title: THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex.
abstract: THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a selective GABA(A) receptor agonist with a preference for delta-subunit containing GABA(A) receptors. THIP is currently being tested in human trials for its hypnotic effects, displaying advantageous tolerance and addiction properties. Since its cellular actions in the neocortex are uncertain, we studied the effects of THIP on neurons in slices of frontoparietal neocortex of 13- to 19-day-old (P13-19) mice. Using whole-cell patch-clamp recordings, we found that the clinically relevant THIP concentration of 1 muM induced a robust tonic GABA(A)-mediated current in layer 2/3 neurons. In comparison, only a minute tonic current was induced by mimicking in vivo endogenous GABA levels. Miniature IPSCs were not affected by 1 muM THIP suggesting an extrasynaptic site of action. The EC(50) for THIP was 44 muM. In accordance with the stronger expression of delta-containing receptors in superficial neocortical layers, THIP induced a 44% larger tonic current in layer 2/3 than in layer 5 neurons. Finally, monitoring spontaneously active neocortical neurons, THIP caused an overall depression of inhibitory activity, while enhancing excitatory activity prominently. Our studies suggest that THIP activates an extrasynaptic GABA(A) receptor-mediated conductance in the neocortex, which may alter the cortical network activity.
authors.affiliation: Synaptic Physiology Laboratory, Institute of Physiology and Biophysics, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: Kim Ryun
authors.initials: KR
authors.lastname: Drasbek
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jensen
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004553:Electric Conductivity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D000700:Analgesics; D006993:Hypnotics and Sedatives; D007555:Isoxazoles; D011963:Receptors, GABA-A; C015542:gaboxadol