title: Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.
abstract: The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV. 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 delta(0/0) mice. Deletion of the delta- but not the alpha(1)-subunit dramatically reduced the THIP (1 mum)-induced inward current in these neurones (WT, -309 +/- 23 pA; delta(0/0), -18 +/- 3 pA; alpha(1) (0/0), -377 +/- 45 pA). Furthermore, THIP selectively decreased the excitability of WT and alpha(1) (0/0) but not delta(0/0) VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents 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 dose-dependent manner. The effect of THIP on rotarod performance was blunted for delta(0/0) but not alpha(1) (0/0) mice. We previously reported that deletion of the alpha(1)-subunit abolished synaptic GABA(A) responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic delta-GABA(A)Rs vs. synaptic alpha(1)-subunit-containing GABA(A)Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.
authors.affiliation: Division of Medical Sciences, Centre for Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Murray B
authors.initials: MB
authors.lastname: Herd
authors.forename: Nicola
authors.initials: N
authors.lastname: Foister
authors.forename: Dev
authors.initials: D
authors.lastname: Chandra
authors.forename: Dianne R
authors.initials: DR
authors.lastname: Peden
authors.forename: Gregg E
authors.initials: GE
authors.lastname: Homanics
authors.forename: Verity J
authors.initials: VJ
authors.lastname: Brown
authors.forename: David J K
authors.initials: DJ
authors.lastname: Balfour
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects* / Q000235:genetics; D018408:Patch-Clamp Techniques / Q000379:methods; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology; D013788:Thalamus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; C546241:Gabra1 protein, mouse; D018684:Glycine Agents; D007555:Isoxazoles; D011963:Receptors, GABA-A; D013331:Strychnine; C015542:gaboxadol; D001640:Bicuculline