Vol. 281, Issue 2, 753-760, 1997

-Hydroxybutyrate Conversion into GABA Induces Displacement of GABA_B Binding that is Blocked by Valproate and Ethosuximide¹

Viviane Hechler, Charline Ratomponirina and Michel Maitre

L.N.M.I.C, UPR 416 CNRS, Centre de Neurochimie, Strasbourg Cedex, France

-Hydroxybutyrate (GHB) has been reported to be a ligand for GABA_B receptor(s), although with low or very low affinity (IC₅₀ = 150-796 µM). In addition, several reports argue for a role of GHB via GABA_B receptors in both in vivo and in vitro electrophysiological experiments. In the present study, we demonstrate that the inhibition of GHB's conversion into GABA by rat brain membranes blocks the ability of GHB to interfere with GABA_B binding. In particular, the inhibition of GHB dehydrogenase by valproate or ethosuximide and the blockade of GABA-T by aminooxyacetic acid induce the disappearance of the GABA-like effect of GHB at GABA_B, but also at GABA_A, receptors. This finding could explain the misinterpretation of in viro or in vivo experiments where GHB possesses a GABA-like effect. But in addition, it is postulated that the normal metabolism of GHB in brain induces GABA_B mechanisms that could be blocked by the administration of valproate or ethosuximide.