Component 3 - Frontolimbic circuits, dopamine and attentional bias to alcohol c

组件 3 - 额叶回路、多巴胺和对酒精的注意力偏差

• 批准号: 8593208
• 负责人: Donita L Robinson
• 金额: $ 21.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8593208
• 关键词: Acute; Address; Alcohol consumption; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Amino Acids; Animal Model; Attention; Behavior; Behavioral; Brain; Chronic; Cues; Data; Dopamine; Dose; Double-Blind Method; Electrochemistry; Ethanol; Functional Magnetic Resonance Imaging; Goals; Heavy Drinking; Human; Image; Individual; Learning; Link; Measurement; Measures; Mediating; Modeling; Molecular; Monitor; Naltrexone; Neural Pathways; Neurobiology; Nucleus Accumbens; Opioid; Opioid Receptor; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacology; Phenylalanine; Placebo Control; Prefrontal Cortex; Process; Rattus; Reaction Time; Recording of previous events; Relapse; Reporting; Research; Rest; Rewards; Risk; Rodent; Role; Scanning; Seeds; Severities; Stimulus; Substance Use Disorder; System; Testing; Therapeutic; Translating; Tyrosine; Ventral Tegmental Area; addiction; alcohol craving; alcohol cue; alcohol exposure; alcohol response; alcohol reward; alcohol seeking behavior; alcohol use disorder; base; binge drinking; classical conditioning; clinically relevant; craving; design; directed attention; drinking; drug seeking behavior; endogenous opioids; in vivo; innovation; mesolimbic system; neural circuit; neuroimaging; new therapeutic target; non-alcoholic; novel strategies; novel therapeutic intervention; optogenetics; problem drinker; programs; relating to nervous system; response; translational study

Attentional bias toward drug-related stimuli is commonly reported in substance use disorders and is positively correlated with craving. By capturing attention and facilitating drug-seeking behavior, alcohol-associated stimuli can promote continued drinking and relapse. The goals of this project are to (1) determine the neuromodulatory role of dopamine in attentional bias to alcohol cues in heavydrinking humans, (2) model early aspects of attentional bias to alcohol cues in rats, and (3) use that animal model to mechanistically probe brain circuits mediating attentional bias, by using pharmacology, electrochemistry, and optogenetics. These goals synergize with the overall aim of the Center to understand alcohol induced pathology in brain circuits that regulate alcohol use. Moreover, this project potentially identifies novel therapeutic targets for alcohol use disorders. The proposed studies test the overall hypothesis that projections from the prefrontal cortex to the mesolimbic system regulate Pavlovianconditioned attentional bias towards alcohol cues in heavy-drinking humans and binge-alcohol-exposed rats. To address this hypothesis, two aims manipulate dopamine function in humans and rats to determine the effects of dopamine on attentional bias to alcohol cues, and a third aim translates human measurements of frontolimbic connectivity to rat studies that activate and inactivate particular neural pathways in order to identify brain circuits mediating attentional bias. Together, these highly innovative studies reveal how chronic alcohol exposure alters appetitive responses to alcohol cues. These translational studies examine pathology in frontolimbic circuits associated with chronic alcohol exposure that manifest In altered attention and response to alcohol-associated stimuli. The combination of human behavior and imaging with rodent measures of behavior, dopamine release and selective manipulation of prefrontal cortical projections provides a mechanistic approach to identify how alcohol cues usurp attention and behavior to perpetuate compulsive alcohol use.

对药物相关刺激的注意偏向在物质使用中很常见 疾病，并与渴望呈正相关。通过吸引注意力和促进毒品寻找 行为，酒精相关的刺激可以促进持续饮酒和复发。本项目的目标 目的是（1）确定多巴胺在酗酒时对酒精线索的注意偏向中的神经调节作用 人类，（2）在大鼠中模拟对酒精线索的注意偏向的早期方面，以及（3）使用该动物 模型来机械地探测大脑回路介导注意力偏差，通过使用药理学， 电化学和光遗传学。这些目标与中心的总体目标协同作用， 酒精会导致调节酒精使用的大脑回路出现病理学变化。此外，该项目可能 确定了酒精使用障碍的新治疗靶点。拟议的研究测试了总体 前额叶皮层到中脑边缘系统的投射调节巴甫洛夫条件反射假说 酗酒的人和酗酒的大鼠对酒精线索的注意偏向。 为了解决这一假设，两个目标操纵人类和大鼠的多巴胺功能，以确定多巴胺的功能。 多巴胺对酒精线索的注意力偏差的影响，第三个目的是将人类测量的 额叶边缘连接到大鼠的研究，激活和抑制特定的神经通路， 识别大脑回路介导的注意力偏差。总之，这些高度创新的研究揭示了慢性疾病 酒精暴露改变了对酒精暗示的食欲反应。这些转化研究检查病理学 在与长期酒精暴露相关的额缘回路中，表现为注意力改变和 对酒精相关刺激的反应人类行为和成像与啮齿动物的结合 行为、多巴胺释放和选择性操纵前额叶皮质投射的测量 提供了一个机械的方法来确定酒精线索如何篡夺注意力和行为，以延续 强迫性饮酒