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

描述(申请人提供)：这是针对NIDA PA-07-329提交的关于尼古丁对性别差异的跨学科行为、神经内分泌和神经成像研究的修订申请(A2)。在成瘾障碍中，尼古丁成瘾是最普遍的疾病之一，与许多潜在的致命疾病(肺癌、心血管疾病和呼吸系统疾病)有关，估计每年导致44.8万人死亡。改善尼古丁成瘾的治疗方法是迫切需要的，我们对尼古丁的基本神经生物学的了解的进步将促进这一过程。我们建议进行临床研究，以检验尼古丁对男性和女性的激素、行为和神经成像影响之间的协变性，以确定是否存在显著的性别差异。女性将在月经周期的卵泡中期和黄体中期进行研究，以确定尼古丁的效果是否受到神经活性性腺类固醇激素变化的影响，性腺类固醇激素定义了月经周期的各个阶段。功能磁共振成像(FMRI)将用于研究大脑活动的区域性变化。静脉注射尼古丁和安慰剂尼古丁对尼古丁受体密度高的大脑区域以及可能是重要药物奖励途径的区域的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联。尼古丁(0、1.0或2.0毫克/70公斤，静脉注射)将在双盲条件下给予。每隔2分钟收集下丘脑-垂体-肾上腺和性腺激素的分析样本，以检查与神经成像激活模式和主观影响报告的时间相关性。我们假设，男性对静脉注射尼古丁的神经元和荷尔蒙的激活和积极的主观反应将比女性更大。我们还假设，女性在月经周期的卵泡期(当神经活性类固醇激素水平较低时)将比在月经周期的黄体期(当神经活性类固醇激素水平较高时)对尼古丁有更大的神经元和激素激活以及对尼古丁的积极反应。由于神经活性类固醇激素正被用于治疗包括药物滥用在内的许多精神疾病，这可能会导致尼古丁成瘾的新疗法。这些翻译研究的结果将增加我们对性、激素和尼古丁滥用相关影响之间的相互作用的理解。这些跨学科的研究将整合行为、激素和神经成像指标，以全面分析性别差异和月经周期的不同阶段如何影响尼古丁滥用的相关影响。了解尼古丁的基本神经生物学的进展将有助于开发更好的药物干预措施来治疗尼古丁成瘾。 与公共健康相关：吸烟成瘾是一个重大的公共健康问题，与许多潜在的致命疾病(肺癌、心血管疾病和呼吸系统疾病)有关，但有效的治疗方法仍然难以找到。对吸烟和其他滥用药物反应的性别差异是疾病进展和复发的重要因素。我们建议研究性别和月经周期的阶段如何影响尼古丁依赖男性和女性的荷尔蒙、神经成像和尼古丁(烟草的主要成瘾成分)的滥用相关影响。

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. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many potentially lethal disorders (lung cancer, cardiovascular and respiratory disease), yet effective treatments remain elusive. Sex differences in response to smoking and other abused drugs are important factors in disease progression and in relapse. We propose to study how sex and phase of the menstrual cycle may influence the hormonal, neuroimaging and abuse-related effects of nicotine (the main addictive component of tobacco) in nicotine- dependent men and women.