Journal
NEUROPHARMACOLOGY
Volume 56, Issue 1, Pages 182-189Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2008.08.004
Keywords
GABA(A) receptor; Delta subunit; Allosteric modulator; Thalamus; Extrasynaptic
Categories
Funding
- Biotechnology and Biological Sciences Research Council [C509923]
- Tenovus Scotland [T03/24]
- Biotechnology and Biological Sciences Research Council [BB/C509923/1] Funding Source: researchfish
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Inhibition in the brain is dominated by the neurotransmitter gamma-aminobutyric acid (GABA); operating through GABA(A) receptors. This form of neural inhibition was presumed to be mediated by synaptic receptors, however recent evidence has highlighted a previously unappreciated role for extrasynaptic GABA(A) receptors in controlling neuronal activity. Synaptic and extrasynaptic GABA(A) receptors exhibit distinct pharmacological and biophysical properties that differentially influence brain physiology and behavior. Here we used a fluorescence-based assay and cell lines expressing recombinant GABA(A) receptors to identify a novel series of benzamide compounds that selectively enhance, or activate alpha 4 beta 3 delta GABA(A) receptors (cf. alpha 4 beta 3 gamma 2 and alpha 1 beta 3 gamma 2). Utilising electrophysiological methods, we illustrate that one of these compounds, 4-chloro-N-[6,8-dibromo-2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS1) potently (low nM) enhances GABA-evoked currents mediated by alpha 4 beta 3 delta receptors. At similar concentrations DS1 directly activates this receptor and is the most potent known agonist of alpha 4 beta 3 delta receptors. 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS2) selectively potentiated GABA responses mediated by alpha 4 beta 3 delta receptors, but was not an agonist. Recent studies have revealed a tonic form of inhibition in thalamus mediated by the alpha 4 beta 2 delta extrasynaptic GABA(A) receptors that may contribute to the regulation of thalamocortical rhythmic activity associated with sleep, wakefulness, vigilance and seizure disorders. In mouse thalamic relay cells DS2 enhanced the tonic current mediated by alpha 4 beta 2 delta receptors with no effect on their synaptic GABA(A) receptors. Similarly, in mouse cerebellar granule cells DS2 potentiated the tonic current mediated by alpha 6 beta delta receptors. DS2 is the first selective positive allosteric modulator of delta-GABA(A) receptors and such compounds potentially offer novel therapeutic opportunities as analgesics and in the treatment of sleep disorders. Furthermore, these drugs may be valuable in elucidating the physiological and pathophysiological roles played by these extrasynaptic GABA(A) receptors. (C) 2008 Elsevier Ltd. All rights reserved.
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