In contrast to the reported response of inbred male mice [Beeker et al. (2)], young male rats with differing preferences for ethanol (P and NP lines) exhibited no significant change in brain cyclic AMP-binding activity following free-choice consumption of ethanol for 28 days. However, for the NP line, phosphorylation of the kinase regulatory subunit (RII) by basal kinase activity in the cytoplasmic fraction was significantly suppressed by free-choice ethanol consumption but the preferring (P) line showed no such changes. Thus the changes in phosphorylating activity appeared to be associated with differences in the animals' responses to ethanol exposure. The lower preference line (NP) consumed a smaller amount of ethanol (mean = 1.7 +/- 0.1 g/kg/24 hours) and showed a significant decrease in phosphorylating activity relative to vehicle-treated animals whereas the high preference line (P) showed no such change in kinase catalytic activity relative to controls, even though these animals consumed a significantly larger dose of ethanol (mean = 5.9 +/- 0.7 g/kg/24 hours). The data suggest that the P and NP lines differ as to their sensitivity to ethanol-induced changes in the phosphorylation of brain protein kinase regulatory subunit, an important parameter in the overall regulation of kinase activity.