title: Norepinephrine transporter inhibition with desipramine exacerbates L-DOPA-induced dyskinesia: role for synaptic dopamine regulation in denervated nigrostriatal terminals.
abstract: Pharmacological dopamine (DA) replacement with Levodopa [L-dihydroxyphenylalanine (L-DOPA)] is the gold standard treatment of 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-hydroxydopamine (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. Whereas DMI alone elicited no dyskinetic effects in lesioned rats, DMI + L-DOPA-treated rats gradually expressed more severe dyskinesia compared with L-DOPA alone over time. At the conclusion of the study, we observed reduced NET expression and norepinephrine-mediated inhibition of DA uptake in the DMI + L-DOPA group compared with L-DOPA-alone group in lesioned striatum. LID severity positively correlated with striatal extracellular signal-regulated protein kinase phosphorylation among the three treatment groups, with increased ppERK1/2 in DMI + L-DOPA group compared with 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.
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Tanya
authors.initials: T
authors.lastname: Chotibut
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Victoria
authors.initials: V
authors.lastname: Fields
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana msalva@lsuhsc.edu.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Salvatore
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000502:physiology*; D003714:Denervation; D003891:Desipramine / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D007980:Levodopa; D048049:Extracellular Signal-Regulated MAP Kinases; D003891:Desipramine; D004298:Dopamine