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: 8413214
• 负责人: ANAT BIEGON
• 金额: $ 27.55万
• 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/8413214
• 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.

描述(由申请人提供)：合成代谢雄激素(AAS)的使用影响到大约1-3%的人口，是一个极具社会、学术和医学意义的问题。与其他非法药物使用人群相比，AAS的使用与暴力死亡率(杀人/自杀)和更早的死亡年龄有关，并且在吸毒者中表现出很大的依赖率。医疗后果可能包括心脏事件、肝脏毒性、骨骼改变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，确定与AAS中毒相关的神经生物学变化对于开发新的有效疗法至关重要，该疗法旨在治疗AAS依赖并限制AAS使用的精神后果。这项拟议的研究旨在确定在一组积极和有经验的使用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中毒与芳香酶可获得性的关系，我们将能够了解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主要是因为它们能够改变外表或提高运动成绩，但AAS中毒综合症的定义可以是AAS使用所产生的令人满意的心理和行为效果，包括社交支配能力、性冲动、攻击性、目标导向行为和自尊的增加，所有这些都在行为去抑制方面有共同的增加。这项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将高于对照组，并且在服用AASS时将进一步升高；2)大脑区域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指标呈正相关。两个特定的目的被用来检验这些假说：A)评估AAS使用对与循环性激素水平有关的局部脑芳香酶可获得性的影响；B)测试AAS使用者局部脑芳香酶可获得性变化与AAS中毒综合征的行为指标(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使用者(n=8)和健康锻炼对照组(n=8)的受控纵向研究中进行测试，这些研究在年龄、锻炼和教育方面匹配。这项研究的结果将被用作AAS依赖的纵向研究的先导数据，在该研究中，我们将检查芳香酶作为重复使用AAS的函数的变化。这一系列研究的目的是开发生物标记物，并调查“现实世界”AAS使用者对AAS反应的个体差异。这项拟议的研究还将为开发预防和治疗AAS成瘾的新治疗靶点提供数据；具体地说，芳香酶抑制剂和雌激素拮抗剂可能被用作治疗AAS中毒的药理药物。这些结果与NIDA的目标一致，即直接为这一人群的预防和治疗工作提供信息。