Elsevier

Progress in Neurobiology

Volume 51, Issue 3, February 1997, Pages 337-361
Progress in Neurobiology

THE γ-HYDROXYBUTYRATE SIGNALLING SYSTEM IN BRAIN: ORGANIZATION AND FUNCTIONAL IMPLICATIONS

https://doi.org/10.1016/S0301-0082(96)00064-0Get rights and content

Abstract

γ-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 γ-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 A9, A10 and A12). Stimulation of these receptors with low amounts of γ-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 γ-hydroxybutyrate induces depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. Some of the electrophysiological effects of GHB are blocked by NCS-382, a γ-hydroxybutyrate receptor antagonist while some others are strongly attenuated by GABAB 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, the γ-hydroxybutyrate concentration in brain easily can be increased more than 100 times. Under these conditions, γ-hydroxybutyrate receptors are saturated and probably desensitized and down-regulated. It is unlikely that GABAB receptors could be stimulated directly by GHB. Most probably, GABA is released in part under the control of GHB receptors in specific pathways expressing GABAB receptors. Alternatively, GABAB receptors might be specifically stimulated by the GABA formed via the metabolism of γ-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 γ-hydroxybutyric and/or GABAB receptors antagonists. Nevertheless, the regulating properties of the endogenous γ-hydroxybutyrate system on the dopaminergic pathways are a cause for the recent interest in synthetic ligands acting specifically at γ-hydroxybutyrate receptors and devoid of any role as metabolic precursor of GABA in brain. © 1997 Elsevier Science Ltd. All Rights Reserved.

Section snippets

INTRODUCTION

Since the early sixties, γ-hydroxybutyrate generally has been thought to be a drug which enters the brain easily and which possesses the general profile of a GABAergic ligand (Laborit, 1964). Up to now, the majority of the research devoted to this compound has focused on the neuropharmacological and neurophysiological aspects of systemic administration. However, GHB is primarily a naturally occurring substance in brain which was identified about 30 years ago and which is synthesized locally (

γ-Hydroxybutyrate is Present in Small Quantities in Mammalian Brain

γ-Hydroxybutyrate real concentration in brain has been a matter of debate because it needs gas chromatography with preferably mass spectrometric detection to measure actual levels (Doherty et al. (1975a), Doherty et al. (1978); Ehrhardt et al., 1988). In addition, endogenous GHB concentrations fluctuate rapidly in the ischaemic brain, so that brain dissection must be carried out rapidly after death (Snead and Morley, 1981; Eli and Cattabeni, 1983; Vayer et al., 1988). The lowest levels of GHB

The γ-Hydroxybutyrate Model of Generalized Absence Seizures in Rodents

The potentiation of the GHB system by administration of low (10–100 mg/kg) or higher (200–400 mg/kg) doses of GHB or GBL induces in most of the animal species studied (chick, cat, rabbit, rat, dog, mice) and also in man, a modification of behaviour and of the EEG trace (Winters and Spooner, 1965; Yamada et al., 1967; Metcalf et al., 1966; Godschalk et al., 1977; Godbout and Pivik (1982), Snead (1984a), Snead (1988), Snead (1992); Brankack et al., 1993). Low doses of GHB cause a rise in states

CONCLUSION

There is little doubt that GHB represents a neuromodulatory signal in brain with a specific organization constituted by GHBergic pathways mainly localized in the rostral part of the brain. Molecular cloning of receptor(s) and enzymes which are part of these pathways will confirm this concept and further clarify the functional role of GHB in brain. One of the main distinctive properties of this system is that the simple hydrocarbon chain of GHB penetrates the brain with no apparent control when

Acknowledgements

This work was supported by grant from DRET 93-172.

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