MUTANT MICE LACKING THE GAMMA-ISOFORM OF PROTEIN-KINASE-C SHOW DECREASED BEHAVIORAL ACTIONS OF ETHANOL AND ALTERED FUNCTION OF GAMMA-AMINOBUTYRATE TYPE-A RECEPTORS

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobut yrate type A (GABA(A)) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determi ne the role of this brain-specific isoenzyme in ethanol sensitivity. W e found that the mutation reduced the amount of PKC gamma immunoreacti vity in cerebellum to undetectable levels without altering the levels of the alpha, beta(I), or beta(II) isoforms of PKC. The mutant mice di splay reduced sensitivity to the effects of ethanol on loss of rightin g reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABA(A) receptor function of isolated,brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studie s show the unique interactions of ethanol with GABA(A) receptors and s uggest protein kinase isoenzymes as possible determinants of genetic d ifferences in response to ethanol.