NR2B antagonist modulates the effect of D1R agonist on the reduced and imbalanced bilateral forelimb use in hemiparkinsonian rats

Objectives: The antiparkinsonian effect of N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B) antagonists remain controversial. To determine the effects of NR2B antagonist on Parkinson's disease (PD), the effect of a single administration of D1R agonist SKF38393 (SKF) and NR2B antagonist ifenprodil or co-administration of ifenprodil and SKF were investigated using the cylinder test. Materials and Methods: The hemiparkinsonian (hemi-PD) rats were divided into 8 groups. The cylinder test was used to estimate the number of forelimb uses in 15 minutes as a measure of motor activity 30 minutes after administration of SKF (1.0, 2.0, 3.0 mg/kg), 0.1 mg/kg ifenprodil or coadministration of SKF and ifenprodil (2.0 mg/kg SKF + 0.1 mg/kg ifenprodil or 3.0 mg/kg SKF + 0.1 mg/kg ifenprodil). Subsequently, to identify the brain areas influenced by SKF and ifenprodil, neurons with SKF-induced c-Fos expression were analyzed in various brain regions in hemi-PD rats following the administration of SKF, with and without ifenprodil. Results: The administration of SKF increased a frequency of forelimb use in a dose-dependent manner (F(3,36) = 4.4, P = 0.0094; PD/vehicle (veh) 21.6 ± 6.3, 2.0 mg/kg SKF 103.4 ± 22.1 P < 0.05 vs. PD/veh; 3.0 mg/kg SKF 120.2 ± 30.5 P < 0.01 vs. PD/veh), mostly via the facilitation of the frequent use of Parkinsonian paw. The combined administration of SKF and ifenprodil completely reversed the SKF-induced abnormality in bilaterally coordinated movement of the forelimb in hemiPD rats without affecting the facilitatory effect of SKF on motor activity (F(2,46) = 3.8, P = 0.0304). The co-administered ifenprodil also modulated the SKF-induced c-Fos expression in the striatum (P < 0.05) and the subthalamic nucleus (STN) (P < 0.01). Conclusions: The ameliorative effect of ifenprodil on the motor deficits in hemi-PD rats resulted from the improvement of the SKF-induced excessive use of Parkinsonian paw, and that the STN and/or the striatum in the lesioned hemisphere are possible targets for the antiparkinsonian effect of the NR2B antagonist.