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


METHODS
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.


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.


CONCLUSIONS
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.
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Francisco J
FJ
Flores
ShiNung
S
Ching
Katharine
K
Hartnack
Amanda B
AB
Fath
Patrick L
PL
Purdon
Matthew A
MA
Wilson
Emery N
EN
Brown
D000778:Anesthetics, Dissociative / Q000008:administration & dosage; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D007649:Ketamine / Q000008:administration & dosage*; D008959:Models, Neurological; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000778:Anesthetics, Dissociative; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine