Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential?

Abstract

Gamma-hydroxybutyrate (GHB) is an endogenous constituent of mammalian brains, synthesized locally from GABA that might play a role as a central neuromodulator (Box 1) 1 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Scopus (775) Google Scholar , 2 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (122) Google Scholar , 3 Maötre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (409) Google Scholar . GHB freely crosses the blood–brain barrier and has been used in anaesthesia, sleep disorders and alcohol and opioid dependence. Recently, the ability of GHB to induce euphoria has resulted in a growing number of illicit self-administrations. Acute overdoses induce confusion, epileptic seizures and coma. Chronic exposure can lead to physical dependence, as evidenced by withdrawal symptoms. The mechanisms by which GHB affects neural functioning and acts as a drug of abuse are still under study. Box 1. Biosynthesis and degradation of γ-hydroxybutyrate in the rat brain GABA is deaminated through GABA transaminase (EC 2.6.19) (a) into succinic semialdehyde (SSA). Oxidation of SSA by the mitochondrial SSA dehydrogenase (b) produces succinic acid, whereas its reduction by the cytosolic SSA reductase (EC 1.1.1.1.2) (c) gives rise to Γ-hydroxybutyric acid (GHB). Less than 0.15% of the metabolic flux coming from GABA takes the reductive pathway and forms GHB. Depending on species, anatomical structures, level of brain maturation and methods of detection, GHB levels range from 0.5–25 pmol mg−1 tissue. The substantia nigra, thalamus and hypothalamus contain the greatest amounts of GHB, whereas the cerebellum and some cortical areas contain the lowest. Degradation of GHB involves its oxidation to SSA, through GHB dehydrogenase (EC 1.1.1.19), (d) followed by entry intro Krebs cycle via succinic acid. A small part of SSA coming from GHB might be retransformed into GABA (e). Substances structurally related to GHB bind to both high- and low-affinity sites and display agonistic (trans-γ-hydroxycrotonic acid, THCA) or antagonistic (NCS382) properties. γ-Butyrolactone (GBL) does not bind to GHB binding sites and is inactive per se. However, as GBL is rapidly and irreversibly hydrolysed into GHB by peripheral gamma-lactonase (f) and as it is more rapidly and more reproducibly absorbed, GBL is often used as a GHB precursor in animal experiments. r(−)-Baclofen is a structural analogue of GABA and a specific agonist of GABAB receptors; it is inactive at GABAA and GHB binding sites. (See 1 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (97) Google Scholar , 2 Maı̂tre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (319) Google Scholar for review.) aSee 3 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Google Scholar . (Online: Fig. I) GABA is deaminated through GABA transaminase (EC 2.6.19) (a) into succinic semialdehyde (SSA). Oxidation of SSA by the mitochondrial SSA dehydrogenase (b) produces succinic acid, whereas its reduction by the cytosolic SSA reductase (EC 1.1.1.1.2) (c) gives rise to Γ-hydroxybutyric acid (GHB). Less than 0.15% of the metabolic flux coming from GABA takes the reductive pathway and forms GHB. Depending on species, anatomical structures, level of brain maturation and methods of detection, GHB levels range from 0.5–25 pmol mg−1 tissue. The substantia nigra, thalamus and hypothalamus contain the greatest amounts of GHB, whereas the cerebellum and some cortical areas contain the lowest. Degradation of GHB involves its oxidation to SSA, through GHB dehydrogenase (EC 1.1.1.19), (d) followed by entry intro Krebs cycle via succinic acid. A small part of SSA coming from GHB might be retransformed into GABA (e). Substances structurally related to GHB bind to both high- and low-affinity sites and display agonistic (trans-γ-hydroxycrotonic acid, THCA) or antagonistic (NCS382) properties. γ-Butyrolactone (GBL) does not bind to GHB binding sites and is inactive per se. However, as GBL is rapidly and irreversibly hydrolysed into GHB by peripheral gamma-lactonase (f) and as it is more rapidly and more reproducibly absorbed, GBL is often used as a GHB precursor in animal experiments. r(−)-Baclofen is a structural analogue of GABA and a specific agonist of GABAB receptors; it is inactive at GABAA and GHB binding sites. (See 1 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (97) Google Scholar , 2 Maı̂tre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (319) Google Scholar for review.) aSee 3 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Google Scholar . (Online: Fig. I) 3-N[1{(s)-3,4-dichlorophenyl}-ethylamino]-2-(s)hydroxypropylcyclo-hexylmethyl phosphinic acid 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate