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Neuronal nitric oxide synthase inhibition attenuates the development of l-DOPA-induced dyskinesia in hemi-Parkinsonian rats.
MedLine Citation:
PMID:  22449381     Owner:  NLM     Status:  Publisher    
Long-term treatment with the dopamine precursor levodopa (l-DOPA) frequently induces dyskinesia in Parkinson's disease patients, which is a major complication of this therapy. Previous studies using animal models show that repeated administration of l-DOPA results in alterations of some signaling molecules, including ΔFosB, phospho-DARPP32 and phosoho-GluA1 (also referred to as GluR1 or GluR-A) AMPA receptor subunits. Moreover, an in vivo microdialysis study showed that l-DOPA increases nitric oxide (NO) production in the striatum. However, it is not known whether NO is involved in the development of dyskinesia. The present study examined the effects of NOS inhibitors on the development of l-DOPA-induced dyskinesia in the rats. Dyskinesia symptoms were triggered by daily administration of l-DOPA for 3-4weeks in unilateral 6-hydroxydopamine lesioned rats. Repeated treatments, 30min prior l-DOPA administration, of the nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester, and the nNOS inhibitor 7-nitroindazole, but not the inducible NOS inhibitor aminoguanidine, attenuated the development of l-DOPA-induced dyskinesia. In agreement with the behavioral analysis, 7-nitroindazole reduced the l-DOPA-induced increases in ΔFosB, phospho-DARPP32 and phospho-GluA1 AMPA receptor subunit levels in the striatum of 6-hydroxydopamine-lesioned rats. Furthermore, aminoguanidine did not affect ΔFosB or phospho-GluA1 AMPA receptor subunit levels. These findings suggest that nNOS-derived NO is involved in the development of l-DOPA-induced dyskinesia through a post-synaptic mechanism.
Kazuhiro Takuma; Tatsunori Tanaka; Tsuyoshi Takahashi; Naoki Hiramatsu; Yuki Ota; Yukio Ago; Toshio Matsuda
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-16
Journal Detail:
Title:  European journal of pharmacology     Volume:  -     ISSN:  1879-0712     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier B.V.
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-871, Japan.
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