Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

Rationale The dopamine (DA) D₃ receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D₃ receptor blockade by the novel D₃ antagonist SB-277011A inhibits cocaines reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.Objective In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.Methods Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10–14 days, followed by a once-daily extinction session for 7–14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl--cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.Results During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 g/0.5 l per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.Conclusions The mesolimic DA D₃ receptor plays an important role in mediating stress-induced reinstatement.