Behavioral and Neural Bases of Combining Oxytocin and Naloxone for Optimally Enhancing Interactive Social Attention

结合催产素和纳洛酮优化增强互动社交注意力的行为和神经基础

• 批准号: 9796897
• 负责人: Steve Wohn Chul Chang
• 金额: $ 61.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796897
• 关键词: Address; Amygdaloid structure; Anterior; Area; Attenuated; Behavior; Behavioral; Brain; Brain region; Cerebrospinal Fluid; Clinical Trials; Combined Modality Therapy; Dose; Eye; Hypothalamic structure; Impairment; Intervention; Intranasal Administration; Life; Link; Mediating; Modeling; Monkeys; Morphine; Naloxone; Neurobiology; Opioid; Opioid Antagonist; Opioid agonist; Oxytocin; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Primates; Reciprocal Social Interaction; Saline; Social Behavior; Social Functioning; Specificity; Sum; Symptoms; System; Testing; Therapeutic; Translating; Treatment Efficacy; Work; autism spectrum disorder; base; cingulate cortex; combinatorial; design; gaze; improved; insight; mu opioid receptors; mu receptors; neurophysiology; nonhuman primate; novel; pre-clinical; receptor; receptor binding; relating to nervous system; response; social; social attention; social deficits; social engagement

Project Summary Several clinical trials have found that intranasal oxytocin (OT) treatment is not practically viable in its current form for improving core social symptoms in autism spectrum disorders (ASD). The current intranasal OT treatment has been criticized for its often weak and inconsistent effects, demanding an important need to explore new ways to improve its efficacy and reliability in modulating the OT system. While much less studied, the central opioid system has also been implicated in ASD based on the opioid dysregulation found in certain cases of ASD, as well as the well-known modulatory effects of opioid agonists, such as morphine, and its receptor antagonists, such as naloxone (NAL), in regulating social behaviors. In this translational non-human primate proposal, we will investigate a new alternative therapeutic option in improving core social functions by exploiting the robust regulatory relationship between the central OT and opioid systems. Our pharmacological study in non-human primates recently provided a proof of concept of this combined pharmacological approach in more effectively modulating social attention. The combined intranasal administration of OT and NAL (OTNAL) enhanced spontaneous social attention and contingent gaze dynamics following interactive eye contact over and beyond the summed effects from administering OT alone and NAL alone, indicating a combinatorial benefit of OTNAL. Capitalizing on this finding, we now propose to determine the optimal doses of OT and NAL in the combined OTNAL format, its corresponding cerebrospinal fluid markers of successful OTNAL interventions, as well as the neurophysiological markers underlying the combinatorial benefits in the domain of social attention. We will first obtain comprehensive dose-response functions for the OTNAL intervention during spontaneously occurring real- life social gaze interactions and assess the corresponding changes in cerebrospinal fluid OT levels due to OTNAL compared to other conditions (Aim 1A, 1B). We will then study how neural activity patterns within and across two key brain nodes in social processing, the amygdala and the anterior cingulate cortex, are impacted by OTNAL (Aim 2). Finally, we will test causal contributions of these two regions for the OTNAL effects by blocking OT-binding receptor types focally in these areas (Aim 3). The results from this work will offer novel mechanistic insights into the combined pharmacological approach using OTNAL to more vigorously promote social engagements in the primate brain. Such results will help set the stage for translating the combinatorial benefit of using intranasal OTNAL for more effectively and reliably reducing core social symptoms in ASD.

项目摘要 几项临床试验发现，鼻内催产素（OT）治疗实际上并不可行 改善自闭症谱系疾病（ASD）中核心社会症状的形式。当前的鼻内OT 治疗通常因其往往弱和不一致的影响而受到批评，要求探索的重要需求 提高其在调节OT系统的功效和可靠性的新方法。虽然研究得多，但中央 基于ASD的某些情况下，阿片类药物系统也与ASD有关。 以及阿片类药物激动剂（例如吗啡及其受体拮抗剂）的众所周知的调节作用， 例如纳洛酮（NAL），用于调节社会行为。在这个转化的非人类灵长类提案中，我们将 调查一种新的替代治疗选择，以利用强大的 中央OT和阿片类药物系统之间的调节关系。我们在非人类的药理研究 灵长类动物最近在更有效地提供了这种联合药理方法的概念证明 调节社会关注。 OT和NAL（OTNAL）增强的鼻内施用联合给药 交互式眼神交流之后，自发的社会关注和偶然的凝视动态超越 单独使用OT和单独管理NAL的总和，表明OTNAL的组合益处。 利用这一发现，我们现在建议确定合并中的OT和NAL的最佳剂量 OTNAL格式，其相应的成功OTNAL干预措施的脑脊液标记以及 在社会关注领域的组合益处的基础神经生理标志物。我们将首先 在自发发生期间，获得OTNal干预的全面剂量反应函数 生活社交目光相互作用并评估脑脊液OT水平的相应变化 与其他条件相比（AIM 1A，1B）。然后，我们将研究内部的神经活动模式和 在社会处理中的两个关键大脑节点中，杏仁核和前扣带回皮层受到影响 由OTNAL（AIM 2）。最后，我们将通过 阻断这些区域中的OT结合受体类型（AIM 3）。这项工作的结果将提供小说 使用OTNAL对合并的药理学方法的机理见解，以更迅速地促进 灵长类动物大脑中的社会活动。这样的结果将有助于为翻译组合奠定舞台 使用鼻内核的好处，以更有效，可靠地减少ASD中的核心社会症状。