γ-Hydroxybutyric acid and its relevance in neurology

Abstract

ACh = acetylcholine; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DA = dopamine; EDS = excessive daytime sleepiness; GABA = γ-aminobutyric acid; GABA-T = GABA transaminase; GAD = glutamic acid decarboxylase; GBL = γ-butyrolactone; GH = growth hormone; GHB = γ-hydroxybutyric acid; GHBDH = GHB dehydrogenase; GIRK = G-protein-coupled inward rectifying K+ channels; 5-HT = serotonin; NADPH = nicotinamide adenine dinucleotide phosphate; NMDA = N -methyld-aspartate; SSA = succinic semialdehyde; SSADH = succinic semialdehyde dehydrogenase deficiency; SSAR = succinic semialdehyde reductase; VGCC = voltage-gated Ca2+ channels; VIAAT = vesicular inhibitory amino acid transporter; VTA = ventral tegmental area. γ-Hydroxybutyric acid (GHB, oxybate) is formed from γ-aminobutyric acid (GABA) in the normal human brain. GHB can also be administered exogenously and readily passes the blood–brain barrier. In the brain, GHB may have a widespread neuromodulatory role that is mediated both by GHB-specific and γ-aminobutyric acid type B (GABAB) receptors. There has been widespread interest in GHB as a result of its emergence as a major recreational drug. Exogenously administered GHB elicits intoxication, withdrawal, tolerance, and addiction. GHB also induces slow wave sleep and has now been approved for treatment of narcolepsy. GHB may also have limited use as an anesthetic and in alcohol dependence and withdrawal. Accumulation of GHB may underlie some of the manifestations of succinic semialdehyde dehydrogenase deficiency (SSADH) in humans. The development of a murine model of this disease, together with that of specific GHB receptor ligands, has provided insights into the physiologic role of GHB in the brain and rationale for therapeutic intervention in neurologic disorders. These subjects have all been extensively reviewed.1–8 GHB is present in the normal brain and serves as both a precursor and a degradation product of GABA1–4 (figure). GABA is formed from glutamate by action of the glutamic acid …