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.