Neuronal systems involved in the initiation of cocaine reinforcement were investigated by identifying brain sites where direct application of the drug was reinforcing. This was accomplished by allowing rats to self-administer picomolar concentrations of cocaine into discrete brain regions. The medial prefrontal cortex supported self-administration, while the nucleus accumbens and ventral tegmental area did not. Self-administration could be attenuated by including equimolar concentrations of the dopaminergic D2-receptor antagonist sulpiride in the microinjection system. These results imply that cocaine reinforcement is mediated in part through a direct action on mesocortical dopaminergic receptors.