STRESSOR CONTROLLABILITY, DRUGS OF ABUSE, AND SEROTONIN

描述：(改编自调查人员摘要)有很大的 对滥用药物的反应存在个体差异，但导致这些差异的原因 分歧还没有得到很好的理解。最近“压力”的经历是一种 已知的在人类和动物中增强药物奖励过程的因素， 但压力的关键方面和涉及的神经机制 并不完全为人所知。这项拟议的研究探索了学位的作用 个体对应激源的行为控制作为一种特征 调节应激源会改变药物的反应性，并将重点放在 应激诱导背侧5-羟色胺能神经元的敏感化 以中缝核(DRN)为中介。需要检验的假设是1) 不可控(但不可控)应激源使DRN 5-羟色胺神经元敏感 一段时间，导致投射区域5-羟色胺的夸大释放 当神经元被激活时；2)伏核(NAC)释放5-羟色胺 和/或DRN投射的神经元的内侧前额叶皮质(MPFC) 增加这些区域产生的细胞外DA水平 药物滥用；3)室旁核释放的5-羟色胺增加 血皮质酮(CORT)水平；4)激活DRN 5-HT的药物 神经元(如吗啡)除了作用于大脑奖赏结构外，还会 因此在NAC/mPFC和CORT中产生更高水平的细胞外DA 最近受到不可控应激源的受试者的血液；4) 因此，无法控制(但不能控制)的压力源将会加剧 对依赖NAC/mPFC DA和/或CORT的药物的行为反应，以及这 激活DRN 5-羟色胺神经元的药物将发生增强作用。条件性的 地点偏好和运动激活是要检查的行为，并且 吗啡、安非他明、海洛因、尼古丁、可卡因和乙醇都是毒品 这一点将受到考验。

DESCRIPTION: (Adapted from the Investigator's Abstract) There are large individual differences in reactivity to drugs of abuse, but the causes of these differences are not well understood. The recent experience of "stress" is a factor known to potentiate drug reward processes in both humans and animals, but the aspects of stress that are critical and the neural mechanisms involved are not fully known. The proposed research explores the role of the degree of behavioral control that the individual has over the stressor as a feature modulating wither the stressor will alter drug reactivity, and focuses on stressor-induced sensitization of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) as a mediator. The hypothesis to be tested is that 1) uncontrollable (but not controllable) stressors sensitize DRN 5-HT neurons for a period of time, leading to exaggerated release of 5-HT in projection regions when the neurons are activated; 2) 5-HT released in the nucleus accumbens (NAc) and/or medial prefrontal cortex (mPFC) by neurons projecting from the DRN increases the extracellular level of DA in the these regions that is produced by drugs of abuse; 3) 5-HT released in the paraventricular nucleus increases the blood levels of corticosterone (CORT); 4) Drugs that activate DRN 5-HT neurons (e.g., morphine) in addition to acting on brain reward structures, will therefore produce greater levels of extracellular DA in the NAc/mPFC and CORT in blood for subjects that have recently received uncontrollable stressors; 4) uncontrollable (but not controllable) stressors will therefore potentiate behavioral responses to drugs that depend on NAc/mPFC DA and/or CORT, and this potentiation will occur for drugs that activate DRN 5-HT neurons. Conditioned place preference and locomotor activation are the behaviors to be examined, and morphine, amphetamine, heroin, nicotine, cocaine, and ethanol are the drugs that will be tested.