Evaluation of the Differential Effects of MK-801 and MMP-2200 on Dopamine Receptor 1- and 2-Agonist-Induced Abnormal Involuntary Movements

Abstract

Specific Aims: The specific aim of this study was to measure the severity of dopamine receptor 1 (D1R)- and dopamine receptor 2 (D2R)-induced abnormal involuntary movements (AIMs) when administered with the NMDA receptor antagonist MK-801 or opioid glycopeptide MMP-2200. Methods: Male Sprague-Dawley rats were injected with 6-hydroxydopamine to cause unilateral loss of dopaminergic neurons in the substantia nigra and subsequent striatal dopamine loss. Levodopa (7 mg/kg; i.p.) injection for 21 consecutive days caused the rats to develop levodopa-induced dyskinesias, termed AIMs in this preclinical rat model. The rats were first primed with the D1R agonist SKF81297, then co-administered with MK-801 or MMP-2200 and AIMs scores were recorded to determine the severity of the dyskinesias. Then the same procedure was performed with the D2R agonist quinpirole. Main Results: MK-801 worsened D1R-induced limb, axial and orolingual (LAO) AIMs (p<0.05) whereas there was no change in locomotor AIM scores. MK-801 reduced D2R-induced LAO AIMs by 89% (p<0.001). However, MK-801 induced ipsiversive rotations, which is a parkinsonian symptom in this model. MMP-2200 had no effect on D1R-induced LAO AIMs but significantly reduced locomotor AIMs by 50% (p<0.05). MMP-2200 significantly decreased both D2R-induced LAO and locomotor AIMs by 40% and 90%, respectively (p<0.01). Conclusion: Both MK-801 and MMP-2200 had differential effects on the rodent direct and indirect striatofugal pathways with regards to AIMs. These results support that MK-801, an NMDA receptor antagonist, and MMP-2200, a mixed mu and delta opioid receptor agonist, modulate levodopa-induced dyskinesias through the dopaminergic and glutaminergic pathways.