Differential effects of traxoprodil and S-ketamine on quantitative EEG and auditory event-related potentials as translational biomarkers in preclinical trials in rats and mice. (July 2020) - Raith, Henrike
Abstract: 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. Highlights: Ketamine induces hyperactivity, whereas traxoprodil does not change locomotion. Ketamine-induced hypothermia and sleep disruption is not evident following traxoprodil treatment. Ketamine mainly increases delta and gamma power whereas traxoprodil leads to a reduction of all power bands. Traxoprodil (supratherapeutic dose) reduces AERP, evoked theta, gamma and theta-ITC similar to clinically relevant ketamine. Clinically relevant dosing of traxoprodil does not impair MMN, while ketamine induces a disruption of deviance detection.