Dopamine D3 Receptors in the Nucleus Accumbens and Central Nucleus of Amygdala are Involved in Incubation of Cocaine Craving in Rats

EL Gardner, X Li, J Li, ZX Xi. National Institute on Drug Abuse, Intramural Research Program, USA

Cue-induced drug-seeking behaviour progressively increases over time of withdrawal from drug self-administration in rats, a phenomenon that is called “incubation of craving”. The underlying mechanisms are reported to be related to increased glutamate transmission in the nucleus accumbens (NAc) and increased phosphorylation of extracellular signal-regulated kinase (ERK) in the central nucleus of the amygdala (CeA). However, it remains unclear whether a dopamine (DA)-related mechanism is also involved in incubation of cocaine craving. Recent studies demonstrate that cue-induced cocaine-seeking is correlated with increased DA D3 receptor expression in the NAc in rats after prolonged withdrawal, suggesting possible involvement of D3 receptors in incubation of cocaine craving. Here we report that systemic administration of SB-277011A, a selective D3 receptor antagonist, significantly and dose-dependently inhibits cue-induced cocaine-seeking, but not sucrose-seeking, in male Long-Evans laboratory rats (weighing approximately 300 grams) after 2, 10, or 30 days of withdrawal from cocaine or sucrose self-administration (n=48 rats). For the cocaine self-administration experiments, rats were intravenously catheterized (external jugular vein) under pentobarbital anaesthesia (65 mg/kg i.p.). Following recovery from surgery, rats were allowed to acquire cocaine self-administration (1 mg/kg/infusion delivered in 0.08 ml over 4.6 sec) in daily 3-hr sessions. Initial reinforcement contingency was FR1, which was increased to FR2 upon acquisition of stable self-administration, at which time the infusion amount was lowered to 0.5 mg/kg/infusion. For the sucrose self-administration experiments, all experimental conditions were the same, except that 1) the rats were not subjected to surgery, 2) active lever presses led to delivery of 0.1 ml of 5% sucrose solution into a liquid food tray on the operant chamber wall; and 3) each daily sucrose self-administration session lasted for 1 hr. To test for incubation of craving, animals were left in their home cages in their colony rooms for 2, 10, or 30 days and then returned to their test chambers for one test of cue-induced reinstatement of lever-pressing behaviour. To determine loci of action in brain, SB-277011A was locally administered into different brain regions in separate groups of rats that had been previously implanted with intracranial cannulae under pentobarbital (65 mg/kg i.p.) anaesthesia using standard surgical and stereotaxic techniques. SB-277011A, when microinjected (0.5 microliters/side 30 min prior to test) into the NAc shell or core (n=8), and CeA (n=8), but not the dorsal striatum (n=8) nor basolateral amygdala (BLA) (n=8), significantly inhibited cue-induced cocaine-seeking behaviour 3 weeks after cocaine withdrawal as compared to vehicle microinjections. These data suggest, first, that DA D3 receptors in the NAc (shell and core) and CeA are importantly involved in cue-induced incubation of cocaine craving in rats, and second, SB-277011A or other D3 receptor antagonists, may be effective in attenuating craving and relapse to drug-seeking behavior. (Supported by NIDA/IRP)