Modification of ethanol effects by bicuculline: genotype-dependent responses and inheritance

Abstract

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.

Convulsant properties of GABA antagonists and anticonvulsant properties of ethanol in selectively bred Long- and Short-Sleep mice

“…Such a tentative hypothesis argues for a complex relationship among seizure susceptibility, hypnotic sensitivity and anticonvulsant properties of ETOH. This is also reflected in other work where we have shown genotype-dependent effects of GABAergic agents on ETOH-induced narcosis Phillips and Dudek 1989). The present data could be interpreted as evidence that anticonvulsant effects of ETOH are genetically unrelated to seizure susceptibility and hypnotic sensitivity, which are, in turn, negatively genetically correlated.…”