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

Background: We have published preclinical evidence and patient case reports showing a long-term reduction of LID after sub-anesthetic ketamine infusion (Bartlett et al. 2016; Sherman et al., 2016). Although the mechanisms are unknown, data from recent literature suggest that high-frequency oscillations (HFO; >100 Hz) and beta-band oscillations (15-30 Hz) in the striatum and cortex could be involved in ketamine’s effects, as well as changes in dendritic spines.

Methods: Preclinical LID model: escalating L-DOPA doses (2 weeks: 6 mg/kg + 2 weeks: 12 mg/kg) to prime unilaterally 6-OHDA-lesioned rats. To mimic a 10-hr patient infusion ketamine (20 mg/kg) was injected 5 x i.p. two hrs apart, L-DOPA was co-injected at the 5^th injection. In a separate pilot study we conducted in vivo electrophysiology (1-hr baseline period followed by the 10-hr ketamine protocol) in awake freely behaving 6-OHDA-lesioned rats implanted with electrode arrays targeting dorsolateral striatum (DLS) and motor cortex (M1).

Results: Ketamine infusion once a week reduced the development of LID and increased phosphorylation of striatal mTOR (n=9 per group, *p<0.05, ANOVA). BDNF levels and dendritic spine density in the striatum are currently investigated. In a separate pilot study TrkB receptors were blocked with ANA-12 during ketamine-exposure. Co-injection of ANA-12 did not reduce the acute, but the sustained anti-dyskinetic effect seen in ketamine-only injected LID rats after 4 days, indicating an involvement of BDNF in the sustained anti-dyskinetic effects of ketamine (n=9-10). In the PD rats ketamine induced sustained gamma (30-60 Hz) and HFO (130-160 Hz) in the DLS and M1, and reduced beta power (n=5, one way ANOVA).  Ketamine triggered strong HFO coherence and a progressive reduction in coherence at bands <30 Hz in M1/DLS, illustrated by an inverse relationship between HFO and beta coherence.

Conclusions: Our pilot data indicate that the anti-dyskinetic activity of sub-anesthetic ketamine infusion is accompanied by activation of striatal mTOR signaling, and reduction of beta band activity and coherence in DLS and M1, supporting the hypothesis of ketamine acting as a “chemical DBS”.

References: Bartlett MJ, Joseph RM, LePoidevin LM, Parent KL, Laude ND, Lazarus LB, Heien ML, Estevez M, Sherman SJ, Falk T; Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesia. Neuroscience Letters 2015; 612:121-5.

Sherman SJ, Estevez M, Magill AR, Falk T; Case reports showing a long-term effect of subanesthetic ketamine infusion in reducing L-DOPA-induced dyskinesias. Case Reports in Neurology 2016; 8:53-58.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mechanisms-of-sub-anesthetic-ketamine-infusions-to-reduce-l-dopa-induced-dyskinesia-effects-on-striatal-mtor-signaling-and-beta-band-oscillations-in-striatum-and-motor-cortex/