Recent electrophysiological and pharmacological data indicate that dopamine enhances the activity of interneurons in the prefrontal cortex (PFC) and induces the release of GABA from these cells. We used in vivo microdialysis to examine the effects of two dopamine receptor antagonists on GABA release in the prefrontal cortex of awake, freely moving rats. Depolarization accomplished by local perfusion of potassium chloride or veratradine markedly increased extracellular GABA levels in the PFC. In contrast, local perfusion of TTX reduced extracellular GABA levels in the PFC. These data indicate that extracellular GABA is derived in part from neurons, and that extracellular levels of the inhibitory amino acid are impulse dependent. The acute administration of haloperidol weakly but significantly decreased extracellular GABA levels in the PFC; no effect of haloperidol on striatal extracellular GABA levels was observed. Systemic administration of the atypical antipsychotic drug clozapine markedly reduced extracellular GABA levels in the PFC, but did not alter striatal GABA levels. Thus, release of GABA from interneurons in the PFC is inhibited by two antipsychotic drugs. These data may suggest that different D2-like dopamine receptors are localized to pyramidal and nonpyramidal neurons in the cortex.