Gamma-hydroxybutyric acid: neurobiology and toxicology of a recreational drug.

gamma-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. GHB was synthesised over 40 years ago and its presence in the brain and a number of aspects of its biological, pharmacological and toxicological properties have been elucidated over the last 20-30 years. However, widespread interest in this compound has arisen only in the past 5-10 years, primarily as a result of the emergence of GHB as a major recreational drug and public health problem in the US. There is considerable evidence that GHB may be a neuromodulator in the brain. GHB has multiple neuronal mechanisms including activation of both the gamma-aminobutyric acid type B (GABA(B)) receptor, and a separate GHB-specific receptor. This complex GHB-GABA(B) receptor interaction is probably responsible for the protean pharmacological, electroencephalographic, behavioural and toxicological effects of GHB, as well as the perturbations of learning and memory associated with supra-physiological concentrations of GHB in the brain that result from the exogenous administration of this drug in the clinical context of GHB abuse, addiction and withdrawal. Investigation of the inborn error of metabolism succinic semialdehyde deficiency (SSADH) and the murine model of this disorder (SSADH knockout mice), in which GHB plays a major role, may help dissect out GHB- and GABA(B) receptor-mediated mechanisms. In particular, the mechanisms that are operative in the molecular pathogenesis of GHB addiction and withdrawal as well as the absence seizures observed in the GHB-treated animals.

From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid.

gamma-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is formed primarily from the precursor gamma-aminobutyric acid (GABA). The properties of GHB suggest that it has a neuromodulatory role in the brain and has the ability to induce several pharmacological and behavioral effects. GHB has been used clinically as an anesthetic and to treat alcoholism and narcolepsy. Furthermore, GHB has emerged recently as a major recreational drug of abuse. GHB appears to have dual mechanisms of action in the brain. Biochemical data suggest that the intrinsic neurobiological activity of GHB might be mediated through the GHB receptor, which is separate and distinct from the GABA(B) receptor. However, many of the pharmacological and clinical effects of exogenously administered GHB, including the properties of addiction, tolerance, withdrawal and intoxication, are probably mediated via the GABA(B) receptor, where GHB might act both directly as a partial agonist and indirectly through GHB-derived GABA.

GABA, gamma-hydroxybutyric acid, and neurological disease.

gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency.

The GABA(A) Receptor: Subunit-Dependent Functions and Absence Seizures.

GABA(A) receptors on thalamic relay and reticular (nRT) neurons play a critical role in thalamocortical mechanisms underlying absence seizures. Studies with absence seizure-prone rats and transgenic mice have taken advantage of differences in the subunit compositions of GABA(A) receptors in the two thalamic cell populations to clarify thalamocortical rhythm generating mechanisms and explain the antiabsence activity of benzodiazepines. The relevance of this work is highlighted by the recent finding of a mutation in the GABA(A) receptor gamma2 subunit in a family with childhood absence seizures.