Division of Stress Neurobiology, Department of Anesthesiology, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Neuropsychopharmacology. 2013 Sep;38(10):1833-43. doi: 10.1038/npp.2013.117. Epub 2013 May 10.
Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased μ-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.
压力与多种精神疾病有关，包括药物滥用。蓝斑-去甲肾上腺素（LC-NE）系统是一个主要的应激反应系统，也是应激神经递质和内源性阿片类物质的交汇点，因此可能是应激影响药物使用行为的一个靶点。由于社会应激是人类常见的应激源，本研究描述了反复社会应激对 LC 神经元活动的持久影响。大鼠通过居民-入侵者模型或对照操作，每天连续接受五次社交应激。与对照组相比，应激大鼠在最后一次操作后 2 天 LC 放电率降低。在最后一次操作后 10 天，两组之间 LC 速率相当。在最后一次操作后 2 或 10 天给予阿片拮抗剂纳洛酮可显著增加 LC 放电率，提示阿片类药物戒断，这种方式在应激大鼠中具有选择性。这伴随着轻度阿片类药物戒断的行为迹象。Western blot 和电子显微镜研究表明，反复的社会应激会降低 LC 中的促肾上腺皮质激素释放因子 1 受体并增加 μ-阿片受体水平。总之，这些结果表明，反复的社会应激会引起 LC 活动的内源性阿片类物质调节，并诱导细胞和物理阿片类物质依赖的迹象，这些迹象在应激后仍会持续存在。这些细胞效应可能使有反复社会应激史的个体易发生物质滥用行为。
