The influence of the medial prefrontal cortex (PFC) on mesolimbic dopamine activity was studied with electrophysiological techniques and in vivo voltammetry in the chloral hydrate-anesthetized male rat. Glutamate injected into the PFC selectively increased burst firing of single dopamine cells in the ventral tegmental area and enhanced the release of dopamine from nerve terminals in the nucleus accumbens. PFC injection of the local anesthetic lidocaine produced the opposite effects on burst firing and terminal release. This selective modulation of the dynamic activity of mesolimbic dopamine neurons by the prefrontal cortex might be important in motivation, learning and schizophrenia.