Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model

Mitchell J. Bartlett, Ria M. Joseph, Lindsey M. LePoidevin, Kate L. Parent, Nicholas D. Laude, Levi B. Lazarus, Michael L Heien, Miguel Estevez, Scott J Sherman, Torsten Falk

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20. mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10. h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.

Original languageEnglish (US)
Pages (from-to)121-125
Number of pages5
JournalNeuroscience Letters
Volume612
DOIs
StatePublished - Jan 26 2016

Fingerprint

Dyskinesias
Ketamine
Anesthetics
Post-Traumatic Stress Disorders
Migraine Disorders
Parkinson Disease
Brain
Depression
Treatment-Resistant Depressive Disorder
Injections
Basal Ganglia
Chronic Pain
Rodentia
Therapeutics
Pharmacokinetics
Pain

Keywords

  • Hypersynchrony
  • NMDA Receptors
  • Opioid receptors
  • Parkinson's disease
  • Preclinical rodent model

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model. / Bartlett, Mitchell J.; Joseph, Ria M.; LePoidevin, Lindsey M.; Parent, Kate L.; Laude, Nicholas D.; Lazarus, Levi B.; Heien, Michael L; Estevez, Miguel; Sherman, Scott J; Falk, Torsten.

In: Neuroscience Letters, Vol. 612, 26.01.2016, p. 121-125.

Research output: Contribution to journalArticle

Bartlett, Mitchell J. ; Joseph, Ria M. ; LePoidevin, Lindsey M. ; Parent, Kate L. ; Laude, Nicholas D. ; Lazarus, Levi B. ; Heien, Michael L ; Estevez, Miguel ; Sherman, Scott J ; Falk, Torsten. / Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model. In: Neuroscience Letters. 2016 ; Vol. 612. pp. 121-125.
@article{5990e399bca84d1897be73a8da562b95,
title = "Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model",
abstract = "Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20. mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10. h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.",
keywords = "Hypersynchrony, NMDA Receptors, Opioid receptors, Parkinson's disease, Preclinical rodent model",
author = "Bartlett, {Mitchell J.} and Joseph, {Ria M.} and LePoidevin, {Lindsey M.} and Parent, {Kate L.} and Laude, {Nicholas D.} and Lazarus, {Levi B.} and Heien, {Michael L} and Miguel Estevez and Sherman, {Scott J} and Torsten Falk",
year = "2016",
month = "1",
day = "26",
doi = "10.1016/j.neulet.2015.11.047",
language = "English (US)",
volume = "612",
pages = "121--125",
journal = "Neuroscience Letters",
issn = "0304-3940",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model

AU - Bartlett, Mitchell J.

AU - Joseph, Ria M.

AU - LePoidevin, Lindsey M.

AU - Parent, Kate L.

AU - Laude, Nicholas D.

AU - Lazarus, Levi B.

AU - Heien, Michael L

AU - Estevez, Miguel

AU - Sherman, Scott J

AU - Falk, Torsten

PY - 2016/1/26

Y1 - 2016/1/26

N2 - Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20. mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10. h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.

AB - Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20. mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10. h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID.

KW - Hypersynchrony

KW - NMDA Receptors

KW - Opioid receptors

KW - Parkinson's disease

KW - Preclinical rodent model

UR - http://www.scopus.com/inward/record.url?scp=84949883964&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949883964&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2015.11.047

DO - 10.1016/j.neulet.2015.11.047

M3 - Article

C2 - 26644333

AN - SCOPUS:84949883964

VL - 612

SP - 121

EP - 125

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

ER -