Quantitative Electroencephalography (qEEG) and event-related potential (ERP) assessment have emerged as powerful tools to unravel translational biomarkers in preclinical and clinical psychiatric drug discovery trials. The aim of the present study was to compare the GluN2B negative allosteric modulator (NAM) traxoprodil (CP-101,606) with the unselective NMDA receptor channel blocker S-ketamine to give insight into central target engagement and differentiation on multiple EEG readouts. For qEEG recordings telemetric transmitters were implanted in male Wistar rats. Recorded EEG data were analyzed using fast Fourier transformation to determine power spectra and vigilance states. Additionally, body temperature and locomotor activity were assessed via telemetry. For recordings of auditory event-related potentials (AERP) male C57Bl/6J mice were chronically implanted with deep electrodes using a tethered system. Power spectral analysis revealed a significant increase in gamma power following ketamine treatment, whereas traxoprodil (6&18 mg/kg) induced an overall decrease primarily within alpha and beta bands. Additionally, ketamine disrupted sleep and enhanced time spent in wake vigilance states, whereas traxoprodil did not alter sleep-wake architecture. AERP and mismatch negativity (MMN) revealed that ketamine (10 mg/kg) selectively disrupts auditory deviance detection, whereas traxoprodil (6 mg/kg) did not alter MMN at clinically relevant doses. In contrast to ketamine treatment, traxoprodil did not produce hyperactivity and hypothermia. In conclusion, ketamine and traxoprodil showed very different effects on diverse EEG readouts differentiating selective GluN2B antagonism from non-selective pan-NMDA-R antagonists like ketamine. These readouts are thus perfectly suited to support drug discovery efforts on NMDA-R and understanding the different functions of NMDA-R subtypes.

中文翻译：

---

在大鼠和小鼠的临床前试验中，曲索非定和S-氯胺酮对定量脑电图和听觉事件相关电位作为翻译生物标志物的差异作用。

定量脑电图（qEEG）和事件相关电位（ERP）评估已成为在临床前和临床精神药物发现试验中揭示转化生物标志物的强大工具。本研究的目的是将GluN2B负变构调节剂（NAM）曲索非（CP-101,606）与非选择性NMDA受体通道阻滞剂S-氯胺酮进行比较，以深入了解中心目标参与和在多个EEG读数上的分化。对于qEEG记录，遥测发射机被植入雄性Wistar大鼠中。使用快速傅立叶变换分析记录的EEG数据，以确定功率谱和警戒状态。另外，通过遥测评估体温和运动活动。为了记录听觉事件相关电位（AERP），使用系留系统将雄性C57Bl / 6J小鼠长期植入深电极。功率谱分析显示，氯胺酮处理后，γ功率显着增加，而曲克托地尔（6＆18 mg / kg）引起总体下降，主要在α和β谱带内。此外，氯胺酮破坏了睡眠并增加了在觉醒状态下花费的时间，而曲索非定并没有改变睡眠-觉醒结构。AERP和失配阴性（MMN）显示，氯胺酮（10 mg / kg）有选择地破坏听觉异常检测，而曲索普地（6 mg / kg）在临床相关剂量下并未改变MMN。与氯胺酮治疗相反，曲索非不会产生过度活跃和体温过低。结论，氯胺酮和曲索地尔对多种脑电图读数显示出非常不同的效果，从而将选择性GluN2B拮抗作用与非选择性泛NMDA-R拮抗剂（如氯胺酮）区分开。因此，这些读数非常适合支持NMDA-R上的药物发现工作，并了解NMDA-R亚型的不同功能。