Repeated administration of cocaine progressively increases drug-induced locomotor activity. This study examined the role of dopamine D(1)- and D(2)-like receptors in the medial prefrontal cortex (mPFC) in mediating these sensitized behaviors. For initiation experiments, animals received bilateral intra-mPFC injections of either saline, the D(1)-like agonist SKF 81297 (3 nmol/side) or the D(2)-like agonist quinpirole (5 nmol/side) 5 min before each of four daily peripheral injections of saline or cocaine (15 mg/kg i.p.). Following 1 week of withdrawal, the animals were challenged with a systemic injection of cocaine. For expression studies, the animals received four daily systemic injections of either saline or cocaine and 1 week later were pre-treated with an intra-mPFC injection of saline, SKF 81297 or quinpirole 5 min before receiving a systemic challenge injection of cocaine. Intra-mPFC injection of quinpirole blocked the initiation and attenuated the expression of cocaine -induced behavioral sensitization. In contrast, intra-mPFC SKF 81297 did not alter the induction or expression of behavioral sensitization to cocaine at the dose tested. In addition, in vivo microdialysis studies demonstrated that intracortical quinpirole administration blocked the initiation and blunted the expression of cocaine-induced neurochemical sensitization, as defined by augmented dopamine concentrations in the nucleus accumbens. Collectively, the results show that activation of D(2)-like receptors in the mPFC may alter the enduring changes responsible for the development of cocaine sensitization.