title: 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.
authors.affiliation: Clinical Department of Neurology, Innsbruck Medical University, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Köllensperger
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D007839:Functional Laterality; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D019578:Multiple System Atrophy / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
chemical_list: D007980:Levodopa; D016627:Oxidopamine; D001058:Apomorphine