Neuroendocrine Factors, Nicotine, and Behavioral Inhibition in Female Smokers

描述(由申请人提供)：性腺神经内分泌功能是与成瘾有关的性别差异的一个关键方面。关注月经周期和卵巢激素对尼古丁影响的调节，可能会阐明女性成瘾的病因机制和基于神经内分泌的治疗方法，或许男性也是如此。因此，该项目测试了一个新的理论模型，该模型提出，行为抑制是一种将月经周期和吸烟驱动的神经内分泌变化联系起来的机制。行为抑制是一种生物行为过程，被认为影响成瘾行为，受到尼古丁的调节，并受到卵巢激素的影响。行为抑制指的是抑制在特定情况下不需要或不适当的习惯性反应的能力，这可能是一个重要的过程，可以：(A)防止不想戒烟的个人的强迫药物使用行为；以及(B)在戒烟尝试期间促进戒烟努力。这个模型声称，急性戒烟期间不良的行为抑制可能在月经周期的卵泡晚期(LF)放大，此时雌激素水平较高，且没有黄体酮的拮抗作用。相比之下，在黄体中期(ML；当雌激素水平适中但黄体酮水平较高时)和卵泡早期(EF；当雌激素和孕激素水平都较低时；“激素基线”)，禁欲期间的行为抑制受损可能不那么明显。尼古丁可以抵消烟草戒断引起的行为抑制受损，特别是在行为抑制缺陷最明显的LF阶段。我们将在安慰剂对照的双盲实验室实验中测试这一模型，实验对象为80名未寻求治疗的绝经前女性日常吸烟者。女性将在戒烟16小时后完成三次实验访问(EF、LF和ML)。在每次访问期间，他们将在会议期间的两个时间点完成基于计算机的行为抑制测量：(1)在访问开始时；(2)在注射透皮贴片之后。这项研究采用混合2(受试者间：尼古丁与安慰剂)x3(受试者内：月经周期阶段)x2(受试者内：尼古丁前与尼古丁后)析因设计。这项研究的主要目的是验证如下假设：与EF和ML阶段相比，在LF阶段，女性将表现出：(1)尼古丁前行为抑制较低，(2)尼古丁诱导的行为抑制增强(后尼古丁)。第二个目的是研究雌激素和孕激素水平的时相变化与行为抑制的时相变化的关系，以阐明月经周期和尼古丁相互作用的神经内分泌途径。该项目将为一项研究计划铺平道路，该计划涉及对女性吸烟和其他成瘾的神经内分泌、药理学和认知基础进行更密集的实验室和临床研究，最终目的是改善女性和两性的成瘾治疗。

DESCRIPTION (provided by applicant): Gonadal neuroendocrine function is a key aspect of sex differences implicated in addiction. Focusing on the menstrual cycle and ovarian hormone modulation of nicotine's effects may elucidate etiologic mechanisms and neuroendocrine-based treatments for addiction among women and perhaps men also. Accordingly, this project tests a novel theoretical model which proposes that behavioral inhibition-a biobehavioral process that putatively influences addictive behavior, is modulated by nicotine, and is affected by ovarian hormones-is a mechanism linking neuroendocrine variation driven by the menstrual cycle and smoking in women. Behavioral inhibition refers to the ability to suppress habitual responses that are not required or appropriate in a given situation, which may be an important process that: (a) prevents compulsive drug use behavior among individuals not wishing to quit; and (b) promotes efforts to abstain during a cessation attempt. This model purports that poor behavioral inhibition during acute tobacco abstinence may be amplified during the menstrual cycle's late follicular phase (LF) when estrogen levels are high and unopposed by progesterone. By contrast, impaired behavioral inhibition during abstinence may be less pronounced during the mid-luteal phase (ML; when estrogen levels are moderate but are opposed by high progesterone levels) and the early follicular phase (EF; when both estrogen and progesterone are low; "hormonal baseline"). Nicotine may offset impaired behavioral inhibition caused by tobacco abstinence, particularly during the LF phase when behavioral inhibition deficits may be most pronounced. We will test this model in a placebo-controlled double-blind lab experiment with 80 non-treatment-seeking pre-menopausal female daily cigarette smokers. Females will complete three experimental visits (EF, LF, and ML) following 16-hr tobacco abstinence. During each visit, they will complete computer-based measures of behavioral inhibition at two time points during the session: (1) at the outset of the visit; and (2) following administration of transdermal patch. Thi study uses a mixed 2 (Between-Subject: Nicotine vs. Placebo) x3 (Within-Subject: Menstrual Cycle Phase) x2 (Within-Subject: Pre vs. Post Nicotine) factorial design. The primary aim of this study is to test the hypotheses that in the LF phase, as compared to the EF and ML phases, women will exhibit: (1) lower pre-nicotine behavioral inhibition and (2) higher nicotine-induced enhancement (Post - Pre nicotine) of behavioral inhibition. The secondary aim is to examine relations of phase-related changes in estrogen and progesterone levels to phase-related changes in behavioral inhibition to shed light on neuroendocrine pathways that underlie menstrual cycle and nicotine interactions. This project will pave the way for a program of research involving more intensive laboratory and clinical studies of neuroendocrine, pharmacological, and cognitive underpinnings of smoking and perhaps other addictions in women, with the ultimate aim of improving addiction treatment among women and across both sexes.