Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid

The present study was aimed at identifying the receptor systems involved in the mediation of the sedative/hypnotic effect of gamma -hydroxybutyric aci d (GHB) in DBA mice. Administration of the putative antagonist of the GHB b inding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382; 50-500 mg/kg, i.p.), significantly increased the duration o f loss of righting reflex induced by GHB (1000 mg/kg, i.p.). In contrast, t he GABA, receptor antagonists, (2 S)(+)-5,5-dimethyl-2-morpholineacetic aci d (SCH 50911; 25-100 mg/kg, i.p.) and (3-aminopropyl)(cyclohexylmethyl)phos phinic acid (CGP 46381; 12.5-150 mg/kg, i.p.), completely prevented the sed ative/hypnotic effect of GHB. SCH 50911 (100 and 300 mg/kg, i.p.) was also capable to readily reverse the sedative/hypnotic effect of GHB (1000 mg/kg, i.p.) in mice that had lost the righting reflex. SCH 50911 (100 mg/kg, i.p .) also completely abolished the sedative/hypnotic effect of the GABAB rece ptor agonist, baclofen. These results indicate that the sedative/hypnotic e ffect of GHB is mediated by the stimulation of GABA(B) receptors and add fu rther support to the hypothesis that the GABA, receptor constitutes a centr al site of action of GHB. (C) 2001 Elsevier Science BN. All rights reserved .