Kappa opioid and oxytocin interactions in social buffering and separation

Kappa 阿片类药物和催产素在社交缓冲和分离中的相互作用

• 批准号: 10375416
• 负责人: Karen L. Bales
• 金额: $ 71.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375416
• 关键词: Acute; Address; Adult; Behavioral; Biological; Brain; Buffers; Callicebus cupreus; Cardiovascular Diseases; Chronic; Diet; Distress; Down-Regulation; Etiology; Exhibits; Female; Health; Health behavior; Hormonal; Hormones; Human; Hypothalamic structure; Image; Individual; Laboratories; Lead; Macaca mulatta; Mental disorders; Modeling; Mus; Neurobiology; Nucleus Accumbens; Opioid; Oxytocin; Pair Bond; Partner in relationship; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Positron-Emission Tomography; Primates; Rattus; Risk; Role; Social Distance; Stress; Stroke; System; Testing; acute stress; biological adaptation to stress; dysphoria; improved; kappa opioid receptors; kappa receptors; male; mortality; neurobiological mechanism; nonhuman primate; preference; receptor binding; response; social; social attachment; social relationships; social separation; social stress; stress management; stressor; survivorship

Project abstract Social connectedness is crucially important to human health, and is increasingly recognized as such, especially in these days of “social distancing”. While strong social relationships may confer a survivorship advantage with large effect sizes similar to those for health behaviors like diet and exercise1, disruption and loss of social relationships carry significant health risks and mortality, including increased risk of mental illness, cardiovascular disease, stroke, etc.2–4. However, neurobiological mechanisms for positive and negative aspects of social connectedness have been under-studied. The κ opioid system, which is systematically activated during stress (including social stress), and oxytocin (OT), a hormone strongly implicated in social connectedness (and in particular, their interactions), have not been fully explored in the contexts of positive and negative effects on social connectedness. In the current proposal, we will investigate biological mechanisms for positive and negative mechanisms of social connectedness (social buffering and separation), particularly in the κ opioid and oxytocin (OT) systems. By using a unique non-human primate model, the titi monkey (Plecturocebus cupreus), we will be able to address mechanism and causality in a way difficult or impossible to do in humans. Titi monkeys are a socially monogamous New World primate. They exhibit all the signs of adult pair-bonding both in the wild5–7 and in the laboratory8–10, including a preference for the familiar partner11; distress upon separation from the partner specifically12; and the ability of the partner to buffer the stress response12; they are thus the perfect primate model in which to study the neurobiology of pair bonding in all its aspects, including social buffering and separation13. This socially monogamous mating system allows us to study adult attachment in adult males as well as females, which is not possible in other common laboratory models like rats, mice, and rhesus monkeys. We have shown the separation response is modulated by opioids and that the OT system is also responsive to separation. We will use C11 PET imaging and pharmacological treatments during social buffering, short term separation, and longer-term separation to test the hypothesis that the κ opioid receptor and OT interact such that activation of the κ system results in inhibition of OT in the nucleus accumbens during social separation and loss; chronically, social separation and loss will result in down-regulation of κ opioid receptors and stimulation of OT in the hypothalamus; while inhibition of κ receptors, and downstream effects on OT, are implicated in the positive, anti-stress components of social bonds. Ultimately, this project will improve our understanding of the neurobiological basis of social connectedness in both its positive and negative aspects, providing for mechanistic connections to human health.

项目摘要社会联系对人类健康至关重要，并且越来越多地 尤其是在“社会距离”的今天。虽然强大的社会关系可能 赋予生存优势，具有与饮食等健康行为相似的大效应量， 运动1，社会关系的中断和丧失会带来重大的健康风险和死亡率，包括 增加患精神疾病、心血管疾病、中风等的风险2 -4.然而，神经生物学机制 对于社会联系的积极和消极方面的研究还不够。κ阿片系统， 它在压力（包括社会压力）期间系统地激活，催产素（OT）是一种强烈刺激的激素。 在社会联系（特别是他们的互动）中，还没有得到充分的探讨。 对社会联系的积极和消极影响的背景。 在目前的建议中，我们将研究生物学机制的积极和消极机制， 社会联系（社会缓冲和分离），特别是在κ阿片和催产素（OT）系统。 通过使用一种独特的非人类灵长类动物模型，titi猴（Plecturocebus cupreus），我们将能够 解决机制和因果关系的方式很难或不可能在人类身上做。蒂蒂猴是一种社会性的 一夫一妻制的新大陆灵长类动物无论是在野外，还是在野外，它们都表现出成年人配对的所有迹象。 实验室8 -10，包括对熟悉的伴侣的偏好11;与伴侣分离时的痛苦 特别是12;以及伴侣缓冲压力反应的能力12;因此它们是完美的灵长类动物 模型，其中研究神经生物学的配对结合的各个方面，包括社会缓冲， 分离13.这种社会性的一夫一妻制交配系统使我们能够研究成年男性的成人依恋， 以及雌性，这在其他常见的实验室模型如大鼠、小鼠和恒河猴中是不可能的。 我们已经表明，分离反应是由阿片类药物调制的，OT系统也对阿片类药物有反应。 分居 我们将在社会缓冲期间使用C11 PET成像和药物治疗，短期 分离和长期分离，以检验κ阿片受体和OT相互作用的假设， κ系统的激活导致在社会分离期间丘脑核中OT的抑制， 长期而言，社会分离和损失将导致κ阿片受体和刺激的下调 下丘脑中的OT;而κ受体的抑制和对OT的下游效应与下丘脑中的OT有关。 积极的，抗压力的社会纽带最终，这个项目将提高我们对 社会联系的积极和消极方面的神经生物学基础，提供 与人类健康的机械联系。