Targeting Dopamine-Mediated Social Reward Sensitivity to Remediate Social Disconnection

社会关系对我们的健康和幸福有很大的贡献。社会脱节是一种常见的 焦虑和抑郁障碍的禁用特征，对我们可用的最好的反应不充分 治疗。这些结果表明，一线治疗没有充分利用 支持与他人建立积极的关系。动物和人类的研究表明，多巴胺系统在 对推动我们的动机和行为的社会奖励线索和机会作出反应的重要作用 更倾向于与他人建立联系。在焦虑和焦虑中观察到降低的社会回报预期 抑郁障碍--指出了一种跨诊断机制，这种机制可能会支撑社会脱节。 以剂量依赖的方式直接调节多巴胺能功能将提供一个强有力的因果检验 社会奖赏中介的脱节途径。这一点很重要，因为一线药物疗法 焦虑和抑郁并不直接针对这个系统，这可能在一定程度上解释了为什么社交脱节 在治疗后的许多患者中持续存在。拟议的两个阶段、里程碑驱动的项目将解决 这一差距是通过检验这样一种假设来实现的，即通过药物调节多巴胺系统将增强社会 奖励预期(治疗目标)，从而改善社会联系(主要结果) 有临床焦虑或抑郁水平的个人。我们将使用以下工具选择性地使用此系统 普拉克索是一种D2/D3多巴胺受体激动剂，可增强纹状体中的多巴胺信号。 从而为机理试验提供了有力的证据。R61项目将评估药物的剂量依赖效应 普拉克索对社会奖励预期期间纹状体激活的影响(主要结果)和机会 向他人披露。次要结果将在二元联系和共享经验期间进行衡量 任务。目标1将检验与安慰剂相比，普拉克索增加社会回报预期的假设 经过6周的治疗。目标2将确定哪种剂量的普拉克索对 社会回报预期。普拉克索血药浓度将用于确认剂量依赖靶点 订婚。如果普拉克索在提高纹状体活性和社会回报预期方面优于安慰剂， R33项目将尝试复制R61的调查结果(目标1)，并检查社会 奖励预期与6周后社交连通性的改善有关(目标2 双盲、随机、安慰剂对照试验(剂量由R61告知)。次要结果将是 积极和消极情绪症状的变化(例如，社交快感缺失、焦虑、抑郁)。一个 探索性目标将检查治疗对负价过程的影响(例如，威胁敏感性)。正性 这些发现将验证CNS修复社会脱节的新目标，该目标可以在更大范围内进行研究 验证性疗效试验。无论研究结果如何，都将获得关于 多巴胺介导的过程的作用，据信支配着我们是否以及如何与他人联系。

Social relationships contribute enormously to our health and well-being. Social disconnection is a common and disabling feature of anxiety and depressive disorders that does not respond sufficiently to our best available treatments. These outcomes suggest first-line treatments do not adequately engage the mechanisms that support positive connections with others. Animal and human research suggests the dopamine system plays an important role in responding to social reward cues and opportunities that drive our motivation and behavior toward connecting with others. Diminished social reward anticipation is observed across anxiety and depressive disorders – pointing to a trans-diagnostic mechanism that may underpin social disconnection. Directly modulating dopaminergic functioning in a dose-dependent manner would provide a strong causal test of social reward-mediated disconnection pathways. This is important because first-line pharmacotherapies for anxiety and depression do not directly target this system, which may explain in part why social disconnection persists for many patients following treatment. The proposed two-phase, milestone-driven project will address this gap by testing the hypothesis that modulating the dopamine system pharmacologically will enhance social reward anticipation (the treatment target) and therefore improve social connectedness (primary outcome) in individuals with clinical levels of anxiety or depression. We will selectively engage this system using pramipexole – a D2/D3 dopamine receptor agonist shown to enhance dopamine signaling in the striatum – thereby providing a strong proof of mechanism test. The R61 project will evaluate dose-dependent effects of pramipexole on striatal activation during social reward anticipation (primary outcome) and opportunities to disclose to others. Secondary outcomes will be measured during dyadic affiliation and shared experiences tasks. Aim 1 will test the hypothesis that pramipexole increases social reward anticipation compared to placebo following 6 weeks of treatment. Aim 2 will determine which dose of pramipexole produces a greater effect on social reward anticipation. Pramipexole blood concentrations will be used to confirm dose-dependent target engagement. If pramipexole is superior to placebo in increasing striatal activation to social reward anticipation, the R33 project will attempt to replicate the R61 findings (Aim 1) and examine whether increases in social reward anticipation are associated with improvements in social connectedness (Aim 2) following a 6-week double-blind, randomized, placebo-controlled trial (dose informed by the R61). Secondary outcomes will be change in positive and negative valence symptoms (e.g., social anhedonia, anxiety, depression). An exploratory aim will examine treatment effects on negative valence processes (e.g., threat sensitivity). Positive findings would validate a new CNS target for remediating social disconnection that could be studied in larger confirmatory efficacy trials. Regardless of study outcomes, important new information will be gained about the role of dopamine-mediated processes that are believed to govern whether and how we connect with others.