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Mechanisms of anabolic androgenic steroid modulation of GABAa receptors.

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Call No.	QP563.G32 Y36 2004
Author	Yang, Paul.
Title	Mechanisms of anabolic androgenic steroid modulation of GABAa receptors.
Date	2004
Abstract	The goal of this thesis has been to characterize the mechanisms of anabolic androgenic steroid (AAS) modulation of γ-aminobutyric acid type A (GABA A ) receptors. I used whole cell patch clamp recording to investigate the effects of AAS on miniature inhibitory postsynaptic currents (mIPSCs) from Purkinje cells, which predominantly express α 1 β 2/3 γ 2 , in intact mouse brain slices. Comparison of these effects of AAS on Purkinje cells with those from native forebrain neurons, believed to predominantly express α 2 β 3 γ x receptors (Jorge-Rivera et al., 2000), suggested that AAS modulation may depend on α subunit composition. Thus, I characterized the effects of the AAS, 17α-methyltestosterone (17α-MeT), on currents elicited by rapid pulses (2-4 ms) of GABA from recombinant α 1 β 3 γ 2L and α 2 β 3 γ 2L receptors. To investigate the effects of receptor occupancy on AAS modulation, I assessed the effects of AAS on currents elicited by μM and mM concentrations of GABA. To investigate the effect of AAS on receptor desensitization kinetics, I assessed the effects of AAS on currents elicited by step (200 ms) and paired pulse application of mM GABA. In addition, modeling was used to determine the kinetic mechanisms underlying AAS modulation of GABA A receptors. To compare the effects of AAS with classic allosteric modulators of GABA A receptor, I also investigated the effects of a benzodiazepine site positive modulator, zolpidem, on these two receptor isoforms and compared it to the effects of AAS. Furthermore, because zolpidem shows decreased efficacy at γ 1 -containing receptors and both neurosteroids and the pyrazolopyridine, tracazolate, show dramatic enhancement of currents elicited by activation of δ-containing receptors, I also assessed whether substitution of a γ 1 or δ subunit for the γ 2L subunit in α 2 β 3 γ 2L receptors had significant effects on AAS modulation. Hypothesis. Although there are reports that AAS produce behavioral effects, the underlying molecular mechanisms of AAS effect in the central nervous system (CNS) are not well understood. I hypothesize that some of the behavioral effects of the AAS may arise from allosteric modulation of GABA A receptors, and that mechanisms of AAS modulation of GABA A receptors are dependent on subunit composition and GABA concentration.
Description	xii, 215 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Leslie P. Henderson.
Subject	GABA -- Receptors. 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.62

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Mechanisms of Anabolic Androgenic Steroid Modulation of GABAA Receptors A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Physiology by Paul Yang DARTMOUTH COLLEGE Hanover, New Hampshire January 20, 2004 Examining Committee: ___________________________ (Chair) Dr. Leslie P. Henderson ___________________________ Dr. John A. Daubenspeck ___________________________ Dr. James C. Leiter ___________________________ Dr. Stefano Vicini ___________________________ Dr. Carol Folt Dean of Graduate Studies

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