Impulsivity and D2 Receptor Function: Behavioral and PET Correlates

冲动性和 D2 受体功能：行为和 PET 相关性

• 批准号: 8058640
• 负责人: Stephanie Mary Groman
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058640
• 关键词: Affinity; Agonist; Behavior; Behavioral; Binding; Blinking; Brain; Brain region; Cerebrum; Cognition; Cognitive; Corpus striatum structure; Decision Making; Deoxyglucose; Development; Disease; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Dose; Drug abuse; Economics; Exhibits; Family; Imaging Techniques; Impulsivity; Individual; Individual Differences; Intake; Investigation; Laboratories; Lead; Left; Link; Measurement; Measures; Mediating; Molecular; Molecular Conformation; Monkeys; Patient Self-Report; Pharmaceutical Preparations; Phenotype; Population; Positron-Emission Tomography; Prevention strategy; Process; Risk; Role; Short-Term Memory; Societies; Substance Addiction; Substance abuse problem; Synapses; System; Techniques; Temperament; Variant; base; behavior measurement; biobehavior; biological systems; caudate nucleus; cognitive control; dopamine system; flexibility; functional outcomes; glucose metabolism; in vivo; insight; neuroimaging; neuromechanism; nonhuman primate; pre-clinical research; radioligand; receptor; receptor expression; receptor function; relating to nervous system; research study; response; social; trait; treatment strategy

DESCRIPTION (provided by applicant): The economic and social burdens on society that are a direct result of substance dependence are enormous. As such, determining the neural mechanisms of phenotypes that confer risk for the development of this disorder is crucial for advancing scientifically-based prevention and treatment strategies. Associations between variation in cognitive processes and substance dependence liability have been demonstrated, and the corticostriatal dopamine system has been implicated in these relationships. Further, recent evidence has demonstrated an important role of the dopamine D2 receptor in controlling aspects of impulsivity, cognitive control and drug abuse. Therefore, the D2 receptor may represent a mechanistic link between cognitive control processes and risk for the development of substance dependence. Because the D2 receptor can exist in two conformational states - a state in which dopamine displays high affinity for the receptor and has greater functional activity, and a state in which dopamine displays less affinity for the receptor and is less functionally active - determining whether variation in receptor availability detected with standard neuroimaging techniques (i.e. PET) reflect variation in receptor state (high versus low) is critical to understanding the relationship between cognitive processes and risk for substance dependence. Because we have found an association between a naturally occurring variation of trait impulsivity and D2 radioligand binding in vivo, this proposal will attempt to examine this question using behavioral pharmacological techniques to probe D2-like receptor states (Aim 1) and using this information to examine a possible neural mechanism by which variation in receptor state may influence global brain function (Aim 2). These results will provide evidence for a mechanism by which variation within a biological system can influence higher- order processes that have direct relevance to substance dependence. The advancements in the characterization of the link between the D2 receptor system and impulsivity offered in this proposal will provide an important step in understanding how manipulations of the dopamine system may be utilized to enhance cognitive control and therefore mitigate risk for the development of substance dependence.

描述（由申请人提供）：物质依赖给社会带来的经济和社会负担是巨大的。因此，确定导致这种疾病发展风险的表型的神经机制对于推进基于科学的预防和治疗策略至关重要。认知过程的变化与物质依赖之间的关联已被证明，皮质纹状体多巴胺系统与这些关系有关。此外，最近的证据表明，多巴胺D2受体在控制冲动、认知控制和药物滥用方面发挥着重要作用。因此，D2受体可能代表了认知控制过程与物质依赖发展风险之间的机制联系。因为D2受体可以以两种构象状态存在——在这种状态下，多巴胺对受体表现出高亲和力，具有更大的功能活性，在这种状态下，多巴胺对受体的亲和力较低，功能活性较低——确定用标准神经成像技术（即PET）检测到的受体可用性的变化是否反映了受体状态的变化（高与低），对于理解认知过程与物质依赖风险之间的关系至关重要。因为我们已经发现了自然发生的性状冲动性变化与体内D2放射配体结合之间的关联，本提案将尝试使用行为药理学技术来探测D2样受体状态（目的1），并利用这些信息来研究受体状态变化可能影响整体大脑功能的可能神经机制（目的2）。这些结果将为生物系统内的变异能够影响与物质依赖直接相关的高阶过程的机制提供证据。本研究提出的D2受体系统与冲动性之间的联系表征的进展将为理解如何利用多巴胺系统的操纵来增强认知控制，从而减轻物质依赖发展的风险提供重要的一步。