Nikulina Ella M, Arrillaga-Romany Isabel, Miczek Klaus A, Hammer Ronald P
Department of Basic Medical Sciences, University of Arizona, College of Medicine-Phoenix, 425 N. Fifth Street, ABC 1, Phoenix, AZ 85004-2157, USA.
Eur J Neurosci. 2008 May;27(9):2272-84. doi: 10.1111/j.1460-9568.2008.06176.x.
Social defeat stress is a salient stressor that induces neuroadaptive changes in the mesocorticolimbic dopaminergic system. Substantial evidence indicates that mu-opioid receptors (MORs) modulate dopamine transmission in the ventral tegmental area (VTA). FosB/DeltaFosB protein accumulation in dopaminergic projections during repeated treatments is thought to be involved in long-term neuroplasticity. In this study we characterize the magnitude and time-course of MOR mRNA expression and FosB/DeltaFosB immunoreactivity in mesocorticolimbic regions following repeated social defeat stress. Effects of brief repeated social defeat stress or control handling procedures were studied in rats either 2 h after the last exposure, or 3, 7, 14, 21 and 28 days later. We found that MOR mRNA expression in the VTA doubled after the last stress compared with handling, and remained 30-70% higher until day 21. The number of FosB/DeltaFosB-labeled neurons in regions of the frontal cortex, nucleus accumbens (NAc) shell and core, and in the medial, central and basolateral amygdala increased significantly immediately after the last stress episode, and remained enhanced for 21 days. Another group of rats received bilateral intra-VTA infusion of the MOR agonist, DAMGO, 7 days after the last stress. Prior social defeat stress augmented DAMGO-induced Fos expression in the NAc shell, suggesting that Fos expression in this region might be the direct result of MOR activity in the VTA. Social defeat stress leads to an increased capacity for MOR activation in the VTA, which may be relevant to enduring FosB/DeltaFosB expression in mesocorticolimbic areas and to the behaviorally sensitized response to psychostimulant drugs.
社会挫败应激是一种显著的应激源，可诱导中脑边缘多巴胺能系统发生神经适应性变化。大量证据表明，μ-阿片受体（MORs）调节腹侧被盖区（VTA）的多巴胺传递。反复给药期间多巴胺能投射中FosB/DeltaFosB蛋白积累被认为与长期神经可塑性有关。在本研究中，我们描述了反复社会挫败应激后中脑边缘区域MOR mRNA表达和FosB/DeltaFosB免疫反应性的程度和时间进程。在最后一次暴露后2小时，或3、7、14、21和28天后，研究了短暂反复社会挫败应激或对照处理程序对大鼠的影响。我们发现，与处理组相比，最后一次应激后VTA中MOR mRNA表达增加了一倍，并且直到第21天一直高出30-70%。最后一次应激发作后，额叶皮质、伏隔核（NAc）壳和核心以及内侧、中央和基底外侧杏仁核区域中FosB/DeltaFosB标记的神经元数量立即显著增加，并持续增强21天。另一组大鼠在最后一次应激7天后接受双侧VTA内注射MOR激动剂DAMGO。先前的社会挫败应激增强了DAMGO诱导的NAc壳中Fos表达，表明该区域的Fos表达可能是VTA中MOR活性的直接结果。社会挫败应激导致VTA中MOR激活能力增加，这可能与中脑边缘区域持久的FosB/DeltaFosB表达以及对精神兴奋剂药物的行为敏化反应有关。
