Ro 15-4513 potentiates, instead of antagonizes, ethanol-induced sleep in mice exposed to small platform stress

Abstract

The effects of ethanol and the benzodiazepine receptor ligand ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513), were examined in NMRI mice exposed to small platform stress. This model contains several factors of stress, like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. In control mice, ethanol exerted an anxiolytic effect in the plus-maze, but did not further enhance the anxiolytic-like effects induced by small platform stress. Ro 15-4513 antagonized ethanol-induced sleep in control animals, but enhanced the hypnotic and lethal actions of ethanol in small platform stressed mice. Small platform stress did not alter the characteristics (KD and Bmax) of [3H]Ro 15-4513 binding to cerebellar membranes. Muscimol-stimulated 36Cl- uptake into brain microsacs was significantly reduced in cortex from small platform stressed animals. Ethanol had no effect on 36Cl- uptake into brain microsacs from cortex or cerebellum. It is proposed that small platform stress alters the activity of the gamma-aminobutyric acid (GABA)A receptor-chloride ionophore complex, causing changes in the interaction between ethanol and Ro 15-4513.