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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

基本信息

批准号：
10630140
负责人：
Steve Wohn Chul Chang
金额：
$ 52.68万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10630140
关键词：
Address Amygdaloid structure Anterior Area Attenuated Behavior Behavioral Brain Brain region Cells 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 Work antagonist autism spectrum disorder base cingulate cortex combinatorial design gaze improved insight mu opioid receptors mu receptors neural neurophysiology nonhuman primate novel pharmacologic pre-clinical receptor receptor binding response social social attention social cognition social deficits social engagement therapeutically effective translational applications translational potential

项目摘要

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已经发现，鼻内催产素（OT）治疗在其目前的治疗中实际上是不可行的。用于改善自闭症谱系障碍（ASD）的核心社会症状。当前的鼻内OT 治疗一直被批评其往往薄弱和不一致的效果，要求一个重要的需要探索新的方法，以提高其效率和可靠性，在调制OT系统。虽然研究得较少，但中央阿片样物质系统也与ASD有关，这是基于在某些ASD病例中发现的阿片样物质失调，以及阿片样物质激动剂如吗啡及其受体拮抗剂的众所周知的调节作用，如纳洛酮（NAL），在调节社会行为。在这个翻译的非人类灵长类动物的建议，我们将研究一种新的替代治疗选择，通过利用强大的中枢OT和阿片系统之间的调节关系。我们在非人类的药理学研究灵长类动物最近提供了这种联合药理学方法的概念证明，调节社会注意力。OT和NAL联合鼻内给药（OTNAL）可增强在交互式目光接触之后自发社会注意和偶然注视动态单独给予OT和单独给予NAL的总效应表明OTNAL的组合益处。利用这一发现，我们现在建议确定OT和NAL在组合中的最佳剂量。 OTNAL格式，其相应的成功OTNAL干预的脑脊液标志物，以及神经生理学标志物在社会注意力领域的组合效益。我们将首先在自发发生的真实的- 生活社会凝视互动，并评估脑脊液OT水平的相应变化， OTNAL与其他条件相比（目标1A，1B）。然后，我们将研究神经活动模式，大脑中两个重要的社交处理节点杏仁核和前扣带皮层受到影响（二）目标（Aim）最后，我们将测试这两个区域对OTNAL效应的因果贡献，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新颖的使用OTNAL的联合药理学方法的机制见解，以更有力地促进灵长类大脑中的社交活动这些结果将有助于为翻译组合使用鼻内OTNAL更有效、更可靠地减少ASD核心社交症状的益处。