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 do paminergic functioning in the nigrostriatal system. The striatal dopam inergic system was not altered by chronic nomifensine treatment. In co ntrast, there were overall decreases of different dopamine (DA) metabo lites in the cell body region in the substantia nigra after nomifensin e treatment, which clearly indicates a diminished DA turnover. These r esults suggest that long-lasting inhibition of the high affinity DA up take system triggers long term regulatory, compensatory mechanisms in the cell body region to preserve normal dopaminergic function in the t erminal field in striatum, We also tested whether transcriptional regu latory mechanisms were altered, We studied the cellular expression of tyrosine hydroxylase (TH) mRNA in substantia nigra by in situ hybridiz ation, and the amount and activity of TH enzyme in the cell body and t erminal field regions. Our results indicate that nomifensine treatment increased TH mRNA levels within individual nigral cells, which parall eled the changes in TH enzyme amount and activity in this brain area, Our data confirm the important role of the high affinity DA uptake sys tem in regulating dopaminergic transmission in the nigrostriatal syste m.