The present study investigated the impact of systemic (i.p.) ethanol administration on extracellular levels of serotonin and glutamate in the prefrontal cortex and the nucleus accumbens in Lewis and Fischer 344 rat strains using in vivo microdialysis. At 1.0 g/kg, ethanol elicited a significant increase in nucleus accumbens-dialysate levels of both 5-HT (44% +/- 16, P = 0.002) and glutmate (90% +/- 43, P = 0.009) in Lewis rats. In Fischer rats, there was no increase in 5-HT (6% +/- 7: P = 0.5), and a trend toward an increase in glutamate (88% +/- 46: P = 0.1). The 0.5 and 2.0 g/kg doses did not result in any significant change in extracellular 5-HT or glutamate in the nucleus accumbens or prefrontal cortex of either strain. The basal levels of glutamate, in both brain regions, were significantly lower in Lewis than in Fischer 344 rats. The basal levels of 5-HT were also lower in the nucleus accumbens of Lewis rats. These findings suggest that enhanced sensitivity of the mesoaccumbens 5-HT or glutamate systems to ethanol and/or inherent low basal levels of 5-HT or glutamate activity may be associated with the predisposition to alcohol-drinking behavior seen in Lewis rats.