Neurobiology of Nicotine: Hormones and Behavior

尼古丁的神经生物学：激素和行为

• 批准号: 6572620
• 负责人: JACK H MENDELSON
• 金额: $ 31.6万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-20 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572620
• 关键词: cardiovascular disorder; clinical research; disease /disorder proneness /risk; dopamine; endocrine disorder; gas chromatography; human subject; hypothalamic pituitary axis; interview; menstrual cycle disorder; neurobiology; neurons; nicotine; nicotinic receptors; patient oriented research; pituitary gonadal axis; radioimmunoassay; smoking; steroid hormone; tobacco abuse

DESCRIPTION (provided by applicant): This is a revision of a new application in response to PA-00-045 Neurobiological and Behavioral Research on Nicotine and Tobacco Components. Nicotine activates a4beta2 nicotinic receptors on mesolimbic dopamine neurons and increases extra cellular dopamine release. The indirect dopamine agonist effects of both nicotine and cocaine are thought to be important for their abuse-related effects. However, it is likely that dopamine is only one of a constellation of neurobiological systems that may contribute to nicotine abuse as well as to cocaine abuse. The role of the endocrine system in modulating the reinforcing effects of drugs is poorly understood, but recent preclinical and clinical studies suggest that hormones may influence the abuse-related effects of cocaine, and these findings have led to novel approaches to treatment. Our preliminary studies indicate that both nicotine and cocaine stimulate anterior pituitary and adrenal hormones, and have similar pharmacodynamic and pharmacokinetic profiles. However, in contrast to cocaine, relatively little is known about the temporal relationships between nicotine-induced alterations in subjective states, hormone release patterns and increases in plasma nicotine levels, or how nicotine's effects may vary as a function of gender and/or menstrual cycle phase. We propose to conduct clinical studies of the acute effects of nicotine on the hypothalamic-pituitary-adrenal axis (HPA) and the hypothalamic-pituitary-gonadal axis (HPG) in men and women who are daily smokers and are nicotine dependent (DSM-IV criteria). Women will be studied at the follicular and the mid-luteal phases of the menstrual cycle to determine if hormone fluctuations across the menstrual cycle influence nicotine's biological and abuse-related effects. The effects of two doses of nicotine and placebo on neuroendocrine, subjective and cardiovascular measures will be studied under double-blind conditions in an own control design. Nicotine will be administered by smoking in a procedure where puff volume, duration and frequency are measured and controlled. However, because other constituents of tobacco smoke may contribute to the effects of smoking, we propose to conduct parallel studies of intravenous nicotine. Examination of nicotine's effects on the endocrine system and correlated changes in subjective and cardiovascular measures will advance our understanding of the biological bases of nicotine's abuse-related effects, as well as its contribution to some reproductive disorders in women who smoke (e.g., early menopause and infertility). Clinical reports suggest that nicotine has anti-estrogenic effects, but there have been no comprehensive studies of nicotine's effects on the HPG axis. This question is important, because gonadal steroid hormones appear to enhance the abuse-related effects of cocaine in preclinical studies and may contribute to gender differences in cocaine's effects. We propose to study the temporal relations between nicotine's effects on gonadal steroid hormones, subjective effects and cardiovascular measures. An increased understanding of nicotine's acute effects on anterior pituitary, gonadal and adrenal hormones may suggest new strategies for the development of antinicotine medications as it has for cocaine.

描述（由申请人提供）：这是对尼古丁和烟草组件的PA-00-045神经生物学和行为研究的新应用程序的修订。尼古丁激活中脱脂胺多巴胺神经元上的A4BETA2烟碱受体，并增加细胞多巴胺的释放。尼古丁和可卡因的间接多巴胺激动剂作用被认为对与滥用相关的影响很重要。但是，多巴胺可能只是神经生物学系统的一个星座，可能导致尼古丁滥用以及可卡因滥用。内分泌系统在调节药物的增强作用中的作用知之甚少，但是最近的临床前和临床研究表明，激素可能会影响可卡因与滥用相关的作用，这些发现导致了新的治疗方法。我们的初步研究表明，尼古丁和可卡因都刺激前垂体和肾上腺激素，并且具有相似的药效和药代动力学特征。然而，与可卡因相比，关于尼古丁诱导的主观状态变化，激素释放模式和血浆尼古丁水平的增加或尼古丁的作用可能随性别和/或月经周期阶段的函数而变化的时间之间的时间关系相对较少。我们建议对尼古丁对下丘脑 - 垂体 - 肾上腺轴（HPA）的急性作用进行临床研究，以及在每天吸烟和尼古丁依赖性的男性和女性中，下丘脑 - 垂体 - 垂体轴（HPG）（HPG）（DSM-IV标准）。妇女将在月经周期的卵泡和中间阶段进行研究，以确定月经周期的激素波动是否影响尼古丁的生物学和滥用相关作用。两种剂量的尼古丁和安慰剂对神经内分泌，主观和心血管措施的影响将在自身控制设计中的双盲条件下进行研究。尼古丁将通过吸烟在测量和控制的粉扑，持续时间和频率的过程中通过吸烟来施用。但是，由于烟草烟雾的其他成分可能会导致吸烟的影响，因此我们建议对静脉注射尼古丁进行平行研究。检查尼古丁对内分泌系统的影响以及主观和心血管措施的相关变化将提高我们对尼古丁滥用相关作用的生物学基础的理解，以及它对吸烟女性的某些生殖疾病的贡献（例如，早期的更年期和不育）。临床报道表明，尼古丁具有抗雌激素作用，但尚无对尼古丁对HPG轴的影响的全面研究。这个问题很重要，因为性腺类固醇激素似乎增强了可卡因在临床前研究中与滥用相关的作用，并且可能导致可卡因作用的性别差异。我们建议研究尼古丁对性腺类固醇激素，主观作用和心血管措施的影响之间的时间关系。人们对尼古丁对垂体，性腺和肾上腺激素的急性影响的越来越多，可能会提出针对可卡因的新策略。