Enhanced striatal cholinergic neuronal activity mediates l -DOPA–induced dyskinesia in parkinsonian mice
Autor: | Lisa Won, Yunmin Ding, Un Jung Kang, Sean Austin O. Lim, Jonathan P. Britt, Daniel S. McGehee |
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Rok vydání: | 2010 |
Předmět: |
medicine.medical_specialty
Dopamine Mice Transgenic Striatum Biology Medium spiny neuron Choline O-Acetyltransferase Levodopa Mice Internal medicine medicine Aminoacetonitrile Animals Premovement neuronal activity Phosphorylation Cholinergic neuron Aphakia Homeodomain Proteins Neurons Dyskinesias Multidisciplinary Dopaminergic Parkinson Disease Choline acetyltransferase Adenosine A2 Receptor Antagonists Disease Models Animal Endocrinology Cholinergic Fibers Gene Expression Regulation nervous system Cholinergic Transcription Factors medicine.drug |
Zdroj: | Proceedings of the National Academy of Sciences. 108:840-845 |
ISSN: | 1091-6490 0027-8424 |
Popis: | 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. |
Databáze: | OpenAIRE |
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