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Titolo:
THE GAMMA-HYDROXYBUTYRATE SIGNALING SYSTEM IN BRAIN - ORGANIZATION AND FUNCTIONAL IMPLICATIONS
Autore:
MAITRE M;
Indirizzi:
CNRS,CTR NEUROCHIM,LAB NEUROBIOL MOL INTERACT CELLULAIRES,UPR 416,5 RUE BLAISE PASCAL F-67084 STRASBOURG FRANCE
Titolo Testata:
Progress in neurobiology
fascicolo: 3, volume: 51, anno: 1997,
pagine: 337 - 361
SICI:
0301-0082(1997)51:3<337:TGSSIB>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUCCINIC SEMIALDEHYDE DEHYDROGENASE; ACID-BINDING-SITES; NADP+-DEPENDENT OXIDOREDUCTASE; GENERALIZED ABSENCE SEIZURES; CULTURED HUMAN-LYMPHOBLASTS; CENTRAL-NERVOUS-SYSTEM; KM ALDEHYDE REDUCTASE; DEVELOPING RAT-BRAIN; 4-HYDROXYBUTYRIC ACIDURIA; SUBSTANTIA-NIGRA;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
236
Recensione:
Indirizzi per estratti:
Citazione:
M. Maitre, "THE GAMMA-HYDROXYBUTYRATE SIGNALING SYSTEM IN BRAIN - ORGANIZATION AND FUNCTIONAL IMPLICATIONS", Progress in neurobiology, 51(3), 1997, pp. 337-361

Abstract

gamma-Hydroxybutyrate is a metabolite of GABA which is synthesized and accumulated by neurons in brain. This substance is present in micromolar quantities in all brain regions investigated as well as in several peripheral organs. Neuronal depolarization releases gamma-hydroxybutyrate into the extracellular space in a Ca2+-dependent manner. Gamma-hydroxybutyrate high-affinity receptors are present only in neurons, with a restricted specific distribution in the hippocampus, cortex and dopaminergic structures of rat brain (the striatum in general, olfactory bulbs and tubercles, frontal cortex, dopaminergic nuclei A(9), A(10)and A(12)). Stimulation of these receptors with low amounts of gamma-hydroxybutyrate induces in general hyperpolarizations in dopaminergic structures with a reduction of dopamine release. However, in the hippocampus and the frontal cortex, it seems that gamma-hydroxybutyrate induces depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. Some of the electrophysiological effects ofGHB are blocked by NCS-382, a gamma-hydroxybutyrate receptor antagonist while some others are strongly attenuated by GABA(B) receptors antagonists. Gamma-hydroxybutyrate penetrates freely into the brain when administered intravenously or intraperitoneally. This is a unique situation for a molecule with signalling properties in the brain. Thus, thegamma-hydroxybutyrate concentration in brain easily can be increased more than 100 times. Under these conditions, gamma-hydroxybutyrate receptors are saturated and probably desensitized and down-regulated. It is unlikely that GABA(B) receptors could be stimulated directly by GHB. Most probably, GABA is released in part under the control of GHB receptors in specific pathways expressing GABA(B) receptors. Alternatively, GABA(B) receptors might be specifically stimulated by the GABA formed via the metabolism of gamma-hydroxybutyrate in brain. In animals and man, these GHBergic and GABAergic potentiations induce dopaminergic hyperactivity (which follows the first phase of dopaminergic terminal hyperpolarization), a strong sedation with anaesthesia and some EEG changes with epileptic spikes. It is presumed that, under pathological conditions (hepatic failure, alcoholic intoxication, succinic semialdehyde dehydrogenase defects), the rate of GHB synthesis or degradation in the peripheral organ is modified and induces increased GHB levels which could interfere with the normal brain mechanisms. This pathological status could benefit from treatments with gamma-hydroxybutyric and/or GABA(B) receptors antagonists. Nevertheless, the regulating properties of the endogenous gamma-hydroxybutyrate system on the dopaminergic pathways are a cause for the recent interest in synthetic ligands acting specifically at gamma-hydroxybutyrate receptors and devoid of any role as metabolic precursor of GABA in brain. (C) 1997 Elsevier ScienceLtd.

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Documento generato il 26/09/20 alle ore 18:27:21