Neuropharmacological investigation of frontostriatal network function and nicotine seeking behavior in current smokers

 描述(由申请人提供)：烟草使用造成巨大的社会、医疗和经济负担，是美国可预防死亡的主要原因。广泛的临床前数据表明，药物应激源增加了滥用药物(包括尼古丁)的药物寻求/自我给药。这种强有力的临床前观察的临床转化一直是有限的。我的赞助人(格林沃尔德博士)是第一个在人类物质使用者中证明这一发现的人。我们实验室的数据表明，药物应激源产生可靠的生理应激反应，在医学上是安全的，并增加药物寻求/自我给药。然而，还没有发表的研究探讨与应激源增强的药物寻求/自我给药相关的神经生物学机制。此应用程序的目的是扩展我的发起人的工作，以调查急性药物应激诱导对额纹状体网络功能、神经化学、主观内部状态和尼古丁寻求/自我给药的影响。额纹状体网络(发自背外侧前额叶皮质[dlPFC])与 与寻求尼古丁/自我管理相关的认知过程，包括：自我控制、延迟满足和吸烟/吸烟提示反应。我们将采用受试者内随机交叉设计，检验联合口服育亨宾[YOH：α2-肾上腺素受体拮抗剂]和氢化可的松[Hyd：糖皮质激素激动剂]相对于安慰剂[乳糖]对当前吸烟者的额纹状体网络功能、dlPFC神经化学、尼古丁寻求/自我给药以及主观效应(情感、焦虑、戒断和渴求)的影响。总体假设：yoh hyd预处理会诱导生理应激反应，减少dlPFC参与，解偶联dlPFC对大脑奖赏区域的控制，减弱认知任务执行中的谷氨酸反应，并增强尼古丁寻求/自我给药。实验设计、方法和假设基于发起人实验室和科学文献提供的强有力的初步数据和已发表的数据。意义：我们的方法将促进与应激源增强的药物寻求/自我给药相关的可信的神经生物学机制的研究，这是一个重要而未被研究的临床现象。该项目代表了对与药物寻求/自我给药相关的神经生物学机制的程序性调查路线的第一次研究。未来的潜在研究将是：A)扩大YOHHID剂量组合，B)研究其他物质依赖人群(例如大麻、可卡因)，以及C)缓释型金刚烷(α2-肾上腺素受体激动剂)或D)可能减弱应激源强化药物寻求/自我给药的痛苦耐受/放松技术。我已经组建了一个由导师组成的协作团队，每个导师都拥有与当前提案相关的独特专业知识，这将为我提供与我的职业目标一致的多学科培训体验。

 DESCRIPTION (provided by applicant): Tobacco use exerts a tremendous societal, healthcare and economic burden, and is the leading cause of preventable death in the United States. Extensive preclinical data indicates pharmacological stressors increase drug seeking/self-administration across drugs of abuse (including nicotine). Clinical translation of thi robust preclinical observation has been limited. My Sponsor (Dr. Greenwald) was first to demonstrate this finding in human substance users. Data from our lab indicate that pharmacological stressors produce a reliable physiological stress response, are medically safe, and increase drug seeking/self-administration. However, no published studies have investigated neurobiological mechanisms associated with stressor-potentiated drug seeking/self-administration. The goal of this application is to expand my Sponsor's work to investigate the effects of an acute pharmacological stress-induction on frontostriatal network function, neurochemistry, subjective internal state, and nicotine seeking/self-administration. The frontostriatal network (emanating from the dorsolateral prefrontal cortex [dlPFC]) is implicated in cognitive processes associated with nicotine seeking/self-administration, including: self-control, delayed gratification, and cigarette/smoking cue reactivity. Using a within-subject randomized crossover design, we will examine the effects of combined oral pretreatment with yohimbine [YOH: α2-adrenoreceptor antagonist] and hydrocortisone [HYD: glucocorticoid agonist] relative to placebo [lactose] on frontostriatal network function, dlPFC neurochemistry, nicotine seeking/self-administration, and subjective effects (affect, anxiety, withdrawal and craving) among current smokers. Overall hypotheses: YOH+HYD pretreatment will induce a physiological stress response, reduce dlPFC engagement, uncouple dlPFC control of brain reward regions, attenuate glutamate response during cognitive task performance, and potentiate nicotine seeking/self- administration. The experimental design, methods, and hypotheses are based on the strong preliminary and published data from the Sponsor's laboratory and the scientific literature. Significance: Our approach will facilitate investigation f plausible neurobiological mechanisms associated with stressor-potentiated drug seeking/self-administration, an important and understudied clinical phenomenon. This project represents the first study of a programmatic line of inquiry into neurobiological mechanisms associated with drug seeking/self-administration. Potential future research studies would; A) expand YOH+HYD dose combinations, B) investigate other substance dependent populations (e.g. marijuana, cocaine), and pretreat with C) extended-release guanfacine (α2-adrenoreceptor agonist) or D) distress tolerance/relaxation techniques which may attenuate stressor-potentiated drug seeking/self-administration. I have assembled a collaborative team of mentors, each possessing unique expertise relevant to the current proposal, which will provide me a multidisciplinary training experience consistent with my career goals.