Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors.
Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.
Quintana
Adrien
A
Institut National de la Santé et de la Recherche Médicale, Unité 836 (INSERM U386), Université Joseph Fourier, Grenoble, France.
Melon
Christophe
C
Kerkerian-Le Goff
Lydia
L
Salin
Pascal
P
Savasta
Marc
M
Sgambato-Faure
Véronique
V
D000704:Analysis of Variance; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000378:metabolism / Q000503:physiopathology*; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D005552:Forelimb / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D009044:Motor Cortex / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018709:Statistics, Nonparametric; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013788:Thalamus / Q000378:metabolism
C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C095106:traxoprodil mesylate