Rationale

Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin’s role in the regulation of anxiety and fear in humans.

Objectives

Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat).

Methods

Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5–7-day wash-out period. Threat consisted of unpleasant electric shocks. The “NPU” threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle).

Results

As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle.

Conclusions

As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

中文翻译：

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新型加压素受体 (V1aR) 拮抗剂 SRX246 可减轻人类实验模型中的焦虑：一项随机概念验证研究

基本原理

精氨酸加压素 (AVP) 是一种神经肽，可调节对威胁的生理和情绪反应。直到最近，还没有针对人类中枢神经系统中的加压素受体 (V1a) 的药物。新型 V1a 受体拮抗剂 SRX246 的开发允许实验验证加压素在调节人类焦虑和恐惧中的作用。

目标

在这里，我们检查了 SRX246 在恐惧（对迫在眉睫的威胁的阶段性反应）和焦虑（对潜在威胁的长期反应）的概念验证转化范式中的影响。

方法

健康志愿者以随机、双盲、平衡的顺序接受 SRX246 和安慰剂，间隔 5-7 天的清除期。威胁包括令人不快的电击。“NPU”威胁测试在可预测的威胁（即，恐惧增强的惊吓）和不可预测的威胁（即，焦虑增强的惊吓）期间探测惊吓反应。

结果

正如预测的那样，SRX246 减少了独立于恐惧增强的惊吓的焦虑增强惊吓。

结论

由于焦虑增强惊吓在焦虑和创伤相关疾病中升高，而传统抗焦虑药如 SSRIs 和苯二氮卓类药物降低，V1a 受体是一个很有前途的新型治疗靶点。