Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Synaptic Plasticity Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
Neuropsychopharmacology. 2019 Oct;44(11):1876-1885. doi: 10.1038/s41386-019-0422-8. Epub 2019 May 27.
Enkephalins, endogenous ligands for delta opioid receptors (DORs), are highly enriched in the nucleus accumbens (NAc). They are implicated in depression but their role in the NAc, a critical brain region for motivated behavior, is not fully investigated. To provide insight into enkephalin function we used a chronic social defeat stress paradigm, where animals are either categorized as susceptible or resilient to stress based on their performance in a social interaction test. Compared to controls, susceptible animals showed reduced enkephalin levels in the NAc. Such decrease in enkephalin levels is not due to a change in mRNA of its precursor protein, proenkephalin, in susceptible mice but is consistent with increased mRNA levels of enkephalinases in the NAc of susceptible animals. Systemic administration of enkephalinase inhibitors or NAc infusion of the DOR agonist, SNC80, caused a resilient outcome to CSDS. Both treatments increased phosphorylation of ERK, which was downregulated by social defeat stress. To further validate these results, we also used Q175 knock-in mice, an animal model of Huntington's disease in which enkephalin levels are reduced in striatum and comorbidity with mood disorders is common. Consistent with data in wild-type mice, Q175 animals showed reduced enkephalin levels in the NAc and enhanced susceptibility to a social defeat stress. Overall, our data implicate that depression-like behavior induced by social defeat stress arises from disrupted DOR signaling resulting from lowered levels of enkephalins, which is partly mediated through elevated expression of enkephalinases.
脑啡肽是 δ 型阿片受体（DOR）的内源性配体，在伏隔核（NAc）中高度富集。它们与抑郁症有关，但它们在 NAc 中的作用，即动机行为的关键大脑区域，尚未得到充分研究。为了深入了解脑啡肽的功能，我们使用了慢性社会挫败应激模型，根据动物在社会互动测试中的表现，将它们分为易受影响或对压力有抵抗力的动物。与对照组相比，易受影响的动物在 NAc 中的脑啡肽水平降低。这种脑啡肽水平的降低不是由于易受影响的小鼠前体蛋白 proenkephalin 的 mRNA 发生变化，而是与易受影响动物 NAc 中脑啡肽酶的 mRNA 水平增加一致。系统性给予脑啡肽酶抑制剂或 NAc 输注 DOR 激动剂 SNC80，可使 CSDS 产生抗应激作用。这两种治疗方法都增加了 ERK 的磷酸化，而社交挫败应激则下调了 ERK 的磷酸化。为了进一步验证这些结果，我们还使用了 Q175 敲入小鼠，这是一种亨廷顿病的动物模型，其纹状体中的脑啡肽水平降低，且常伴有情绪障碍共病。与野生型小鼠的数据一致，Q175 动物在 NAc 中显示出脑啡肽水平降低，并易受社会挫败应激影响。总的来说，我们的数据表明，社交挫败应激引起的类似抑郁的行为源于 DOR 信号的中断，这是由于脑啡肽水平降低所致，而这种中断部分是通过脑啡肽酶表达升高介导的。
