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

性别与尼古丁成瘾：激素、行为和神经影像

• 批准号: 8212186
• 负责人: NANCY K. MELLO
• 金额: $ 69.3万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212186
• 关键词: Acute; Adrenal hormone preparation; Affect; Age; Alcohol abuse; Amygdaloid structure; Anterior Hypothalamus; Anterior Pituitary Hormones; Area; Attention; Behavior; Behavioral; Biological; Brain; Brain imaging; Cardiovascular Diseases; Cerebellum; Cessation of life; Clinical Research; Cognitive; Crossover Design; Data; Dependence; Dextroamphetamine; Disease; Disease Progression; Dopamine; Dose; Double-Blind Method; Drug Interactions; Drug abuse; Endocrine; Functional Magnetic Resonance Imaging; Gender; Gonadal Hormones; Gonadal Steroid Hormones; Hormonal; Hormones; Hypothalamic structure; Interdisciplinary Study; Intervention; Lead; Lung diseases; Luteal Phase; Malignant neoplasm of lung; Measures; Menstrual cycle; Mental disorders; National Institute of Drug Abuse; Neurobiology; Neurons; Neurosecretory Systems; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Pituitary Gland; Placebos; Progesterone; Public Health; Reaction; Relapse; Reporting; Rewards; Sampling; Sex Characteristics; Smoking; System; Thalamic structure; Time; Tobacco; United States National Institutes of Health; Woman; addiction; base; caudate nucleus; cigarette smoke-induced; cigarette smoking; density; drug of abuse; drug reward; effective therapy; improved; men; neural patterning; neuroimaging; neurosteroids; novel; novel strategies; proliferative phase Menstrual cycle; public health relevance; putamen; relating to nervous system; response; sex; sex cycle; smoking cessation; steroid hormone; therapy development; translational study

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.

描述（由申请人提供）：这是一份修订后的申请（A2），用于对尼古丁反应的性别差异进行跨学科行为、神经内分泌和神经影像学研究，以响应NIDA PA-07-329。在成瘾性疾病中，尼古丁成瘾是最普遍的成瘾性疾病之一，与许多潜在的致命疾病（肺癌、心血管和呼吸系统疾病）有关，估计每年导致448，000人死亡。我们迫切需要改进尼古丁成瘾的治疗方法，而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。我们建议进行临床研究，以检查尼古丁对尼古丁依赖男性和女性的激素、行为和神经影像学影响之间的协方差，以确定是否存在显著的性别差异。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。 功能性磁共振成像（fMRI）将用于研究大脑活动的区域变化。随着时间的推移，将测量IV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赏途径的区域的神经元活动的影响，并将其与主观和激素反应相关联。尼古丁（0、1.0或2.0 mg/70 kg，IV）将在双盲条件下给药。将每2分钟采集一次用于下丘脑-垂体-肾上腺和性腺激素分析的样本，以检查神经成像激活模式和主观效应报告的时间协方差。 我们假设，神经元和激素的激活和积极的主观反应，静脉注射尼古丁管理将在男性比女性更大。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低时）比在月经周期的黄体期（当神经活性类固醇激素水平高时）对尼古丁有更大的神经元和激素激活和积极反应。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，这可能会导致尼古丁成瘾的新疗法。这些转化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、激素和神经影像学措施，以全面分析性别差异和月经周期阶段如何影响尼古丁的滥用相关效应。对尼古丁的基本神经生物学的了解将有助于开发更好的药理学干预措施来治疗尼古丁成瘾。 公共卫生相关性：吸烟成瘾是一个主要的公共卫生问题，与许多潜在的致命疾病（肺癌，心血管和呼吸系统疾病）有关，但有效的治疗方法仍然难以捉摸。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尼古丁（烟草的主要成瘾成分）的激素，神经成像和滥用相关影响。