Brain aromatase availability in steroid users: PET studies with [11C]vorozole

描述（由申请人提供）：合成代谢雄激素类固醇（AAS）的使用影响了大约1-3%的人口，是一个引起社会、学术和医学极大兴趣的问题。AAS的使用与暴力死亡率（他杀/自杀）的增加和比其他非法药物使用人群更早死亡有关，并且在使用者中显示出很大的依赖性。医疗后果可能包括心脏事件、肝毒性、骨骼变化和甲状腺功能减退的风险增加，以及总体上更高的死亡率和发病率。目前，还没有治疗AAS依赖或中毒的方法。作为第一步，表征与AAS中毒相关的神经生物学变化对于开发新的有效治疗方法来治疗AAS依赖和限制AAS使用的精神后果至关重要。提出的研究旨在确定一些关键的神经生物学过程负责一组活跃的和有经验的AAS使用男性AAS中毒。通过研究AAS中毒与芳香化酶可用性的关系，我们将能够了解AAS代谢与核心心理和行为变化之间的功能关系，从而加强AAS的使用。虽然服用AAS主要是为了改变外表或提高运动成绩，但AAS中毒综合征可以通过使用AAS的理想心理和行为影响来定义，包括社会支配地位、性冲动、攻击性、目标导向行为和自尊的增加，这些都有一个共同的行为解除抑制的增加。该研究旨在检验两个新的假设：1)AAS使用者的脑芳香化酶水平高于对照组，并且在服用AAS后会进一步升高；2)区域脑芳香化酶可用性与冲动、攻击和对愉悦的敏感性的行为和自我报告测量呈正相关。为了验证这些假设，我们制定了两个具体目标：A)评估AAS使用对与循环性腺激素水平相关的区域脑芳香化酶可用性的影响；B)测试区域脑芳香化酶可用性变化与AAS使用者AAS中毒综合征（攻击性、性活动、冲动和寻求感觉）的行为测量之间的相关性。这些目标将在男性AAS使用者（n=8）和健康运动控制组（n=8）的对照纵向研究中进行检验，这些控制组的年龄、运动和教育程度相匹配。这项研究的结果将被用作AAS依赖性纵向研究的试点数据，其中我们将检查芳香化酶的变化作为重复使用AAS的函数。这一系列研究将旨在开发生物标记物，并调查“现实世界”AAS用户对AAS反应的个体差异。该研究还将为开发新的治疗靶点提供数据，以预防和治疗AAS成瘾；具体来说，芳香化酶抑制剂和雌激素拮抗剂可作为药物治疗AAS中毒。这些结果与NIDA的目标是一致的，即直接为该人群的预防和治疗工作提供信息。

DESCRIPTION (provided by applicant): Anabolic Androgenic Steroid (AAS) use affects about 1-3% of the population and is an issue of great social, academic, and medical interest. AAS use is associated with increased rates of violent death (homicide/suicide) and earlier age of death than other illicit drug-using populations, and exhibits a significant rate of dependency among users. Medical consequences may include increased risk for cardiac events, liver toxicity, skeletal changes, and hypothyroidism, and overall higher mortality and morbidity. Currently, there are no treatments for AAS dependence or intoxication. As a first step, characterizing the neurobiological changes associated with AAS intoxication will be essential to the development of novel and effective therapeutics designed to treat AAS dependence and limit the psychiatric consequences to AAS use. The proposed study aims to identify some of the key neurobiological processes responsible for AAS intoxication in a group of active and experienced AAS- using men. By studying AAS intoxication in relation to aromatase availability, we will be able to understand functional relationships between AAS metabolism and the core psychological and behavioral changes that reinforce AAS use. Although AASs are taken primarily for their ability to change appearance or increase athletic performance, the AAS intoxication syndrome can be defined by the desirable psychological and behavioral effects of AAS use that include increases in social dominance, sex drive, aggression, goal directed behavior, and self-esteem, which all share a common increase in behavioral disinhibition. The study aims to examine two novel hypotheses: 1) AAS users will have higher levels of brain aromatase than controls, and will have further elevated levels when taking AASs; 2) Regional brain aromatase availability will be positively correlated with behavioral and self-report measures of impulsivity, aggression, and sensitivity to pleasure. Two specific aims were developed to test these hypotheses: A) To evaluate the effect of AAS use on regional brain aromatase availability in relation to circulating gonadal hormone levels; B) To test for a correlation between change in regional brain aromatase availability and behavioral measures of the AAS intoxication syndrome (aggression, sexual activity, impulsivity, and sensation seeking) in AAS users. These aims will be tested in a controlled longitudinal study of male AAS users (n=8) and healthy exercising controls (n=8) matched on age, exercise, and education. The results of this study will be used as pilot data for a longitudinal study of AAS dependence in which we will examine the changes in aromatase as a function of repeated AAS use. This line of research will be aimed at developing biomarkers and investigating individual differences in AAS response among "real world" AAS users. The proposed study will also provide data to develop novel therapeutic targets to prevent and treat AAS addiction; specifically, aromatase inhibitors and estrogen antagonists may be used as pharmacological agents to treat AAS intoxication. These outcomes are in concordance with NIDA's goals to directly inform prevention and treatment efforts in this population. PUBLIC HEALTH RELEVANCE: Contrary to that of other drugs of abuse, the intoxication syndrome of anabolic-androgenic steroid (AAS) use is characterized by a significant increase in impulsivity and aggression coinciding with desired changes in muscularity and strength. The mechanisms behind these neurobiological changes have yet to be identified, however recent animal studies have found a strong link between elevated estrogen levels and aggression. Findings from the proposed study will be the first to propose a neurological and hormonal basis for an AAS intoxication syndrome marked by increased aggression and impulsivity, and will be the first study utilizing neuroimagery on AAS users.