Genetic influences on the interaction between
ethanol (ETOH) and
gamma-aminobutyric acid (
GABA)
neurotransmitter systems were evaluated with a survey of responses to coadministration of ETOH and a
GABA antagonist,
bicuculline, in a battery of inbred mouse strains. The selectively bred ETOH-sensitive Long-Sleep (LS) mice, the relatively ETOH-resistant Short-Sleep (SS) mice, and a genetically heterogeneous stock (GHS) were also evaluated. The effect of
bicuculline on ETOH-induced sedation,
hypothermia, and blood
ethanol content upon recovery from sedation was assessed. Inheritance of these responses was also examined using F1 hybrids. The effect of
bicuculline on ETOH-produced
narcosis varied widely among stocks and included antagonism, potentiation, and no effect. Changes in ETOH-induced
narcosis produced by
bicuculline were accompanied by changes in blood
ethanol concentrations consistent with an hypothesis of altered central nervous system sensitivity to ETOH. Knowledge of a strain's seizure susceptibility to the
GABA antagonist or of its sensitivity to the
hypnotic effects of ETOH were of no predictive value in estimating the outcome of coadministration studies, suggesting at least partially separate genetic influences on each phenotype. In cross-breeding studies there was commonly dominance toward a profile of
bicuculline antagonism of ETOH
narcosis but different patterns of dominance were observed for seizure susceptibility, again indicating separate genetic control. The results suggest considerable complexity of GABAergic involvement in genotype-dependent ETOH sensitivity.