GAMMA-HYDROXYBUTYRATE, A PUTATIVE NEUROTRANSMITTER IN THE CENTRAL NERVOUS-SYSTEM

Abstract

.gamma.-Hydroxybutyrate (GHB) fulfills the main criteria of a neurotransmitter; it is unevenly distributed in CNS: it is synthesized from succinic semi-aldehyde by a specific semi-aldehyde succinic reductase localized in neurons, in some dendrites and synaptic terminals; GHB is released by tissue slice depolarization, this release being reduced by 50-60% in a Ca2+ free medium. Tetrodotoxin and verapamil strongly inhibited the depolarization evoked-release; high affinity heterogeneously distributed binding sites for .gamma.-hydroxybutyrate exist in the brain. This binding does not require Na+. The bound .gamma.-hydroxybutyric acid is not displaceable by GABA or GABA agonists. Binding sites are enriched in the synaptosomal fraction; after micro-iontophoretic application, GHB exerts a depressant action on nigral and neocortical cells which is resistant to the presence of bicuculline methiodide. In neuronal cultures, GHB causes a hyperpolarization similar to that produced by GABA; high affinity uptake system for GHB exists both in purified plasma membrane vesicles and in brain tissue slices. This uptake is dependent on an Na+ gradient and is inhibited by ouabain and dinitrophenol; GABA does not modify GHB uptake by rat brain slices; GABA derived GHB has a turnover time almost 3 times faster than that of whole brain serotonin, 6-8 times as rapid as that of whole brain dopamine and 13-19 times as rapid as that of whole brain norepinephrine.