Kappa opioid receptor and social stress in males and females

Kappa 阿片受体与男性和女性的社会压力

基本信息

批准号：
8990988
负责人：
BRIAN C TRAINOR
金额：
$ 38.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990988
关键词：
Affect Agonist Animals Antidepressive Agents Anxiety Behavior Behavioral Biochemical California Chronic Cocaine Corticosterone Cues Data Diagnosis Dose Exhibits Extracellular Signal Regulated Kinases Female Health Hydrocortisone Immunohistochemistry Individual Link Long-Term Effects MAPK14 gene Mediating Mental Depression Mental disorders Modeling Mus Neurons Nucleus Accumbens Opioid Receptor Pathway interactions Phenotype Property Prosencephalon Psychosocial Stress Receptor Activation Receptor Inhibition Receptor Signaling Regulation Relapse Reporting Rewards Risk Factors Serotonin Signal Transduction Site Social Interaction Stimulus Stress Testing Woman Work antidepressant effect desensitization dorsal raphe nucleus dysphoria hypothalamic-pituitary-adrenal axis interest male men mitogen-activated protein kinase p38 neuroadaptation new therapeutic target novel paraventricular nucleus preference receptor research study reuptake serotonergic regulation social social stress

项目摘要

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.

描述（由申请人提供）：社会心理压力是抑郁症和焦虑等精神疾病的重要危险因素。将Kappa阿片受体（KO）作为一种新的治疗靶点的兴趣越来越多。据报道，kor的激动剂会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的厌恶特性的理解存在一个重大差距。研究表明，KOR介导压力对行为的影响主要集中于压力的短期影响（15分钟）。但是，经过两天的社会心理压力，kor失去了厌恶性。我们假设，社会心理压力的这种长期影响会引起神经适应的神经适应，从而从根本上改变了Kor的影响。这是一个关键的想法，因为该领域正在研究Kor拮抗剂具有抗抑郁剂特性的假设。我们的假设表明，Kor激动剂将对承受长期社会心理压力的个体具有更强的抗抑郁特性。 Kappa阿片类药物受体通过抑制背侧raphe核（DRN）5-羟色胺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HPA轴的敏感性增加有关，而抑制型HPA轴则可以增加DRN 5-羟色胺神经元的基线活性。通过研究一夫一妻制的加利福尼亚小鼠，我们是唯一能够研究社会失败在男性和女性中的影响的实验室群体之一。暴露于失败的女性对不威胁社会刺激的社会回避。我们假设失败的压力会导致Kor对DRN的抑制作用脱敏，从而有助于社会回避。我们预测，这种影响在女性中比男性更大。如果KOR对DRN的抑制在压力男性中更强，那么社会回避显示会减少，基线皮质酮水平应很高。这正是我们观察到的。有趣的是，据报道，被诊断出患有抑郁症的妇女表现出更强的避免社交线索，而最近的工作表明，基线皮质醇水平升高在抑郁症的男性中更有可能发生。首先，我们使用位置偏好研究来检查失败压力如何影响Kor的厌恶和有益的特性。其次，我们使用多标记免疫组织化学检查在背侧raphe核（DRN）中，在5-羟色胺神经元中，在5-羟色胺神经元（DRN）中，KOR诱导的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，我们使用特定地点操纵来测试5-羟色胺信号传导的变化是否介导了Kor对厌恶，社交相互作用和皮质酮的影响。