SPECIFIC LESIONS IN THE EXTRAPYRAMIDAL SYSTEM OF THE RAT-BRAIN INDUCED BY 3-NITROPROPIONIC ACID (3-NPA)

The irreversible mitochondrial toxin 3-nitropropionic acid (3-NPA) is a specific inhibitor of succinate dehydrogenase. We performed stereota xic unilateral injections of 3-NPA into the nigrostriatal dopaminergic pathway in rats in order to examine its specific effects on the dopam ine system. The 3-NPA-treated rats displayed unidirectional apomorphin e-induced rotations, suggesting that 3-NPA selectively damages dopamin ergic neurons when injected into the nigrostriatal pathway, In situ hy bridization 7 weeks postinjection indicated a decrease in tyrosine hyd roxylase (TH) mRNA to 30% of the noninjected side in the substantia ni gra pars compacta (P < 0.05) and decreased to 62% of the noninjected s ide in the ventral tegmental area (VTA) (nonsignificant) of 3-NPA-lesi oned rats. The number of TH mRNA positive cells showed statistically s ignificant decreases in substantia nigra and VTA (P < 0.001) within th e lesioned side, In contrast, expression of mRNAs encoding choline ace tyltransferase, p75 low-affinity NGF receptor, neurotrophin tyrosine k inase receptors Trk and TrkB, and brain-derived neurotrophic factor sh owed neuronal sparing in several other regions of the brain, The resul ts suggest that the nigrostriatal dopaminergic system might be selecti vely vulnerable to 3-NPA and demonstrate that it is possible to employ 3-NPA in a model of partial lesion of the nigrostriatal dopaminergic system resembling early stages of Parkinson's disease. (C) Academic Pr ess, Inc.