Stressor Controllability, Drugs of Abuse, and Serotonin

描述(由申请人提供)：压力是一个主要因素，它与基因构成和吸毒经历相互作用，决定了对成瘾和复发的易感性。生物体对压力源的行为控制程度可以说是迄今发现的压力源对行为和生理影响的最有力的调节器，而对压力源的缺乏控制已被发现是人类层面上瘾的诱因。将进行的研究集中在行为控制的作用，即缺乏对压力的控制，以确定压力对滥用药物的行为和神经化学反应的影响。相对于可控的应激，不可控的应激可以使中缝背核(DRN)内的5-羟色胺(5-HT)神经元敏化，从而使这些神经元在一段时间内以夸大的方式对输入做出反应，在投射区域释放过量的5-羟色胺。在过去的资助期间进行的研究表明，不可控应激在许多天内增强了吗啡诱导的条件性位置偏爱、精神运动反应、伏隔核多巴胺释放和血浆皮质酮(CORT)，而完全相等的可控应激不会。此外，不可控制的应激诱导DRN 5-羟色胺神经元的敏化和过量的5-羟色胺的释放被证明是产生这些现象所必需的，皮质醇的增加也是如此。此外，初步数据表明，内侧前额叶皮质(MPFC)释放的5-羟色胺(5-HT)对先前不可控应激产生的吗啡增强的行为和神经化学反应至关重要。这项新拟议工作的目的是确定a)5-羟色胺和皮质醇是否在mPFC内作用于对吗啡产生夸大反应&这种反应是如何发生的；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)控制应激如何防止应激源增加对滥用药物的反应并增强韧性。这项研究应该对产生脆弱性的神经机制提供洞察力，即对压力对药物滥用反应的调节作用的弹性，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.