Most cases of Parkinson's disease (PD) are sporadic, suggesting an environmental influence on individuals affected by this neurodegenerative disorder. Environmental stresses often lead to changes in the regulation of splicing of pre-mRNA transcripts and this may lead to the pathogenesis of the disease. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model was used to examine the changes in the splicing of the fosB and rgs9 transcripts. The ratio of DeltafosB/fosB transcript was decreased in the substantia nigra and unchanged in the striatum after acute MPTP treatment. The DeltafosB/fosB transcript ratio decreased initially and then increased in the striatum of chronically MPTP-treated animals due to different degrees of reduction for the splice variants over time, whereas the ratio was unchanged in the substantia nigra. The ratio of rgs9-2/rgs9-1 transcript decreased in the substantia nigra of mice after acute MPTP treatment and increased temporarily in the striatum after chronic MPTP treatment. There was an increase in the DeltaFosB/FosB and RGS9-2/RGS9-1 protein ratios 3 weeks and 3 days post-treatment, respectively, in chronically treated mice. The data indicate that the pattern of splice isoforms of fosB and rgs9 reflects the brain's immediate and long-term responses to the physiological stress associated with Parkinsonism.