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

 描述（由申请人提供）：烟草使用造成了巨大的社会、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，药理学应激增加了药物滥用（包括尼古丁）的药物寻求/自我给药。这一稳健的临床前观察结果的临床转化有限。我的申办者（Greenwald博士）是第一个在人类物质使用者中证明这一发现的人。来自我们实验室的数据表明，药理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/自我管理。然而，没有发表的研究调查与应激增强药物寻求/自我管理相关的神经生物学机制。本申请的目的是扩展我的申办者的工作，以研究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（源自背外侧前额叶皮层[dlPFC]）与以下因素有关： 与尼古丁寻求/自我给药相关的认知过程，包括：自我控制、延迟满足和香烟/吸烟提示反应。使用受试者内随机交叉设计，我们将检查育亨宾[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]联合口服预处理相对于安慰剂[乳糖]对额纹网络功能、dlPFC神经化学、尼古丁寻求/自我给药以及当前吸烟者的主观影响（情感、焦虑、戒断和渴望）。总体假设：YOH+HYD预处理将诱导生理应激反应，减少dlPFC参与，解偶联大脑奖励区域的dlPFC控制，减弱认知任务执行期间的谷氨酸反应，并增强尼古丁寻求/自我给药。实验设计、方法和假设均基于申办方实验室和科学文献的有力初步和已发表数据。重要性：我们的方法将有助于调查合理的神经生物学机制与压力增强药物寻求/自我管理，一个重要的和未充分研究的临床现象。 该项目代表了第一个研究与药物寻求/自我管理相关的神经生物学机制的程序线。潜在的未来研究将：A）扩展YOH+HYD剂量组合，B）研究其他物质依赖人群（例如大麻、可卡因），并使用C）缓释胍法辛（α2-肾上腺素受体激动剂）或D）可能减弱应激增强的药物寻求/自我给药的痛苦耐受/放松技术进行预治疗。我已经组建了一个由导师组成的协作团队，每个人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相一致的多学科培训经验。

 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.