Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine
Raveena Parmar, Jasmine Meredith, Mitchell J Bartlett, Emma E Smith, Jeanelle Castro, Scott Sherman, Gaurav Chattree, Kathy Steece-Collier, Torsten Falk
bioRxiv November 3, 2026 preprint DOI: 10.64898/2026.10.27.762361 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal experiment |
|---|---|
| Population | Male Sprague Dawley rats primed with L-DOPA to establish dyskinesia |
| Interventions | Ketamine Quinpirole SKF-81297 L-DOPA |
| Dose | low-dose ketamine (exact dose not stated) |
| Duration | AIMs scored on treatment day (D0) and after washout on D4 and D7 |
| Measures | Abnormal involuntary movements (AIMs) scores (limb, axial, orolingual) |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine significantly reduced quinpirole-induced total AIMs compared with vehicle on the treatment day, and this reduction persisted on days 4 and 7 after washout. Ketamine did not reduce SKF-81297-induced AIMs. The authors suggest that D2-like receptor-mediated or indirect-pathway mechanisms, but not direct-pathway mechanisms, may contribute to ketamine's anti-dyskinetic effects. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 4
- Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors. Molecular Pharmacology October 17, 2024
- Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model. Neuropharmacology October 1, 2024
- Decoupling of motor cortex to movement in Parkinson's dyskinesia rescued by sub-anaesthetic ketamine. Brain June 3, 2025
- Ten-Hour Exposure to Low-Dose Ketamine Enhances Corticostriatal Cross-Frequency Coupling and Hippocampal Broad-Band Gamma Oscillations. Frontiers in Neural Circuits 2018