Sex/Gender and Nicotine Addiction: Hormones, Behavior and Neuroimaging

描述（由申请人提供）：这是针对 NIDA PA-07-329 提交的针对尼古丁反应性别差异的跨学科行为、神经内分泌和神经影像学研究的修订申请 (A2)。在成瘾性疾病中，尼古丁成瘾是最普遍的一种，并且与许多潜在致命疾病（肺癌、心血管和呼吸系统疾病）相关，估计每年导致 448,000 人死亡。迫切需要改进尼古丁成瘾的治疗方法，并且我们对尼古丁基本神经生物学的理解的进步将促进这种治疗。我们提出临床研究来检查尼古丁对尼古丁依赖男性和女性的激素、行为和神经影像影响之间的协方差，以确定是否存在显着的性别差异。将在月经周期的卵泡中期和黄体中期对女性进行研究，以确定尼古丁的作用是否受到定义月经周期阶段的神经活性性腺类固醇激素变化的影响。 功能磁共振成像（fMRI）将用于研究大脑活动的区域变化。静脉注射尼古丁和安慰剂尼古丁对烟碱受体高密度大脑区域以及可能是重要药物奖赏途径的区域神经元活动的影响将随着时间的推移进行测量，并与主观和激素反应相关。尼古丁（0、1.0 或 2.0 毫克/70 公斤，静脉注射）将在双盲条件下施用。每 2 分钟收集一次用于分析下丘脑-垂体-肾上腺和性腺激素的样本，以检查与神经影像激活模式和主观效应报告的时间协方差。 我们假设男性对静脉注射尼古丁的神经元和激素激活以及积极的主观反应会比女性更大。我们还假设，与月经周期的黄体期（神经活性类固醇激素水平较高）相比，女性在月经周期的卵泡期（此时神经活性类固醇激素水平较低）神经元和激素激活程度更高，并对尼古丁产生积极反应。由于神经活性类固醇激素被用于治疗包括药物滥用在内的许多精神疾病，因此这可能会带来尼古丁成瘾的新疗法。这些转化研究的结果将增进我们对性、激素和尼古丁滥用相关影响之间相互作用的理解。这些跨学科研究将整合行为、激素和神经影像学测量，以全面分析性别差异和月经周期阶段如何影响尼古丁滥用相关的影响。了解尼古丁基本神经生物学的进展将为开发更好的药物干预措施来治疗尼古丁成瘾提供信息。

DESCRIPTION (provided by applicant): This is a revised application (A2) for interdisciplinary behavioral, neuroendocrine and neuroimaging studies of sex differences in response to nicotine submitted in response to NIDA PA-07-329. Among the addictive disorders, nicotine addiction is one of the most pervasive, and is associated with a number of potentially lethal diseases (lung cancer, cardiovascular and respiratory disease) that result in an estimated 448,000 deaths each year. Improved treatments for nicotine addiction are urgently needed, and will be facilitated by advances in our understanding of the basic neurobiology of nicotine. We propose clinical studies to examine the covariance between the hormonal, behavioral and neuroimaging effects of nicotine in nicotine- dependent men and women to determine if there are significant sex differences. Women will be studied during the mid-follicular and the mid-luteal phase of the menstrual cycle to determine if the effects of nicotine are influenced by changes in the neuroactive gonadal steroid hormones that define phases of the menstrual cycle. Functional magnetic resonance imaging (fMRI) will be used to study regional changes in brain activity. The effects of IV nicotine and placebo nicotine on neuronal activity in brain areas with a high density of nicotinic receptors, and also in regions that may be important drug reward pathways will be measured over time, and correlated with subjective and hormonal responses. Nicotine (0, 1.0 or 2.0 mg/70 kg, IV) will be administered under double-blind conditions. Samples for analysis of hypothalamic-pituitary-adrenal and gonadal hormones will be collected every 2 min to examine the temporal covariance with neuroimaging activation patterns and reports of subjective effects. We hypothesize that neuronal and hormonal activation and positive subjective responses to IV nicotine administration will be greater in men than in women. We also hypothesize that women will have greater neuronal and hormonal activation and positive responses to nicotine during the follicular phase of the menstrual cycle (when neuroactive steroid hormone levels are low) than during the luteal phase of the menstrual cycle (when neuroactive steroid hormone levels are high). Because the neuroactive steroid hormones are being used to treat a number of psychiatric disorders including drug abuse, this could lead to novel treatments for nicotine addiction. The results of these translational studies will increase our understanding of the interaction between sex, hormones, and the abuse-related effects of nicotine. These interdisciplinary studies will integrate behavioral, hormonal and neuroimaging measures to provide a comprehensive analysis of how sex differences and phases of the menstrual cycle may affect the abuse- related effects of nicotine. Advances in understanding the basic neurobiology of nicotine will inform efforts to develop better pharmacologic interventions to treat nicotine addiction.