Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice.
J Neurosci
; 34(8): 3090-4, 2014 Feb 19.
Article
en En
| MEDLINE
| ID: mdl-24553948
ABSTRACT
3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.
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Bases de datos:
MEDLINE
Asunto principal:
Sistema Nervioso Parasimpático
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Levodopa
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Neostriado
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Trastornos Parkinsonianos
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Discinesia Inducida por Medicamentos
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Antiparkinsonianos
Límite:
Animals
Idioma:
En
Revista:
J Neurosci
Año:
2014
Tipo del documento:
Article