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

项目概要 多项临床试验发现，鼻内催产素 (OT) 治疗在目前的情况下实际上并不可行。 改善自闭症谱系障碍 (ASD) 核心社会症状的形式。目前鼻内OT 治疗因其效果往往较弱且不一致而受到批评，迫切需要探索 提高其调节 OT 系统效率和可靠性的新方法。尽管研究较少，但中央 基于在某些自闭症谱系障碍病例中发现的阿片类药物失调，阿片类药物系统也与自闭症谱系障碍有关， 以及阿片类激动剂（例如吗啡）及其受体拮抗剂众所周知的调节作用， 例如纳洛酮（NAL），用于调节社会行为。在这个翻译性非人类灵长类动物提案中，我们将 研究一种新的替代治疗方案，通过利用强大的功能来改善核心社会功能 中央 OT 和阿片类药物系统之间的监管关系。我们对非人类的药理学研究 灵长类动物最近提供了这种组合药理学方法更有效的概念证明 调节社会注意力。 OT 和 NAL 联合鼻内给药 (OTNAL) 增强 互动眼神接触后的自发社会关注和偶然注视动态 单独使用 OT 和单独使用 NAL 的效果总和，表明 OTNAL 的组合益处。 利用这一发现，我们现在建议确定联合治疗中 OT 和 NAL 的最佳剂量。 OTNAL 格式、成功 OTNAL 干预的相应脑脊液标志物，以及 社会关注领域组合效益背后的神经生理学标记。我们首先会 获得 OTNAL 干预的全面剂量反应函数 生活社交凝视互动并评估脑脊液 OT 水平的相应变化 OTNAL 与其他条件的比较（目标 1A、1B）。然后我们将研究内部和外部的神经活动模式如何 社会处理中两个关键的大脑节点——杏仁核和前扣带皮层——受到影响 由 OTNAL（目标 2）。最后，我们将测试这两个区域对 OTNAL 效应的因果贡献： 集中阻断这些区域的 OT 结合受体类型（目标 3）。这项工作的结果将提供新颖的 使用 OTNAL 更积极地促进联合药理学方法的机制见解 灵长类动物大脑中的社交活动。这些结果将有助于为翻译组合奠定基础 使用鼻内 OTNAL 可以更有效、更可靠地减少自闭症谱系障碍 (ASD) 的核心社会症状。

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.