Previous studies proposed the existence of a relationship between epilepsy and ethanol. Ethanol may have either proconvulsive or anticonvulsive effects on epileptic activity in different experimental epilepsy models. The influence of high dose ethanol intake and its withdrawal on the anticonvulsant effect of alpha-tocopherol was examined after intracortical injection of penicillin (500 units) to induce epileptiform activity. Thirty minutes after penicillin injection, the most effective dose of alpha-tocopherol (500 mg/kg) was administrated intramuscularly (i.m.). Ethanol-treated rats received a daily dose of 9.0 g/kg of 30% ethanol solution via an oesophageal probe for 15 days. All rats in the withdrawal group were anesthetized for induction of penicillin-induced epileptiform activity 28 h after the last ethanol administration. The epileptiform activity was verified by electrocorticographic (ECoG) recordings. Ethanol, in a dose of 9 g/kg, significantly decreased the mean frequency of penicillin-induced epileptiform ECoG activity without changing the amplitude. The mean frequency of ECoG activity was decreased in the 60 and 70 min period from penicillin injection in the ethanol-treated + alpha-tocopherol and ethanol withdrawal + alpha-tocopherol groups compared with the penicillin-injected (500 units, i.e.) group, respectively. alpha-Tocopherol was more effective in decreasing the mean frequency of epileptiform activity in the ethanol + alpha-tocopherol group than in other alpha-tocopherol administrated groups. Ethanol withdrawal caused an increase in frequency of epileptiform activity in the withdrawal + alpha-tocopherol group compared with other a-tocopherol administrated groups. alpha-Tocopherol did not affect the amplitude of epileptiform activity in any group. Possible mechanisms of ethanol influence on the neuroprotective actions of alpha-tocopherol are still a crucial issue associated with epilepsy. (c) 2006 Elsevier Inc. All rights reserved.