title: Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.
abstract: It is well known that nitric oxide (NO) interacts with dopamine (DA) within the striatal circuitry. The anti-dyskinetic properties of NO synthase (NOS) inhibitors demonstrate the importance of NO in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Here, we investigated the ability of a daily co-treatment of the preferential neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg), with L-DOPA (30 mg/kg) to counteract LID in unilaterally 6-OHDA-lesioned rats. We analyzed striatal nNOS-expressing interneurons, DA and 5-HT neurochemistry in the striatum and alterations of the Fos-B/ΔFosB expression in the corticostriatal, nigrostriatal and mesolimbic pathways. Prolonged administration of 7-NI inhibited the manifestation of chronic L-DOPA treatment-induced abnormal involuntary movements (AIMs). LID was associated with an up-regulation in the number of nNOS-expressing interneurons in the lateral but not medial striatum. nNOS inhibition reduced the number of nNOS-expressing interneurons. The anti-dyskinetic effects of 7-NI correlated with a reduction in DA and 5-HT turnover in the striatum. At postsynaptic striatal sites, 7-NI prevented L-DOPA-induced Fos-B/ΔFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/ΔFosB expression in nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive interneurons in the striatum. These results provide further evidence of the molecular mechanisms by which NOS-inhibiting compounds attenuate LID. The involvement of NO with DA and 5-HT neurochemistry may contribute to the understanding of this new, non-dopaminergic therapy for the management of LID.
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology, University of São Paulo, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; Department of Behavioral Neurosciences, Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: Fernando Eduardo
authors.initials: FE
authors.lastname: Padovan-Neto
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology, University of São Paulo, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cavalcanti-Kiwiatkoviski
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology, University of São Paulo, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; Department of Behavioral Neurosciences, Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Ruither Oliveira Gomes
authors.initials: RO
authors.lastname: Carolino
authors.affiliation: Department of Behavioral Neurosciences, Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil.
authors.forename: Janete
authors.initials: J
authors.lastname: Anselmo-Franci
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology, University of São Paulo, Av. Café S/N, 14040-904 Ribeirão Preto, SP, Brazil; Department of Behavioral Neurosciences, Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil. Electronic address: eadelbel@forp.usp.br.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del Bel
mesh_terms: D000818:Animals; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D007980:Levodopa; D016627:Oxidopamine; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole
keywords: 6-OHDA; Dopamine; Nitric oxide; Nitric oxide synthase inhibitors; Parkinson's disease; Serotonin; Turnover; l-DOPA-induced dyskinesia