title: Neuronal nitric oxide synthase inhibition attenuates the development of L-DOPA-induced dyskinesia in hemi-Parkinsonian rats.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ota
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use*; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D021122:Protein Subunits / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D007191:Indazoles; D007980:Levodopa; D019331:NG-Nitroarginine Methyl Ester; D009419:Nerve Tissue Proteins; D052248:Nitric Oxide Synthase Type I; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; C483820:Fosb protein, rat; C497930:Ppp1r1b protein, rat; C496322:Nos1 protein, rat; C080122:7-nitroindazole