Individual differences in ethanol preference may be linked to differences in the functional activity of forebrain monoamine systems or their sensitivity to modification by ethanol. To test this hypothesis, basal extracellular concentrations of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens as well as the effects of repeated ethanol pretreatment on the basal release of these transmitters were examined in alcohol-preferring (P), alcohol-nonpreferring (NP), and genetically heterogeneous Wistar rats. All animals received i.p. injections of ethanol (1.0 g/kg) or saline for 5 consecutive days. Fifteen hours after the final pretreatment, basal extracellular concentrations and "in vivo extraction fraction" values for DA and 5-HT were determined by no-net-flux in vivo microdialysis. In ethanol-naive rats, significant line differences were observed with high basal 5-HT release in P rats, low 5-HT release in NP rats, and intermediate 5-HT levels in Wistar rats. No differences among groups were noted in basal DA release. Ethanol pretreatment decreased basal extracellular 5-HT levels in P rats whereas increasing 5-HT efflux was seen in the Wistar and NP lines. In addition, ethanol pretreatment increased extracellular DA concentrations in Wistar and P rats, but not in NP rats. The results confirm a relationship between the functional status of forebrain DA and 5-HT systems and ethanol preference or aversion. Moreover, the data suggest that ethanol exposure can alter basal DA and 5-HT in the nucleus accumbens and that vulnerability to ethanol-induced changes in monoamine neurotransmission may be a factor in genetically determined ethanol preference.