Stressor Controllability, Drugs of Abuse, and Serotonin

描述（由申请人提供）：压力是与基因组成和药物经历相互作用的主要因素，决定成瘾和复发的易感性。生物（从大鼠到人类）对压力源的行为控制程度可以说是迄今为止发现的最有效的压力源行为和生理影响调节剂，而对压力源缺乏控制已被发现是人类水平上成瘾的一个易感因素。研究的重点是行为控制和缺乏对压力的控制在确定压力对滥用药物的行为和神经化学反应的影响中的作用。相对于可控压力而言，不可控压力已被证明能使中隔背核（DRN）内的5-羟色胺能（5-HT）神经元敏感，因此在一段时间内，这些神经元以夸张的方式对输入作出反应，在投射区释放过量的5-HT。在过去的资助期间进行的研究表明，不可控的压力会增强吗啡诱导的条件位置偏好、精神运动反应、伏隔核多巴胺释放和血浆皮质酮（CORT），持续数天，而完全相同的可控压力则不会。此外，DRN 5-HT神经元的不可控应激诱导敏化和过量5-HT的释放被证明是产生这些现象的必要条件，正如增强的CORT增加一样。此外，初步数据表明，正是内侧前额叶皮层（mPFC）释放的5-羟色胺对先前无法控制的压力产生的吗啡增强行为和神经化学反应至关重要。新提出的工作的目的是确定a) 5-HT和CORT是否在mPFC内产生对吗啡的过度反应以及这种反应是如何发生的；b)如果无法控制的压力以激活DRN 5-HT神经元的方式经历，是否会增强对阿片类药物以外药物的行为和神经化学反应；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。这项研究将提供对压力对药物滥用反应的调节作用产生脆弱性和恢复力的神经机制的见解，并提出对抗压力有害影响的方法。

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.