Extracellular single unit recording techniques were used to characterize the effect of cocaine on the response of identified medial prefrontal cortex (mPFC) neurons to electrical stimulation of the ventral tegmental area (VTA) in chloral hydrate anesthetized rats. The select population of neurons studied were identified as cortical efferent cells by action potential characteristics and antidromic activation from the VTA. Stimulation of the VTA also induced a synaptically mediated inhibition of the spontaneous activity of the mPFC neurons. Administration of 2.0 mg/kg cocaine (IV) produced an increase in the duration of the VTA stimulus-evoked inhibition that differed significantly from the effect of 4.0 mg/kg procaine (IV). In contrast, microiontophoretic cocaine and procaine produced no significant changes in the duration of the VTA stimulus-evoked inhibition. This study provides evidence that systemic but not microiontophoretic cocaine administration enhances dopamine receptor-mediated inhibitory VTA input to a select population of mPFC efferent neurons.