Gender Effects on Amphetamine-Induced Dopamine Release and Subjective Responses

描述(申请人提供)：药物影响的性别差异对于了解药物使用的神经学基础、病因学、流行病学、毒性、预防和治疗是一个新出现的重要领域。现在有确凿的证据表明，5-羟色胺神经递质系统的性别差异可能解释了男性和女性抑郁和焦虑的比例以及对SSRIs的治疗反应的差异。与拟议的研究更相关的是，性别差异在人类吸烟和戒烟的动态中得到了证实。这些差异被归因于卵巢类固醇激素对尼古丁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的、年龄匹配的男性和女性服用苯丙胺的多巴胺释放(DAR)的性别差异；这是第一次在人类受试者中证明基于性别的DAR差异。本研究无论从基础科学角度还是从临床干预角度都具有很高的意义。利用正电子发射计算机断层扫描，这项拟议的研究将研究在健康、年龄匹配的男性和女性服用苯丙胺后，DAR基于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进行扫描。受试者将完成安非他明主观影响的测量。此外，我们将获得男性和女性受试者的性激素/神经类固醇概况，并确定与DAR的关系。如果我们关于性激素/神经类固醇在DAR中作用的假设得到支持，这些发现将对理解兴奋剂使用障碍的病因学、流行病学、神经毒性以及预防和治疗具有重要意义。此外，这些结果的科学和临床重要性不仅限于成瘾，还包括其他与纹状体中的多巴胺有关的障碍，包括精神分裂症、帕金森氏症、亨廷顿氏症和强迫症。与公共健康相关：我们的实验室最近发现，与年龄匹配的女性相比，健康的年轻成年男性释放更多的多巴胺，这是一种影响兴奋剂的奖赏和兴奋效果的大脑化学物质，并且报告称，与年龄匹配的女性相比，服用安非他明后，男性更喜欢服用安非他明。这项拟议的研究将研究这些性别差异，以及苯丙胺对女性月经周期的影响，以及性激素(雌激素、孕激素和睾酮)在改变药物对多巴胺影响方面的作用。这些发现将对我们进一步了解大脑功能的正常性别差异和这些影响的激素机制具有相当大的公共卫生意义，从而为更好地理解药物滥用和其他神经精神障碍的这些因素铺平道路。

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.