γ-Hydroxybutyric Acid (GHB) is not an agonist of extrasynaptic GABAA receptors

Connelly, William M., Errington, Adam Clarke ORCID: https://orcid.org/0000-0002-2171-389X and Crunelli, Vincenzo ORCID: https://orcid.org/0000-0001-7154-9752 2013. γ-Hydroxybutyric Acid (GHB) is not an agonist of extrasynaptic GABAA receptors. PLoS ONE 8 (11) , e79062. 10.1371/journal.pone.0079062

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Abstract

γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	Q Science > QH Natural history > QH301 Biology
Publisher:	Public Library of Science
ISSN:	1932-6203
Date of First Compliant Deposit:	30 March 2016
Last Modified:	04 May 2023 17:40
URI:	https://orca.cardiff.ac.uk/id/eprint/58111

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