Multimodal Imaging of Progesterone/Neurosteroid Effects in Nicotine Addiction

描述(申请人提供)：使用多模式成像方法，我们打算研究孕酮(PRAG)及其神经类固醇代谢物别孕酮(ALLO)对脑神经化学(伽马氨基丁酸；GABA和谷氨酸；GLUT浓度)、工作记忆中的神经元激活(背侧前额叶皮质；DLPFC)和静息状态连接(背侧前扣带；dACC和腹侧纹状体；VS)的影响。尼古丁依赖在美国仍然是一个严重的公共卫生问题，每年造成约2000亿美元的医疗支出和生产力损失。美国人的亚群受到尼古丁依赖的影响并不均衡，因为与男性相比，女性尤其容易受到尼古丁依赖对健康的不利影响，社会经济地位较低的人比社会经济地位高的人更有可能吸烟。有趣的是，在男性和女性中，以女性为主的性激素项目对戒酒期间的认知和尼古丁渴望以及再次接触药物时的尼古丁渴求都有积极的影响，这表明这种激素可能具有治疗作用。临床前研究表明，Prog在尼古丁依赖中的作用主要是通过对GABA能功能的变态调节来实现的。为了将这一研究路线转化到人体实验室，50名男性和50名女性尼古丁依赖者将参与一项关于PROG的双盲、安慰剂对照交叉研究，该研究包括两个戒烟试验(每个试验4天)、吸烟地形图和脑成像(质子磁共振波谱；1H-MRS和功能磁共振成像(fMRI；静息状态和认知任务表现))。Prog到Allo的转换通过受试者水平的特征(如抑郁症病史)进行修改，将使用标准的GC-MS方法进行测量。检查dACC以及与纹状体和前额叶皮质的连接性的假设驱动的分析将使用基于种子的标准相关性分析来检查，而DLPFC在静止时的神经化学和工作记忆任务表现中的神经激活是其他主要结果。脑成像在7特斯拉的超高磁场下进行，以最大限度地提高1H-MRS测量GABA和GLUT的信噪比，同时允许共同定位功能磁共振实验的感兴趣区域。这些脑成像结果以及Prog向Allo的转化程度、性别和吸烟的地形结果，将为Prog/神经类固醇以及其他GABA激动剂作为尼古丁依赖治疗药物的潜力提供关键的新信息。

DESCRIPTION (provided by applicant): Using a multi-modal imaging approach, we intend to investigate the impact of progesterone (PROG) and its neurosteroid metabolite, allopregnanolone (ALLO) on brain neurochemistry (gamma aminobutryic acid; GABA and glutamate; Glut concentrations), neuronal activation during working memory (dorsal lateral prefrontal cortex; DLPFC) and resting state connectivity (dorsal anterior cingulate; dACC and ventral striatum; VS). Nicotine dependence remains a critical public health issue in the United States, costing approximately 200 billion dollars each year in medical expenditures and lost productivity. Subgroups of Americans are unevenly affected by nicotine dependence as females compared to males are particularly at risk for the adverse health effects of nicotine dependence and individuals of lower versus higher socioeconomic status are more likely to smoke. Interestingly, the predominantly female sex hormone PROG exerts a positive effect on cognition and nicotine craving during abstinence and drug liking during re-exposure in both males and females, suggesting a possible therapeutic role for the hormone. Preclinical studies indicate that the effect of PROG in nicotine dependence would be mediated primarily through ALLO modulation of GABAergic function. To translate this line of investigation to the human laboratory, 50 men and 50 women with nicotine dependence will participate in a double blind, placebo-controlled crossover study of PROG that requires two abstinence trials (4 days each), smoking topography sessions and brain imaging (proton magnetic resonance spectroscopy; 1H-MRS and functional magnetic resonance imaging (fMRI; resting state and during cognitive task performance) pre and post each trial. PROG conversion to ALLO, which is modified by subject-level characteristics such as history of major depression, will be measured using standard GC-MS methods. Hypothesis-driven analyses examining dACC and connectivity with the striatum and prefrontal cortex will be examined using standard seed-based correlation analyses while DLPFC neurochemistry at rest and neural activation during working memory task performance are other primary outcomes. Brain imaging is conducted at the ultra-high magnetic field of 7 Tesla in order to maximize the signal to noise for 1H-MRS measurement of GABA and Glut, while allowing co-localization of regions of interest for the fMRI experiments. These brain imaging outcomes along with degree of conversion of PROG to ALLO, sex and smoking topography outcomes, will be provide critical new information regarding the potential for PROG/neurosteroids, as well as other GABA agonists, to be developed as treatments for nicotine dependence.