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

Abstract

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.