Strain differences in susceptibility to the convulsant actions of 3-carbomethoxy-beta-carboline

NIH mice were found to be approximately three-fold more sensitive than NIH General Purpose mice to the convulsant actions of 3-carbomethoxy-beta-carboline. The convulsant action of 3-carbomethoxy-beta-carboline has been previously demonstrated to be mediated via an interaction with C.N.S. benzodiazepine receptors. The characteristics of the benzodiazepine receptor from the two strains appeared to be identical with respect to both binding affinity and capacity for [3H]3-carbomethoxy-beta-carboline and [3H]diazepam, as well as the relative decreases in apparent receptor affinity for [3H] 3-carbomethoxy-beta-carboline in the presence of 10 microM gamma-aminobutyric acid. Although the rate of degradation of 3-carbomethoxy-beta-carboline in plasma was similar in the two strains, a marked difference in brain levels of the drug (or an active metabolite) was observed after in vivo administration. These results suggest that pharmacokinetic, rather than pharmacodynamic factors are primarily responsible for the observed strain differences in sensitivity to 3-carbomethoxy-beta-carboline.