title: Role of GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid.
abstract: The present study was aimed at identifying the receptor systems involved in the mediation of the sedative/hypnotic effect of gamma-hydroxybutyric acid (GHB) in DBA mice. Administration of the putative antagonist of the GHB binding 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 of loss of righting reflex induced by GHB (1000 mg/kg, i.p.). In contrast, the GABA(B) receptor antagonists, (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911; 25-100 mg/kg, i.p.) and (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381; 12.5-150 mg/kg, i.p.), completely prevented the sedative/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 GABA(B) receptor agonist, baclofen. These results indicate that the sedative/hypnotic effect of GHB is mediated by the stimulation of GABA(B) receptors and add further support to the hypothesis that the GABA(B) receptor constitutes a central site of action of GHB.
authors.affiliation: Bernard B. Brodie Department of Neuroscience, University of Cagliari, S.S. 554 Km. 4.5, I-09042 Monserrato, CA, Italy. mauro.carai@ns.crs4.it
authors.forename: M A
authors.initials: MA
authors.lastname: Carai
authors.forename: G
authors.initials: G
authors.lastname: Colombo
authors.forename: G
authors.initials: G
authors.lastname: Brunetti
authors.forename: S
authors.initials: S
authors.lastname: Melis
authors.forename: S
authors.initials: S
authors.lastname: Serra
authors.forename: G
authors.initials: G
authors.lastname: Vacca
authors.forename: S
authors.initials: S
authors.lastname: Mastinu
authors.forename: A M
authors.initials: AM
authors.lastname: Pistuddi
authors.forename: C
authors.initials: C
authors.lastname: Solinas
authors.forename: G
authors.initials: G
authors.lastname: Cignarella
authors.forename: G
authors.initials: G
authors.lastname: Minardi
authors.forename: G L
authors.initials: GL
authors.lastname: Gessa
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D006885:Hydroxybutyrates / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000502:physiology*; D012018:Reflex / Q000187:drug effects
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D000927:Anticonvulsants; D001567:Benzocycloheptenes; D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D006885:Hydroxybutyrates; D006993:Hypnotics and Sedatives; D009025:Morpholines; D018080:Receptors, GABA-B; C066471:NCS 382; C111420:4-hydroxybutyric acid; D001418:Baclofen