Although anabolic-androgenic steroids (AAS) have legitimate medical uses, they are also drugs of abuse. AAS are taken in large quantities by athletes and others to increase performance, with negative long- term health consequences. In 1991, testosterone was declared a controlled substance. Nonetheless, illicit use of AAS continues to increase, particularly among adolescents. Indeed, the incidence of steroid use among high school seniors is comparable to that for cocaine or heroin. Although users defend performance enhancing substances as a healthy lifestyle choice, clinical studies and anecdotal reports present a different picture. Many AAS users meet DSM criteria for psychoactive substance dependence, including continued use despite negative side effects, and withdrawal symptoms when steroids are discontinued. Ultimately, unlike other illicit drugs, AAS have only a limited capacity for acute intoxication. Instead, a key danger of AAS abuse reflects the likelihood that users will engage in behaviors that pose risks to themselves and those around them. Understanding behavioral effects of AAS use in humans is complicated by the user's motivation for increased strength and muscle mass. Furthermore, we cannot control for preexisting psychopathology or for variability in the type or dose of AAS, and it is unethical to test high doses of AAS in normal volunteers. Animal studies can evaluate responses to AAS in an experimental context where appearance and athletic performance are irrelevant. Therefore, we use rats treated chronically with high-dose testosterone to model human AAS use. In humans, AAS increase risk-taking: fighting, unsafe sex, drinking and driving, carrying a weapon. Our studies in rats demonstrate that AAS separately modify decision making on tests of effort, punishment, delay and probability discounting. The proposed studies will build on these recent findings to test the hypothesis that AAS impair complex decision making and cooperation, and these effects are mediated by dopamine (DA) acting via D1- (D1R) and D2-like receptors (D2R) in subnuclei of the nucleus accumbens (Acb). In operant discounting tasks, rats choose between a small reward (1 sugar pellet) vs a large reward (3-4 pellets) which is discounted (made less desirable) by some cost. Chronic high-dose testosterone makes rats less sensitive to physical effort, punishment or delay, but more sensitive to uncertainty. Studies in Aim 1 go beyond simple discounting tasks to model decision-making in a natural environment, presenting cognitively-demanding choices with conflicting costs, and incorporating social interaction.
Aim 2 will explore neurobiologic mechanisms for impaired decision making with AAS. As part of the mesolimbic DA system, Acb is central to motivated behavior and decision-making, and DA dysfunction impairs decision making. We will test intra-Acb implants of testosterone (Aim 2A), and pharmacologic manipulation of DAR in Acb during effort- and probability discounting (Aim 2B) and reciprocal cooperation (Aim 2C). Together, these studies will provide insight into the cognitive changes induced by AAS, and the mechanisms through which these occur.

Public Health Relevance

Anabolic-androgenic steroids (AAS) are performing-enhancing substances that are also drugs of abuse. The dangers of AAS abuse are not limited to the medical consequences of high-dose steroids themselves, but result from risk-taking in non-social (drinking and driving) and social contexts (aggression, sexual violence, unprotected sex). As a model for AAS abuse, male rats will be treated chronically with high-dose testosterone. Studies in this proposal will determine if chronic high-dose testosterone impairs risky decision-making in complex social and non-social contexts. We further hypothesize that testosterone reduces the tolerance for uncertainty by reducing dopaminergic receptors in the nucleus accumbens shell. At the same time, testosterone increases the willingness to work for food reward through increasing dopaminergic D2 receptors in the nucleus accumbens core. This reduces sensitivity to punishment, thereby increasing risk-taking behavior. These studies will provide insight into the cognitive effects of illicit AAS use.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA029613-08
Application #
9666880
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Grant, Steven J
Project Start
2010-07-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Wallin-Miller, Kathryn G; Kreutz, Frida; Li, Grace et al. (2018) Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors. Psychopharmacology (Berl) 235:959-969
Wallin-Miller, Kathryn; Li, Grace; Kelishani, Diana et al. (2018) Anabolic-androgenic steroids alter decision making in a balanced rodent model of the Iowa gambling task. Behav Neurosci 132:152-160
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Wallin, Kathryn G; Alves, Jasmin M; Wood, Ruth I (2015) Anabolic-androgenic steroids and decision making: Probability and effort discounting in male rats. Psychoneuroendocrinology 57:84-92
Wallin, Kathryn G; Wood, Ruth I (2015) Anabolic-androgenic steroids impair set-shifting and reversal learning in male rats. Eur Neuropsychopharmacol 25:583-90

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