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 社会联系对于人类健康至关重要，并且日益重要 被认为是这样的，尤其是在当今“社交距离”的时代，尽管牢固的社会关系可能会被认为是这样的。 赋予生存优势，其影响大小类似于饮食和健康行为等 运动1、社会关系的破坏和丧失会带来重大的健康风险和死亡率，包括 精神疾病、心血管疾病、中风等的风险增加。2-4。 社会联系的积极和消极方面尚未得到充分研究。 在压力（包括社交压力）期间会系统地激活催产素 (OT)，这是一种强效激素 与社会联系（特别是他们的互动）有关的因素尚未在 对社会联系的积极和消极影响的背景。 在当前的提案中，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 阿片类药物和催产素 (OT) 系统中。 通过使用独特的非人类灵长类动物模型，蒂蒂猴（Plecturocebus cupreus），我们将能够 以人类难以或不可能做到的方式解决机制和因果关系，蒂蒂猴是一种社交动物。 一夫一妻制的新世界灵长类动物在野外5-7和野外都表现出成年配对的所有迹象。 实验室8-10，包括对熟悉的伴侣的偏好11； 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，用于研究配对关系各个方面的神经生物学，包括社交缓冲和 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年依恋作为分离 以及雌性，这在大鼠、小鼠和恒河猴等其他常见实验室模型中是不可能的。 我们已经证明分离反应是由阿片类药物调节的，并且 OT 系统也对 分离。 我们将在短期社会缓冲期间使用 C11 PET 成像和药物治疗 分离和更长期的分离来检验 κ 阿片受体和 OT 相互作用的假设 κ 系统的激活导致在社交分离和社交分离期间伏隔核中 OT 的抑制 丧失；长期而言，社会分离和丧失将导致 κ 阿片受体的下调和刺激 下丘脑 OT 的抑制；而 κ 受体的抑制以及对 OT 的下游影响与 最终，这个项目将增进我们对社会纽带的积极、抗压成分的理解。 社会联系积极和消极方面的神经生物学基础，提供了 与人类健康的机械联系。