Spontaneous and RO 15-1788-induced reversal of subsensitivity to GABA following chronic benzodiazepines

Abstract

Chronic daily injections of diazepam (5 mg/kg i.p.) for 21-30 days have previously been shown to cause a selective subsensitivity to microiontophoretically applied GABA in serotonergic dorsal raphe neurons in the rat. Following termination of chronic benzodiazepine treatment, GABAergic sensitivity remained depressed for up to 96 h even though pharmacologically active concentrations of diazepam and its active metabolites could no longer be detected in brain tissue. In contrast, a single injection of the specific benzodiazepine antagonist, RO 15-1788, given 22 h prior to electrophysiological recording, restored GABAergic sensitivity to the control range. Sensitivity of dorsal raphe neurons to serotonin was not altered by either chronic treatment with or withdrawal from diazepam. These results indicate that (1) RO 15-1788 can accelerate the time course of withdrawal and (2) administration of this benzodiazepine antagonist can induce a persistent change in GABAergic responsiveness.