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和焦虑等精神疾病的重要风险因素。靶向κ阿片受体（KOR）作为一种新的治疗靶点越来越受到关注。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，我们对KOR的厌恶属性的理解存在重大差距。研究表明，KOR介导的压力对行为的影响主要集中在短期的压力效应（15分钟）。然而，经过两天的心理社会压力，KOR失去了令人厌恶的特性。我们假设，这种长期的心理社会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，KOR激动剂将有更强的抗抑郁特性的个人暴露于长期的心理社会压力。κ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肾上腺素能紧张。增加的多巴胺能紧张性与对威胁的敏感性增加和HPA轴抑制增加有关，心理社会应激可以增加DRN 5-羟色胺神经元的基线活性。通过研究一夫一妻制的加州小鼠，我们是唯一一个有能力研究社会失败对雄性和雌性的影响的实验室小组。失败的女性表现出对非威胁性社会刺激的社会回避。我们假设，失败压力的结果脱敏的抑制作用KOR的DRN，这有利于社会回避。我们预测，这种影响是女性比男性更大。如果压力大的男性对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很高。这正是我们所观察到的。有趣的是，据报道，被诊断患有抑郁症的女性表现出更强的回避社交线索的能力，而最近的研究表明，基线皮质醇水平升高更有可能发生在患有抑郁症的男性身上。 首先，我们使用位置偏好研究来研究如何失败压力影响厌恶和奖励属性的KOR。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激酶（p38）的变化。这些途径被KOR激活。最后，我们使用网站特定的操作，以测试是否KOR厌恶，社会互动和皮质酮介导的KOR信号的变化。

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.