Enhanced striatal cholinergic neuronal activity mediates L-DOPA—induced dyskinesia in parkinsonian mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 2; pp. 840 - 845
• Main Authors: Ding, Yunmin, Won, Lisa, Britt, Jonathan P., Lim, Sean Austin O., McGehee, Daniel S., Kang, Un Jung, Palmiter, Richard D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.01.2011; National Acad Sciences
• Subjects: 6-Hydroxydopamine; Acetylcholine receptors (muscarinic); Adenosine A2 Receptor Antagonists - chemistry; Aminoacetonitrile - analogs & derivatives; Aminoacetonitrile - pharmacology; Animal models; Animals; Aphakia - metabolism; Behavioral neuroscience; Biological Sciences; Cells; Choline O-Acetyltransferase - metabolism; Cholinergic Fibers - metabolism; Cholinergic nerves; Cholinergics; Data processing; Disease Models, Animal; Dopamine; Dopamine - genetics; Dyskinesia; Dyskinesias - metabolism; Excitability; Extracellular signal-regulated kinase; Firing rate; Gene expression; Gene Expression Regulation; Homeodomain Proteins - genetics; Interneurons; Kinases; Lesions; Levodopa; Levodopa - metabolism; Mice; Mice, Transgenic; Movement disorders; Neostriatum; Neurodegenerative diseases; Neurons; Neurons - metabolism; Parkinson disease; Parkinson Disease - metabolism; Parkinson's disease; Phosphorylation; Proteins; Receptors; Rodents; Signal transduction; spiny neurons; Transcription Factors - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1006511108

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 kinase 1/2 (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.