Enhanced dopamine transmission in the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug-seeking behavior. However, the contribution of each dopamine receptor subtype to this behavior remains unclear. The present experiments were designed to assess the role of D2-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule of reinforcement. After approximately 18 days of cocaine self-administration, the animals underwent an extinction phase during which cocaine was replaced with saline. Daily extinction sessions were conducted until responding was less than 10% of the response rate maintained by cocaine self-administration. Following the extinction phase, priming-induced reinstatement of cocaine-seeking behavior was assessed. A range of doses of antagonists selective for D2- (sulpiride, 0.2 or 2.0 microg), D3- (U99194A, 3.9 or 7.8 microg), or D4- (L-750,667, 5.5 or 11 microg) dopamine receptors were microinjected into either the nucleus accumbens core, shell or lateral septum prior to a priming injection of cocaine (10 mg/kg, i.p.). Following administration into the shell, but not core or lateral septum, sulpiride dose-dependently attenuated reinstatement induced by a cocaine priming injection. In contrast, U99194A and L-750,667 failed to influence cocaine seeking at any of the doses tested in either accumbal subregion. Collectively, these findings indicate that activation of D2 dopamine receptors mediates cocaine priming-induced reinstatement of cocaine seeking in a region-specific manner within the nucleus accumbens.