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

项目摘要 一些临床试验发现，鼻腔内注射催产素(OT)在目前的情况下并不可行 用于改善自闭症谱系障碍(ASD)核心社会症状的表格。目前的鼻腔催产素 治疗因其效果往往很弱和不一致而受到批评，这需要重要的探索 提高其在调节OT系统中的有效性和可靠性的新方法。虽然研究要少得多，但中央银行 基于在某些ASD病例中发现的阿片类药物调节失调，阿片系统也被认为与ASD有关， 以及众所周知的阿片激动剂，如吗啡，及其受体拮抗剂的调节作用， 如纳洛酮(NAL)，在调节社会行为方面。在这个翻译的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，通过利用健壮的 中枢催产素和阿片系统之间的调节关系。我们在非人类体内的药理研究 灵长类动物最近提供了一个概念的证据，这种结合的药理学方法在更有效地 调节社会注意力。OT和NAL(OTNAL)联合鼻腔给药的疗效观察 互动眼神接触后的自发社会注意和偶发凝视动态 单独使用OT和单独使用NAL的总和效果，表明OTNAL的联合益处。 基于这一发现，我们现在建议确定联合应用OT和NAL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 社会注意领域中潜在的组合益处的神经生理学标记物。我们将首先 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(目标1A、1B)进行比较。然后我们将研究神经活动模式是如何在和 在社会加工过程中的两个关键大脑节点--杏仁核和前扣带回皮质--受到影响 OTNAL(目标2)。最后，我们将通过以下方式测试这两个区域对OTNAL效应的因果贡献 在这些区域集中阻断OT结合受体类型(目标3)。这项工作的结果将为我们提供新的 对使用OTNAL更有力地促进联合药理学方法的机械论见解 灵长类动物大脑中的社交活动。这样的结果将有助于为组合词的翻译奠定基础 鼻腔使用OTNAL可更有效、更可靠地减少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.