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

BACKGROUND AND PURPOSE: Explorations 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 APPROACH: The 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 RESULTS: Thio-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 ∼30% of that of GABA at α(5)β(3)γ(2S), α(4)β(3)δ and α(6)β(3)δ and somewhat lower efficacies at the corresponding α(5)β(2)γ(2S), α(4)β(2)δ and α(6)β(2)δ subtypes (maximal responses of 4–12%). In contrast, it was an extremely low efficacious agonist at the α(1)β(3)γ(2S), α(1)β(2)γ(2S), α(2)β(2)γ(2S), α(2)β(3)γ(2S), α(3)β(2)γ(2S) and α(3)β(3)γ(2S) 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 IMPLICATIONS: The 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