Midazolam-ethanol interactions and reversal with a benzodiazepine antagonist

The purpose of these experiments was to analyze the cerebrovascular and cerebral metabolic effects of midazolam, a short-acting water-soluble benzodiazepine, and to investigate its interaction with alcohol in rats. A benzodiazepine antagonist, 3-carbo-t-butoxy-beta-carboline (beta-CCT), was used to test the role of the benzodiazepine receptor in midazolam-alcohol effects. Experiments were carried out under 70% N2O, 30% O2 anesthesia. Rats were tested with intraperitoneal injections of 0.75-5 mg/g ethanol, intravenous infusions of 0.57, 5.75 mg/kg midazolam, and 1.15 mg/kg beta-CCT separately and in combination. Cortical cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was determined from cortical CBF and arterial-sagittal sinus blood samples 20 min after ethanol treatment and/or after a 15-min drug infusion. Alcohol alone produced dose-related increases in plasma ethanol concentrations but no depression in CMRO2 except at the highest dose (5 mg/g). Midazolam infusions alone decreased cortical CBF and CMRO2 35-40%, while 2.5 mg/g alcohol (which did not depress CMRO2 alone) combined with midazolam produced a 70% depression of cortical CBF and metabolism. An infusion of beta-CCT given alone increased CMRO2 alone and reversed the depression in both cortical CBF and CMRO2 produced by midazolam plus alcohol. These results indicate that the ability of alcohol to potentiate benzodiazepine-induced sedation is not simply an additive effect but may be related to the facilitation by alcohol of benzodiazepine receptor binding. The fact that beta-CCT reversed midazolam-ethanol-induced depression suggests that the effect may be mediated through the benzodiazepine receptor.