Anabolic-androgenic steroids promote risky decision making

 说明(申请人提供)：虽然合成代谢-雄激素(AAs)具有合法的医疗用途，但它们也是滥用的药物。运动员和其他人大量服用AAS以提高成绩，这会对长期健康造成负面影响。1991年，睾酮被宣布为受控物质。尽管如此，AAS的非法使用仍在继续增加，特别是在青少年中。事实上，高中生使用类固醇的发生率与使用可卡因或海洛因的比例相当。尽管使用者辩称提高运动能力的物质是一种“健康的生活方式选择”，但临床研究和轶事报道呈现了一幅不同的图景。许多AAS使用者符合DSM的精神活性物质依赖标准，包括尽管有负面副作用仍继续使用，以及当类固醇停用时出现戒断症状。归根结底，与其他非法药物不同，AAS对急性中毒的能力有限。相反，滥用AAS的一个关键危险反映了用户参与对自己和周围人构成风险的行为的可能性。由于使用者增加力量和肌肉质量的动机，理解使用AAS对人类的行为影响是复杂的。此外，我们无法控制先前存在的精神病理学或AAS类型或剂量的可变性，在正常志愿者中测试高剂量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，我们使用长期服用高剂量睾酮的大鼠来模拟人类AAS的使用。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。我们在大鼠身上的研究表明，AAS分别改变了努力、惩罚、延迟和概率折扣测试中的决策。拟议的研究将建立在这些最新发现的基础上，以检验AAS损害复杂的决策和合作的假设，这些影响是由伏核(ACB)亚核中的多巴胺(DA)通过D1-(D1R)和D2样受体(D2R)介导的。在可操作的折扣任务中，老鼠在小奖励(1颗糖丸)和大奖励(3-4粒)之间进行选择，后者会因某些成本而被打折(变得不那么令人满意)。长期高剂量的睾丸素使大鼠对体力、惩罚或拖延不那么敏感，但对不确定性更敏感。目标1中的研究超越了简单的任务折扣，模拟了自然环境中的决策，提出了具有相互冲突的成本的认知要求高的选择，并纳入了社会互动。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是动机行为和决策的中枢，而DA功能障碍影响决策。我们将测试ACB内植入睾酮(目标2A)，以及在努力和概率折扣(目标2B)和互惠合作(目标2C)期间ACB对DAR的药理操作。总而言之，这些研究将提供对AAS引起的认知变化的洞察，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.