Ketamine supresses REM sleep and markedly increases EEG gamma oscillations in the Wistar Kyoto rat model of treatment-resistant depression.

Wistar-Kyoto (WKY) rats exhibit depression-like characteristics and decreased sensitivity to monoamine-based antidepressants, making them a suitable model of treatment-resistant depression (TRD). Ketamine has emerged recently as a rapidly acting antidepressant with high efficacy in TRD. Our aim was to determine whether subanaesthetic doses of ketamine can correct sleep and electroencephalogram (EEG) alterations in WKY rats and whether any ketamine-induced changes differentially affect WKY rats compared to Sprague-Dawley (SD) rats. Thus, we surgically implanted 8 SD and 8 WKY adult male rats with telemetry transmitters and recorded their EEG, electromyogram, and locomotor activity after vehicle or ketamine (3, 5 or 10 mg/kg, s.c.) treatment. We also monitored the plasma concentration of ketamine and its metabolites, norketamine and hydroxynorketamine in satellite animals. We found that WKY rats have an increased amount of rapid eye movement (REM) sleep, fragmented sleep-wake pattern, and increased EEG delta power during non-REM sleep compared to SD rats. Ketamine suppressed REM sleep and increased EEG gamma power during wakefulness in both strains, but the gamma increase was almost twice as large in WKY rats than in SD rats. Ketamine also increased beta oscillations, but only in WKY rats. These differences in sleep and EEG are unlikely to be caused by dissimilarities in ketamine metabolism as the plasma concentrations of ketamine and its metabolites were similar in both strains. Our data suggest an enhanced antidepressant-like response to ketamine in WKY rats, and further support the predictive validity of acute REM sleep suppression as a measure of antidepressant responsiveness.