title: Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist.
abstract: The aim of this study was to reexamine the concept that gamma-hydroxybutyric acid (GHB) is a weak but selective agonist at gamma-aminobutyric acidB (GABAB) receptors, using binding experiments with several radioligands. Ki values of GHB were similar (approximately equal to 100 microM) in three agonist radioligand assays for GABAB receptors, [3H]baclofen (beta-para-chlorophenyl-gamma-aminobutyric acid), [3H]CGP 27492 (3-aminopropyl-phosphinic acid) and [3H]GABA, in the presence of the GABAA receptor agonist isoguvacine with rat cortical, cerebellar and hippocampal membranes. In competition experiments between GHB and the GABAB receptor antagonist, [3H]CGP 54626 (3-N [1-{(S)-3,4-dichlorophenyl}-ethylamino]-2-(S)-hydroxypropyl cyclo-hexylmethyl phosphinic acid), the IC50 values were significantly increased with 300 microM of 5'-guanyl-imidodiphosphate (Gpp(NH)p), which suggested that guanine nucleotide binding proteins (G-proteins) modulate GHB binding on GABAB receptors. The inhibition by GHB of [3H]CGP 27492 binding in cortical membranes was not altered in the presence of 0.3 or 3 mM of the two GHB dehydrogenase inhibitors, valproate and ethosuximide. Thus, GHB is not reconverted into GABA by GHB dehydrogenase. Taken together, the results of this study demonstrated that GHB is an endogenous weak but selective agonist at GABAB receptors.
authors.affiliation: Unité INSERM U.398, Neurobiologie et Neuropharmacologie des Epilepsies Généralisées, Faculté de Médecine, Strasbourg, France. U398@Neurochem u-strasbg.fr
authors.forename: P
authors.initials: P
authors.lastname: Mathivet
authors.forename: R
authors.initials: R
authors.lastname: Bernasconi
authors.forename: J
authors.initials: J
authors.lastname: De Barry
authors.forename: C
authors.initials: C
authors.lastname: Marescaux
authors.forename: H
authors.initials: H
authors.lastname: Bittiger
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D005013:Ethosuximide / Q000494:pharmacology; D018755:GABA Agonists / Q000378:metabolism* / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism*; D012978:Sodium Oxybate / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C061388:3-aminopropylphosphinic acid; C107353:CGP 54626; D006165:Guanylyl Imidodiphosphate; D005680:gamma-Aminobutyric Acid; D005013:Ethosuximide; D014635:Valproic Acid; D012978:Sodium Oxybate; D001418:Baclofen