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: 10548748
• 负责人: Karen L. Bales
• 金额: $ 67.39万
• 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/10548748
• 关键词: Acute; Address; Adult; Behavioral; Biological; Brain; Buffers; Callicebus cupreus; Cardiovascular Diseases; Chronic; 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; Positron-Emission Tomography; Primates; Rattus; Risk; Role; Social Distance; Stress; Stroke; System; Testing; acute stress; biological adaptation to stress; diet and exercise; dysphoria; improved; kappa opioid receptors; kappa receptors; male; mortality; neurobiological mechanism; nonhuman primate; pharmacologic; 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.

项目摘要社会连通性对人类健康至关重要，并日益 尤其是在当今“社交疏远”的时代。虽然强大的社会关系可能 与饮食和饮食等健康行为相似的大效应大小的生存优势 锻炼1、社会关系的中断和丧失具有重大的健康风险和死亡率，包括 增加精神疾病、心血管疾病、中风等风险。2-4然而，神经生物学机制 因为社会联系的积极和消极方面一直没有得到充分的研究。κ阿片系统， 在压力(包括社交压力)和催产素(OT)，这是一种强烈的荷尔蒙 与社会联系(特别是它们的相互作用)有关的，在 对社会连通性产生积极和消极影响的背景。 在目前的提案中，我们将研究积极和消极机制的生物学机制 社会联系(社会缓冲和分离)，特别是在κ阿片和催产素(OT)系统中。 通过使用一种独特的非人类灵长类动物模型，Titi猴子(Plecturocebus Cupreus)，我们将能够 以一种人类很难或不可能做到的方式解决机制和因果关系。提提猴是一种社会性的 一夫一妻制的新大陆灵长类动物。它们表现出所有成年配对的迹象，无论是在野外5-7还是在 实验室8-10，包括对熟悉的伴侣的偏爱11；与伴侣分离时的痛苦 特别是伴侣缓冲压力反应的能力；因此它们是完美的灵长类 该模型从各个方面研究配对结合的神经生物学，包括社会缓冲和 分离13.这种社会一夫一妻制的交配系统使我们能够研究成年雄性的成年依恋 以及雌性，这在其他常见的实验室模型中是不可能的，如大鼠、小鼠和恒河猴。 我们已经证明了分离反应是由阿片类药物调制的，并且OT系统也对 分离。 我们将在社会缓冲期间使用C11 PET成像和药物治疗，短期内 分离，以及较长期的分离，以检验κ阿片受体和OT相互作用的假设 κ系统的激活导致伏隔核在社会分离和 丢失；长期而言，社会分离和丢失将导致κ阿片受体和刺激的下调 而抑制κ受体，以及对OT的下游影响，都与 社会纽带中积极的、抗压力的成分。最终，这个项目将提高我们对 社会联系的神经生物学基础从积极和消极两个方面，为 与人类健康的机械性联系。