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

描述(申请人提供)：药物滥用影响全球数百万人，开始于基于遗传、环境和心理因素的脆弱性背景。对与药物滥用有关的心理特征的调查显示，冲动是引发、维持和复发可卡因等滥用药物的主要风险因素。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。尽管在理解冲动的一般神经生物学方面取得了重大进展，但我们对决定个体冲动差异如何可能导致成瘾易感性的因素的了解存在根本差距。利用冲动行为和寻找可卡因的动物模型，本研究的目的是确定先天高和低冲动(HI和LI)杂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施加抑制控制的皮质结构，如前额叶皮质(PFC)。密集的5-羟色胺(5-HT)神经支配严重改变了PFC的抑制控制，5-HT2A受体(5-HT2AR)已被证明在PFC的冲动动作和对可卡因相关线索的反应性中发挥重要作用。我们的初步数据有力地表明，5-HT2AR的功能调节有助于个体固有冲动的差异。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的基础。具体目标包括：(1)使用生化和药理学方法确定HI和LI大鼠之间5-HT2AR可获得性和表达的差异；(2)确定HI和LI大鼠对5-HT2AR激动剂和拮抗剂效应的药理敏感性；(3)评估合成缺失PFC 5-HT2AR表达对冲动性和可卡因寻找行为的影响。完成这些目标将为申请者提供新概念和新方法方面的培训，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基因技术的神经科学应用。在这些目标中提出的实验有望为5-HT2AR作为内在冲动的驱动器以及作为冲动行为和寻找可卡因行为的机械积分器的作用提供新的见解。这一提议将推动我们目前对5-HT2AR在冲动中的作用的了解，从而对为什么一些人比其他人更冲动有一个新的理解。这一贡献意义重大，因为其结果将有助于开发治疗干预措施，以管理成瘾障碍和其他冲动特征为特征的精神障碍的冲动控制。

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.