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.
Highlights
Introduction cHydroxybutyric acid (GHB) is a naturally occurring GABA metabolite, a recreational drug and is used therapeutically as a treatment for the symptoms of narcolepsy and to treat alcohol dependence and withdrawal [1]
It is well established that GHB is an agonist at GABAB receptors, evidence suggests that it has some behavioural effects via another site: the GHB receptor
A recent study by Absalom et al, (2012) suggests that the GHB receptor is the a4b1d GABAA receptor, and that GHB is a direct agonist at these receptors [20]
Summary
Introduction cHydroxybutyric acid (GHB) is a naturally occurring GABA metabolite, a recreational drug and is used therapeutically as a treatment for the symptoms of narcolepsy and to treat alcohol dependence and withdrawal [1]. GHB causes dose-dependent sedation, ataxia and hypothermia, the molecular mechanism of action is unclear. GHB binds with low micromolar affinity to GABAB receptors and many of its effects can be directly ascribed to activation of these receptors. Pretreatment with specific GABAB receptor antagonists prevents GHB-induced hypothermia, ataxia and sedation, effects which GABAB(1)2/2 mice are resistant to [2,3,4,5]. GHB binds to this site with nano- to micromolar affinity and is antagonised by the compound NCS382. The purported specific GHB receptor agonist c-hydroxyvaleric acid mimics some of the effects of GHB (e.g. ataxia, sedation) without binding to the GABAB receptor [10]. One report shows that GHB reduces GABA release via a presynaptic mechanism that is blocked by NCS-382 [11]. The exact molecular nature of the GHB receptor is unclear
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