Anabolic-androgenic steroids enhance motivation

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。不适当和过度的激励性行为是AAS在人类中最广泛报道的精神副作用。性行为和性暴力的加剧也被注意到。此外，AAS与多药滥用有关，最明显的是阿片类药物。我们希望了解为什么AAS滥用会使个人倾向于进行不适当和过度的攻击、性行为和药物使用，并揭开潜在的神经机制。特别是，我们的目标是解决公众的一个主要误解，即‘Roid愤怒代表着失去控制，一种对最小挑衅的突然和夸张的反应。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)仍然敏感。这为滥用AAS的行为影响提出了一种新的解释。目前的建议侧重于我们的假设，即青春期长期接触AAS不适当地增加了对奖励刺激的反应，包括自然奖励(性、攻击性)和滥用药物。这项拟议中的研究将调查青春期大鼠中高剂量雄激素如何改变奖励过程。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。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美性方面，而不是交配或打架的欲望动机。重要的是，性、战斗和吸毒都在加强，而且每一种都对雄激素敏感。因此，我们假设，AAS通过增加这些类固醇敏感行为的奖赏价值，增加了社会行为的表达和药物自我给药。目标1将确定AAS是否会增加攻击动机(目标1A)、交配动机(目标1B)和吗啡自我给药动机(目标1C)。目标2将探索这些效应的神经机制。我们将确定睾酮是否是增强伏隔核多巴胺活性对性刺激的反应的许可信号(目标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体的水平来确定这些反应的基本机制。总而言之，这些研究将为AAS增强动机和奖励的潜力以及实现这一目标的机制提供洞察力。

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.