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 (5-20mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10h 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.
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Bartlett
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ, USA.
authors.forename: Ria M
authors.initials: RM
authors.lastname: Joseph
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: LePoidevin
authors.affiliation: Department of Chemistry & Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Parent
authors.affiliation: Department of Chemistry & Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Laude
authors.affiliation: Department of Chemistry & Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Lazarus
authors.affiliation: Department of Chemistry & Biochemistry, University of Arizona, Tucson, AZ, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Heien
authors.affiliation: Neurometrica, LLC, Eugene, OR, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Estevez
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Sherman
authors.affiliation: Department of Neurology, University of Arizona, Tucson, AZ, USA. Electronic address: tfalk@u.arizona.edu.
authors.forename: Torsten
authors.initials: T
authors.lastname: Falk
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D007649:Ketamine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011957:Receptors, Opioid / Q000819:agonists*; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D007980:Levodopa; D007649:Ketamine
keywords: Hypersynchrony; NMDA Receptors; Opioid receptors; Parkinson’s disease; Preclinical rodent model