Increased activity and expression of tyrosine hydroxylase in the rat substantia nigra after chronic treatment with nomifensine.

We have studied the effect of chronic treatment with nomifensine on dopaminergic functioning in the nigrostriatal system. The striatal dopaminergic system was not altered by chronic nomifensine treatment. In contrast, there were overall decreases of different dopamine (DA) metabolites in the cell body region in the substantia nigra after nomifensine treatment, which clearly indicates a diminished DA turnover. These results suggest that long-lasting inhibition of the high affinity DA uptake system triggers long term regulatory, compensatory mechanisms in the cell body region to preserve normal dopaminergic function in the terminal field in striatum. We also tested whether transcriptional regulatory mechanisms were altered. We studied the cellular expression of tyrosine hydroxylase (TH) mRNA in substantia nigra by in situ hybridization, and the amount and activity of TH enzyme in the cell body and terminal field regions. Our results indicate that nomifensine treatment increased TH mRNA levels within individual nigral cells, which paralleled the changes in TH enzyme amount and activity in this brain area. Our data confirm the important role of the high affinity DA uptake system in regulating dopaminergic transmission in the nigrostriatal system.