The atypical antidepressant mianserin, administered at doses of 1, 5 and 10 mg/kg SC, dose-dependently increased up to about 6 times extracellular dopamine in the medial prefrontal cortex of the rat, as estimated by vertical concentric microdialysis probes. Mianserin failed to modify extracellular dopamine in the nucleus accumbens. Mianserin also dose-dependently increased extracellular noradrenaline in the prefrontal cortex. Yohimbine, an alpha2 antagonist, increased extracellular dopamine in the prefrontal cortex but the maximal increase was lower than that elicited by mianserin. Yohimbine also increased extracellular noradrenaline in the prefrontal cortex, but to a lesser extent than dopamine. Clonidine, an alpha2 antagonist, decreased extracellular dopamine and noradrenaline in the prefrontal cortex but failed to affect extracellular dopamine in the nucleus accumbens. Ritanserin, a 5HT2 antagonist, at doses of 1.0 mg/kg, failed to increase extracellular dopamine in the prefrontal cortex, but significantly potentiated the increase in extracellular noradrenaline due to yohimbine. Ritanserin failed to potentiate the increase in extracellular noradrenaline elicited by yohimbine in the prefrontal cortex. The results are interpreted to indicate that mianserin increases extracellular DA as a result of the concurrent blockade of alpha2 and 5HT2 receptors. Failure to affect extracellular dopamine in the nucleus accumbens is explained as due to the lack of a significant effect of alpha2 and 5HT2 tone on DA release in the nucleus accumbens as compared to the prefrontal cortex. The results are consistent with the postulated relationship between antidepressant drug action and the ability to increase extracellular dopamine in the prefrontal cortex.