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The Journal of Neuroscience, January 15, 1999, 19(2):610-618

Chronic Antidepressant Administration Increases the Expression of cAMP-Specific Phosphodiesterase 4A and 4B Isoforms

Michihiro Takahashi¹, Rose Terwilliger¹, Caryl Lane³, Peter S. Mezes³, Marco Conti², and Ronald S. Duman¹

¹ Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut 06508, ² Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Center, Stanford, California 94305, and ³ Central Research Division, Pfizer Inc., Groton, Connecticut 06340

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity were significantly increased in rat frontal cortex by chronic administration of each of the four classes of antidepressants. We also found that antidepressant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and reward that could also contribute to the anhedonia often observed in depressed patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic administration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system. The possibility that targeted inhibition of these PDE4 subtypes may produce an antidepressant effect is discussed.

Key words: phosphodiesterase; frontal cortex; nucleus accumbens; sertraline; desipramine; electroconvulsive seizure; serotonin; norepinephrine

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192610-09$05.00/0

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