Neurobiology of Nicotine: Hormones and Behavior

描述（由申请人提供）：这是对PA-00-045尼古丁和烟草成分的神经生物学和行为研究的新申请的修订。尼古丁激活中边缘多巴胺神经元上的a4beta2尼古丁受体，增加细胞外多巴胺的释放。尼古丁和可卡因的间接多巴胺激动剂作用被认为是与滥用相关的重要作用。然而，多巴胺很可能只是导致尼古丁滥用和可卡因滥用的一系列神经生物系统中的一个。内分泌系统在调节药物强化效应中的作用尚不清楚，但最近的临床前和临床研究表明，激素可能影响可卡因的滥用相关效应，这些发现导致了新的治疗方法。我们的初步研究表明，尼古丁和可卡因都能刺激垂体前叶和肾上腺激素，并且具有相似的药效学和药代动力学特征。然而，与可卡因相比，人们对尼古丁引起的主观状态改变、激素释放模式和血浆尼古丁水平增加之间的时间关系知之甚少，也不知道尼古丁的影响是如何随着性别和/或月经周期阶段而变化的。我们建议在每日吸烟者和尼古丁依赖者（DSM-IV标准）中进行尼古丁对下丘脑-垂体-肾上腺轴（HPA）和下丘脑-垂体-性腺轴（HPG）的急性影响的临床研究。将对处于卵泡期和黄体中期的妇女进行研究，以确定整个月经周期中的激素波动是否会影响尼古丁的生物效应和与滥用有关的效应。两种剂量的尼古丁和安慰剂对神经内分泌、主观和心血管指标的影响将在双盲条件下进行研究。尼古丁将通过吸烟的过程来施用，在此过程中，吸烟量、持续时间和频率都是被测量和控制的。然而，由于烟草烟雾的其他成分也可能导致吸烟的影响，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测量的相关变化将促进我们对尼古丁滥用相关影响的生物学基础的理解，以及它对吸烟妇女的一些生殖障碍（例如，早期绝经和不孕症）的贡献。临床报告表明尼古丁具有抗雌激素作用，但尼古丁对HPG轴的影响尚未有全面的研究。这个问题很重要，因为在临床前研究中，性腺类固醇激素似乎增强了可卡因与滥用有关的影响，并可能导致可卡因影响的性别差异。我们建议研究尼古丁对性腺类固醇激素的影响、主观影响和心血管指标之间的时间关系。对尼古丁对垂体前叶、性腺和肾上腺激素的急性影响的进一步了解，可能会为开发抗尼古丁药物提供新的策略，就像开发抗可卡因药物一样。

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.