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Allosteric modulation of GABAa receptors by anabolic-androgenic steroids.

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Call No.	QP563.G32 J66 2005
Author	Jones, Brian Leslie.
Title	Allosteric modulation of GABAa receptors by anabolic-androgenic steroids.
Date	2005
Abstract	Anabolic-androgenic steroids (AAS) are synthetic derivatives of the gonadal hormone, testosterone. Despite their many untoward side effects, AAS are wildly abused for their ergogenic properties. AAS have numerous effects on many organ systems, including the central nervous system where they produce specific effects on behavior in both animals and humans. Interestingly, some of these behavioral effects of AAS occur too quickly to be produced by androgen receptor mediated changes in gene expression and instead appear to result from their ability to modulate neurotransmission mediated by ?-aminobutyric acid type A (GABA A ) receptors. The biophysical and pharmacological properties of GABA A receptors are dependent on the types of GABA A receptor subunits of which they are composed. Because particular GABA A receptor subunits are expressed in specific brain regions, drugs that interact with GABA A receptor isoforms can have specific behavioral effects. I hypothesized that the specific behavioral effects of AAS are underpinned by differential modulation of GABA A receptors composed of different subunits. Consequently, the goal of this thesis has been to characterize the ability of AAS to exert subunit-specific modulation of GABA A receptors. To this end, I have used patch clamp recordings, kinetic modeling, and biochemical techniques to study how AAS alter the functional properties of GABA A receptors composed of different GABA A receptor subunits. This work demonstrated that AAS differentially modulate tonic and phasic currents at ? 1 -and ? 2 -containing GABA A receptors in a manner that is consistent with their anxiolytic properties. Additionally, I found that AAS were positive modulators of ? 2 -containing receptors, but negative modulators of [varepsilon]-containing receptors. Kinetic modeling and site directed mutagenesis suggest that AAS interact with a binding pocket located in the membrane spanning region of the GABA A receptor. This work provides insights into the mechanisms by which AAS can alter behavior and contributes to the body of knowledge of the properties of specific GABA A receptor subtypes.
Description	269 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Henderson, Leslie P. ; Daubenspeck, John A. ; Leiter, James C. ; Nattie, Eugene E. ; Forman, Stuart A.
Subject	GABA -- Receptors. Allosteric regulation. ; Anabolic steroids -- Physiological effect. ; Androgens -- Physiological effect. ; Receptors
College	Dartmouth Medical School -- Department of Physiology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1659

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