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Specific γ‐hydroxybutyrate‐binding sites but loss of pharmacological effects of γ‐hydroxybutyrate in GABA B(1) ‐deficient mice
Author(s) -
Kaupmann Klemens,
Cryan John F.,
Wellendorph Petrine,
Mombereau Cedric,
Sansig Gilles,
Klebs Klaus,
Schmutz Markus,
Froestl Wolfgang,
Van Der Putten Herman,
Mosbacher Johannes,
BräunerOsborne Hans,
Waldmeier Peter,
Bettler Bernhard
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2003.03013.x
Subject(s) - gabab receptor , gamma hydroxybutyrate , chemistry , gamma aminobutyric acid , receptor , antagonist , neurotransmitter , pharmacology , metabolite , biochemistry , biology
γ‐Hydroxybutyrate (GHB), a metabolite of γ‐aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. γ‐Hydroxybutyrate and its prodrug, γ‐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 GABA B and/or specific GHB receptors, the latter corresponding to high‐affinity [ 3 H]GHB‐binding sites coupled to G‐proteins. To investigate the contribution of GABA B receptors to GHB actions we studied the effects of GHB in GABA B(1) −/− mice, which lack functional GABA B receptors. Autoradiography reveals a similar spatial distribution of [ 3 H]GHB‐binding sites in brains of GABA B(1) −/− and wild‐type mice. The maximal number of binding sites and the K D values for the putative GHB antagonist [ 3 H]6,7,8,9‐tetrahydro‐5‐hydroxy‐5 H ‐benzocyclohept‐6‐ylidene acetic acid (NCS‐382) appear unchanged in GABA B(1) −/− compared with wild‐type mice, demonstrating that GHB‐ are distinct from GABA B ‐binding sites. In the presence of the GABA B receptor positive modulator 2,6‐di‐tert‐butyl‐4‐(3‐hydroxy‐2,2‐dimethyl‐propyl)‐phenol GHB induced functional GTPγ[ 35 S] responses in brain membrane preparations from wild‐type but not GABA B(1) −/− mice. The GTPγ[ 35 S] responses in wild‐type mice were blocked by the GABA B 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 GTPγ[ 35 S] responses are mediated by GABA B receptors. Following GHB or GBL application, GABA B(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 GABA B receptor dependent. The molecular nature and the signalling properties of the specific [ 3 H]GHB‐binding sites remain elusive.