European Journal of Pharmacology 480 (2003) 151–162 www.elsevier.com/locate/ejphar Serotonin and drug reward: focus on 5-HT2C receptors Guy A. Higginsa,*, Paul J. Fletcherb a Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA b Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 Accepted 25 August 2003 Abstract Pharmacological manipulation of the 5-hydroxytryptamine (5-HT; serotonin) system has long been associated with a regulation of feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related behaviours, particularly drug reward. The second part of this article considers what we believe to be strong emerging pharmacological and genetic evidence that many of these effects are mediated through 5-HT2C receptor signalling mechanisms. Finally, we consider the potential for selective 5-HT2C agonists as therapies for substance abuse disorders and the medical implications for different 5-HT2C receptor isoforms generated by RNA editing. D 2003 Elsevier B.V. All rights reserved. Keywords: Cocaine; 5-HT (5-hydroxytryptamine, serotonin); 5-HT2C receptor knockout mouse; Drug self-administration; Feeding behaviour; RNA editing 1. Introduction tory behaviours in general (Amit et al., 1991; Sellers et al., 1992; Higgins et al., 1992b). Until its withdrawal in 1997 from worldwide markets Traditionally the behavioural and neurochemical effects due to an association with valvular heart disease, the 5- of drugs of abuse have been most closely associated with the hydroxytryptamine (5-HT) releaser/reuptake inhibitor D-fen- functioning of dopamine systems, and particularly the fluramine (ReduxR) was a widely prescribed and effica- mesolimbic dopamine system projecting from the ventral cious anorectic used to treat obesity (Rothman and tegmental area to the nucleus accumbens. However, several Baumann, 2002). It has now been superceded by the mixed other neurotransmitter systems have been linked to drug 5-HT/noradrenaline reuptake inhibitor sibutramine reward, either as modulators of dopamine function or as (MeridiaR) (Heal et al., 1998), which recently gained substrates, that function independently of dopamine (e.g., approval for this condition. Together with an extensive Bardo, 1998; Laviolette and van der Kooy, 2001; Wise, preclinical literature (e.g., Blundell, 1984; Simansky, 2002). These include glutamate, g-aminobutyric acid 1996), these clinical findings attest to a widely accepted (GABA), acetylcholine, various peptides, notably the en- role of 5-HT systems in the control of feeding behaviour. dogenous endorphins and enkephalins and 5-HT. The pur- However, in addition to food, indirect 5-HT receptor ago- pose of this article is to review work that has explored the nists such as D-fenfluramine and selective 5-HT reuptake role of 5-HT in modulating drug reward. In particular, we inhibitors also reduce the intake of other rewarding stimuli focus on the role of the 5-HT2C receptor. including drugs of abuse. Indeed, some workers have noted a very limited separation between effective doses required to reduce food intake and, for example, ethanol self-adminis- 2. 5-HT and reward—brief overview tration, suggesting that such drugs may affect consumma- Most of the early studies in this area involved the use of treatments that induce generalized increases or decreases in brain 5-HT function. These include indirect agonists, and * Corresponding author. Tel.: +1-908-740-3648; fax: +1-908-740- lesioning of 5-HT pathways induced by the selective sero- 3294. tonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). E-mail address: [email protected] (G.A. Higgins). The primary emphasis here is on studies that have investi- 0014-2999/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2003.08.102 152 G.A. Higgins, P.J. Fletcher / European Journal of Pharmacology 480 (2003) 151–162 gated the effects of serotonergic manipulations on drug self- methysergide, cyproheptadine and cinanserin (Leccese and administration, or drug seeking behaviour. Where relevant, Lyness, 1984) reduced responding in a manner similar to the studies using other types of reward-related behaviours are nonselective indirect agonists. Regarding cocaine self-ad- mentioned, particularly those using drug-induced condi- ministration, two reports (Loh and Roberts, 1990; Roberts et tioned place preference and responding for brain stimulation al., 1994) have found that responding for cocaine under a reward. progressive ratio schedule is enhanced by intracerebroven- tricularly injected 5,7-DHT, as well as by local application 2.1. Effects of nonselective increases in 5-HT function of this neurotoxin into the amygdala, but not the nucleus accumbens (Loh and Roberts, 1990). Numerous studies have shown that various aspects of The effects of 5-HT depletion on cocaine seeking behav- drug reward are modified by treatments that elevate seroto- iour following extinction of self-administration behaviour nin function in a generalized manner. These treatments have also been examined. Both p-chlorophenylalanine include selective serotonin reuptake inhibitors, e.g., fluox- (PCPA) and central 5,7-DHT treatment attenuated reinstate- etine, the 5-HT precursor L-tryptophan and the 5-HT releas- ment of cocaine-seeking behaviour elicited by cues previ- er/reuptake inhibitor D-fenfluramine. Fluoxetine reduces ously associated with cocaine (Tran-Nguyen et al., 1999, both amphetamine (Fletcher et al., 1999a; Leccese and 2001). In contrast 5,7-DHT lesions enhanced responding for Lyness, 1984) and cocaine (Carroll et al., 1990; Howell cues associated with sucrose (Tran-Nguyen et al., 2001) or and Byrd, 1995; Peltier and Schenk, 1993; Porrino et al., water (Fletcher et al., 1999b), and increased the priming 1989; Richardson and Roberts, 1991) self-administration in effect of experimenter administered cocaine (Tran-Nguyen a number of studies from different laboratories. Similarly, L- et al., 2001). tryptophan reduces responding for amphetamine (Smith et al., 1986) and cocaine (McGregor et al., 1993). In at least 2.3. Effects of receptor selective agents on drug self- some of these studies, drug reinforcement was delivered on administration a progressive ratio schedule, where treatment-induced reductions in responding are often taken as evidence for Over the last decade, our understanding of central 5-HT reductions in the reinforcing efficacy of the self-adminis- systems in terms of receptor pharmacology, distribution and tered drug. The effects of D-fenfluramine on cocaine self- function has progressed considerably. At least 14 distinct 5- administration do not appear to have been reported although HT receptors have now been cloned, the majority of which this treatment has been shown to reduce responding for appear to play functional roles in the central nervous system methamphetamine (Munzar et al., 1999) and heroin (Hig- (CNS) (see Hoyer and Martin, 1997; Barnes and Sharp, gins et al., 1994; Wang et al., 1995). 1999; Hoyer et al., 2002 for recent reviews). Not surpris- Recent studies have extended these analyses to examine ingly, the roles of several 5-HT receptor subtypes on drug the impact of serotonergic agents on cocaine-seeking in reward have been examined although this has not yet been animals whose responding for cocaine had been extin- done in a systematic fashion, perhaps in part because of the guished. Both acute (Burmeister et al., 2003) and chronic lack of availability of truly selective ligands for all of the (Baker et al., 2001) injections of fluoxetine attenuated receptor subtypes. The following section briefly summarises reinstatement of responding elicited by cocaine-paired cues, some of the major findings regarding the effects of ligands though not by priming effects of cocaine itself. Acute for the various 5-HT1, 5-HT2, 5-HT3 and 5-HT6 receptors injections of D-fenfluramine had a similar effect (Burmeister on drug reward. et al., 2003). 2.3.1. 5-HT1A receptors 2.2. Effects of nonselective reductions in 5-HT function 5-HT1A receptors are located postsynaptically, as well as on 5-HT cell bodies in the dorsal and median raphe nuclei, A number of early studies demonstrated that widespread where they function as autoreceptors. As a result, 5-HT1A depletion of 5-HT following intracerebroventricular injec- receptor stimulation can result in either increased or de- tion of 5,7-DHT increased responding for infusions of creased 5-HT neurotransmission. Factors such as dose and amphetamine on a fixed ratio schedule (Leccese and Lyness, route of injection (systemic versus intracerebral) are likely 1984; Lyness et al., 1980). A more recent study did not to be major determinants of the net effect of 5-HT1A replicate this finding using 5,7-DHT injected into the dorsal receptor stimulation. Only a few studies have examined and median raphe nuclei, and additionally found that the effects of 5-HT1A receptor agonists on drug self-admin- responding on a progressive ratio schedule was not altered istration, with inconclusive results. In rats, a moderately by this means of depleting 5-HT (Fletcher et al., 1999a). high dose of the prototypic 5-HT1A receptor agonist 8-OH- The situation is further complicated by the fact that while DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) (0.5 mg/ the nonselective 5-HT receptor antagonist metergoline also kg) reduced responding for cocaine on a fixed ratio schedule increased responding for amphetamine (Lyness and Moore, (Peltier and Schenk, 1993). This effect is somewhat difficult 1983), other nonselective receptor antagonists including to interpret both in terms of the behavioural significance of G.A. Higgins, P.J. Fletcher / European Journal of Pharmacology 480 (2003) 151–162 153 the reduction in responding as well as the impact that this tor can function as a post-synaptic receptor, a terminal dose of 8-OH-DPAT has on 5-HT neurotransmission. autoreceptor modulating 5-HT release, and a heteroreceptor Conflicting results have been found in nonhuman primates modulating the release of other neurotransmitters (Barnes using other 5-HT1A receptor agonists.