Gender Effects on Amphetamine-Induced Dopamine Release and Subjective Responses

描述（由申请人提供）：药物作用的性别差异是了解药物使用的神经学基础、病因学、流行病学、毒性、预防和治疗的一个新的重要领域。现在有确凿的证据表明，在5-羟色胺神经递质系统中存在性别差异，这可能解释了男性和女性抑郁和焦虑的比率以及对SSRIs的治疗反应的差异。与拟议的研究更相关的是，在人类吸烟和戒烟的动力学方面已经证实了性别差异。这些差异归因于卵巢类固醇激素对烟碱受体的急性和慢性影响，尽管研究结果尚未得出结论。使用正电子发射技术（PET），我们最近报道了健康，年龄匹配的男性和女性中多巴胺释放（DAR）对安非他明给药的强烈性别差异;这是人类受试者中基于性别的DAR差异的首次证明。本研究从基础科学和临床干预的角度都具有重要意义。使用PET，拟议的研究将检查健康，年龄匹配的男性和女性服用安非他明后DAR性别差异的可能机制。女性受试者将在月经周期的黄体期和卵泡期接受扫描。受试者将完成苯丙胺主观效应的测量。此外，我们将获得男性和女性受试者的性激素/神经类固醇谱，并确定与DAR的关系。如果我们的假设的性激素/神经类固醇在DAR的作用得到支持，这些发现将是重要的，在了解病因学，流行病学，神经毒性，预防和治疗兴奋剂使用障碍。此外，这些结果的科学和临床重要性不仅限于成瘾，还包括涉及纹状体多巴胺的其他疾病，包括精神分裂症、帕金森病、亨廷顿病和强迫症。公共卫生相关性：我们的实验室最近发现，健康的年轻成年男性释放更多的多巴胺，这是一种大脑化学物质，会影响兴奋剂药物的奖励和欣快效果，并报告与年龄匹配的女性相比，安非他明管理后更大的“高”和“药物喜好”。拟议的研究将研究这些性别差异，安非他明的影响是否在月经周期中改变女性，以及性激素（雌激素，孕酮和睾酮）在修改药物对多巴胺的影响中的作用。研究结果将有相当大的公共卫生意义，进一步了解正常性别差异的大脑功能和激素机制，这些影响，从而铺平了道路，以更好地了解这些因素在药物滥用和其他神经精神疾病。

DESCRIPTION (provided by applicant): Sex differences in drug effects is an area of emerging importance for understanding the neurological bases, etiology, epidemiology, toxicity, prevention and treatment of drug use. There is now solid evidence of gender differences in the serotonin neurotransmitter system that may account for differences in rates of depression and anxiety in men and women and therapeutic responses to SSRIs. Of even greater relevance to the proposed study, gender differences have been confirmed in the dynamics of tobacco smoking and cessation in humans. These differences have been attributed to acute and chronic effects of ovarian steroid hormones on nicotinic receptors, although findings have not been conclusive. Using positron emission technology (PET), we recently have reported robust sex differences in dopamine release (DAR) to amphetamine administration in healthy, age-matched men and women; this is the first demonstration of gender-based DAR differences in human subjects. This research has high significance from both a basic science and clinical intervention perspective. Using PET, the proposed study will examine possible mechanisms for gender-based differences in DAR following amphetamine administration in healthy, age-matched men and women. Female subjects will be scanned during both the luteal and follicular phases of their menstrual cycle. Subjects will complete measures of subjective effects of amphetamine. In addition, we will obtain a sex hormone/neurosteroid profile on male and female subjects and determine the relationship to DAR. If our hypotheses of the roles of sex hormones/neurosteroids in DAR are supported, these findings will be important in understanding the etiology, epidemiology, neurotoxicity, prevention and treatment of stimulant use disorders. Further, the scientific and clinical importance of the results extends beyond addiction to include other disorders involving dopamine in the striatum, including schizophrenia, Parkinson's disease, Huntington's disease and obsessive-compulsive disorder. PUBLIC HEALTH RELEVANCE: Our laboratory has recently found that healthy, young adult men release more dopamine, a brain chemical that influences the rewarding and euphoric effects of stimulant drugs, and report greater "high" and "drug liking" following amphetamine administration compared with age-matched women. The proposed research will study these sex differences, whether the effects of amphetamine change in women during the menstrual cycle, and the role of sex hormones (estrogen, progesterone and testosterone) in modifying drug effects on dopamine. Findings will have considerable public health significance in furthering our understanding of normal sex differences in brain function and hormonal mechanisms for these effects, thus paving the way to better understand these factors in substance abuse and other neuropsychiatric disorders.