Skip Navigation



Cerebral Cortex Advance Access published online on October 12, 2005
Cerebral Cortex, doi:10.1093/cercor/bhj055
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
16/8/1134    most recent
bhj055v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Drasbek, K. R.
Right arrow Articles by Jensen, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Drasbek, K. R.
Right arrow Articles by Jensen, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Article

THIP, a Hypnotic and Antinociceptive Drug, Enhances an Extrasynaptic GABAA Receptor-mediated Conductance in Mouse Neocortex

Kim Ryun Drasbek 1 and Kimmo Jensen 1*

1 Synaptic Physiology Laboratory, Institute of Physiology and Biophysics, University of Aarhus, DK-8000 Aarhus C, Denmark

* To whom correspondence should be addressed.
Kimmo Jensen, E-mail: kimmo{at}fi.au.dk


  Abstract

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a selective GABAA receptor agonist with a preference for {delta}-subunit containing GABAA 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 µM induced a robust tonic GABAA-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 µM THIP suggesting an extrasynaptic site of action. The EC50 for THIP was 44 µM. 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 GABAA receptor-mediated conductance in the neocortex, which may alter the cortical network activity.

Keywords: {delta}-subunit; extrasynaptic receptors; GABA; mouse; neocortex; THIP.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
D. Belelli, N. L. Harrison, J. Maguire, R. L. Macdonald, M. C. Walker, and D. W. Cope
Extrasynaptic GABAA Receptors: Form, Pharmacology, and Function
J. Neurosci., October 14, 2009; 29(41): 12757 - 12763.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. M. Holm, J. L. Nieto-Gonzalez, I. Vardya, C. B. Vaegter, A. Nykjaer, and K. Jensen
Mature BDNF, But Not proBDNF, Reduces Excitability of Fast-Spiking Interneurons in Mouse Dentate Gyrus
J. Neurosci., October 7, 2009; 29(40): 12412 - 12418.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. PsychiatryHome page
J. G. Maldonado-Aviles, A. A. Curley, T. Hashimoto, A. L. Morrow, A. J. Ramsey, P. O'Donnell, D. W. Volk, and D. A. Lewis
Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia
Am J Psychiatry, April 1, 2009; 166(4): 450 - 459.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
E. I. Krook-Magnuson, P. Li, S. M. Paluszkiewicz, and M. M. Huntsman
Tonically Active Inhibition Selectively Controls Feedforward Circuits in Mouse Barrel Cortex
J Neurophysiol, August 1, 2008; 100(2): 932 - 944.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
I. Vardya, K. R. Drasbek, Z. Dosa, and K. Jensen
Cell Type-Specific GABAA Receptor-Mediated Tonic Inhibition in Mouse Neocortex
J Neurophysiol, July 1, 2008; 100(1): 526 - 532.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. B. Herd, A. R. Haythornthwaite, T. W. Rosahl, K. A. Wafford, G. E. Homanics, J. J. Lambert, and D. Belelli
The expression of GABAA {beta} subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells
J. Physiol., February 15, 2008; 586(4): 989 - 1004.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Szabadics, G. Tamas, and I. Soltesz
Different transmitter transients underlie presynaptic cell type specificity of GABAA,slow and GABAA,fast
PNAS, September 11, 2007; 104(37): 14831 - 14836.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J. Glykys and I. Mody
The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus
J. Physiol., August 1, 2007; 582(3): 1163 - 1178.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
K. R. Drasbek, K. Hoestgaard-Jensen, and K. Jensen
Modulation of Extrasynaptic THIP Conductances by GABAA-Receptor Modulators in Mouse Neocortex
J Neurophysiol, March 1, 2007; 97(3): 2293 - 2300.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Fang, L. Deng, C. A. Keller, M. Fukata, Y. Fukata, G. Chen, and B. Luscher
GODZ-Mediated Palmitoylation of GABAA Receptors Is Required for Normal Assembly and Function of GABAergic Inhibitory Synapses
J. Neurosci., December 6, 2006; 26(49): 12758 - 12768.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J.-s. Qi, J. Yao, C. Fang, B. Luscher, and G. Chen
Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures
J. Physiol., December 1, 2006; 577(2): 579 - 590.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. Chandra, F. Jia, J. Liang, Z. Peng, A. Suryanarayanan, D. F. Werner, I. Spigelman, C. R. Houser, R. W. Olsen, N. L. Harrison, et al.
GABAA receptor {alpha}4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol
PNAS, October 10, 2006; 103(41): 15230 - 15235.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.