Unravelling the brain targets of gamma-hydroxybutyric acid.
Gamma-hydroxybutyric acid (GHB) is a naturally occurring gamma-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 GABAB 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; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB 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 GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
Crunelli
Vincenzo
V
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK. crunelli@cardiff.ac.uk
Emri
Zsuzsa
Z
Leresche
Nathalie
N
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004832:Epilepsy, Absence / Q000209:etiology; D058786:GABA-B Receptor Agonists; D006801:Humans; D006885:Hydroxybutyrates / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D012894:Sleep Stages / Q000187:drug effects; D019966:Substance-Related Disorders / Q000209:etiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D058786:GABA-B Receptor Agonists; D006885:Hydroxybutyrates; D008024:Ligands; D018080:Receptors, GABA-B; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid