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Review
Pharmacological and genetic interventions inserotonin (5-HT)2C receptors to alter drug abuse anddependence processes
Małgorzata Filipa, b,⁎, Umberto Spampinatoc, d, Andrew C. McCrearye, Edmund Przegalińskia
aLaboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences,Krakow, PolandbDepartment of Toxicology, Faculty of Pharmacy, Jagiellonian University, Krakow, PolandcInserm U862, Neurocentre Magendie, Physiopathology of Addiction group, Bordeaux, FrancedUniversity of Bordeaux, Bordeaux, FranceeBrains-On-Line, Groningen, The Netherlands
A R T I C L E I N F O
⁎ Corresponding author at: Laboratory of DrugAcademy of Sciences, Krakow, Poland. Fax: +
Article history:Accepted 15 March 2012Available online 23 March 2012
The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)2C re-ceptors and their relationship to drug dependence. We have focused our discussion onthe impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illus-trated by reference to data using pharmacological and genetic tools. The neurochemicalmechanism of the interaction between 5-HT2C receptors, with focus on the mesocorticolim-bic dopaminergic system, and drugs of abuse (using cocaine as an example) is discussed. Fi-nally, we integrate recent nonclinical and clinical research and information with marketedproducts possessing 5-HT2C receptor binding affinities. Accordingly, available nonclinicaldata and some clinical observations targeting 5-HT2C receptors may offer innovative trans-lational strategies for combating drug dependence.This article is part of a Special Issue entitled: Brain Integration.
Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish48 12 637 45 00.. Filip).nocorticotropic hormone; DA, dopamine; GABA, γ-aminobutyric acid; PFC, prefrontal cortex;ra; VTA, ventral tegmental area
Drug dependence is a chronic and relapsing brain disorder, inwhich compulsive drug-seeking and drug-taking behaviors per-sist, despite negative consequences. Relapse, accompanied bypsychiatric, somatic and vegetative disturbances can be trig-gered, even after long periods of abstinence. Abused drugs in-duce a spectrum of behavioral effects in humans, includingfeelings of pleasure (“high”) and euphoria. A hallmark of abuseddrugs, even having different mechanisms of action, is that theyall impinge and increase dopamine (DA) neurotransmissionwithin themesolimbic circuitry of thebrain (the so-called rewardsystem) (Filip et al., 2010). Although, impairment evoked bydrugs of abuse starts in the brain areas processing reward, thedisruptions target the whole brain and lead to dysfunctions oflearning, executive functions, cognitive awareness and emotion.
In keepingwith the ability of abused drugs to impact DAneu-ronal activity in themammalian brain (Berg et al., 2008), the cen-tral serotonin (5-hydroxytryptamine; 5-HT)2C receptor has beenshown to modulate the neurochemical and behavioral effectsof abused drugs, such as cocaine, and it is currently consideredas a potential target for improved treatment of drug abuse anddependence (Bubar and Cunningham, 2006; Di Giovanni et al.,2006; Di Matteo et al., 2001; Filip et al., 2010; Higgins andFletcher, 2003). The aim of this review is therefore to bringfocus on 5-HT2C receptors and their potential therapeutic rele-vance to drug dependence. We concentrate on the contributionof 5-HT2C receptors inmodulating the effects of different classesof abused drugs that have been tested in behavioral assays, andwhere necessary have drawn on specific examples to illustrateimportant concepts. Additionally, the neurochemical mecha-nism interactions between 5-HT2C receptors and abused drugs(using cocaine as an example) are discussed. The targeting of 5-HT2C receptors may offer innovative translational strategies forcombating drug dependence, andwe briefly discuss recent clini-cal developments, potential development candidates and mar-keted products.
2. Serotonin and 5-HT2C receptors
5-HT receptors have been classified using amino acid sequences,signal transduction mechanisms, pharmacological properties
and functional criteria, and are currently divided into seven re-ceptor families (5-HT1-7). At the present time fourteen receptorsubtypes have been described (Hannon and Hoyer, 2008; Hoyeret al., 2002), along with a variety of splice variants. Among the5-HT2 receptor family three subtypes have been distinguished,including 5-HT2A, 5-HT2B and 5-HT2C receptors, based mainlyon structural (amino acid sequence) and pharmacological differ-ences (Hannon andHoyer, 2008). Here, we restrict our discussionto the 5-HT2C receptor.
2.1. 5-HT2C receptor structure and its cellular effectors
The 5-HT2C receptor was one of the first 5-HT receptors to becloned; its gene is mapped to human chromosome Xq24 andcomprises 458, 459 or 460 amino acids in humans, mice andrats, respectively (Berg et al., 2008; Hannon and Hoyer, 2008).This receptor undergoes post-transcriptional modification,yielding thirty two different mRNAs. Finally, twenty four 5-HT2C receptor proteins result from RNA editing at four or fiveediting sites for adenine deaminases in rodents and humans,respectively. In addition to the multiple editing variants twonon-functional short splice variants also exist (Hannon andHoyer, 2008).
The 5-HT2C receptor is a seven-transmembrane G-protein-coupled receptor, and following activation there is concurrentstimulation of several intracellular pathways. The 5-HT2C re-ceptor contains three intracellular loops with correspondingphosphorylation sites (Müller and Carey, 2006). The main 5-HT2C receptor-coupled intracellular pathway involves phos-pholipase C activation (via Gq/11proteins), followed by thebreakdown of phosphatidylinositol, and leading to the gener-ation of the secondary messengers, inositol triphosphate anddiacylglycerol. Other recognized effectors that directly coupleto 5-HT2C receptors are phospholipase A2, phospholipase D(via Gα13 proteins), extracellular signal-regulated kinase(ERK), G protein-coupled receptor kinase (GRK) and arrestin(for review: Berg et al., 2008).
2.2. 5-HT2C receptor brain localization
A remarkable density of 5-HT2C receptors is present in themammalian choroid plexus, where they mediate the produc-tion of cerebrospinal fluid. The distribution in other central
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nervous system structures (i.e., limbic and subcortical areas,hypothalamus) is much lower. In situ hybridization histo-chemistry has revealed receptor messenger RNA in monkeyand human brains in the choroid plexus, cerebral cortex, hip-pocampus, amygdala, components of the basal ganglia, thesubstantia nigra (SN), the substantia innominata and theventromedial hypothalamus (López-Giménez et al., 2001;Pasqualetti et al., 1999). Autoradiographic studies have identi-fied these receptors in the anterior olfactory nucleus, olfactorytubercle, lateral amygdaloid nucleus, cerebral cortex, nucleusaccumbens (NAC), dorsal striatum, hippocampus, amygdalaand SN (Abramowski et al., 1995; Mengod et al., 1996). Recentdouble-label fluorescence immunochemistry analyses discov-ered 5-HT2C receptor neuronal localization in the rat ventraltegmental area (VTA) (Bubar and Cunningham, 2007).
The widespread distribution of 5-HT2C receptors in thebrain suggests that they may be expressed by neurons withdifferent phenotypes. In fact, data indicate that 5-HT2C recep-tors are localized to neuropeptidergic (enkephalin, substanceP, dynorphin), 5-HT-ergic, DA-ergic neurons, GABA-ergic, cho-linergic and glutamatergic pyramidal neurons (for review seeCarr et al., 2002; Mengod, 2011; Vysokanov et al., 1998), seeSection 3.5.
2.3. 5-HT2C receptor pharmacology
A variety of drugs possess high affinity for 5-HT2C receptors.For the scope of the present manuscript we restrict our de-scription to some of the “classical” and more recently de-scribed relatively selective pharmacological tools used in thedelineation of 5-HT2C receptor function (see Table 1, for thechemical names of these ligands), particularly those used indrug abuse and dependence research. Additionally, we intro-duce 5-HT2C receptor ligands which have already beenmarketed or are undergoing clinical trials.
5-HT2C receptor pharmacological tools can be split intothree categories: agonists (leading to an increase in activationof 5-HT2C receptors), antagonists (which bind 5-HT2C receptorsand antagonize the function of the receptor agonists or in-verse agonists), and inverse agonists which reduce the consti-tutive activity of a receptor leading to a reduced receptorresponse (for review Berg et al., 2006). In pharmacologicalanalyses functional selectivity mediated via differential acti-vation of secondary messenger systems (see below) may alsobe of critical relevance (e.g., Berg et al., 2006).
Historically, the non-selective 5-HT2C receptor ligands firstdescribed were the agonists: DOB, DOI, mCPP, MK 212, TFMPPfollowed shortly after by the description of the non-selectiveantagonist ritanserin (Baumann et al., 2005). Their limitationas research tools remains the general lack of selectivity atthe 5-HT2C receptor, with comparable affinity for the three 5-HT2 receptor subtypes and sometimes, affinity at otherreceptors (see Table 1). Later, Ro 60-0175, Ro 60-0332 andtheir congeners were described, however, they lack 5-HT2C re-ceptor selectivity, but nevertheless are extremely valuable re-search tools (Table 1). The most selective ligands haverecently been synthesized, and display at least 100-fold ormore selectivity for 5-HT2C vs. other 5-HT or other neurotrans-mitter binding sites. These compounds include: CP 809191,lorcaserin, WAY-163909, WAY-161503, vabicaserin and VER-
3323 (Table 1). In the last decade other 5-HT2C receptor ligandssuch as BVT-933 (PRX-00933), trans-PAT and YM-348 havebeen reported, but these drugs either show weak 5-HT2C re-ceptor selectivity (Table 1) or have limited binding and/or lim-ited activity information.
Themost selective 5-HT2C receptor antagonist described todate is RS 102221 (Table 1), and while some functional studiesand behavioral investigations related to drug abuse anddependence were described with this drug (see below), it haslimited use due to poor brain availability (unpublishedauthors' information). However, SB 242084A, was recentlydescribed and is a selective 5-HT2C receptor neutral antagonist(Bromidge et al., 1997; Kennett et al., 1997). The moleculeeffectively crosses the blood–brain barrier and possesses atleast 100-fold selectivity for 5-HT2C receptors vs. other recep-tor binding sites. Other receptor antagonists have beenemployed in pharmacological studies (e.g., SDZ SER-082 orSR 46349B), but these compounds provide limited 5-HT2C re-ceptor selectivity (Table 1). SB-206553 (Kennett et al., 1997)and SB 243213 (Berg et al., 2006) are subclasses of 5-HT2C re-ceptor ligands that behave as inverse agonists, due to thefact that 5-HT2C receptors are constitutively active, althoughSB-243213 does act as a neutral antagonist in vivo (Berg etal., 2006).
A variety of other 5-HT2C receptor ligands remain in pre-clinical development (Table 1; see Lee et al., 2010 for extensivereview). For example, chromane derivatives (e.g., WAY-261240) or heteroarylpiperazines were developed by Pfizer orWyeth. Heteroaryl-fused azepine derivatives from Pfizer,Bayer or Forest and NPS were reported. Allelix have developedpyridooxazepines, and piperazine derivatives were disclosedby Takeda. Roche in-licensed a platform from Vernalis includ-ing azaindolines, indulines, benzylmorpholine and trypt-amine derivatives, which were disclosed in the patentliterature. Athersys Incorporated disclosed ATHX-105, whichappears to have a partial clinical hold imposed by the FDA(2009). The latter company additionally reported diazabicyclo[3.3.0]octane derivatives showing 5-HT2C receptor selectivity.Biovitrium disclosed BVT-933 and the company entered intoa co-licensing agreement with GSK, subsequently enteringphase IIb clinical trials. However, this may now have beendiscontinued (Lee et al., 2010). Astellas has concentrated onfuroindazole and benzazepine derivatives, and developedYM-348 (Lee et al., 2010).
It should not be forgotten that there are clinically approvedantipsychotics (e.g. clozapine and olanzapine) that have rele-vant affinity for 5-HT2C receptors. Other drugs used to treatdepression, such as amitryptaline, clomipramine, mianserin,mirtazapine, nafazodone and trazodone show 5-HT2C receptorefficacy and antagonistic profile (for review Millan, 2005). Thenon-selective agent agomelatine has received marketingauthorization as an antidepressant drug; it is a non-selectiveligand having affinity for melatonin MT1/MT2 receptors and5-HT2C receptors (Ki=708 nM), but with weak 5-HT2C receptorfunctional activity (Kb=870–1230 nM). However, it apparentlypossesses in vivo 5-HT2C receptor antagonist effects (Millanet al., 2003).
5-HT2C receptor agonists, have and continue to receive ex-tensive drug discovery efforts (Jensen et al., 2010), and the dis-covery landscape is much more crowded than the publication
Table 1 – Binding affinities and functional activity of 5-HT2C receptor ligands.
5-HT2C
receptorligand
Chemical name 5-HT2A
Ki (nM)5-HT2B
Ki (nM)5-HT2C
Ki (nM)5-HT2C
Functionalactivity (nM)
AgonistsAL-38022A (S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine 2.2 a 2.0 a 0.51 a 0.30 a
CP-809,101 2-(3-chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine 6.0 b 64 b 1.6 b 0.11 b
DOI 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane 50 c 39 c 15 c 0.87 a
VER-3323 (S)-2-(6-bromo-2,3-dihydro-indol-1-yl)-1-methyl-ethylamine 355 f 30 f 5.6 f –WAY-161503 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-
Table showing relevant 5-HT2C receptor agonists, antagonists and inverse agonists, their receptor binding affinities (Ki) at 5-HT2A, 5-HT2B and 5-HT2C receptors. Functional activity at 5-HT2C receptors is also shown.a May et al. (2009).b Siuciak et al. (2007).c Kennett (1998).d Thomsen et al (2008).e Martin et al. (1998).f Knight et al. (2004).g Cussac et al. (2002).h Booth et al. (2009).i Dunlop et al. (2011).j Rosenzweig-Lipson et al. (2006).k Dunlop et al. (2005).l Dekeyne et al. (2008).m Bonhaus et al. (1997).n Bromidge et al.(1997).o Kennett et al.(1997).p Rinaldi-Carmona et al.(1992).q Nozulak et al. (1995).r Kennett et al. (1996).s Wood et al. (2001b).
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literature suggest (Lee et al., 2010). Among 5-HT2C receptor ag-onists, the most clinically advanced is lorcaserin. Arena Phar-maceuticals submitted a new drug application for lorcaserinin December 2009. Since that time clinical data reportedbody weight reduction in obese patients, together with im-provement of glycemic control and blood pressure (for reviewsee Lee et al., 2010). Wyeth (now Pfizer) developed vabicaserinwhich was still in clinical trials for schizophrenia and bipolardisorder (in 2010), but had already been halted for the treat-ment of major depression (Lee et al., 2010). Apart from actionsin psychiatric disorders (Dremencov et al., 2005; Hill andReynolds, 2007; Millan, 2005; Nilsson, 2006; Siuciak et al.,2007), 5-HT2C receptors are also known to be involved in anarray of behavioral functions such as decisionmaking and im-pulsive behavior in animals (Fletcher et al., 2007, 2011;Robinson et al., 2008), which might also impact abuse.
2.4. 5-HT2C receptor functions
Pharmacological or genetic manipulation of 5-HT2C recep-tors leads to several functional effects at the electrophysi-ological, neurochemical, endocrinological or behaviorallevel. Thus, stimulation of 5-HT2C receptors induces neuro-nal depolarization in several brain structures, regulatingthe release of DA, noradrenaline and acetylcholine (DeDeurwaerdère and Spampinato, 1999; Fink and Gothert,2007; Lucas and Spampinato, 2000; Marquis et al., 2007).5-HT2C receptors modulate hypothalamic–pituitary–adrenalaxis function; thus following their stimulation, corticotro-pin releasing hormone, ACTH, oxytocin, prolactin and va-sopressin secretion are all affected (Giorgetti and Tecott,2004; Heisler et al., 2007; Hoyer et al., 2002; Jørgensen,2007; Kimura, et al., 2008). 5-HT2C receptor activationevokes hyperthermia, hypophagia, hypolocomotion, andsexual responses (penile erection). Agonists also elicit adiscriminative stimulus (Giorgetti and Tecott, 2004; Hoyeret al., 2002; Leysen, 2004), have anxiogenic effects, andcontrol pain perception (Heisler et al., 2007; Kayser et al.,2007). Recently it was suggested that 5-HT2C receptor over-activity might contribute to depressive and anxiety symp-toms in some patients; yet be involved in some of thenegative or unwanted effects of antidepressant drugs, par-ticularly selective serotonin reuptake inhibitors (Berg et al.,2006; Cryan and Lucki, 2000). Many researchers suggestthat 5-HT2C receptors control compulsivity and impulsivi-ty, as well as being a key contributor to neurological disor-ders such as Parkinson's and Alzheimer's diseases (Berg etal., 2008; Filip and Bader, 2009).
Studies performed in transgenic mice with a selective dele-tion of 5-HT2C receptors indicated that these animals areobese and hyperphagic, show reduced satiety and have higherinsulin and leptin levels than their wild-type counterparts(Heisler et al., 1998; Nonogaki et al., 1998; Tecott andAbdallah, 2003; Tecott et al., 1995). They also suffer from spon-taneous convulsions and cognitive impairment (Tecott et al.,1995). Importantly, some of these effects (hyperphagic andproconvulsive) are not mimicked by 5-HT2C receptor antago-nists, suggesting that 5-HT2C receptor knock-out animalsmay have some developmental or neuroadaptive phenomena(Leysen, 2004; Tecott et al., 1995).
2.5. 5-HT2C receptor–dopamine interaction: neurochemicaland functional aspects in vivo
During the last decade, a sizable body of evidence has shownthat the central 5-HT2C receptors play amajor role inmodulat-ing the activity of the nigrostriatal and mesocorticolimbicsystem and affect GABAergic and glutamatergic pathways(Alex and Pehek, 2007; Berg et al., 2008). Along with theirdense localization in brain DA-ergic regions (Clemett et al.,2000; Eberle-Wang et al., 1997; Pompeiano et al., 1994),5-HT2C receptors exert tonic and phasic inhibitory controlson DA neuronal function in vivo. This was first demonstratedin electrophysiological studies employing nonselective 5-HT2C
receptor compounds (Prisco et al., 1994), and later confirmedwith several electrophysiological and biochemical studiesusingmore selective 5-HT2C receptor antagonists and agonists(for review see Alex and Pehek, 2007). Thus, the basal firingrate of DA neurons in the SN pars compacta and the VTA aswell as the release of DA at terminals within the striatum, theNAC and the medial prefrontal cortex (PFC), is increased anddecreased by the peripheral administration of 5-HT2C receptorantagonists and agonists, respectively (De Deurwaerdère andSpampinato, 1999, 2001; Di Giovanni et al., 1999, 2002; Gobertet al., 2000). Recently, studies in transgenic mice with geneticdeletion of the 5-HT2C receptor displayed increased activity ofSN pars compacta DA-ergic neurons and elevated basal extra-cellular DA concentrations in the dorsal striatum (Abdallah etal., 2009). 5-HT2C receptors also control DA neurons under acti-vated conditions, by modulating DA neuronal firing (Pierucci etal., 2004; Porras et al., 2002) and DA release (Di Matteo et al.,2004; Hutson et al., 2000; Lucas et al., 2000; Navailles et al.,2004; Porras et al., 2002; Pozzi et al., 2002). Specifically, studieswith drugs stimulating the release of DA through different cel-lular mechanisms (cocaine, amphetamine, morphine, haloper-idol and phencyclidine) have shown that 5-HT2C receptorsexert preferential control on DA exocytosis (Navailles et al.,2004; Willins and Meltzer, 1998), most likely by regulating DAneuronal firing (Navailles et al., 2004).
Mesencephalic regions containing DA cell bodies (VTA andSN) have been proposed as a key site of action for the inhibito-ry control of the mesocorticolimbic and nigrostriatal DA path-ways by 5-HT2C receptors (Abdallah et al., 2009; Di Matteo etal., 2001; Navailles et al., 2004, 2006b). Control of DA neuronalactivity is classically thought to be indirect and to involve in-teractions at a so-called GABA–DA interface (Di Matteo et al.,2001; Navailles et al., 2004), in agreement with the presenceof 5-HT2C receptor transcript and protein in VTA and SNGABA neurons (Bubar and Cunningham, 2007; Eberle-Wanget al., 1997) and with their ability to modulate GABA functionwithin these brain regions (Bankson and Yamamoto, 2004; DiGiovanni et al., 2001; Invernizzi et al., 2007). However, the ab-sence of effect of intra-VTA administered 5-HT2C receptor ag-onists and antagonists on basal DA release in the NAC(Navailles et al., 2006b, 2008) does not support this view, andfurther microiontophoretic studies assessing the influence of5-HT2C agents on DA neuronal firing are necessary to addressthis issue. Furthermore, the finding that DA neurons in theVTA co-express the protein for the 5-HT2C receptor (Bubarand Cunningham, 2007; Ji et al., 2006) raises the possibility ofdirect excitatory control of DA neuronal function. Thus,
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modulatory effects on VTADA neuronal firing and NAC DA re-lease could result from a functional balance betweenboth populations of 5-HT2C receptors located on GABA andDA neurons in the VTA (Navailles et al., 2008).Most, but notall, intracranial microinjection studies have provided evi-dence that 5-HT2C receptors present within DA terminal re-gions are capable of modulating DA neuronal activity, byexerting not only inhibitory but also excitatory controls onDA release. That striatal 5-HT2C receptors exert a facilitatorycontrol of DA release in the rat striatum was first reportedby Lucas and Spampinato (2000), but not confirmed by subse-quent studies (Alex et al., 2005). Accumbal 5-HT2C receptorshave been shown to inhibit (Dremencov et al., 2005), facilitate(Yan, 2000) or not affect (Navailles et al., 2006b, 2008) basal DArelease in the NAC. These 5-HT2C receptors have been shownto exert concentration-dependent excitatory and inhibitoryeffects on activated DA release in the NAC (Navailles et al.,2008). At variance with the accumbens and the dorsal stria-tum, compelling evidence indicates that 5-HT2C receptors lo-calized in the medial PFC do not modulate basal or activatedDA release in this region (Alex et al., 2005; Pehek et al., 2006;Pozzi et al., 2002). However, as in the case of NAC DA release(Navailles et al., 2006b), PFC DA release is sensitive to VTA 5-HT2C receptor inhibitory modulation (Pozzi et al., 2002). Fur-thermore, as previously suggested by behavioral investiga-tions (Filip and Cunningham, 2003), recent neurochemicalstudies have shown that medial PFC 5-HT2C receptors exert apositive modulation on activated DA release in the NAC. In-deed, intra-PFC administration of 5-HT2C receptor agonists(Ro 60-0175) and antagonists (SB 242084, SB 243213) has beenshown to increase and decrease, respectively, the release ofDA induced by cocaine or morphine in the NAC (Leggio et al.,2009a, b). Of note, as previously observed in the VTA and theNAC (Navailles et al., 2006b, 2008), blockade of medial PFC 5-HT2C receptors has no influence on basal DA outflow in theNAC, a finding which likely reflects the existence of a low en-dogenous 5-HT tone at medial PFC 5-HT2C receptors (Leggio etal., 2009a, b). In agreement with these results, basal locomotoractivity, a response typically related to increased NAC DArelease (Dunnett and Robbins, 1992), is unaltered by 5-HT2C
receptor blockade in either brain regions (Filip andCunningham, 2002, 2003; Fletcher et al., 2004; McMahon etal., 2001). These findings together emphasize that, at differ-ence with 5-HT2C receptors located in subcortical regions(Navailles et al., 2006b), medial PFC 5-HT2C receptors have noinfluence on NAC DA outflow in resting conditions, but afforda facilitatory control on NAC DA release only under activatedconditions.
Taken together the studies discussed above indicate anoverall inhibitory control of central 5-HT2C receptors on DAascending pathways. This may be considered as a compositeresponse involving functional balances between excitatoryand inhibitory inputs to DA neurons related to different 5-HT2C receptor populations located within multiple brain DAareas (Leggio et al., 2009a, b; Navailles et al., 2008). Althoughthe neuronal circuits underlying the effects remain to be de-termined (Filip and Cunningham, 2003; Leggio et al., 2009a;Navailles et al., 2008), 5-HT2C receptor-dependent control ofDA release in DA terminal regions, in keeping with the expres-sion of 5-HT2C receptors on GABA cells (Eberle-Wang et al.,
1997; Liu et al., 2007) and glutamate pyramidal neurons (Carret al., 2002; Vysokanov et al., 1998), may involve local GABAcircuits and/or negative feedback loops to the VTA and theSN, as well as polysynaptic circuits including glutamate path-ways relying the PFC to the VTA and the NAC (Leggio et al.,2009a; Sesack et al., 2003).
A major step-forward in understanding the functional roleof the 5-HT2C receptor has come from microdialysis studiesshowing that 5-HT2C constitutive receptor activity participatesin the tonic inhibitory control of DA ascending pathways invivo (De Deurwaerdère et al., 2004). In agreement with thepharmacological characteristics of inverse agonist activity(Aloyo et al., 2009; Berg et al., 2005) and consistent with invitro studies (Berg et al., 2006; Chanrion et al., 2008; DeDeurwaerdère et al., 2004), it has been shown that the pur-ported 5-HT2C receptor antagonist SB 206553, behaves in vivoas an inverse agonist at 5-HT2C receptors (Berg et al., 2006;De Deurwaerdère et al., 2004; Leggio et al., 2009b; Navailles etal., 2006a). Indeed, SB 206553-stimulated DA release is insensi-tive to the decrease in 5-HT terminal activity induced byeither intra-raphe injections of 5,7-dihydroxytryptamine neu-rotoxin, or by peripheral administration of the 5-HT1A recep-tor agonist 8-OH-DPAT (De Deurwaerdère et al., 2004). Also,the 5-HT2C receptor antagonists SB 242084 and SB 243213 pre-vent the increase in striatal and NAC DA release induced by SB206553 and reverses the decrease in DA release produced bythe 5-HT2C receptor agonist Ro 60-0175 in both brain regions(Berg et al., 2006; De Deurwaerdère et al., 2004). Together,these findings indicate that the effect of SB 206553 on in vivoDA release is independent of the changes in extracellularlevels of 5-HT, and therefore likely related to its inverse ago-nist properties at 5-HT2C receptors to silence their level of con-stitutive activity in vivo.
Of note, intracranialmicroinjection studies have also shownthat the control exerted by 5-HT2C constitutive receptor activityon DA neurons occurs in a brain region-dependentmanner andthat the NACmay represent a primary site of action for the reg-ulatory effects of constitutive receptor activity on the basal ac-tivity of the mesoaccumbens DA pathway (Leggio et al., 2009b;Navailles et al., 2006b). Interestingly, it has been suggested(Navailles et al., 2006b), that the region-dependent effect ofthe inverse agonist SB 206553 could be related to differentlevels of 5-HT2C receptor constitutive activity in the VTA andthe NAC, resulting from pre-RNA editing of the 5-HT2C receptor.This may represent a mechanism which generates receptorpopulations with different levels of constitutive activity(Werry et al., 2008). However, a recent study has reported that5-HT2C receptor mRNA editing is significantly higher in theNAC compared with both the medial PFC and the VTA, therebyfavoring the presence of a 5-HT2C receptor population with at-tenuated constitutive activity in the NAC (Dracheva et al.,2009). Nevertheless, as discussed elsewhere (Dracheva et al.,2009), the ultimate functional impact of the receptor (includingthe level of constitutive activity) could not be unambiguouslypredicted by the pattern of 5-HT2C receptors alone, and factorsother than mRNA editing must be considered (mRNA expres-sion level, cellular localization and the resulting impact on dif-ferent neuronal circuits, intracellular versus cell surfacelocalization etc.). These results add a further level of complexi-ty in understanding the interactions between 5-HT2C receptors
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and DA neuronal activity in vivo. To summarize, activated NACDA outflow undergoes opposite excitatory and inhibitory con-trols involving 5-HT2C receptors localized to the medial PFCand to subcortical regions (the NAC and VTA), respectively(Leggio et al., 2009a, 2009b; Navailles et al., 2008).Conversely,basal DA outflow undergoes unidirectional tonic and phasic in-hibitory controls involving 5-HT2C receptors located within theNAC and the VTA (Leggio et al., 2009b; Navailles et al., 2006b).Finally, whereas the NAC represents a primary action site forthe inhibitory effect of the constitutive activity of 5-HT2C recep-tors on basal DA outflow (Navailles et al., 2006b), the constitu-tive activity of medial PFC 5-HT2C receptors intervenes merelyin the facilitatory control of activated DA outflow (Leggio etal., 2009b).
In conclusion, the findings reported, provide insight intothe dominant role of the 5-HT2C receptor in regulating theneurochemistry of ascending DA-ergic circuitry. The 5-HT2C
receptor appears to possess the unique ability to regulate DArelease by combined actions involving the effects of endoge-nous 5-HT and constitutive receptor activity at different 5-HT2C receptor populations present in multiple brain regions.However, the functional significance of constitutive 5-HT2C re-ceptor activity in pathological conditions depending uponmesolimbic DA dysfunction, such as depression, schizophre-nia, Parkinson's disease or drug abuse and dependence(Bubar and Cunningham, 2006; Giorgetti and Tecott, 2004;Meltzer et al., 2003; Millan, 2005; Schapira et al., 2006; Woodet al., 2001a), remains unclear, and further studies are neededto address this issue.
3. 5-HT2C receptors and drugs of abuse in pre-clinical research
Illegal (e.g., psychostimulants, opioids, cannabinoids) andlegal (alcohol, nicotine) drugs of abuse create a complex be-havioral pattern composed of drug intake, withdrawal,seeking and relapse. In laboratory animals addictive drugsproduce several behavioral responses that partly resemblesome of the symptoms seen in humans (acute or chronic psy-chomotor stimulation, subjective effects, rewarding/reinfor-cing properties and relapse). However, the most frequentlyused animal models or screening tests in drug abuse and de-pendence research include: drugs of abuse-evoked locomotorhyperactivity, conditioned locomotion, sensitization, drug-discrimination, reward and reinstatement of seeking behav-ior. While some of these paradigms may not recapitulatehuman abuse and dependence they have been and remainhighly valuable tools for delineating the interaction of phar-macological targets with abused drugs.
3.1. Drugs of abuse-evoked acute locomotor hyperactivation
The acute enhancement of locomotor activity in animals fol-lowing injection with abused drugs in rodents and the expres-sion of this most basic preclinical behavioral outcome provideimportant information on the potential pharmacologicalproperties of these drugs. This behavior appears highly de-pendent on stimulation of the mesoaccumbal DA-ergic, or
reward, pathway from the VTA to the NAC (e.g., Filip andSiwanowicz, 2001; Hedou et al., 1999; Heidbreder et al., 1999).
An early report with the 5-HT2C/2B inverse agonist SB206553 indicated that acute pretreatment with this drug al-tered hyperactivity induced by cocaine bidirectionally whichwas dependent on the dose of SB 206653 (McCreary andCunningham, 1999). Further studies revealed a putative inhib-itory role of 5-HT2C on the modulation locomotor effects of co-caine (Table 2). Thus, the 5-HT2C receptor agonists MK 212(Filip et al., 2004; Neisewander and Acosta, 2007) or Ro 60-0175 (Grottick et al., 2000) significantly attenuated acutecocaine-evoked hyperactivity, while the 5-HT2C receptor an-tagonists SDZ SER-082 (Filip et al., 2004) or SB 242084(Fletcher et al., 2002, 2006) potentiated the locomotor stimu-lant effect of cocaine. In line with enhancement seen follow-ing 5-HT2C receptor antagonists, mutant mice devoid of 5-HT2C receptors display increased sensitivity to the locomotorstimulant effects of cocaine (Rocha et al., 2002).
The bidirectional scenario related to 5-HT2C receptors–cocaine interaction was observed following ligand infusionsinto the rat brain (Table 2). Thus, the inhibitory effect oncocaine hyperactivity was mimicked following microinjec-tions of 5-HT2C receptor agonists into the VTA (Ro 60-0175,Fletcher et al., 2004) or into the PFC (MK 212; Filip andCunningham, 2003) while intra-NAC infusions of MK 212or Ro 60-0175 resulted in an enhancement of cocaine loco-motion (Filip and Cunningham, 2002). Pharmacologicalblockade of 5-HT2C receptors by cortical microinjections ofRS 102221 evoked increases (Filip and Cunningham, 2003)while intra-NAc infusions attenuated the hyperactivity tosystemic cocaine (McMahon et al., 2001). However, thereare also reports showing no alteration of cocaine hyperac-tivity by microinjection of RS 102221 into the VTA(McMahon et al., 2001) or by infusions of SB 242084 intothe NAC (Zayara et al., 2011). Together, these findings dem-onstrate that the behavioral effect of cocaine is generatedby activation of 5-HT2C receptors by multiple componentsof the mesocorticoaccumbens DA pathways, and that dif-ferences in the behavioral outcome following systemiccocaine administration may impact different central popu-lations of 5-HT2C receptors(see Sections 3.4 and 4).
With respect to 5-HT2C receptor control over locomotor ef-fects of amphetamines in rodents, it was reported that theselective 5-HT2C receptor agonist WAY-163909 reduced am-phetamine (Marquis et al., 2007)- or methamphetamine(Steed et al., 2011)-induced locomotor activity. However, thesame inhibitory effects were observed with the antagonistRS 102221 when tested for effects onMDMA-induced hyperloco-motion (Conductier et al., 2005). Other authors describedenhancement (Fletcher et al., 2006; Steed et al., 2011), or no effect(Ball and Rebec, 2005) following 5-HT2C receptor antagonism onamphetamine, methamphetamine or MDMA hyperlocomotionin rats (see Table 2).
Similarly, nicotine hyperactivation in rodents also appearsunder the regulation of 5-HT2C receptors, as the agonists Ro 60-0175 (Grottick et al., 2001; Zaniewska et al., 2009), WAY-163909(Zaniewska et al., 2009) or lorcaserin (Higgins et al., 2012) potent-ly attenuated this action of nicotine. Furthermore, the effects ofRo 60-0175 and WAY-163909 were attenuated by a behaviorallyinactive dose of the 5-HT2C receptor antagonist SB 242084
Table 2 – 5-HT2C receptor function and drug of abuse-evoked hyperlocomotion.
Drug of abuse (dose; route ofadministration)
Species (sex) 5-HT2C receptor ligand (dose-range, routeof administration)/function
Rats W (male) WAY 1663909 (0.75, 1, 1.5 mg/kg; ip) — agonist ↓ Zaniewska et al. (v)
↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar . Effective doses are marked in bold.
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(Grottick et al., 2001; Zaniewska et al., 2009). SB 242084 givenalone augmented nicotine hyperactivation (Fletcher et al.,2006; Zaniewska et al., 2009) as well as locomotor effects tolower doses of morphine (Fletcher et al., 2006; Table 2).
In summary, 5-HT2C receptors are involved in control-ling acute locomotor effects of abused drugs. Specifically,the pharmacological effects of 5-HT2C receptor ligandsfollowing systemic, intra-VTA or intra-PFC injections, en-hanced or attenuated, respectively, acute locomotor effectsof drugs of abuse. Interestingly, in contrast to the 5-HT2C
receptor subpopulation localized in the VTA or PFC,accumbal 5-HT2C receptors mediate opposite behavioralactions when combined with abused substances. It shouldbe stressed that the interaction of 5-HT2C receptor ligandswith abused drugs in locomotor activity studies (as wellas drug discrimination; see Section 2.4) is probably thebest characterized behavioral assay which fits well with neu-rochemical observations (see Sections 2.5 and 4). Together,these findings indicate different function of 5-HT2C receptorpopulations located within multiple brain areas rich in DA(Leggio et al., 2009a, b; Navailles et al., 2008). These effectsmay relate to 5-HT2C receptor (mRNA) editing processes fol-lowed by changes in constitutive activity and ligand re-sponses. Further, effects in this rather rudimentary paradigmprovide extremely important insight into the pharmacologicaleffects of abused drugs.
3.2. Drugs of abuse-evoked conditioned locomotion
Repeated pairings of a test environment with drugs of abuseevoke enhancement of locomotion (so-called conditioned lo-comotion) following exposure to this environment (e.g., Liuand Cunningham, 2006; Michel et al., 2003; Zaniewska et al.,2009). Being a simple conditioning model, devoid of face valid-ity, it was proposed to provide important insight into theneural adaptations that occur during the association of re-peated drug exposure with environment (e.g., DiFranza andWellman, 2005).
The involvement of 5-HT2C receptors in controlling theexpression of cocaine- or nicotine-induced conditioned hy-peractivity has been demonstrated (Table 3). Thus, the
selective 5-HT2C receptor antagonist SB 242084 enhanced,while the agonist MK 212 significantly decreased cocaine-induced conditioned hyperactivity evoked by repeated(7 days) pairing of cocaine with a test chamber followed by a2-day withdrawal (Liu and Cunningham, 2006). Similarly, inrats repeatedly treated with nicotine (5 days) in the experi-mental chambers, the 5-HT2C receptor agonists Ro 60-0175 orWAY 163909 decreased the expression of nicotine-inducedconditioned hyperactivity seen following a 5-day withdrawalfrom repeated nicotine treatment; whereas, SB 242084 was in-active in this model (Zaniewska et al., 2009). Together, thesefindings indicate the potential of 5-HT2C receptor agonists toprevent drug-associated conditioned environmental associa-tions evoked by the presentation of the environmentalstimulus.
3.3. Drugs of abuse-evoked locomotor sensitization
Repeated, intermittent administration of addictive drugs in-duces sensitization to their locomotor effects. Sensitizationhas been described to bear a resemblance to drug addiction.It is a long-lasting phenomenon predicting the addictive prop-erty of a drug combined with forms of neuronal adaptationsthought to resemble those that might be responsible for ad-dictive behaviors (Robinson and Berridge, 1993; Steketee andKalivas, 2011).
The studies into the contribution of 5-HT2C receptor to the de-velopment of locomotor sensitization upon repeated, intermit-tent treatment with abused drugs have shown that 5-HT2C
receptor antagonists (SDZ SER-082, SB 242084) and agonists (MK212, Ro 60-1075, WAY 163909) did not alter the locomotor effectsof challenge dose of the relevant abused drug (Table 4). Two ex-ceptions exist and show blockade of nicotine-induced sensitiza-tion by the 5-HT2C receptor agonist Ro 60-0175 (Grottick et al.,2001) and of amphetamine-induced sensitization by the 5-HT2C
receptor antagonist RS 102221 (Lanteri et al., 2008).In the expression phase of sensitization more unequiv-
ocal results indicate that systemic administration of 5-HT2C receptor agonists reduces the augmented locomotorresponse to the challenge dose of either cocaine ornicotine (Filip et al., 2004; Zaniewska et al., 2010). Thus,
Table 4 – 5-HT2C receptor function and drug of abuse-evoked sensitization.
Drug of abuse (dose; route ofadministration)
Species (sex) 5-HT2C receptor ligand (dose-range, route ofadministration)/function
Rats W (male) WAY 163909 (1.5, 3 mg/kg; ip) — agonist — Zaniewska etal. (2010)
↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar; NAC — nucleus accumbens. Effective doses are marked in bold.
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pharmacological stimulation of 5-HT2C receptors, appearsto protect against neuroplasticity in the rat brain evokedby repeated abused drug administration (Table 4). In con-trast to the systemic 5-HT2C receptor antagonist injec-tions, 5-HT2C receptors localized to the NAC appearessential for the expression of sensitization, as evidencedwith direct microinfusions of SB 242084 prior to cocaine(Zayara et al., 2011) or ethanol challenge (Andrade et al.,2011). Whether agonists, antagonists or even inverse ago-nists of 5-HT2C receptors have therapeutic utility in thetreatment of addiction (in terms of neuroadaptationsafety) is an open question requiring further studies. In-terestingly, repeated treatment with 5-HT2C receptor an-tagonists or agonists (Zaniewska et al., 2010), or withmianserin, an antidepressant drug having high affinityfor 5-HT2C receptors failed to protect against already
developed sensitization to nicotine or ethanol (Ferrazand Boerngen-Lacerda, 2008).
3.4. Drugs of abuse-evoked discrimination
Drugs of abuse produce an interoceptive stimulus that allowsanimals to distinguish the psychoactive drug from its vehiclein a drug discrimination paradigm. In this model, an animalis trained to perform a certain instrumental reaction (e.g.,lever pressing) in response to a conditioned stimulus, signal-ing the availability of a reinforcer (e.g., water in water-deprived animals or food in food-deprived animals). After along phase of training, animals discriminate between thetraining substance and vehicle. To some extent, since thedrugs of abuse are administered intermittently several timesa week, this pattern resembles, the addiction cycle with
Table 5 – 5-HT2C receptor function and drug of abuse-evoked discrimination.
Training drug of abuse(dose; route of administration)
Species (sex) 5-HT2C receptor ligand (dose-range,route of administration)/function
Change References
Substitution studiesCocaine (10 mg/kg; ip) Rats SD (male) RS 102221 (1.5, 5 μg; intra-PFC) — antagonist — Filip and Cunningham (2003)Cocaine (10 mg/kg; ip) Rats W (male) SDZ SER 082 (0.5, 1 mg/kg; ip) — antagonist — Filip et al. (2006)Cocaine (10 mg/kg; ip) Rats SD (male) MK 212 (0.25, 0.5, 1 mg/kg) — agonist — Callahan and Cunningham,
Ethanol (1000 mg/kg; ip) Rats W (male) SB 206553 (1 mg/kg; ip) — antagonist — Maurel et al. (1998)
↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar; NAC — nucleus accumbens, PFC — prefrontal cortex. Effective doses are marked in bold.
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alternating phases of maintenance, reinstatement of drugabuse and exposure to secondary conditioners. In the drugdiscrimination model, examination of a drug other than thetraining substance enables the determination of its ability toelicit the same, or at least closely similar interoceptive cueas the training drug. In the substitution tests, compoundsare tested to see if they “mimic” the effects of the training sub-stance, or if compounds alter the discriminability of the train-ing drug in combined treatments (i.e. augmentation orantagonist tests).
Several pharmacological analyses indicate that 5-HT2C re-ceptors affect the expression of the subjective effects ofabused drugs (Table 5). The first report showed that the 5-HT2C/2B receptor agonist MK 212 did not substitute for cocaine,while given in combination with cocaine it partially antago-nized its discriminative stimulus effects in rats (Callahanand Cunningham, 1995). In direct contrast to MK 212, the 5-HT2C/2B receptor antagonist SDZ SER-082 when given in com-bination with cocaine shifted the dose–response curve for
cocaine to the left while in substitution studies no generaliza-tion for cocaine was seen (Filip et al., 2006).
Interestingly, substitution tests in rats trained to dis-criminate nicotine from vehicle showed that 5-HT2C recep-tor ligands, including the selective receptor agonists Ro60-0175 or WAY 163909 and the selective antagonist SB242084, showed no generalization to the nicotine cue. Incombination studies, fixed doses of SB 242084 did not alterthe dose–response curve of nicotine, while Ro 60-0175 andWAY 163909 attenuated the discriminative stimulus effectsof nicotine, increasing its ED50 values for nicotine(Zaniewska et al., 2007). Moreover, findings from anotherlaboratory showed that MK 212 attenuated the nicotinecue (Batman et al., 2005), but only partially (reduction by40% only), in contrast to Ro 60-0175 and WAY 163909(Quarta et al., 2007; Zaniewska et al., 2007).
There are also animal data indicating that 5-HT2C receptorsmay be involved in the ethanol cue. Thus, the mixed 5-HT2C/1B
receptor agonist mCPP completely generalized to the ethanol
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cue in rats (Maurel et al., 1998). These effects appeared to beunder the control of 5-HT2C receptors since combination stud-ies demonstrated that the 5-HT2C receptor antagonist SB206553 completely blocked effects of mCPP.
Table 6 – 5-HT2C receptor function and drug of abuse-evokpreference procedures.
Drug of abuse (training dose;route of administration;
Conditioned place preferenceCocaine (20 mg/kg, ip) c Rats W (male) SB 242084 (Cocaine (20 mg/kg, ip) d Rats W (male) SB 242084 (Cocaine (20 mg/kg, ip) e Rats W (male) SB 242084 (Nicotine (0.6 mg/kg; sc) d Rats SD (male) WAY 16150THC (0.3 mg/kg; ip) d Rats W (male) Ro 60-0175
↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar; PFC — prefrontal cortex, VTA — vevariable ratio . Effective doses are marked in bold.a Cocaine dose-range (0.625–0.125 mg/kg/infusion).b Effect significantly attenuated by the pretreatment with SB 242084 (0.5c Development phase.d Expression phase.e Recall phase.
The pharmacological analyses discussed above thereforedirectly indicate that tonic stimulation of 5-HT2C receptors isnot required for subjective effects of drugs of abuse belongingto different classes, however pharmacological stimulation of
ed reward in self-administration and conditioned place
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5-HT2C receptors appears to have inhibitory influence on thecocaine, ethanol and nicotine interceptive cues.
Microinjection studies also demonstrated in rats implantedwith bilateral cannulae aimed at the PFC thatMK 212 attenuat-ed the stimulus effects of cocaine, while the antagonist RS102221 enhanced the recognition of cocaine cue (Filip andCunningham, 2003). It has also been reported that 5-HT2C re-ceptor stimulation or blockade in the rat PFC did not mimiccocaine-lever responding following injections of the receptorligands alone. These findings strongly suggest that local stim-ulation of 5-HT2C receptors in the PFC reduces the recognitionof the stimulus effects of cocaine. In direct opposition to thefunction of 5-HT2C receptors localized in the PFC, bilateralintra-NAC microinfusion of MK 212 or Ro 60-0175 evoked 37–48% cocaine-lever responding, and produced a leftward shiftin the cocaine dose–response cue. Moreover, intra-NAC infu-sion of RS 102221 attenuated the stimulus effects of cocaine(Filip and Cunningham, 2002). In conclusion, these results,bearing a remarkable similarity to acute locomotor activationassays (see Section 2.1), indicate that 5-HT2C receptors local-ized in several brain areas possess different modalities inmodulating the cocaine discriminative stimulus in rats.
3.5. Drugs of abuse-evoked reward
Rewarding properties are known to be responsible for theinitiation of the addictive process and are most frequentlystudied in self-administration paradigms. In this model,based on the positive reinforcement of instrumentalresponding; the reaction of an animal (e.g., lever pressing)is rewarded by a dose of the drug (e.g., administrated via in-travenous route). Drug-induced reinforcement is easily quan-tified by measuring the number of drug injections, and theresponse rate to the drug-associated lever under a fixedratio; decrease in responding is usually interpreted as an en-hancement of the reinforcing properties of a drug. However,correct interpretation requires an evaluation across a rangeof self-administered doses in order to assess shifts in dose–response functions. The implementation of a progressiveratio, with a decrease in responding indicates an attenuationof rewarding and motivational effects of a drug, is oftenused. Another valid procedure for the investigation of the re-warding properties of drugs of abuse is the conditioned placepreference in which an animal is trained for several sessionsto associate the injection of an abused drug or vehicle withdifferent environmental cues (color, odor, surface structureetc.). It is important to mention that place-conditioning pro-cedures and self-administration paradigms differ in theirdegree of construct validity because they study different as-pects of reward; i.e., place-conditioning procedures indirectlyevaluate the acute rewarding properties of a drug, whereasself-administration procedures directly determine the rein-forcing properties of a drug. The third valid procedure forthe investigation of the rewarding properties of drugs ofabuse is electrical self-stimulation, whereby animals aretrained to press a lever to obtain impulses delivered by astimulator to an electrode implanted in a specific brainstructure (e.g., medial forebrain bundle or hypothalamus).In this latter model drugs of abuse lower the self-stimulation threshold.
Literature indicates that pharmacological blockade of 5-HT2C receptor sites with the selective antagonist SB 242084under fixed ratio schedules gave rise to a significant increasein responses at the lowest, but not highest, doses of cocaine(Cunningham et al., 2011; Fletcher et al., 2002) as well as en-hancing both the development and expression of cocaine con-ditioned place preference (Capriles et al., 2011) in rats(Table 6). Interestingly, the potentiating effects of SB 242084was a long-lasting phenomenon (seen 30 days after the lastconditioning session), and was dependent on the behavioralphenotype of the rat (effects were more evident in so-calledlower-responder animals) (Capriles et al., 2011). In the caseof ethanol reward, there was no differentiation in SB 242082-induced enhancement between high and low ethanol drink-ing rats (Tomkins et al., 2002). These data fit very well withstudies in mice with constitutive genetic deletion of 5-HT2C
receptors; receptor knock-out mice showed elevation of thelevels of lever pressing for cocaine injections in an intrave-nous operant self-administration model under a progressiveratio schedule of reinforcement, indicating that the drugis more reinforcing in these animals (Rocha et al., 2002). The5-HT2C receptor antagonist, SDZ SER-082, did not alter theresponse of rats maintained under a fixed ratio schedule ofreinforcement towards cocaine (Filip, 2005), however, thelack of 5-HT2C receptor selectivity and a high affinity andefficacy at 5-HT2B receptors (Table 1) may account for itsnegative effect.
In direct contrast to genetic or pharmacological antago-nism, the 5-HT2C receptor agonist Ro 60-0175 reduced cocaineself-administration in rats maintained on fixed ratio and pro-gressive ratio reinforcement schedules (Fletcher et al., 2008;Grottick et al., 2000) (Table 6), supporting the conclusion thatpharmacological stimulation of 5-HT2C receptors inhibits therewarding and/or motivational properties of cocaine. Inother studies, Ro 60-0175 and lorcaserin potently reduced nic-otine self-administration (Fletcher et al., 2012; Grottick et al.,2001; Levin et al., 2011) while Ro 60-0175 attenuated motiva-tional responding for ethanol maintained under fixed ratioschedule of reinforcement (Tomkins et al., 2002). Using condi-tioned place preference procedures, Ro 60-0175 exhibited in-hibitory actions when tested against tetrahydrocannabinol(THC)-induced reward (Ji et al., 2006), while WAY 161503, a se-lective 5-HT2C receptor agonist, did not significantly alternicotine-induced context of place conditioning (Hayes et al.,2009). The latter observations confirm a pivotal role of 5-HT2C receptors on different types of reinforcers (cocaine, nico-tine, ethanol, THC). Moreover, it was established that the in-hibitory effects of 5-HT2C receptor agonists toward themotivational actions of abused drugs did not exhibit toler-ance, as exemplified during 8 or 10 day repeated administra-tion with Ro 60-0175 (Fletcher et al., 2008) or lorcaserin(Levin et al., 2011). Brain microinjection studies revealed thatintra-VTA localized receptors are involved in the interactionof 5-HT2C receptors with cocaine as local injections of Ro 60-0175 reduced cocaine-maintained reinforcement under fixedand progressive ratios (Fletcher et al., 2004). These inhibitoryeffects following MK 212 microinjections were not seen inthe PFC (Pentkowski et al., 2010; Table 6). Recently, it wasfound that 5-HT2C receptors exert a modulatory role in VTAintracranial self-stimulation (ICSS) as systemic administration
Table 7 – 5-HT2C receptor function and changes in drug of abuse-evoked reward in ICSS procedures.
ICSS behavior (area withelectrode implantation)
Drug of abuse (training dose;route of administration)
Species(sex)
5-HT2C receptor ligand (dose-range,route of administration)/function
Change References
VTA — Rats SD(male)
SB 242084 (1 mg/kg; ip) –antagonist — Hayes et al.(2009)
VTA — Rats SD(male)
WAY 161503 (0.3, 0.6, 1mg/kg; sc)— agonist ↓ Hayes et al.(2009)
WAY 161503 (0.15, 0.3 μg; intra-NAC shell)— agonist
↓ Katsidoni etal. (2011)
LH Cocaine (5 mg/kg; ip) Rats SD(male)
WAY 161503 (0.15, 0.3 μg; intra-NAC core)— agonist
↓ Katsidoni etal. (2011)
LH Cocaine (5 mg/kg; ip) Rats SD(male)
WAY 161503 (0.15, 0.3 μg; intra-PFC) —agonist
↓ Katsidoni etal. (2011)
LH Cocaine (5 mg/kg; ip) Rats SD(male)
WAY 161503 (0.15, 0.3 μg; intra-VTA) —agonist
— Katsidoni etal. (2011)
↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar; LH — lateral hypothalamus, NAC — nucleus accumbens, PFC — prefrontal cortex, VTA — ventral tegmentalarea,. Effective doses are marked in bold.
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of the 5-HT2C receptor agonist WAY 161503 significantly in-creased rate-frequency thresholds; the 5-HT2C antagonist SB242084 had no effect in this model (Hayes et al., 2009) and theNAC was excluded as a possible locus of effect (Table 7). Morerecently Katsidoni et al. (2011) confirmed that 5-HT2C receptoractivation with the selective agonist WAY 161503 plays an in-hibitory role in the ICSS behavior evoked by an electrode stim-ulation at the level of the lateral hypothalamus while theantagonist SB 242084 did not influence the ICSS threshold. In-terestingly,WAY 161503, at a dose that by itself was ineffectiveto alter brain stimulation reward, counteracted the reward-facilitating effects of cocaine whereas SB 242084 synergizedwith cocaine and decreased the ICSS threshold. Moreover, byusing intracranial injections of WAY 161503 these authorsestablished that 5-HT2C receptors localized to the NAC sub-areas and the PFC (but not the VTA) were critically involvedfor the 5-HTmodulation of the reward facilitating effects of co-caine (Table 7).
3.6. Drugs of abuse-evoked reinstatement of drug seeking
The most problematic feature of drug dependence therapy isrelapse prevention. This phase of addiction can be modeledin animal studies via measures of reinstated drug-seeking inanimals extinguished from drug self-administration training(for review, Steketee and Kalivas, 2011). In fact, animals thatare extinguished from self-administration training readilyrelapse(e.g., restore operant responding on the lever previous-ly associated with self-administered of abused drug) due todrug priming, conditioned cue or stress or a combination ofsuch parameters.
Data indicate that 5-HT2C receptor blockade with SB 242084or SDZ SER-082 failed to alter cocaine priming-induced rein-statement (Table 8; Burmeister et al., 2004; Filip, 2005;Neisewander and Acosta, 2007; see also Fletcher et al., 2002), in-dicating that 5-HT2C receptors do not control cocaine relapse. Onthe other hand, 5-HT2C receptor activation “weakens” cocainepriming, as seen following pretreatment with MK 212 (Table 8;Neisewander and Acosta, 2007) or Ro 60-0175 (Grottick et al.,2000). Moreover, direct brain microinfusions of 5-HT2C receptorligands revealed that the stimulation of receptors localized inthe medial PFC attenuates the incentive motivational effectsproduced by sampling cocaine (Pentkowski et al., 2010).
Response-contingent presentations of the cocaine-associated cues or a pharmacological stressor (yohimbine)evoked reinstatement of extinguished cocaine-seeking,and this behavior was attenuated by systemic or intra-PFCinjections with the 5-HT2C receptor agonists MK 212 or Ro60-0175 (Table 8; Burbassi and Cervo, 2008; Fletcher et al.,2008; Neisewander and Acosta, 2007; Pentkowski et al.,2010), while 5-HT2C receptor antagonists were inactive inthis model (Table 8; Burbassi and Cervo, 2008; Burmeisteret al., 2004; Filip, 2005; Fletcher et al., 2008; Neisewanderand Acosta, 2007; Pentkowski et al., 2010). Recently Ro 60-0175 and lorcaserin were found as effective blockers of nic-otine priming or cue-evoked reinstatement of drug seeking(Fletcher et al., 2012; Higgins et al., 2012), and taken togeth-er with the data summarized above show that 5-HT2C
stimulation effectively attenuates the different aspects ofdrug-controlled seeking behavior, indicating that selective5-HT2C receptor agonists may be a useful pharmacologicalstrategy for treatment of drug abuse.
Table 8 – 5-HT2C receptor function and reinstatement of seeking-behavior.
Drug of abuse (training dose;route of administration;
schedule of reinforcement)
Reinstatement Species (sex) 5-HT2C receptor ligand(dose-range, route of
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4. Neurochemical mechanisms of interactionsbetween 5-HT2C receptors and drugs of abuse:focus on cocaine
During recent years, studies focusing on the mesoaccumbensDA system, in keeping with its importance in mediating thebehavioral effects of drug of abuse (Kalivas and Volkow,2005), have highlighted the potential of central 5-HT2C recep-tors to control cocaine abuse and dependence (Bubar andCunningham, 2006; Di Giovanni et al., 2006; Di Matteo et al.,2001; Filip et al., 2010; Higgins and Fletcher, 2003). Indeed, 5-HT2C receptor ligands have been shown to consistently modu-late DA-dependent behavioral and neurochemical effectsinduced by cocaine (Bubar and Cunningham, 2006; Filip etal., 2010; Fletcher et al., 2006, 2008; Higgins and Fletcher,2003; Liu and Cunningham, 2006: Navailles et al., 2004;Neisewander and Acosta, 2007). Although cocaine-inducedbehavior (hyperlocomotion, self-administration and discrimi-native stimulus effects) is classically thought to result fromincreased DA release in the NAC (Di Chiara, 2002; Dunnettand Robbins, 1992), the analysis of the available data revealsthat changes of NAC DA release cannot account for all of theeffects of 5-HT2C receptor ligands on DA-dependent behaviorsinduced by cocaine, and the neurochemical mechanisms un-derlying these interactions remain to be determined. Periph-eral administration of 5-HT2C receptor antagonists increasesboth behavioral (Bubar and Cunningham, 2006; Filip et al.,2004, 2006; Fletcher et al., 2006; Higgins and Fletcher, 2003)and neurochemical (Navailles et al., 2004) effects of cocaine.Intra-VTA injection of 5-HT2C receptor agonist or antagonistalso elicits parallel changes of NAC DA efflux (Navailleset al., 2008) and DA-dependent behaviors evoked by cocaine(Fletcher et al., 2004; McMahon et al., 2001). Also, intra-NACshell administration of 5-HT2C receptor agonist or antagonist fa-cilitates both cocaine-induced behavior (Filip and Cunningham,2002; McMahon et al., 2001) and NAC DA release (Navailles etal., 2008), although this latter effect is observed only after the in-fusion of low concentration of 5-HT2C receptor ligands (Navailleset al., 2008). In line with the existence of a facilitatory controlexerted by NAC 5-HT2C receptors on DA function, it has been re-cently reported that intra-NAC infusion of the selective 5-HT2C
receptor antagonist SB 242084 reduces acute cocaine-elevatedNAC DA and glutamate release, as well as the expression ofcocaine-induced locomotor sensitization (Zayara et al., 2011).Conversely, systemic pretreatment with 5-HT2C receptor ago-nists (MK 212, Ro 60-0175) has no influence on cocaine-stimulated accumbal DA outflow (Navailles et al., 2004), but po-tently reduces the hyperlocomotive and reinforcing propertiesof cocaine (Filip et al., 2004; Fletcher et al., 2008; Higgins andFletcher, 2003; Neisewander and Acosta, 2007). In addition, localinjection of 5-HT2C receptor compounds into the medial PFC fa-cilitates accumbal DA outflow (Leggio et al., 2009a), but inhibits
Notes to Table 8↑ — enhancement, ↓ — reduction, — — no effect.SD — Sprague–Dawley; W — Wistar; AC — anterior cingulate, IF —ventral tegmental area, FR — fixed ratio, PR — progressive ratio, V
behavioral responses induced by cocaine (Filip andCunningham, 2003). As discussed elsewhere (Leggio et al.,2009a; Navailles et al., 2004, 2008), it is unlikely that the differentexperimental procedures used in behavioral and neurochemicalstudies, including anesthesia, may account for the different ef-fect of 5-HT2C receptor agents on the neurochemical and behav-ioral responses induced by cocaine. More likely, these findingssuggest that 5-HT2C receptors may facilitate cocaine-inducedDA behaviors independently from a net action on NAC DA out-flow, by controlling DA transmission downstream from DAneurons (Leggio et al., 2009a; Navailles et al., 2004, 2008). Interest-ingly, in support to this hypothesis, recent data from ourlaboratory have shown that the peripheral administrationof the 5-HT2C receptor agonist Ro 60-0175 is capable of inhi-biting cocaine-induced phosphorylation of the DA and cyclic3′,5′-adenosine monophosphate regulated phosphoprotein(DARPP-32) in the NAC (unpublished results), a protein locat-ed on DA neurons and involved in the mediation of reinfor-cing effects of cocaine by processes acting independentlyfrom changes of DA release itself (Svenningsson et al., 2002;Zachariou et al., 2002).
In conclusion, the overall inhibitory effect exerted by the 5-HT2C receptor on cocaine-induced DA outflow results from afunctional balance between excitatory and inhibitory effects in-volving different populations of 5-HT2C receptors localizedwithin the medial PFC, VTA and NAC (Filip and Cunningham,2002, 2003; Leggio et al., 2009a; Navailles et al., 2004, 2008).Furthermore, in keeping with the differential effects of 5-HT2C
receptor agents on DA release and DA-dependent behaviors in-duced by cocaine (Filip and Cunningham, 2003; Leggio et al.,2009a; Navailles et al., 2004, 2008), these findings indicate that5-HT2C receptors can modulate mesoaccumbal DA activity bycontrolling NAC DA transmission independently of changesof DA release itself. This gives new insights into the role ofthe 5-HT2C receptor in the regulation of mesoaccumbens DAneurochemical functions, and its potential for improved treat-ments of cocaine abuse and dependence (Bubar andCunningham, 2006; Di Giovanni et al., 2006; Filip et al., 2010;Higgins and Fletcher, 2003; Zayara et al., 2011).
5. Final conclusions
Due to the specific brain localization (mainlymesocorticolimbicareas) and the relationship with DA or other neurotransmittersystems, central 5-HT2C receptors may be regarded as media-tors of the effects induced by exposure to several drugs of abuse.
Themassive effort in nonclinical research in the last decadehas revealed that pharmacological manipulation of 5-HT2C
receptors can efficiently alter drug-taking and -seeking behav-ior (Tables 2–8). Consistent behavioral data strongly implicatethe importance of 5-HT2C receptor agonists in the control ofthe reinstatement mechanisms, and when extrapolated to
infralimbic, PFC — prefrontal cortex, PL — prelimbic, VTA —R — variable ratio. Effective doses are marked in bold.
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abstinent human addicts, suggest that these drugs may havetherapeutic potential for preventing cue-controlled cravingand relapse. Moreover, 5-HT2C receptors are a significant playerimplicated in food intake (Fletcher et al., 2009, 2010; Somervilleet al., 2007), and consequently many of the receptor agonistsmodulate not only motivational and conditioned aspects ofdrug-directed behaviors, but also have prominent effects onconsummatory behaviors in general.
It should bementioned that the impulsiveness, compulsiv-ity, anxiety, depression and/or aggression (Filip and Bader,2009) may be key determinants and/or consequences of druguse and addiction. 5-HT2C receptor-dependent mechanismsmay also effectively regulate drug intoxication or drug with-drawal states. For example, during 3-day withdrawal from re-peated nicotine injections in rats 5-HT2C receptor stimulationeffectively counteracted depression-like effects (Zaniewska etal., 2010) and deep-sequencing technique linked with realtime polymerase chain reaction (RT-PCR) showed a potent(50%) decrease in 5-HT2C receptor mRNA in the hippocampus(Zaniewska et al., 2011).
In the search for attractive pharmacotherapeutic approachesfor the treatment of drug addiction, 5-HT2C receptors have beenattributed a particular role, but there are many important issuesto be addressed in the future: 1) the degree to which 5-HT2C re-ceptor ligand actions affect themotivational and conditioned as-pects of drug-directed behaviors in relation to the observednonspecific (side) effects (e.g., locomotor behavior, emotionalstate, food intake); 2) the contribution of different brain popula-tion of 5-HT2C receptors (see Sections 2.5 and 4) in the contextof drug addiction; 3) the precise explanation of ligand intrinsic ef-ficacy (see Section 2.3) and the receptor constitutive activity (seeSection 2.3). It is also important to mention that 5-HT2C receptoragonists reduce spontaneous locomotion (see Section 2.4). Thisbehavioral outcome may upset reinforcing and seeking behav-iors evoked by drugs of abuse, and this limitation should betaken into account in the interpretation of all data, includingclinical findings.
So far, there are very limited clinical trials on the role of 5-HT2C receptors in drug addiction and the results remain in-conclusive. Thus, polymorphisms (−759 C/T and −697 G/C) ofthe 5-HT2C receptor gene were associated with smoking initi-ation in male Caucasians (Iordanidou et al., 2010); but another5-HT2C receptor gene polymorphism (rs6318) was not associ-ated with smoking behavior in women (Lerer et al., 2006). Fur-thermore, non-selective 5-HT2C receptor agonists (mCPP orMK 212) gave rise to an ethanol-like subjective effect (Leeand Meltzer, 1991), had an intoxicating ethanol-like effect orelicited a state of “feeling drunk” (George et al., 1997), or de-creased the craving for cocaine in addicts (Buydens-Branchey et al., 1997, 1998). However, more thorough studiesare warranted to assess the direct effect of 5-HT2C receptor ag-onists in reducing drug abuse and dependence especially inlight of recent research and development activities, and posi-tive clinical experiences in other indication areas.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This study was supported by the statutory funds of Instituteof Pharmacology (Kraków, Poland), the Department of Toxi-cology, Faculty of Pharmacy, Jagiellonian University (Kraków,Poland), the Institut National de la Recherche et de la Sante´(INSERM) and Bordeaux 2 University. We are very grateful toMrs. Andrea McCreary and Mrs. Agata Suder for editorialassistance.
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