Neurons of the ventral tegmental area of Tsai (VTA) are important in mediation of the rewarding effects of drugs of abuse, including ethanol. We have demonstrated previously that ethanol excites neurons of the VTA recorded in a brain slice preparation. In the present study, we tested the interaction between serotonin and ethanol on putative dopamine neurons of the VTA. As reported previously, ethanol (20-160 mM) excited VTA neurons in a concentration-dependent manner. Serotonin (1-50 microM) produced only minor increases or decreases of the firing rate. In the presence of serotonin, the potency of ethanol was increased significantly. This potentiation of ethanol excitation by serotonin was seen in VTA slices taken from Sprague-Dawley, Fischer 344 and Lewis rats. The effect of 160 mM ethanol on VTA neurons from Fischer 344 rats, for example, was increased from 38.5 +/- 6.1% before serotonin to 77.4 +/- 16.7% after administration of 10 microM serotonin. Two serotonergic agonists, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride and alpha-methylserotonin, also potentiated the ethanol-induced excitation. The action of serotonin to increase the potency of ethanol to excite VTA neurons may be an important factor in the rewarding effects of ethanol, and might be exploited to develop effective pharmacotherapeutic agents for the treatment of alcohol craving.