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Molecular Pharmacology

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Research ArticleArticle

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

Tanya Chotibut, Victoria Fields and Michael F. Salvatore
Molecular Pharmacology December 2014, 86 (6) 675-685; DOI: https://doi.org/10.1124/mol.114.093302
Tanya Chotibut
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana
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Victoria Fields
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana
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Michael F. Salvatore
Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana
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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.

Footnotes

    • Received April 17, 2014.
    • Accepted September 10, 2014.
  • This work was supported in part by the Ike Muslow Predoctoral Fellowship Award (to T.C.) and an award (to M.F.S.) through the Edward P. Stiles Trust Fund-Louisiana State University Health Sciences Center-Shreveport and the Biomedical Research Foundation of Northwest Louisiana.

  • dx.doi.org/10.1124/mol.114.093302.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (6)
Molecular Pharmacology
Vol. 86, Issue 6
1 Dec 2014
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Research ArticleArticle

Norepinephrine Transporter and L-DOPA Dyskinesia

Tanya Chotibut, Victoria Fields and Michael F. Salvatore
Molecular Pharmacology December 1, 2014, 86 (6) 675-685; DOI: https://doi.org/10.1124/mol.114.093302

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Research ArticleArticle

Norepinephrine Transporter and L-DOPA Dyskinesia

Tanya Chotibut, Victoria Fields and Michael F. Salvatore
Molecular Pharmacology December 1, 2014, 86 (6) 675-685; DOI: https://doi.org/10.1124/mol.114.093302
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