Loss of dopaminergic responsiveness in a double lesion rat model of the Parkinson variant of multiple system atrophy.

The Parkinson variant of multiple system atrophy (MSA-P) is a distinct atypical parkinsonian disorder with a loss of dopaminergic neurons comparable to that found in Parkinson's disease (PD). The additional loss of striatopallidal projections is thought to account for levodopa unresponsiveness in MSA-P. Whereas histological features of MSA-P have been successfully reproduced in the double lesion rat model, loss of levodopa responsiveness has so far not been demonstrated. In the current study, 6-hydroxydopamine (6-OHDA) induced Unilateral lesions of the substantia nigra produced a marked contralateral forelimb stepping deficit, which improved significantly after challenge with levodopa (P < 0.001). This response was abolished by the subsequent striatal quinolinic acid (QA) lesion. In the cylinder test, the marked asymmetry observed after 6-OHDA lesioning was reversed by levodopa to baseline levels. After QA, cylinder test performance under levodopa failed to reach baseline (P = 0.001) or 6-OHDA + levodopa (P = 0.002) levels. Nigral cell loss (90% +/- 5%) correlated with both stepping test (r = 0.608; P = 0.008) and cylinder test results (r = 0.656; P = 0.005). Lesion extent of the dorsal striatum correlated significantly with the loss of levodopa response (r = 0.593; P = 0.01) in the stepping test. These findings contribute further to the behavioral characterization of the double lesion rat model of MSA, improving its value in the evaluation of future neurorestorative strategies. (C) 2006 Movement Disorder Society.