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.

项目摘要社会联系对人类健康基本重要，并且越来越多 因此，尤其是在当时的“社会疏远”时期。牢固的社会关系可能 会议的生存优势，其效果大小类似于饮食和饮食等健康行为的效果。 练习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 增加了精神疾病，心血管疾病，中风等的风险2-4。但是，神经生物学机制 对于社会联系的积极和负面方面，人们已经研究了。 κ阿片类药物系统， 在压力（包括社会压力）和氧气（OT）中，它是系统地激活的，氧气（OT）强烈地激活 在社会联系（尤其是它们的互动）中实施，尚未在 积极和负面影响对社会联系的背景。 在当前的建议中，我们将研究生物学机制 社会联系（社会缓冲和分离），特别是在κ阿片类药物和催产素（OT）系统中。 通过使用独特的非人类私人型号Titi Monkey（Plecturocebus Cupreus），我们将能够 在人类中难以或不可能做的方式解决机制和因果关系。蒂蒂猴子在社会上 一夫一妻制的新世界灵长类动物。它们在Wild5-7和 实验室8-10，包括对熟悉的合作伙伴的偏爱；与伴侣分开时的困扰 具体12；以及伴侣缓冲压力响应的能力12；因此，他们是完美的隐私 在各个方面，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男性的成人依恋 以及女性，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。 我们已经显示了分离反应由阿片类药物调节，OT系统也对 分离。 我们将在社交缓冲期间使用C11 PET成像和药物治疗 分离和长期分离以检验κ阿片类受体和OT相互作用的假设 κ系统的激活导致在社交分离和 损失;长期以来，社会分离和损失将导致κ阿片类受体的下调和刺激 下丘脑中的OT；虽然抑制κ受体和对OT的下游影响与 社会纽带的积极，反压力的组成部分。最终，该项目将提高我们对 社会联系在其积极和负面方面的神经生物学基础， 与人类健康的机械联系。