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Early induction of CREB activation and CREB-regulating signalling by antidepressants

Daniela Tardito1, Laura Musazzi, Ettore Tiraboschi

  • 1Center of Neuropharmacology, Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Italy.

The International Journal of Neuropsychopharmacology
|April 30, 2009
PubMed

Insights

Antidepressant treatment rapidly activates cAMP response-element binding protein (CREB) in rat brains, with distinct temporal profiles in the hippocampus versus prefrontal cortex. This rapid activation suggests CREB signaling is an early mediator of antidepressant action.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Antidepressant efficacy is linked to neuroplasticity and gene expression changes.
  • Activation of cAMP response-element binding protein (CREB) and its signaling pathways are key mechanisms.
  • Understanding the temporal dynamics of these changes is crucial.

Purpose of the Study:

  • Investigate the time course of intracellular changes induced by antidepressants.
  • Examine the relationship between signaling cascade activation and CREB activation.
  • Determine if these changes vary across different brain regions.

Main Methods:

  • Rats were treated with fluoxetine or reboxetine for 1, 2, or 3 weeks, with some groups undergoing a 1-week washout.
  • Western blot analysis using phospho-antibodies measured CREB activation (Ser133 phosphorylation) and signaling cascade effectors.
  • Analysis was performed on nuclear and cytosolic fractions from the hippocampus and prefrontal/frontal cortex (P/FC).

Main Results:

  • CREB activation peaked rapidly, reaching maximum levels after only 1 week of antidepressant treatment.
  • In the hippocampus, early and robust CREB activation correlated with signaling cascade activation.
  • Distinct temporal activation patterns were observed in the P/FC compared to the hippocampus.
  • Nuclear alphaCaM kinase II was inactivated, contrasting with the activation of MAP-ERKs and CaM kinase IV, alongside CREB activation.

Conclusions:

  • Antidepressant-induced CREB activation occurs rapidly and is region-specific.
  • The findings highlight the complex temporal dynamics of molecular pathways mediating antidepressant effects.
  • Differential modulation of signaling molecules like alphaCaM kinase II suggests intricate regulatory mechanisms in antidepressant action.

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