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 GABA B 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 GABA A receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABA A receptors, where GHB acts as an agonist with an EC 50 of 140 nM. We investigated three neuronal cell types that express a tonic GABA A 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 GABA A 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 GABA B 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. © 2013 Connelly et al.
Connelly, W. M., Errington, A. C., & Crunelli, V. (2013). γ-Hydroxybutyric acid (GHB) is not an agonist of extrasynaptic GABAa receptors. PLoS ONE, 8(11). https://doi.org/10.1371/journal.pone.0079062