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

药物滥用影响着全世界数百万人，并且开始于基于遗传，环境和心理因素的脆弱性背景。对与药物滥用相关的心理特征的调查显示，冲动是开始、维持和复发滥用药物（如可卡因）的主要风险因素。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。尽管在理解冲动性的一般神经生物学方面取得了重大进展，但我们对决定冲动性个体差异如何赋予成瘾脆弱性的因素的认识存在根本性差距。使用动物模型的冲动行为和可卡因寻求，本建议的目的是确定神经生物学的差异之间固有的高和低冲动（HI和LI）远交大鼠和这些差异的可卡因寻求行为的易感性。支持冲动行为的神经系统包括奖励和动机的边缘系统调节器以及施加抑制控制的皮质结构，如前额叶皮质（PFC）。来自PFC的抑制性控制被密集的5-羟色胺（5-HT）神经支配严重改变，并且5-HT 2A受体（5-HT 2AR）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起重要作用。我们的初步数据强烈表明，5-HT 2AR功能调节有助于内在冲动的个体差异。我们推测PFC中功能亢进的5-HT 2AR张力是高冲动行为和可卡因寻求行为的易感性的基础。具体目标包括：（1）使用生物化学和药理学方法确定HI和LI大鼠之间5-HT 2AR可用性和表达的差异;（2）确定HI与LI大鼠对5-HT 2AR激动剂和拮抗剂作用的药理学敏感性;（3）评估PFC 5-HT 2AR表达的合成耗竭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。在这些目标内提出的实验预计将提供新的见解5-HT 2AR作为固有冲动的驱动程序和作为冲动行为和可卡因寻求行为的机械集成器的作用。这项提议将推进我们目前对5-HT 2AR在冲动性中功能的认识，从而对为什么有些人比其他人更冲动有新的理解。这一贡献是重要的，因为结果将告知努力开发治疗干预的冲动控制成瘾性障碍以及其他精神疾病，其中冲动是一个贡献的功能。 公共卫生相关性：药物成瘾是一种非常普遍和昂贵的疾病，与冲动控制缺陷有关。我们的目标是促进我们对神经生物学因素的理解，这些因素导致冲动行为的脆弱性和药物复发的不稳定性，重点是5-HT 2AR作为冲动行为和可卡因寻求行为的机械整合剂的作用。这一贡献将为制定治疗干预措施以管理成瘾性疾病的冲动控制以减少复发和促进戒断的努力提供信息。

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.