An electrophysiological study was performed to investigate the effects of cis-N-[4-[4-(1,2-benz-isozole-3-yl)-1-piperazinyl]butyl]cyclohexan e-1,2-dicarboximide hydrochloride (perospirone), a novel antipsychotic agent with high affinities for D2/5-HT2-receptors, on the dopaminergic (DA) neurons in the ventral tegmental area (VTA) using chloral hydrate-anesthetized rats. DA neurons and non-DA neurons in VTA were identified according to the configurations of their action potentials and firing rates. Spontaneous firing of DA neurons was dose-dependently decreased by i.v. injection of methamphetamine (MAP). Most non-DA neurons were unaffected by MAP up to 2 mg/kg, but the firing was increased with MAP in 2 of 7 neurons. Perospirone injected intravenously reversed the MAP-induced decrease in spontaneous firing of DA neurons in a dose-dependent manner. In addition, i.v. injection of perospirone also inhibited the MAP-induced increase in firing of the 2 non-DA neurons. Similarly, inhibition of spontaneous firing in DA neurons by microiontophoretically applied DA was antagonized during iontophoretic application of perospirone. However, the firing of non-DA neurons, which were insensitive to DA, was not affected by iontophoretically applied perospirone. Since the DA neurons are inhibited by DA via D2-receptors, these findings suggest that perospirone acts on the D2-receptors to antagonize the dopaminergic inhibition of DA neurons in VTA.