Anabolic-androgenic steroids promote risky decision making

 描述（由申请人提供）：虽然合成代谢雄激素类固醇（AAS）具有合法的医疗用途，但它们也是滥用药物。AAS被运动员和其他人大量服用以提高成绩，对健康产生了长期的负面影响。1991年，睾酮被宣布为受管制物质。然而，非法使用AAS的情况继续增加，特别是在青少年中。事实上，高中生使用类固醇的发生率与可卡因或海洛因相当。尽管使用者将提高成绩的物质辩护为“健康的生活方式选择”，但临床研究和轶事报告呈现出不同的画面。许多AAS使用者符合精神活性物质依赖的DSM标准，包括尽管有负面副作用仍继续使用，以及停止使用类固醇时出现戒断症状。最终，与其他非法药物不同，AAS只有有限的急性中毒能力。相反，AAS滥用的一个关键危险反映了用户可能会参与对自己和周围人构成风险的行为。了解AAS在人类中使用的行为影响是复杂的，因为用户的动机是增加力量和肌肉质量。此外，我们无法控制预先存在的精神病理学或AAS类型或剂量的变异性，并且在正常志愿者中测试高剂量的AAS是不道德的。动物研究可以在外观和运动表现无关的实验环境中评估对AAS的反应。因此，我们使用长期高剂量睾酮治疗的大鼠来模拟人类AAS使用。 在人类中，AAS增加了冒险行为：打架，不安全的性行为，酒后驾车，携带武器。我们在大鼠中的研究表明，AAS分别修改的努力，惩罚，延迟和概率折扣测试的决策。拟议的研究将建立在这些最新的研究结果，以检验假设，即AAS损害复杂的决策和合作，这些影响是由多巴胺（DA）通过D1-（D1 R）和D2-样受体（D2 R）在亚核的丘脑（Acb）的作用。在操作性折扣任务中，大鼠在小奖励（1个糖丸）与大奖励（3-4个糖丸）之间进行选择，大奖励被折扣（不太可取）一些成本。长期高剂量的睾酮使大鼠对体力劳动、惩罚或拖延不太敏感，但对不确定性更敏感。目标1中的研究超越了简单的折扣任务，在自然环境中模拟决策，提出具有冲突成本的认知要求选择，并纳入社会互动。目的2探讨AAS决策障碍的神经生物学机制。作为中脑边缘DA系统的一部分，Acb对动机性行为和决策至关重要，DA功能障碍会损害决策。我们将测试Acb内睾酮植入（Aim 2A），以及在努力和概率折扣（Aim 2B）和互惠合作（Aim 2C）期间Acb中DAR的药理学操作。总之，这些研究将深入了解AAS引起的认知变化，以及这些变化发生的机制。

 DESCRIPTION (provided by applicant): 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.