title: Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice.
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.
authors.affiliation: Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yunmin
authors.initials: Y
authors.lastname: Ding
authors.forename: Lisa
authors.initials: L
authors.lastname: Won
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Britt
authors.forename: Sean Austin O
authors.initials: SA
authors.lastname: Lim
authors.forename: Daniel S
authors.initials: DS
authors.lastname: McGehee
authors.forename: Un Jung
authors.initials: UJ
authors.lastname: Kang
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001035:Aphakia / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics; D020820:Dyskinesias / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D007980:Levodopa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018398:Homeodomain Proteins; C424127:SL 327; D014157:Transcription Factors; C433629:homeobox protein PITX3; D000607:Aminoacetonitrile; D007980:Levodopa; D002795:Choline O-Acetyltransferase; D004298:Dopamine