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Related Experiment Videos

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

D H Manier1, R C Shelton, F Sulser

  • 1Department of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-2647, USA.

Journal of Neural Transmission (Vienna, Austria : 1996)
|January 17, 2002
PubMed
Summary

Chronic antidepressant use desensitizes beta-adrenoceptor signaling. This study found that noradrenergic antidepressants like desipramine reduce nuclear CREB-P in rat brains and human cells, suggesting a broader impact on the norepinephrine pathway in depression.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Chronic noradrenergic antidepressant administration desensitizes beta-adrenoceptor coupled adenylate cyclase.
  • The impact of this desensitization on downstream signaling pathways remains incompletely understood.

Purpose of the Study:

  • To investigate whether the desensitization of the beta-adrenoceptor system by noradrenergic antidepressants affects downstream signaling.
  • To determine the effect of chronic desipramine (DMI) and reboxetine administration on nuclear CREB-phosphorylation (CREB-P) in rat frontal cortex and human fibroblasts.

Main Methods:

  • Determined nuclear CREB-P levels in rat frontal cortex after acute and chronic administration of desipramine (DMI) or reboxetine.
  • Assessed nuclear CREB-P in human fibroblasts after 48-hour incubation with DMI, reboxetine, or venlafaxine.

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Main Results:

  • Chronic DMI or reboxetine administration significantly decreased nuclear CREB-P in rat frontal cortex.
  • Incubation of human fibroblasts with DMI or reboxetine, but not venlafaxine, significantly reduced nuclear CREB-P.
  • These findings suggest noradrenergic antidepressants have direct effects beyond beta-adrenoceptors.

Conclusions:

  • Chronic antidepressant treatment leads to a net deamplification of the norepinephrine-mediated signal transduction cascade.
  • This deamplification may contribute to normalizing increased noradrenergic activity observed in major depression.