Presynaptic Mechanisms for Variability in Human Dopamine Function and Impulsivity

人类多巴胺功能和冲动变异的突触前机制

• 批准号: 8358461
• 负责人: Joshua William Buckholtz
• 金额: $ 25.35万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358461
• 关键词: Address; Affinity; Alcohol or Other Drugs use; Amphetamines; Architecture; Autoreceptors; Behavior; Binding; Biochemical; Biological; Brain; Brain Chemistry; Brain imaging; Choice Behavior; Cognition; Collection; Corpus striatum structure; Cues; Data; Data Set; Decision Making; Development; Dextroamphetamine; Dimensions; Dopamine; Dopamine D2 Receptor; Drug Addiction; Exanthema; Exposure to; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Goals; Human; Image; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Influentials; Intervention; Investigation; Lead; Learning; Ligands; Link; Measures; Mediator of activation protein; Midbrain structure; Modeling; Neurobiology; Operant Conditioning; Participant; Pathway interactions; Patient Self-Report; Patients; Performance; Personality; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Predisposition; Process; Psychological reinforcement; Publishing; Regulation; Relative (related person); Reporting; Research; Research Design; Research Proposals; Rewards; Risk; Risk Factors; Role; Scanning; Signal Transduction; Substance Use Disorder; Substance abuse problem; System; Testing; Time; Tracer; Translating; Translational Research; Variant; Work; addiction; adverse outcome; base; behavior measurement; cost; dopaminergic neuron; drug craving; drug seeking behavior; genetic risk factor; human data; neurobiological mechanism; novel; pre-clinical; presynaptic; prevent; programs; reinforcer; response; reward circuitry; time use; trait; transmission process; young adult

DESCRIPTION (provided by applicant): Individuals vary widely in their capacity to deliberate on the potential adverse consequences of their choices before they act. Highly impulsive people frequently make rash, destructive decisions, and impulsivity is one of the most compelling markers of vulnerability for the development of drug addiction. Importantly, impulsive traits are heritable, state-independent, and temporally stable developmental predictors of addiction risk, suggesting that they reflect underlying causal (i.e. genetic) risk factors. Given that the costs associated with substance abuse have been estimated to reach nearly $500 Billion/year, understanding the pathophysiological mechanisms through which such factors act to influence impulsivity and addiction susceptibility represents a critical goal for scientific investigation. Te long-term objective of our research is to define the precise neurobiological pathways that translate causal risk factors into deleterious decision-making biases and manifestly impulsive behavior. To that end, we have recently reported several findings suggesting a novel systems-level biological mechanism that may be critical in determining individual differences in impulsivity: reduced midbrain dopamine (DA) autoreceptor control over striatal DA release. First, individuals with high levels of impulsivity show lower midbrain D2-like autoreceptor levels as measured by Positron Emission Tomography (PET) with the D2/D3-selective tracer 18F-fallypride. Second, the magnitude of DA released within the striatum following administration of the stimulant drug d-Amphetamine (AMPH) was dramatically increased in individuals with high levels of impulsivity. Finally, midbrain D2-like autoreceptor levels inversely predicted the magnitude of AMPH-induced striatal DA release (which, in turn, positively predicted drug craving), and causal modeling demonstrated that the impact of lower midbrain autoreceptor levels on impulsivity was due to the associated dysregulation of striatal DA release. However, several critical questions remain, which will be addressed by scanning 16 participants with [18F]fallypride and a measure of DA synthesis capacity, [18F]fDOPA. First, we will examine the generalizability of DA circuit dysregulation to distinct forms of impulsive behavior. Participants will also be assessed on behavioral measures of impulsivity that relate to two distinct subcomponents: impulsive action and impulsive choice. This will permit us to determine the selectivity of relationships among objective behavioral measures of these distinct facets of impulsivity and presynaptic DA dysfunction. Second, we will elucidate the specific biochemical mechanism underpinning DA circuit dysregulation. By employing a novel multi-tracer PET approach that enables us to measure both midbrain D2 autoreceptors and striatal DA synthesis, we are able to test the hypothesis that diminished midbrain DA autoreceptor control leads to enhanced striatal DA transmission in impulsivity by dysregulating striatal DA synthesis. Finally, we will assess the implications of this dysregulation for current models of compulsive reward-seeking in addiction. Current influential models of striatal dysfunction in addiction emphasize the role of aberrant reward learning processes in the development of substance abuse, and they imply a facilitation of such maladaptive learning in individuals who have greater phasic DA responses to rewards. We will use model-based fMRI during an instrumental learning task to test the hypothesis that impulsivity is associated with potentiated reinforcement learning, and to determine if individual differences in presynaptic DA function (PET) predict DA-dependent striatal reinforcement learning signals (fMRI). Overall, this project utilizes a multi-level (brain chemistry, brain function, personality, cognition, and behavior) analytical approach to discover specific systems-level neurobiological mechanisms through which a heritable addiction susceptibility factor acts to put individuals at risk. By obtaining a fundamental understanding of the relationships between impulsivity, mesostriatal DA circuit function, and reinforcement learning in healthy young adults, we lay the foundation for future studies in patients and unaffected relatives. PUBLIC HEALTH RELEVANCE: Impulsivity is a robust risk factor for the development of substance use disorders. This proposal aims to test hypotheses about the specific neurobiological mechanisms that lead to individual differences in impulsivity. This work will form the basis of a translational research program that is centered on the development of novel interventions to prevent and treat substance use disorders.

描述（由申请人提供）：个人在行动之前的选择可能不利后果的能力差异很大。高度冲动的人经常做出皮疹，破坏性的决定和冲动性，是吸毒成瘾发展的最引人注目的脆弱性标志之一。重要的是，冲动性状是成瘾风险的遗传性，独立且在时间上稳定的发展预测因素，表明它们反映了基本的因果关系（即遗传）风险因素。鉴于据估计，与药物滥用相关的成本估计达到近5000亿美元，因此了解了这种因素来影响冲动性和成瘾易感性的病理生理机制，这是科学研究的关键目标。我们研究的长期目标是定义将因果风险因素转化为有害决策偏见和明显冲动行为的精确神经生物学途径。为此，我们最近报道了一些发现，提出了一种新型的系统级生物学机制，这对于确定冲动性的个体差异至关重要：中脑多巴胺（DA）自身受体控制减少了纹状体DA释放。首先，具有高水平的冲动性的个体显示了通过正电子发射断层扫描（PET）和D2/D3选择性示踪剂18F-屈服的较低的中脑D2样的自身受体水平。其次，在高水平的冲动性的个体中，给予刺激性药物D-苯丙胺（AMPH）后，纹状体内释放的DA幅度显着增加。最后，中脑D2样的自身受体水平成反比AMPH诱导的纹状体DA释放的幅度（又又积极地预测了药物的渴望），而因果模型表明，下脑中自身受体自身受体水平对脉冲释放的脉冲释放的影响是造成脉冲释放的相关失调引起的。但是，仍然存在几个关键问题，这将通过扫描16位参与者[18F] Fallypride和DA合成能力的度量[18F] FDOPA来解决。首先，我们将研究DA电路失调对不同形式的冲动行为的普遍性。参与者还将根据与两个不同的亚组成部分相关的冲动行为度量进行评估：冲动行动和冲动性选择。这将使我们能够确定这些不同的冲动性和突触前DA功能障碍的客观行为度量之间关系的选择性。其次，我们将阐明基于DA回路失调的特定生化机制。通过采用一种新型的多跟踪PET方法，使我们能够测量中脑D2自身受体和纹状体DA合成，我们能够测试以下假设，即中脑DA自动感受器的控制减少会导致通过表面上的纹状体DA综合通过疾病障碍。最后，我们将评估这种失调对成瘾中强迫奖励的当前模型的含义。当前成瘾中纹状体功能障碍的有影响力的模型强调了 异常奖励学习过程在滥用药物滥用的发展中的作用，这意味着对对奖励有更大反应的个人的适应不良学习的促进。我们将在工具学习任务中使用基于模型的fMRI来测试冲动性与增强的增强学习有关的假设，并确定突触前DA功能（PET）中的个体差异是否可以预测DA依赖性纹状体增强学习信号（FMRI）。总体而言，该项目利用多层次（大脑 化学，大脑功能，人格，认知和行为）分析方法，以发现特定的系统级神经生物学机制，通过这些方法，可遗传的成瘾易感性因素可以使个人处于危险之中。通过对健康年轻人的冲动性，中纹DA回路功能和增强学习之间的关系有基本的了解，我们为未来的患者研究和未受影响的亲戚奠定了基础。 公共卫生相关性：冲动是发展物质使用障碍的强大风险因素。该提案旨在测试有关导致冲动性个体差异的特定神经生物学机制的假设。这项工作将构成一项转化研究计划的基础，该计划集中于开发新的干预措施，以预防和治疗药物使用障碍。

项目成果

Selective Mapping of Psychopathy and Externalizing to Dissociable Circuits for Inhibitory Self-Control.

• DOI: 10.1177/2167702616631495
• 发表时间: 2016-05
• 期刊: Clinical psychological science : a journal of the Association for Psychological Science
• 作者: Rodman AM;Kastman E;Dorfman HM;Baskin-Sommers A;Kiehl KA;Newman JP;Buckholtz JW
• 通讯作者: Buckholtz JW