Sex/Gender Factors in Nicotine Addiction

尼古丁成瘾的性别因素

• 批准号: 8281706
• 负责人: SIMON Barak CAINE
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281706
• 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）：这是一份修订后的申请，标题为“尼古丁成瘾中的性别/性别因素”，是为了回应PA-07-329而提交的。吸烟是最普遍的成瘾性疾病之一，并且与许多使人衰弱的疾病（例如，肺癌、中风、心血管和呼吸系统疾病、骨质疏松症），估计每年导致438，000人死亡。尼古丁成瘾中的性和性别因素知之甚少，我们假设激素环境是吸烟滥用相关效应的关键影响因素。我们建议进行临床前行为研究，以确定性别和月经周期阶段如何影响尼古丁自我给药，以及神经活性性腺类固醇激素（雌二醇、睾酮和孕酮）的急性和慢性治疗如何改变尼古丁的强化作用。非人灵长类动物是药物自我给药的极好模型，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比例时间表进行，该时间表要求连续尼古丁注射的反应次数增加。因变量将是自我给药的尼古丁注射次数、操作性应答率和累进比率“断点”，即，动物对尼古丁停止反应的比率。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，以客观定义月经周期的阶段，并区分排卵和无排卵月经周期。我们假设，女性将自我管理更多的尼古丁，并达到更高的突破点的渐进比例计划比男性。接下来，我们将在基础类固醇激素水平较低的性腺切除男性和女性中检查神经活性性腺类固醇激素（雌二醇、睾酮和孕酮）急性和慢性治疗对尼古丁自我给药剂量效应曲线的影响。我们假设雌二醇和睾酮会增强尼古丁的增强作用，孕酮会在更大程度上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，将在性腺切除术前后比较雄性和雌性单独使用性腺类固醇激素的强化作用。神经活性类固醇激素提供了一种新的方法来治疗一些精神疾病以及药物滥用。这些研究可能会转化为治疗尼古丁成瘾的新的更有效的方法，并将促进我们对其基础神经生物学的理解。公共卫生相关性：吸烟成瘾是一个主要的公共卫生问题，与许多使人衰弱和致命的疾病（肺癌、中风、心血管和呼吸系统疾病、骨质疏松症）有关，但有效的治疗方法仍然难以捉摸。我们建议研究性和神经活性性腺类固醇如何影响男性和女性尼古丁（烟草的主要成瘾成分）的滥用相关效应。我们假设，神经活性性腺类固醇激素可能提供一种新的生物学方法来治疗尼古丁成瘾，部分原因是这些神经活性激素被用于治疗一些精神疾病，包括抑郁症和焦虑症，并可能在药物依赖的治疗应用。