Serotonin 5-HT2A Receptor Integration of Impulsivity and Cocaine Cue Reactivity

冲动性和可卡因提示反应性的血清素 5-HT2A 受体整合

• 批准号: 8398741
• 负责人: Latham Fink
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398741
• 关键词: Abstinence; Affect; Agonist; Animal Model; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Characteristics; Cocaine; Cocaine Dependence; Complement; Cues; Data; Disease; Dose; Drug Addiction; Drug abuse; Exhibits; GTP-Binding Proteins; Genetic; Goals; HTR2A gene; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Intake; Investigation; Knowledge; Ligands; Limbic System; Maintenance; Mediating; Membrane; Mental disorders; Metabolism; Methodology; Methods; Modeling; Motivation; Neurobiology; Neuropharmacology; Neurotransmitters; Outcome; Phenotype; Play; Predisposition; Prefrontal Cortex; Prevention strategy; Psychological Factors; Rattus; Receptor Signaling; Regulation; Relapse; Relative (related person); Research; Rewards; Risk Factors; Role; Self Administration; Serotonin; Signal Transduction; Structure; Support System; Synapses; System; Testing; Therapeutic Intervention; Training; Variant; Viral Vector; addiction; base; cocaine use; cue reactivity; design; drug of abuse; drug relapse; genetic technology; innovation; insight; nerve supply; neurochemistry; novel; pre-clinical; preclinical study; psychologic; receptor; receptor expression; receptor function; relating to nervous system; research study; small hairpin RNA; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Drug abuse affects millions of people worldwide and begins against a backdrop of vulnerability based upon genetic, environmental, and psychological factors. Investigations into psychological characteristics associated with drug abuse have revealed impulsivity as a major risk factor for initiation, maintenance, and relapse to drugs of abuse such as cocaine. Thus, understanding the neurobiological substrates of impulsivity is critical for developing prevention and treatment strategies. Despite significant advances in understanding the general neurobiology of impulsivity, there is a fundamental gap in our knowledge of the factors that determine how individual differences in impulsivity that may confer addiction vulnerability. Using animal models of impulsive action and cocaine-seeking, the objective of this proposal is to identify neurobiological differences between inherently high and low impulsive (HI and LI) outbred rats and relate those differences to the susceptibility to cocaine-seeking behavior. The neural systems supporting impulsive action include limbic system regulators of reward and motivation as well as cortical structures that exert inhibitory control, such as the prefrontal cortex (PFC). Inhibitory control from the PFC is heavily modified by dense serotonin (5-HT) innervation, and the 5- HT2A receptor (5-HT2AR) has been shown to play an important role within the PFC in both impulsive action and reactivity to cocaine-associated cues. Our preliminary data strongly suggest that 5-HT2AR functional regulation contributes to individual differences in inherent impulsivity. We hypothesize that hyperfunctional 5-HT2AR tone in the PFC underlies a predisposition to high impulsive action and cocaine-seeking behavior. Specific objectives include: (1) determine differences in 5-HT2AR availability and expression between HI and LI rats using biochemical and pharmacological methods; (2) identify pharmacological sensitivity of HI vs. LI rats to the effects of a 5-HT2AR agonist and antagonist; (3) assess the effects of synthetic depletion of PFC 5-HT2AR expression on impulsivity and cocaine-seeking behavior. Completion of these objectives will provide the applicant with training in new concepts and methodologies, including the neurobiology of impulsivity and addiction, the design and interpretation of behavioral and neurochemical experiments, principles and methods of neuropharmacology, and the neuroscientific application of genetic technology. The experiments proposed within these objectives are expected to provide novel insights into the role of the 5-HT2AR as a driver of inherent impulsivity and as a mechanistic integrator of impulsive action and cocaine-seeking behavior. This proposal will advance our current knowledge of 5-HT2AR function in impulsivity toward a new understanding of why some individuals are more impulsive than others. This contribution is significant because the outcomes will inform efforts to develop therapeutic intervention for the management of impulse control in addictive disorders as well as other psychiatric disorders in which impulsivity is a contributing feature. PUBLIC HEALTH RELEVANCE: Drug addiction is a highly prevalent and costly disorder associated with deficits in impulse control. Our goal is to advance our understanding of neurobiological factors that contribute to the vulnerability to impulsive behavior and susceptibiliy to drug relapse, focusing on the role of the 5-HT2AR as a mechanistic integrator of impulsive action and cocaine-seeking behavior. This contribution will inform efforts to develop therapeutic interventions to manage impulse control in addictive disorders in order to reduce occurrence of relapse and promote abstinence.

描述（由申请人提供）：药物滥用影响着全世界数百万人，并且是在基于遗传、环境和心理因素的脆弱性背景下开始的。对与药物滥用相关的心理特征的调查显示，冲动是开始、维持和复发滥用可卡因等药物的主要危险因素。因此，了解冲动的神经生物学基础对于制定预防和治疗策略至关重要。尽管在理解冲动的一般神经生物学方面取得了重大进展，但我们对决定冲动的个体差异如何导致成瘾脆弱性的因素的了解仍然存在根本差距。该提案的目的是利用冲动行为和寻求可卡因的动物模型，确定固有高冲动和低冲动（HI 和 LI）近交大鼠之间的神经生物学差异，并将这些差异与可卡因寻求行为的易感性联系起来。支持冲动行为的神经系统包括奖赏和动机的边缘系统调节器以及发挥抑制控制的皮质结构，例如前额皮质（PFC）。 PFC 的抑制控制受到密集的血清素 (5-HT) 神经支配的影响，并且 5-HT2A 受体 (5-HT2AR) 已被证明在 PFC 内的冲动行为和对可卡因相关线索的反应中发挥着重要作用。我们的初步数据强烈表明，5-HT2AR 功能调节导致固有冲动的个体差异。我们假设 PFC 中功能亢进的 5-HT2AR 音调是高冲动行为和寻求可卡因行为倾向的基础。具体目标包括：（1）利用生化和药理学方法确定HI和LI大鼠之间5-HT2AR可用性和表达的差异； (2) 确定 HI 与 LI 大鼠对 5-HT2AR 激动剂和拮抗剂作用的药理学敏感性； (3) 评估 PFC 5-HT2AR 表达的合成损耗对冲动和可卡因寻求行为的影响。完成这些目标将为申请人提供新概念和方法的培训，包括冲动和成瘾的神经生物学、行为和神经化学实验的设计和解释、神经药理学的原理和方法以及遗传技术的神经科学应用。在这些目标中提出的实验预计将为 5-HT2AR 作为内在冲动的驱动因素以及作为冲动行为和可卡因寻求行为的机械整合者的作用提供新的见解。该提议将推进我们目前对 5-HT2AR 在冲动中的功能的了解，从而对为什么有些人比其他人更冲动有一个新的理解。这一贡献意义重大，因为结果将为开发治疗干预措施提供信息，以管理成瘾性疾病以及以冲动为主要特征的其他精神疾病的冲动控制。 公共卫生相关性：吸毒成瘾是一种非常普遍且代价高昂的疾病，与冲动控制缺陷有关。我们的目标是加深对导致冲动行为脆弱性和药物复发易感性的神经生物学因素的理解，重点关注 5-HT2AR 作为冲动行为和可卡因寻求行为的机械整合器的作用。这一贡献将为开发治疗干预措施的努力提供信息，以管理成瘾性疾病的冲动控制，以减少复发的发生并促进戒断。