Stressor Controllability, Drugs of Abuse, and Serotonin

描述（由申请人提供）：压力是一个主要因素，与基因组成和药物经验相互作用，以确定成瘾和复发的脆弱性。生物体（大鼠到人类）对压力源的行为控制程度可以说是迄今发现的压力源的行为和生理影响的最有效调节剂，对压力源缺乏控制已被发现是人类成瘾的诱发因素。将要进行的研究集中在行为控制和缺乏对压力的控制在确定压力对药物滥用的行为和神经化学反应的影响方面的作用。相对于可控制的应激，不可控制的应激已被证明使中缝背核（DRN）内的5-HT能神经元敏感，使得这些神经元在一段时间内以夸张的方式对输入作出反应，在投射区域释放过量的5-HT。在过去的资助期间进行的研究表明，不可控制的压力加强吗啡诱导的条件性位置偏好，心理反应，核多巴胺释放，血浆皮质酮（CORT）的一段时间很多天，而完全相同的可控压力没有。此外，不可控制的应激诱导的DRN 5-HT神经元的敏化和过量5-HT的释放被证明是产生这些现象所必需的，因为是增强的CORT增加。此外，初步数据表明，这是5-HT释放在内侧前额叶皮层（mPFC），是至关重要的增强行为和神经化学反应，吗啡产生的先前无法控制的压力。这项新工作的目的是确定a）5-HT和CORT是否在mPFC中起作用，产生对吗啡的过度反应，以及这是如何发生的; B）如果无法控制的应激以激活DRN 5-HT神经元的方式经历，是否会增强对阿片类药物以外的药物的行为和神经化学反应;以及c）对压力的控制如何防止压力源增加对滥用药物的反应并赋予弹性。这项研究应该提供洞察力的神经机制，产生脆弱性和弹性的调节作用的压力对药物滥用的反应，并建议方法，以打击压力的有害影响。

DESCRIPTION (provided by applicant): Stress is a major factor that interacts with genetic makeup & drug experience to determine vulnerability to addiction & relapse. The degree of behavioral control that an organism (rat to human) has over a stressor is arguably the most potent modulator of the behavioral & physiological impact of stressors yet discovered, & a lack of control over stressors has been found to be a predisposing factor to addiction at the human level. The research to be conducted focuses on the role of behavioral control & lack of control over stress in determining the impact of stress on behavioral and neurochemical responses tro drugs of abuse. Uncontrollable, relative to controllable stress, has been shown to sensitize serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN) so that for a period of days these neurons respond to input in an exaggerated fashion, releasing excessive amounts of 5-HT in projection regions. Research conducted during the past grant period has shown that uncontrollable stress potentiates morphine-induced conditioned place preference, psychomotor responses, nucleus accumbens dopamine release, and plasma corticosterone (CORT) for a period of many days, whereas exactly equal controllable stress does not. Furthermore, uncontrollable stress-induced sensitization of DRN 5-HT neurons & release of excessive 5-HT was shown to be necessary to produce these phenomena, as was the potentiated CORT increase. Moreover, preliminary data suggest that it is 5-HT released in the medial prefrontal cortex (mPFC) that is critical to the augmented behavioral and neurochemical responses to morphine produced by prior uncontrollable stress. The Aims of the new proposed work are to determine a) whether 5-HT and CORT act within the mPFC to produce exaggerated responses to morphine & how this occurs; b) whether uncontrollable stress would potentiate behavioral & neurochemical responses to drugs other than opiates if they are experienced in a way that activates DRN 5-HT neurons; and c) how control over stress prevents stressors from increasing reactivity to drugs of abuse & confers resilience. This research should provide insights into the neural mechanisms that produce vulnerability & resilience to the modulatory effects of stress on reactions to drugs of abuse & suggest methods to combat the deleterious effects of stress.