Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014216-02
Application #
6379152
Study Section
Special Emphasis Panel (ZHD1-MRG-C (01))
Program Officer
Riddle, Robert D
Project Start
2000-09-28
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$238,500
Indirect Cost
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Henderson, L P; Penatti, C A A; Jones, B L et al. (2006) Anabolic androgenic steroids and forebrain GABAergic transmission. Neuroscience 138:793-9
Penatti, C A A; Porter, D M; Jones, B L et al. (2005) Sex-specific effects of chronic anabolic androgenic steroid treatment on GABA(A) receptor expression and function in adolescent mice. Neuroscience 135:533-43
Yang, Paul; Jones, Brian L; Henderson, Leslie P (2005) Role of the alpha subunit in the modulation of GABA(A) receptors by anabolic androgenic steroids. Neuropharmacology 49:300-16
Yang, Paul; Jones, Brian L; Henderson, Leslie P (2002) Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors. Neuropharmacology 43:619-33