The sedative and hypnotic agent THIP is a GABA A receptor agonist that preferentially activates δ-subunit containing GABA A receptors (δ-GABA A Rs). To clarify the role of δ-GABA A Rs in mediating the sedative actions of THIP, we have utilised mice lacking the α1 or δ subunit in a combined electrophysiological and behavioural analysis.Whole-cell patch-clamp recordings were obtained from thalamic ventrobasal (VB) neurones at a holding potential of −60mV. Application of bicuculline to wild type (WT) VB neurones revealed a GABA A R-mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of δ 0/0 mice. Deletion of the δ, but not the α1 subunit, dramatically reduced the THIP (1µM)-induced inward current in these neurones (WT = −309 ± 23 pA; δ 0/0 = −18 ± 3 pA; α1 0/0 = −377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and α1 0/0 , but not δ 0/0 VB neurones. THIP did not affect the properties of mIPSCs in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dosedependent manner. The effect of THIP on rotarod performance was blunted for δ 0/0 , but not α1 0/0 mice. We previously reported deletion of the α1 subunit to abolish synaptic GABA A responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic δ-GABA A Rs vs synaptic α1-GABA A Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.
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