Objective: To evaluate mechanism of long-term activity of sub-anesthetic ketamine infusion to reduce L-DOPA-induced dyskinesias (LID).

Background: Ketamine is an anesthetic that, when administered as an infusion at sub-anesthetic doses, has been shown in the clinic to be effective for treatment of chronic pain and treatment-resistant depression. In a separate abstract we present patient case reports showing also a long-term reduction of LID (Sherman and Falk). Although the mechanisms are unknown, data from recent publications suggest that high-frequency oscillations (HFO; >100 Hz) and beta-band oscillations (13-30 Hz) in the striatum and cortex could be involved.

Methods: We used the standard preclinical rat LID model (7 mg/kg L-DOPA to prime unilaterally 6-hydroxydopamine-lesioned rats). To mimic a patient infusion for the 10 hr ‘infusion’ paradigm ketamine was injected 5 x i.p. two hrs apart, 7 mg/kg L-DOPA was co-injected at the 5th injection, and then the AIMs scores were evaluated. In a 2nd experiment we conducted in vivo electrophysiology in awake freely behaving naïve rats implanted with arrays of electrodes targeting dorsolateral striatum (DLS), somatosensory cortex, and motor cortex (M1).

Results: Ketamine (5-20 mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements (AIMs), only when sub-anesthetic ketamine was given for ten hrs (n=5) and not with a single acute (n=10) ketamine injection. A significant anti-dyskinetic effect of the 20 mg/kg ketamine ‘infusion’ remained 55 days later. Pharmacokinetic data show that ketamine ‘infusion’ did not lead to increased levels of ketamine compared to a single i.p. injection, or long-term accumulation of the major metabolites. The repeated sub-anesthetic ketamine doses induced sustained gamma (30-60 Hz) and HFO (130-160 Hz) in the DLS and M1 (n=4), suggesting an additive effect. HFO and beta-band coherence were significantly anti-correlated, suggesting a competitive role for ketamine-induced changes in oscillatory activity and a potential mechanism (i.e., beta-band suppression) in reducing LID. These changes in oscillatory patterns are reminiscent of Deep Brain Stimulation (DBS).

Conclusions: Our data indicate that sub-anesthetic ketamine infusion might work as a ‘chemical’ DBS, leading to reduction of LID by desynchronizing hypersynchronous electrical activity in M1.

Society for Neuroscience Meeting 2015, Chicago.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preclinical-evaluation-of-sub-anesthetic-ketamine-infusion-to-reduce-l-dopa-induced-dyskinesias-is-it-a-chemical-dbs/