Objective: Preclinical evaluation of low-dose ketamine treatment on dyskinesia induced by direct or indirect striatofugal pathway activation.

Background: Ketamine infusions are effective therapy for depression and chronic pain. Our prior preclinical data shows that low-dose ketamine treatment can attenuate development of L-DOPA-induced dyskinesia (LID) and reduce existing LID long-term. This long-term reduction (≥3 mo) was also seen in a Phase 1 clinical trial after 10-hour treatment. Ketamine is known to be a NMDA receptor antagonist and a positive allosteric modulator of opioid receptors. Our prior preclinical work showed that a highly-selective NMDA receptor antagonist (MK-801) and a mu/delta opioid receptor agonist (MMP-2200) both had differential effects on dyskinesia elicited by either dopamine 1 receptor-like (D1R) or dopamine 2 receptor-like (D2R) specific agonists.

Method: Male Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine to create a hemi PD model (n=9/group). PD rats were primed with daily injections of L-DOPA (6 mg/kg, i.p.; with 14 mg/kg benserazide) for 21 days, then a stable baseline of DR2-like dyskinesia (0.2 mg/kg quinpirole, i.p.) was established. Abnormal involuntary movements (AIMs; limb, axial and orolingual) were measured by a blinded observer for 3 hours.

Results: On Day 0 after 10-hr-treatment with vehicle or ketamine (20 mg/kg, i.p.) D2R-like induced AIMs were tested and the vehicle group had a mean AIMs score of 64 and the ketamine-treated group of 20 (p<0.001). On days 4 and 7 after quinpirole treatment alone, the ketamine-treated rats still showed a >50% reduction in their AIMs compared to vehicle (p<0.001) indicating the long-term effect that was prior shown for LID rats is also present. Statistics: Mann-Whitney tests corrected for multiple comparison.

Conclusion:

Our results show that dyskinesia induced by a D2R-like agonist was acutely reduced by a low-dose ketamine treatment and the reduction was still present at the end of the experiment 1-week after ketamine-treatment. We are currently testing the effect of ketamine on dyskinesia induced by a D1R-like agonist (SKF81297; 0.8 mg/kg, s.c.) in a separate cohort, and will report on the comparison. This data shows a contribution of the indirect striatopallidal pathway to the anti-dyskinetic effects of ketamine and provides further support for the repurposing of subanesthetic ketamine for individuals with LID.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/low-dose-ketamine-reduces-dopamine-2-receptor-like-agonist-induced-dyskinesia-in-a-preclinical-model/