Proceedings of The Physiological Society
University of Manchester (2010) Proc Physiol Soc 19, C113
Analysis of dopamine and serotonin neurochemistry during 7-nitroindazole-evoked decrease in L-DOPA-induced dyskinesias
E. Del Bel1,2, F. E. Padovan-Neto1,2, R. Szawka1, F. S. Guimaraes2,1, C. A. da-Silva1, J. Anselmo-Franci1
1. Physiology, FORP-University of Sao Paulo, Ribeir?o Preto, Sao Paulo, Brazil. 2. Pharmacology, University of Sao Paulo-FMRP, Ribeirao Preto, Sao Paulo, Brazil.
Long-term use of L-3, 4-dihydroxyphenylalanine (L-DOPA) in Parkinsonian patients leads to side-effects such as dyskinesias or abnormal involuntary movements (AIMS). We described previously (Padovan-Neto et al., 2009) that nitric oxide synthase (NOS) inhibition is able to reduce L-DOPA-AIMS in experimental Parkinsonism. Because the mechanism of this effect is poorly understood, it is of interest to determine whether the NOS inhibitor, 7-nitroindazole (7NI), would affect striatal levels of catecholamines and indoleamines in 6-hydroxydopamine (6-OHDA)-lesioned rats with L-DOPA induced AIMs (6-OHDA administered stereotaxically under ketamine (100mg/kg)/xylazine (14mg/kg) anaesthesia (ip). Male Wistar rats (180-200gm) with unilateral 6-OHDA lesion of the medial forebrain bundle or sham animals (n=5-7/group) were treated chronically (21 days) with L-DOPA (30mg/kg, gavage) to induce AIMs. Comparisons were made between dyskinetic and sham (non-dyskinetic) L-DOPA-treated rats, receiving either saline or 7-NI (30mg/kg, ip). Striatal levels of dopamine (DA), DOPAC (DA metabolite), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA, a 5-HT metabolite) were measured by HPLC. As the nigrostriatal DA system has functional and neurochemical asymmetry, measurements were made separately in each brain side. In all 6-OHDA lesioned rats, L-DOPA induced AIMs were decreased by administration of 7-NI (P<0.05, n=6-7, ANOVA). Lesioned rats presented a decrease in striatal DA (side vs. lesion, F1,23=37.7 p<0.001) and an increase in DA turnover (DOPAC/DA, side vs. lesion, F1,23=5.71, p<0.025) in the lesioned side (LS). Similar effects were found with 5HT (side vs. lesion, 5HT, F1,23=51.1, p<0.001; 5HIAA/5HT, F1,23=13.2, p=0.001). Acute 7NI treatment also induced a further decrease in DA levels in the LS but an increase in the non-lesioned side (NLS, drug vs. side, F1,23=4.77, p<0.039). No drug effect was found on DA turnover. 7NI increased 5HT levels in the NLS but not in the LS (side vs. lesion, F1,23= 12.8, p=0.002) and decreased 5HT turnover on both sides (drug factor, F1,23=6.94, p<0.015. These results confirm that 7NI administration decrease L-DOPA induced AIMs. Dyskinetic animals show an increase in DA turnover (DOPAC/DA levels) which may help to maintain DA levels in the DA-depleted striatum accounting for part of the therapeutic benefit of L-DOPA. However, this may also be related to the dyskinesias induced by this drug. Interestingly, 7NI, a preferential inhibitor of neuronal nitric oxide synthase, was able to prevent both this turnover increase and attenuate the drug-induced dyskinesias. This effect could involve changes in DA availability in the lesioned side. Effects on the serotonin system may be the result of competitive L-DOPA uptake into serotonergic neuron terminals in preference to tryptophan.
Where applicable, experiments conform with Society ethical requirements