The relatively selective 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [+/-)-DOI) ejected by microiontophoresis at low currents potentiates glutamate (GLU)-induced excitation and at higher currents (greater than 20 nA) invariably inhibits both spontaneous and GLU-induced activity of cells in the medial prefrontal cortex (mPFc). The inhibitory action of DOI is blocked by the 5-HT2 antagonists, ritanserin, metergoline and spiperone, but not other receptor antagonists. Microiontophoresis of 1 M Mg2+ for 5-20 min did not alter DOI's inhibitory effect suggesting that DOI's action is a direct one. These results show that DOI predominantly inhibits mPFc neuronal activity and this inhibitory action is mediated by 5-HT2 receptors.