Considerable evidence suggests that the medial prefrontal cortex (mPFC) is an important region in mediating certain behavioral and neurochemical responses to cocaine. However, a role for cortical dopamine (DA) receptor subtypes in modulating these responses has yet to be elucidated.This study investigated the effects of intra-mPFC administration of DA agonists on the acute motor-stimulant response to cocaine. In addition, in vivo microdialysis techniques were employed to determine the effects of intracortical injection on cocaine-induced extracellular DA concentrations in the nucleus accumbens (NAC).One week following bilateral cannulae implantation over the mPFC and the NAC (for dialysis experiments), male Sprague-Dawley rats received an intra-mPFC injection of saline, the DA D2-like agonist quinpirole (0.015, 0.05, 0.15, 0.5, 1.5, or 5.0 nmol per side) or the partial DA D1-like agonist SKF 38393 (0.5, 1.5, or 5.0 nmol per side) approximately 5 min before peripheral administration of saline or cocaine (15 mg/kg, i.p.). For dialysis experiments, only the highest dose of quinpirole was examined.Pretreatment with quinpirole produced a dose-dependent decrease in cocaine-induced motor activity, with the highest doses resulting in a complete abolition of the acute motor-stimulant response to cocaine. In contrast, intra-mPFC administration of SKF 38393 was not shown, at the doses tested, to alter cocaine-induced motor activity. In agreement with the behavioral effects, intra-mPFC quinpirole injection (5 nmol per side) significantly blocked cocaine-induced DA overflow in the NAC.The results of the present study provide additional support that the mPFC is a neural substrate through which cocaine, in part, produces its motor-stimulant effects. In addition, these data suggest that modulation of cortical DA D2 receptors can block acute cocaine-induced behavioral (locomotor activity) and neurochemical (DA concentrations in the NAC) responses in the rat.