CHRONIC IMIPRAMINE ADMINISTRATION ALTERS THE ACTIVITY AND PHOSPHORYLATION STATE OF TYROSINE-HYDROXYLASE IN DOPAMINERGIC REGIONS OF RAT-BRAIN

In the present study the influence of imipramine, a tricyclic antidepr essant, on the expression and function of tyrosine hydroxylase (TH) in dopaminergic vat brain regions was examined. Chronic administration o f imipramine (18 days) decreased levels of TH enzyme activity in ventr al tegmental area (VTA) and substantia nigra (SN), dopaminergic cell b ody regions, as well as in caudate-putamen (CP), nucleus accumbens (AC E), prefrontal cortex (PFC), and olfactory tubercle (OT), dopaminergic terminal fields. These effects were dependent on chronic drug treatme nt, as imipramine administration for 1 or 7 days did not significantly influence levels of TH activity in either SN or VTA. In contrast to d rug regulation of enzyme activity, chronic imipramine treatment did no t decrease levels of TH immunoreactivity in any of the dopaminergic ce ll body or terminal field regions studied, although levels of TH immun oreactivity were decreased in locus coeruleus (LC) as previously repor ted. However, imipramine treatment increased levels of TH back phospho rylation in VTA, suggesting that the antidepressant-induced decrease i n levels of TH activity is a result of decreased phosphorylation of th e enzyme. These results demonstrate that imipramine treatment regulate s levels of TH enzyme activity in dopaminergic brain regions, and may account for some of the previously observed effects of these drugs on dopaminergic function. Finally, imipramine regulation of TH enzyme act ivity in VTA and immunoreactivity in LC was observed in Sprague Dawley , but not Wistar rats, demonstrating that different vat strains exhibi t different biochemical responses to antidepressant treatment.