Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine

Parmar, R.; Meredith, J. R.; Bartlett, M. J.; Smith, E. G. E.; Castro, J. M.; Sherman, S. J.; Chattree, G.; Steece-Collier, K.; Falk, T.

doi:10.64898/2026.10.27.762361

bioRxiv · 10.64898/2026.10.27.762361

Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine

Parmar, R.·Meredith, J. R.·Bartlett, M. J.·Smith, E. G. E.·Castro, J. M.·Sherman, S. J.·Chattree, G.·Steece-Collier, K.·Falk, T.

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Abstract

L-DOPA remains the most effective symptomatic treatment for Parkinson's disease, but chronic administration is frequently complicated by L-DOPA-induced dyskinesia (LID). Our prior work has established that sub-anesthetic ketamine can reduced LID acutely and has a long-lasting neuroplastic effect. This study tested whether low-dose ketamine reduces dyskinesia induced specifically by dopamine D2R-like or D1R-like receptor activation. Male Sprague Dawley rats were primed with daily L-DOPA to establish dyskinesia and then challenged with quinpirole, a D2R-like receptor agonist, or SKF-81297, a D1R-like receptor agonist, to induce abnormal involuntary movements (AIMs). After stable AIM baselines were established, animals received agonist plus vehicle or agonist plus ketamine. Limb, axial, and orolingual AIMs were scored on the acute treatment day (D0) and after washout on D4 and D7. Quinpirole and SKF-81297 reliably produced stable total LAO AIM scores following L-DOPA priming. Ketamine significantly reduced only quinpirole-induced, but not SKF-81297-induced, total AIMs compared with vehicle on D0, demonstrating an acute anti-dyskinetic effect. This reduction persisted after washout, with ketamine-treated animals continuing to show significantly lower AIMs on D4 and D7. Time-course analyses further showed reduced AIMs expression across the post-quinpirole observation period on D0 and at multiple time points on D7. These findings demonstrate that ketamine suppresses quinpirole-induced dyskinesia in L-DOPA-primed male rats and suggest that D2R-like receptor-mediated or indirect pathway-related mechanisms, but not direct pathway-related mechanisms, may contribute to ketamine's anti-dyskinetic effects. Together, these results extend prior work on ketamine by linking its sustained anti-dyskinetic effects to dyskinesia driven by D2R-like receptor stimulation in vivo.

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Parmar, R., Meredith, J. R., Bartlett, M. J., Smith, E. G. E., Castro, J. M., Sherman, S. J., Chattree, G., Steece-Collier, K., Falk, T.. 2026-11-03. Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine. https://doi.org/10.64898/2026.10.27.762361

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