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疾病的重要危险因素。阿片受体（kappa opioid receptor， KOR）作为一种新的治疗靶点，受到越来越多的关注。据报道，KOR激动剂可诱导烦躁不安并调节下丘脑-垂体-肾上腺轴（HPA）。新的证据表明，在我们对KOR的厌恶性质的理解上存在重大差距。研究表明，KOR介导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，经过两天的社会心理压力后，KOR失去了它的厌恶性质。我们假设，这种长期的社会心理压力的影响诱导神经适应，从根本上改变了KOR的影响。这是一个关键的想法，因为该领域正在假设KOR拮抗剂具有抗抑郁特性。我们的假设表明，对于长期暴露于心理社会压力的个体，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隔背核（DRN）血清素神经元的活性来抑制血清素能张力。血清素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，社会心理压力可以增加DRN血清素神经元的基线活性。通过研究一夫一妻制的加利福尼亚老鼠，我们是唯一有能力研究社会失败对雄性和雌性的影响的实验室小组之一。面对失败的女性对非威胁性的社会刺激表现出社会回避。我们假设失败压力导致KOR对DRN抑制作用的脱敏，从而促进社会回避。我们预测这种影响在女性中比男性更大。如果有压力的男性对DRN的KOR抑制更强，那么社交回避表现出减少，基线皮质酮水平应该很高。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表现出更强的社交暗示回避，而最近的研究表明，基线皮质醇水平升高更有可能发生在抑郁症男性身上。首先，我们使用位置偏好研究来检验失败压力如何影响KOR的厌恶和奖励特性。其次，我们使用多标记免疫组织化学方法检测了KOR诱导的中背核（DRN）血清素神经元细胞外信号调节激酶（ERK）和p38 MAP激酶（p38）的变化。这些通路由KOR激活。最后，我们使用特定部位操作来测试血清素能信号的变化是否介导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.