Luigi Pulvirenti

Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens

The purpose of this study was to assess the role of endogenous dopamine and glutamate systems within the nucleus accumbens in modulating responses for oral ethanol reinforcements (10% w/v) in a free-choice operant task. Pretreatment with both systemic (100 µg/kg) and intra-nucleus accumbens microinjection of fluphenazine (2 and 4 µg), a dopamine receptor antagonist, significantly decreased responding for ethanol, without significantly affecting responses for water. Ethanol self-administration was also attenuated by microinjection into the nucleus accumbens of 2-amino-5-phosphopentanoic acid (AP-5, 3 and 6 µg), a competitive NMDA receptor antagonist. These results suggest that dopamine and glutamate neurotransmission in the nucleus accumbens may regulate ethanol self-administration and its reinforcing effects.

NMDA receptors in the nucleus accumbens modulate intravenous cocaine but not heroin self-administration in the rat

The role of endogenous glutamate neurotransmission within the nucleus accumbens in the modulation of intravenous (i.v.) cocaine and heroin self-administration in rats was analyzed. APV (2-amino-5-phosphonovaleric acid), a blocker of glutamate receptors of the N-methyl-D-aspartate (NMDA) type, was microinfused within the nucleus accumbens of the ventral striatum of rats trained to lever press for i.v. cocaine or heroin self-administration. APV, at the dose of 1.5 and 3.0 micrograms/side, reduced the rewarding value of cocaine while it left heroin self-administration unaffected. These results suggest that integrity of NMDA receptor function within the nucleus accumbens may be of importance for the maintenance of i.v. cocaine, but not heroin self-administration in rats.

Nucleus Accumbens NMDA Antagonist Decreases Locomotor Activity Produced by Cocaine, Heroin or Accumbens Dopamine, But Not Caffeine

Glutamatergic afferents to the nucleus accumbens (NAC) have been suggested to modulate psychostimulant-induced locomotor activation. The purpose of this study was 1) to determine the importance of nucleus accumbens N-methyl-D-aspartate (NMDA) glutamate receptors in the control of psychostimulant-induced locomotion, 2) to determine whether NMDA receptor modulation of psychostimulant-induced locomotion occurs presynaptic to or postsynaptic to NAC dopamine terminals, and 3) to determine whether NMDA receptors also modulate opiate- and caffeine-induced locomotor activation. For this purpose, rats treated with cocaine (10 mg/kg IP), dopamine (20 micrograms directly into the NAC), heroin (0.5 mg/kg SC), or caffeine (10 mg/kg SC) were challenged with intra-NAC microinfusion of 2-amino-5-phosphonovaleric acid (APV), a selective NMDA receptor antagonist. APV reduced locomotor activation induced by cocaine, heroin and intra-NAC dopamine, but not caffeine. These results suggest that NAC glutamate modulates psychomotor stimulation at the level of the NAC through an interaction with the integrated output of this region.

Modulation of locomotor activity by NMDA receptors in the nucleus accumbens core and shell regions of the rat

Two subdivisions of the nucleus accumbens (NAC), the core and the shell, have been recently identified on the basis of immunohistochemical differences and neural connections. A major neural input to the NAC is provided by glutamatergic afferents of allocortical origin and there is evidence that glutamate can modulate psychomotor activation and drug reinforcement. This study was undertaken to explore whether selective pharmacological blockade of NMDA neurotransmission within the core and the shell region affected differentially spontaneous and cocaine-induced locomotor activity. We report that intra-NAC microinfusion of aminophosphonovaleric acid (AP-5) (0.75-3.0 micrograms/side, 1.5-6.0 micrograms total dose) within the core but not the shell region reduced cocaine-induced locomotion in a dose-dependent manner. In contrast, microinfusion of the same doses of AP-5 within the shell region caused a dose-dependent increase of spontaneous locomotion, while microinfusion within the core region was ineffective. These results indicate that blockade of NMDA receptors in the core and the shell of the NAC elicited different effects on spontaneous and cocaine-induced locomotion. This suggests that these substructures may subserve different functions within the integrated output of the NAC, functions that may vary according to the state of arousal.

Dopamine receptor agonists, partial agonists and psychostimulant addiction

Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats

In order to study a possible modulatory effect of glutamatergic afferents to the nucleus accumbens (NAC) on psychostimulant-induced locomotion, L-glutamic acid diethyl ester (GDEE), a glutamate antagonist, was injected in the NAC of rats acutely treated with cocaine, amphetamine or caffeine. GDEE at the doses of 5, 10, and 20 micrograms/side significantly reduced locomotion induced by cocaine (20 mg/kg, i.p.). Amphetamine-induced hyperactivity was also reduced by GDEE, whereas caffeine-induced hyperactivity was not significantly decreased by GDEE. This suggests that glutamatergic afferents to the NAC modulate the effects of psychostimulants and also dopamine function in the mesolimbic system.

Effect of Aripiprazole, a Partial Dopamine D2 Receptor Agonist, on Increased Rate of Methamphetamine Self-Administration in Rats with Prolonged Session Duration

Aripiprazole is a dopamine (DA) D2 receptor partial agonist, approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia. DA receptor partial agonists have been previously assessed as potential therapeutic agents for cocaine dependence. The present experiment examined the effect of aripiprazole on methamphetamine self-administration in a rodent model of an increasing drug self-administration with prolonged session duration. Wistar rats were allowed to self-administer methamphetamine (0.05 mg/kg/injection, intravenously) in either 1-h (short access: ShA rats) or 6-h sessions (long access: LgA rats). After 15 sessions, the dose–response function of methamphetamine was determined under either a progressive- or a fixed-ratio schedule. Next, the effect of aripiprazole (0.3–10 mg/kg, subcutaneuously (s.c.)) on the dose–response function was examined. LgA rats exhibited an increasing rate of methamphetamine self-administration. Responding for methamphetamine by LgA rats was higher than that of ShA rats under both schedules. Pretreatment with aripiprazole shifted the dose–response function of methamphetamine to the right in both LgA and ShA rats. However, the effect of aripiprazole was greater in LgA than ShA rats. In in vitro receptor binding assay, no change in the level of D2 DA receptors in the nucleus accumbens and the striatum was found in any group. The present data suggest increased sensitivity of the dopaminergic system to aripiprazole in LgA rats compared with ShA rats. However, mechanisms other than downregulation of D2 DA receptors in the nucleus accumbens and the striatum may be responsible for the increased sensitivity of the dopaminergic function in LgA rats.

SDZ-205,152, a Novel Dopamine Receptor Agonist, Reduces Oral Ethanol Self-Administration in Rats

The effects of SDZ-205,152, a synthetic mixed D1/D2 dopamine receptor agonist, was investigated in rats trained to orally self-administer ethanol (10% w/v) in a free-choice, two-lever operant task. Pretreatment with SDZ-205,152, at doses of 0.5-5.0 mg/kg subcutaneously 30 min prior to limited access to 10% ethanol and water, selectively reduced ethanol-reinforced responding without affecting responses for water. These results demonstrate that ethanol-reinforced responding was attenuated by SDZ-205,152 and suggests that dopamine neural systems may mediate, in part, the reinforcing properties associated with voluntary ethanol self-administration.

GABA and nucleus accumbens glutamate neurotransmission modulate ethanol self-administration in rats

Previous research suggests that ethanol (EtOH) facilitates the activity of the yaminobutyric acid (GABA)/benzodiazepine (BZ) receptor complex1 and inhibits the activity of the N-methyl-waspartate (NMDA) subtype of the glutamate receptor.2 The nucleus accumbens (N.Acc.) is a mesolimbic-forebrain region that receives glutamatecgic afferent projections from the amygdala and hippocampus3 and is an important neumnatomical substrate for the reinforcing effects of psychostimulant drugs.4 The present study examined the effects of isopmpylbicyclophosphate (IPPO), a picrotoxin ligand5 and RO 15-4513, a BZ inverse agonist, in rats trained to orally selfadminister EtOH in a fi-ee-choice operant task. To examine the role of glutamate receptors in mediating EtOH reinfbrcement, the effects of systemic administration of acamprosate, a non-selective glutamate receptor antagonist6 and microinjection of 2-amino-5-phosphopentanoic acid (AP-5), a competitive NMDA receptor antagonist, into the nucleus accumbens were tested. Male rats were trained to orally self-administer EtOH in a fi-ee-choice operant task using a variant of Samson’s sucrose fading techniquq7 with saccharin used to overcome EtOH’s taste aversive properties. Behavioral testing was conducted in operant

Dextromethorphan reduces intravenous cocaine self-administration in the rat

Dextromethorphan is a widely used antitussive agent with non-competitive antagonistic effects at the excitatory amino acid receptors of the NMDA type. Since excitatory amino acid neurotransmission has been implicated in cocaine dependence, the aim of the present study was to evaluate the effects of acute systemic administration of dextromethorphan in rats trained to self-administer cocaine intravenously. The experiments were designed to evaluate the effects of dextromethorphan on responding for cocaine and cocaine reward magnitude. The hypothesis was that dextromethorphan could attenuate specific aspects of cocaine-seeking behavior thus providing a preclinical rationale for its clinical use. The results reported reveal that acute pretreatment with dextromethorphan (10-50 mg/kg i.p.) significantly reduced cocaine self-administration in rats self-administering the drug intravenously in a simple continuous reinforcement schedule. In addition, acute pretreatment with an effective dose of dextromethorphan (25 mg/kg) decreased cocaine self-administration in rats tested at various doses of cocaine (0.12-0.5 mg/injection). Finally, dextromethorphan (25 mg/kg) also reduced the absolute reward magnitude of cocaine as measured by responding for cocaine in a progressive ratio schedule. These results encourage further experimental and clinical studies to evaluate the potential use of dextromethorphan during various phases of the natural history of cocaine dependence in humans.