The orthosteric GABAA receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors

Background and PurposeExplorations into the heterogeneous population of native GABA type A receptors (GABA(A)Rs) and the physiological functions governed by the multiple GABA(A)R subtypes have for decades been hampered by the lack of subtype-selective ligands. Experimental ApproachThe functional properties of the orthosteric GABA(A) receptor ligand 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) have been investigated in vitro, ex vivo and in vivo. Key ResultsThio-4-PIOL displayed substantial partial agonist activity at the human extrasynaptic GABA(A)R subtypes expressed in Xenopus oocytes, eliciting maximal responses of up to approximate to 30% of that of GABA at (532S), (43) and (63) and somewhat lower efficacies at the corresponding (522S), (42) and (62) subtypes (maximal responses of 4-12%). In contrast, it was an extremely low efficacious agonist at the (132S), (122S), (222S), (232S), (322S) and (332S) GABA(A)Rs (maximal responses of 0-4%). In concordance with its agonism at extrasynaptic GABA(A)Rs and its de facto antagonism at the synaptic receptors, Thio-4-PIOL elicited robust tonic currents in electrophysiological recordings on slices from rat CA1 hippocampus and ventrobasal thalamus and antagonized phasic currents in hippocampal neurons. Finally, the observed effects of Thio-4-PIOL in rat tests of anxiety, locomotion, nociception and spatial memory were overall in good agreement with its in vitro and ex vivo properties. Conclusion and ImplicationsThe diverse signalling characteristics of Thio-4-PIOL at GABA(A)Rs represent one of the few examples of a functionally subtype-selective orthosteric GABA(A)R ligand reported to date. We propose that Thio-4-PIOL could be a useful pharmacological tool in future studies exploring the physiological roles of native synaptic and extrasynaptic GABA(A)Rs.