Accumulating evidence indicates that dopamine (DA) D 3 receptor antagonists appear highly promising in attenuating cocaine reward and relapse in preclinical models of addiction. In the present study, we investigated the effects of the novel D 3 -selective antagonist NGB 2904 (N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) on cocaine self-administration, cocaine-enhanced brain stimulation reward (BSR), and cocaine-triggered reinstatement of drug-seeking behavior in male Long-Evans rats. We found that: (1) acute intraperitoneal (i.p.) administration of NGB 2904 (0.1-10 mg/kg) failed to alter cocaine self-administration (0.5 mg/kg/infusion) under fixed-ratio 2 (FR2) reinforcement, but 1 or 5 mg/kg NGB 2904 significantly lowered the break-point for cocaine self-administration under progressive-ratio (PR) reinforcement; (2) cocaine (1, 2, and 10 mg/kg) significantly enhanced electrical BSR (decreased brain reward thresholds), while NGB 2904 significantly inhibited the enhancement of BSR elicited by 2 mg/kg, but not 10 mg/kg of cocaine; (3) NGB 2904 alone neither maintained self-administration behavior nor altered brain reward thresholds; and (4) NGB 2904 significantly inhibited cocaine-triggered reinstatement of extinguished drug-seeking behavior, but not sucrose-plus-sucrose-cue-triggered reinstatement of sucrose-seeking behavior. Overall, these data show that the novel D 3 -selective antagonist NGB 2904 attenuates cocaine's rewarding effects as assessed by PR self-administration, BSR, and cocaine-triggered reinstatement of cocaine-seeking behavior. Owing to these properties and to its lack of rewarding effects (as assessed by BSR and by substitution during drug self-administration), NGB 2904 merits further investigation as a potential agent for treatment of cocaine addiction.

Repeated cocaine produces enduring neuroadaptations in glutamate transmission in the nucleus accumbens that are thought to contribute to addiction. Group II metabotropic glutamate autoreceptors (mGluR2/3) regulate glutamate release, and this study investigates whether repeated cocaine injection produces longlasting alterations in mGluR2/3 content, phosphorylation, and physiology. Rats were administered cocaine daily for 1 week, and 3 weeks after the last injection, mGluR2/3 protein levels were altered in the accumbens and prefrontal cortex (PFC) but not in the dorsal striatum or ventral tegmental area. The level of mGluR2/3 dimer was elevated in the accumbens and PFC and the monomer was reduced in the PFC only. Furthermore, the relative Ser phosphorylation state of the monomer was elevated in both the accumbens and PFC of cocaine-pretreated subjects, whereas the dimer demonstrated negligible phosphorylation in either treatment group. These changes in mGluR2/3 level and phosphorylation state were associated with reduced mGluR2/3 agonist-induced guanosine 5Ј-3-O -(thio)triphosphate binding in the accumbens and PFC, but not in the dorsal striatum. Stimulation of mGluR2/3 reduces extracellular glutamate by inhibiting Ca 2ϩ

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in the treatment of cocaine addiction.