Activity-State Dependent Reversal of Ketamine-Induced Resting State EEG Effects by Clozapine and Naltrexone in the Freely Moving Rat

Ketamine is a non-competitive N-Methyl-D-aspartate receptor (NMDAR) antagonist used in the clinic to initiate and maintain anaesthesia; it induces dissociative states and has emerged as a breakthrough therapy for major depressive disorder. Using local field potential recordings in freely moving rats, we studied resting state EEG profiles induced by co-administering ketamine with either: clozapine, a highly efficacious antipsychotic; or naltrexone, an opioid receptor antagonist reported to block the acute antidepressant effects of ketamine. As human electroencephalography (EEG) is predominantly recorded in a passive state, head-mounted accelerometers were used with rats to determine active and passive states at a high temporal resolution to offer the highest translatability. In general, pharmacological effects for the three drugs were more pronounced in (or restricted to) the passive state. Specifically, during inactive periods clozapine induced increases in delta (0.1-4 Hz), gamma (30-60 Hz) and higher frequencies (>100 Hz). Importantly, it reversed the ketamine-induced reduction in low beta power (10-20 Hz) and potentiated ketamine-induced increases in gamma and high frequency oscillations (130-160 Hz). Naltrexone inhibited frequencies above 50 Hz and significantly reduced the ketamine-induced increase in high frequency oscillations. However, some frequency band changes, such as clozapine-induced decreases in delta power, were only seen in locomoting rats. These results emphasise the potential in differentiating between activity states to capture drug effects and translate to human resting state EEG. Furthermore, the differential reversal of ketamine-induced EEG effects by clozapine and naltrexone may have implications for the understanding of psychotomimetic as well as rapid antidepressant effects of ketamine.