Null mutants of the neural-specific gamma-isotype of protein kinase C (gamma-PKC) have demonstrated differential responses to acute administration of ethanol in comparison with wild-type animals. Previous studies have shown that the mutants are less sensitive to ethanol-induced loss of righting response. Null mutants also consume more ethanol and exhibit less behavioral inhibition. In order to determine if these sensitivity differences extend to ethanol activation of locomotor activity in an open-field arena, baseline activity and the effect of two low doses of ethanol were assessed in gamma-PKC null mutants and wild-type littermates. Null mutants demonstrated higher levels of baseline activity than did their wild-type counterparts. Further analysis revealed that a 1.0 g/kg dose of ethanol increased locomotor activity in males and females of both genotypes, whereas only null mutant males were activated by a 1.25 g/kg ethanol dose. The current study demonstrates that male gamma-PKC null mutants exhibit increased sensitivity to activating doses of ethanol in contrast to previous findings of decreased sensitivity to higher, depressive doses. This reflects the pleiotropic effects of the gamma-PKC null mutation on the behavioral effects of ethanol.