Abstract

Pharmacological dopamine (DA) replacement with Levodopa (L-DOPA) is the gold standard treatment for Parkinson's disease (PD). However, long term L-DOPA treatment is complicated by eventual debilitating abnormal involuntary movements termed L-DOPA induced dyskinesia (LID), a clinically significant obstacle for the majority of patients who rely on L-DOPA to alleviate PD-related motor symptoms. The manifestation of LID may in part be driven by excessive extracellular DA derived from L-DOPA, but potential involvement of DA reuptake in LID severity or expression is unknown. We recently reported that in 6-OHDA-lesioned striatum, norepinephrine transporter (NET) expression increases and may play a significant role in DA transport. Furthermore, L-DOPA preferentially inhibits DA uptake in lesioned striatum. Therefore we hypothesized that desipramine (DMI), a NET antagonist, could affect the severity of LID in an established LID model. While DMI alone elicited no dyskinetic effects in lesioned rats, DMI + L-DOPA treated rats gradually expressed more severe dyskinesia compared to L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and NE inhibition of DA uptake in the DMI + L-DOPA group compared to L-DOPA alone group in lesioned striatum. LID severity positively correlated with striatal ERK phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI + L-DOPA group compared to the L-DOPA- and DMI-alone groups. Taken together, these results indicate that the combination of chronic L-DOPA and NET-mediated DA reuptake in lesioned nigrostriatal terminals may have a role in LID severity in experimental Parkinsonism.