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）：合成代谢的雄激素类固醇（AAS）的使用影响约1-3％的人口，这是一个很大的社会，学术和医学利益的问题。与其他非法毒品人群相比，AAS的使用与暴力死亡率提高（凶杀/自杀）和更早的死亡年龄有关，并且在用户之间表现出显着的依赖率。医疗后果可能包括增加心脏事件的风险，肝毒性，骨骼变化以及甲状腺功能减退症以及总体上更高的死亡率和发病率。当前，没有治疗AAS依赖性或中毒的治疗方法。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依赖并限制AAS使用的精神病后果的新颖有效的治疗剂至关重要。拟议的研究旨在确定在一组活跃和经验丰富的AAS中，导致AAS中毒的一些关键神经生物学过程。通过研究与芳香酶可用性有关的AAS中毒，我们将能够理解AAS代谢与增强AAS使用的核心心理和行为变化之间的功能关系。尽管AAS是主要是为了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AAS使用的理想心理和行为影响来定义，其中包括增加社会优势，性欲，侵略性，目标定向行为和自尊心，这在行为抑制行为抑制行为中都有共同的增长。该研究旨在检查两个新的假设：1）AAS使用者的脑芳香酶水平要高于对照，并且在服用AASS时的水平将进一步升高； 2）区域大脑芳香酶的可用性将与冲动，侵略性和对愉悦感的敏感性的行为和自我报告衡量。开发了两个特定的目的来检验这些假设：a）评估AAS使用对循环性腺激素水平的区域脑芳香酶可用性的影响； b）测试AAS使用者中AAS中毒综合征（侵略性，性活动，冲动和寻求感觉）的区域脑芳香酶的可用性变化与行为度量之间的相关性。这些目标将在对男性AAS使用者（n = 8）的受控纵向研究中进行测试，并且在年龄，运动和教育方面匹配健康的锻炼控制（n = 8）。这项研究的结果将用作对AAS依赖性的纵向研究的试验数据，其中我们将检查芳香酶的变化，这是重复使用AAS的函数。这一研究将旨在开发生物标志物并调查“现实世界” AAS用户中AAS响应中的个体差异。拟议的研究还将提供数据以开发新的治疗靶标，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以用作治疗AAS中毒的药理剂。这些结果与NIDA的目标一致，旨在直接为该人群的预防和治疗工作提供信息。 公共卫生相关性：与其他滥用药物相反，合成代谢赋予类固醇（AAS）使用的中毒综合征的特征是冲动性和侵略性显着增加，与肌肉性和力量的所需变化相吻合。这些神经生物学变化背后的机制尚未确定，但是最近的动物研究发现，雌激素水平升高与攻击之间存在很强的联系。拟议研究的发现将是第一个提出AAS中毒综合征的神经系统和激素基础，该综合征的攻击性和冲动性增加，这将是第一个利用AAS使用神经模拟的研究。