Kappa opioid receptor and social stress in males and females

描述(由申请人提供)：心理社会压力是抑郁症和焦虑症等精神障碍的重要风险因素。靶向kappa阿片受体(KOR)作为一种新的治疗靶点越来越受到人们的关注。据报道，KOR的激动剂可以引起烦躁不安，并调节下丘脑-垂体-肾上腺轴(HPA)。新的证据表明，我们对朝鲜民主主义人民共和国令人厌恶的性质的理解存在很大差距。研究表明，KOR调节应激对行为的影响，主要集中在应激的短期影响(15分钟)。然而，在两天的心理社会压力之后，KOR失去了令人厌恶的特性。我们假设，心理社会压力的这种长期影响诱导了神经适应，从根本上改变了KOR的效果。这是一个关键的想法，因为该领域的工作是基于KOR拮抗剂具有抗抑郁特性的假设。我们的假设表明，对于长期处于心理社会压力下的个人，KOR激动剂将具有更强的抗抑郁特性。Kappa阿片受体通过抑制中缝背核(DRN)5-羟色胺神经元的活动来抑制5-羟色胺能张力。5-羟色胺能张力的增加与对威胁的敏感性增加和对HPA轴的抑制增加有关，而心理社会应激可以增加DRN-5-羟色胺神经元的基线活性。通过对加州一夫一妻制小鼠的研究，我们是少数几个有能力研究社会失败对男性和女性影响的实验室小组之一。面对失败的雌性表现出对非威胁性社会刺激的社交回避。我们假设，失败应激导致KOR对DRN的抑制效应脱敏，从而促进社交回避。我们预测，这种影响在女性身上比在男性身上更大。如果压力较大的男性对DRN的KOR抑制更强，那么社交回避就会减少，基线皮质酮水平应该会很高。这正是我们所观察到的。有趣的是，据报道，被诊断为抑郁症的女性对社交暗示表现出更强烈的回避，而最近的研究表明，抑郁症男性更有可能出现皮质醇水平升高的情况。首先，我们使用位置偏好研究来检验失败压力如何影响KOR的厌恶和回报特性。其次，我们用多标记免疫组织化学方法检测KOR诱导的中缝背核(DRN)5-羟色胺神经元细胞外信号调节激酶(ERK)和p38-MAP-K(P38)的变化。这些通路是由KOR激活的。最后，我们使用特定部位的操作来测试5-羟色胺能信号的变化是否中介KOR对厌恶、社会互动和皮质酮的影响。

DESCRIPTION (provided by applicant): Psychosocial stress is an important risk factor for psychiatric disorders such as depression and anxiety. There has been increasing interest in targeting kappa opioid receptors (KOR) as a novel therapeutic target. Agonists for KOR have been reported to induce dysphoria and regulate the hypothalamic-pituitary-adrenal axis (HPA). New evidence suggests that there is a major gap in our understanding of the aversive properties of KOR. Studies showing that KOR mediates effects of stress on behavior primarily focus on short term effects of stress (15 min). However, after two days of psychosocial stress KOR loses its aversive properties. We hypothesize that this long term effect of psychosocial stress induces a neuroadaptation that fundamentally alters the effects of KOR. This is a critical idea because the field is working on the assumption that KOR antagonists have antidepressant properties. Our hypothesis suggests that KOR agonists will have stronger antidepressant properties for individuals exposed to long term psychosocial stress. Kappa opioid receptors inhibit serotonergic tone by inhibiting the activity of dorsal raphe nucleus (DRN) serotonin neurons. Increased serotonergic tone is linked to increased sensitivity to threat and increased inhibition o the HPA axis, and psychosocial stress can increase baseline activity of DRN serotonin neurons. By studying monogamous California mice, we are one of the only lab groups with the capability to study the effects of social defeat in both males and females. Females exposed to defeat exhibit social avoidance to non- threatening social stimuli. We hypothesize that defeat stress results in desensitization of the inhibitory effects of KOR on the DRN, which facilitates social avoidance. We predict that this effect is greater in females than males. If KOR inhibition of the DRN is stronger in stressed males, then social avoidance show be diminished and baseline corticosterone levels should be high. This is exactly what we have observed. Intriguingly, women diagnosed with depression have been reported to show stronger avoidance of social cues while recent work suggests that elevated baseline cortisol levels are more likely to occur in men with depression. First we use place preference studies to examine how defeat stress affects the aversive and rewarding properties of KOR. Second, we use multilabel immunohistochemistry to examine KOR induced changes in extracellular signal regulated kinase (ERK) and p38 MAP kinase (p38) in serotonin neurons in the dorsal raphe nucleus (DRN). These pathways are activated by KOR. Finally, we use site specific manipulations to test whether changes in serotonergic signaling mediate the effects of KOR on aversion, social interaction, and corticosterone.