The role of dopamine receptor signaling in the rat nucleus accumbens in cocaine-induced reinstatement

Drug-induced relapse of cocaine self-administration among human addicts is modeled in laboratory animals by administering noncontingent priming drug injections following the extinction of cocaine self-administration behavior. Evidence from these studies indicates that drug priming-induced reinstatement of cocaine-seeking behavior is largely mediated by activity of the neurotransmitter dopamine within the mesolimbic reward circuitry of the brain. The studies described here examined the role of dopamine transmission and signaling in the nucleus accumbens core and shell during cocaine prime-induced reinstatement of drug-seeking behavior. Selective antagonists for the D1-like (SCH-23390), D2- (Sulpiride), D3- (U99194A) and D4- (L-750,667) dopamine receptors were microinjected into either the nucleus accumbens core or shell prior to a priming injection of cocaine. Following administration into the shell, SCH 23390 and sulpiride dose-dependently attenuated cocaine prime-induced reinstatement. Sulpiride also produce a non-specific decrease in reinstatement responding following microinjection into the core at the highest dose tested. In contrast, U99194A and L-750,667 failed to influence cocaine-seeking at any of the doses tested. Collectively, these findings suggest that activation of D1-like or D2 dopamine receptors mediate cocaine priming-induced reinstatement of cocaine seeking in a region-specific manner within the mesocorticolimbic dopamine system.; The contribution of calcium transmission and signaling downstream from accumbal dopamine receptors was also examined. Systemic administration of the voltage-gated L-type calcium channel blocker diltiazem inhibited reinstatement initiated by a priming cocaine injection. Microinjection of diltiazem directly into the shell also attenuated drug priming-induced reinstatement, as well as reinstatement produced by intra-accumbal administration of a D1-agonist. These alterations in behavior were not correlated with a change in L-type calcium channel mRNA in the shell following 24 hour withdrawal from cocaine self-administration, although there was a slight decrease in expression in the core subregion. Further demonstration of the importance of D1-regulated calcium influx was obtained by microinfusion of the CaMKII inhibitor KN-93 into the nucleus accumbens shell, which attenuated the ability of a priming injection of cocaine to elicit reinstatement. Collectively, these findings suggest that enhanced dopaminergic signaling via selective dopamine receptor subtypes in the nucleus accumbens shell mediate the biological processes underlying relapse to drug-seeking behavior.