Activation of the NMDA receptor involved in the alleviating after-effect of repeated stimulation of the subthalamic nucleus on motor deficits in hemiparkinsonian rats

Abstract

To test the hypothesis that the cellular mechanism whereby chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) induces the improvement of motor deficits lasting after stimulation in the hemiparkinsonian (hemi-PD) rat involves the NMDA receptor-dependent processes in neurons receiving afferents from the STN, we examined whether the NMDA receptor antagonist prevents the alleviating after-effect of repeated STN-DBS on motor deficits in hemi-PD. The cylinder test was performed before and after repeated STN-DBS over 3 days in hemi-PD that received a unilateral injection of 6-OHDA into the medial forebrain bundle 3 weeks prior to STN-DBS experiments. No significant improvement in the reduced frequency of forelimb use and forelimb-use asymmetry was seen in the cylinder test after the single STN-DBS, while, when the STN-DBS was applied three times at intervals of 24 h, the improvement became apparent and significant only in the reduced frequency of forelimb use (akinesia) after termination of the stimulation, suggesting the alleviating after-effect of chronic stimulation. Then, the effects of intraperitoneal administration of the non-competitive NMDA receptor antagonist MK-801 and the competitive NMDA receptor antagonist CPP on the alleviating after-effect of the STN-DBS were examined in cylinder tests performed before and after repeated STN-DBS for 3 days in hemi-PD. Both MK-801 (0.1 mg/kg) and CPP (0.5 mg/kg) completely prevented the improvement of the akinetic motor deficit after repeated STN-DBS. These results support the hypothesis that activation of the NMDA receptor and subsequent cellular processes in neurons receiving the afferents from the STN may involve in the mechanism underlying the alleviating after-effect of chronic STN-DBS on the akinetic motor deficit in hemi-PD.