Social isolation stress has been demonstrated to decrease the hypnotic activity of ethanol in rodents. In this study, the role of central corticotropin-releasing factor (CRF) and GABA A/benzodiazepine (BZD) receptor systems in the social isolation stress-induced decrease in the hypnotic activity of ethanol in mice was investigated by examining the effect of α-helical CRF 9–41 ( αhCRF) and flumazenil, antagonists of CRF and BZD receptors, respectively, on ethanol-induced sleep in group-housed and socially isolated mice. We also tested whether social isolation stress affects the ability of ethanol to enhance the GABA-induced 36Cl − influx into a synaptoneurosomal preparation of mouse forebrain. Social isolation stress significantly decreased both the ethanol (4 g/kg i.p.)-induced and pentobarbital (50 mg/kg i.p.)-induced sleeping times, while this stress had no effect on chloral hydrate (325 mg/kg i.p.)-induced sleep. The i.c.v. injection of αhCRF (6.5 nmol) and flumazenil (33 nmol) antagonized the social isolation stress-induced decrease in the ethanol sleep without affecting ethanol sleep in group-housed animals. Social isolation stress significantly attenuated the ability of GABA to stimulate 36Cl − influx but this stress had no effect on the ability of ethanol to enhance GABA-induced 36Cl − influx. These results suggest that the functional changes in central CRF and GABA A/BZD receptor systems are involved in the social isolation stress-induced decrease in the hypnotic activity of ethanol in mice. © 1997 Elsevier Science B.V. All rights reserved.