The effects of zonisamide on L-DOPA–induced dyskinesia in Parkinson's disease model mice

Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain and shows motor dysfunctions. Zonisamide (ZNS, 1,2-benzisoxazole-3-methanesulfonamide), which was originally developed as an antiepileptic drug, was also found to have beneficial effects on motor symptoms in PD. In the current study, we have investigated the behavioral and physiological effects of ZNS on L-DOPA–induced dyskinesia (LID) in PD model mice. Chronic administration of L-DOPA plus ZNS in PD model mice was shown to increase the duration and severity of LID compared with PD model mice that were treated with L-DOPA alone. To elucidate the neural mechanism of the effects of ZNS on LID, we examined neuronal activity in the output nuclei of the basal ganglia, i.e., the substantia nigra pars reticulata (SNr). Chronic administration of L-DOPA plus ZNS in PD mice decreased the firing rate in the SNr while they showed apparent LID. In addition, chronic treatment of L-DOPA plus ZNS in PD mice changed cortically evoked responses in the SNr during LID. In the control state, motor cortical stimulation induces the triphasic response composed of early excitation, inhibition, and late excitation. In contrast, L-DOPA plus ZNS–treated PD mice showed longer inhibition and reduced late excitation. Previous studies proposed that inhibition in the SNr is derived from the direct pathway and releases movements, and that late excitation is derived from the indirect pathway and stops movements. These changes of the direct and indirect pathways possibly underlie the effects of ZNS on LID.