EFFECTS OF BENZODIAZEPINE AGONIST, ANTAGONIST AND INVERSE AGONIST ON ETHANOL-INDUCED CHANGES IN BETA-ENDORPHIN LEVELS IN SPECIFIC RAT-BRAIN REGIONS

The present study was conducted to evaluate and compare effects of the benzodiazepine agonist diazepam, antagonist flumazenil and inverse agonist RO 15-4513 on ethanol-induced changes in beta-endorphin (beta-EN) levels in specific rat brain regions. Male Sprague-Dawley rats (150-200 g) adapted to a 12-hour light: 12-hour dark illumination cycle were used in this study. Ethanol (3 g/kg as 22.5% solution in saline), flumazenil (10 mg/kg), RO 15-4513 (10 mg/kg), diazepam (2 mg/kg) or a combination of ethanol (3 g/kg) and flumazenil (10 mg/kg), RO 15-4513 (10 mg/kg) or diazepam (2 mg/kg) were administered intraperitoneally to rats at 7.00 h. Control animals were injected with saline. Animals were sacrificed by decapitation 1 h after injection; the brains were immediately removed; the cortex, hippocampus and hypothalamus were dissected and their beta-EN levels measured by radioimmunoassay. Ethanol administration significantly increased beta-EN levels in the hippocampus and hypothalamus but had no effect on beta-EN levels in the cortex. Similar increases in beta-EN levels in the hippocampus and hypothalamus also occurred following either flumazenil or diazepam. On the other hand, RO 15-4513 significantly increased beta-EN levels in the cortex and hypothalamus. When flumazenil was concurrently administered with ethanol, it completely reversed the ethanol effects in the hippocampus but failed to do so in the hypothalamus. Concurrent administration of RO 15-4513 with ethanol also reversed the ethanol-induced rise of beta-EN in the hypothalamus. However, concurrent administration of diazepam and ethanol did not block the increase in beta-EN levels. These findings suggest that ethanol-induced effects on beta-EN levels in specific rat brain regions may be mediated through the gamma-aminobutyric acid/benzodiazepine receptor complex.