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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Won, Lisa Mcgehee, Daniel S. Ding, Yunmin Kang, Un Jung Britt, Jonathan P. Lim, Sean Austin O. |
| Description | Author Affiliation: Ding Y ( Department of Neurology, University of Chicago, Chicago, IL 60637, USA.); |
| Abstract | Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cholinergic Fibers Metabolism Dyskinesias Gene Expression Regulation Levodopa Neurons Parkinson Disease Adenosine A2 Receptor Antagonists Chemistry Aminoacetonitrile Analogs & Derivatives Pharmacology Animals Aphakia Choline O-Acetyltransferase Disease Models, Animal Dopamine Genetics Homeodomain Proteins Mice Mice, Transgenic Phosphorylation Transcription Factors Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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