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

I Ghorayeb, P.O Fernagut, L Hervier, B Labattu, B Bioulac, F Tison
Neuroscience. 2002-12-01; 115(2): 533-546
DOI: 10.1016/s0306-4522(02)00401-3

Ghorayeb I(1), Fernagut PO, Hervier L, Labattu B, Bioulac B, Tison F.

Author information:
(1)Laboratoire de Neurophysiologie, CNRS-UMR 5543, Université Victor
Segalen-Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux Cedex, France.

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.