Chronic ethanol treatment alters the behavioral effects of Ro 15-4513, a partially negative ligand for benzodiazepine binding sites.

Pentylenetetrazol (PTZ)-induced convulsion were studied in control, chronic ethanol-maintained, and ethanol-withdrawal rats. The convulsive doses of PTZ varied among the different groups of rats. Ethanol-maintained rats required higher doses of PTZ to produce convulsions, compared to control and ethanol-withdrawal rats. The partially negative ligands for benzodiazepine binding sites, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (20 mg/kg, i.p.) produced proconvulsant effect in saline (control) and ethanol-withdrawal rats as they potentiated the effect of subconvulsive dose of PTZ. A higher dose of Ro 15-4513 (4 mg/kg, i.p.), but not FG 7142 (up to 80 mg/kg, i.p.), also produced proconvulsant effect in ethanol-maintained rats. Furthermore, Ro 15-4513 (5, 10 mg/kg, i.p.), but not FG 7142 (up to 80 mg/kg, i.p.), produced clonic-tonic seizures of short duration in ethanol-withdrawal rats. These effects of Ro 15-4513 and FG 7142 were reversed by diazepam (2 mg/kg, i.p.), as well as by the GABA-neutral Ro 15-1788 (10 mg/kg, i.p.), thereby, indicating the involvement of central benzodiazepine receptors in the action of Ro 15-4513 and FG 7142. These observations suggest that chronic ethanol treatment selectively alters the receptor sensitivity to Ro 15-4513, an ethanol antagonist and partially negative ligand for BZ sites, and this observation supports the notion that ethanol effects are more susceptible to reversal by the imidazobenzodiazepine as compared to other negative ligand for BZ binding sites.