Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism

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Neurochem. Int. Vol. 26, No. 4, pp. 305 336, 1995 Copyright © 1995 Elsevier Science Ltd

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INVITED REVIEW

N E U R O T R A N S M I T T E R A N D N E U R O M O D U L A T O R Y M E C H A N I S M S INVOLVED IN ALCOHOL ABUSE A N D

ALCOHOLISM

IGAL NEVO* and MICHEL HAMON INSERM U.288, Neurobiologie Cellulaire et Fonctionnelle, Facult6 de M6decine Piti6-Salp~tri~re,

91, boulevard de l'H6pital, 75634 Paris Cedex 13, France

CRITIQUES

by: R. D. MYERS, B. A. MCMILLEN and A. ADELL; and B. E. LEONARD

Abstract--Acute or chronic consumption of alcohol interferes differentially with transmission processes in the CNS, affecting many-- if not all--of the known neurotransmitter systems. Conversely, selective pharmacological manipulations of some of these neurotransmitter systems have been shown to reduce ethanol intake and preference as well as the severity of the ethanol withdrawal syndrome in animal models, certain compounds having even been employed successfully in the clinic. This review examines the studies which have attempted to elucidate the roles of these neurotransmitter systems in the mechanisms involved in the various aspects of alcohol abuse and alcoholism, with an emphasis on recent developments. The brain's major amino acid transmitter systems--inhibitory 7-aminobutyric acid (GABA) and excitatory glu- t amate -have been widely studied over the past decade, with the general consensus that acute ethanol facilitates GABAergic transmission (by enhancing chloride conductance through the GABAA receptor) and inhibits glutamatergic function (by decreasing cationic conductance through the NMDA receptor). Conversely, the development of tolerance associated with chronic ethanol consumption leads to a reduced GABAergic and increased glutamatergic function. Interactions between ethanol and the monoaminergic transmitter systems are complex. Dopaminergic and noradrenergic mechanisms, along with the endogenous opioid systems of the brain, seem to be implicated in the rewarding effects of ethanol via activation of positive reinforcement pathways, while the serotonergic system mediates negative reinforcement. A number of ligands of the dopaminergic, serotonergic and opioidergic receptors involved in ethanol consumption- related behaviors have been recognized for their effects in reducing ethanol preference and/or alleviating symptoms of the ethanol withdrawal syndrome in various animal models. Several of these substances are being used with success clinically. Studies of the central cholinergic system in alcoholics have provided clues to the mechanisms underlying the deleterious effects of ethanol on learning and memory, and evidence of a reduced central cholinergic activity has been reported in alcohol-dependent patients. Interestingly, acetylcholine-rich grafts and cholinomimetic drugs have been found to ameliorate ethanol-induced behavioral deficits in alcoholized rats. More generally, basic studies on alcohol's effects on central neurotransmission certainly hold the key to the development of new strategies for the treatment of alcoholism.

E thano l is the second mos t commonly abused psychotropic drug after caffeine, and in mos t of the world today, a lcohol ism has emerged as a major social and heal th problem. The neurobiological consequences of e thanol abuse have been shown to be quite serious;

pro longed exposure of rats to e thanol results in dendritic hyper t rophy and neurona l loss in various bra in regions (Riley and Walker, 1978 ; Pierce et al., 1993), while chronic e thanol abuse in h u m a n s is associated with diffuse cortical and cerebellar a t rophy, degener- a t ion of cerebellar Purkinje cells, and reduct ion in the size and n u m b e r of neurons in the f ronta l cortex * Author to whom all correspondence should be addressed.

305

3()6 Invited Reviev,

(Charness ez al., 1989). It therefore follows that a great deal of effort has been devoted to the elucidation of the neurobiological mechanisms underlying the urge to consume alcohol.

There is convincing evidence that genetic factors can contribute to the predisposition to alcoholism, and that there are subtypes of alcoholics who are affected to different degrees by environmental and genetic factors (Cloninger, 1987). In this respect, the development of animal models in which rodents will voluntarily consume ethanol solutions over water in a free-choice situation has been of great use in the search for the neurobiological substrate(s) of ethanol preference and reinforcement. Such models can be divided into two principal categories: (1) animals induced to prefer ethanol over water in a free-choice situation subsequent to behavioral conditioning or pharmacological manipulations, and (2) genetically selected strains of animals bred for differences in ethanol preference, initial sensitivity, or severity of withdrawal. An early study by Fuller (1964), which was confirmed in later investigations (Belknap et al.,

1993), of a number of inbred mouse strains found that C57BL/6J mice voluntarily consume more than l0 g/kg of ethanol per day, while mice of the DBA/2J strain strongly avoid ethanol, typically consuming 0.1-2 g/kg per day. Several rat strains exhibiting a preference for ethanol have been developed (see Table 1 ), including the UChB (high alcohol-consuming) and UChA (low alcohol-consuming) lines bred at the Uni-

versity of Chile (Mardones, 1960), the AA (alcohol- preferring) and ANA (alcohol-avoiding) lines bred in the laboratories of Alko Ltd, the Finnish State Alco- hol Company (Eriksson, 1968L the P (alcohol-preferring) and NP (alcohol non-preferring) lines of the University of Indiana (Lumeng et al., 1977), the HAD (high alcohol-drinking) and LAD (low alcohol-drinking) lines, developed by the same group from a foun- dation stock of the genetically heterogeneous N/Nih rat (Lumeng et al., 1986), and the sP (Sardinian alcohol-preferring) and sNP (Sardinian alcohol non-preferring) lines developed at the University of Cagliari (Fadda et al., 1989). Alcohol-preferring rats from these strains will voluntarily consume sufficient quan- tities of 10-30% ethanol solutions (i.e. at the same ethanol concentrations as those found in many alcoholic beverages) to attain pharmacologically relevant blood alcohol concentrations. In addition, they win work to obtain ethanol, and will develop tolerance and physical dependence (Hunt, 1993). Rodent lines have also been selectively bred for an initial sensitivity to acute ethanol (Table 1 ). These include the AT (alcohol tolerant) and ANT (alcohol non-tolerant) lines of rats outbred for differential ethanol-induced motor impairment on the tilting plane (Eriksson and Rusi, 1981 ), the HAS (high alcohol-sensitive) and LAS (low alcohol-sensitive) rat lines selected for ethanol- induced ataxia from a genetically heterogeneous N/Nih breeding stock (Palmer et al., 1987), the SS (short-sleep, ethanol-insensitive) and LS (long-sleep,

Table I. Rodent lines bred for differences in ethanol preference, initial sensitivity to acute ethanol, or severity of ethanol withdrawal syndrome (see text for details)

(a) I, ines hred /br d([l~'rence.s in ethum*l pr{j~,rence

Alcohol-preferring Alcohol non-preferring Species References

UChB UChA rat Mardones (1960) C57BL,'6J DBA/2J mouse Fuller (I 964)

AA ANA rat Eriksson (1968) P NP rat Lumeng et al. (19771

HAD LAD rat Lumeng et al. (1986) sP sNP rat Fadda et al. (1989)

(h) Lines bred/or d([lerences in initial sensitivity to acute ethanol

Low sensitivity High sensitivity

SS LS mouse McClearn and Kakihana (1973) AT ANT rat Eriksson and Rusi (1981)

LAS HAS rat Palmer et al. (1987) HOT COLD mouse Phillips et al. (1990)

(c) Lines bred./or d![]~,rences in severity o/ethanol withdrawal syndrome

Withdrawal-seizure Withdrawal-seizure resistant prone

WSR WSP mouse Crabbe et al. (1985)

Invited Review 307

ethanol-sensitive) lines of mice selected from a genetically heterogeneous stock (HS/Ibg) for differential sensitivity to the acute hypnotic effect of ethanol as determined by sleep time, i.e. the duration of loss of the righting reflex (McClearn and Kakihana, 1973), and the COLD (ethanol-sensitive) and HOT (ethanol- resistant) mouse lines genetically selected for their hypothermic response to acute ethanol (Phillips et al., 1990). Finally, two lines of mice have been genetically selected for resistance (withdrawal-seizure resistant, WSR) and susceptibility (withdrawal-seizure prone, WSP) to handling-induced convulsions during ethanol withdrawal by Crabbe et al. (1985).

Prior to the early 1970s, the generally accepted view was that ethanol exerted its central effects via a non- specific fluidization of neuronal membranes (e.g. Seeman, 1972), since it was considered doubtful, given the simple chemical structure of ethanol, that a specific receptor for this molecule could exist. As the role of neurotransmitters and their receptors in the CNS began to be better understood, it became apparent that ethanol was in fact able to alter central neurotransmission. It is now clear that there is no single neurotransmitter system which can be selected as being responsible for mediating all of the central effects of ethanol, and that ethanol in fact has many targets in the CNS. This review will provide an overview of the numerous studies which have attempted to elucidate the role of the brain's neurotransmitter systems in mediating the reinforcing effects of ethanol and the neurobiological consequences of alcohol abuse.

AMINO ACID NEUROTRANSMITFERS

Since the early 1980s, many studies have con- centrated on defining a role for the brain's major inhibitory and excitatory amino acid neurotransmitters, y-aminobutyric acid (GABA) and glutamate, respectively, in the central actions of ethanol.

Inhibitory Amino Acids

G amma-aminobutyric acid ( G A B A ) A great deal of effort has been devoted to examining

the relationship between ethanol's CNS actions and the GABAA receptor, a GABA-gated chloride channel which contains multiple binding sites. In addition to a site which binds the agonists GABA and muscimol and the antagonist bicuculline, there is also a binding site for benzodiazepine (BZD) agonists, antagonists and inverse agonists, a site which binds the chloride

channel antagonists picrotoxin and t-butyl- bicyclophosphorothionate (TBPS), and a recognition site for depressant/anticonvulsant barbiturates. Moreover, this receptor is composed of distinct protein subunits, each of which has 1-6 variants (~j~,/~-3, YJ 3, 6 and p~ 2) which can be arranged in different combinations, producing a number of possible isoforms.

Behavioral studies. Behavioral studies have demonstrated the ability of GABA mimetic drugs to potent- iate ethanol's sedative and incoordinating effects in rodents, whereas GABA antagonists and inverse agonists have been shown to attenuate these effects (Allan and Harris, 1987a).

In addition, the BZD partial inverse agonist Ro 15- 4513 was shown to block the high-dose depressant effects of ethanol on spontaneous locomotor activity, without affecting its low-dose stimulatory effects (Becker, 1988), a finding which further supports a role for the GABAA receptor complex in mediating the central depressant effects of ethanol. Moreover, rodent strains selected for differences in ethanol sensitivity have been found to display differential sensitivities to BZD (Marley et al., 1988), and, reciprocally, mice selected for differential diazepam sensitivity display differences in ethanol effects (Gallaher and Gionet, 1988). As expected from the existence of a BZD- ethanol link, it has been shown that chronic ethanol administration confers cross-tolerance to BZD with respect to several different behavioral parameters (L6 et al., 1986).

Most data linking the GABAergic system to ethanol actions are concerned with the mediation of the direct CNS effects of ethanol. There are also several lines of evidence, however, which support a role for this neurotransmitter system in ethanol-induced positive reinforcement, by way of an enhancement of GABA- ergic function. Notably, an early study demonstrated the maintenance of alcohol preference during alcohol withdrawal with the BZD agonist diazepam (Deutsch and Walton, 1977). In more recent studies, the partial inverse agonist at the BZD receptor, Ro 15-4513, was found to reduce ethanol intake by several lines of rats, including an alcohol-preferring strain, without modifying other consummatory behaviors (e.g. McBride et al., 1988). The same effect was observed with the BZD inverse agonist Ro 19-4603 in another alcohol-preferring rat strain (Balakleevsky et al., 1990).

In addition to GABAA receptors, the guanine nucleotide-binding protein-coupled GABAB receptor might also participate in the GABAergic mediation of at least some of the central effects of ethanol. In

308 Invited Review

particular, Allan and Harris (1989) showed that the GABAB antagonist, phaclofen, blocked ethanol- induced hypothermia, motor incoordination, narcosis and locomotor stimulation in mice, while exhibiting no effects when administered alone. More recently, Humeniuk et al. (1993), using a number of GABA, agonists and antagonists, concluded that the GABAu receptor may indeed be involved in the locomotor stimulation induced by low doses of ethanol, and that it is an agonist rather than antagonist activity at this receptor which would lead to an attenuation of the effects of ethanol.

Biochemical and electrophysioloqical studies. Studies conducted in the 1970s showed that barbiturates and BZD produce many of their CNS effects by enhancing GABAergic inhibition by way of allosteric modulation of the GABAA receptor (see Harris et al., 1992). As initial studies demonstrated a certain similarity in the actions of BZD and ethanol, this led to the suggestion that these two classes of drugs may share a common mechanism of action (Frye eta[ . , 1980).

Nevertheless, studies performed in rodents subsequent to acute or chronic exposure to ethanol (producing brain ethanol concentrations corresponding to moderate-to-severe intoxication, i.e. up to 100 raM) have generally found little or no change in the binding of antagonists or agonists to the GABA site on GABAA receptors (Unwin and Taberner, 1980; Buck and Harris, 1990a,b). However, certain studies did note an increase in the density of low-affinity GABAA receptors in mouse and rat brain upon acute ethanol intoxication and a decrease when the rodents were subjected to chronic ethanol intoxication (e.g. Ticku and Burch, 1980). In a study comparing the AT and ANT rat lines, Korpi et al. (1992a) noted a lower binding of the GABA,~ agonist [~H]muscimol to GABAA receptors in the ANT rats.

Whereas tolerance to the effects of chronic ethanol administration on chloride movements develops, the sensitivity of the chloride channel to GABA is not reduced (Allan and Harris, 1987b). This would seem to suggest that a part of the GABAA receptor complex other than that which binds GABA may be affected ; indeed, Mhatre et al. (1988) noted an increase in the binding of the BZD partial inverse agonist [~H]Ro 15- 4513 in the cerebral cortex and cerebellum, but not in the hippocampus or striatum, of rats chronically intoxicated by intragastric intubation, although another group had previously t\mnd no change m BZD inverse agonist binding in any of the brain areas examined after chronic ethanol intubation of rats (Tam- borska and Marangos, 1986). Subsequently, however. Mhatre and Ticku (1989) showed that the binding

o1" BZD inverse agonists following chronic ethanol exposure of cultured spinal cord neurons was increased for 24 h after removal of ethanol from the culture medium, with a reversal of the effect within 48 h, a time course corresponding to the appearance and disappearance of anxiety and seizures subsequent to ethanol withdrawal in vivo. Moreover, Korpi et al.

(1992a) found an enhanced affinity for [3H]Ro 15- 4513 in the alcohol-sensitive ANT rats as compared to their AT counterparts. In contrast, binding of BZD agonists and antagonists in rodents subjected to chronic ethanol intoxication has generally been found to be unchanged (e.g. Buck and Harris, 1990b). One group, however, noted a reduction in the density of [3H]flunitrazepam binding in the frontal cortex (Freund and Ballinger, 1988) and hippocampus (Freund and Ballinger, 1989) of alcoholics, with no changes in other areas examined. Conversely, an enhancement by ethanol of the binding of [3H]flu- mazenil (Ro 15-1788) in several mouse brain regions has been reported by Mosaddeghi et al. (1992).

In an in vitro study of the GABAA receptor complex's picrotoxin/convulsant site, high concentrations (EC~0 ~ 500 raM) of ethanol (lethal in vi~;o) were found to inhibit [35S]TBPS binding (Thyagarajan and Ticku, 1985),

In vitro studies of 3~'C1 uptake by isolated brain membrane vesicles and cultured mammalian brain cells have demonstrated a potentiation of GABA-activated chloride flux by moderate concentrations ( < 100 raM) of ethanol (Suzdak et al., 1986a ; Aguayo, 1990), an effect which could be blocked by the GABA antagonists picrotoxin and bicuculline as well as by the BZD partial inverse agonist Ro 15-4513 (Suzdak el al., 1986b). According to Hunt (1993), this effect could provide a molecular basis to account at least in part for the central depressant action of ethanol. Moreover, it would appear that GABA-mediated chloride movements are differentially affected by ethanol in genetically selected rodent strains, as ethanol has a greater efficacy in promoting GABA-mediated chloride influx in mice selectively bred for high ethanol sensitivity than in their low ethanol-sensitive counterparts (Allan et al., 1988); in high and low alcohol- sensitive rats, it is also the ethanol-insensitive line which displays resistance to ethanol enhancement of GABA-activated chloride influx (Harris and Allan, 1989).

Several groups have also examined the effects of ethanol on mRNA levels of the different GABAA receptor subunits. Montpied et al. (1991) noted that chronic ethanol treatment produces a decrease in the levels of ~t and ~_,, but not :<, subunit mRNA in the

Invited Review 309

rat cerebral cortex, an effect also found with acute ethanol administration (Morrow et al., 1989). In a study using alcoholized WSP and WSR mice, Buck et al. (1991) demonstrated that chronic ethanol treatment increases the content of y3 mRNA in both lines, and decreases the content of ~ mRNA in WSP but not WSR mice, and that of ~6 in WSR but not WSP mice. Conversely, Hirouchi et al. (1993) found that ~ subunit mRNA was significantly increased in mice exposed to continuous ethanol inhalation for more than 5 days (resulting in dependence upon ethanol), but returned to its normal level 8 h after termination of the ethanol inhalation. Studies on the encoded pro- teins themselves indicated a reduction in the levels of the :q, ~2 and ~3 subunits in the cerebral cortex and of the ~1 subunit in the cerebellum of chronically ethanol- intoxicated rats (Mhatre et al., 1993).

It should be noted that whereas a majority of studies have come out in favor of a modulation of GABA receptor sensitivity by ethanol, others do not agree with this view (Mancillas et al., 1986; White et al., 1990). Differences in the methods used for the prep- aration of the tissues, in the housing conditions, and in the method of sacrifice of the animals might account for these discrepancies. For instance, membrane vesicles prepared from the cerebral cortex of individually housed rats have been shown to exhibit lower values of GABA-stimulated chloride influx than their pair- housed counterparts (Thielen et al., 1993). Regional differences in the subunit composition of GABAA receptors could also contribute to the variable results from one group to another, if sensitivity to ethanol depends on a specific ~f17 combination (Criswell et al., 1993). In fact, Wafford et al. (1991) had previously shown that the 72L variant (the ~2 subunit has two slice variants which vary by eight amino acids, the "long" (72L) and the "short" (72S) forms) was necessary for a potentiation of GABA A receptor function by ethanol and BZD. According to Criswell et al. (1993), ethanol would enhance GABA response in areas where type-l-BZD binding, of composition ~Jfl~Y2, is especially abundant : medial septum, inferior colliculus, substantia nigra reticulata, ventral pal- lidum and diagonal band of Broca, but not in areas where it is poorly represented : lateral septum, ventral tegmental area and hippocampus. Interestingly, most electrophysiological investigations concluding on a lack of effect of ethanol on GABAergic responses came from studies in the hippocampus (e.g. Mancillas et al., 1986).

To date, the situation regarding the effects of ethanol on central GABAergic neurotransmission is therefore far from being completely elucidated. It would

appear that acute ethanol, at high doses, generally facilitates GABAergic neurotransmission, whereas chronic ethanol would exert the opposite effect (see Fig. 1). Whether such long-term changes in GABA- ergic systems participate in the tolerance/dependence phenomena associated with chronic ethanol exposure is still a matter for debate.

Glycine (at strychnine-sensitive receptors)

Gonzalez (1993) recently showed that there was no difference between chronically alcoholized or ethanol- withdrawn rats and ethanol-naive controls in the sensitivity of these animals to seizures induced by the glycine antagonist strychnine, in spite of the increased sensitivity of similarly treated animals to seizures induced by the GABAA antagonist picrotoxin. He concluded that ethanol exposure and withdrawal may not significantly alter the function of glycinergic neurotransmission and that the ethanol withdrawal syndrome is likely to be indicative of alterations in specific neuronal mechanisms, rather than of a gen- eralized state of CNS hyperexcitability. However, Criswell et al. (1993) claim that there exist ethanol- sensitive and -insensitive responses in the brain for glycine (as for GABA and glutamate--see respective sections) ; there is some evidence that ethanol affects responses to glycine on a regionally specific basis, with an enhancement of responses in the spinal cord (Celantano et al., 1988), but no effect in the cortex of the cat (Nestoros, 1980) or in the inferior colliculus of the rat (Simson et al., 1991). Moreover, binding studies in the hippocampus of ethanol-fed mice found no change in the number ofglycine binding sites (Snell et al., 1991).

The sum of these results would seem to suggest that glycinergic synapses per se are not a major target for ethanol under acute or chronic conditions.

Exci tatory Amino Acids

Glutamate Evidence has accumulated over the past decade

that, in contrast to its potentiation of GABA inhibitory function, acute ethanol can antagonize the effects of glutamate, the other major brain amino acid neurotransmitter, which is involved in the mediation of excitatory synaptic transmission. For instance, systemic injection of ethanol (2 g/kg) was shown to inhibit the excitation of noradrenergic locus coeruleus neurons as produced by microiontophoretic application of glutamate, N M D A or quisqualate, while the response of these neurons to similarly applied

31(I Invited Review

Ethanol

q picro

BA ;cimol

cuculline

agonists I . . . . . . ~ antagonists

inverse agonists

Fig. 1. Summary of the effects of acute and chronic exposure to ethanol (in unselected animal strains) on the interaction of various ligands with their respective binding sites on the GABAA receptor. • positive

effect, @ negative effect.

acetylcholine was unaffected by the ethanol treatment (Engberg and Hajos, 1992).

Glutamate receptors in the mammalian CNS are divided into three principal subtypes, based on ligand specificity : ionotropic e-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid (AMPA) 'kainate, metabotropic quisqualate, and ionotropic N-methyl-D-aspartate (NMDA) receptors. The NMDA receptor, which is coupled to a voltage-sensitive ton channel per- meable to calcium and monovalent cations such as sodium and potassium, has been implicated in the mechanisms involved in a number of physiological and pathological processes, ranging from the synaptic plasticity underlying learning and memory (Cotman et al., 1989) to the development of epileptiform

seizures (Dingledine et al., 1986) and neurotoxicity (Lovinger, 1993a).

Ethanol and N M D A receptors. Applied acutely at concentrations known to correspond to blood alcohol levels associated with moderate alcohol intake in humans (Wallgren and Barry, 1970), ethanol has been shown by electrophysiological techniques to potently and selectively inhibit the action of agonists at the NMDA receptor (Hoffman et al., 1989; Lovinger et

al.. 1989). In addition, in vivo microdialysis studies demonstrated a decrease in the extracellular concentrations of glutamate in the striatum after administration of 2 g/kg ethanol to awake rats, as well as an inhibition by ethanol of the striatal release of glutamate induced by local application of NMDA

Invited Review 311

(Carboni et al., 1993). Using electrophysiological techniques, and employing selective antagonists of the non-NMDA glutamate receptor subtypes in order to isolate NMDA-mediated EPSPs, Lovinger et al. (1990) showed that ethanol-induced inhibition at the NMDA receptor concerns the agonist action of both the endogenous ligand, glutamate, and exogenous NMDA. These authors also presented evidence indicating that the potency of different alcohols for inhibiting the NMDA-activated current is linearly related to their potency for producing intoxication, suggesting that ethanol-induced inhibition of NMDA-mediated responses may contribute to ethanol intoxication. In a recent study, Simson et al. (1993) found that ethanol, applied locally via electro- osmosis, potently inhibited NMDA-evoked neuronal activity in the inferior colliculus and hippocampus, but not in the lateral septum. They suggest that there may exist two types of N M D A receptor--one sensitive to ethanol and the other insensitive.

Through a process referred to as excitotoxicity, excessive neuronal stimulation by glutamate leads to degeneration of neurons and subsequently to neuronal death. While the activation of non-NMDA receptors (especially of the kainate subtype) is known to be able to contribute to neurotoxicity, it is the large increase in intracellular calcium provoked by NMDA receptor stimulation which is though to be a key event in initiating the neurotoxic processes leading to delayed neuronal death (Chandler et al., 1993). Chronic ethanol consumption has also been reported to cause neurotoxicity, with dendritic hypertrophy and neuronal loss in the hippocampus (dentate gyrus) and cerebellum of rats (Riley and Walker, 1978 ; Pierce et al., 1993), and with diffuse cortical and cerebellar atrophy, degeneration of cerebellar Purkinje cells, and selective reduction in the size and number of neurons in the frontal cortex in humans (Charness et al., 1989). However, as the mechanism for this neuronal cell loss is unknown, it has been postulated that a potentiation by chronically administered ethanol of endogenous glutamatergic function (Iorio et al., 1992) may account in part for alcohol's neurotoxicity. Indeed, whereas acute ethanol can block NMDA toxicity in neurons cultured from rat cerebral cortex (Lustig et al., 1992), recent studies have shown that chronic exposure of rat cerebrocortical cultures to ethanol is able to enhance the neurotoxic potency of NMDA (Chandler et al., 1993 ;Ahern et al., 1994).

Glycine modulatory site (strychnine-insensitive). Although it is generally accepted that ethanol can inhibit NMDA receptor function, there is little evidence as to the mechanism by which this inhibition is

produced. Woodward and Gonzales (1990) suggested that ethanol may be acting at a strychnine-insensitive glycine binding site, where an interaction between N M D A or glutamate and glycine may be necessary for NMDA receptor-mediated effects (Forsythe et al., 1988), to produce its inhibition of NMDA-mediated processes ; this suggestion was based on the ability of exogenously added glycine to completely reverse the inhibitory effects of ethanol on NMDA-stimulated endogenous dopamine release from rat striatal slices (Woodward and Gonzales, 1990). Other studies added their support to this hypothesis by demonstrating the ability of glycine or glycine agonists to reverse the inhibitory effects of ethanol on NMDA- stimulated increases in intracellular calcium in rat neurons (Rabe and Tabakoff, 1990). According to Peoples and Weight (1992), glycine and ethanol (50 mM) interact in a non-competitive manner in inhibiting NMDA-activated currents. This view is supported by a recent study in which Woodward (1994), using a selective competitive glycine antagonist, showed that ethanol did not significantly alter the glycine antagonist's inhibitory potency, which would be expected if the two compounds were competing for the glycine site.

Ethanol and n o n - N M D A receptors. As agonists of the AMPA/kainate receptor subtype--also coupled to an ion channel--produce neurotoxic effects as well, it was of interest to examine whether ethanol exerts the same actions on this subtype as on the N M D A receptors. In an electrophysiological study of the effect of ethanol on kainate, AMPA and N M D A receptor- operated channels, Dildy-Mayfield and Harris (1992), using Xenopus oocytes expressing mRNA from rat hippocampus and cerebellum, demonstrated a similar degree of inhibition by ethanol of NMDA and non- NMDA ion channel-coupled receptors; in certain regions, the ethanol sensitivity of some non-NMDA receptors was even found to surpass that of the N M D A subtypes. Other studies, however, failed to find a difference in the electrophysiological responsiveness to AMPA and kainate of neurons in hippocampal slices from rats exposed to ethanol in utero as compared with controls (Martin et al., 1992). Fur- thermore, in a study of recombinant AMPA-type glutamate receptors expressed in mammalian cells, Lovinger (1993b) showed that inhibition of kainate- activated current could be observed, but only in the presence of intoxicating ethanol concentrations ; however, the potency of ethanol for inhibiting current in cortical neurons was lower than that for inhibiting the function of the recombinant receptors. Nevertheless, as the concentrations of ethanol which affect recom-

312 Invited Review

binant AMPA receptors are within the range of concentrations found during moderate to severe intoxication, the author suggests that if receptors with such sensitivity are present in vivo, they may contribute to intoxication ; this speculation is supported by a report suggesting that #7 vivo ethanol administration inhibits neuronal firing stimulated by the AMPA receptor agonist quisqualate in the locus coeruleus (Engberg and Hajos, 1992). In a study of metabotropic glutamate receptor function in offspring of prenatally ethanol-exposed rats, Queen et al. (1993) found a reduction in metabotropic glutamate receptor-activated phosphoinositide hydrolysis when a 5% (but not 3.35%) ethanol solution was given to the pregnant dams. As metabotropic receptor activation has been implicated in the facilitation of NMDA receptor-dependent long-term potentiation (LTP), the authors argue that the effect of higher blood ethanol concentrations, which will also affect the metabotropic receptor subtype, may lead to an even greater impact of prenatal ethanol exposure on LTP than occurs when NMDA receptor function alone is affected by maternal consumption of more moderate quan- tities of ethanol.

Receptor hhldin9 studies. Studies on tile effects of ethanol on the receptor binding sites for excitatory amino acids have produced contradictory results (a general summary of the actions of ethanol on the NMDA receptor is provided in Fig. 2). Whilst an early study had shown that acute and chronic administration of small to moderate doses of ethanol increased [~H]glutamate binding to rat brain synaptic membranes (Michaelis et a/., 1978). Savage et al.

(1992) reported a reduction in the density of NMDA- sensitive [~H]glutamate binding sites in the hippocampal formation of 45-day old rat offspring who had been exposed to alcohol throughout the gestational period, although they did not observe this reduction in other brain regions containing relatively high densities of NMDA receptors. In an #l vitro binding assay using rat cortical membranes, De Montis et ul. (1991) showed that low concentrations (0.1 10 I*M) of ethanol increased the affinity of [3H]MK-801 binding, without modifying the B~,~. while higher concentrations (1 100 raM) failed to modify [3H]MK-801 binding, and even higher concentrations (200 mM) actually caused a negative modulation of the binding of the radioligand. On the other hand, chronic exposure of rodents to ethanol leads to an increase in the number of [3H]MK-801 binding sites in certain brain areas (Snell et al., 1993), reflecting an up-regulation of NMDA receptors ; this more closely reflects what one would expect to find upon chronic ethanol

intoxication, given the inhibition of NMDA receptor- mediated activity produced by acute ethanol. More- over, a recent study by Trevisan et al. (1994) demonstrated the ability of chronic ethanol exposure to dramatically up-regulate NMDA receptor subunit 1 protein ~an essential component of the NMDA receptor--in the hippocampus but not in the nucleus accumbens, cerebral cortex, or striatum of the rat. In contrast, the ethanol treatment did not modify the levels of receptor subunits which make up the AMPA- type receptor, nor did chronic treatment with other psychotropic drugs mimic the effects of ethanol on the levels of NMDA receptor subunit 1 (Trevisan et al.,

1994). Behavioral studies. In behavioral studies, support

can be found for the idea that ethanol may function as a selective NMDA receptor antagonist at low concentrations. Indeed, in pigeons and mice (Grant et al.,

1991) and in rats (Grant and Colombo, 1992) trained to discriminate ethanol from vehicle, the noncompetitive NMDA antagonists dizocilpine (MK- 801) and phencyclidine (PCP) substituted fully for ethanol, and drug discrimination procedures in rats have shown that ethanol is able to act as an antagonist of NMDA discrimination and to produce discriminative stimulus effects similar to those of competitive and noncompetitive NMDA antagonists (Balster et al., 1992). In addition, ethanol was found to be able to attenuate NMDA-mediated thermal hyperalgesia produced both after acute intrathecal NMDA administration and in a model of neuropathic pain (Meller et al., 1993), Reciprocally, NMDA receptor antagonists are able to modulate alcohol preference (Lamblin et al., 1993) and to prevent the effects associated with the ethanol withdrawal syndrome (Liljequist, 1991). In line with this last finding, a greater number ofhippocampal MK-801 binding sites has been found in WSP mice than in the WSR line (Valverius et al., 1990).

Several laboratories have reported evidence tbr the involvement of the NMDA receptor in forms of synaptic plasticity such as LTP (Collingridge et al., 1983 ; Harris et al., 1984), a base for memory formation (Teyler and DiScenna, 1984). Thus, the inhibition by ethanol of the initiation of LTP in the hippocampus (Morrisett and Swartzwelder, 1993) is consistent with the negative influence of ethanol on NMDA-mediated synaptic transmission (see above). The possible link between LTP and memory formation might explain why ethanol, after acute (Mello, 1972), chronic (Walker and Hunter, 1978) or prenatal (Streissguth et al., 1990) exposure, exerts deleterious effects on learning and retention.

Invited Review 313

Acute Ethanol

glycine D-serine

o 6 6 5,7-dichlorokynurenate )-AP5

2PP

. . . . . . ~ agonists antagonists I

Fig. 2. Effects of acute and chronic exposure to ethanol (in unselected animal strains) on the interaction of various ligands with their respective binding sites on the glutamatergic NMDA receptor. *Low concentrations only. HA966 = (RS)-3-amino-l-hydroxypyrrolidin-2-one; MK-801 = dizocilpine; PCP = phencyclidine; D-AP5 =D(-)-2-amino-5-phosphonopentanoic acid; CPP= 3-((RS)-2-carboxy-piper-

azin-4-yl)-propyl-1-phosphonic acid. ~ positive effect, ~ negative effect.

DOPAMINE The existence of a dopaminergic substrate for the

facilitation of brain reward mechanisms became apparent from early studies showing that antagonism of the dopaminergic system could attenuate brain stimulation reward and block the reinforcing effects of cocaine and amphetamine (Kelly et al., 1975). Moreover, the inhibition of dopamine (DA) uptake by both of these drugs and the release of DA by amphetamine, having as an effect the potentiation of the actions of DA postsynatpically and, behaviorally, the facilitation of intracranial self-stimulation (Stein, 1964), strengthen the case for an implication of the

dopaminergic system in the abuse potential of a drug and brain reward (Wise and Bozarth, 1987). A brain microdialysis study examining the differential involvement of the anatomically and functionally distinct subdivisions of the dopaminergic system has further shown that drugs abused by humans stimulate DA release from the major terminal area of the mesolimbic DA system (the nucleus accumbens) to a far greater degree than from the dorsal caudate nucleus, the major terminal area of the nigrostriatal DA pathway, while drugs with aversive properties reduced DA release in these two areas (Di Chiara and Imperato, 1988).

Numerous studies provide evidence that alcohol-

314 Invited Review

preferring rats consume ethanol for its central reinforcing actions. Indeed, it has been shown that P rats will voluntarily self-administer ethanol intra- gastrically (Waller et al., 1984) or intracerebrally (Gatto et al.. 1990). Interestingly, lower concentrations of DA and its metabolites have been found in the nucleus accumbens of P (Murphy et al., 1987) and HAD (Gongwer et al., 1989) rats than in their NP and LAD counterparts. It therefore follows that much effort has been devoted to determining whether DA also underlies ethanol preference.

In 1974, Seeman and Lee showed that high brain ethanol concentrations could release DA in the striatum, although low to moderate concentrations were found to have no effect. Later studies, however, using more moderate ( 1 3 g/kg) doses of ethanol, were able to demonstrate an increase in DA turnover and release (Imperato and Di Chiara, 1986) in various brain areas during ethanol intoxication, and conversely, a dra- matic decrease in DA release during ethanol withdrawal in the nucleus accumbens (Diana et al., 1993) and striatum (Rossetti et al., 1992a), which could be reversed by a challenge ethanol dose. Electro- physiological studies demonstrated the ability of low doses of acute ethanol to increase the firing rate of DA neurons in the substantia nigra (Mereu et al.,

1984) and ventral tegmental area (VTA) in rivo (Gessa et al., 1985) and in vitro (Brodie e t a [ . . 1990). Conversely, the number of spontaneously active DA neurons in the VTA (Shen and Chiodo. 1993) and their firing rates (Diana et al., 1993) are reduced during acute ethanol withdrawal, both of which changes can be reversed by ethanol administration (Diana el a/.. 1993). Diana et al. (1993) suggested that the depressed activity of the mesolimbic DA system during the ethanol withdrawal syndrome may be relevant to the dysphoric state associated with ethanol withdrawal in humans.

Receptor binding studies have been conducted m unselected animal lines exposed to ethanol and tbl- lowing ethanol withdrawal, as well as in selected alcohol-preferring and non-preferring rat lines. In an initial study using the AA and ANA rat lines, Korpi et al. (1987) found a modest reduction in D~ receptor number in the caudate nucleus of AA rats, but concluded that the difference observed between the two lines was too small to be considered of importance for genetically determined differences in alcohol preference. A later study by Stefanini el a/. (1992) in sP rats confirmed the modest decrease observed by Korpi et al. (1987) in the caudate, but also noted decreases in limbic areas, notably in the nucleus accumbens and olfactory tubercle ; they found these differences to be

due to a decrease in B ...... with no change in Kd. In the light of these results, they claimed that a link probably exists between ethanol preference and the reduction in D: receptor number in these limbic areas, as D: receptors in the accumbens and olfactory tubercle are the first target of DA released by mesolimbic DA nerve terminals. Recently, McBride et al. (1993a) provided further confirmation for a decrease in the density of D 2 receptors in P rats ; their autoradiographical study showed a reduction in D: receptor labeling in the caudate-putamen, nucleus accumbens and VTA of P rats. and binding assays using membrane preparations indicated that this difference in the caudate- putameu was due to a decrease in B ....... with no change in the affinity of the receptors. A study by De Montis et al. (1993) revealed that sP rats also present modi- lications in D~ receptor binding ; while no change was detected in the caudate-putamen, the limbic areas of the sP rats presented a lower B ...... of D~ sites, with no change in Kd. Moreover, the sP rats exhibited a less pronounced responsiveness than their sNP counterparts to DA-stimulated adenylate cyclase activity.

Support for a reduced D2 receptor function in alcoholism was provided by a clinical study of the growth hormone response to the DA agonist apomorphine a well-accepted measure of postsynaptic D~ receptor function (Nair et al.. 1982). While early studies had demonstrated an increase in postsynaptic [), receptor function during the early alcohol withdrawal period in alcoholic patients (Anunziato et al.,

1983), Balldin et al. (1993) showed that long-term abstinent alcoholic subjects had a significantly lower maximal growth hormone response to apomorphine than control subjects.

Studies using unselected rat lines have produced less easily interpretable results than those obtained with alcohol-preferring strains. Certain studies found binding (B ...... but not Kd) to Dt (Hruska, 1988: Log- rano et al., 1993) and D~ (Hruska, 1988) receptors to be increased following chronic ethanol treatment, but Lucchi et al. (1988) found a decrease in D~ binding and Fuchs et al. (1987) reported that ethanol can reverse the up-regulation of D~ receptors due to chronic haloperidol treatment. Hamdi and Prasad (1992) suggested that in rats, chronic ethanol intake may cause a time-dependent bidirectional change in striatal D~ receptors, as they found an initial decrease in B ..... (with no change in Ka) of these receptors during the first week of consumption of an ethanol liquid diet, followed by a reversal of this effect and an increased B .... during the second week with this regimen. The latter change was still present during the third week. although to a lesser extent, and by the

Invited Review 315

fourth week, there was once again a significantly lower density of D~ receptors ; Bmax values stabilized to control levels from the sixth week on, in spite of continuous ethanol liquid diet.

An autoradiographical study by Rommelspacher et

al. (1992) concluded that there was a decrease in the number (but not the affinity) of D2 receptor binding sites in the caudate nucleus, nucleus accumbens and olfactory tubercle of unselected rats 24 h after alcohol withdrawal. However, May (1992) failed to confirm this observation and found no alteration in the Bmax or Kd values of striatal D~ or D2 receptors in ethanol- withdrawn rats. Nevertheless, this author noted that the high affinity (G-protein-coupled) state of the Dt receptor had a 5-fold increase in affinity for DA in ethanol-withdrawn rats as compared to control animals (May, 1992).

A great deal of attention has also been devoted to behavioral studies examining the effects of various manipulations of dopaminergic neurotransmission on ethanol intake (see Table 2). An early study by Myers and Melchior (1975) suggested a potential role for DA in the mediation of ethanol drinking behavior by showing that intracerebroventricular injection of the DA (and noradrenergic) neurotoxin 6-hydroxydopamine (6-OHDA) resulted in a decreased preference for ethanol in the rat, a result which was replicated by several other groups (e.g. Brown and Amit, 1977). Kiianmaa et al. (1975), however, found that 6-OHDA lesions of the mesencephalic tegmental area enhanced ethanol intake. Consistent with the data reported by Ld et al. (1981 a), it is possible that the mechanism underlying this enhancement of ethanol intake is by an impairment of the mechanism leading to ethanol tolerance. A more recent study also man- aged to induce significant increases in ethanol preference by specific 6-OHDA lesions of the nucleus

accumbens and olfactory tubercle--two areas of the limbic system implicated in DA-mediated reward pathways--but not of adjacent brain areas in the rat (Quarfordt et al., 1991). The authors proposed that the resulting degeneration of DA-containing fibers and terminals causes a reversal of the rat's recognized aversion to ethanol by blunting the drug's aversive qualities. In contrast, Rassnick et al. (1993a) found no alteration in ethanol self-administration in trained rats by 6-OHDA lesions of the nucleus accumbens and olfactory tubercle, concluding that while the mesolimbic DA system may contribute to the reinforcing actions of ethanol, it is not critical for maintaining ethanol reinforcement. These apparently contradictory results may derive from the different animal strains (Sprague Dawley in the study by Quar- fordt et al. (1991) and Wistar in that of Rassnick et

al. (1993a)) and experimental paradigms (free-choice between water and different concentrations (3-30%) of ethanol in the study by Quarfordt et al. (1991), and self-administration of water or a 10% ethanol solution by lever-pressing in that of Rassnick et al. (1993a)) employed in the two studies.

Despite early reports that treatments with the DA receptor antagonists haloperidol (Davis et al., 1978) or pimozide (Brown et al., 1982) were ineffective in altering ethanol consummatory behavior, thereby suggesting that the DA system was apparently not involved in the reinforcing effects of ethanol (see review by Deitrich, 1976), later findings have been more favorable toward a role for DA in the mechanism underlying ethanol preference. Notably, in a double-blind clinical trial with 50 chronic alcoholics, the rated craving for alcohol was reduced from strong to very mild by administration of the DA agonist bromocriptine (Borg, 1983). In addition, a positive correlation seems to exist between DA activity and

Table 2. Effects of pharmacological manipulations modifying the CNS activity of monoaminergic systems on alcohol consumption in unselected rat lines (or clinical trials ; see text for details)

Monoamine CNS Alcohol System Activity Drinking References

7 7 Hodge et al. (1992) /~ ~ Borg (1983) ; Rassnick et al. (1993) ; Lan~a (1994)

DA "~ ,7 Kiianmaa et al, (1975) ; L~ et al. (1981a) ; Quarfordt et al. (1991) x, x, Myers and Melchior (1975) ; Samson et al. (1993) ; Hodge et al. (1993) N Davis et al. (1978) ; Brown et al. (1982) ; Rassnick et al. (1993a)

NE 7 ~ Docherty et al. (1993) "~ "~ Brown and Amit (1977) ; Davis et al. (1978) ; Amit and Brown (1982)

7 ~ Myers et al. (1972) ; Krasner et al. (1975) ; Naranjo et al. (1986) ; Bruno (1989) ; Gill and 5-HT Amit (1989) ; Lu et al. (1993)

"x, Myers and Veale (1968) ; Schreiber et al. (1993)

7 increase ; "~ decrease ; no change.

316 Invited Review

ethanol-reinforced responding, as microinjections of the non-specific DA agonist d-amphetamine and the D2/D3 agonist quinpirole into the nucleus accumbens increase ethanol-reinforced lever pressing (Hodge et

al., 1992), while responding is decreased when the D, antagonist raclopride is injected into this area (Sam- son et al., 1993) or upon i.p. injection of the mixed D~/D 2 agonist SDZ-205,152 (Rassnick e ta / . , 1993b). Consistent with the idea that reductions in responding lbllowing antagonist injection into the nucleus accumbens may be due to decreased DA activity, the injection of quinpirole into the VTA, which decreases cell firing rates, presumably by activating somatodendritic DA autoreceptors (Chiodo, 1988), also resulted in a decrease in ethanol-reinforced responding (Hodge et

al_ 1993). In a study using P rats, Weiss et al. (1990) showed

that i.p. injection of these rats with bromocriptine produced a shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. This finding was confirmed by Dyr et al. (1993) in HAD rats, with the D2/D3 agonist quinpirole causing a decrease in alcohol drinking with no concomitant decrease in the intake of food or a palatable saccharin solution in these animals. However, the D: antagonist, spiperone, had a differential effect on alcohol intake according to the dose administered, with no effect at the lowest dose, an increase at the intermediate dose, and a decrease at the highest dose administered. An increase in ethanol consumption with intermediate doses of another Dr antagonist, sulpiride, microinjected directly into the nucleus accumbens, was also reported in P rats (Levy et al., 1991). The interpretation proposed for this phenomenon was that an intermediate dose of these antagonists may cause a partial blockade of D 2 receptors, the effect of which would logically be a reduction in the reinforcing efficacy of ethanol. This would lead the P rats to increase their already high ethanol intake in an attempt to overcome the reduced reinforcing efficacy of ethanol. On the other hand, the complete blockade of D: receptors produced by higher doses would completely eliminate the reinforcing effects of ethanol, thus producing a decrease in alcohol consumption. A decrease in alcohol intake has also been shown to occur in rats systemically treated with high doses of the D2 antagonists pimozide and haloperidol (Pfeffer and Samson, 1988).

Very recently, Langa (1994) found a 40 50% reduction in voluntary ethanol intake by rats which had received intrastriatal transplantation of fetal dopaminergic grafts from the ventral mesencephalon, but not in those which were sham-operated or in which

the transplanted grafts were devoid of DA cells. The author concluded that a reduction in chronic alcohol intake may result from an increase in tonus of the dopaminergic mesolimbic system.

The past few years have seen the development of a controversy over the possible genetic implication of the D2 receptor gene in alcoholism. A first report by Blum et al. (1990) found a correlation between alcoholism and the A1 allele of the Taq 1 restriction fragment length polymorphism (RFLP) in the Y region of the D2 receptor gene. This conclusion was subsequently confirmed in a number of studies (for review, see Noble, 1993). In contrast, a number of other studies disagreed with this association (Bolos et

al., 1990; Gelernter et al., 1993). In support of the original findings of Blum et al. (1990), a comp- lementary receptor binding study by the same group (Noble et al., 1991)--using the same sample of brain tissues from deceased alcoholics and nonalcoholics as had been employed for the first study--found that individuals with the AI allele had less D~ receptor binding sites (lower Bm~) in the caudate nuclei than those without the allele ; in fact, a progressive decrease in D_~ receptor binding site density was observed with A2/A2, A1/A2 and A1/A1 genotypes, respectively. Moreover, in a more recent study of a new RFLP located closer to the regulatory regions of the D2 receptor gene, Blum et al. (1993) found an increased prevalence of the 5' Taq l BI allele in alcoholics as compared to nonalcoholics or less severe alcoholics, with no difference between less severe alcoholics and nonalcoholics ; the authors concluded that both the 5' and 3' regions of the D2 receptor gene are associated with severe alcoholism, suggesting that this gene may have an etiological role in some severe alcoholics. Detractors of this theory, however, claim that the reported positive associations between alcoholism and the A I polymorphism result from an inappropriate selection of controls, as alcoholics were not excluded in some instances, and in other studies, the sample of alcoholics did not distinguish between different degrees of severity of the disease (Noble and Blum, 1991). Moreover, Barr and Kidd (1993) showed that ethnic makeup can generate significant population differences in allele frequencies of the D2 receptor gene, varying from prevalences of as low as 0.09 for Yemenite Jews to as high as 0.75 for the Muskoke Amerindians. Thus, due to the significant het- erogeneity among both the alcoholic and control groups used in the studies to date, Gelernter et al. (1993) undertook a reanalysis of the data presented in the literature as a whole, in which the samples with the highest and lowest A1 allele frequencies were

Invited Review 317

removed. The conclusion of this analysis was that the difference between alcoholics and controls was not statistically significant.

In a recent development, a common study was undertaken by many of the authors who had fueled the debate over the putative existence of an association between alcoholism and the Taq I A1 RFLP (Gejman et al., 1994). In this examination of the abnormalities of the D2 receptor gene coding sequences possibly associated with schizophrenia or alcoholism, it was revealed that, although there exist 3 infrequent DNA variants that predict altered amino acid sequence of the receptor, none of these is associated with either alcoholism or schizophrenia, and there are thus no structural coding abnormalities in the D2 receptor gene in alcoholism or schizophrenia. It should be noted that the results of this study do not exclude the existence of a genetic defect in the O2 receptor gene, which could be located in a part of the genomic region not examined, such as exon 1 (a noncoding exon), introns, promoter (located at least 250 kb from the site of the Taq I A RFLP), or other regulatory sequences. However, as explained by Gejman et al. (1994), a valid, etiologically significant disease associated with an RFLP that is not in the coding or regulatory region of a known gene implies that there exists a mutation in that gene within a small distance of the RFLP; thus, the observed absence of a structural mutation in the gene renders interpretations of the association reported by many authors rather difficult.

Another receptor thought to play an important role in the reward process of addiction behavior is the D3 receptor, which is specifically located in the limbic areas of the brain, notably in the nucleus accumbens. However, a recent investigation on three independent brain tissue samples from the groups of Blum, Noble and Geijer (in which a positive association between the D2 receptor gene and alcohol dependence had previously been reported) indicates that there was no difference in the frequencies of the alleles of the Bal I RFLP of the D3 receptor gene between alcoholic and control subjects (P. Gorwood, personal com- munication). This suggests that there is no association between a given polymorphism of the D3 receptor gene and alcoholism.

NOREPINEPHRINE

The involvement of norepinephrine (NE) in alcoholism has also been widely examined. A number of early studies implicated noradrenergic systems in the mediation of ethanol self-administration, as neurochemical lesions of noradrenergic neurons

(Brown and Amit, 1977) or inhibition of NE synthesis (Davis et aL, 1978) were found to result in a suppression of voluntary ethanol consumption (see Table 2). Despite the suggestion that DA may be the substrate of all reward (Wise, 1980), but congruent with a number of early studies which had observed increases in NE turnover following the administration of ethanol (e.g Corrodi et aL, 1966), Amit and Brown (1982) therefore suggested that ethanol reinforcement may be an exception, in that the reward mechanism through which it acts appears to be subserved by noradrenergic rather than dopaminergic mechanisms.

However, the NE and DA systems should not necessarily be completely dissociated from one another, with respect to their involvement in the mediation of ethanol reinforcement, as evidence for the participation of dopaminergic mechanisms in this phenomenon has repeatedly been reported in the literature (see above). In this context, Wise and Bozarth (1985) proposed that while DA is likely to be the principal transmitter responsible for the central mediation of ethanol reward, ethanol reinforcement may occur via inhibition of noradrenergic activity in the locus coeruleus, the effect of which would be a release of DA neurons from tonic noradrenergic inhibition.

The effects of chronic or acute ethanol treatment on the noradrenergic system have also been examined. Early studies showed that single-dose ethanol administration stimulates the synthesis and turnover of cerebral NE without modifying its concentrations (e.g. Carlsson and Lindqvist, 1973). However, rat pups exposed to ethanol pre- or postnatally were found to have lower whole brain and hypothalamic levels of NE (Detering et al., 1980). A more recent study using the technique of in vivo brain microdialysis found that long-term alcohol treatment of non-selected rats resulted in an increased release of the catecholamine in the hippocampus (Huttunen, 1991), and a chronoamperometric study in the cerebellar cortex of unselected rats found that ethanol, applied locally, inhibited NE reuptake (Lin et al., 1993). Upon acute ethanol administration to unselected rats, Ros- setti et al. (1992b) found a biphasic effect on NE release in the frontal cortex, as a low dose (0.2 g/kg) raised NE outflow, while a higher dose (2 g/kg) inhibited the release of NE ; the authors suggest that the decrease in cortical NE output may reflect the sedative-hypnotic properties of ethanol at high doses, whereas the increased NE release may represent a biochemical correlative of the arousal and increased alertness elicited by low doses of ethanol.

Studies with genetically selected lines of rodents

318 Invited Review

have shown differential cerebral noradrenergic activities. Hetlevuo et al. (1990) demonstrated that the basal utilization rate of NE was similar between the AT and ANT rat lines, although the increased formation of the NE metabolite MHPG by the AT rats suggested that these rats had a higher noradrenergic activity in the limbic forebrain, hypothalamus and cerebellum. In addition, higher NE levels in the midbrain of LS mice than in their SS counterparts were reported by Sbafik et al. (1991).

In man, cerebrospinal fluid (CSF) levels of the NE metabolite MOPEG (which are considered to reflect central noradrenergic function) are increased following absorption of ethanol (Borg el al., 1983). A genetic component in alcoholism-related noradrenergic transmission has also been raised, as alcohol-dependent subjects have higher MOPEG levels than control subjects, while non-intoxicated subjects who have a family history of alcoholism have lower inherent MOPEG levels (Borg et al. 1983). A later study by Liljeberg et al. (1987) showed that CSF MOPEG levels are negatively correlated with the degree of alcohol craving, as well as with signs of euphoria and various intellectual capacities.

Studies of the effects of ethanol on central adrenergic receptors have produced somewhat equivocal findings. In a study of 17-day old offspring exposed to ethanol in u tero , Wigal et al. (1990) noted a reduction in the number (Bm~,x) of /~-adrenoceptor binding sites in the hippocampus with no change in Kd, while Hadjivanova et al. (1991) found an increase in the affinity (decrease in Kd) of these receptors, with no change in their B ...... in the hippocampus of 8-week old rats perinatally exposed to ethanol. On the other hand, Rommelspacher et al. (1989) found that ethanol prevented a decrease in the number of//-adrenoceptor binding sites in the cerebral cortex induced by chronic treatment of rats with the tricyclic antidepressant desipramine. However, Wong et al. (1988) failed to observe any significant difference in binding to ~-, ~-2- and fi-adrenergic receptors in cerebral cortical and hippocampal membranes between P and NP rats, and Pandey et al. (1992) did not find any change in ~- adrenoceptor binding in the cerebral cortex of unselected rats after short- and long-term ethanol administration. In a study of postmortem brains of ethanol-intoxicated nonalcoholic subjects and matched controls, Meana et al. (1992) showed that acute ethanol intoxication did not produce any changes in ~2-adrenoceptor binding. In contrast, Hu et al.

(1993) observed an increase in the binding of the ~2- adrenoceptor antagonist [3H]rauwolscine to the neuronal cell line NG108-15 after long-term (2 days)

treatment with 100 mM ethanol, as well as a large increase in the cell levels of ~2H- and ~2c-adrenoceptor mRNAs, leading the authors to suggest that clinically attainable concentrations of ethanol can regulate ~- adrenoceptor gene expression within the time frame of a single drinking session.

A limited number of investigations have also employed specific ligands of the adrenergic receptors in order to study the involvement of the noradrenergic system in the central effects of alcohol. In these studies, ~_~-adrenoceptor antagonists of different chemical classes were shown to be able to reverse the ataxic (Durcan et al., 1991, 1992) and hypothermic (Durcan et al., 1991) effects of ethanol in mice. In another study, Docherty et al. (1993) induced a reduction in the rats' intake of ethanol in a limited access procedure by administration of the fl-adrenergic agonist iso- proterenol via metered aerosol inhalation just before ethanol availability.

SEROTONIN

Since Myers and Veale first implicated an alteration of the cerebral metabolism of serotonin (5-hydroxytryptamine: 5-HT) in alcohol-related consummatory behavior in 1968, the indoleamine has increasingly become the focus of attention of investigators striving to determine the nature of the biochemical basis of the preference for ethanol. Myers and Veale (1968) noted a reduction in the rats' preference for a solution of ethanol in a wide range of concentrations upon oral administration of p-chlorophenylalanine (p-CPA), a tryptophan hydroxylase inhibitor which lowers 5-HT content in the brain without significantly altering levels of other neurotransmitters. Such a reduction in ethanol preference by depleters of cerebral 5-HT has since been confirmed by numerous other authors, both in normal outbred and alcohol-preferring rat strains (Frey et al., 1970 ; Schreiber et al., 1993), as well as in clinical studies in humans (Naranjo e t al. , 1986). In 1975, Frankel et al. provided the first evidence that serotonergic neurotransmission was involved in the development of tolerance to the effects of ethanol, by demonstrating an impairment of the acquisition of tolerance by p - C P A administration. The same group (L~ et al., 1981b) subsequently showed that a similar effect could be obtained by degeneration of brain 5- HT neurons with the neurotoxin 5,7-dihydroxy- tryptamine (5,7-DHT) or by electrolytic lesions of the median raphe nucleus (an area with a high concentration of serotonergic cell bodies), and that conversely, the augmentation of brain serotonergic neurotransmission by administration of tryptophan

Invited Review 319

had the result of facilitating the development of tolerance to the effects of ethanol (L~ et al., 1979).

Today, there is considerable evidence from both animal and human studies that 5-HT plays a role in the modulation of alcohol intake and/or dependence, and in the development of tolerance to ethanol. Para- doxically (in view of the findings of decreased ethanol consumption by depleters of cerebral 5-HT), the general consensus is that there exists an inverse relationship between the functioning of the cerebral serotonergic system and ethanol drinking preference (see Table 2). Pharmacological manipulations that reduce cerebral 5-HT concentrations increase ethanol intake in animals; conversely, procedures which increase 5-HT release or turnover produce a reduction in ethanol intake. Thus, substances which increase serotonergic neurotransmission, such as the 5-HT pre- cursors 5-hydroxytryptophan (5-HTP) and tryptophan, 5-HT uptake inhibitors, 5-HT releasers, and specific 5-HT receptor agonists, have been found to reduce ethanol consumption in both humans and lab- oratory animals. Moreover, studies using genetically bred lines of alcohol-preferring, alcohol-naive rats (P/NP, HAD/LAD) have demonstrated lower basal concentrations of 5-HT and its main metabolite, 5- hydroxyindoleacetic acid (5-HIAA) (Murphy et al., 1987; Gongwer et al., 1989), as well as a decreased turnover rate (Morinan, 1987) and a reduction in the number of 5-HT fibers (Zhou et al. 1991), in various brain areas of these rats as compared to their genetically bred, non alcohol-preferring counterparts. However, other authors using different lines of alcohol-preferring and non-preferring rats (AA/ANA) have failed to find such differences (Ahtee and Eriks- son, 1972; Korpi et al., 1988).

The lesion of serotonergic cell bodies results in an increase in ethanol consumption in alcohol non-preferring rats, while no such effect is observed in their alcohol-preferring counterparts (Ferreira and Soares- da-Silva, 1991), presumably due to their initial low basal cerebral 5-HT contents. The results of these animal studies are complemented by clinical findings, which tend to support the idea o fa hypofunctioning of the 5-HT system in alcoholic patients; indeed, drugs which activate serotonergic transmission appear to be of therapeutic value in reducing ethanol consumption (Sellers et al., 1992). In addition, a decrease in CSF tryptophan levels was observed following acute ethanol consumption by healthy volunteers, this tending to indicate an increase in 5-HT synthesis during ethanol intoxication, while abstinent alcoholic patients presented elevated basal CSF tryptophan levels and low CSF levels of 5-HIAA, which would further support

the view that alcoholics have a lower inherent 5-HT turnover (Beck et al., 1984). The idea that alcoholic subjects have lower baseline 5-HIAA levels in the CSF was first proposed in 1979 by Ballenger and his co- workers. These levels are transiently elevated during acute ethanol consumption, but during non-consuming periods, there occurs a further depletion, which merely serves to aggravate the cycle. This and other evidence along the same line has led to the formulation of a hypothesis whereby subjects pre- disposed to the consumption of alcohol would have lower, genetically determined 5-HT brain levels, and that drinking reflects an attempt to correct the initial deficit in 5-HT neurotransmission. The genetic component of the predisposition to alcoholism is supported by the finding of low central serotonergic transmission in non-drinking adult children of alcoholics (Hunt, 1990), and by an increased platelet 5-HT uptake in alcoholics and their descendants (Ernouf et al., 1993). In addition, a significant association between a particular genotype (LL) of the enzyme that catalyzes the rate-limiting step in the biosynthesis of 5-HT, tryptophan hydroxylase, and low CSF 5-HIAA concentrations has recently been reported in impulsive alcoholic violent offenders (Nielsen et al., 1994).

Receptor studies

Binding studies in animal models of alcoholism and using postmortem human brain samples from alcoholics unfortunately do not provide a very clear picture of the possible effects of alcohol on 5-HT receptors (for a general overview, see Fig. 3). One reason for inconsistencies in the results is likely differences in the animal models and mode of ethanol administration, which often vary significantly from one group to another. Wong et al. (1988) found an increased [3H]5-HT binding to 5-HT~ receptors in cortical and hippocampal membrane preparations of P rats, as compared to their NP counterparts; this same group later examined binding of [3H]8-OH- DPAT to 5-HTIA receptors in cortical and hippocampal membrane preparations of P rats, where they found a higher density of binding sites (Bmax) and higher affinity (lower Kd) in both areas (Wong et al., 1990). In a subsequent study, a higher Bmax was found, with no significant change in Kd, for binding of [3H]8- OH-DPAT to 5-HT~A receptors in cortical membrane preparations of P rats (Wong et al., 1993). An increase in 5-HT~A receptor binding in the medial nucleus accumbens and medial prefrontal cortex has also been reported by McBride et al. (1990), who used a quantitative autoradiographie technique for measurement

320 Invited Review'

~5-HT Neuron~

Firing

Somato-Dendrific Autoreceptors:

©

- - Pre-synaptic - ~ Receptors:

/ / - - ~ 5-~IT - / I Ethan°ll

V -- ~'O V ~ N~[, Post-syna tic I ( ~ Recep~

Fig. 3. EffEcts of acute and chronic exposure to ethanol (in unselected animal strains) on the variouf 5-HT receptor subtypes. • positive effect. O negative effect.

Invited Review 321

of these receptors in P rats. The authors' interpretation of these results is that an up-regulation of 5-HT1A receptors may have developed in the P rats as a compensatory mechanism to adapt to a lower 5- HT innervation (Zhou et al., 1991) and/or function. However, Korpi et al. (1992b) found no change in [3H]5-HT binding to 5-HTj receptors in various brain regions of AA as compared to ANA rats, and another group (Ulrichsen, 1991), in a study of 5-HTIA receptors during severe chronic ethanol intoxication and withdrawal in the rat, observed a decrease in the Bma x of [3H] 8-OH-DPAT binding in hippocampal (but not cortical) membrane preparations, with no change in Kd, in both the intoxication and withdrawal phases. Pandey et al. (1992) also noted no change in [3H]8- OH-DPAT binding in cortical or hippocampal membranes of rats subjected to short-term or long-term ethanol treatment or upon withdrawal. However, in the human brain postmortem, Dillon et al. (1991) found a decreased binding of [3H]8-OH-DPAT to 5- HTIA receptors in several cortical gyri of alcoholics.

Studies of the 5-HT2A receptor subtype produced results showing either decreases in various brain areas of alcohol-preferring rats as compared to non-preferring rats (McBride et al., 1990, 1993b), or no change (Wong et al., 1988; Korpi et al., 1992b) in the density of corresponding binding sites. In man, Simonsson and Ailing (1988) demonstrated a reduced function of the 5-HT2A receptor on platelets obtained from alcoholics, shortly after a period of abuse, by examining 5-HT-stimulated phosphoinositide hydrolysis; a subsequent study (Simonsson et al., 1992) detected no difference between post-withdrawal alcoholics and controls, showing that this reduction in 5-HT2 receptor function is a state-dependent rather than a trait-dependent marker. A decrease in 5-HT2A receptor number and 5-HT-stimulated [3H]inositol-1- phosphate formation has been found in rat cerebral cortex after long-term ethanol exposure and withdrawal by Pandey et al. (1992), who attributed these changes to a possible reduction in coupling of 5-HT2A receptors to G-protein or phospholipase C.

Very little data is available concerning the binding of specific ligands to the other subtypes of 5-HT receptors. One study found a lower density of 5-HTIB receptors, as measured by [125I](-)iodocyanopindolol binding, in the medial nucleus accumbens of P rats as compared to NP rats (McBride et al., 1990), while another study found no difference in [3H]LY 278584 binding to 5-HT3 receptors in various brain regions of AA and ANA rats (Korpi et al., 1992b). Nevertheless, a direct effect of alcohol on the 5-HT3 receptor has been reported by Lovinger and White (1991), who

found that 5-HT3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons is potentiated by ethanol.

Pharmacological manipulations affecting ethanol consumption

5 - H T precursor loading. In 1972, Myers et al. demonstrated the inhibitory effect of i.p. and i.c.v. 5- HTP, the precursor of 5-HT, on ethanol consumption in the rat. This effect was also observed by Alvarado et al. (1990) in UChB rats, which exhibited a decrease in specific appetite for ethanol (i.e. no change in food or total fluid intake) upon i.p. 5-HTP administration. The same, specific effect was obtained upon administration of an L-5-HTP derivative, triptosine, to outbred rats with an experimentally-induced preference for ethanol (Ernouf et al., 1992). However, it cannot be excluded that these decreases in consumption may be provoked by a taste aversion to ethanol induced by such compounds (Zabik and Roache, 1983).

Serotonin uptake modulators. Specific 5-HT uptake blockers have long been known to have a suppressant effect on ethanol consumption in animal models, including alcohol-preferring rat strains, and have been shown to be of therapeutic value in reducing ethanol intake in problem drinkers (Naranjo et al., 1986). In fact, most work to date at the preclinical and clinical levels, with respect to treatment of problem drinking via modulation of the serotonergic system, has been done with 5-HT uptake blockers such as fluvoxamine, fluoxetine, citalopram and zimelidine (Gill and Amit, 1989). Overall, clinical studies with these and other uptake inhibitors have yielded positive results in the short-term management of problem drinkers (Nar- anjo et al., 1986, 1992), although none have demonstrated clinical efficacy in the long-term treatment of the heavy drinker (Thomas, 1991).

However, analogous to the effects described above upon administration of the 5-HT synthesis inhibitor pCPA, there is a general consensus that the effects of 5-HT uptake inhibitors in decreasing ethanol consumption are secondary to their actions on consummatory behaviors in general, and on caloric regulation (Myers and Quarfordt, 1991). Indeed, most animal studies carried out to date with 5-HT uptake inhibitors have found a decrease in food and/or total fluid consumption concomitant to the reduction in ethanol drinking, and clinical studies often report a weight loss in subjects treated with these compounds. Nevertheless, in a study examining the effects of fluoxetine on the intragastric self-administration of ethanol in the P line of rats, Murphy et al. (1988) found that 10 mg/kg of this drug actually increased

322 Invited Review

sell-administration of water and drinking of a flavored solution associated with the ingestion of ethanol, with no significant reduction in food intake, while reducing self-administration of a 20% ethanol solution. In addition, using an ethanol-reinforced responding paradigm, Haraguchi et al. (1990) observed no decrease in body weight in nonfood- or fluid-deprived rats upon fluoxetine administration, at doses producing a decrease in the oral self-administration of 10% ethanol, and Lu et al. (1993) found that fluoxetine reduced both ethanol and water consumption in rats, although the suppression of ethanol intake was significantly greater than that of water intake. Also in man, Naranjo et al. (1992) noted no change in subjects' body weights or self-reported consumption of non-alcoholic drinks upon treatment with citalopram. Thus, according to some authors, the ethanol intake- reducing effect of the 5-HT uptake inhibitors would primarily be due to their actions on satiety mechanisms in general, while others contend that these drugs exert a greater effect on ethanol drinking than on other ingestive behaviors. This latter view is supported by studies examining the consumption of palatable substances, which have shown that the effects of 5-HT uptake blockers are greater upon substances with more pronounced reinforcing efficacies (Leander, 1987).

Studies have also been carried out with a 5-HT uptake enhancer which, one might imagine, should have the effect of increasing ethanol intake. Para- doxically, Daoust et al. (1992) found that the 5-HT uptake enhancer tianeptine also decreased ethanol intake in rats in which a preference for ethanol had been induced by alcoholization. Contrary to what was obtained for most of the 5-HT uptake blockers, however, tianeptine had no inhibitory effect on food intake. The common effect of tianeptine and the uptake blockers may derive from the fact that both classes of drugs enhance 5-HT metabolism/function through an increased availability oftryptophan for 5- HT synthesis, due to their common inhibitory influence on liver tryptophan pyrrolase activity.

5 - H T releasers. As with 5-HT uptake inhibitors, 5- HT releasers, such as fenfluramine or dexfen- fluramine, have generally been found to decrease ethanol consumption in animal models of alcoholism (Krasner et al., 1975 ; Lu et al., 1993), consistent with the idea that increasing 5-HT concentrations in the synaptic cleft attenuates ethanol intake. In common with the uptake blockers, 5-HT releasers may act via a potent anorectic effect, yet the results obtained by Lu et al. (1993) showed that the ethanol intake-reducing effect of fenfluramine is signiiicantly greater than

that on the reduction of water or sucrose solution intake.

Spec!/ ic 5 - H T receptor [igands. Studies using alcohol-preferring rodent strains (Kostowski and Dyr, 1992), monkeys (Collins and Myers, 1987), and clinical studies in humans (Bruno, 1989) have nearly all reported a decrease in alcohol consumption with the 5-HTIA agonists buspirone, ipsapirone, 8-OH-DPAT, or gepirone; furthermore, in most cases, the effect observed was specific for ethanol consumption, as food and/or total fluid intake was either not affected or increased. Moreover, Schreiber et al. (1993) demonstrated that the ethanol preference-reducing effect of ipasapirone (injected s.c.) could be completely blocked by the (non-selective) 5-HTIA antagonist spiperone (s.c.). The same authors also reported a reduction in the ethanol consumption of alcohol- preferring rats by microinjection of 8-OH-DPAT into the dorsal raphe nucleus (a brain area rich in somatodendritic 5-HTiA autoreceptors), with no significant effect observed upon injection into the nucleus accumbens: based on these data, Schreiber et al. (1993) suggested that 5-HT~A receptor agonists reduced ethanol preference via stimulation of presynaptic autoreceptors on raphe cell bodies. Interestingly, Blomqvist et al. (1994) recently demonstrated the ability of the 5-HT~A receptor agonists 8-OH-DPAT, ipsapirone and buspirone to antagonize ethanol- stimulated locomotor activity, an effect which has been proposed to be homologous to ethanol's reinforcing properties (Wise and Bozarth, 1987).

In a number of studies, administration of 5-HT3 receptor antagonists (e.g. ondansetron, ICS 205-930, MDL 72222, zacopride) has also been shown: (i) to attenuate volitional ethanol consumption in various animal models (Knapp and Pohorecky, 1992), in alcohol-preferring rats (Fadda et al., 1991 ; Meert, 1993) and in human alcohol abusers (Toneatto et al., 1991) ; (ii) to attenuate ethanol-induced hyperlocomotion (Rajachandran et al., 1993); (iii) to block the discriminative stimulus effects of ethanol (Grant and Barrett, 1991); (iv) to prevent or antagonize the behavioral consequences of ethanol withdrawal in rats (Kostowski et al., 1993); (v) to antagonize ethanol- stimulated DA release in the nucleus accumbens (Car- boni et al., 1989; see also below); and (vi) to reduce the desire to drink and prevent withdrawal in human subjects (Fozard, 1992). Taken together, these data suggest that 5-HT3 receptor antagonists may bring about their inhibitory effect on voluntary ethanol consumption by reducing both ethanol's rewarding and intoxicating properties. Nevertheless, once again, the degree of specificity of the actions of these drugs on

Invited Review 323

ethanol consumption is questionable, with many inconsistencies from one study to the other with regard to the effects of 5-HT3 antagonists on general consummatory behavior (Sellers et al., 1992).

The 5-HTIDt~ receptor (5-HT m in rodents ; see Hum- phrey et aL, 1993) is probably another subtype to be implicated in the phenomenon of alcoholism. Indeed, following the observation by George et al. (1990) of an ethanol-like behavioral response in abstinent alcoholics upon administration of the non-selective 5- HT agonist mCPP (m-chlorophenylpiperazine), which acts at 5-HTID#, 5-HT2A and 5-HT2c receptors, Grant and Colombo (1993) noted the ability of the non-selective 5-HT agonist TFMPP (m-trifluoro- methyl-phenylpiperazine), which has a similar affinity for the 5-HTID~, 5-HT~D~, 5-HT~A, and 5-HT2c receptors, to substitute for the discriminative stimulus effects of ethanol; as investigations of the discriminative stimulus effects of TFMPP have min- imized a role for 5-HT~A and 5-HT2c receptors, a 5- HTIDa mechanism has been suggested for the mediation of this effect of ethanol. Nevertheless, further investigations with more selective ligands of 5- HTID~.qDt3 receptors are needed to actually assess the involvement of these receptors in alcohol abuse and alcoholism.

The 5-HT2 receptor family has also, of late, become the focus of attention. Indeed, decreases in alcohol consumption have been observed with 5-HT2A/2C agonists such as DOI and MK212, although with a concomitant decrease in food intake (Sellers et al., 1992). According to certain studies, the 5-HT2A/2c antagonist ritanserin attenuates alcohol consumption in rats with a developed preference for ethanol without affecting other consummatory behaviors (Panocka and Massi, 1992; Meert, 1993) and in chronic alcoholics (Monti and Alterwain, 1991). However, these findings were not confirmed by Myers and Lank- ford (1993), who claimed that the former results were most likely due to the fact that a low concentration (3 %) ethanol solution, rather than the rats' maximally preferred concentration, was used in previous studies (Panocka and Massi, 1992 ; Meert, 1993). Long-term treatment with the 5-HT2 antagonist amperozide (which also possesses some DA-releasing properties), on the other hand, was found to irreversibly suppress ethanol drinking, without producing any apparent side effects, in rats in which alcohol preference was pharmacologically induced with the aldehyde dehydrogenase inhibitor cyanamide (Myers et al., 1993a). Similar results were obtained in P rats, while no effect was observed on their NP counterparts, pre-

sumably due to their initial low level of alcohol consumption (Myers et al., 1993b). A recent study tested a promising new drug, FG 5893, a "novel second- generation amperozide-like drug", which combines 5- HT1A agonist and 5-HT2 antagonist properties (Singh et al., 1993). Administration of this compound resulted in a significant, long-lasting reduction in intake of a maximally preferred concentration of ethanol in rats with cyanamide-induced alcohol preference, while producing no change in body weight, food intake or total fluid consumption. These results thus corroborate previous evidence implicating 5- HT~A and 5-HT2 receptor subtypes in the addictive property of alcohol. Given these promising initial results, further animal (and possibly clinical) studies with drugs sharing a similar mechanism of action are warranted.

Serotonin-dopamine interactions

The involvement of the mesolimbic DA system in mechanisms of positive reinforcement is well documented (see above). In vivo microdialysis studies in the nucleus accumbens have shown that ethanol administration (by i.p. injection or by local application through the microdialysis probe) will preferentially stimulate DA (Imperato and Di Chiara, 1986; Yoshimoto et aL, 1991) but also 5-HT (Yoshi- moto et al., 1991) release in this area and 5-HT release in the frontal cortex of sP rats (Portas et al., 1994). Electrophysiological data agree with the latter observations, since ethanol concentrations corresponding to those attained during moderate alcohol intoxication in vivo enhance the firing rate of dorsal raphe nucleus neurons (Chu and Keenan, 1987). Several observations support the existence of functional interactions between 5-HT and DA neurotransmission, notably within the context of the central reinforcing effect of ethanol. In fact, Herv6 et al. (1987) have shown that 5-HT neurons in anterior raphe nuclei extend processes which make synaptic contacts on DA cells located in the VTA and which project into the nucleus accumbens. Furthermore, microinjections of 5-HT into the VTA (Guan and McBride, 1989) or of excitatory agents directly into the dorsal raphe nucleus (Yoshimoto and McBride, 1992) are capable of enhancing the release of DA in the nucleus accumbens. One line of evidence indicates that the mechanism of this excitatory action of 5-HT may be via the 5-HT3 receptor, whose stimulation by agonists increases DA release in the nucleus accumbens (Jiang et al., 1990). Indeed, systemic administration (Car- boni et al., 1989) or local application through a microdialysis probe (Yoshimoto et al., 1991) of 5-HT3

324 Invited Review

antagonists has been shown to attenuate the stimulatory effects of ethanol (i.p. or local application) on DA release in the nucleus accumbens. This may be the mechanism by which drugs which antagonize 5-HT~ receptor function act to produce their observed behavioral effects on ethanol preference (see above).

MONOAMINE OXIDASE

In the early attempts to elucidate the neurobiological bases of alcohol intoxication, particular attention was paid to the main enzymatic pathway responsible for the degradation of the catecholamines and serotonin, that catalyzed by monoamine oxidase (MAO, EC 1.4.3.4). The brain is known to contain both of the isozyme forms of the enzyme, MAO-A and MAO-B, whereas platelets contain only the -B'" form. While MAO-A is mainly localized in catecholamine-containing neurons in the brain, the serotonergic neurons of the raphe complex and glial cells contain predominantly the "B'" form ot" the enzyme (Abell et al., 1988).

Observations as to the inhibitory effects of ethanol in vitro Oll the activity of this enzyme were made as early as the 1960's (Maynard and Schenker, 1962). Sub- sequently, Feldstein et al. (1964) demonstrated a decreased urinary recovery of 5-HIAA (the main metabolite of 5-HT, obtained by degradation by MAO) upon ethanol consumption. However, Palaic et al. (1971) found no change in brain MAO activity after either acute or chronic ethanol treatment.

Following the introduction of the estimation of platelet MAO activity in the mid 1960s (Paasonen and Sol- atunturi, 1965), a large number of studies on the connections between platelet MAO activity and alcoholism began to appear in the early 1970s. Because of the accessibility of platelets, the study of MAO activity in humans was made possible, with the hope that platelet MAO activity might reflect MAO-B expression in the CNS (Youdim, 1988). The general consensus is that subjects exhibiting alcohol abuse present lower platelet MAO activity than controls (e.g. Oreland et al., 1981). Schuckit et al. (1982) demonstrated that even nonalcoholic relatives of alcoholics had a reduced platelet MAO activity as compared to controls with no alcoholic relatives.

An in t:itro study of MAO activity in human tissues by Tabakoff et al. (1985) provided evidence that ethanol inhibits MAO-B in platelets, and that it was this form of the enzyme which is also preferentially inhibited by ethanol in the brain. Conversely, the effect of ethanol on the "A" isoform of the enzyme may be different, as Kono et al. (1993) showed that the incubation of cub

tured human placental cells (which contain only MAO- A) with pharmacologically relevant concentrations of ethanol (3(7>70 raM) significantly increased MAO activity.

ACETYLCHOLINE

Chronic ethanol intake is known to provoke a loss of memory and cognitive impairment in man (Lish- man, 1990) and to disrupt memory processes in various animal models (Arendt et al. , 1989; Hodges et

al., 1991 ; Beracochea e t al. , 1992). By virtue of the implication of the cholinergic system in cognition and memory (Drachman, 1977), numerous studies have tbcused on the involvement of acetylcholine (ACh) in ethanol-induced impairment of cognitive functions. It thus appeared that chronic alcoholic subjects with KorsakoWs syndrome, a disease characterized by an irreversible loss of memory, confabulation and dis- orientation (Lishman, 1990), exhibited a loss of cholinergic neurons in the nucleus basalis of Meynert (Arendt et al., 1983). Moreover, the activity of choline acetyltransferase (CHAT), the enzyme for ACh synthesis, was found to be reduced in several brain areas of chronic alcoholics (Antuono et al. , 1980).

The loss of cholinergic neurons observed in chronic alcoholic subjects was replicated by Arendt et al.

(1988) using an animal model after prolonged (12 weeks) ethanol intake. These authors also reported decreases in ACh content and in the activities of both ChAT and acetylcholinesterase (ACHE), the enzyme which degrades ACh, in various brain areas of the rats which had been exposed to ethanol for 12 weeks. These results were later confirmed by another study, in which 28 weeks of ethanol intake provoked profound decreases in ChAT and AChE activities and ACh levels in various brain areas of alcoholized rats, as well as decreases in ACh synthesis and release (evoked #7 v i tro by K + depolarization), and in high affinity choline uptake (Arendt et al., 1989). Chronic ethanol treatment was also found to decrease the cholinergic facilitation of population spikes in the CAI region of the hippocampus without affecting cholinergic inhibition of field EPSPs, indicating that alcohol appears to selectively disrupt a subset of cholinergic effector systems within hippocampal neurons (Rothberg et al.,

1993). In further support of the idea that chronic ethanol

provokes a depression of brain cholinergic activity, an interesting series of experiments demonstrated that grafting of ACh-rich fetal basal forebrain transplants into the cortex and hippocampus of alcoholized rats improved cholinergic and behavioral deficits and

Invited Review 325

memory functions impaired by treatment with ethanol (Arendt et al. , 1989 ; Hodges e t al. 1991). Moreover, cholinomimetic drugs have been shown to ameliorate behavioral performances impaired by chronic ethanol. In particular, physostigmine completely reversed alcohol-induced deficits in T-maze spontaneous alter- nation rates (Beracochea et al. , 1992). Furthermore, performance of alcohol-treated rats in the radial maze was improved by the cholinergic agonists arecoline and nicotine (and disrupted by the antagonists scop- olamine and mecamylamine ; Hodges et al. , 1991).

Chronic ethanol, both in man and in animal models, has also been shown to produce changes in cholinergic receptor binding sites. Hellstr/Sm-Lindahl et al. (1993) noted marked reductions in the total number of muscarinic receptors, as well as m~ and m2 subtypes, in the thalamus of a group of old (>59 yr), but not young (19-57 yr), alcoholics (in post-mortem brain samples), whereas the age-related decrease in cortical muscarinic receptor binding sites did not differ between controls and chronic alcoholics. The same study detected no difference in cortical and thalamic nicotinic receptor binding sites between alcoholics and controls. Other authors also reported losses of muscarinic receptors in various brain areas (Antuono e t al. , 1980), including the frontal cortex, hippocampus and putamen of human alcohol abusers (Freund and Ballinger, 1991). Conversely, Hu e t al. (1993) found that long-term (2 days) treatment of NGI08-15 cells with ethanol increased the binding of the muscarinic acetylcholine receptor antagonist [3H]quinuclidinyl benzilate (which labels total muscarinic binding sites) and Pick et al. (1993) noted that exposure of mouse pups to ethanol increased the density of muscarinic receptors in the hippocampus. In contrast, Rothberg e t al. (1993) failed to find a difference between control and chronically alcoholized rats in muscarinic receptor subtype (m~-ms) densities in the hippocampus. Wahlstr6m and Nordberg (1991) also observed no differences in muscarinic or nicotinic receptor binding in various brain areas between groups of differentially alcoholized rats and controls.

ENDOGENOUS OPIOIDS

There is considerable evidence that the reinforcing effects of ethanol are also mediated, at least in part, by the brain's endogenous opioid systems, and that these systems may contribute to the adaptive neuronal responses provoked by ethanol intoxication. It is known, for example, that a number of the behavioral and pharmacological effects of ethanol, such as hypothermia, euphoria, analgesia and motor activation, as

well as the development of tolerance and dependence, are similar to those produced by opiates (Kalant, 1977). Moreover, the opiate antagonist naloxone has been shown to be able to inhibit the development of dependence to ethanol in mice (Blum e t al. , 1977), while cross-tolerance can develop between ethanol and the opiate agonist morphine (Khanna et al. , 1979). Interestingly, Blum e t al. (1983) found that there is an inverse correlation between ethanol consumption and brain levels of the endogenous opioid peptide Met-enkephalin, and a recent study by Gian- oulakis e t al. (1992) has revealed differences between AA and ANA rats in the hypothalamic mRNA contents of proopiomelanocortin, the precursor of the endogenous opioid//-endorphin, and in the content of/%endorphin-like immunoreactivity in distinct brain areas.

The traditional view of the involvement of endogenous opioids in the voluntary consumption of alcohol is referred to as the opioid deficiency hypothesis (Reid e t al. , 1991), which states that, analogous to what is believed to be the case for serotonergic neurotransmission (see section on Serotonin), alcoholics suffer from a deficiency in central opioidergic neural activity, which is compensated for by the consumption of alcohol. The mechanism for this compensation may be via an alteration of the binding properties of the opiate receptors or of the release and synthesis of the endogenous opioids themselves. Alternatively, by- products of ethanol metabolism, the tetrahydro- isoquinolines and fl-carbolines (condensation products of acetaldehyde with catecholamines and indoleamines, respectively), may mediate ethanol reinforcement through interactions with central endogenous opiate systems (Davis and Walsh, 1970).

Two opioid receptors have been more particularly implicated in alcohol effects, the p and 6 subtypes. An early study by Altshuler et al. (1980) revealed that the blockade of these receptors by naltrexone reduced rhesus monkeys' intravenous self-administration of ethanol, suggesting that opiate receptor blockade had diminished the reinforcing properties of ethanol. Simi- larly, naloxone (Weiss e t al. , 1990; Hyytig and Sin- clair, 1993), naltrexone (Altshuler e t al. , 1980) and the opioid antagonist nalmefene (Hubbell et al. , 1991) reduce rats' preference for ethanol. Furthermore, Froehlich e t al. (1991 ) demonstrated the efficacy of the selective 6-opioid antagonist ICI 174,864 in reducing ethanol consumption in rats, as well as the ability of thiorphan, an enkephalinase inhibitor which has the effect of potentiating activation of the 6-receptor, to increase ethanol intake. However, Hyytig (1993)

326 Invited Review

found that the #-opioid antagonist CTOP suppressed alcohol drinking in AA rats, while the ,5-opioid antagonist ICI 174,864 was without effect. Conversely, low doses of morphine (1 2 mg/kg) increased ethanol preference in rats (Hubbell et al., 1993).

Certain functional consequences of ethanol intake may also be mediated by the opioidergic system, as naloxone has proven effective in attenuating the ethanol withdrawal syndrome (Blum et al., 1977), and ICI 174,864, microinjected into discrete brain regions, has been shown to block ethanol-induced hypothermia and sedation (Widdowson, 1987).

Based on these observations in animal studies, naltrexone has been applied with success in the treatment of alcohol dependence in man (Volpicelli et al., 1992).

It is well accepted that the stimulation of DA release in the nucleus accumbens is a prerequisite for the expression of the rewarding properties of systemically injected morphine (Di Chiara and lmperato, 1988). Such a release is also observed upon microinjection of the endogenous opioid peptide Met-enkephalin into the VTA (Di Chiara and lmperato, 1988). Moreover, chronic morphine treatment has been shown to produce a significant decrease in DA transporter density in the anterior basal forebrain, an area which includes the nucleus accumbens, without producing any effect on binding to the DA transporter in striatal membranes or on binding to the 5-HT transporter in these areas (Simantov, 1993). These results support the data obtained in other studies, which had suggested that opiate reward is dependent upon a dopaminergic substrate (Bozarth and Wise, 1981). In a recent study employing the technique of in vivo microdialysis, Benjamin el al. (1993) found the administration of naltrexone to reverse the ethanol-induced DA release in the nucleus accumbens. Similarly, Acquas et al. (1993) observed an inhibition of ethanol-stimulated (but not cocaine-stimulated) DA release in the nucleus accumbens using naltrindole, a specific antagonist of the (5-receptor subtype. These observations support the findings of a previous in vitro study by Widdowson and Holman (1992), which showed that both naloxone and ICI 174,864 inhibited the increase in DA release induced by the addition of 75 mM ethanol to the incubation medium of rat striatal slices.

Clearly, all these results correspond with the idea that ethanol affects DA neurotransmission through the activation of an opioid intermediary link ending with the stimulation of ~ and/or ll receptors.

One of the mechanisms which can mediate the potentiation by ethanol of the opioidergic modulation of neural reward mechanisms is via adaptive changes in the density or affinity ofopioid receptors. A number

of studies have demonstrated the ability of acute ethanol exposure to selectively inhibit opioid binding to ~%opioid receptors by promoting ligand dissociation (e.g. Charness et al., 1983), whereas long-term ethanol exposure up-regulates 6-opioid receptors in NG 108- 15 cells (Charness et al., 1983) and in rodent brain (Gianoulakis, 1983), and increases 6-opioid receptor gene expression (Charness et al., 1993) in NG 108-15 cells.

OTHER NEUROPEPTIDES

In addition to the endogenous opioids, a number of other neuropeptides have been examined for their involvement in the mechanisms underlying alcoholism and/or the CNS actions of ethanol. Notably, the brain-gut neuropeptides cholecystokinin (CCK) and bombesin have been shown to inhibit intake of alcohol solutions and feeding behaviors in a variety of species (e.g. Kulkosky and Glazner, 1988), including rats selectively bred for ethanol sensitivity (Kulkosky et

al., 1993). The reduction in free choice of ethanol solutions observed in non-deprived animals (Toth et

al.. 1990) suggests that these neuropeptides may function endogenously in the control of the motivation to consume alcohol, as signals of satiation with ethanol (Kulkosky et al., 1989). In addition, there is evidence for the involvement of neurotensin in the effects of ethanol. In particular, a down-regulation of the receptors of this peptide was observed upon chronic administration of ethanol to mice (Campbell and Erwin, 1993). Furthermore, genetic-based differences in the brain levels of this peptide and its receptors have been described in mice bred for differential sensitivity to ethanol (Erwin et al., 1993). A role for the tachykinins in alcohol preference has also been proposed, as selective agonists at the NK3 tachykinin receptors have been shown to selectively inhibit alcohol intake in sP rats (Ciccocioppo et al., 1994).

CONCLUSION

As this review has shown, the CNS effects of ethanol are multifaceted, with diverse actions on several neurotransmitter systems.

When a low dose of alcohol is ingested, the dopa- mineric, serotonergic and noradrenergic systems are stimulated (Engel and Liljequist, 1983). While activation of the dopaminergic system will initiate positive reinforcement mechanisms in the brain's limbic structures, enhancement of noradrenergic neurotransmission, releasing NE particularly in the hypothalamus and midbrain, might be associated with

Invited Review 327

ethanol-induced euphoria and a general excitation of central functions. However, during acute intoxication after intake of a high dose of alcohol, a feeling of psychic and motor inhibition will prevail, characterized by a generally sedated and dysphoric state accompanied by anxiolysis and muscle relaxation; this aspect is presumably mediated by reduction of dopaminergic and noradrenergic transmission on the one hand, and by ethanol-induced enhancement of the binding of GABA to the GABAA receptor complex on the other hand, resulting in a potentiation of GABA's general central depressant actions.

Upon prolonged alcohol consumption, tolerance and physical dependence will develop, rendering neuronal function "normal" in the presence of ethanol and "abnormal" in its absence (Charness et al., 1989). However, potentiation by chronic ethanol of glutamatergic function will enhance the endogenous amino acid's neurotoxic effects, possibly initiating a process leading to delayed neuronal death. Loss of cholinergic neurons, concomitant with a global ethanol-induced inhibition of cholinergic function, may contribute to the well-documented memory-dis- rupting effects of chronic alcohol consumption.

Upon withdrawal of ethanol following a period of chronic consumption, decreased release or hypo- sensitivity of the catecholamine receptors may account for irritability, while post-withdrawal modi- fications in GABAergic function may contribute to a lowering of the threshold for the appearance of withdrawal seizures. These symptoms can be readily reversed by intake of a moderate dose of alcohol, thus improving, for a short period of time, CNS functions.

It is likely that the reinforcing properties of ethanol are mediated mainly by the dopaminergic system. In turn, the ethanol-induced increase in DA release in the nucleus accumbens, which presumably represents the neurobiological substrate for reward, may be modulated by serotonergic and opioidergic neurotransmission. Indeed, the release of DA is facilitated by the activation of 5-HT3 receptors, as blockade of these receptors prevents the DA release observed upon administration of ethanol. Similarly, blockade of/~- and/or ~i-opioid receptors also inhibits the ethanol- stimulated release of DA, suggesting a facilitatory role for the brain's endogenous opioids in the development of ethanol preference.

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Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism

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