Specific γ-hydroxybutyrate-binding sites but loss of pharmacological effects of γ-hydroxybutyrate in GABAB(1)-deficient mice.

Autor: Kaupmann, Klemens, Cryan, John F., Wellendorph, Petrine, Mombereau, Cedric, Sansig, Gilles, Klebs, Klaus, Schmutz, Markus, Froestl, Wolfgang, Van Der Putten, Herman, Mosbacher, Johannes, Bräuner‐Osborne, Hans, Waldmeier, Peter, Bettler, Bernhard
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Zdroj: European Journal of Neuroscience; Nov2003, Vol. 18 Issue 10, p2722-2730, 9p
Abstrakt: 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 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-5 H-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 GTPγ[35S] responses in brain membrane preparations from wild-type but not GABAB(1)−/− mice. The GTPγ[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 GTPγ[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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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