Anabolic-androgenic steroids enhance motivation

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，并对健康产生长期的负面影响。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。不适当的和过度的激动行为（'类固醇愤怒）是AAS在人类中最广泛报道的精神病副作用。还注意到性行为和性暴力的加剧。此外，AAS与多种药物滥用有关，特别是阿片类药物。我们希望了解为什么AAS滥用倾向于个人从事不适当的和过度的侵略，性行为和药物使用，并解开潜在的神经机制。特别是，我们的目标是解决一个主要的公众误解，即“类固醇愤怒代表失去控制，对最小的挑衅突然和夸张的反应。相反，研究表明，AAS治疗的大鼠对社会互动的背景（个人和环境）保持敏感。这为AAS滥用的行为效应提供了新的解释。目前的建议侧重于我们的假设，即在青春期长期暴露于AAS不适当地增加了对奖励刺激的反应，包括自然奖励（性，侵略）和滥用药物。拟议的研究将调查青春期大鼠的高剂量雄激素如何改变奖励过程。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。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。在这方面，动物也表现出AAS诱导的攻击和性行为。然而，这些研究强调的是行为的完成性方面，而不是交配或战斗的欲望动机。重要的是，性，战斗和吸毒都是强化的，每一个都对雄激素敏感。因此，我们假设AAS通过增加这些类固醇敏感行为的奖励值来增加社会行为和药物自我给药的表达。目标1将确定AAS是否增加攻击（目标1A）、交配（目标1B）和吗啡自我给药（目标1C）的动机。目的2将探讨这些影响的神经机制。我们将确定睾酮是否是一个允许的信号，以增强多巴胺的活性在丘脑核反应性刺激（目的2A）。目的2B将通过测量酪氨酸羟化酶、多巴胺D1和D2受体以及多巴胺转运蛋白的水平来确定这些反应的基本机制。总之，这些研究将深入了解AAS增强动机和奖励的潜力，以及发生这种情况的机制。

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. Inappropriate and excessive agonistic behavior ('roid rage) is the most widely-reported psychiatric side effect of AAS in humans. Heightened sexuality and sexual violence have also been noted. Furthermore, AAS are linked with polydrug abuse, most notably opioids. We hope to understand why AAS abuse predisposes individuals to engage in inappropriate and excessive aggression, sexual behavior and drug use, and to unravel the underlying neural mechanisms. In particular, we aim to address a major public misconception that 'roid rage represents a loss of control, a sudden and exaggerated response to a minimal provocation. Instead, research suggests that AAS-treated rats remain sensitive to the context (individual and environment) of social interactions. This suggests a new explanation for behavioral effects of AAS abuse. The current proposal focuses on our hypothesis that chronic exposure to AAS during adolescence inappropriately increases responsiveness to rewarding stimuli, both natural rewards (sex, aggression) and drugs of abuse. The proposed studies will investigate how high-dose androgens in adolescent rats alter reward processes. Understanding behavioral effects of AAS use in humans is complicated by the user's motivation for increased strength and muscle mass. Animal studies can evaluate responses to AAS in an experimental context where appearance and athletic performance are irrelevant. In this regard, animals also demonstrate AAS-induced aggression and sexual behavior. Yet, these studies have emphasized consummatory aspects of behavior, not the appetitive motivation for mating or fighting. Importantly, sex, fighting and drug use are each reinforcing, and each is sensitive to androgens. Accordingly, we hypothesize that AAS increase expression of social behaviors and drug self-administration by increasing the reward value of these steroid-sensitive behaviors. Aim 1 will determine if AAS increase motivation for aggression (Aim 1A), mating (Aim 1B) and morphine self- administration (Aim 1C). Aim 2 will explore neural mechanisms for these effects. We will determine if testosterone is a permissive signal to enhance dopamine activity in the nucleus accumbens in response to sexual stimuli (Aim 2A). Aim 2B will determine fundamental mechanisms underlying these responses by measuring levels of tyrosine hydroxylase, dopamine D1 and D2 receptors, and the dopamine transporter. Together, these studies will provide insight into the potential for AAS to enhance motivation and reward, and the mechanisms through which this occurs.