulation of the brain 5-HT system results within

minutes in a behavioral pattern that was summarized as ‘‘5-HT

syndrome’’. In rodents it includes hindlimb abduction, forepaw

treading, lateral head weaving, resting tremor, hindlimb rigidity

and a Straub tail. Further signs can be an outstretched or

flattened body posture, hyperreactivity, hyperlocomotion,

intense salivation, backward walk and piloerection (Graham-

Smith, 1971; Jacobs and Klemfuss, 1975; Lucki and Wieland,

1990). In monkeys, head weaving, hindlimb extension and

upper limb fluttering, but no flattened body posture were

reported (Mizuta et al., 1990). 5-HT1A-Rs are essentially

involved in the mediation of several symptoms of the 5-HT

syndrome, such as hyperlocomotion, forepaw treading, head

weaving and flat body posture, but not in Straub tail and the

resting tremor (Hjorth et al., 1982; Lucki et al., 1984;

Tricklebank et al., 1984; Dourish et al., 1985a,b; Mizuta et al.,

1990; Bickerdike et al., 1995). While the full agonist 8-OH-

DPAT (1–10 mg/kg, i.p.) induced all symptoms of the 5-HT

syndrome in rats, the partial agonists, buspirone and ipsapirone,

elicited only some of them. In fact, they also behaved as

antagonists in blocking forepaw treading, head weaving and

tremor induced by 8-OH-DPAT (Smith and Peroutka, 1986;

Maj et al., 1987). Pretreatment with reserpine, which reduces 5-

HT (and other monoamines), prevented the 5-HT1A-R agonist-

induced ambulation and head weaving, but not the forepaw

treading and flat body posture (Tricklebank et al., 1984, 1986).

The administration of the 5-HT1A-R antagonist WAY 100635

(0.1 and 1.5 mg/kg, s.c.), did not induce head weaving in rats

(Herges and Taylor, 1998). These data suggested a possible role

for presynaptic 5-HT1A-Rs in head weaving and a role of

postsynaptic 5-HT1A-Rs in forepaw treading and the flat body

posture of the 5-HT syndrome. However, flat body posture was

also reported after application of 8-OH-DPAT into the DRN,

but not the MRN, suggesting a different contribution of the 5-

HT1A-autoreceptors in the raphe nuclei (Higgins and Elliott,

1991). In contrast to these data are findings by Yamada et al.

(1988) that the 5-HT syndrome induced by 8-OH-DPAT is not

affected by 5-HT depletion with PCP, and that only head

weaving is diminished after reserpine pretreatment in mice. The

authors concluded that the 5-HT syndrome is primarily

mediated by postsynaptic 5-HT1A-Rs in mice (Yamada et al.,

1988). This view is further supported by the finding that

application of WAY 100635 into the DRN or MRN did not

influence head weaving (Herges and Taylor, 1999). Several

behaviors of the 5-HT syndrome, such as flat body posture and

forepaw treading, develop tolerance after repeated (three times,

1 mg/kg, s.c.) (Larsson et al., 1990), but not after a single

treatment with 8-OH-DPAT (Kennett et al., 1987). The

tolerance effects appear without an altered 8-OH-DPAT binding

in the brain and persist for one, but not for 2 weeks (Larsson

et al., 1990).

4.2.2. Psychostimulant-induced behavioral stereotypies

Psychostimulant drugs at high doses or after repeated

moderate doses are well known to induce behavioral

stereotypies, which overlap with some symptoms, but do not

completely resemble the 5-HT syndrome. After higher doses of

COC (�15 mg/kg, i.p.), or after binge exposure profound

behavioral stereotypies occur. Hyperlocomotor effects tend to

be burst-like (Segal and Kuczenski, 1997a), or are no longer

observed (Downs and Eddy, 1932; Scheel-Kruger et al., 1977;

Tyler and Tessel, 1979; Kuczenski et al., 1991). It should be

noted that the dose–response curve for the locomotor effects of

COC in mice may not only be phase-shifted between different

strains, but can have a very unique shape (Ruth et al., 1988).

AMPH, METH and MDMA can also induce behavioral

stereotypies. AMPH- and METH-induced behavioral stereo-

typies can occur at doses as low as 0.5 mg/kg (s.c.) (Segal,

1975; Segal and Kuczenski, 1997b). While at low doses of

AMPH (0.5–2 mg/kg, s.c.) head movements and sniffing

behavior are observed, at higher doses (>5 mg/kg, s.c.), or after

prolonged and escalating treatment, oral stereotypies predo-

minate (Kuczenski and Segal, 1989; Segal et al., 2005). At such

doses, AMPH can evoke a profound hyperthermia (Carey,


1979). For METH a prominent sniffing response was reported

at high doses (�10 mg/kg) (Witkin et al., 1999). Behavioral

stereotypies, such as low body posture, head weaving and

forepaw treading, that resemble the 5-HT syndrome, were

reported for MDMA after doses �2.5 mg/kg (i.p.) (Spanos and

Yamamoto, 1989; Fone et al., 2002). Psychostimulant-induced

behavioral stereotypies are usually characterized by the animal

sitting with a hunched back in a corner of the cage while

sniffing, liking, biting of cage wire, showing repetitive yaw

movements and head weaving (Downs and Eddy, 1932; Fog,

1969; Scheel-Kruger et al., 1977; Kuczenski and Segal, 1989).

Comparing the stereotypies induced by COC and AMPH,

Scheel-Kruger et al. (1977) noted that COC never attained the

compulsiveness and restrictiveness of the AMPH-induced

stereotypies. Not only the hyperlocomotor effects underwent a

sensitization with repeated treatment, but also the behavioral

stereotypies after COC (Downs and Eddy, 1932; Post and Rose,

1976), AMPH and METH (Kuczenski and Segal, 1997, 1999).


stereotypies

Although the 5-HT syndrome and the role of the 5-HT1A-Rs in

its symptoms has received much attention, as have the

psychostimulant-induced behavioral stereotypies, little research

has been devoted to the role of 5-HT1A-Rs in psychostimulant-

induced behavioral stereotypies (Table 2). At the systemic level,

5-HT1A-R antagonism with WAY 100635 (0.1 and 1.5 mg/kg,

s.c.) potentiated COC (15 mg/kg)-induced head weaving

stereotypies when administered 60 min before COC (Herges

and Taylor, 1998). An enhancement of COC (15 mg/kg, i.p.)-

induced head weaving was mimicked by application of WAY

100635 into the DRN, but not the MRN (Herges and Taylor,

1999). These studies suggested an inhibitory role of 5-HT1A-Rs

in the expression of psychostimulant-induced behavioral

stereotypies. In particular, psychostimulant-induced head weav-

ing seems to be attenuated by DRN 5-HT1A-autoreceptors.

Interestingly, head weaving as part of the 5-HT syndrome, is

induced by DRN 5-HT1A-R stimulation. The basis for these

seemingly contradictory findings remains to be determined.

4.3. Grooming behavior

4.3.1. Role of the 5-HT1A-receptors in grooming behavior

Self-grooming is a spontaneously emitted behavior that is

suppressed by systemic 5-HT1A-R stimulation with 8-OH-DPAT

and augmented by antagonism of the 5-HT1A-R with WAY

100635 in rats (Jackson et al., 1998; Carey et al., 2001; Muller

et al., 2002a). The suppressive effect of 8-OH-DPATwas evident

with low and high doses of 8-OH-DPAT (Carey et al., 2004a,b)

and was seen after local application of 8-OH-DPAT into the DRN

and MRN (Higgins and Elliott, 1991). While the significance of

these effects on grooming behavior remains an open question, the

impact of the 5-HT1A-Rs is reliable and robust.

4.3.2. Psychostimulant effects on grooming behavior

COC not only enhances the expression of some sponta-

neously emitted behaviors, but can also suppress other

spontaneous behaviors. It should be noted that these behaviors,

such as grooming or feeding, are not compatible with

locomotion and rearing. The suppression of these behaviors

may, therefore, be a result of a shift in the expression of

dominant behaviors (Wolgin and Hertz, 1995). One of the most

sensitive effects of COC is the suppression of grooming

behavior, which was observed at doses as low as 5 mg/kg (i.p.)

in rats and at all higher doses tested (Van der Hoek and Cooper,

1990; Cooper and Van der Hoek, 1993; Carey et al., 2001,

2002a). Bodycare activity was also suppressed in marmoset

monkeys after treatment with COC (De Souza Silva et al.,

2006a,b) and after treatment with the amphetamine derivate,

diethylpropion (Mello et al., 2005).

4.3.3. 5-HT1A-receptors in suppression of grooming

behavior by psychostimulants

COC-induced suppression of grooming behavior was

influenced neither by systemic pretreatment with low or high

doses of 8-OH-DPAT, nor with WAY 100635 (Carey et al.,

2001, 2002a,b, 2004a; Muller et al., 2002a, 2003b) (Table 3).

Further support for the view, that 5-HT1A-Rs do not play a role

in psychostimulant-induced suppression of grooming behavior,

comes from a study in monkeys. WAY 100635 (0.2–0.8 mg/kg,

i.p.) failed to modulate the suppression of bodycare activities,

induced by the low potency psychostimulant diethylpropione

(Mello et al., 2005). Also, local application studies did not find

evidence for a contribution of single 5-HT1A-R populations to

psychostimulant-induced suppression of grooming. Neither

postsynaptic 5-HT1A-R activation in the Nac or ventral

hippocampus, nor activation of 5-HT1A-autoreceptors with 8-

OH-DPAT, had an effect on COC-induced suppression of

grooming behavior (Carey et al., 2004a; Muller et al., 2004a,b).

The latter observations are in line with the tonic suppression of

spontaneous grooming behavior by the 5-HT1A-Rs. Additional

activation of the 5-HT1A-Rs by a psychostimulant-induced

overshoot of 5-HT can only potentiate this effect, which,

however, may be masked by a floor effect. The observation, that

5-HT1A-antagonism did not reverse this effect of COC,

suggests that other non-serotonergic effects contribute to the

profound suppression of grooming behavior following psy-

chostimulant drug treatment.

4.4. Feeding behavior

4.4.1. Role of the 5-HT1A-receptors in feeding behavior

An important role for the 5-HT1A-Rs was reported in feeding

behavior. Systemic administration of the 5-HT1A-R agonist 8-

OH-DPAT (0.015–4 mg/kg) increased eating and drinking

behavior in non-deprived rats (Dourish et al., 1985a, 1985b;

Bendotti and Samanin, 1986, 1987; Blanchard et al., 1992;

Balleine et al., 1996; Voigt et al., 2002). In food-deprived rats a

decrease (Dourish et al., 1985b) as well as an increase

(Ebenezer, 1992a) in feeding behavior was observed. Interest-

ingly, this increase was observed at low, 5-HT1A-autoreceptor

preferring doses of 8-OH-DPAT, but not at higher doses, that

also activate postsynaptic 5-HT1A-Rs (Ebenezer, 1992a). An

attenuation of the hyperphagic effect of 8-OH-DPAT has been

Table 3

The effects of 5-HT1A-receptor agonist and antagonist on grooming, feeding and anxiety-related behaviors after treatment with cocaine, amphetamine,

methamphetamine and MDMA


Grooming Cocaine Decrease See text

Agonist: 8-OH-DPAT 0.01 Rat – Carey et al. (2004a)

0.025 Rat – Carey et al. (2004a)


0.2 Rat – Carey et al. (2001, 2002a,b, 2004a)

0.2 Rat – Muller et al. (2003b)



Antagonist: WAY 100635 0.4 Rat – Carey et al. (2001)

0.4 Rat – Muller et al. (2002a)


Feeding Cocaine Decrease See text

Agonist: 8-OH-DPAT 0.2 Rat – Muller et al. (2003b)

Antagonist: WAY 100635 0.4 Rat – Muller et al. (2002a)

Anxiety/aggression Cocaine Increase See text

Agonist: Buspirone 0.5 Rat – Paine et al. (2002)

1 Rat – Paine et al. (2002)

Agonist: 8-OH-DPAT 0.1 Hamster # Knyshevski et al. (2005)

0.3 Hamster # Knyshevski et al. (2005)


1 Hamster # Knyshevski et al. (2005)


MDMA Increase See text

Agonist: Buspirone 2.5 Rat # Bhattacharya et al. (1998)

If not indicated otherwise drug doses refer to systemic administration ("/# significant increase or decrease; – no significant change).


reported after pretreatment with 8-OH-DPAT, buspirone or

ipsapirone (Kennett et al., 1987). 8-OH-DPAT (0.015–

0.0625 mg/kg) also increased lever-pressing reinforced by

food pellets (Ebenezer, 1992a,b; Balleine et al., 1996). The

increase in food consumption and operant performance for

food, induced by 5-HT1A-R activation, was shown not to be due

to an increase in chewing or gnawing behavior (Dourish et al.,

1988; Ebenezer, 1992b), nor to an increase in the incentive

value of the food (Fletcher, 1987; Balleine et al., 1996). The 5-

HT1A-R activation-induced increase in food consumption was

abolished after a serotonergic lesion with the 5-HT neurotoxin,

5,7-dihydroxytryptamine (5,7-DHT) (i.c.v.), or by PCP

pretreatment, indicating a role for 5-HT1A-autoreceptors

(Bendotti and Samanin, 1986; Dourish et al., 1986). Further

evidence showed that microinjections of 8-OH-DPAT into the

DRN or MRN increased eating behavior (Bendotti and

Samanin, 1986). These findings support the view that

activation of 5-HT1A-autoreceptors in the DRN and MRN

reduces the serotonergic tone in terminal areas like the

hypothalamus (Voigt et al., 2004), and, thereby, prevents the

serotonergic inhibition of feeding behavior mediated by non-5-

HT1A-Rs (Lucki and Wieland, 1990; Leibowitz and Alexander,

1998). A reduction in the serotonergic tone in terminal areas,

induced by 5-HT1A-autoreceptor activation, may affect

spontaneously emitted behavior in a way that it reduces

locomotor activity and grooming, but facilitates feeding

behavior.

4.4.2. Psychostimulant-induced suppression of feeding

behavior

COC, AMPH, METH and MDMA were found to suppress

eating and drinking behavior in rodents (van Rossum and

Simons, 1969; Carey and Goodall, 1975; Heffner et al., 1977;

Balopole et al., 1979; Rapoza and Woolverton, 1991; Cooper and

Van der Hoek, 1993; Conductier et al., 2005) and in monkeys

(Foltin et al., 1990). As a consequence, long-term psychosti-

mulant administration can prevent normal weight gain in rodents

and primates (Herman et al., 1971; Tang and Kirch, 1971;

Griffiths et al., 1976; Yeh and Haertzen, 1991; Foltin, 2001).

The enhancing as well as the suppressive acute effects of

medium doses of COC on behavior usually set in immediately

after application and last for up to 2 h (Lau et al., 1991; Cooper

and Van der Hoek, 1993; Muller et al., 2002a,b, 2003b). This

time period may be called the ‘‘acute phase’’. However, there is

evidence for behavioral rebound effects between 2 and 4 h after

application, which may be called the ‘‘late acute phase’’.

Particularly, eating, drinking and grooming behaviors are

enhanced in the late acute phase after COC and MDMA

treatment (Balopole et al., 1979; Foltin et al., 1990; Muller

et al., 2004b; Conductier et al., 2005).


suppression of feeding

Little is known about the role of 5-HT1A-Rs in psychos-

timulant-induced suppression of eating and drinking behavior


(Table 3). Neither the 5-HT1A-R agonist 8-OH-DPAT nor the

antagonist WAY 100635 administered systemically modified

the effects of COC on eating or drinking behavior in rats

(Muller et al., 2002a, 2003b). Also, neither the systemic nor the

intra-Nac application of 8-OH-DPAT had an effect on COC-

induced inhibition of eating and drinking behavior within 2 h

after acute COC application (Muller et al., 2003b, 2004b).

However, during 2–4 h after an acute COC challenge (10 mg/

kg, i.p.) there occurred a rebound effect on eating and drinking

behavior. While not affecting the acute COC effect, local

stimulation of 5-HT1A-Rs in the ventral striatal area blocked the

rebound effect on eating and drinking behavior 2–4 h after an

acute COC challenge (Muller et al., 2004b). Thus, ventral

striatal 5-HT1A-Rs may be involved in the effects of COC on the

regulation of eating and drinking behavior in the long run. The

absence of an effect during the early anorectic action of COC

may represent a floor effect. Overall, 5-HT1A-autoreceptor

activation and the subsequent reduction in serotonergic tone in

terminal areas appear to facilitate feeding behavior. The

psychostimulant-induced increase in 5-HT in these terminal

areas counteracts this effect. Since systemic application of a 5-

HT1A-R antagonist did not reverse psychostimulant-suppres-

sion of feeding behavior, it is also unlikely that postsynaptic 5-

HT1A-Rs are involved in the suppressory action of the

overshoot of 5-HT. However, postsynaptic 5-HT1A-Rs may

play a role in the feeding rebound response in the late acute

phase after psychostimulant treatment. This response was

effectively blocked by ventral striatal 5-HT1A-R activation. In

the rebound phase, when extracellular 5-HT levels reach

baseline or fall below it (Muller et al., 2004b), a reduced

activation of postsynaptic 5-HT1A-Rs, in particular in the

ventral striatum, may contribute to the feeding rebound

response.

4.5. Anxiety

4.5.1. The 5-HT1A-receptors and anxiety

Several anxiolytic drugs appear to display 5-HT1A-R agonist

properties (Traber and Glaser, 1987; Griebel, 1995). An

essential role of 5-HT1A-Rs in emotional behavior has now

been demonstrated by a multitude of pharmacological studies

as well as in 5-HT1A-R knock-out mice. Mainly anxiolytic and

antidepressant actions were reported in numerous investiga-

tions employing 5-HT1A-R agonists systemically in different

anxiety tests in rodents (Engel et al., 1984; Kinney et al., 1998;

Chojnacka-Wojcik and Przegalinski, 1991; Blanchard et al.,

1992; Stefanski et al., 1992; Sommermeyer et al., 1993;

Collinson and Dawson, 1997; Dekeyne et al., 2000) and in non-

human primates (Costall et al., 1992; Barros et al., 2001).

However, the anxiolytic effects depend to some extent on the

particular animal model used (De Vry, 1995). Unconditioned

and conditioned stressors are known to increase extracellular 5-

HT activity in the brain (Shimizu et al., 1992; Yoshioka et al.,

1995; Kirby et al., 1997; Rueter et al., 1997; Amat et al.,

1998a,b). Acute anxiolytic effects of the 5-HT1A-R agonists are

most likely mediated by their property to reduce 5-HT levels in

terminal areas (Iversen, 1984; Graeff et al., 1996). Rather

controversial effects have been reported for several 5-HT1A-R

antagonists in rodent tests of anxiety, as for instance for NAN-

190, (S)-UH-301 and WAY 100135 (Moreau et al., 1992;

Charrier et al., 1994; Rodgers and Cole, 1994; Griebel et al.,

1999). Surprisingly, investigations of the profile of the selective

and silent 5-HT1A-R antagonist WAY 100635 in different

rodent tests of anxiety ranged from anxiolysis (Fletcher et al.,

1996; Cao and Rodgers, 1997, 1998; Griebel et al., 1999, 2000),

no effect (Stanhope and Dourish, 1996; Collinson and Dawson,

1997; Bell et al., 1999; Dekeyne et al., 2000), to anxiogenesis

(Groenink et al., 1995). Studies in non-human primates,

however, reported anxiolytic-like actions for (S)-UH-301

(Moreau et al., 1992) and for WAY 100635 (Barros et al.,

2003). The predominant anxiolytic role of 5-HT1A-Rs in the

brain was confirmed in 5-HT1A-R knock-out mice which

displayed an enhanced anxiogenic-like phenotype (Heisler

et al., 1998; Parks et al., 1998; Ramboz et al., 1998;

Klemenhagen et al., 2006). It should be noted that the

anxiogenic phenotype could not be replicated in all background

strains when more extensive testing was used (Groenink et al.,

2003). It was concluded that ‘‘under non-stress conditions

neither extracellular 5-HT levels, nor behavioral and physio-

logical parameters, are altered in 5-HT1A-R knock-out mice,

indicating that these mice are not constitutionally more

anxious’’ (Groenink et al., 2003). However, under stress

conditions, which lead to a 5-HT increase, adaptive mechan-

isms, which compensate for the lack of 5-HT1A-Rs, are no

longer sufficient to oppose the 5-HT increase, thus, leading to

an increase in anxious behavior and an exaggerated autonomic

response (Groenink et al., 2003). It was shown that 5-HT1A-Rs

in the brain do not contribute in an uniform way to the

anxiolytic effects of the 5-HT1A-R agonist treatment (De Vry,

1995). 5-HT1A-autoreceptors in the DRN and MRN were

independently shown to contribute most potently to the

anxiolytic effects of 5-HT1A-R agonists in various test

paradigms in rats (Higgins et al., 1992; Schreiber and De

Vry, 1993a; Andrews et al., 1994; File et al., 1996; Maurel

Remy et al., 1996; De Almeida et al., 1998), most likely by

reducing serotonergic tone in terminal areas. Also, the

observation that the anxiolytic effects of intra-hippocampal

and intra-striatal application of 8-OH-DPAT are preserved after

ibotenic acid lesions of these areas supports a presynaptic

mediation of the anxiolytic effects (Jolas et al., 1995). The

stimulation of postsynaptic 5-HT1A-Rs, in particular in the

hippocampus, yielded anxiolytic (Eison et al., 1986; Kostowski

et al., 1989; Chojnacka-Wojcik and Przegalinski, 1991;

Schreiber and De Vry, 1993a; Stefanski et al., 1993; Netto

and Guimaraes, 1996; Menard and Treit, 1998), no effects (File

and Gonzalez, 1996; Menard and Treit, 1998), as well as

anxiogenic effects in rats (Andrews et al., 1994; File et al.,

1996). The direction of effect depends at least in part on the

paradigm used (Menard and Treit, 1998). Local 8-OH-DPAT

administration in the medial septum or the amygdala increased

anxiety (Hodges et al., 1987; De Almeida et al., 1998).

However, also anxiolytic effects were reported after 8-OH-

DPAT application into the medial septum in a shock probe

burying test, but not in the elevated plus maze test of anxiety


(Menard and Treit, 1998; Micheau and van Marrewijk, 1999). A

recent study in mice overexpressing the 5-HT1A-R in the outer

cortical layers (I–III) and in the dentate gyrus did not find

altered anxiety related behaviors (Bert et al., 2006).

At the present stage, research suggests that primarily 5-

HT1A-autoreceptors in the DRN and MRN mediate the

anxiolytic effects of the 5-HT1A-R agonists, most likely by

reducing the serotonergic tone in terminal areas of the 5-HT

projections. The literature on postsynaptic 5-HT1A-R involve-

ment in emotional behavior is contradictory, possibly suggest-

ing a different role for several postsynaptic 5-HT1A-R

populations in anxiety.

4.5.2. Psychostimulant effects on anxiety

Psychostimulant drugs can have anxiogenic effects, which

are tolerated by human users and animals during compulsive

drug taking (Gawin and Kleber, 1986; Gawin, 1991; Deroche-

Gamonet et al., 2004). Acute COC treatment (1 and 10, but not

25 mg/kg, i.p.) increases anxiety-related behaviors, as shown in

studies using a black-white box test in mice (Costall et al.,

1989). COC (10 and 20 mg/kg, i.p.) also increased anxiety in

the elevated plus maze test in rats and mice (Yang et al., 1992;

Rogerio and Takahashi, 1992a,b; Paine et al., 2002). Interest-

ingly, the anxiogenic effects of 1 mg/kg (i.p.) COC were shown

to attenuate with repeated treatment after only 3 days (Costall

et al., 1989). No effect of acute COC treatment (1–20 mg/kg,

i.p.) on aggression was found in resident-intruder tests in rats

(Long et al., 1996). In contrast, isolation-induced fighting was

significantly enhanced after 10 and 35 mg/kg (i.p.) adminis-

tration of COC in mice (Hadfield et al., 1982). Enhanced escape

and flight responses were reported following COC (10–30 mg/

kg, i.p.) in mice confronted with an anaesthetized rat as threat

stimulus, and in rats after 4 mg/kg (i.v.) COC in a runway test

(Blanchard et al., 1999). Repeated treatment with low (0.5–

1 mg/kg, i.p.), but not high doses of COC, can induce

aggressive behavior in rats (Long et al., 1996) and hamsters

(Harrison et al., 2000; Deleon et al., 2002), as measured with

the resident-intruder paradigm. Attack and escape behaviors

were also investigated in squirrel monkeys after treatment with

COC using a shock-induced biting paradigm. This study found

an increase in the escape response, as well as in attack behavior,

after treatment with COC (0.3–1 mg/kg, s.c.) (Emley and

Hutchinson, 1983). These observations suggest that the putative

aggression-inducing effects of an acute psychostimulant

treatment may depend on the paradigm used.

It was shown that the anxiogenic effects of COC (together

with the reinforcing effects) can be associated with a particular

environment. During re-exposure, this conditioned fear effect

may influence the operant behavior that is associated with the

self-administration of the drug. This particular psychostimulant

effect was demonstrated in an operant runway model of self-

administration for COC (Ettenberg and Geist, 1991, 1993;

Raven et al., 2000). Animals learned that reaching a goal box of

a straight-arm runway is associated with an i.v. drug

application. Testing the animals in a drug-free state led them

to run from a start box to the goal box. However, before they

entered the goal box, they stopped, showing a retreat behavior,

which was interpreted as an approach-avoidance conflict,

reflecting the previously experienced anxiogenic effects of the

drugs. A similar behavior was observed when food and a shock

were applied in the goal box (Geist and Ettenberg, 1997).

Retreat behavior, induced by COC and by pairing food with

foot shock, was blocked by pretreatment with the anxiolytic

drug diazepam, supporting the view of a conditioned fear effect

(Ettenberg and Geist, 1991; Geist and Ettenberg, 1997). Since

these conditioned effects are expressed in an undrugged state,

they may not necessarily preclude the reversal of acute COC

effects (1 mg/kg, i.p.) after repeated application, which was

found to become rather anxiolytic after only 3 days of twice

daily treatment (Costall et al., 1989).

AMPH (4 mg/kg) was shown to induce anxiogenic effects in

the elevated plus maze test in mice (Lin et al., 1999). D-AMPH

also increased defensive behaviors and flight responses in rats

(Markham et al., 2006). An increase in the escape response and

in attack behavior after treatment with AMPH (0.125–1.0 mg/

kg, s.c.) was found in squirrel monkeys in a shock-induced

biting paradigm, also supporting an anxiogenic effect of AMPH

(Emley and Hutchinson, 1983). METH was also shown to have

acute and enduring anxiogenic effects (Hayase et al., 2005), and

to increase conditioned fear responses still 5 days after repeated

treatment (Tsuchiya et al., 1996). Application of MDMA had a

biphasic effect on anxiety measured in the elevated plus maze

test in mice. A low dose of 4 mg/kg MDMA let to an anxiogenic

response, whereas at a high dose (20 mg/kg) became anxiolytic

(Lin et al., 1999). Anxiogenic as well as anxiolytic behavior

was confirmed in a study by Maldonado and Navarro (2001) in

a mouse social encounter test. Also in rats, a biphasic effect was

observed in the elevated plus maze test of anxiety. At low doses

of 7.5 mg/kg, MDMA led to an anxiogenic-like behavioral

profile, while a high dose of 15 mg/kg was anxiolytic (Ho et al.,

2004). MDMA (8 and 15 mg/kg) reduced aggressive behaviors

and social investigation, but defense/submission and avoid-

ance/flee behaviors were augmented (Maldonado and Navarro,

2001). In contrast, a clear anxiogenic profile of 5 and 10 mg/kg

MDMA was reported in the elevated plus maze and social

interaction test in rats (Bhattacharya et al., 1998). Repeated

MDMA treatment resulted also in an increased level of anxiety

many days after the last injection. Increased anxiety was

measured 29 days after the last MDMA treatment in a social

interaction test (Fone et al., 2002), and 4 weeks and 3 months

thereafter in emergence-, social interaction- and elevated plus

maze tests of anxiety in rats (Morley et al., 2001; Gurtman

et al., 2002). For these long-term effects on anxiety, the

neurotoxic effects of MDMA in the 5-HT system (Schmidt,

1987b; Schmidt and Taylor, 1988) were claimed to be an

essential mechanism (Gurtman et al., 2002), although,

potentially, they could also be a result of conditioned responses

to handling by the investigator.

4.5.3. 5-HT1A-receptors in psychostimulant effects on

anxiety

A study in rats, which investigated the effects of acute COC

application and withdrawal from a chronic COC regimen on

anxiety in the elevated plus maze, did not find an effect of the


5-HT1A-R agonist buspirone (0.5 and 1 mg/kg) on acute COC-

induced anxiety, nor on anxiety induced by COC withdrawal

(Paine et al., 2002) (Table 3). Bhattacharya et al. (1998)

investigated the effects of buspirone on MDMA-induced

anxiety in the elevated plus maze test in rats. In this study, a

higher dose of buspirone (2.5 mg/kg) reversed the anxiogenic

effects of 5 and 10 mg/kg MDMA (Bhattacharya et al., 1998).

Although, little is known about the participation of 5-HT1A-Rs

in anxiety induced by psychostimulants, given the knowledge

on the mechanisms of 5-HT1A-R agonist-induced anxiolysis, a

5-HT1A-R mechanism in psychostimulant-induced anxiety

appears likely. It was shown that stimulation of 5-HT1A-

autoreceptors in the DRN and in the MRN has anxiolytic effects

by reducing the serotonergic tone in terminal areas. In

opposition to this effect, psychostimulants increase terminal

5-HTactivity, which may contribute to the anxiogenic effects. It

may be speculated that 5-HT1A-autoreceptor activation could

limit the anxiogenic psychostimulant effect by reducing the

magnitude of the 5-HT increase. Such a mechanism is

consistent with effects on aggressive behavior. It was shown

that repeated treatment with low doses of COC (0.5 mg/kg)

induced aggressive behavior in hamsters. The expression of this

behavior was attenuated by pre-treatment with 8-OH-DPAT

(Knyshevski et al., 2005). However, to draw a valid conclusion

on the participation of 5-HT1A-Rs in the anxiogenic and

aggressive effects of psychostimulants, further research is

required.

4.6. Discriminative stimulus properties

4.6.1. 5-HT1A-receptor stimulation and inhibition

In animal studies, discriminative stimulus properties are

assessed by pairing a drug cue with the availability of food or

water reward when pressing one of two levers. If a certain drug

can be readily differentiated from saline, responding takes

place on the rewarded lever. This paradigm allows the

prerequisites in the brain for drug discrimination to be

investigated, as well as the ability of a pharmacological

treatment to substitute for the drug as a pharmacological cue.

The systemic stimulation of 5-HT1A-Rs can be distinguished

from saline as a discriminative stimulus by rats (Glennon,

1986). While non-5-HT1A-R-, D2- and a2-receptor agonists do

not substitute for 8-OH-DPAT, a full substitution was observed

for the partial agonists, buspirone and ipsapirone (Glennon,

1986; Cunningham et al., 1987; Schreiber et al., 1995).

Thereby, the potency to generalize to the 8-OH-DPAT cue

correlated with the affinity to rat hippocampal 5-HT1A-Rs.

Furthermore, the discriminative stimulus properties of the 8-

OH-DPAT cue were blocked by several 5-HT1A-R antagonists,

supporting an involvement of the 5-HT1A-R (Schreiber et al.,

1995; Sanchez et al., 1996). In contrast to 8-OH-DPAT, the

discriminative stimulus properties of buspirone partially

depend on its D2 antagonist action (Rijnders and Slangen,

1993). In a local application study, Schreiber and De Vry

(1993b) showed that application of 8-OH-DPAT into the DRN

and hippocampus substituted for the systemic 8-OH-DPAT cue.

These findings suggested an involvement of both pre- and

postsynaptic 5-HT1A-Rs in the discriminative stimulus proper-

ties of 8-OH-DPAT (Schreiber and De Vry, 1993b).

4.6.2. Psychostimulant discriminative stimulus properties

Reports by human psychostimulant users and systematic

studies in humans suggest that psychostimulants may have

euphoric effects with the very first usage, and may be

discriminable from other substances by their subjective effects.

Animal models, however, can only indirectly asses these effects

after acute application (Berridge, 2000; Burgdorf et al., 2001).

Although, there are powerful models to measure the

discriminative stimulus properties and the reinforcing effects

of psychostimulants, all these models require extensive training

and many drug applications to detect behavioral changes

indicative of discriminative stimulus properties or reinforcing

effects. COC, AMPH, METH and MDMA can be discriminated

from saline by pigeons (Johanson and Barrett, 1993; Sasaki

et al., 1995), rats (Schechter, 1988; Baker et al., 1997) and mice

(Snoddy and Tessel, 1983; Witkin et al., 1999). Furthermore,

AMPH and METH mimic the discriminative stimulus proper-

ties of COC in pigeons (Johanson and Barrett, 1993) and in

monkeys (Schama et al., 1997).

4.6.3. 5-HT1A-receptors and psychostimulant

discriminative stimulus properties

The discriminative stimulus effects of psychostimulant

drugs in animals serve as a model for the subjective drug effects

in humans. Stimulation of 5-HT1A-Rs with 8-OH-DPAT, or the

partial agonists, buspirone and gepirone, does not substitute for

COC in rats (Table 4) (Callahan and Cunningham, 1997). The

discriminative stimulus properties of COC were also not

modulated by medium doses of the partial 5-HT1A-R agonist,

buspirone or the full agonist, 8-OH-DPAT, in rats (Rapoza,

1993; Przegalinski and Filip, 1997; Callahan and Cunningham,

1995, 1997). Buspirone and 8-OH-DPAT, however, reduced the

discriminative stimulus properties of COC when administered

at higher doses. At these doses, both agonists also suppressed

general responding (Rapoza, 1993; Callahan and Cunningham,

1995, 1997), which suggests rather unspecific effects. The

authors explained this finding in part by the prominent actions

of buspirone, but not gepirone, at the D2 DA-R (Van

Wijngaarden et al., 1990), which was shown to block the

discriminative stimulus properties of the D2 DA-R agonist,

apomorphine, in rats and monkeys (Kamien and Woolverton,

1990; Rijnders and Slangen, 1993). A study in pigeons reported

a partial substitution for COC (1.0 or 1.7 mg/kg, i.m.) by 8-OH-

DPAT (0.03–0.17 mg/kg) in two of four animals tested, and a

partial blockade of the discriminative stimulus effects of COC

by the 5-HT1A-R antagonist NAN-190 (Johanson and Barrett,

1993). Since, only four animals were tested in this study and

statistical results are somewhat unclear, conclusions must be

limited. The 5-HT1A-R antagonist NAN-190 neither substituted

for COC, nor altered its discriminative stimulus properties in

rats (Callahan and Cunningham, 1995).

The discriminative stimulus properties of AMPH were

not modulated by 8-OH-DPAT in rats (Przegalinski and Filip,

1997). This observation was confirmed in rats, since 8-OH-DPAT

Table 4

The effects of 5-HT1A-receptor agonist and antagonist on the discriminative stimulus properties of cocaine, amphetamine, methamphetamine and MDMA


Discriminative stimulus Cocaine Yes See text

Agonist: Buspirone 2 Rat – Rapoza (1993)

2.5 Rat – Callahan and Cunningham (1997)

4 Rat – Rapoza (1993)

5 Rat (#) Callahan and Cunningham (1997)

8 Rat (#) Rapoza (1993)


16 Rat (#) Rapoza (1993)


Agonist: Gepirone 2.5 Rat – Callahan and Cunningham (1997)

5 Rat – Callahan and Cunningham (1997)

20 Rat – Callahan and Cunningham (1997)

Agonist: 8-OH-DPAT 0.1 Rat – Przegalinski and Filip (1997)




0.8 Rat (#) Callahan and Cunningham (1995)

1.6 Rat (#) Callahan and Cunningham (1995)

Antagonist: NAN-190 0.1 Rat – Callahan and Cunningham (1995)




Agonist: Buspirone 2.5 Rat No substitution Callahan and Cunningham (1997)

5 Rat No substitution Callahan and Cunningham (1997)


Agonist: Gepirone 2.5 Rat No substitution Callahan and Cunningham (1997)



Agonist: 8-OH-DPAT 0.2 Rat No substitution Callahan and Cunningham (1995)

0.4 Rat No substitution Callahan and Cunningham (1995)



Antagonist: NAN-190 0.1 Rat No substitution Callahan and Cunningham (1995)




Amphetamine Yes See text

Agonist: Buspirone 0.41 Monkey # Nader and Woolverton (1994)

Agonist: Gepirone 1.82 Monkey # Nader and Woolverton (1994)

Agonist: 8-OH-DPAT 0.01 Rat – Young et al. (2006)

0.03 Rat – Young et al. (2006)

0.03 Monkey # Nader and Woolverton (1994)






Agonist: Buspirone 0.3 Monkey No substitution Nader and Woolverton (1994)

0.56 Monkey No substitution Nader and Woolverton (1994)

Agonist: Gepirone 0.3 Monkey No substitution Nader and Woolverton (1994)


1 Monkey No substitution Nader and Woolverton (1994)

Agonist: 8-OH-DPAT 0.01 Rat No substitution Young et al. (2006)

0.03 Rat No substitution Young et al. (2006)








Methamphetamine Yes See text

Agonist: Buspirone 0.56 Rat – Munzar et al. (1999)

1 Rat – Munzar et al. (1999)


5.6 Rat – Munzar et al. (1999)

Agonist: 8-OH-DPAT 0.0056 Rat – Munzar et al. (1999)




Antagonist: WAY 100635 0.1 Rat – Munzar et al. (1999)




Agonist: Buspirone 1 Rat No substitution Munzar et al. (1999)

3 Rat (Partial subst.) Munzar et al. (1999)

5.6 Rat (Partial subst.) Munzar et al. (1999)

10 Rat (Partial subst.) Munzar et al. (1999)

Agonist: 8-OH-DPAT 0.03 Rat No substitution Munzar et al. (1999)

0.1 Rat No substitution Munzar et al. (1999)

0.3 Rat No substitution Munzar et al. (1999)

0.56 Rat (Partial subst.) Munzar et al. (1999)

MDMA Yes See text

Agonist: 8-OH-DPAT 0.1 Rat – Glennon and Young (2000)

0.3 Rat – Glennon and Young (2000)

Antagonist: NAN-190 0.05 Rat – Glennon et al. (1992)

0.2 Rat – Glennon et al. (1992)

0.6 Rat – Glennon et al. (1992)

Antagonist: WAY 100135 2.5 Rat – Baker et al. (1997)

5 Rat – Baker et al. (1997)

10 Rat – Baker et al. (1997)

Agonist: R(+)8-OH-DPAT 0.2 Rat Substitution Glennon and Young (2000)

Agonist: S(�)8-OH-DPAT 0.4 Rat Substitution Glennon and Young (2000)

Agonist: 8-OH-DPAT 0.3 Rat Substitution Glennon and Young (2000)

0.4 Rat No substitution Schechter (1988)



If not indicated otherwise, drug doses refer to systemic administration ("/# significant increase or decrease; – no significant change). ( ) Indicates additional inhibitory

effects on general activity.


(0.01–0.5 mg/kg) neither generalized to 1 mg/kg d-AMPH when

given alone, nor antagonized its stimulus effects when given in

combination (Young et al., 2006). However, pretreatment with

0.1 mg/kg 8-OH-DPATappeared to potentiate the discriminative

stimulus properties of a subthreshold dose of d-AMPH, thus,

shifting the dose–response curve of the d-AMPH discrimination

to the left. The authors concluded that d-AMPH is a more

effective discriminative stimulus in the presence of 8-OH-DPAT

(Young et al., 2006). A study in rhesus monkeys found no

substitution for the effects of intra-gastrically applied AMPH by

buspirone, gepirone or 8-OH-DPAT. Nevertheless, this study

reported an inhibition of the discriminative stimulus properties of

AMPH (0.03–1.0 mg/kg) by these 5-HT1A-R agonists (Nader

and Woolverton, 1994). The potency to block the AMPH

(0.56 mg/kg) discriminative stimulus effects was 8-OH-

DPAT > buspirone > gepirone with ED50 values of 0.03, 0.41

and 1.82 mg/kg (i.m.), respectively. Considering the high

effectiveness of 8-OH-DPAT in this study, the ED50 suggests

that the observed effects may be primarily mediated by 5-HT1A-

autoreceptor activation rather than by affecting all 5-HT1A-R

populations of the brain. In contrast, the lack of an AMPH

substitution was evident at much higher doses of 8-OH-DPAT

(0.1 and 0.33 mg/kg), which are known to affect 5-HT1A-

autoreceptors and postsynaptic 5-HT1A-Rs (Nader and Wool-

verton, 1994). Also, the studies which failed to find an inhibitory

effect for 8-OH-DPAT used concentrations in this range. Thus, it

may be speculated that some of the seemingly contradictory

findings may be due to dose differences which result in the

preferential activation of 5-HT1A-autoreceptors at low doses, or

in the activation of 5-HT1A-autoreceptors and postsynaptic

receptors at higher doses. Accordingly, the present data suggest

that 5-HT1A-autoreceptors in the raphe nuclei might inhibit the

discriminative stimulus properties of psychostimulants. This

effect, however, may be cancelled out by the additional activation


of (some) postsynaptic 5-HT1A-R populations. At least the

postsynaptic 5-HT1A-Rs in the VTA and the SN, the origin of the

mesocorticolimbic and nigrostriatal DA projections, do not

appear to be involved in a facilitatory contribution of postsy-

naptic 5-HT1A-R populations to the discriminative stimulus

properties of COC. The local application of 8-OH-DPAT into the

VTA or SN neither substituted for COC, nor modulated its

discriminative stimulus properties (De La Garza et al., 1998).

A study in pigeons showed that 8-OH-DPAT at high doses

(0.1–1.0 mg/kg, i.m.) substituted for METH, at least in 50% of

the animals tested. Low doses of 8-OH-DPAT (0.003–0.03 mg/

kg, i.m.), but not higher doses, blocked the discriminative

stimulus properties of METH in pigeons, which might be

mediated by presynaptic 5-HT1A-autoreceptors (Sasaki et al.,

1995). However, since only four pigeons were tested, it appears

difficult to draw sound conclusions from this study concerning

effective dose ranges. The systemic application of high doses of

8-OH-DPAT (0.56 mg/kg) and buspirone (3–10 mg/kg) par-

tially generalized to a training dose of METH under a fixed-

ratio schedule of food presentation in rats. Effective doses,

however, markedly decreased general responding. The partial

generalization was antagonized by the 5-HT1A-R antagonist,

WAY 100635 (Munzar et al., 1999). At all doses tested neither

8-OH-DPAT (0.0056–0.56 mg/kg) nor buspirone (0.56–5.6 mg/

kg) altered the discriminative stimulus properties of METH in

rats. WAY 100635 also failed to affect the discriminative

stimulus properties (Munzar et al., 1999).

Only a minor role for 5-HT1A-Rs was found for the

discriminative stimulus properties of MDMA. Stimulation of 5-

HT1A-Rs with 8-OH-DPAT did not substitute for MDMA in rats

(Schechter, 1988). Another study in rats, however, found a

substitution for the MDMA stimulus. A detailed investigation

revealed an ED50 value for racemic 8-OH-DPAT of 0.3 mg/kg,

and for the isomers R(+)8-OH-DPAT and S(�)8OH-DPAT of

0.2 and 0.4 mg/kg, respectively (Glennon and Young, 2000).

Racemic 8-OH-DPAT (0.1 and 0.3 mg/kg), in contrast, did not

change the discriminative stimulus properties of MDMA

(Glennon and Young, 2000). Pretreatment with the 5-HT1A-R

antagonist, NAN-190, somewhat attenuated the discriminative

stimulus effects of MDMA in rats, but this effect failed to reach

statistical significance (Glennon et al., 1992). WAY 1001635

also had little effect on the discrimination of either optical

isomer of MDMA (Baker et al., 1997).

Taken together, the available evidence clearly demonstrates

that 5-HT1A-R agonists as well as psychostimulants possess

discriminative stimulus properties. However, most studies show

that 5-HT1A-R agonists neither substitute for psychostimulant

drugs, nor do 5-HT1A-R antagonists modulate the discriminative

stimulus properties of psychostimulants. From these findings, it

may be concluded that 5-HT1A-Rs do not play a major role in the

discriminative stimulus properties of psychostimulant drugs.

Since, 5-HT1A-R agonist and antagonist pretreatments pro-

foundly modulate the 5-HTresponse to psychostimulants (Muller

et al., 2002b, 2003b; Andrews et al., 2005), it may even be

speculated that this modulation and the subsequent hyper- or

hypoactivation of other 5-HT-Rs are not the central mechanism

mediating psychostimulants discriminative stimulus properties.

4.7. Learning, memory and reinforcement

4.7.1. The role of the 5-HT1A-receptors

4.7.1.1. Learning and memory. Recent theories consider the

establishment of drug addiction-related behaviors as an

aberrant learning process (Di Chiara, 2002; Robinson and

Berridge, 2003; Everitt and Robbins, 2005), which involves

brain circuits, transmitter systems and neuronal changes that

also underlie ‘‘normal’’ learning and memory processes

(Nestler, 2002; Hyman, 2005). A plethora of studies suggests

that disturbances of the serotonergic system cause malfunctions

in learning, consolidation and retrieval of information involving

several types of memory (Jacobs and Azmitia, 1992; Meneses,

1999). 5-HT1A-Rs were shown to be involved in these effects in

a variety of learning paradigms. A pretraining injection of a 5-

HT1A-R agonist impaired the learning of a conditioned

appetitive response in rats (Meneses and Hong, 1994a), and

of a conditioned fear response in mice (Quartermain et al.,

1993). Also passive avoidance learning was impaired in mice

(Mendelson et al., 1993). In monkeys buspirone and 8-OH-

DPAT retarded the acquisition of an appetitively motivated

operant response (Winsauer et al., 1996). The deficit in

response acquisition may coincide with a reduction in

spontaneous behavioral alternations induced by 8-OH-DPAT

(Yadin et al., 1991; Seibell et al., 2003). Post-training, 5-HT1A-

R agonists improved performance in a conditioned response

task (Meneses and Hong, 1994b), but had no effect on the

retrieval of a conditioned fear response (Quartermain et al.,

1993), or the learning of a passive avoidance task (Mendelson

et al., 1993). Stimulation of 5-HT1A-Rs by systemic 8-OH-

DPAT also impaired learning and retrieval of a spatial

discrimination task in the water maze, but not of a visual

discrimination task (Carli et al., 1995a). 5-HT1A-R antagonist

studies suggest that the 5-HT1A-Rs are not a prerequisite for

drug free spatial learning. As such, the application of WAY

100635 failed to modify the acquisition of a spatial memory

task (Carli et al., 1995b). However, this is in contrast to a study

with 5-HT1A-R knock-out mice, which reported deficits in these

mice in spatial, but not in non-spatial water maze learning

(Sarnyai et al., 2000). These data support the view that 5-HT1A-

Rs essentially contribute to spatial learning, but are not

necessary for non-spatial learning (Sarnyai et al., 2000).

It was shown that the impairment of spatial learning in the

water maze induced by systemic 8-OH-DPAT application, was

preserved in rats that received a serotonergic lesion with 5,7-

DHT, suggesting the involvement of postsynaptic 5-HT1A-Rs

(Carli and Samanin, 1992). A local application study

demonstrated impairments in learning and retrieval in a spatial

memory task by selective stimulation of 5-HT1A-Rs in the

dorsal hippocampus (Carli et al., 1992). Furthermore, the

impairment in spatial learning induced by systemic application

of 8-OH-DPAT was antagonized by intra-hippocampal infusion

of the 5-HT1A-R antagonist, WAY 100135, supporting a critical

role of hippocampal 5-HT1A-Rs (Carli et al., 1995a).

Interestingly, local application of an 5-HT1A-R antagonist into

the dorsal hippocampus did not affect the acquisition of a


spatial memory task (Carli et al., 1995a,b), suggesting that tonic

activation of dorsal hippocampal 5-HT1A-Rs is not required for

spatial memory acquisition. Also, postsynaptic 5-HT1A-Rs in

the medial septum, the origin of cholinergic afferents of the

hippocampus, appear to disrupt the acquisition of water maze

learning and retrieval, possibly by a reduction of the cholinergic

tonus in the hippocampus (Bertrand et al., 2000). However, not

only spatial learning was disrupted by 5-HT1A-R activation in

the dorsal hippocampus. Guimaraes et al. (1993) showed that

also the consolidation of stressful memories of a restraint,

which led to elevated levels of anxiety in an elevated plus maze

test, was disrupted by local application of 8-OH-DPAT into the

dorsal hippocampus of rats. Post-trial application of 8-OH-

DPAT into the lateral septum also impaired passive avoidance

learning (Lee et al., 1992). Nevertheless, there is also evidence

for a presynaptic mechanism in the 5-HT1A-R-mediated effects

on memory. It was shown that chronic treatment with the 5-HT

synthesis inhibitor, PCP, blocked the pre- and post-training

effects of systemic 8-OH-DPAT injection in an autoshaping

learning task (Meneses and Hong, 1994b). Intra-MRN, but not

intra-DRN application of 8-OH-DPAT attenuated behavioral

extinction in an operant task (Fletcher, 1993). Overall, 5-HT1A-

R agonists at low autoreceptor preferring doses tend to improve

learning, whereas postsynaptic 5-HT1A-Rs preferentially

impair learning (Meneses, 1999).

4.7.1.2. Conditioned place preference. When the effects of a

pharmacological treatment are repeatedly paired with a certain

place context, and in a free choice this place is preferred over

another, originally equally preferred place, a conditioned place

preference (CPP) is inferred. If the paired place is avoided in the

test, a conditioned place aversion (CPA) is concluded

(Tzschentke, 1998; Bardo and Bevins, 2000). The ability of

a pharmacological treatment to induce CPP is seen as an

indicator of its rewarding and positive reinforcing properties,

whereas, a CPA suggests aversive properties of a drug

treatment.

Several studies showed that stimulation of 5-HT1A-Rs serves

not only as a discriminative stimulus, but also has reinforcing

effects. The partial 5-HT1A-R agonists buspirone (1 and 3 mg/

kg, s.c.) and gepirone (3 mg/kg, s.c.), were shown to induce

CPP in rats (Neisewander et al., 1990). Also, the systemic

application of low to medium doses of 8-OH-DPAT (0.1–

0.25 mg/kg), which may predominantly stimulate 5-HT1A-

autoreceptors, induced CPP in rats. The CPP induced by 8-OH-

DPAT is comparable with that induced by 1.5 mg/kg (s.c.)

AMPH. In contrast, high doses of 8-OH-DPAT (�0.5 mg/kg),

which, in addition, activate postsynaptic 5-HT1A-Rs, induced a

CPA, indicting an aversive effect (Papp and Willner, 1991;

Shippenberg, 1991; Fletcher et al., 1993a,b). The 5-HT

synthesis inhibitor, PCP, abolished the 8-OH-DPAT-induced

CPP, but had no effect on CPA. These findings provide indirect

evidence for an involvement of presynaptic 5-HT1A-Rs in the

reinforcing effects of low and medium doses of 8-OH-DPAT

(Papp and Willner, 1991). Direct evidence, however, comes

from a study by Fletcher et al. (1993b), which demonstrated

that intra-DRN as well as intra-MRN 8-OH-DPAT injection can

induce a CPP in rats. Taken together, the available literature

suggests that 5-HT1A-autoreceptor activation has reinforcing

effects, which are ‘‘overwritten’’ when, in addition, post-

synaptic 5-HT1A-Rs are activated. Postsynaptic 5-HT1A-Rs

seem to exert predominantly aversive effects.

4.7.1.3. Self-administration. Self-administration of a drug is

another important test in the study of reward/reinforcement

properties of drugs. The self-administration of a receptor

agonist is a powerful indicator for the reinforcing effects of the

receptor activation. 5-HT1A-R-receptor agonists, like buspirone

(Balster and Woolverton, 1982; Griffiths et al., 1991) or

tandospirone (Sannerud et al., 1993), however, are not self-

administered by monkeys. Accordingly, no reinforcing effects

of the 5-HT1A-R stimulation can be concluded from this

paradigm. It has to be noted that the systemic self-

administration in these studies probably caused an activation

of 5-HT1A-autoreceptors and postsynaptic 5-HT1A-receptors.

From the available data, it can not be ruled out that 5-HT1A-

autoreceptor activation alone may have reinforcing effects, as

demonstrated in place preference studies.

4.7.1.4. Intracranial self-stimulation. Another method to

determine the reinforcing effects of 5-HT1A-R agonism or

antagonism is to measure its effects on threshold of reinforcing

brain stimulation. In this paradigm, subjects perform an operant

task reinforced by electrical stimulation of the lateral

hypothalamus (Markou and Koob, 1992). An increase in the

stimulation threshold that is required to maintain brain

stimulation reinforcement by a treatment indicates a reduced

reward value of the electrical stimulation. Systemic adminis-

tration of the 5-HT1A-R agonist 8-OH-DPAT yielded a biphasic

effect on the threshold of brain stimulation reward in rats.

Systemic application of low, 5-HT1A-autoreceptor preferring

doses 8-OH-DPAT (0.003 and 0.03 mg/kg) lowered reward

thresholds and enhanced responding. In contrast, high doses 8-

OH-DPAT (0.1 and 0.3 mg/kg) that also stimulate postsynaptic

5-HT1A-Rs, increased the reward threshold (Montgomery et al.,

1991; Harrison and Markou, 2001). The non-selective 5-HT1A-

R agonist buspirone, in contrast, only reduced brain stimulation

reward (Montgomery et al., 1991), which may, however, be

mediated by a D2 DA mechanism (Van Wijngaarden et al.,

1990). Application of the 5-HT1A-R antagonist p-MPPI

reversed both 8-OH-DPAT effects, but did not have an effect

alone on reward thresholds (Harrison and Markou, 2001;

Markou et al., 2005). Local application of 8-OH-DPAT into the

DRN or MRN showed dissociable effects. Activation of 5-

HT1A-autoreceptors in the MRN lowered reward thresholds

(Fletcher et al., 1995; Harrison and Markou, 2001), while intra-

DRN 5-HT1A-autoreceptor stimulation was without an effect

(Harrison and Markou, 2001). At this point, it may be

speculated that the reinforcing effects of the 5-HT1A-

autoreceptor stimulation coincides with anxiolytic effects,

and that additional postsynaptic 5-HT1A-R stimulation by

higher doses of 8-OH-DPAT may coincide with the anxiogenic

effects. The reinforcing effects of 5-HT1A-R stimulation were

shown to require DA receptors (Papp and Willner, 1991;


Shippenberg, 1991), which, however, may be activated

downstream by an interaction of the 5-HT1A-R stimulation

with dopaminergic activity. Overall, evidence suggests that

systemic 5-HT1A-R stimulation with low to medium doses of an

agonist can serve as a discriminative drug cue, which, in

addition, has reinforcing effects. At high doses, the 5-HT1A-R

stimulation becomes aversive and induces avoidance behavior.

While pre- and postsynaptic 5-HT1A-Rs are responsible for the

discriminative stimulus properties, evidence suggests only a

presynaptic 5-HT1A-R involvement in the positive reinforcing

effects, as determined by place preference, self-administration

and brain stimulation reward studies.

4.7.2. Psychostimulant effects

4.7.2.1. Conditioned place preference. Chronic treatment

with psychostimulant drugs leads to the development of

various addiction-related behaviors that are expressed in an

undrugged state. After only a few pairings of the acute

psychostimulant effects with a specific test environment, a

preference for this environment, compared to other areas in a

test arena, is evident when the animal has a choice in an

undrugged state (Bardo et al., 1995; Tzschentke, 1998). CPP

can be induced by COC, AMPH, METH and MDMA in rats

(Spyraki et al., 1987; Durazzo et al., 1994; Herzig et al., 2005)

and mice (Cabib et al., 2000). A metaanalysis of CPP studies

showed that the strongest behavioral effects were obtained in

rats with 3–10 mg/kg (i.p.) COC and 0.3–3 mg/kg (i.p.) AMPH

(Bardo et al., 1995; Tzschentke, 1998).

4.7.2.2. Drug-seeking and self-administration. Chronic psy-

chostimulant treatment may lead to drug-seeking behavior. In

animal models this can be measured by second-order

reinforcement paradigms of psychostimulant self-administra-

tion. In this paradigm, animals learn to perform an operant

response to receive a sensory stimulus (secondary reinforcer),

which was previously associated with the delivery of the

psychostimulant drug. However, responding is only maintained

when animals also receive a drug injection at a higher rate of

responding (Arroyo et al., 1998; Ito et al., 2004). Animals will

work to obtain both, stimuli that are associated with the drug

(conditioned reinforcers) as well the drug itself. The motivation

to self-administer psychostimulant drugs can be measured in

fixed-ratio and progressive-ratio schedules of reinforcement.

The response level at which the animal ceases to respond (the

break point) in a progressive-ratio schedule of reinforcement is

an indicator of the motivational level (Depoortere et al., 1993;

Richardson and Roberts, 1996; Roberts et al., 2002). In the self-

administration paradigm, a discrete sensory stimulus signals

that bar pressing results in the delivery of a certain amount of

the drug. However, the behavior that was initiated in a drug-free

state is after the first self-administered drug dose compromised

by the acute pharmacological effect of the drug in the brain. The

continued behavioral activity that leads to further doses of the

drug may, therefore, be generated in a different functional state

of the brain.

Several studies have shown drug-seeking and self-admin-

istration of COC, AMPH, METH and MDMA in rodents (Yokel

and Pickens, 1973; Arroyo et al., 1998; Witkin et al., 1999),

dogs (Risner and Jones, 1980) and monkeys (Johanson et al.,

1976; Bedford et al., 1980; Ritz and Kuhar, 1989; Howell and

Byrd, 1995; Fantegrossi et al., 2002, 2004) under different

schedules of reinforcement. An inverted U-shaped dose–

response function was established for infusion of COC and

MDMA under fixed-ratio schedules (Spealman, 1993; Arroyo

et al., 1998; Fantegrossi et al., 2002, 2004). Under a

progressive-ratio schedule, responding for COC and the self-

administered amount of COC increases with the dose of COC

obtained in each infusion (Depoortere et al., 1993). Rats learn

to self-administer COC in different time spans. In some animals

self-administration of COC eventually becomes compulsive

(Deroche-Gamonet et al., 2004; Vanderschuren and Everitt,

2004), and may, when access is unlimited, result in death within

a few weeks (Johanson et al., 1976; LeSage et al., 1999).

4.7.2.3. Reinstatement of self-administration. If the beha-

vioral activity that led to drug administration is no longer

followed by the drug, the behavior undergoes extinction.

Extinguished self-administration behavior, however, can be

reinstated by cues signaling the availability of the drug or by

application of the drug itself (deWit and Stewart, 1981; Arroyo

et al., 1998). Reinstatement of drug self-administration is

considered to be one of the most powerful paradigms to model

an important addiction-related behavior in humans. It was

found that COC, as well as COC-associated cues can reinstate

the self-administration of COC in rats (deWit and Stewart,

1981; Arroyo et al., 1998). Furthermore, one psychostimulant

drug can reinstate the self-administration of another psychos-

timulant drug, as it was shown by the reinstatement of COC

self-administration by an injection of AMPH (deWit and

Stewart, 1981).

4.7.2.4. Withdrawal syndrome. When the administration of a

psychostimulant drug is abruptly discontinued in humans, a

severe withdrawal syndrome, characterized by dysphoria,

anhedonia depression, anxiety and psychomotor alterations,

is observed (American Psychiatric Association, 1994). While

the dysphoria and depression may disappear after a few days, a

sensitized hyperlocomotor response and sensitized behavioral

stereotypies are still observed after years of abstinence (Kramer

et al., 1967; Gawin and Kleber, 1986; Gawin, 1991). Rats

withdrawn from repeated COC administration show an

enhanced level of anxiety, as determined in the elevated plus

maze test (Paine et al., 2002), and by the discriminative

stimulus substitution for the anxiogenic compound pentylene-

tetrazol (Wood and Lal, 1987). Withdrawal from continuous or

escalating administration of AMPH results in a decrease in

spontaneous locomotor activity (Herman et al., 1971; Lynch

and Leonard, 1978; Paulson et al., 1991). Behavioral

sensitization to an AMPH challenge in the hyperlocomotor

response and behavioral stereotypies were observed already 1

day after withdrawal (Bonhomme et al., 1995) and may persist

for 1 year or more (Paulson et al., 1991). During withdrawal,

thresholds to maintain intracranial self-stimulation are

increased in rats, which indicates a higher reward threshold


in the brain consistent with a decreased hedonic tone (Markou

et al., 2005).

4.7.3. 5-HT1A-receptors in psychostimulant memory and

reinforcing effects

4.7.3.1. Conditioned place preference. When the influence of

a certain receptor is investigated in place preference studies its

role in establishment and expression of CPP can be

distinguished. Here, establishment refers to the actual

conditioning procedure, in which the animal is in a drugged

state and associates the reinforcing effects of the drug with

spatial cues. It is generally accepted that by Pawlowian

conditioning spatial cues become secondary reinforcers.

Psychostimulants may also lead to reinforcement of prevailing

behavior in the conditioning compartment by instrumental

conditioning. The expression of CPP is observed in an

undrugged state, and inferred when the drug paired compart-

ment is preferred over a non-paired compartment (Tzschentke,

1998; Bardo and Bevins, 2000).

The 5-HT1A-R agonist 8-OH-DPAT (0.125 and 0.5, but not

0.25 mg/kg) facilitates the expression of COC-induced CPP in

mice (Ali and Kelly, 1996) (Table 5). The same authors,

however, also reported a failure of the partial 5-HT1A-R

agonist, buspirone, to modify the establishment, as well as the

expression, of COC-induced CPP (Ali and Kelly, 1997). A CPP

study in mice showed that the 5-HT1A-R antagonist, WAY

100635 (2 mg/kg, i.p.), did not affect the establishment of

AMPH-induced CPP (Budygin et al., 2004). Although not

much is known about the role of 5-HT1A-Rs in the establish-

ment and expression of psychostimulant-induced CPP, the

available data suggest no contribution to the establishment, but

a possible facilitatory role in psychostimulant CPP expression.

4.7.3.2. Drug-seeking and self-administration. Peltier and

Schenk (1993) reported a decrease in COC self-administration

after pretreatment with the 5-HT1A-R agonist 8-OH-DPAT

(0.5 mg/kg) (Table 5). Homberg et al. (2004) investigated the

effects of 8-OH-DPAT and buspirone on COC self-adminis-

tration in a progressive-ratio and a fixed-ratio schedule of

reinforcement. In the progressive-ratio schedule, 8-OH-DPAT

(1.0 but not 0.5 mg/kg) increased absolute responding for COC,

while it significantly reduced responding in a fixed-ratio

schedule. Buspirone, in contrast, reduced responding for COC

partially in a progressive-ratio schedule, but enhanced it in a

fixed-ratio schedule. The authors interpreted their findings as a

preferential decrease in COC self-administration by 5-HT1A-R

activation (Homberg et al., 2004). This interpretation was

supported by findings in mice showing an inhibitory effect of 8-

OH-DPAT (0.3 mg/kg) in a progressive-ratio schedule of COC

self-administration (Parsons et al., 1998). One study investi-

gated the effects of the 5-HT1A-R agonist, ipsapirone, on oral

COC self-administration in rats. In that study COC and

ipsapirone (10 mg/kg/day) were mixed in the drinking fluid

with unrestricted access. This study, however, did not find an

effect of ipsapirone on voluntary oral COC consumption

(Mosner et al., 1997). Several studies investigated the effects of

5-HT1A-R agonists on COC self-administration in non-human

primates. Gold and Balster (1992) compared the effects of the

two partial 5-HT1A-R agonists, buspirone and gepirone, on the

self-administration of COC in a fixed-ratio schedule in rhesus

monkeys. At medium doses buspirone (0.1–0.56 mg/kg, i.v.)

increased self-administration of COC, at the highest dose of

buspirone (1.0 mg/kg) a significant decrease was observed.

Gepirone did not affect self-administration of COC at any dose

tested (0.03–1.0 mg/kg, i.v.). The highest doses of both drugs

also disrupted the consumption of food. When buspirone and

gepirone administration (0.1 mg/kg/day) was repeated over 10

days, no effect on the self-administration of COC was evident

(Gold and Balster, 1992). Since buspirone has a much higher

affinity to D2 DA-Rs than gepirone (Van Wijngaarden et al.,

1990), the effects of buspirone on the self-administration of

COC may have been mediated by a dopaminergic mechanism

(Gold and Balster, 1992). A study in cynomolgus monkeys,

where animals could respond for different doses of COC or

food in a fixed-ratio schedule of reinforcement, found that the

5-HT1A-R agonist 8-OH-DPAT (0.01 and 0.03 mg/kg, i.v.)

increased the choice of COC over food, but only when a low

dose COC (0.003 mg/kg/infusion, i.v.) was tested, which was

originally not preferred over food. In this condition, 8-OH-

DPAT seemed to increase the reinforcing strength of COC. At

COC doses (0.01 and 0.03 mg/kg/infusion, i.v.), which were

originally preferred to the food, 8-OH-DPAT pretreatment did

not modify responding (Czoty et al., 2005). Although, 5-HT1A-

R knock-out mice were generated by several groups (Heisler

et al., 1998; Parks et al., 1998; Ramboz et al., 1998), only

129Sv/ter 5-HT1A-R knock-out mice have been tested

regarding psychostimulant-induced behavior. These mice,

however, acquired COC self-administration in the same rate

as their wild type littermates, and showed the same regular

within-session responding (Rocha et al., 1998b) . The role of 5-

HT1A-Rs in the self-administration of AMPH and its derivates

has received little attention. A study by Fletcher et al. (2002)

showed that intra-Nac application of 8-OH-DPAT did not affect

the self-administration of d-AMPH in rats in a progressive-ratio

schedule of reinforcement.

In summary, it appears that 5-HT1A-R agonists are not self-

administered. The majority of studies in rodents and monkeys

suggest that activation of 5-HT1A-Rs attenuates the self-

administration of COC, while the effects for other abused

psychostimulants have not been investigated so far. Impor-

tantly, the inhibitory action was often effective only at high

doses of the agonists. The dose–response curves suggest that

the stimulation of postsynaptic 5-HT1A-Rs is required for the

inhibitory effect. At this point, it may be interesting to

recapitulate that the 5-HT1A-autoreceptor stimulation has

anxiolytic effects, which may add to the reinforcing effects

during the self-administration of the drug. In contrast,

postsynaptic 5-HT1A-R stimulation has anxiogenic effects.

Accordingly, the limitation of COC self-administration by high

doses of 5-HT1A-R agonists may be due to a potentiated

anxiogenic action of COC (Yang et al., 1992; Rogerio and

Takahashi, 1992a,b). Indirect evidence for a postsynaptic

mechanism comes also from studies that modulate 5-HT levels

by other treatments. The 5-HT precursor, L-tryptophan, the

Table 5

The effects of 5-HT1A-receptor agonist and antagonist on conditioned place preference, drug-seeking, self-administration and reinstatement of self-administration

induced by cocaine, amphetamine, methamphetamine and MDMA


Conditioned place preference Cocaine Yes See text

Agonist: 8-OH-DPAT 0.125 Rat "b Ali and Kelly (1996)

0.25 Rat –b Ali and Kelly (1996)

0.5 Rat "b Ali and Kelly (1996)

Agonist: Buspirone 0.5 Rat –a Ali and Kelly (1997)

0.5 Rat –b Ali and Kelly (1997)

1 Rat –a Ali and Kelly (1997)

1 Rat –b Ali and Kelly (1997)

2 Rat –a Ali and Kelly (1997)

2 Rat –b Ali and Kelly (1997)

AMPH Yes See text

Antagonist: WAY 100635 2 Mouse –a Budygin et al. (2004)

Drug-seeking and self-administration Cocaine Yes See text

Agonist: Buspirone 0.01 Monkey –d Gold and Balster (1992)

0.03 Monkey –d Gold and Balster (1992)

0.1 Monkey "/–d Gold and Balster (1992)

0.3 Monkey "d Gold and Balster (1992)

0.56 Monkey "d Gold and Balster (1992)

1 Monkey #d Gold and Balster (1992)

1.25 Rat #c Homberg et al. (2004)

1.25 Rat "d Homberg et al. (2004)

2.5 Rat #c Homberg et al. (2004)

2.5 Rat "d Homberg et al. (2004)

Agonist: Gepirone 0.03 Monkey –d Gold and Balster (1992)



1 Monkey –d Gold and Balster (1992)

Agonist: Ipsapirone 10 Rat – Mosner et al. (1997)

Agonist: 8-OH-DPAT 0.01, i.v. Monkey "/–d Czoty et al. (2005)

0.03, i.v. Monkey "/–d Czoty et al. (2005)

0.1, i.v. Monkey –d Czoty et al. (2005)

0.03 Mouse –c Parsons et al. (1998)

0.3 Mouse #c Parsons et al. (1998)

0.5 Rat # Peltier and Schenk (1993)

0.5 Rat –c Homberg et al. (2004)

0.5 Rat –d Homberg et al. (2004)

1 Mouse –c Parsons et al. (1998)

1 Rat "c Homberg et al. (2004)

1 Rat #d Homberg et al. (2004)

Reinstatement of self-administration Cocaine By cocaine See text

Antagonist: WAY 100635 0.1 Rat – Schenk (2000)

0.1 Rat # Burmeister et al. (2004)

0.3 Rat # Schenk (2000)

0.3 Rat # Burmeister et al. (2004)

1 Rat # Schenk (2000)

1 Rat # Burmeister et al. (2004)

By cue See text

Antagonist: WAY 100635 0.1 Rat – Cervo et al. (2003)

0.1 Rat – Burmeister et al. (2004)

0.3 Rat – Cervo et al. (2003)

0.3 Rat – Burmeister et al. (2004)

1 Rat – Cervo et al. (2003)

1 Rat – Burmeister et al. (2004)

If not indicated otherwise, drug doses refer to systemic administration ("/# significant increase or decrease; – no significant change).a Establishment of conditioned place preference.b Expression of conditioned place preference.c Progressive ratio schedule of reinforcement.d Fixed ratio schedule of reinforcement.



SSRIs, fluoxetine and sertraline, and the 5-HT releaser,

fenfluramine, increase extracellular 5-HT levels in terminal

areas, which is in opposition to the decrease mediated by 5-

HT1A-autoreceptor stimulation. All treatments that increase 5-

HT levels, however, attenuated the self-administration of COC

(Carroll et al., 1990a,b; Glowa et al., 1997; Glatz et al., 2002).

Overall, the available evidence shows a predominantly

inhibitory role of, most likely, postsynaptic 5-HT1A-Rs in

the self-administration of COC. Whether this conclusion can be

generalized to AMPH, METH and MDMA awaits further

investigation.

4.7.3.3. Reinstatement of self-administration. Of increasing

importance in addiction research is the question whether a

pharmacological treatment can prevent the reinstatement of

previously extinguished drug-seeking behavior. Schenk (2000)

investigated the effects of the 5-HT1A-R antagonist, WAY

100635, on COC-induced reinstatement of COC-seeking

behavior in rats (Table 5). The pretreatment with WAY

100635 (0.3 and 1.0 but not 0.1 mg/kg, s.c.) blocked the

reinstatement of COC-seeking by an injection of COC. The

same dose of WAY 100635 did not affect oral self-

administration of the artificial sweetener, saccharin, thus,

indicating that WAY 100635 did not induce a generalized

anhedonia (Schenk, 2000). In contrast to the attenuating effects

on COC-induced reinstatement of COC-seeking behavior in

rats, WAY 100635 (0.1–1.0 mg/kg, s.c.) did not affect the

reinstatement elicited by a COC-associated cue (Cervo et al.,

2003). Both findings were replicated in a study by Burmeister

et al. (2004). The authors reported a failure of WAY 100635

(0.1–1.0 mg/kg, s.c.) to block cue-induced reinstatement of

COC-seeking, but an attenuating effect of the same doses of

WAY 100635 on the COC-induced reinstatement of COC-

seeking behavior (Burmeister et al., 2004). In summary, the

available data suggest a facilitatory role for 5-HT1A-Rs in the

reinstatement of COC-seeking behavior induced by COC, but

not when induced by sensory cues. Interestingly, COC and

AMPH, as well as visual stimulation cause a temporary

increase in extracellular 5-HT activity in neocortical associa-

tion cortices in relation to locomotor activation. However, the

psychostimulant-induced increase is many times higher

and longer than the stimulus-induced increase (Muller et al.,

2007; Pum et al., submitted for publication). A drug cue

may, therefore, have a stronger influence, in particular on

postsynaptic 5-HT1A-Rs, which might explain the differential

involvement of 5-HT1A-Rs in drug- and cue-induced reinstate-

ment of drug-seeking behavior.

4.7.3.4. Withdrawal. To target the aversive effects of with-

drawal is an important component of a potential treatment

strategy for psychostimulant addiction. 5-HT1A-R ligands have

been investigated for their efficacy to reduce the increased

reward threshold during psychostimulant withdrawal. The 5-

HT1A-R antagonist, p-MPPI, did not affect the increase in

brain-stimulation reward threshold after withdrawal from

repeated AMPH administration in rats. However, co-adminis-

tration of the SSRIs, paroxetine or fluoxetine, with p-MPPI

reduced the duration of the reward deficits significantly

(Harrison et al., 2001; Markou et al., 2005). Although very

little is known about the role of 5-HT1A-Rs in psychostimulant

withdrawal effects, the present data suggest a possible

beneficial effect when administered in combination with a

treatment that increases 5-HT activity.

5. 5-HT1A-receptor modulation of the neurochemical

effects of psychostimulants

5-HT1A-Rs in the brain do not only modulate addiction-

related behaviors of psychostimulant drugs, but also modulate

their neurochemical responses in various brain regions. It

generally is difficult to discern whether changes in a

psychostimulant-induced neurochemical effect (e.g. the DA

increase in the Nac) induced by pretreatment with a 5-HT1A-R

agonist or antagonist are causally related to the observed

change in the behavioral effects of the drug (Kalivas, 2005). At

the present stage, the observed neurochemical effects of a 5-

HT1A-R manipulation may well be a key to the psychostimulant

behavioral effects, but, alternatively, they may be a result of the

behavioral change, or even a ‘‘neurochemical epiphenomenon’’

in regard of the observed behavior. In the latter case, the

neurochemical effect may be without any causal relationship to

the respective behavior.

A prominent neurochemical effect of psychostimulant drugs

is the increase in the extracellular activity of DA in structures of

the mesocorticolimbic DA system, which is usually regarded as

causally related to many behavioral effects of psychostimulant

drugs (Koob et al., 1998; Wise, 2002). The first choice to

investigate the putative neurochemical mechanism for a blunted

behavioral psychostimulant effect is, therefore, to look at the

DA response in the Nac.

A study in mice showed that the 5-HT1A-R agonist

osemozotan potentiates the COC (15 mg/k)-induced increase

in extracellular DA in the PFC (Nakamura et al., 2006). The

effect of WAY 100635 on the extracellular DA activity in the

Nac after COC (10 mg/kg, i.p.) was investigated by in-vivo

microdialysis studies in freely moving rats. Although, WAY

100635 (0.4 mg/kg, i.p) blocked the acute hyperlocomotor

effects of COC, it did not modify the COC-induced increase in

extracellular DA levels in the Nac, suggesting that the COC-

induced DA increase in the Nac may be a necessary, but is not a

sufficient condition for the expression of the hyperlocomotor

effects of COC (Muller et al., 2002a). Another in vivo

microdialysis study in freely moving rats using the 5-HT1A-R

antagonist, p-MPPF (30 mg/kg, i.p.), as a pretreatment,

however, found a potentiated response of DA to COC

(25 mg/kg, i.p.) in the Nac (Andrews et al., 2005). A recent

study in mice reported that WAY 100635 (1 mg/kg) did not

modulate the COC (15 mg/kg)-induced increase of DA in the

PFC, but this effect was paralleled by a potentiated behavioral

response to COC (Nakamura et al., 2006).

The 5-HT1A-R agonist, 8-OH-DPAT (0.025–1 mg/kg, s.c.),

alone blocked the AMPH-induced increase in extracellular DA

levels in the Nac, the striatum and in the mPFC (Ichikawa et al.,

1995; Kuroki et al., 1996). The 5-HT1A-R antagonist WAY


100635 (0.1 and 1 mg/kg) did not modulate the increase of DA

in the Nac and PFC induced by AMPH (1 mg/kg) (Ichikawa

et al., 1995; Kuroki et al., 1996). However, in the striatum WAY

100635 tended to potentiate the DA response to AMPH

(Ichikawa et al., 1995; Kuroki et al., 1996). Although the 5-

HT1A-R antagonist was without effect on the increase in DA

induced by AMPH in the Nac and the mPFC, it reversed the

attenuating effects of 8-OH-DPAT. In contrast, no effect on the

METH-induced increase in extracellular DA levels in the PFC

was found after pretreatment with the 5-HT1A-R agonist,

osemozotan (0.3 and 1 mg/kg, i.p.), in mice (Ago et al., 2006a).

An enhanced DA response to COC in the Nac was reported

after pharmacological stimulation of local 5-HT1A-autorecep-

tor populations. An extensive local application study investi-

gated the effects of 8-OH-DPAT application into the DRN and

MRN on COC (15 mg/kg, i.p.)-induced DA and glutamate

levels in the Nac of freely moving rats (Szumlinski et al., 2004).

In this study, agonism of the 5-HT1A-Rs in the DRN not only

led to a potentiated hyperlocomotor response to COC, but also

to a potentiated DA and glutamate response in the Nac. In

contrast, 5-HT1A-R agonism in the MRN neither affected the

behavioral response to COC nor the DA or glutamate response

in the Nac (Szumlinski et al., 2004). These findings suggest a

link between 5-HT1A-autoreceptors in the DRN, but not in the

MRN, and the control of the DA (and glutamate) response to

COC in the Nac. Overall, the data suggest that 5-HT1A-Rs are

not a prerequisite for the psychostimulant-induced DA-increase

in the Nac, the striatum or the mPFC. However, additional

stimulation of certain 5-HT1A-R populations, such as the 5-

HT1A-autoreceptors in the DRN, may further add to the DA

increase in the Nac.

If an attenuated DA response in the Nac is not the

neurochemical mechanism behind the 5-HT1A-R antagonist-

mediated inhibition of psychostimulant behavioral effects, the

search for a causally related neurochemical system had to be

expanded. Akin to the DA system the 5-HT system is closely

linked to the expression of the behavioral effects of

psychostimulant drugs (Walsh and Cunningham, 1997; Muller

et al., 2003a; Hall et al., 2004). Psychostimulant drugs are well

known to increase extracellular 5-HT activity (Table 1). Given

the crucial position of 5-HT1A-Rs in the 5-HT system, and its

role in the regulation of the firing frequency of 5-HT neurons,

5-HT synthesis and release, a modulation of this increase

appears to be a good candidate for a causal neurochemical

mechanism for the observed behavioral alterations. Indeed,

several studies showed that a modulation of the acute 5-HT

response after psychostimulant application by agonism or

antagonism of the 5-HT1A-Rs parallels the altered behavioral

effects. As such, the COC (10 and 15 mg/kg)-induced increase

in extracellular 5-HT levels in the Nac, the ventral

hippocampus, and the PFC was potentiated by pretreatment

with WAY 100635 (0.4 or 1 mg/kg) (Muller et al., 2002b;

Nakamura et al., 2006). This potentiation was paralleled by an

attenuation of the hyperlocomotor effects of COC in rats

(Muller et al., 2002b), but a potentiation in mice (Nakamura

et al., 2006). A potentiated 5-HT response to COC (25 mg/kg,

i.p.) in the Nac of rats was replicated in a study by Andrews

et al. (2005) using the 5-HT1A-R antagonist p-MPPF (30 mg/

kg, i.p.). These observations are further supported in a study by

Kuroki et al. (1996), showing a tendency for a potentiation of

the AMPH-induced 5-HT increase in the mPFC. In accordance

with these studies, the 5-HT1A-R agonist, 8-OH-DPAT

(0.2 mg/kg, i.p.), attenuated the COC (10 mg/kg, i.p.)-induced

5-HT increase in the Nac and the ventral hippocampus, parallel

to a largely potentiated hyperlocomotor response (Muller

et al., 2003b). Also, the AMPH (1 mg/kg, s.c.)-induced

increase in mPFC 5-HT levels was attenuated by pretreatment

with 8-OH-DPAT (0.05 mg/kg, s.c.) (Kuroki et al., 1996).

Similar neurochemical effects were shown in mice, where the

5-HT1A-R agonist osemozotan attenuated the COC (15 mg/

kg)- and the METH (1 mg/kg)-induced 5-HT increase in the

PFC (Nakamura et al., 2006; Ago et al., 2006a). Most likely,

the psychostimulant-induced increase of 5-HT in somatoden-

dritic regions of the 5-HT neurons activates the inhibitory 5-

HT1A-autoreceptors and decreases the activity of the 5-HT

neurons (Pitts and Marwah, 1986, 1987; Lakoski and

Cunningham, 1988; Rutter et al., 1995). Blockade or activation

of the 5-HT1A-autoreceptors can, thus, inhibit or potentiate the

effects of the somatodendritically increased levels of 5-HT on

the activity of 5-HT neurons. The combined effects of a local

reuptake blockade or release of 5-HT in terminal regions by a

psychostimulant drug and the 5-HT1A-receptor antagonism, or

agonism, add up, and, most likely, result in a potentiation or

attenuation of the extracellular 5-HT levels in the terminal

regions of the 5-HT projections (Muller et al., 2002b, 2003b).

Overall, the presently available data show that 5-HT1A-Rs limit

the psychostimulant-induced increase in terminal 5-HT levels,

while having little or no influence on the DA response.

Although, a functional 5-HT system is necessary to express the

acute and long-term behavioral effects of psychostimulant

drugs (Lipska et al., 1992; Tran-Nguyen et al., 1999; Hall et al.,

2004), an overshooting increase of 5-HT, which exceeds the

DA response, may limit the expression of the behavioral effects

of psychostimulant drugs (Layer et al., 1992). Accordingly,

using a 5-HT1A-R antagonist pretreatment results in an

imbalance in the DA/5-HT response to a psychostimulant

drug, shifting the response largely to 5-HT. Many of the above

discussed studies support the view that such an imbalance in

the DA/5-HT response could be causally related to the

attenuated behavioral effects of psychostimulants by 5-HT1A-

R ligands. Support for this hypothesis comes from other

studies. A selective enhancement of 5-HT levels in the brain by

local 5-HT administration (i.c.v.) was shown to block the acute

hyperlocomotor effects of AMPH (2.5 mg/kg, i.p.) in rats

(Warbritton et al., 1978). Intra-Nac 5-HT application also

reduced d-AMPH self-administration behavior in a progres-

sive-ratio schedule of reinforcement (Fletcher et al., 2002).

This hypothesis is further supported by studies using the 5-HT

precursor, L-tryptophan, SSRIs or 5-HT releasers as a

pretreatment to test COC addiction-related behaviors. L-

tryptophan, the SSRIs, fluoxetine and sertraline, and the 5-HT

releaser, fenfluramine, were reported to decrease COC-

induced hyperlocomotion in rats (Molina et al., 2001),

attenuate COC self-administration in rats (Carroll et al.,


1990a, 1990b; Glatz et al., 2002) and monkeys (Glowa et al.,

1997), reduce COC-seeking behavior during extinction,

reduce reinstatement of COC-seeking behavior (Burmeister

et al., 2003), and attenuate the preference of COC-withdrawn

subjects for a COC-paired environment (Harris et al., 2001).

However, these pretreatments may also increase the dopami-

nergic effects of COC to a certain extent (Clark et al., 1996;

Bubar et al., 2003), and enhance COC-induced hyperlocomo-

tion (Herges and Taylor, 1998; Bubar et al., 2003). None-

theless, self-administration studies with synthetic AMPH

analogs show that, given a comparable DA releasing action of

these compounds, the potency to be self-administered by

monkeys is reduced by an increasing potency to release 5-HT

(Ritz and Kuhar, 1989; Wee et al., 2005).

The influence of local 5-HT1A-R populations on the local 5-

HT response to COC was investigated at the autoreceptor level

in the DRN and MRN and at the level of postsynaptic 5-HT1A-

Rs in the ventral hippocampus and ventral striatum by means of

in vivo microdialysis. Local application of 8-OH-DPAT into

either the DRN or MRN reduced the COC (15 mg/kg, i.p.)-

induced 5-HT increase in the Nac. Interestingly, only intra-DRN,

but not intra-MRN 8-OH-DPAT injection potentiated the acute

hyperlocomotor effects of COC in this study (Szumlinski et al.,

2004). At the postsynaptic level, the local application of 8-OH-

DPAT into the ventral striatum failed to influence the increase

of 5-HT in the Nac after COC (10 mg/kg, i.p.) treatment.

Nevertheless, the local application potentiated the acute

hyperlocomotor effects of COC (Muller et al., 2004b). In

contrast, the local agonism of hippocampal 5-HT1A-Rs by 8-OH-

DPAT reduced the effect of COC (10 mg/kg, i.p.) on extracellular

levels of 5-HT in the ventral hippocampus, but not in the Nac.

This local modulation of the 5-HT response to COC was

paralleled by an attenuated hyperlocomotor response (Muller

et al., 2004a). These data suggest that, in the hippocampus, a

COC-induced increase of 5-HT is not only under inhibitory

control of postsynaptic 5-HT1A-Rs, but may also limit the

expression of the acute hyperlocomotor effects of COC. It

appears that, not only the contribution of the different 5-HT

receptor subtypes to psychostimulant-induced behavior is

different in various brain regions (Muller and Huston, 2006),

but also the contribution to the psychostimulant-induced increase

in 5-HT. However, in order to make definitive statements about

the composition of the neurochemical responses required to

express the various behavioral effects of psychostimulant drugs,

further research is necessary.

The majority of studies support the view that many, if not all,

addiction-related behaviors induced by psychostimulant drugs

depend in their expression crucially on the ratio of the DA-5-HT

response in terminal areas. Extant data show that 5-HT1A-Rs are

located in several crucial positions in the brain to change this ratio

inaway to reduce orenhance the5-HTresponse relative to theDA

response. For this mechanism, mainly 5-HT1A-autoreceptors are

responsible, in a way, that their selective (or preferential)

antagonism potentiates the terminal 5-HT response during

psychostimulant treatment. This may be achieved even

systemically by using low doses of a 5-HT1A-R antagonist

(Carey et al., 2004a,b). In contrast, at the terminal level a

maximized stimulation of postsynaptic 5-HT1A-Rs, that can be

potentiated by 5-HT1A-R agonists, ‘‘translates’’ the increase in

extracellular 5-HTinto changes of neuronal activity and function,

and leads to an attenuation of addiction-related behaviors.

6. The effects of psychostimulants on 5-HT1A-receptor

binding

Extensive research in recent years revealed that 5-HT1A-Rs

are essentially involved in the translation of the psychostimulant-

induced changes in extracellular 5-HT activity into the acute, as

well as long-term behavioral effects of psychostimulant drugs of

abuse. Facing an intense hyperactivation of the 5-HT system, it

may not be surprising that, not only tissue and extracellular levels

of 5-HT in the brain change (Schmidt, 1987a; Schmidt et al.,

1987; Gough et al., 1991; Johnson et al., 1993), but that also 5-

HT1A-R affinity and density may adapt. These changes may

contribute to withdrawal behavior, drug-seeking behavior and

the reinstatement of drug self-administration when the organism

is in a drug-free state. And it may essentially contribute to the

alterations in the behavioral and neurochemical response after

reinitiated drug intake. The reversal of changes in 5-HT1A-R

sensitivity and expression in drug addicts may, therefore,

contribute to a therapy of drug addiction (Akbari et al., 1994;

Johns et al., 2002; Chen et al., 2005).

Repeated treatment with COC (15 mg/kg, i.p.) for 7 days

reduced [3H]-8-OH-DPAT binding selectively in the central

medial amygdala of adult rats, but not in other brain areas.

(Cunningham et al., 1992). No effect on [3H]-8-OH-DPAT

affinity (Kd) and binding density (Bmax) in the hippocampus was

found after repeated treatment with COC (20 mg/kg, i.p.) twice

daily for 14 days (Johnson et al., 1993), or on [3H]-8-OH-DPAT

affinity and binding density in the cortex, hippocampus and

striatum after nine injections with COC (10 mg/kg, i.p.) (Javaid

et al., 1993). Another study, which applied a more intense

treatment of 14 days three times daily COC (15 mg/kg, i.p.),

could not replicate the reduced [3H]-8-OH-DPAT binding in the

central medial amygdala. Instead, a reduced [3H]-8-OH-DPAT

binding in the ventromedial hypothalamus and in the dentate

gyrus was reported (Perret et al., 1998). The inhibitory response

of single 5-HT neurons in the DRN to an 8-OH-DPAT challenge

was, however, increased in COC (15 mg/kg, i.p. for 7 days)-

treated animals, indicating an enhanced sensitivity of the 5-

HT1A-autoreceptors after repeated treatment (Cunningham

et al., 1992). Chronic COC treatment (15 mg/kg, i.p.), twice

daily for 14 days increased also the sensitivity of the

hyperpolarizing response of neurons in the dorsolateral septum

to 5-HT stimulation (Simms and Gallagher, 1996). The authors

suggest that an up-regulation of the 5-HT1A-R in this region

may be responsible for this effect. In contrast to these findings,

chronic COC application (40 mg/kg, s.c.) for 14 days resulted

only in a marginal increase in 5-HT1A-R sensitivity to an 8-OH-

DPAT or a NAN-190 challenge at the behavioral level (King

et al., 1993a,b). This observation was further supported in a

study by Baumann and Rothman (1995), who showed that

chronic COC exposure (15 mg/kg, i.p.) for 7 days did not affect

5-HT syndrome behavior induced by a 8-OH-DPAT challenge


after 42 h of withdrawal. However, the stimulation of the

prolactin and ACTH plasma concentrations, induced by 8-OH-

DPAT, was diminished after COC treatment, indicating a

reduced function of possibly postsynaptic hypothalamic 5-

HT1A-Rs (Levy et al., 1994; Baumann and Rothman, 1995).

Repeated treatment with AMPH (5 mg/kg, i.p.), twice daily

for 6 days, increased [3H]-8-OH-DPAT binding in the DRN, but

not in the MRN. This effect was evident 1 day after the last

injection, and was still observed 15 days thereafter (Bonhomme

et al., 1995).

A single dose of MDMA (30 mg/kg, i.p.) increased [3H]-8-

OH-DPAT binding (Bmax) in the FC and hypothalamus, but

not in the DRN. Repeated MDMA treatment for 4 days (20

and 30 mg/kg, i.p) increased binding in the FC, but reduced

binding in the hippocampus and DRN. Parallel to these

changes, 5-HT1A-R gene expression was increased in the FC,

but reduced in the hippocampus and DRN. The treatment with

MDMA did not change 5-HT1A-R affinity in the FC and DRN

(Aguirre et al., 1995, 1997, 1998). A behavioral study did not

find major changes in 5-HT1A-R function 30 days after

cessation of repeated (�)MDMA (20 mg/kg, s.c.) treatment

twice daily for 4 days in rats. Neither the hyperlocomotor

response, nor flat body posture, was significantly different

after an 8-OH-DPAT challenge (0.25–1.0 mg/kg, s.c.)

compared to a saline control. Only reciprocal forepaw

treading stereotypy was significantly reduced after MDMA

treatment (Granoff and Ashby, 2001).

Overall, binding studies do not show a very clear picture.

The studies with COC found reduced receptor binding in

restricted brain areas, but none of them could be clearly

replicated so far. AMPH, in contrast, seems to increase 5-HT1A-

R gene expression and 5-HT1A-R binding in the FC, and

possibly reduce the binding in the hippocampus and DRN.

However, these findings also await confirmation. MDMA

treatment, although largely reducing 5-HT content in the brain,

had no obvious effect on 5-HT1A-R affinity. Accordingly,

systematic changes in 5-HT1A-R affinity and density seem not

to be a promising candidate to explain the long-lasting

behavioral changes after long-term psychostimulant exposure.

However, to our knowledge, there are presently no studies

available which measured 5-HT1A-R binding in animals that

really established addiction-related behavior. Therefore, it may

still be too early to exclude changes of 5-HT1A-R binding as a

contributing mechanism in the establishment of psychostimu-

lant addiction.

7. Conclusion

In the quest to understand the mechanisms of how

neurotransmitters and their membrane receptors organize

the behavioral effects of psychostimulant drugs, the role of the

5-HT1A-Rs can only be a small part of a big picture. Given the

complexity of the mechanisms, there seems to be no other way

than looking at each receptor component separately. The 5-

HT1A-R does not appear to be ‘‘the one’’ central mediator of

the psychostimulant-induced 5-HT increase into behavior (e.g.

Muller and Huston, 2006). 5-HT1A-Rs rather contribute to the

effects of the whole 5-HT-R assembly. Furthermore, it was

shown that different 5-HT1A-R populations can influence

addiction-related behaviors in different directions. Accord-

ingly, a simple 5-HT1A-R agonist or antagonist treatment

seems not very promising as a sole therapeutic approach to

treat psychostimulant addiction. Nevertheless, the many

studies of the last years show unequivocally a crucial

participation of various brain 5-HT1A-R populations in the

orchestration of different psychostimulant addiction-related

behaviors. But not all behavioral effects of psychostimulants

are directly addiction-related. 5-HT1A-Rs, however, contribute

also to non-addiction-related behavioral effects. Mechanisti-

cally, it appears that the common 5-HT increase, which is

induced by all abused psychostimulant drugs discussed here,

activates 5-HT1A-Rs. Thereby, 5-HT1A-autoreceptor activa-

tion in the DRN attenuates the overall 5-HT response in the

terminal areas of the 5-HT projections. The psychostimulant-

induced 5-HT increase, however, seems to limit the expression

of addiction-related behaviors, especially when the 5-HT

response becomes stronger than the DA response. As such, 5-

HT1A-autoreceptors predominantly facilitate psychostimu-

lant-induced behavior by an attenuation of the terminal 5-HT

increase. Postsynaptic 5-HT1A-Rs are involved in some, but

not all brain regions in the regulation of the local increase in 5-

HT by feedback projections to the raphe nuclei. On the other

hand, they can influence the expression of the behavioral

effects of a psychostimulant drug. Thereby, they mostly limit

the expression of addiction-related behaviors. 5-HT1A-auto-

receptors and postsynaptic 5-HT1A-Rs play not only complex,

but opposite roles in many behavioral effects of the

psychostimulants, COC, AMPH, METH and MDMA. Accord-

ingly, it may not be surprising that simultaneous stimulation, or

inhibition, of both receptor populations may sometimes result

in contradictory findings, or, even, in a canceling-out null-

effect. In a therapeutic approach, however, which may want to

make use of the preclinical findings, this may be overcome best

by targeting only the pharmacologically more sensitive 5-

HT1A-autoreceptors with low doses of a systemically applied

5-HT1A-R antagonist.

With an increasing knowledge of the role of the 5-HT1A-Rs

in normal behavior, also their contribution to aberrant behavior

becomes more clear. To understand normal function is,

therefore, a necessary prerequisite for an understanding of

psychostimulant addiction. The 5-HT system, in general,

appears to have a complex role in drug addiction, with the 5-

HT1A-Rs in crucial positions to regulate its basal activity and

acute responses. The apparently important role of these 5-

HT1A-Rs may, therefore, encourage more research to find a

way to exploit this central role to treat patients with the

behaviorally and emotionally very complex disorder of drug

addiction.

Acknowledgements

This work was supported by grant HU 306/23-5 from the

Deutsche Forschungsgemeinschaft, a NIDA grant DA R01 DA

05366-17 and a VA Merit Review grant.


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Serotonin and psychostimulant addiction: Focus on 5-HT1A-receptors

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