A 'single toxin-double lesion' rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis.

Previous attempts to reproduce striatonigral degeneration, the core pathology underlying Parkinsonism in multiple system atrophy, have been impeded by interactions in the neurotoxins used to replicate striatal and nigral degeneration in rodents. To overcome these interactions, we have developed a new model of striatonigral degeneration which uses a single unilateral administration of 1-methyl-4-phenylpyridinium ion (MPP(+)) into the rat striatum. Spontaneous and drug-induced rotational behaviour, thigmotactic scanning, stepping adjusting steps and paw reaching deficits were compared in four groups of animals: group 1 (control), group 2 (20 microg quinolinic acid), group 3 (20 microg 6-hydroxydopamine), and group 4 (90 nmol MPP(+)). MPP(+) administration resulted in the absence of the amphetamine-induced ipsilateral bias observed in the 6-hydroxydopamine group and of the apomorphine-induced ipsilateral bias observed in the quinolinic acid group. There was no thigmotactic scanning asymmetry in the MPP(+)-injected rats compared to the quinolinic acid- and the 6-hydroxydopamine-injected rats. MPP(+) elicited a bilateral stepping adjustment deficit similar to that found in the quinolinic acid group when compared to controls. MPP(+) also elicited a more severe and significant contralateral deficit in paw reaching compared to controls, 6-hydroxydopamine and quinolinic acid groups. Histopathology revealed a significant reduction of the lesioned striatal surface (-47.53%) with neuronal loss and increased astrogliosis in the MPP(+) group grossly similar to that found in the quinolinic acid group. Contrary to the latter group, however, loss of intrastriatal and striatal-crossing fibre bundles was observed in the MPP(+) group as there was also some retrograde degeneration in the ipsilateral thalamic parafascicular nucleus. The mean loss of dopaminergic cells in the ipsilateral substantia nigra pars compacta in MPP(+) rats was less marked (-48.8%) than in the 6-hydroxydopamine rats (-63.6%) and was not significant in quinolinic acid rats (-5.2%). This study shows that a single unilateral intrastriatal administration of MPP(+) induces a unique motor behaviour resulting from both nigral and striatal degeneration, but also from possible extrastriatal damage. This 'single toxin-double lesion' paradigm may thus serve as a rat model of striatonigral degeneration.