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 hig...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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IOP Publishing
2017
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| Online Access: | http://hdl.handle.net/1721.1/107204 https://orcid.org/0000-0002-8974-9717 https://orcid.org/0000-0001-5651-5060 https://orcid.org/0000-0001-7149-3584 https://orcid.org/0000-0003-2668-7819 |
| _version_ | 1811096079760883712 |
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| author | Hartnack, Katharine Fath, Amanda B Flores Plaza, Francisco Javier Ching, Shinung Brown, Emery Neal Purdon, Patrick Lee Wilson, Matthew A. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Hartnack, Katharine Fath, Amanda B Flores Plaza, Francisco Javier Ching, Shinung Brown, Emery Neal Purdon, Patrick Lee Wilson, Matthew A. |
| author_sort | Hartnack, Katharine |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:38:01Z |
| format | Article |
| id | mit-1721.1/107204 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:38:01Z |
| publishDate | 2017 |
| publisher | IOP Publishing |
| record_format | dspace |
| spelling | mit-1721.1/1072042022-10-02T08:36:27Z A PK–PD model of ketamine-induced high-frequency oscillations Hartnack, Katharine Fath, Amanda B Flores Plaza, Francisco Javier Ching, Shinung Brown, Emery Neal Purdon, Patrick Lee Wilson, Matthew A. 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 Brown, Emery N Flores Plaza, Francisco Javier Ching, Shinung Purdon, Patrick L. Wilson, Matthew A Brown, Emery Neal 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. National Institutes of Health (U.S.) (Pioneer Award DP1-OD003646) Burroughs Wellcome Fund (Career Award at the Scientific Interface) National Institutes of Health (U.S.) (Grant 5R01MH061976) National Institutes of Health (U.S.) (New Innovator Award DP2-OD006454) 2017-03-07T15:44:46Z 2017-03-07T15:44:46Z 2015-08 2015-03 Article http://purl.org/eprint/type/JournalArticle 1741-2560 1741-2552 http://hdl.handle.net/1721.1/107204 Flores, Francisco J et al. “A PK–PD Model of Ketamine-Induced High-Frequency Oscillations.” Journal of Neural Engineering 12.5 (2015): 056006. https://orcid.org/0000-0002-8974-9717 https://orcid.org/0000-0001-5651-5060 https://orcid.org/0000-0001-7149-3584 https://orcid.org/0000-0003-2668-7819 en_US http://dx.doi.org/10.1088/1741-2560/12/5/056006 Journal of Neural Engineering Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf IOP Publishing Brown |
| spellingShingle | Hartnack, Katharine Fath, Amanda B Flores Plaza, Francisco Javier Ching, Shinung Brown, Emery Neal Purdon, Patrick Lee Wilson, Matthew A. A PK–PD model of ketamine-induced high-frequency oscillations |
| title | A PK–PD model of ketamine-induced high-frequency oscillations |
| title_full | A PK–PD model of ketamine-induced high-frequency oscillations |
| title_fullStr | A PK–PD model of ketamine-induced high-frequency oscillations |
| title_full_unstemmed | A PK–PD model of ketamine-induced high-frequency oscillations |
| title_short | A PK–PD model of ketamine-induced high-frequency oscillations |
| title_sort | pk pd model of ketamine induced high frequency oscillations |
| url | http://hdl.handle.net/1721.1/107204 https://orcid.org/0000-0002-8974-9717 https://orcid.org/0000-0001-5651-5060 https://orcid.org/0000-0001-7149-3584 https://orcid.org/0000-0003-2668-7819 |
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