A PK–PD model of ketamine-induced high-frequency oscillations
Name
Flores et al. - 2015 - PK-PD model.pdf
Description
Main article
Size
4.26 MB
Format
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Checksum (MD5)
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Author(s)
Hartnack, Katharine
Fath, Amanda B
Flores Plaza, Francisco Javier
Ching, Shinung
Brown, Emery Neal
Purdon, Patrick Lee
Wilson, Matthew A.
Date Issued
August 2015
Journal
Journal of Neural Engineering
Publisher
IOP Publishing
Citation
Flores, Francisco J et al. “A PK–PD Model of Ketamine-Induced High-Frequency Oscillations.” Journal of Neural Engineering 12.5 (2015): 056006.
Version
Author's final manuscript
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 nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic–pharmacodynamics (PK–PDs) 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 an 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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1088/1741-2560/12/5/056006
