Coincidence of seizure susceptibility to caffeine and to the benzodiazepine inverse agonist, DMCM, in SWR and CBA inbred mice.

Several lines of evidence suggest that the convulsant actions of caffeine are mediated through benzodiazepine receptors. A pharmacogenetic approach has been used to further explore the relationship of these receptors to caffeine-induced seizures. The susceptibility of two inbred strains of mice (CBA and SWR) to the convulsant actions of picrotoxinin, strychnine, Ro 5-4864 and DMCM was examined. Previous studies have demonstrated these two strains differ in their susceptibilities to the convulsant action of caffeine. While no differences were observed between these two strains in susceptibility to tonic seizures induced by picrotoxinin, RO 5-4864 or strychnine, SWR mice were significantly less sensitive to tonic seizures induced by DMCM compared to CBA mice (CD50 values in CBA and SWR mice were 6 and 12 mg/kg IP). Both clonazepam and the benzodiazepine receptor antagonist, Ro 15-1788, significantly blocked caffeine-induced seizures. Further, when subconvulsant doses of caffeine and DMCM were combined, a synergistic action was observed. Taken together, these findings support the hypothesis that the convulsant actions of caffeine result from an action at benzodiazepine receptors, and that the hyporesponsiveness of the SWR strain to both caffeine- and DMCM-induced seizures could result from an inherited abnormality in these sites.