Sex, GABA and Nicotine: A 1H-MRS Study

描述（由申请人提供）：虽然男性和女性在吸烟行为方面存在一些值得注意的差异，但最终没有什么比戒烟能力的差异更令人担忧。尽管对于女性戒烟不太成功的原因有多种解释，但观察到女性在戒烟期间更容易出现抑郁症状，这是一个已知的复发风险因素，可能是这种性别特异性再犯的关键因素。一些证据表明，尼古丁对γ -氨基丁酸（GABA）的调节可能在性、抑郁和吸烟再犯之间的相互作用中起着重要作用。利用质子磁共振波谱（1H-MRS），我们的研究小组发现单极抑郁症和经前焦虑症患者枕叶皮质GABA浓度降低。最近，我们发表了来自健康吸烟男性和女性的试点数据，表明尼古丁引起的皮质GABA水平的改变仅在女性中发现，其特征是在卵泡期GABA水平降低，GABA水平在月经周期中消失。因此，吸烟女性大脑皮层GABA水平的降低可能会增加她们患抑郁症的风险，从而破坏她们戒烟的努力。因此，我们建议采用1H-MRS测量更多健康吸烟和不吸烟女性和男性枕皮质GABA水平，以确认性别和月经周期阶段对尼古丁引起的皮质GABA浓度变化的影响。此外，女性将被邀请进行10-14天的戒断，使用应急管理，以便我们可以检查基线GABA和GABA变化与戒断和出现负面影响和渴望之间的关系。这个项目既新颖又及时，因为它直接响应了NIDA的任务，即检查性别特定因素对药物滥用/依赖障碍的影响，以加强长期戒断。与公众健康相关：本提案中概述的研究不仅将进一步加深我们对尼古丁对脑化学影响的了解，还可能导致新的药物，以促进女性和/或其他在戒烟期间有抑郁风险的人戒烟。

DESCRIPTION (provided by applicant): While there are several note-worthy differences between males and females with regard to smoking behavior, ultimately none are as worrisome as the disparity in ability to quit smoking. Although multiple explanations for why women are less successful in their abstinence attempts have been proffered, the observation that women are more likely to experience emergence of depressive symptoms during smoking cessation, a known risk factor for relapse, may be a critical contributor to this sex-specific recidivism. Several lines of evidence suggest that nicotine modulation of gamma-aminobutyric acid (GABA) may play an important role in this interplay between sex, depression and smoking recidivism. Using proton magnetic resonance spectroscopy (1H-MRS), our group has found reductions in occipital cortex GABA concentrations in subjects with unipolar depression and premenstrual dysphoric disorder. Recently, we have published pilot data from healthy smoking men and women indicating that nicotine induced alterations in cortical GABA levels are found solely in women and are characterized by reduced GABA levels in the follicular phase and abolished menstrual cyclicity in GABA levels. Reductions in cortical GABA levels in women who smoke may therefore render them at increased risk for depression, which sabotages their attempts to quit. Thus, we propose to employ 1H-MRS to measure GABA levels in the occipital cortex of a larger group of healthy smoking and nonsmoking women and men to confirm the impact of sex as well as menstrual cycle phase on nicotine-induced alterations in cortical GABA concentrations. In addition, women will be invited to undergo 10-14 days of abstinence using contingency management so that we may examine the relationship between baseline GABA and changes in GABA with abstinence and emergence of negative affect and craving. This project is both novel and timely as it responds directly to the mandate from NIDA to examine the impact of sex-specific factors on substance abuse/dependence disorders in order to enhance long-term abstinence. RELEVANCE TO PUBLIC HEALTH: The study outlined in this proposal will not only further our knowledge regarding the influence of nicotine on brain chemistry, it may also lead to new medications to enhance smoking cessation in females and/or others at risk for depression during smoking abstinence.