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）的使用影响约1-3%的人口，是一个巨大的社会，学术和医学利益的问题。与其他非法药物使用人群相比，AAS的使用与暴力死亡（杀人/自杀）率的增加和死亡年龄的提前有关，并显示出使用者的依赖率很高。医学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症的风险增加，以及总体死亡率和发病率升高。目前，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将是必不可少的开发新的和有效的治疗方法，旨在治疗AAS依赖和限制精神病的后果，AAS使用。拟议的研究旨在确定一些关键的神经生物学过程负责AAS中毒的一组积极和经验丰富的AAS使用的男子。通过研究AAS中毒与芳香化酶可用性的关系，我们将能够理解AAS代谢与加强AAS使用的核心心理和行为变化之间的功能关系。虽然AAS主要用于改变外观或提高运动表现的能力，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，包括社会支配力，性欲，侵略性，目标导向行为和自尊的增加，所有这些都在行为去抑制中共同增加。该研究旨在检验两个新的假设：1）AAS使用者的大脑芳香化酶水平高于对照组，并且在服用AAS时水平会进一步升高; 2）区域大脑芳香化酶的可用性与冲动性，侵略性和对快乐的敏感性的行为和自我报告措施呈正相关。两个具体的目的是为了测试这些假设：A）评估AAS使用对局部脑芳香化酶可用性与循环性腺激素水平的关系的影响; B）测试AAS使用者局部脑芳香化酶可用性的变化与AAS中毒综合征（攻击性、性活动、冲动性和感觉寻求）的行为测量之间的相关性。这些目标将在男性AAS用户（n=8）和健康锻炼对照组（n=8）的年龄，运动和教育相匹配的对照纵向研究中进行测试。这项研究的结果将被用作试点数据的AAS依赖性的纵向研究中，我们将检查芳香化酶的变化作为一个功能，重复使用AAS。这一系列研究的目的是开发生物标志物，并调查“真实的世界”AAS用户中AAS反应的个体差异。拟议的研究还将提供数据，以开发新的治疗靶点，以预防和治疗AAS成瘾;具体而言，芳香酶抑制剂和雌激素拮抗剂可用作治疗AAS中毒的药理学药物。这些结果与NIDA的目标是一致的，直接告知在这一人群中的预防和治疗工作。 公共卫生相关性：与其他滥用药物相反，合成代谢雄激素类固醇（AAS）使用的中毒综合征的特征是冲动和攻击性显著增加，与肌肉发达和力量的预期变化相一致。这些神经生物学变化背后的机制尚未确定，但最近的动物研究发现雌激素水平升高与攻击性之间存在密切联系。这项研究的结果将首次提出AAS中毒综合征的神经和激素基础，其特征是侵略性和冲动性增加，并且将是第一项利用AAS用户神经成像的研究。

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.