Unravelling the brain targets of γ-hydroxybutyric acid

• Published in: Current opinion in pharmacology Vol. 6; no. 1; pp. 44 - 52
• Main Authors: Crunelli, Vincenzo, Emri, Zsuzsa, Leresche, Nathalie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2006; Elsevier
• Subjects: Animals; Brain - drug effects; Brain - metabolism; Cognitive Sciences; Epilepsy, Absence - etiology; GABA-B Receptor Agonists; gamma-Aminobutyric Acid - metabolism; Humans; Hydroxybutyrates - adverse effects; Hydroxybutyrates - metabolism; Hydroxybutyrates - pharmacology; Life Sciences; Ligands; Mice; Mice, Knockout; Neurons and Cognition; Receptors, GABA-B - genetics; Receptors, GABA-B - metabolism; Sleep Stages - drug effects; Substance-Related Disorders - etiology; Gamma-hydroxybutyric acid (GHB); GABAB receptors; gamma-aminobutyric acid (GABA); neurotransmitter; memory impairment; neuromodulator; GABAB receptor knockout mice
• ISSN: 1471-4892; 1471-4973
• DOI: 10.1016/j.coph.2005.10.001

γ-Hydroxybutyric acid (GHB) is a naturally occurring γ-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABA B receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABA B receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABA B receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABA B receptor-mediated actions of GHB are caused by GHB itself acting directly on GABA B receptors or by a GHB-derived GABA pool (or both).