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GABAERGIC MECHANISMS of OPIATE REINFORCEMENT ZHENG-XIONG XI and ELLIOT A

GABAERGIC MECHANISMS of OPIATE REINFORCEMENT ZHENG-XIONG XI and ELLIOT A

Alcohol & Alcoholism Vol. 37, No. 5, pp. 485Ð494, 2002

GABAERGIC MECHANISMS OF REINFORCEMENT ZHENG-XIONG XI and ELLIOT A. STEIN1*

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425 and 1Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA

(Received 20 February 2002; accepted in revised form 27 March 2002)

Abstract — The neurobiological mechanisms of opiate-induced reinforcement are still not completely understood. Over the past two decades, the vast majority of studies have focused on the role of the mesolimbic dopamine (DA) system. However, current studies strongly suggest that opiate actions on γ-aminobutyric acid (GABA)-ergic cells in both the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) appear to play critical roles. In this review, we focus on the neurochemical substrates of opiate reinforcement and review the role of DA and non-DA substrates, including , GABA, glutamate and serotonin on opiate-reinforced behaviour and the activity of dopaminergic and GABAergic neurons in the VTA and the NAcc.

INTRODUCTION (VTA) in the midbrain and projects to several forebrain regions including the nucleus accumbens (NAcc) and medial Opiate abuse remains a major social problem in European and prefrontal cortex (mPFC) (Kalivas, 1993; White, 1996). Far Eastern countries and has been making a comeback in the However, it is still unclear precisely how abused activate USA over the last several years. are commonly used this system and how this system mediates reinforcement. clinically to relieve pain and treat chronic diarrhoea. However, To this end, three major animal models, i.e. self- repeated administration also produces tolerance, positive administration (SA), intracranial self-stimulation (ICSS) and reinforcement (reward), physical dependence, and, upon drug conditioned place preference (CPP), have been established cessation, a physical withdrawal syndrome, drug craving and and widely used to identify the neuroanatomical and neuro- relapse. The precise mechanisms underlying opiates’ addictive chemical mechanisms of drug reinforcement. Several review effects are still incompletely understood although it has been articles have described various aspects of opiate reward and known for almost three decades that their central nervous addiction, including the use of experimental animal models, system (CNS) effects are mediated by activating opiate µ, δ opiate pharmacology, neural reward circuits, memory, or κ receptors. With the aid of selective receptor ligands and conditioned environmental associations, long-term neuro- the subsequent cloning of opiate receptors, it is clear that adaptations and individual genetic vulnerability (Martin, the majority of ’s CNS actions, or that of its predrug, 1983; Schulteis and Koob, 1996; Nestler and Aghajanian, 1997; , are mediated by µ-receptors. Bardo, 1998; Shippenberg and Elmer, 1998; Williams et al., In a classical theory of addiction, Wicker and colleagues 2001). In this review, we focus on the neurochemical substrates hypothesized that, since withdrawal is a physical expression of of opiate reinforcement and review the role of DA and non-DA distress, featuring hyperalgesia, gastrointestinal cramps, joint substrates, including opioid, GABA, glutamate and serotonin and muscle aches, etc., opiate addiction results, at least in part, on opiate-reinforced behaviour and the activity of dopaminergic from the need to reduce such distress. Accordingly, craving and GABAergic neurons in the VTA and the NAcc. would be a negatively reinforced behaviour related to avoidance of withdrawal distress (see review by Di Chiara and North, 1992). However, this hypothesis has been challenged on both OPIATE µ AND κ RECEPTOR-MEDIATED POSITIVE experimental and clinical grounds, as the degree of physical AND NEGATIVE REINFORCEMENT dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence Accumulating experimental evidence indicates that selective prevent recidivism. Moreover, the motivational (affective) activation of µ (and perhaps δ) or κ receptors produces properties of withdrawal are independent of intensity and pat- opposite behavioural and physiological effects. For example, tern of the physical symptoms of withdrawal (see reviews by acute administration of µ- causes and feelings Di Chiara and North, 1992; Schulteis and Koob, 1996). of well-being and liking in human subjects, while κ agonists As such, an alternative hypothesis states that the meso- produce dysphoria and effects (Kumor et al., corticolimbic (MCL) dopamine (DA) system plays a critical 1986; Pfeiffer et al., 1986). These observations are further role in mediating the positive reinforcing effects of a variety confirmed in experimental animals. For example, opiate µ of abused drugs including , , agonists are self-administered systemically or locally into the and opiates (Koob, 1992; Di Chiara, 1995; Wise, 1996). This VTA or NAcc (Bozarth and Wise, 1981; Devine and Wise, anatomical pathway originates from the ventral tegmental area 1984; Goeders et al., 1984). Injections of morphine or other µ agonists into the VTA or NAcc induce a CPP (Phillips and LePiane, 1980; Olds, 1982; Van der Kooy et al., 1982; Mucha κ *Author to whom correspondence should be addressed at: Behavioral Neuro- and Herz, 1986; Bals-Kubik et al., 1993). In contrast, agonists science Branch, Intramural Research Program, National Institute on Drug generally lack reinforcing effects (see review by Dykstra Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. et al., 1997) or produce conditioned place aversion (Tang and

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© 2002 Medical Council on 486 Z.-X. XI and E. A. STEIN Collins, 1985; Bals-Kubik et al., 1989; Barr et al., 1994). To further verify the linkage between opiate-reinforced Moreover, co-administration of κ agonists antagonizes the SA behaviour and NAcc DA release, we (Xi et al., 1998) reinforcing effects of morphine in both SA and CPP para- used in vivo fast-cyclic voltammetry (FCV) to monitor the digms, an effect that can be blocked by pretreatment with the fluctuations in extracellular DA concentration during heroin κ antagonist nor-binaltorphimine (nor-BNI) (Funatada et al., SA in the rat. These experiments demonstrated that heroin SA 1993; Glick et al., 1995; Bolanos et al., 1996; Kuzmin et al., behaviour caused a dose-dependent, -reversible in- 1997; Xi et al., 1998). These data suggest that both endogen- crease in DA efflux in the NAcc that was inversely proportional ous endorphin/ (µ/δ opioid system) and to the number of heroin injections. Additionally, activation (κ opioid system) may tonically modulate brain reward systems. of κ receptors by U50,488H or significantly decreased basal DA release and antagonized the SA- stimulated DA release. These data are taken as direct evidence DA-DEPENDENT MECHANISMS OF OPIATE in support of the DA hypothesis of opiate reinforcement. REINFORCEMENT The mechanisms underlying these opposite cellular and behavioural actions have been attributed to the distinct cellular A large body of experimental evidence supports the DA locations of µ and κ receptors within the mesolimbic DA sys- hypothesis of opiate reinforcement. For example, chemical tem, i.e. µ receptors are predominantly located on GABAergic lesions of VTA DA neurons or DA terminals in the NAcc cells in the VTA and NAcc, while κ receptors are mainly following 6-hydroxydopamine (6-OHDA) administration not located on dopaminergic terminals in the NAcc (Dilts and only inhibits the acquisition and maintenance of heroin or Kalivas, 1989; Johnson and North, 1992; Svingos et al., 1999). morphine SA (Spyraki et al., 1983; Smith et al., 1985), but Thus, µ receptor activation in the VTA selectively hyper- also suppresses opiate-induced conditioned preference or polarizes GABAergic interneurons, thereby disinhibiting aversion (Spyraki et al., 1983; Shippenberg et al., 1993). VTA DA neurons and increasing DA release in the NAcc and Similarly, blockade of D1 receptors with SCH23390 or the mPFC (Di Chiara and Imperato, 1988; Johnson and North, SCH39166, or D3 receptors with 7-hydroxy-di-n-propylamino 1992). In contrast, activation of κ receptors produces a tetralin, attenuates the acquisition of morphine-induced CPP decrease in DA release in the NAcc (Di Chiara and Imperato, behaviour (Leone and Di Chiara, 1987; Shippenberg and 1988; Xi et al., 1998). A similar mechanism may also be in- Herz, 1988; Daly and Waddington, 1993; Shippenberg et al., volved in the opposite actions of µ and κ agonists on analgesia, 1993; Acquas and Di Chiara, 1994). Further, when an electrode and learning and memory-related long-term potentiation in the is implanted into either the VTA or the medial forebrain (see review by Pan, 1998). bundle of the , a fibre tract containing ascending DA fibres, animals easily learn to respond on a lever to receive a train of electrical stimulation, thus activating the mesolimbic GABA-MEDIATED DISINHIBITION DA circuit, and increasing NAcc DA release. Morphine or OF VTA DA NEURONS heroin can both decrease the threshold for eliciting ICSS and shift the frequency or currentÐresponse function to the Since opiate receptor activation generally inhibits individual left (Esposito and Kornetsky, 1978; Van Wolfswinkel and Van neurons, opiate-induced DA release was initially hypothesized Ree, 1985; Hubner and Kornetsky, 1992). Taken together, to be mediated by a disinhibitory mechanism, i.e. opiates inhibit these data suggest that the mesolimbic DA system may be the VTA GABAergic interneurons to decrease GABA release, substrate upon which opiates act to produce their reinforcing which subsequently disinhibits VTA DA neurons, leading to effects (Bozarth and Wise, 1987). an increase in NAcc DA release (Kelley et al., 1980). Several Considerable evidence suggests that both the positive lines of experimental evidence support this hypothesis. For (rewarding) and negative (aversive) reinforcement of opiate example, systemic or microiontophoretically applied morphine µ and κ receptor agonists are mediated by the mesolimbic DA into the VTA increases the firing rate of DA neurons and system (Koob and Nestler, 1997; Pan, 1998; Shippenberg and inhibits the firing rate of inhibitory GABAergic interneurons Elmer, 1998). Electrophysiological studies have demonstrated (Kelley et al., 1980; Gysling and Wang, 1983; Mathews and that systemic or iontophoretic administration of morphine German, 1984; Johnson and North, 1992). Similarly, micro- excites DA cells in the VTA and the substantia nigra (Gysling dialysis and electrochemical studies demonstrated an and Wang, 1983; Matthews and German, 1984), whereas increased NAcc DA release following heroin administration U50,488H (κ ) inhibits DA cells (Walker et al., 1987). (Rada et al., 1991; Spanagel et al., 1992; Kiyatkin et al., 1993; Microdialysis studies have also consistently demonstrated that Xi et al., 1998). Further, anatomical evidence suggests that intracerebroventricular or VTA microinjections of µ agonists opiate µ receptors in the VTA are located predominantly cause a significant increase in extracellular DA (Mulder et al., on GABAergic interneurons (Mansour et al., 1988; Dilts 1984; Di Chiara and Imperato, 1988; Narita et al., 1992; and Kalivas, 1989), and systemic administration of morphine Spanagel et al., 1992; Devine et al., 1993; Xi et al., 1998), inhibits GABA release in the midbrain (Renno et al., 1992) while κ agonists significantly decrease extracellular NAcc and substantia nigra (Starr, 1985). Finally, to determine the DA (Di Chiara and Imperato, 1988; Narita et al., 1992; causal relationship between GABA and DA or heroin SA Devine et al., 1993; Ronken et al., 1993; Spanagel et al., 1994; behaviour, γ-vinyl GABA (GVG) was either systemically Xi et al., 1998). This ‘push–pull’ or reciprocal modulation or locally administered into the VTA, NAcc or VP, which of the mesolimbic DA system by µ and κ receptors may, in significantly elevated extracellular GABA levels by part, underlie the neurochemical mechanisms of opiate irreversibly inhibiting GABA transaminase (Xi and Stein, reinforcement. 2000). Figure 1 shows a typical in vivo electrochemical GABAERGIC MECHANISMS OF OPIATE REINFORCEMENT 487

Fig. 1. Electrochemical recording of effects of heroin on dopamine (DA)-dependent currents. This is a representative original electrochemical recording demonstrating that intravenous injection of heroin increases the DA-dependent oxidation (OX) and reduction (RED) currents in the nucleus accumbens (NAcc), which was reversed following ventral tegmental area (VTA) administration of γ-vinyl GABA, an irreversible GABA transaminase inhibitor. γ-vinyl GABA alone decreased the basal levels of the DA signals, which lasted for >1 h. (See Xi et al., 1998 for details of method.) recording demonstrating that intravenous heroin (0.06 mg/kg) and NAcc DA release (Xi and Stein, 1998, 1999) and injection significantly increases DA-dependent electro- morphine-induced CPP (Tsuji et al., 1996). To evaluate the chemical signals in the NAcc, which is completely blocked or potential preclinical implications of in the treatment reversed following GVG microinjection into the VTA. GVG of opiate addiction, baclofen, when systemically co- alone significantly lowered the basal levels of DA-dependent administered with heroin, significantly blocked the heroin- signals, an effect that lasted for >1 h of the recording period. induced increase in DA signals (Fig. 2Ba, Bc) and heroin Consistent with the reduction in the DA-dependent signals, SA behaviour (Fig. 3C). In contrast, co-administration of local administration of GVG into the VTA significantly blocked the GABAA agonist muscimol with heroin failed to alter heroin SA behaviour (Fig. 3A). Similarly, systemic or regional SA behaviour (data not shown). Paradoxically, muscimol, administration of GVG intracerebroventricularly or into the when administered either intravenously or locally into the

VP, but not NAcc, dose-dependently antagonized heroin VTA, increased DA release in the NAcc by activating GABAA reinforcement in rats (Xi and Stein, 2000). receptors, an effect that was also prevented by blocking VTA

GABAB receptors (Xi and Stein, 1998). These results suggest that VTA GABAA receptors are predominantly located on GABAB RECEPTOR INVOLVEMENT IN HEROIN- GABAergic interneurons or afferents, and the excitatory effect INDUCED DA RELEASE AND REINFORCEMENT of GABAA agonists is similarly mediated by a disinhibitory mechanism. However, two other groups have shown that

To further determine which receptor subtype(s) underlies GABAA antagonists can be self-administered into the VTA this GABAergic disinhibitory mechanism, we observed the in mice by a DA-dependent mechanism (David et al., 1997; effects of GABAA and GABAB agonists or antagonists on Ikemoto et al., 1997a,b), suggesting that GABAA receptors heroin-induced DA release and SA behaviour (Xi and Stein, located on VTA DA neurons also play a role in modulating 1998, 1999). Figure 2 shows another original in vivo NAcc DA release and drug reinforcement. Taken together, electrochemical recording demonstrating heroin increased these data support the hypothesis that VTA GABAB receptors DA signal (Fig. 2Aa), an effect that was blocked or reversed may play an essential role in mediating opiate reinforcement. following blockade of VTA GABAB receptors by 2-OH- (Fig. 2Ab, Ac). Since 2-OH-saclofen alone significantly elevated extracellular DA (Fig. 2Ab), it is suggested OPIATE RECEPTOR-MEDIATED INHIBITION that VTA DA neurons are tonically inhibited by endogenous OF VTA DA NEURONS GABA, which is consistent with a microdialysis study by

Smolders et al. (1995). Similarly, activation of VTA GABAB In contrast to the current predominant hypothesis that opiate receptors by baclofen blocks both heroin SA behaviour µ receptors are only distributed on secondary GABAergic 488 Z.-X. XI and E. A. STEIN

γ Fig. 2. Effects of blockade of -aminobutyric acid B (GABAB) receptors on dopamine signals in the ventral tegmental area (VTA). Shown are representative original electrochemical recordings from two rats demonstrating that blockade of VTA GABAB receptors by 2-OH-saclofen (2 µM) increases dopamine (DA)-dependent signals and reverses the heroin-induced increase in DA signals (A). In contrast, systemic co-administration of baclofen (1 mg/kg) with heroin (0.06 mg/kg) also blocked the heroin-induced increase in DA, while baclofen alone decreased DA signal in the nucleus accumbens (B). OX, oxidation; RED, reduction.

interneurons, but not on primary DA cells (Johnson and North, NON-DA MECHANISMS OF OPIATE REINFORCEMENT 1992), our experimental studies demonstrated that some IN THE NAcc opiate receptors are also located on VTA DA neurons, which may produce direct inhibition of DA release in the NAcc. For Several lines of evidence suggest that non-DA mechanisms example, Figs 1 and 2 show a consistent decrease in also play an important role in mediating opiate reinforcement. DA-dependent signals in the NAcc by heroin following First, as discussed above, heroin or other opiate agonists are pre-activation of VTA GABA receptors indirectly by GVG or both self-administered directly into the NAcc and can produce blockade of GABAB receptors by 2-OH-saclofen. In addition, a CPP when passively administered into the NAcc. Although we also observed a small positive peak that overlayed on a opiates may produce an increase in NAcc DA indirectly by significantly decreased DA signal in ~30Ð40% of the rats inhibiting NAcc GABAergic cells that subsequently decrease tested. Further, a similar decrease in DA-dependent electro- GABA release in both the VTA and the VP, it is possible that chemical signals during heroin self-administration behaviour this initial inhibition of NAcc GABAergic cells directly was observed previously by Kiyatkin et al. (1993). Since both contributes to opiate reinforcement. Second, results from DA the increase and the decrease in the DA signal after heroin administration and chemical lesion studies SA can be blocked by the opiate antagonist naloxone (Xi are not always consistent with the DA hypothesis discussed et al., 1998; Z. X. Xi and E. A. Stein, unpublished work), above. For example, Pettit et al. (1984) demonstrated that these data together support the hypothesis that VTA DA 6-OHDA injections into the NAcc selectively attenuated neurons are modulated by both a direct opiate receptor- cocaine, but not heroin SA in rats trained to self administer mediated inhibition and an indirect GABA-mediated cocaine and heroin on alternate days. These DA lesions also disinhibition. Thus, the final amount of DA released after failed to modify the conditioned aversion produced by heroin administration will depend on the net effect of these systemic or intra-NAcc administration of the µ antagonists opposing actions. naloxone or Cys-Tyr-Om-Pen- (Shippenberg and GABAERGIC MECHANISMS OF OPIATE REINFORCEMENT 489 GABA-MEDIATED OPIATE REINFORCEMENT IN THE NAcc

Since the majority of neurons in the NAcc are GABAergic, which predominantly project to the VTA and the VP (Walaas and Fonnum, 1981; Groenewegen and Russchen, 1984; Chang and Kitai, 1985; Kalivas et al., 1993), it was hypothesized that opiate receptor-mediated inhibition of the medium spiny GABAergic neurons may directly mediate opiate reinforcement (Xi and Stein, 2000) and locomotor behaviours (Mogensen and Nielson, 1983). In support of this hypothesis, systemic or local administration of morphine, heroin or DA into the NAcc inhibits NAcc neuronal activity (De France et al., 1985; Hakan and Henriksen, 1989; Chang et al., 1997; Lee et al., 1999). DA receptor activation in the NAcc inhibits GABA release in the VTA and the VP (Swerdlow et al., 1990; Bourdelais and Kalivas, 1992; Cameron and Williams, 1994). This NAcc GABAergic neuronal inhibition can be antagonized by elevating endogenous GABA concentration in the VTA or the VP with GABA transaminase inhibitors or GABA uptake inhibitors, which can dose-dependently reduce heroin- reinforced SA behaviour (Xi and Stein, 2000). In addition, chemical lesions of VP neurons with block both heroin and cocaine SA behaviour (Hubner and Koob, 1990), whereas intra-pallidal administration of opiates also modulates GABA release within the VP (Napier and Mitrovic, 1999). Taken together, the medium spiny GABAergic pro- jecting neurons in the NAcc may act functionally as a final common target to both DA and non-DA or neuromodulators. DA may play the critical role in mediating opiate reinforcement, because a functional positive feedback pathway exists to facilitate NAcc DA release, i.e. opiate/DA-mediated inhibition of NAcc GABAergic neurons decreases GABA release in the VTA, which subsequently dis- Fig. 3. Modulation of heroin self-administration (SA) by changes in inhibits VTA DA neurons to facilitate DA release in the NAcc. GABA concentration and receptor blockade. The figure shows that elevation of extracellular GABA concentration in the ventral tegmental area (VTA) or activation of GABAB receptors blocks heroin SA. (A) 50 µg (but not 10 µg) of γ-vinyl GABA (GVG) GLUTAMATE MODULATION OF VTA DA NEURONS pretreatment into the VTA blocked SA behaviour during the In addition to receiving a tonic GABAergic modulation, maintenance of heroin SA. (B) Intra-VTA administration of the GABAB agonist baclofen (Bacl) dose-dependently blocked heroin SA, VTA DA neurons also receive excitatory glutamatergic inputs manifested as an increase in SA rate at a low dose and eventually blocked arising from the mPFC, the pedunculopontine region and the SA behaviour after a high dose. (C) Dose-dependent inhibition of SA subthalamic nucleus (Kalivas, 1993; White, 1996). One role of behaviour by systemic co-administration of baclofen. this glutamatergic innervation is to mediate a switch from pacemaker-like firing in VTA DA cells to a burst-firing pattern (Gariano and Groves, 1988; Johnson et al., 1992). Pharma- cological stimulation of ionotropic or metabotropic glutamate Bals-Kubik, 1995). Similarly, systemic or intra-NAcc adminis- receptors in the VTA elicits an increase in exploratory motor tration of the D1 antagonist SCH23390, the D2 antagonists behaviour and promotes DA release in the NAcc and the PFC pimozide, sulpiride and spiroperidol, or the mixed antagonists (Kalivas et al., 1989; Suaud-Chagny et al., 1992; Taber and and α-flupenthixol, also fail to alter heroin SA Fibiger, 1995; Swanson and Kalivas, 2000). Since blockade of (Smith and Davis, 1973; Ettenberg et al., 1982; van Ree and presynaptic glutamate release by prevents the develop- Ramsey, 1987; Shippenberg and Herz, 1988; Gerrits et al., ment of morphine-induced CPP (Tzschentke and Schmidt, 1994; Shippenberg and Bals-Kubik, 1995). Third, DA levels 1998), and over-expression of the GluR1 subunit of α-amino- in the NAcc are increased (Wise et al., 1995; Xi et al., 1998), 3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors decreased (Kiyatkin et al., 1993; Xi et al., 1998; Xi and Stein, in the VTA by viral-mediated gene transfer increases 1999) or unchanged (Hemby et al., 1995) during heroin SA, as morphine’s and rewarding properties (Carlezon assessed by in vivo voltammetry or microdialysis. Taken together, et al., 1997, 2000), glutamate transmission in the VTA also these data suggest that in addition to DA, other non-DA com- appears to importantly participate in opiate reinforcement. ponents may also be involved in the maintenance of opiate In support of this hypothesis, systemic administration of the reinforcement (Hakan and Henriksen, 1989; Xi and Stein, 2000). N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 490 Z.-X. XI and E. A. STEIN not only blocks morphine-induced CPP and behavioural SEROTONIN (5-HT) INVOLVEMENT IN OPIATE sensitization (Jezioski et al., 1994; Tzschentke and Schmidt, REINFORCEMENT 1995), but also prevents the acquisition of intravenous morphine SA in mice (Semenova et al., 1999). Direct Several studies suggest an involvement of 5-HT in mediating administration of NMDA and AMPA antagonists into the VTA opiate reinforcement. For example, the acute administration similarly attenuates heroin reinforcement in rats (Xi and of morphine significantly enhances 5-HT turnover in the rat Stein, 2002). Moreover, the opioid NMDA antagonists dextro- diencephalon (Grauer et al., 1992), and increases 5-HT release and acamprosate have been shown clinically in both the NAcc and the dorsal raphe nucleus, the latter to reduce withdrawal symptoms, drug craving and relapse of which projects to the NAcc (Broderick, 1985; Tao and to heroin, cocaine and ethanol (Herman and O’Brien, 1997; Auerbach, 1994). Direct infusion of morphine into the dorsal Spanagel and Zieglgansberger, 1997), while acamprosate also raphe nucleus, but not into the NAcc, increases 5-HT release prevents, in morphine-dependent rats, the acquisition of in the NAcc, suggesting an effect mediated by a disinhibitory naloxone-induced place aversion (Kratzer and Schmidt, mechanism (Tao and Auerbach, 1994). However, the exact 1998). However, David et al. (1998) reported that both NMDA role of 5-HT and its mechanisms in mediating opiate reinforce- and AMPA receptor antagonists can be self-administered ment remains unclear. For example, systemic administration into the VTA in mice, suggesting that glutamatergic inputs of the 5-HT uptake inhibitor dexfenfluramine reduces heroin onto VTA GABAergic neurons may tonically inhibit VTA DA SA, an effect that can be completely blocked by the 5-HT1 neurons in some species or under certain conditions. receptor antagonist metergoline, and partially blocked by the

5-HT2 receptor antagonist ritanserin, suggesting primary mediation by 5-HT1 receptors (Higgins et al., 1993, 1994; GLUTAMATE MODULATION OF NAcc GABAergic Wang et al., 1995). Similarly, 5,7-dihydroxytryptamine NEURONS (5,7-DHT) lesions of NAcc 5-HT innervation significantly increases morphine SA behaviour and drug intake (Smith In contrast to its actions within the VTA, neither NMDA nor et al., 1987) but prevents morphine-induced CPP (Spyraki non-NMDA antagonists injected into the NAcc alter morphine- et al., 1988). In contrast, the 5-HT3 agonist 2-methylserotonin induced CPP (Layer et al., 1993) or heroin SA behaviour increases DA release in the NAcc and mPFC (Jiang et al.,

(Pulvirenti et al., 1992). The exact role of glutamatergic 1990; Chen et al., 1992), while the 5-HT3 antagonists afferents into the NAcc in mediating opiate reinforcement is ondansetron, MDL 7222 or ICS 205930 inhibit morphine-induced far from clear. Both NMDA and non-NMDA receptors are DA release, locomotion and CPP (Nomikos and Spyraki, 1988; located postsynaptically on GABAergic projection neurons, Carboni et al., 1989; Imperato and Angelucci, 1989; Higgins but not on presynaptic DA terminals (Sesack and Pickel, 1992; et al., 1992; Pei et al., 1993). These data suggest that activation

Doherty and Gratton, 1997). Further, glutamatergic projec- of 5-HT3 receptors may facilitate opiate reinforcement. Since tions from mPFC into the NAcc form excitatory synapses with experiments also show that blockade of 5-HT3 receptors by medium spiny GABAergic neurons (Sesack and Pickel, 1992). BRL 46470A neither prevents nor reverses morphine-induced Thus, activation of NMDA/AMPA receptors should excite VTA DA neuronal firing (Gifford and Wang, 1994) nor modifies NAcc GABAergic cells, thereby increasing GABA release psychostimulant-induced alterations in NAcc DA release in the VTA and the VP and inhibiting VTA DA neurons. (Grant, 1995), it is suggested that both pre- and postsynaptic

However, it remains unclear whether opiate administration 5-HT3 receptors may modulate opiate reinforcement (Van elevates extracellular glutamate in the VTA and the NAcc. An Bockstaele et al., 1996). Taken together, 5-HT1 and 5-HT3 increase in VTA glutamate would facilitate opiate reinforce- receptors appear to modulate opiate reinforcement in a ment by activating VTA DA cells via NMDA/AMPA receptors, reciprocal fashion, with the final effect of serotonin depending whereas an increase in NAcc glutamate would reduce opiate upon the net balance of these actions on NAcc GABAergic cells. reinforcement by activating NAcc GABAergic neurons. In support of such mechanisms, several -like NMDA receptor antagonists have been reported to be self- INTRACELLULAR G PROTEIN INVOLVEMENT IN administered into the NAcc (Carlezon and Wise, 1996), an OPIATE REINFORCEMENT effect that may be mediated by blocking glutamate effects onto NAcc GABAergic neurons. In the light of this hypothesis, Recent studies have begun to examine the cellular trans- it is perhaps not surprising that blockade of either NMDA duction mechanisms that underlie effects common to drugs or AMPA receptors had no effect on opiate reinforcement acting at G-protein coupled membrane receptors (including

(Pulvirenti et al., 1992; Layer et al., 1993) since NAcc opiates, DA, GABAB, 5-HT and metabotropic glutamate GABAergic cells may already have been maximally inhibited receptors). The role of second messenger systems in the by both exogenous opiates and endogenous DA. This hypoth- acquisition or maintenance of opiate SA has been investigated esis also accounts for the ineffectiveness of baclofen, GVG by directly inactivating Gi/o proteins in the VTA or NAcc with and (a GABA uptake inhibitor) in the NAcc on pertussis (Self and Stein, 1993; Self et al., 1994; Nestler heroin SA behaviour, although these drugs all dose-dependently and Aghajanian, 1997). The antagonist effects of pertussis reduce heroin reinforcement when systemic or locally toxin were not unique with respect to heroin, as intra-NAcc administered into the VTA or the VP (Xi and Stein, 1999, also antagonized cocaine SA reinforce (Self

2000). Clearly, more studies are required to elucidate the role et al., 1994), suggesting that intracellular Gi/o proteins may act of glutamate in both the VTA and the NAcc in mediating as a common signal pathway-mediating reinforcement of opiate reinforcement. psychostimulants and opiates. GABAERGIC MECHANISMS OF OPIATE REINFORCEMENT 491

GENERAL CONCLUSIONS AND COMMENTS to modulate opiate reinforcement by activation of 5-HT1 and/or 5-HT3 receptors. Tremendous progress in understanding the neurochemical In view of the above neurochemical framework, a more mechanisms of opiate reinforcement have been made during complete understanding of the mechanisms responsible for the past few decades. It now seems clear that a complex mediating the reinforcing properties of opiates will follow neurochemical circuit mediates opiate reinforcement in which from studies designed to clarify the relative role of each VTA DA neurons and NAcc GABAergic neurons play a non-DA component, the interactions between DA and non-DA critical role (Fig. 4). In the NAcc, DA and non-DA substrates, components in specific MCL components including the VTA, including opioid , GABA, glutamate and 5-HT, mediate NAcc and VP and the roles of glutamate and serotonin. opiate reinforcement by differentially modulating NAcc GABAergic projection neurons. Based upon this simplified Acknowledgements — Our studies were supported in part by grants DA09465 circuit, the main neurochemical mechanisms responsible for and a NIDA/INVEST fellowship. mediating opiate reinforcement are currently understood to include the following. (1) Activation of µ or κ receptors, which are differentially distributed on GABAergic cells in the VTA REFERENCES and NAcc and DA terminals in the NAcc, respectively, produces Acquas, E. and Di Chiara, G. (1994) D1 receptor blockade stereo- rewarding and aversive effects by increasing or decreasing, specifically impairs the acquisition of drug-induced place preference respectively, NAcc DA release. (2) Activation of VTA opiate and place aversion. Behavioral Pharmacology 5, 555Ð569. µ receptors decreases GABA release from VTA GABAergic Bals-Kubik, R., Herz, A. and Shippenberg, T. S. 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