Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy)

This study characterizes paw reaching, stepping and balance abnormalities i n a double lesion rat model of striatonigral degeneration, the core patholo gy underlying levodopa unresponsive parkinsonism associated with multiple s ystem atrophy. Extensive unilateral nigral or striatal lesions induced by 6 -hydroxydopamine or quinolinic acid, respectively, produced a similarly mar ked contralateral paw reaching deficit without further deterioration follow ing a secondary (complementary) lesion of ipsilateral striatum or substanti a nigra. Contralateral stepping rates were reduced by unilateral 6-hydroxyd opamine lesions without further deterioration following the secondary stria tal lesion. In contrast, initial unilateral striatal quinolinic acid inject ions induced bilateral stepping deficits that significantly worsened contra laterally following the secondary nigral lesion. Contralateral sidefalling rates were significantly increased following primary nigral and striatal le sions. Secondary nigral but not secondary striatal lesions worsened contral ateral sidefalling rates. Histological studies revealed subtotal (>90%) dep letion of dopaminergic neurons in substantia nigra pars compacta and variab le degrees of striatal degeneration depending on the lesion sequence. Anima ls pre lesioned with 6-hydroxydopamine showed significantly larger residual striatal surface areas following the secondary striatal quinolinic acid le sion compared to animals with primary striatal quinolinic acid lesions (P < 0.001). These findings are in line with previous experimental studies demo nstrating that striatal dopamine depletion confers neuroprotection against subsequent excitotoxic injury. Whether loss of dopaminergic neurons protect s against the striatal disease process occurring in multiple system atrophy (Parkinson-type) remains to be elucidated. In summary, this is the first experimental study to investigate spontaneous motor behaviour in a unilateral double lesion rat model. Our observations are consistent with a complex interaction of nigral and striatal lesions pr oducing distinct behavioural and histological changes depending on the lesi on sequence. Tests of forelimb akinesia and complex motor behaviour appear to provide a reliable tool that will be helpful for monitoring the effects of interventional strategies such as embryonic neuronal transplantation in the rat model of striatonigral degeneration. (C) 2000 IBRO. Published by El sevier Science Ltd. All rights reserved.