Increased Ro15-4513-induced seizures following multiple ethanol withdrawals

Clinical research into the etiology of ethanol withdrawal seizures has shown an increase in the number and severity of seizures with increasing numbers of withdrawal episodes. The aim of the present study was to determine the effects of multiple ethanol withdrawals on the seizure sensitivity to the GABA(A) receptor inverse agonist Ro15-4513. In this study, three groups of laboratory rats received varying amounts of either continuous or intermittent ethanol exposure. A fourth group (Naive) received no ethanol exposure. Eight hours following the last withdrawal from chronic ethanol exposure, animals were tested for sensitivity to Ro15-4513-induced motor convulsions. Seizure sensitivity was significantly increased in all ethanol-treated groups compared to ethanol-naive controls, which did not exhibit any convulsive responses to this dose of Ro15-4513. Furthermore, rats exposed to multiple ethanol withdrawals exhibited significantly higher sensitivity to drug-induced seizures than did animals experiencing only a single ethanol withdrawal. Although the specific mechanism of this enhanced convulsant effect of Ro15-4513 following multiple ethanol withdrawals remains to be determined, these results suggest an involvement of GABA(A)-benzodiazepine receptors in this multiple withdrawal phenomenon.