Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425 and
1 Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Received 20 February 2002; 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 -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 opioid, GABA, glutamate and serotonin on opiate-reinforced behaviour and the activity of dopaminergic and GABAergic neurons in the VTA and the NAcc.
INTRODUCTION
Opiate abuse remains a major social problem in European and Far Eastern countries and has been making a comeback in the USA over the last several years. Opiates are commonly used clinically to relieve pain and treat chronic diarrhoea. However, repeated administration also produces tolerance, positive reinforcement (reward), physical dependence, and, upon drug cessation, a physical withdrawal syndrome, drug craving and relapse. The precise mechanisms underlying opiates addictive effects are still incompletely understood although it has been known for almost three decades that their central nervous system (CNS) effects are mediated by activating opiate µ, or
receptors. With the aid of selective receptor ligands and the subsequent cloning of opiate receptors, it is clear that the majority of morphines CNS actions, or that of its predrug, heroin, are mediated by µ-receptors.
In a classical theory of addiction, Wicker and colleagues hypothesized that, since withdrawal is a physical expression of distress, featuring hyperalgesia, gastrointestinal cramps, joint and muscle aches, etc., opiate addiction results, at least in part, from the need to reduce such distress. Accordingly, craving 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 experimental and clinical grounds, as the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Moreover, the motivational (affective) properties of withdrawal are independent of intensity and pattern of the physical symptoms of withdrawal (see reviews by Di Chiara and North, 1992
; Schulteis and Koob, 1996
).
As such, an alternative hypothesis states that the mesocorticolimbic (MCL) dopamine (DA) system plays a critical role in mediating the positive reinforcing effects of a variety of abused drugs including cocaine, amphetamine, nicotine and opiates (Koob, 1992; Di Chiara, 1995
; Wise, 1996
). This anatomical pathway originates from the ventral tegmental area (VTA) in the midbrain and projects to several forebrain regions including the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) (Kalivas, 1993
; White, 1996
). However, it is still unclear precisely how abused drugs activate this system and how this system mediates reinforcement. To this end, three major animal models, i.e. drug self-administration (SA), intracranial self-stimulation (ICSS) and conditioned place preference (CPP), have been established and widely used to identify the neuroanatomical and neurochemical mechanisms of drug reinforcement. Several review articles have described various aspects of opiate reward and addiction, including the use of experimental animal models, opiate receptor pharmacology, neural reward circuits, memory, conditioned environmental associations, long-term neuroadaptations and individual genetic vulnerability (Martin, 1983
; Schulteis and Koob, 1996
; Nestler and Aghajanian, 1997
; Bardo, 1998
; Shippenberg and Elmer, 1998
; Williams et al., 2001
). In this review, we focus on the neurochemical substrates of opiate reinforcement and review the role of DA and non-DA substrates, including opioid, GABA, glutamate and serotonin on opiate-reinforced behaviour and the activity of dopaminergic and GABAergic neurons in the VTA and the NAcc.
OPIATE µ AND RECEPTOR-MEDIATED POSITIVE AND NEGATIVE REINFORCEMENT
Accumulating experimental evidence indicates that selective activation of µ (and perhaps ) or
receptors produces opposite behavioural and physiological effects. For example, acute administration of µ-agonists causes euphoria and feelings of well-being and liking in human subjects, while
agonists produce dysphoria and psychotomimetic effects (Kumor et al., 1986
; Pfeiffer et al., 1986
). These observations are further confirmed in experimental animals. For example, opiate µ agonists are self-administered systemically or locally into the VTA or NAcc (Bozarth and Wise, 1981
; Devine and Wise, 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 and Herz, 1986
; Bals-Kubik et al., 1993
). In contrast,
agonists generally lack reinforcing effects (see review by Dykstra et al., 1997
) or produce conditioned place aversion (Tang and Collins, 1985
; Bals-Kubik et al., 1989
; Barr et al., 1994
). Moreover, co-administration of
agonists antagonizes the reinforcing effects of morphine in both SA and CPP paradigms, an effect that can be blocked by pretreatment with the
antagonist nor-binaltorphimine (nor-BNI) (Funatada et al., 1993
; Glick et al., 1995
; Bolanos et al., 1996
; Kuzmin et al., 1997
; Xi et al., 1998
). These data suggest that both endogenous endorphin/enkephalin (µ/
opioid system) and dynorphin (
opioid system) may tonically modulate brain reward systems.
DA-DEPENDENT MECHANISMS OF OPIATE REINFORCEMENT
A large body of experimental evidence supports the DA hypothesis of opiate reinforcement. For example, chemical lesions of VTA DA neurons or DA terminals in the NAcc following 6-hydroxydopamine (6-OHDA) administration not only inhibits the acquisition and maintenance of heroin or morphine SA (Spyraki et al., 1983; Smith et al., 1985
), but also suppresses opiate-induced conditioned preference or aversion (Spyraki et al., 1983
; Shippenberg et al., 1993
). Similarly, blockade of D1 receptors with SCH23390 or SCH39166, or D3 receptors with 7-hydroxy-di-n-propylamino tetralin, attenuates the acquisition of morphine-induced CPP behaviour (Leone and Di Chiara, 1987
; Shippenberg and Herz, 1988
; Daly and Waddington, 1993
; Shippenberg et al., 1993
; Acquas and Di Chiara, 1994
). Further, when an electrode is implanted into either the VTA or the medial forebrain bundle of the hypothalamus, 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 DA circuit, and increasing NAcc DA release. Morphine or heroin can both decrease the threshold for eliciting ICSS and shift the frequency or currentresponse function to the left (Esposito and Kornetsky, 1978
; Van Wolfswinkel and Van Ree, 1985
; Hubner and Kornetsky, 1992
). Taken together, these data suggest that the mesolimbic DA system may be the substrate upon which opiates act to produce their reinforcing effects (Bozarth and Wise, 1987
).
Considerable evidence suggests that both the positive (rewarding) and negative (aversive) reinforcement of opiate µ and receptor agonists are mediated by the mesolimbic DA system (Koob and Nestler, 1997
; Pan, 1998
; Shippenberg and Elmer, 1998
). Electrophysiological studies have demonstrated that systemic or iontophoretic administration of morphine excites DA cells in the VTA and the substantia nigra (Gysling and Wang, 1983
; Matthews and German, 1984), whereas U50,488H (
agonist) inhibits DA cells (Walker et al., 1987
). Microdialysis studies have also consistently demonstrated that intracerebroventricular or VTA microinjections of µ agonists cause a significant increase in extracellular DA (Mulder et al., 1984
; Di Chiara and Imperato, 1988
; Narita et al., 1992
; Spanagel et al., 1992
; Devine et al., 1993
; Xi et al., 1998
), while
agonists significantly decrease extracellular NAcc DA (Di Chiara and Imperato, 1988
; Narita et al., 1992
; Devine et al., 1993
; Ronken et al., 1993
; Spanagel et al., 1994
; Xi et al., 1998
). This pushpull or reciprocal modulation of the mesolimbic DA system by µ and
receptors may, in part, underlie the neurochemical mechanisms of opiate reinforcement.
To further verify the linkage between opiate-reinforced SA behaviour and NAcc DA release, we (Xi et al., 1998) used in vivo fast-cyclic voltammetry (FCV) to monitor the fluctuations in extracellular DA concentration during heroin SA in the rat. These experiments demonstrated that heroin SA behaviour caused a dose-dependent, naloxone-reversible increase in DA efflux in the NAcc that was inversely proportional to the number of heroin injections. Additionally, activation of
receptors by U50,488H or Dynorphin A significantly decreased basal DA release and antagonized the SA-stimulated DA release. These data are taken as direct evidence in support of the DA hypothesis of opiate reinforcement.
The mechanisms underlying these opposite cellular and behavioural actions have been attributed to the distinct cellular locations of µ and receptors within the mesolimbic DA system, i.e. µ receptors are predominantly located on GABAergic cells in the VTA and NAcc, while
receptors are mainly located on dopaminergic terminals in the NAcc (Dilts and Kalivas, 1989
; Johnson and North, 1992
; Svingos et al., 1999
). Thus, µ receptor activation in the VTA selectively hyperpolarizes GABAergic interneurons, thereby disinhibiting VTA DA neurons and increasing DA release in the NAcc and the mPFC (Di Chiara and Imperato, 1988
; Johnson and North, 1992
). In contrast, activation of
receptors produces a decrease in DA release in the NAcc (Di Chiara and Imperato, 1988
; Xi et al., 1998
). A similar mechanism may also be involved in the opposite actions of µ and
agonists on analgesia, and learning and memory-related long-term potentiation in the hippocampus (see review by Pan, 1998
).
GABA-MEDIATED DISINHIBITION OF VTA DA NEURONS
Since opiate receptor activation generally inhibits individual neurons, opiate-induced DA release was initially hypothesized to be mediated by a disinhibitory mechanism, i.e. opiates inhibit VTA GABAergic interneurons to decrease GABA release, which subsequently disinhibits VTA DA neurons, leading to an increase in NAcc DA release (Kelley et al., 1980). Several lines of experimental evidence support this hypothesis. For example, systemic or microiontophoretically applied morphine into the VTA increases the firing rate of DA neurons and inhibits the firing rate of inhibitory GABAergic interneurons (Kelley et al., 1980
; Gysling and Wang, 1983
; Mathews and German, 1984
; Johnson and North, 1992
). Similarly, microdialysis and electrochemical studies demonstrated an increased NAcc DA release following heroin administration (Rada et al., 1991
; Spanagel et al., 1992
; Kiyatkin et al., 1993
; Xi et al., 1998
). Further, anatomical evidence suggests that opiate µ receptors in the VTA are located predominantly on GABAergic interneurons (Mansour et al., 1988; Dilts and Kalivas, 1989
), and systemic administration of morphine inhibits GABA release in the midbrain (Renno et al., 1992
) and substantia nigra (Starr, 1985
). Finally, to determine the causal relationship between GABA and DA or heroin SA behaviour,
-vinyl GABA (GVG) was either systemically or locally administered into the VTA, NAcc or VP, which significantly elevated extracellular GABA levels by irreversibly inhibiting GABA transaminase (Xi and Stein, 2000
). Figure 1
shows a typical in vivo electrochemical recording demonstrating that intravenous heroin (0.06 mg/kg) injection significantly increases DA-dependent electrochemical signals in the NAcc, which is completely blocked or reversed following GVG microinjection into the VTA. GVG alone significantly lowered the basal levels of DA-dependent signals, an effect that lasted for >1 h of the recording period. Consistent with the reduction in the DA-dependent signals, local administration of GVG into the VTA significantly blocked heroin SA behaviour (Fig. 3A
). Similarly, systemic or regional administration of GVG intracerebroventricularly or into the VP, but not NAcc, dose-dependently antagonized heroin reinforcement in rats (Xi and Stein, 2000
).
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GABAB RECEPTOR INVOLVEMENT IN HEROIN-INDUCED DA RELEASE AND REINFORCEMENT
To further determine which receptor subtype(s) underlies this GABAergic disinhibitory mechanism, we observed the effects of GABAA and GABAB agonists or antagonists on heroin-induced DA release and SA behaviour (Xi and Stein, 1998, 1999
). Figure 2
shows another original in vivo electrochemical recording demonstrating heroin increased DA signal (Fig. 2Aa), an effect that was blocked or reversed following blockade of VTA GABAB receptors by 2-OH-saclofen (Fig. 2Ab, Ac). Since 2-OH-saclofen alone significantly elevated extracellular DA (Fig. 2Ab), it is suggested that VTA DA neurons are tonically inhibited by endogenous GABA, which is consistent with a microdialysis study by Smolders et al. (1995). Similarly, activation of VTA GABAB receptors by baclofen blocks both heroin SA behaviour and NAcc DA release (Xi and Stein, 1998
, 1999
) and morphine-induced CPP (Tsuji et al., 1996
). To evaluate the potential preclinical implications of baclofen in the treatment of opiate addiction, baclofen, when systemically co-administered with heroin, significantly blocked the heroin-induced increase in DA signals (Fig. 2Ba, Bc
) and heroin SA behaviour (Fig. 3C
). In contrast, co-administration of the GABAA agonist muscimol with heroin failed to alter SA behaviour (data not shown). Paradoxically, muscimol, when administered either intravenously or locally into the VTA, increased DA release in the NAcc by activating GABAA 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 GABAergic interneurons or afferents, and the excitatory effect of GABAA agonists is similarly mediated by a disinhibitory mechanism. However, two other groups have shown that GABAA antagonists can be self-administered into the VTA in mice by a DA-dependent mechanism (David et al., 1997
; Ikemoto et al., 1997a
,b
), suggesting that GABAA receptors located on VTA DA neurons also play a role in modulating NAcc DA release and drug reinforcement. Taken together, these data support the hypothesis that VTA GABAB receptors may play an essential role in mediating opiate reinforcement.
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OPIATE RECEPTOR-MEDIATED INHIBITION OF VTA DA NEURONS
In contrast to the current predominant hypothesis that opiate µ receptors are only distributed on secondary GABAergic interneurons, but not on primary DA cells (Johnson and North, 1992), our experimental studies demonstrated that some opiate receptors are also located on VTA DA neurons, which may produce direct inhibition of DA release in the NAcc. For example, Figs 1 and 2
show a consistent decrease in DA-dependent signals in the NAcc by heroin following pre-activation of VTA GABA receptors indirectly by GVG or blockade of GABAB receptors by 2-OH-saclofen. In addition, we also observed a small positive peak that overlayed on a significantly decreased DA signal in
3040% of the rats tested. Further, a similar decrease in DA-dependent electrochemical signals during heroin self-administration behaviour was observed previously by Kiyatkin et al. (1993). Since both the increase and the decrease in the DA signal after heroin SA can be blocked by the opiate antagonist naloxone (Xi et al., 1998
; Z. X. Xi and E. A. Stein, unpublished work), these data together support the hypothesis that VTA DA neurons are modulated by both a direct opiate receptor-mediated inhibition and an indirect GABA-mediated disinhibition. Thus, the final amount of DA released after heroin administration will depend on the net effect of these opposing actions.
NON-DA MECHANISMS OF OPIATE REINFORCEMENT IN THE NAcc
Several lines of evidence suggest that non-DA mechanisms also play an important role in mediating opiate reinforcement. First, as discussed above, heroin or other opiate agonists are both self-administered directly into the NAcc and can produce a CPP when passively administered into the NAcc. Although opiates may produce an increase in NAcc DA indirectly by inhibiting NAcc GABAergic cells that subsequently decrease GABA release in both the VTA and the VP, it is possible that this initial inhibition of NAcc GABAergic cells directly contributes to opiate reinforcement. Second, results from DA receptor antagonist administration and chemical lesion studies are not always consistent with the DA hypothesis discussed above. For example, Pettit et al. (1984) demonstrated that 6-OHDA injections into the NAcc selectively attenuated cocaine, but not heroin SA in rats trained to self administer cocaine and heroin on alternate days. These DA lesions also failed to modify the conditioned aversion produced by systemic or intra-NAcc administration of the µ antagonists naloxone or Cys-Tyr-Om-Pen-amide (Shippenberg and Bals-Kubik, 1995). Similarly, systemic or intra-NAcc administration of the D1 antagonist SCH23390, the D2 antagonists pimozide, sulpiride and spiroperidol, or the mixed antagonists haloperidol and
-flupenthixol, also fail to alter heroin SA (Smith and Davis, 1973
; Ettenberg et al., 1982
; van Ree and Ramsey, 1987
; Shippenberg and Herz, 1988
; Gerrits et al., 1994
; Shippenberg and Bals-Kubik, 1995
). Third, DA levels in the NAcc are increased (Wise et al., 1995
; Xi et al., 1998
), decreased (Kiyatkin et al., 1993
; Xi et al., 1998
; Xi and Stein, 1999
) or unchanged (Hemby et al., 1995
) during heroin SA, as assessed by in vivo voltammetry or microdialysis. Taken together, these data suggest that in addition to DA, other non-DA components may also be involved in the maintenance of opiate reinforcement (Hakan and Henriksen, 1989
; Xi and Stein, 2000
).
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 ibotenic acid 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 projecting neurons in the NAcc may act functionally as a final common target to both DA and non-DA neurotransmitters 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 disinhibits VTA DA neurons to facilitate DA release in the NAcc.
GLUTAMATE MODULATION OF VTA DA NEURONS
In addition to receiving a tonic GABAergic modulation, VTA DA neurons also receive excitatory glutamatergic inputs arising from the mPFC, the pedunculopontine region and the subthalamic nucleus (Kalivas, 1993; White, 1996
). One role of 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
). Pharmacological stimulation of ionotropic or metabotropic glutamate receptors in the VTA elicits an increase in exploratory motor behaviour and promotes DA release in the NAcc and the PFC (Kalivas et al., 1989
; Suaud-Chagny et al., 1992
; Taber and Fibiger, 1995
; Swanson and Kalivas, 2000
). Since blockade of presynaptic glutamate release by riluzole prevents the development of morphine-induced CPP (Tzschentke and Schmidt, 1998
), and over-expression of the GluR1 subunit of
-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the VTA by viral-mediated gene transfer increases morphines stimulant and rewarding properties (Carlezon et al., 1997
, 2000
), glutamate transmission in the VTA also appears to importantly participate in opiate reinforcement.
In support of this hypothesis, systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 not only blocks morphine-induced CPP and behavioural sensitization (Jezioski et al., 1994; Tzschentke and Schmidt, 1995
), but also prevents the acquisition of intravenous morphine SA in mice (Semenova et al., 1999
). Direct administration of NMDA and AMPA antagonists into the VTA similarly attenuates heroin reinforcement in rats (Xi and Stein, 2002
). Moreover, the opioid NMDA antagonists dextromethorphan and acamprosate have been shown clinically to reduce withdrawal symptoms, drug craving and relapse to heroin, cocaine and ethanol (Herman and OBrien, 1997
; Spanagel and Zieglgansberger, 1997
), while acamprosate also prevents, in morphine-dependent rats, the acquisition of naloxone-induced place aversion (Kratzer and Schmidt, 1998
). However, David et al. (1998) reported that both NMDA and AMPA receptor antagonists can be self-administered into the VTA in mice, suggesting that glutamatergic inputs onto VTA GABAergic neurons may tonically inhibit VTA DA neurons in some species or under certain conditions.
GLUTAMATE MODULATION OF NAcc GABAergic NEURONS
In contrast to its actions within the VTA, neither NMDA nor non-NMDA antagonists injected into the NAcc alter morphine-induced CPP (Layer et al., 1993) or heroin SA behaviour (Pulvirenti et al., 1992
). The exact role of glutamatergic afferents into the NAcc in mediating opiate reinforcement is far from clear. Both NMDA and non-NMDA receptors are located postsynaptically on GABAergic projection neurons, but not on presynaptic DA terminals (Sesack and Pickel, 1992
; Doherty and Gratton, 1997
). Further, glutamatergic projections from mPFC into the NAcc form excitatory synapses with medium spiny GABAergic neurons (Sesack and Pickel, 1992
). Thus, activation of NMDA/AMPA receptors should excite NAcc GABAergic cells, thereby increasing GABA release in the VTA and the VP and inhibiting VTA DA neurons. However, it remains unclear whether opiate administration elevates extracellular glutamate in the VTA and the NAcc. An increase in VTA glutamate would facilitate opiate reinforcement by activating VTA DA cells via NMDA/AMPA receptors, whereas an increase in NAcc glutamate would reduce opiate reinforcement by activating NAcc GABAergic neurons. In support of such mechanisms, several phencyclidine-like NMDA receptor antagonists have been reported to be self-administered into the NAcc (Carlezon and Wise, 1996
), an effect that may be mediated by blocking glutamate effects onto NAcc GABAergic neurons. In the light of this hypothesis, it is perhaps not surprising that blockade of either NMDA or AMPA receptors had no effect on opiate reinforcement (Pulvirenti et al., 1992
; Layer et al., 1993
) since NAcc GABAergic cells may already have been maximally inhibited by both exogenous opiates and endogenous DA. This hypothesis also accounts for the ineffectiveness of baclofen, GVG and nipecotic acid (a GABA uptake inhibitor) in the NAcc on heroin SA behaviour, although these drugs all dose-dependently reduce heroin reinforcement when systemic or locally administered into the VTA or the VP (Xi and Stein, 1999
, 2000
). Clearly, more studies are required to elucidate the role of glutamate in both the VTA and the NAcc in mediating opiate reinforcement.
SEROTONIN (5-HT) INVOLVEMENT IN OPIATE REINFORCEMENT
Several studies suggest an involvement of 5-HT in mediating opiate reinforcement. For example, the acute administration of morphine significantly enhances 5-HT turnover in the rat diencephalon (Grauer et al., 1992), and increases 5-HT release in both the NAcc and the dorsal raphe nucleus, the latter of which projects to the NAcc (Broderick, 1985
; Tao and Auerbach, 1994
). Direct infusion of morphine into the dorsal raphe nucleus, but not into the NAcc, increases 5-HT release in the NAcc, suggesting an effect mediated by a disinhibitory mechanism (Tao and Auerbach, 1994
). However, the exact role of 5-HT and its mechanisms in mediating opiate reinforcement remains unclear. For example, systemic administration of the 5-HT uptake inhibitor dexfenfluramine reduces heroin SA, an effect that can be completely blocked by the 5-HT1 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
; Wang et al., 1995
). Similarly, 5,7-dihydroxytryptamine (5,7-DHT) lesions of NAcc 5-HT innervation significantly increases morphine SA behaviour and drug intake (Smith et al., 1987
) but prevents morphine-induced CPP (Spyraki et al., 1988
). In contrast, the 5-HT3 agonist 2-methylserotonin increases DA release in the NAcc and mPFC (Jiang et al., 1990
; Chen et al., 1992
), while the 5-HT3 antagonists ondansetron, MDL 7222 or ICS 205930 inhibit morphine-induced DA release, locomotion and CPP (Nomikos and Spyraki, 1988
; Carboni et al., 1989
; Imperato and Angelucci, 1989
; Higgins et al., 1992
; Pei et al., 1993
). These data suggest that activation of 5-HT3 receptors may facilitate opiate reinforcement. Since experiments also show that blockade of 5-HT3 receptors by BRL 46470A neither prevents nor reverses morphine-induced VTA DA neuronal firing (Gifford and Wang, 1994
) nor modifies psychostimulant-induced alterations in NAcc DA release (Grant, 1995
), it is suggested that both pre- and postsynaptic 5-HT3 receptors may modulate opiate reinforcement (Van Bockstaele et al., 1996
). Taken together, 5-HT1 and 5-HT3 receptors appear to modulate opiate reinforcement in a reciprocal fashion, with the final effect of serotonin depending upon the net balance of these actions on NAcc GABAergic cells.
INTRACELLULAR G PROTEIN INVOLVEMENT IN OPIATE REINFORCEMENT
Recent studies have begun to examine the cellular transduction mechanisms that underlie effects common to drugs acting at G-protein coupled membrane receptors (including opiates, DA, GABAB, 5-HT and metabotropic glutamate receptors). The role of second messenger systems in the acquisition or maintenance of opiate SA has been investigated by directly inactivating Gi/o proteins in the VTA or NAcc with pertussis toxin (Self and Stein, 1993; Self et al., 1994
; Nestler and Aghajanian, 1997
). The antagonist effects of pertussis toxin were not unique with respect to heroin, as intra-NAcc pertussis toxin also antagonized cocaine SA reinforce (Self et al., 1994
), suggesting that intracellular Gi/o proteins may act as a common signal pathway-mediating reinforcement of psychostimulants and opiates.
GENERAL CONCLUSIONS AND COMMENTS
Tremendous progress in understanding the neurochemical mechanisms of opiate reinforcement have been made during the past few decades. It now seems clear that a complex neurochemical circuit mediates opiate reinforcement in which VTA DA neurons and NAcc GABAergic neurons play a critical role (Fig. 4). In the NAcc, DA and non-DA substrates, including opioid peptides, GABA, glutamate and 5-HT, mediate opiate reinforcement by differentially modulating NAcc GABAergic projection neurons. Based upon this simplified circuit, the main neurochemical mechanisms responsible for mediating opiate reinforcement are currently understood to include the following. (1) Activation of µ or
receptors, which are differentially distributed on GABAergic cells in the VTA and NAcc and DA terminals in the NAcc, respectively, produces rewarding and aversive effects by increasing or decreasing, respectively, NAcc DA release. (2) Activation of VTA opiate µ receptors decreases GABA release from VTA GABAergic interneurons or afferents that subsequently disinhibit VTA DA neurons and increase NAcc DA release predominantly via GABAB receptors. (3) Inhibition of medium spiny GABAergic neurons in the NAcc by DA and opiates can synergistically facilitate opiate reinforcement. (4) An increase in glutamatergic afferents into the VTA may facilitate opiate reinforcement by activating VTA DA neurons, while an increased glutamatergic activity in the NAcc may decrease opiate action by activating NAcc GABAergic cells. Similarly, the reinforcing effect of ionotropic glutamate antagonists in the NAcc may be mediated by blocking NMDA/AMPA receptors, thereby decreasing excitability of the NAcc medium spiny GABAergic neurons. (5) An increase in NAcc 5-HT by opiates also seems to modulate opiate reinforcement by activation of 5-HT1 and/or 5-HT3 receptors.
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ACKNOWLEDGEMENTS
Our studies were supported in part by grants DA09465 and a NIDA/INVEST fellowship.
FOOTNOTES
* Author to whom correspondence should be addressed at: Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
REFERENCES
Acquas, E. and Di Chiara, G. (1994) D1 receptor blockade stereospecifically impairs the acquisition of drug-induced place preference and place aversion.Behavioral Pharmacology 5, 555569.[ISI][Medline]
Bals-Kubik, R., Herz, A. and Shippenberg, T. S. (1989) Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated.Psychopharmacology 98, 203206.[ISI][Medline]
Bals-Kubik, R., Ableitner, A., Herz, A. and Shippenberg, T. S. (1993) Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.Journal of Pharmacology and Experimental Therapeutics 264, 489495.[Abstract]
Bardo, M. T. (1998) Neuropharmacological mechanism of drug reward: beyond dopamine in the nucleus accumbens.Critical Reviews in Neurobiology 12, 3767.[ISI][Medline]
Barr, G. A., Wang, S. and Carden, S. (1994) Aversive properties of the kappa opioid agonist U50,488 in the week old rat pup.Psychopharmacology 113, 422428.[ISI][Medline]
Bolanos, C. A., Garmsen, G. M., Clair, M. A. and McDougall, S. A. (1996) Effects of the kappa-opioid receptor agonist U-50,488 on morphine-induced place preference conditioning in the developing rat.European Journal of Pharmacology 317, 18.[ISI][Medline]
Bourdelais, A. and Kalivas, P. W. (1992) Apomorphine decreases extracellular GABA in the ventral pallidum of rats with 6-OHDA lesions in the nucleus accumbens.Brain Research 577, 306311.[ISI][Medline]
Bozarth, M. A. and Wise, R. A. (1981) Intracranial self-administration of morphine into the ventral tegmental area in rats.Life Sciences 28, 551555.[ISI][Medline]
Bozarth, M. A. and Wise, R. A. (1987) A psychomotor stimulant theory of addiction.Psychological Review 94, 469492.[ISI][Medline]
Broderick, P. A. (1985) Opiate regulation of mesolimbic serotonin release: in vivo semiderivative electrochemical analyses.Neuropeptides 5, 587590.[ISI][Medline]
Cameron, D. L. and Williams, J. T. (1994) Cocaine inhibits GABA release in the VTA through endogenous 5-HT.Journal of Neuroscience 14, 67636767.[Abstract]
Carboni, E., Acquas, E., Leone, P. and Di Chiara, G. (1989)5-HT3 receptor antagonists block morphine and nicotine but not amphetamine induced reward.Psychopharmacology97, 175178.[ISI][Medline]
Carlezon, W. A., Jr and Wise, R. A. (1996) Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.Journal of Neuroscience 16, 31123122.
Carlezon, W. A., Jr, Boundy, V. A., Haile, C. N., Lane, S. B., Kalb, R. G., Neve, R. L. and Nestler, E. J. (1997) Sensitization to morphine induced by viral-mediated gene transfer.Science 277, 812814.
Carlezon, W. A., Jr, Haile, C. N., Coopersmith, R., Hayashi, Y., Malinow, R., Neve, R. L. and Nestler, E. J. (2000) Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1. Journal of Neuroscience 220, RC62 (15).
Chang, H. T. and Kitai, S. T. (1985) Projection neurons of the nucleus accumbens: an intracellular labeling study.Brain Research 347, 112116.[ISI][Medline]
Chang, J. Y., Zhang, L., Janak, P. H. and Woodward, D. J. (1997) Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats.Brain Research 754, 1220.[ISI][Medline]
Chen, J., Pareders, W., Van Praag, H. M., Lowinson, J. H. and Gardner, E. L. (1992) Presynaptic dopamine release is enhanced by 5-HT3 receptor activation in medial preferental cortex of freely moving rats.Synapse 10, 264266.[ISI][Medline]
Daly, S. A. and Waddington, J. L. (1993) Behavioral effects of the putative D3 dopamine receptor antagonist 7-OH-DPAT in relation to other D2-like agonists.Neuropharmacology 32, 509514.[ISI][Medline]
David, V., Durkin, T. P. and Cazala, P. (1997) Self-administration of the GABAA antagonist bicuculine into the ventral tegmental area in mice: dependence on D2 dopaminergic mechanism.Psychopharmacology 130, 8590.[ISI][Medline]
David, V., Durkin, T. P. and Cazala, P. (1998) Rewarding effects elicited by the microinjection of either AMPA or NMDA glutamatergic antagonists into the ventral tegmental area revealed by an intracranial self-administration paradigm in mice.European Journal of Neuroscience 10, 13941402.[ISI][Medline]
De France, J. F., Sikes, R. W. and Chronister, R. B. (1985) Dopamine action in the nucleus accumbens.Journal of Neurophysiology 54, 15681577.
Devine, D. P. and Wise, R. A. (1994) Self-administration of morphine, DAMGO and DPDPE into the ventral tegmental area of rats.Journal of Neuroscience 14, 19781984.[Abstract]
Devine, D. P., Leone, P., Pocock, D. and Wise, R. A. (1993) Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies.Journal of Pharmacology and Experimental Therapeutics 266, 12361246.[Abstract]
Di Chiara, G. and Imperato, A. (1988) Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.Journal of Pharmacology and Experimental Therapuetics 244, 10671080.[Abstract]
Di Chiara, G. and North, R. A. (1992) Neurobiology of opiate abuse (Review).Trends in Pharmacological Sciences 13, 185193.[ISI][Medline]
Di Chiara, G. (1995) The role of dopamine in drug abuse viewed from the perspective of its role in motivation.Drug and Alcohol Dependence 38, 95137.[ISI][Medline]
Dilts, R. P. and Kalivas, P. W. (1989) Autoradiographic localization of µ-opioid and neurotensin receptor within the mesolimbic dopamine system.Brain Research 488, 311327.[ISI][Medline]
Doherty, M. D. and Gratton, A. (1997) NMDA receptors in nucleus accumbens modulate stress-induced dopamine release in the nucleus accumbens and ventral tegmental area.Synapse 26, 225234.[ISI][Medline]
Dykstra, L. A., Preston, K. L. and Bigelow, G. E. (1997) Discriminative stimulus and subjective effects of opioids with mu and kappa activity: data from laboratory animals and human subjects (Review).Psychopharmacology 130, 1427.[ISI][Medline]
Esposito, R. and Kornetsky, C. (1978) Opioids and rewarding brain stimulation.Neuroscience and Biobehavioral Reviews 2, 115122.[ISI]
Ettenberg, A., Pettit, H. O., Bloom, F. E. and Koob, G. F. (1982) Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems.Psychopharmacology 78, 204209.[ISI][Medline]
Funatada, M., Suzuki, T., Narita, M., Misawa, M. and Nagase, H. (1993) Blockade of morphine reward through the activation of kappa-opioid receptors in mice.Neuropharmacology 32, 13151323.[ISI][Medline]
Gariano, R. F. and Groves, P. M. (1988) Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anterior cingulate cortices.Brain Research 462, 194198.[ISI][Medline]
Gerrits, M. A., Ramsey, N. F., Wolterink, G. and van Ree, J. M. (1994) Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat.Psychopharmacology 114, 486496.[ISI][Medline]
Gifford, A. N. and Wang, R. Y. (1994) The effect of 5HT3 receptor antagonists on the morphine-induced excitation of A10 dopamine cells: electrophysiological studies.Brain Research 638, 325328.[ISI][Medline]
Glick, S. D., Maisonneuve, I. M., Raucci, J. and Archer, S. (1995) Kappa opioid inhibition of morphine and cocaine self-administration in rats.Brain Research 681, 147152.[ISI][Medline]
Goeders, N. E., Lane, J. D. and Smith, J. E. (1984) Self-administration of methionine enkephalin into the nucleus accumbens.Pharmacology, Biochemistry and Behavior 20, 451455.[ISI][Medline]
Grant, K. A. (1995) The role of 5-HT3 receptors in drug-dependence.Drug and Alcohol Dependence 38, 155171.[ISI][Medline]
Grauer, S. M., Tao, R. and Auerbach, S. B. (1992) Morphine induces an increase in extracellular serotonin in rat diencephalon.Brain Research 599, 277282.[ISI][Medline]
Groenewegen, H. J. and Russchen, F. T. (1984) Organization of the efferent projections of the nucleus accumbens to pallidal, hypothalamic, and mesencephalic structures: a tracing and immunohistochemical study in the cat.Journal of Comparative Neurology 223, 347367.[ISI][Medline]
Gysling, K. and Wang, R. Y. (1983) Morphine-induced activation of A10 dopamine neurons in the rat.Brain Research 277, 119127.[ISI][Medline]
Hakan, R. L. and Henriksen, S. J. (1989) Opiate influences on nucleus accumbens neuronal electrophysiology: dopamine and non-dopamine mechanisms.Journal of Neuroscience 9, 35383546.[Abstract]
Hemby, S. E., Martin, T. J., Co, C., Dworkin, S. I. and Smith, J. E. (1995) The effects of intravenous heroin administration on extracellular nucleus accumbens dopamine concentrations as determined by in vivo microdialysis.Journal of Pharmacology and Experimental Therapuetics 273, 591598.[Abstract]
Herman, B. H. and OBrien, C. P. (1997) Clinical medication development for opiate addiction: focus on nonopioids and opioid antagonists for the amelioration of opiate withdrawal symptoms and relapse prevention.Seminars in Neuroscience 9, 158164.[ISI]
Higgins, G. A., Joharchi, N., Nguyen, P. and Sellers, E. M. (1992) Effects of the 5-HT3 receptor antagonists, MDL72222, and ondansertron on morphine place conditioning.Psychopharmacology 106, 315320.[ISI][Medline]
Higgins, G. A., Wang, Y. and Sellers, E. M. (1993) Preliminary findings with the indirect 5-HT agonist dexfenfluramine on heroin discrimination and self-administration in rats.Pharmacology, Biochemistry and Behavior 45, 963966.[ISI][Medline]
Higgins, G. A., Wang, Y., Corrigall, W. A. and Sellers, E. M. (1994) Influence of 5-HT3 receptor antagonists and the indirect 5-HT agonist, dexfenfluramine, on heroin self-administration in rats.Psychopharmacology 114, 611619.[ISI][Medline]
Hubner, C. B. and Koob, G. F. (1990) The ventral pallidum plays a role in mediating cocaine and heroin self-administration in the rat.Brain Research 508, 2029.[ISI][Medline]
Hubner, C. B. and Kornetsky, C. (1992) Heroin, 6-acetylmorphine and morphine effects on threshold for rewarding and aversive brain stimulation.Journal of Pharmacology and Experimental Therapeutics 260, 562567.[Abstract]
Ikemoto, S., Kohl, R. R. and McBride, W. J. (1997a) GABAA receptor blockade in the anterior ventral tegmental area increases extracellular levels of dopamine in the nucleus accumbens of rats.Journal of Neurochemistry 69, 137143.[ISI][Medline]
Ikemoto, S., Murphy, J. M. and McBride, W. J. (1997b) Self-administration of GABAA antagonists directly into the ventral tegmental area and adjacent regions.Behavioral Neuroscience 111, 369380.[ISI][Medline]
Imperato, A. and Angelucci, L. (1989)5-HT3 receptors control dopamine release in the nucleus accumbens of freely moving rats.Neuroscence Letters 101, 214217.
Jezioski, M., White, M. E. and Wolf, M. E. (1994) MK-801 prevents the development of behavioral sensitization during repeated morphine administration.Synapse 16, 137147.[ISI][Medline]
Jiang, L. H., Ashby, C. R., Kasser, R. J. and Wang, R. Y. (1990) The effects of intraventricular administration of the 5-HT3 receptor agonist 2-methylserotonin on the release of dopamine in the nucleus accumbens: an in vivo chronocoulometric study.Brain Research 513, 156160.[ISI][Medline]
Johnson, S. W. and North, R. A. (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons.Journal of Neuroscience 12, 483488.[Abstract]
Johnson, S. W., Seutin, V. and North, R. A. (1992) Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump.Science 258, 665667.[ISI][Medline]
Kalivas, P. W. (1993) Neurotransmitter regulation of dopamine neurons in the ventral tegmental area.Brain Research Reviews 18, 75113.[ISI][Medline]
Kalivas, P. W., Duffy, P. and Barrow, J. (1989) Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes.Journal of Pharmacology and Experimental Therapeutics 251, 378387.[Abstract]
Kalivas, P. W., Churchill, L. and Klitenick, M. A. (1993) GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area.Neuroscience 57, 10471060.[ISI][Medline]
Kelley, A. E., Stinus, L. and Iversen, S. D. (1980) Interaction between -ala2-met-enkephalin, A10 dopaminergic neurons and spontanous behavior in the rat.Behavioral Brain Research 1, 334.[ISI][Medline]
Kiyatkin, E. A. (1993) Behavioral significance of phasic changes in mesolimbic dopamine-dependent electrochemical signal associated with heroin self-injections.Journal of Neural Transmission 96, 197214.
Kiyatkin, E. A., Wise, R. A. and Gratton, A. (1993) Drug- and behavior-associated changes in dopamine-related electrochemical signals during intravenous heroin self-administration in rats.Synapse 14, 6072.[ISI][Medline]
Koob, G. F. (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways.Trends in Pharmacological Sciences 13, 177184.[ISI][Medline]
Koob, G. F. and Nestler, E. J. (1997) The neurobiology of drug addiction.Journal of Neuropsychiatry and Clinical Neurosciences 9, 482497.[Abstract]
Kratzer, U. and Schmidt, W. J. (1998) The anti-craving drug acamprosate inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats.Neuroscience Letters 252, 5356.[ISI][Medline]
Kumor, K. M., Haertzen, C. A., Johnson, R. E., Kocher, T. and Jasinski, D. (1986) Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo.Journal of Pharmacology and Experimental Therapeutics 238, 960968.[Abstract]
Kuzmin, A. V., Semenova, S., Gerrits, M. A., Zvartau, E. E. and Van Ree, J. M. (1997) Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice.European Journal of Pharmacology 321, 265271.[ISI][Medline]
Layer, R. T., Uretsky, N. J. and Wallace, L. J. (1993) Effects of AMPA/kainate receptor antagonist DNQX in the nucleus accumbens on drug-induced conditioned place preference.Brain Research 617, 267273.[ISI][Medline]
Lee, R. S., Criado, J. R., Koob, G. F. and Henriksen, S. J. (1999) Cellular responses of nucleus accumbens neurons to opiate-seeking behavior: I. Sustained responding during heroin self-administration.Synapse 33, 4958.[ISI][Medline]
Leone, P. and Di Chiara, G. (1987) Blockade of D-1 receptors by SCH-23390 antagonized morphine and amphetamine induced place preference conditioning.European Journal of Pharmacology 135, 251254.[ISI][Medline]
Mansour, A., Kachaturian, H., Lewis, M. E., Akil, H. and Watson, S. J. (1998) Anatomy of CNS opioid receptors.Trends in Neurosciences 11, 306314.
Martin, W. R. (1983) Pharmacology of opioids (Review).Pharmacological Reviews 35, 283323.[Abstract]
Mathews, R. T. and German, D. C. (1984) Electrophysiological evidence of excitation of rat ventral tegmental area dopamine neurons by morphine.Neuroscience 11, 617625.[ISI][Medline]
Mogenson, G. J. and Nielson, M. A. (1983) Evidence that an accumbens to subpallidal GABAergic projection contributes to locomotor activity.Brain Research Bulletin 11, 309314.[ISI][Medline]
Mucha, R. F. and Herz, A. (1986) Preference conditioning produced by opioid active and inactive isomers of levorphanol and morphine in rat.Life Sciences 38, 244249.
Mulder, A. H., Wardeh, G., Hogenboom, F. and Frankhuyzen, A. L. (1984) - and µ-opioid receptor agonists differentially inhibit striatal dopamine and acetylcholine release.Nature (London) 308, 278280.[ISI][Medline]
Napier, T. C. and Mitrovic, I. (1999) Opioid modulation of ventral pallidal inputs.Annals of the New York Academy of Sciences 877, 176201.
Narita, M., Suzuki, T., Funada, M., Misawa, M. and Nagase, H. (1992) Blockade of the morphine-induced increase in turnover of dopamine on the mesolimbic dopamine system by -opioid receptor activation in mice.Life Sciences 52, 397404.[ISI]
Nestler, E. J. and Aghajanian, G. K. (1997) Molecular and cellular basis of addiction.Science 278, 5863.
Nomikos, G. and Spyraki, C. (1988) Effects of ritanserin on the rewarding effects of -amphetamine, morphine, and diazepam revealed by conditioned place preference in rats.Pharmacology, Biochemistry and Behavior 30, 853858.[ISI][Medline]
Olds, M. E. (1982) Reinforcing effects of morphine in the nucleus accumbens.Brain Research 237, 429440.[ISI][Medline]
Pan, Z. Z. (1998) µ-Opposing actions of the -opioid receptor.Trends in Pharmacological Sciences, 19, 9498.[ISI][Medline]
Pei, Q., Zetterstrom, T., Leslie, R. A. and Grahame-Smith, D. G. (1993)5-HT3 receptor antagonists inhibit morphine-induced stimulation of mesolimbic dopamine release and function in the rat.European Journal of Pharmacology 230, 6368.[ISI][Medline]
Pettit, H. O., Ettenberg, A., Bloom, F. E. and Koob, G. F. (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.Psychopharmacology 84, 167173.[ISI][Medline]
Pfeiffer, A., Brantle, V., Herz, A. and Emerich, H. M. (1986) Psychotomimesis mediated by opiate receptors.Science 233, 774776.[ISI][Medline]
Phillips, A. G. and LePiane, G. (1980) Reinforcing effects of morphine microinjection into the ventral tegmental area.Pharmacology, Biochemistry and Behavior 12, 965968.[ISI][Medline]
Pulvirenti, L., Maldonado-Lopez, R. and Koob, G. F. (1992) NMDA receptors in the nucleus accumbens modulate intravenous cocaine but not heroin self-administration in the rat.Brain Research 594, 327330.[ISI][Medline]
Rada, P., Mark, G. P., Pothes, E. and Hoebel, B. G. (1991) Systemic morphine simultaneously decreases extracellular acetylcholine and increases dopamine in the nucleus accumbens of freely moving rats.Neuropharmacology 30, 11331136.[ISI][Medline]
Renno, W. M., Mullett, M. A. and Beitz, A. J. (1992) Systemic morphine reduces GABA release in the lateral but not the medial portion of the midbrain periaqueductal gray of the rat.Brain Research 594, 221223.[ISI][Medline]
Ronken, E., Mulder, A. H. and Schoffelmeer, A. N. (1993) Interacting presynaptic -opioid and GABAA receptors modulate dopamine release from rat striatal synaptosomes.Journal of Neurochemistry 61, 16341639.[ISI][Medline]
Schulteis, G. and Koob, G. F. (1996) Reinforcement process in opiate addiction: a homeostatic model.Neurochemical Research 21, 14371454.[ISI][Medline]
Self, D. W. and Stein, L. (1993) Pertussis toxin attenuates intracranial morphine self-administration.Pharmacology, Biochemistry and Behavior 46, 689695.[ISI][Medline]
Self, D. W., Terwilliger, R. Z., Nestler, E. J. and Stein, L. (1994) Inactivation of Gi and Go proteins in nucleus accumbens reduces both cocaine and heroin reinforcement.Journal of Neuroscience 14, 62396247.[Abstract]
Semenova, S., Danysz, W. and Bespalov, A. (1999) Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naïve mice.European Journal of Pharmacology 378, 18.[ISI][Medline]
Sesack, S. R. and Pickel, V. M. (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area.Journal of Comparative Neuroscience 320, 145160.
Shippenberg, T. S. and Bals-Kubik, R. (1995) Involvement of the mesolimbic dopamine system in mediating the aversive effects of opioid antagonists in rat.Behavioral Pharmacology 6, 99106.[ISI][Medline]
Shippenberg, T. S. and Elmer, G. I. (1998) The neurobiology of opiate reinforcement.Critical Reviews in Neurobiology 12, 267303.[ISI][Medline]
Shippenberg, T. S. and Herz, A. (1988) Motivational effects of opioids: influence of D1 versus D2 receptor antagonists.European Journal of Pharmacology 151, 233242.[ISI][Medline]
Shippenberg, T. S., Bals-Kubik, R. and Herz, A. (1993) Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 and D-2 dopamine receptors.Journal of Pharmacology and Experimental Therapuetics 265, 5359.[Abstract]
Smith, J. E., Guerin, G. F., Co, C., Barr, T. S. and Lane, J. D. (1985) Effects of 6-OHDA lesions of the central medial nucleus accumbens on rat intravenous morphine self-administration.Pharmacology, Biochemistry and Behavior 23, 843849.[ISI][Medline]
Smith, J. E., Schultz, K. and Co, C. (1987) Effects of 5,7-dihydroxytryptamine lesions of the nucleus accumbens on intravenous morphine self-administration.Pharmacology, Biochemistry and Behavior 26, 607611.[ISI][Medline]
Smith, S. G. and Davis, W. M. (1973) Haloperidol effects on morphine self-administration: testing for pharmacological modulation of the primary reinforcement mechanism.Psychological Record 23, 215221.[ISI]
Smolders, I., Klippel, N. D., Sarre, S., Ebinger, G. and Michotte, Y. (1995) Tonic GABAergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat.European Journal of Pharmacology 284, 8391.[ISI][Medline]
Spanagel, R. and Zieglgansberger, W. (1997) Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes.Trends in Pharmacological Sciences 18, 5457.[ISI][Medline]
Spanagel, R., Herz, A. and Shippenberg, T. S. (1992) Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.Proceedings of the National Academy of Sciences of the United States of America 89, 20462050.[Abstract]
Spanagel, R., Almeide, O. F. X., Bartl, C. and Shippenberg, T. S. (1994) Endogenous -opioid system in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release.Psychopharmacology 115, 121127.[ISI][Medline]
Spyraki, C., Fibiger, H. C. and Phillips, A. G. (1983) Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system.Psychopharmacology 79, 278283.[ISI][Medline]
Spyraki, C., Nomikos, G. G., Galanopoulous, P. and Daifotis, Z. (1988)Drug-induced place preferences in rats with 5,7-dihydroxytryptamine lesions of the nucleus accumbens.Behavioral Brain Research 29, 127134.[ISI][Medline]
Starr, M. S. (1985) Multiple opiate receptors may be involved in suppressing -aminobutyrate release in substantia nigra.Life Sciences 37, 22492255.[ISI][Medline]
Suaud-Chagny, M. F., Chergui, K., Chouvet, G. and Gonon, F. (1992) Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area.Neuroscience 49, 6372.[ISI][Medline]
Svingos, A. L., Colago, E. E. O. and Pickel, V. M. (1999) Cellular sites for dynorphin activation of opioid receptors in the rat nucleus accumbens shell.Journal of Neuroscience 19, 18041813.
Swanson, C. J. and Kalivas, P. W. (2000) Regulation of locomotor activity by metabotropic glutamate receptors in the nucleus accumbens and ventral tegmental area.Journal of Pharmacology and Experimental Therapeutics 292, 406414.
Swerdlow, N. R., Braff, D. L. and Geyer, M. A. (1990) GABAergic projection from nucleus accumbens to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats.Brain Research 532, 145150.
Taber, M. T. and Fibiger, H. C. (1995) Electrical stimulation of the prefrontal cortex increases dopamine release in the nucleus accumbens of the rat: modulation by metabotropic glutamate receptors.Journal of Neuroscience 15, 38963904.[Abstract]
Tang, A. H. and Collins, R. J. (1985) Behavioral effects of a novel kappa opioid analgesic, U50-488, in rats and rhesus monkeys.Psychopharmacology 85, 309314.[ISI][Medline]
Tao, R. and Auerbach, S. (1994) Anesthetics block morphineinduced increases in serotonin release in rat CNS.Synapse 18, 307314.[ISI][Medline]
Tsuji, M., Nakagawa, Y., Ishibashi, Y., Yoshii, T., Takashima, T., Shimada, M. and Suzuki, T. (1996) Activation of ventral tegmental GABAB receptors inhibits morphine-induced place preference in rats.European Journal of Pharmacology 313, 169173.[ISI][Medline]
Tzschentke, T. M. and Schmidt, W. J. (1995) N-Methyl-d-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats.Neuroscience Letters 193, 3740.[ISI][Medline]
Tzschentke, T. M. and Schmidt, W. J. (1998) Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole.Neuroscience Letters 242, 114116.[ISI][Medline]
Van Bockstaele, E. J., Chan, J. and Pickel, V. M. (1996) Pre- and postsynaptic sites for serotonin modulation of GABA-containing neurons in the shell region of the rat nucleus accumbens.Journal of Comparative Neurology 371, 116128.[ISI][Medline]
Van der Kooy, D., Mucha, R. F., OShaughnessy, M. and Bucenieks, P. (1982) Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference.Brain Research 243, 107117.[ISI][Medline]
van Ree, J. M. and Ramsey, N. F. (1987) The dopamine hypothesis of opiate reward challenged.European Journal of Pharmacology 134, 239243.[ISI][Medline]
Van Wolfswinkel, L. and Van Ree, J. M. (1985) Effects of morphine and naloxone on thresholds of ventral tegmental electrical self-stimulation.Naunyn-Schmiedebergs Archives of Pharmacology 330, 8492.[ISI][Medline]
Walaas, I. and Fonnum, F. (1981) Biochemical evidence of -aminobutyrate containing fibers from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat.Neuroscience 5, 6372.[ISI]
Walker, J. M., Thompson, L. A., Frascella, J. and Friedrich, M. W. (1987) Opposite effects of µ and opiates on the firing-rate of dopamine cells in the substantia nigra of the rat.European Journal of Pharmacology 134, 5359.[ISI][Medline]
Wang, Y., Joharchi, N., Fletcher, P. J., Sellers, E. M. and Higgins, G. A. (1995) Further studies to examine the nature of dexfenfluramine-induced suppression of heroin self-administration.Psychopharmacology 120, 134141.[ISI][Medline]
White, F. J. (1996) Synaptic regulation of mesocorticolimbic dopamine neurons.Annual Review of Neuroscience 19, 405436.[ISI][Medline]
Williams, J. T., Christie, M. J. and Manzoli, O. (2001) Cellular and synaptic adaptations mediating opiate dependence.Physiological Review 81, 299343.
Wise, R. A. (1996) Neurobiology of addiction.Current Opinion in Neurobiology 6, 243251.[ISI][Medline]
Wise, R. A., Leone, P., Rivest, R. and Leeb, K. (1995) Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration.Synapse 21, 140148.[ISI][Medline]
Xi, Z. X. and Stein, E. A. (1998) Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors an in vivo electrochemical study.Brain Research 798, 156165.[ISI][Medline]
Xi, Z. X. and Stein, E. A. (1999) Baclofen inhibits heroin self-administration and mesolimbic dopamine release.Journal of Pharmacology and Experimental Therapeutics 290, 13691374.
Xi, Z. X. and Stein, E. A. (2000) Increased mesolimbic GABA concentration blocks heroin self-administration behavior in rats.Journal of Pharmacology and Experimental Therapeutics 294, 613619.
Xi, Z. X. and Stein, E. A. (2002) Blockade of ionotropic glutamatergic transmission in the ventral tegemental area reduces heroin reinforcement. Psychopharmacology, in press.
Xi, Z. X., Fuller, S. A. and Stein, E. A. (1998) Dopamine release in the nucleus accumbens during heroin self-administration is modulated by opioid receptors: an in vivo fast-cyclic voltammetry study.Journal of Pharmacology and Experimental Therapeutics 284, 151161.