Sex/Gender Factors in Nicotine Addiction

尼古丁成瘾的性别因素

• 批准号: 8100284
• 负责人: NANCY K. MELLO
• 金额: $ 34.14万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100284
• 关键词: Acute; Animals; Anxiety; Attenuated; Behavioral; Blood - brain barrier anatomy; Cardiovascular Diseases; Cessation of life; Chronic; Cocaine; Data; Disease; Dopamine; Dose; Drug Addiction; Drug abuse; Estradiol; Female; Gender; Goals; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Human; Injection of therapeutic agent; Lead; Lung diseases; Luteal Phase; Macaca; Macaca mulatta; Malignant neoplasm of lung; Measures; Menstrual cycle; Mental Depression; Mental disorders; Modeling; Monkeys; Moods; Neurobiology; Neurosecretory Systems; Nicotine; Nicotine Dependence; Osteoporosis; Pharmaceutical Preparations; Phase; Primates; Progesterone; Property; Public Health; Rattus; Reporting; Research; Research Design; Resources; Schedule; Self Administration; Self-Administered; Series; Sex Characteristics; Smoking; Smoking Cessation Intervention; Specificity; Stroke; Testosterone; Therapeutic; Tobacco; Translating; Woman; addiction; cigarette smoking; deprivation; design; effective therapy; male; neurosteroids; nicotine abuse; nonhuman primate; novel; novel strategies; pre-clinical; proliferative phase Menstrual cycle; psychostimulant; receptor; response; sex; sex cycle; steroid hormone; steroid hormone receptor

DESCRIPTION (provided by applicant): This is a revised application entitled "Sex/Gender Factors in Nicotine Addiction" submitted in response to PA-07-329. Cigarette smoking is one of the most prevalent addictive disorders and is associated with a number of debilitating diseases (e.g., lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis) that result in an estimated 438,000 deaths each year. Sex and gender factors in nicotine addiction are poorly understood, and we hypothesize that the hormonal milieu is one critical influence on the abuse-related effects of smoking. We propose preclinical behavioral studies to determine how sex and menstrual cycle phase influence nicotine self-administration, and how acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) alters the reinforcing effects of nicotine. Nonhuman primates are excellent models of drug self-administration and neuroendocrine control of the macaque menstrual cycle is very similar to that of women. Nicotine self- administration will be maintained on a progressive-ratio schedule that requires an increasing number of responses for successive nicotine injections. The dependent variables will be the number of nicotine injections self-administered, the rate of operant responding, and the progressive ratio "break point", i.e., the ratio at which animals stop responding for nicotine. In studies designed to examine the influence of sex and the menstrual cycle on nicotine self- administration, progesterone and estradiol levels will be measured to objectively define phases of the menstrual cycle and to distinguish between ovulatory and anovulatory menstrual cycles. We hypothesize that females will self-administer more nicotine and reach higher break points on a progressive ratio schedule than males. Next, we will examine the effects of acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) on nicotine self-administration dose-effect curves in gonadectomized males and females where basal steroid hormone levels are low. We hypothesize that estradiol and testosterone will enhance the reinforcing effects of nicotine, and that progesterone will attenuate the reinforcing effects of nicotine in females to a greater extent than in males. Steroid hormone receptor antagonists will be used to determine the hormone specificity of behavioral effects observed. Finally, the reinforcing effects of gonadal steroid hormones alone will be compared in males and females before and after gonadectomy. The neuroactive steroid hormones provide a novel approach to the treatment of a number of psychiatric disorders as well as drug abuse. The proposed studies may translate into new and more effective approaches to the treatment of nicotine addiction and will advance our understanding of its basic neurobiology. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many debilitating and lethal disorders (lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis), yet effective treatments remain elusive. We propose to study how sex and neuroactive gonadal steroids influence the abuse-related effects of nicotine (the main addictive component of tobacco) in males and females. We hypothesize that the neuroactive gonadal steroid hormones may offer a novel biologic approach to the treatment of nicotine addiction, in part because these neuroactive hormones are being used to treat a number of psychiatric disorders, including depression and anxiety, and may have therapeutic applications in drug dependence.

描述（由申请人提供）：这是一个题为“尼古丁成瘾中的性别/性别因素”的修订申请，该申请响应PA-07-329。吸烟是最普遍的成瘾性疾病之一，与许多令人衰弱的疾病（例如肺癌，中风，心血管和呼吸道疾病，骨质疏松症）有关，每年估计会导致438,000人死亡。尼古丁成瘾中的性别和性别因素知之甚少，我们假设荷尔蒙环境对吸烟的滥用作用是一个关键影响。我们提出了临床前行为研究，以确定性别和月经循环阶段如何影响尼古丁的自我给药，以及通过神经活性性腺类固醇激素（雌二醇，睾丸激素和孕酮）如何改变了烟碱的增强作用。非人类灵长类动物是药物自我给药的出色模型，猕猴月经周期的神经内分泌控制与女性非常相似。尼古丁自我给药将按照渐进式比率时间表进行维持，该时间表需要越来越多的尼古丁注射响应。因变量将是尼古丁注射的数量自我管理，操作者的响应速度和渐进比率“断裂点”，即动物停止对尼古丁的反应的比率。在旨在检查性别和月经周期对尼古丁自我给药的影响的研究中，将测量孕酮和雌二醇水平，以客观地定义月经周期的阶段，并区分产卵和发出的月经周期。我们假设女性比男性比男性更高的尼古丁自我管理，并在渐进率的时间表上达到更高的突破点。接下来，我们将研究急性和慢性治疗对基底肌动型男性和女性的尼古丁自我给药剂量效应曲线的神经活性类固醇激素（雌二醇，睾丸激素和孕酮）对基底类固醇激素水平较低的尼古丁自助剂剂量效应曲线的影响。我们假设雌二醇和睾丸激素将增强尼古丁的增强作用，而孕酮会比男性更大程度地减弱尼古丁在女性中的增强作用。类固醇激素受体拮抗剂将用于确定观察到的行为效应的激素特异性。最后，在促性腺切除术前后，将比较单独的性腺类固醇激素的增强作用。神经活性类固醇激素为治疗多种精神疾病和药物滥用提供了一种新颖的方法。拟议的研究可能转化为治疗尼古丁成瘾的新方法，并将促进我们对其基本神经生物学的理解。公共卫生相关性：对吸烟的成瘾是一个主要的公共卫生问题，与许多衰弱和致死性疾病（肺癌，中风，心血管和呼吸道疾病，骨质疏松症）有关，但有效治疗仍然难以捉摸。我们建议研究性别和神经性性腺类固醇如何影响尼古丁（烟草的主要成瘾成分）对男性和女性的滥用相关作用。我们假设神经活性性性腺类固醇激素可能为治疗尼古丁成瘾提供一种新型的生物学方法，部分原因是这些神经活性激素被用于治疗多种精神疾病，包括抑郁症和焦虑，并且可能在药物依赖性中具有治疗性应用。