Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA-B1-deficient mice

Klemens Kaupmann, John F Cryan, Petrine Wellendorph, Cedric Mombereau, Gilles Sansig, Klaus Klebs, Markus Schmutz, Wolfgang Froestl, Herman van der Putten, Johannes Mosbacher, Hans Bräuner-Osborne, Peter Waldmeier, Bernhard Bettler

    145 Citations (Scopus)

    Abstract

    gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.
    Original languageEnglish
    JournalEuropean Journal of Neuroscience
    Volume18
    Issue number10
    Pages (from-to)2722-30
    ISSN0953-816X
    Publication statusPublished - Nov 2003

    Keywords

    • 4-Butyrolactone
    • Adjuvants, Anesthesia
    • Animals
    • Anticonvulsants
    • Autoradiography
    • Baclofen
    • Behavior, Animal
    • Benzocycloheptenes
    • Binding, Competitive
    • Body Weight
    • Brain
    • Cell Membrane
    • Chromatography, High Pressure Liquid
    • Dihydroxyphenylalanine
    • Dose-Response Relationship, Drug
    • Drug Interactions
    • Electrochemistry
    • Electroencephalography
    • GABA-B Receptor Agonists
    • Guanosine 5'-O-(3-Thiotriphosphate)
    • Mice
    • Mice, Inbred BALB C
    • Mice, Knockout
    • Motor Activity
    • Organophosphorus Compounds
    • Phenols
    • Radioligand Assay
    • Receptors, GABA-B
    • Sodium Oxybate
    • Time Factors
    • gamma-Aminobutyric Acid

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