Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats

Author(s)

Padovan-Neto, Fernando Eduardo ^{[1, 2, 3]} ; Cavalcanti-Kiwiatkoviski, Roberta ^[1] ; Gomes Carolino, Ruither Oliveira ^{[1, 2]} ; Anselmo-Franci, Janete ^[2] ; Del Bel, Elaine ^{[1, 2, 3]}

Affiliation

^[1] Univ Sao Paulo, Sch Odontol, Dept Morphol Physiol & Pathol, BR-14040904 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Sch Med, Dept Behav Neurosci, BR-14040904 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, BR-14040904 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Neuropharmacology; v. 89, p. 87-99, FEB 2015.
• Web of Science Citations: 18

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/AFosB 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/AFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/AFosB 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. (C) 2014 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 09/08181-9 - Basal ganglia neuroplasticity: role of nitric oxide on Parkinsons Disease and L-Dopa-induced dyskinesias
• Grantee: Fernando Eduardo Padovan Neto
• Support Opportunities: Scholarships in Brazil - Doctorate