A PK–PD model of ketamine-induced high-frequency oscillations

Abstract

Objective Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a High-Frequency Oscillation (HFO) which power is modulated non-linearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PD) of ketamine and the observed HFO power. Approach In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by a high-frequency oscillation (HFO) observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.

Electroencephalographic slow wave dynamics and loss of behavioural responsiveness induced by ketamine in human volunteers

“…Flores and co-workers 19 modelled the time course of high frequency (∼140 Hz) electrocorticogram oscillations in rats after i.p. ketamine.…”

Differential frontal alpha oscillations and mechanisms underlying loss of consciousness: a comparison between slow and fast propofol infusion rates

“…The existence of frontal alpha power following propofol administration is thought to result from an increase in thalamocortical synchrony above the observable levels during wakefulness . The occurrence of this phenomenon diminishes or inactivates the functional coupling between regions that maintain consciousness . The presence of frontal alpha power bands strongly suggests that loss of consciousness was achieved by the action of propofol on cortico‐thalamic dynamics in the slow infusion group .…”

“…Data are shown from a representative channel (R1). occurrence of this phenomenon diminishes or inactivates the functional coupling between regions that maintain consciousness[6,17,20]. The presence of frontal alpha power bands strongly suggests that loss of consciousness was achieved by the action of propofol on corticothalamic dynamics in the slow infusion group[17].…”

Network and synaptic mechanisms underlying high frequency oscillations in the rat and cat olfactory bulb under ketamine-xylazine anesthesia

“…NMDAR antagonists like ketamine or phencyclidine, induce short-lasting psychotic states and is used to study synaptic mechanisms of psychoses in animal models [Frohlich and Van Horn, 2014]. To date, many groups, including our own, have shown that low-doses of ketamine (or related NMDA receptor antagonists) produce HFO in many cortical and subcortical areas [Hunt et al, 2006, Phillips et al, 2012, Caixeta et al, 2013, Flores et al, 2015, Kealy et al, 2017, Amat-Foraster et al, 2019]. However, there are important gaps in understanding ketamine-dependent HFO in the brain, most notably, what are the network and synaptic mechanisms underlying this activity, and does it occur in higher mammals.…”