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Neuropsychopharmacology (1995) 12 113-121.
Chronic Imipramine Administration Alters the Activity and Phosphorylation State of Tyrosine Hydroxylase in Dopaminergic Regions of Rat Brain
Diane L Rosin Ph.D, Kate Melia Ph.D, Amy M Knorr Ph.D, Eric J Nestler MD, Robert H Roth Ph.D and Ronald S Duman Ph.D |
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Departments of Pharmocology and Psychiatry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510
Departments of Pharmocology and Psychiatry and Laboratory of Molecular Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, 34 Park Street, New Haven, Connecticut
Correspondence: Dr Ronald S Duman, Departments of Psychiatry, Yale University School of Medicine, 34 park street, New Haven, CT, 06508
Department of Pharmacology, University of Virginia School of Medicine, 1300 Jefferson Park Avenue, Charlottesville, VA 22908.
Department of Psychiatry, Millhauser Laboratories, New York University, 550 First Avenue, New York, NY 10016.
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ABSTRACT
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In the present study the influence of imipramine, a tricyclic antidepressant, on the expression and function of tyrosine hydroxylase (TH) in dopaminergic rat brain regions was examined. Chronic administration of imipramine (18 days) decreased levels of TH enzyme activity in ventral tegmental area (VTA) and substantia nigra (SN), dopaminergic cell body regions, as well as in caudate-putamen (CP), nucleus accumbens (ACB), prefrontal cortex (PFC), and olfactory tubercle (OT), dopaminergic terminal fields. These effects were dependent on chronic drug treatment, as imipramine administration for 1 or 7 days did not significantly influence levels of TH activity in either SN or VTA. In contrast to drug regulation of enzyme activity, chronic imipramine treatment did not decrease levels of TH immunoreactivity in any of the dopaminergic cell body or terminal field regions studied, although levels of TH immunoreactivity were decreased in locus coeruleus (LC) as previously reported. However, imipramine treatment increased levels of TH back phosphorylation in VTA, suggesting that the antidepressant-induced decrease in levels of TH activity is a result of decreased phosphorylation of the enzyme. These results demonstrate that imipramine treatment regulates 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 activity in VTA and immunoreactivity in LC was observed in Sprague Dawley, but not Wistar rats, demonstrating that different rat strains exhibit different biochemical responses to antidepressant treatment.
Keywords: DA, dopamine; TH, tyrosine hydroxylase; LC, locus coeruleus; SN, substantia nigra; VTA, ventral tegmental area; CP, caudate-putamen; PFC, medical prefrontal cortex; OT, olfactory tubercles; ACB, nucleus accumbens |
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