Get access

Chronic Antidepressant Administration Alters the Subcellular Distribution of Cyclic AMP-Dependent Protein Kinase in Rat Frontal Cortex

Authors

  • Eric J. Nestler,

    1. Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut, U.S.A.
    Search for more papers by this author
  • Rose Z. Terwilliger,

    1. Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut, U.S.A.
    Search for more papers by this author
  • Ronald S. Duman

    Corresponding author
    1. Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut, U.S.A.
    Search for more papers by this author

Address correspondence and reprint requests to Dr. R. S. Duman at Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, U.S.A.

Abstract

Abstract: The influence of chronic administration of antidepressants on cyclic AMP-dependent protein kinase activity was examined in rat frontal cortex. Chronic administration of imipramine, tranylcypromine, or electroconvulsive seizures decreased cyclic AMP-dependent protein kinase activity in soluble fractions by ∼25%, whereas enzyme activity was increased in the particulate fractions by ∼20%. In contrast, enzyme activity in crude homogenates was not altered. This effect appears to be specific to antidepressant jdrugs, because representatives of several other classes of psychotropic drugs—namely, haloperidol, morphine, and diazepam—failed to alter either soluble or particulate levels of cyclic AMP-dependent protein kinase activity in this brain region following chronic administration. When the total particulate fraction was subfractionated, it was found that chronic imipramine treatment significantly increased the activity of cyclic AMP-dependent protein kinase in crude nuclear fractions but not in crude synaptosomal or microsomal fractions. Taken together, the data raise the possibility that chronic antidepressant treatments may stimulate the translocation of cyclic AMP-dependent protein kinase from the cytosol to the nucleus. This effect would represent a novel action of antidepressants that could contribute to the long-term adaptive changes in brain thought to be essential for the blinical actions of these treatments.

Ancillary