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γ-Hydroxybutyric Acid

Neurobiology and Toxicology of a Recreational Drug

  • GHB Symposium
  • Published:
Toxicological Reviews

Abstract

γ-Hydroxybutyric acid (GHB) is a short-chain fatty acid that occurs naturally in mammalian brain where it is derived metabolically from γ-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 γ-aminobutyric acid type B (GABAB) receptor, and a separate GHB-specific receptor. This complex GHB-GABAB 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 GABAB 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.

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Acknowledgements

This work was supported in part by the Canadian Institutes of Health Research (grant # 14329 MOP), the National Institutes of Health (grant # NS40270), an endowment from the Bloorview Childrens Hospital Foundation, a personal award to CGT Wong from the Heart and Stroke Foundation of Canada, and members of the Partnership for Pediatric Epilepsy Research (including the American Epilepsy Society, the Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures [F.A.C.E.S.], Neurotherapy Ventures Charitable Research Fund, and Parents Against Childhood Epilepsy [P.A.C.E.]). The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    C. Guin Ting Wong, Katherine F. Y. Chan &  O. Carter Snead III

  2. Brain and Behavior Research Program, The Hospital for Sick Children, Toronto, Ontario, Canada

    C. Guin Ting Wong &  O. Carter Snead III

  3. Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Katherine F. Y. Chan &  O. Carter Snead III

  4. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA

    K. Michael Gibson

  5. Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    O. Carter Snead III

  6. Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

    O. Carter Snead III

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Wong, C.G.T., Chan, K.F.Y., Gibson, K.M. et al. γ-Hydroxybutyric Acid. Toxicol Rev 23, 3–20 (2004). https://doi.org/10.2165/00139709-200423010-00002

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