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

类固醇使用者脑芳香酶的可用性：[11C]伏罗唑的 PET 研究

• 批准号: 8226959
• 负责人: ANAT BIEGON
• 金额: $ 30.33万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226959
• 关键词: Adult; Affect; Age; Aggressive behavior; Amygdaloid structure; Anabolic steroids; Androgens; Androstenedione; Animals; Anti-Anxiety Agents; Appearance; Aromatase; Aromatase Inhibitors; Athletic; Behavior; Behavioral; Binding; Biological Markers; Brain; Brain region; Cardiac; Cessation of life; Clinical; Complex; Cytochrome P450; DSM-IV; Data; Dependency; Development; Disinhibition; Dopamine; Drug Addiction; Drug usage; Education; Enzymes; Esthesia; Estradiol; Estrogen Antagonists; Estrogens; Estrone; Ethnic Origin; Euphoria; Event; Exercise; Exhibits; Family; Goals; Gonadal Hormones; Grant; Hepatotoxicity; Homicide; Hormonal; Human; Hypothyroidism; Illicit Drugs; Impulsive Behavior; Impulsivity; Individual Differences; Intoxication; Kinetics; Knock-out; Laboratories; Length; Libido; Link; Longitudinal Studies; Measures; Medial; Mediating; Medical; Morbidity - disease rate; Nandrolone Decanoate; Neurobiology; Neurocognitive; Neuroendocrinology; Neurologic; Outcome; Patient Self-Report; Performance; Pharmaceutical Preparations; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Preoptic Areas; Prevention; Process; Race; Receptor Activation; Regulation; Relative (related person); Research; Risk; Risk-Taking; Rodent; Role; Scanning; Severities; Sex Behavior; Social Dominance; Steroids; Structure of terminal stria nuclei of preoptic region; Suicide; Syndrome; Testing; Testosterone; Thalamic structure; Therapeutic; Time; Tracer; Validation; Variant; Ventral Tegmental Area; Violence; Vorozole; addiction; base; behavior measurement; design; discounting; drug of abuse; experience; field study; hypothalamic pituitary gonadal axis; interest; male; malignant breast neoplasm; meetings; member; men; mortality; new therapeutic target; novel; pleasure; prevent; psychologic; receptor; response; self esteem; skeletal; social; steroid dependence; steroid metabolism; time interval; uptake

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.

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、学术和医学关注的问题。与其他非法药物使用人群相比，使用 AAS 与暴力死亡率（他杀/自杀）增加和死亡年龄提前有关，并且使用者之间表现出显着的依赖性。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，以及总体更高的死亡率和发病率。目前，尚无针对 AAS 依赖或中毒的治疗方法。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旨在治疗 AAS 依赖和限制 AAS 使用的精神后果的新型有效疗法至关重要。拟议的研究旨在确定一组活跃且经验丰富的使用 AAS 的男性中导致 AAS 中毒的一些关键神经生物学过程。通过研究 AAS 中毒与芳香酶可用性的关系，我们将能够了解 AAS 代谢与强化 AAS 使用的核心心理和行为变化之间的功能关系。虽然 AAS 的主要用途是改变外表或提高运动表现，但 AAS 中毒综合症可以通过使用 AAS 产生的理想心理和行为影响来定义，包括社会支配地位、性欲、攻击性、目标导向行为和行为的增加。自尊，所有这些都有一个共同的特征，那就是行为去抑制的增加。该研究旨在检验两个新的假设：1）AAS 使用者的大脑芳香酶水平比对照组更高，并且在服用 AAS 时，其水平会进一步升高； 2）区域大脑芳香酶的可用性将与冲动、攻击性和对快乐的敏感性的行为和自我报告测量呈正相关。制定了两个具体目标来检验这些假设：A) 评估 AAS 使用对与循环性腺激素水平相关的区域脑芳香酶可用性的影响； B) 测试 AAS 用户区域大脑芳香酶可用性的变化与 AAS 中毒综合征的行为测量（攻击性、性活动、冲动和感觉寻求）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) 的对照纵向研究中进行测试，这些对照组的年龄、锻炼情况和教育程度相匹配。本研究的结果将用作 AAS 依赖性纵向研究的试点数据，其中我们将检查芳香酶随重复使用 AAS 的变化。该研究系列旨在开发生物标志物并调查“现实世界”AAS 用户中 AAS 反应的个体差异。拟议的研究还将提供数据来开发新的治疗靶点来预防和治疗 AAS 成瘾；具体地，芳香酶抑制剂和雌激素拮抗剂可以用作治疗AAS中毒的药物。这些结果符合 NIDA 的目标，即直接为该人群的预防和治疗工作提供信息。 公共健康相关性：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点是冲动性和攻击性显着增加，同时肌肉和力量发生所需的变化。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。拟议研究的结果将首次提出以攻击性和冲动性增加为特征的 AAS 中毒综合征的神经学和激素基础，并且将是第一项针对 AAS 用户利用神经意象的研究。