Neuroendocrine Factors, Nicotine, and Behavioral Inhibition in Female Smokers

描述（申请人提供）：性腺神经内分泌功能是涉及成瘾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，可能会阐明病因机制和基于神经内分泌的女性成瘾治疗，也可能是男性。因此，本项目测试了一个新的理论模型，该模型提出行为抑制——一种假定影响成瘾行为的生物行为过程，受尼古丁调节，并受卵巢激素影响——是一种将月经周期和女性吸烟驱动的神经内分泌变异联系起来的机制。行为抑制是指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：(a)防止不希望戒烟的个人的强迫性吸毒行为；(b)提倡在戒烟过程中努力戒酒。该模型表明，急性戒烟期间不良的行为抑制可能会在月经周期的卵泡晚期（LF）期间被放大，此时雌激素水平高且黄体酮不对抗。相反，禁欲期间的行为抑制受损在黄体中期（ML，雌激素水平适中但孕酮水平较高）和卵泡早期（EF，雌激素和孕酮均较低，“激素基线”）可能不太明显。尼古丁可以抵消由戒烟引起的行为抑制受损，特别是在行为抑制缺陷最明显的LF期。我们将在一个安慰剂对照的双盲实验室实验中测试这个模型，实验对象是80名不寻求治疗的绝经前女性每日吸烟者。在戒烟16小时后，女性将完成三次实验性访问（EF、LF和ML）。在每次访问期间，他们将在两个时间点完成基于计算机的行为抑制测量：(1)访问开始时；(2)经皮贴敷后。本研究采用混合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：尼古丁前后）析因设计。本研究的主要目的是验证以下假设：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（尼古丁后-尼古丁前）较高。第二个目的是研究雌激素和孕激素水平的阶段性变化与行为抑制的阶段性变化之间的关系，以揭示月经周期和尼古丁相互作用背后的神经内分泌途径。这个项目将为一个研究项目铺平道路，该项目涉及更多的实验室和临床研究，包括神经内分泌、药理学和认知基础，以及女性吸烟和其他成瘾的基础，最终目的是改善女性和两性之间的成瘾治疗。

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.