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Research ArticleArticle

Long-Term Exposure to the Atypical Antipsychotic Olanzapine Differently Up-Regulates Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylation in Subcellular Compartments of Rat Prefrontal Cortex

Fabio Fumagalli, Angelisa Frasca, Maria Spartà, Filippo Drago, Giorgio Racagni and Marco Andrea Riva
Molecular Pharmacology April 2006, 69 (4) 1366-1372; DOI: https://doi.org/10.1124/mol.105.019828
Fabio Fumagalli
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Angelisa Frasca
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Maria Spartà
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Filippo Drago
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Giorgio Racagni
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Marco Andrea Riva
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Abstract

Antipsychotics are the drugs of choice for the treatment of schizophrenia. Besides blocking monoamine receptors, these molecules affect intracellular signaling mechanisms, resulting in long-term synaptic alterations. Western blot analysis was used to investigate the effect of long-term administration (14 days) with the typical antipsychotic haloperidol and the atypical olanzapine on the expression and phosphorylation state of extracellular signal-related kinases (ERKs) 1 and 2 (ERK1/2), proteins involved in the regulation of multiple intracellular signaling cascades. A single injection of both drugs produced an overall decrease in ERK1/2 phosphorylation in different subcellular compartments. Conversely, long-term treatment with olanzapine, but not haloperidol, increased ERK1/2 phosphorylation in the prefrontal cortex in a compartment-specific and time-dependent fashion. In fact, ERK1/2 phosphorylation was elevated in the nuclear and cytosolic fractions 2 h after the last drug administration, whereas it was enhanced only in the membrane fraction when the animals were killed 24 h after the last injection. This effect might be the result of an activation of the mitogen-activated protein kinase pathway, because the phosphorylation of extracellular signal-regulated kinase kinase 1/2 was also increased by long-term olanzapine administration. Our data demonstrate that long-term exposure to olanzapine dynamically regulates ERK1/2 phosphorylation in different subcellular compartments, revealing a novel mechanism of action for this atypical agent and pointing to temporally separated locations of signaling events mediated by these kinases after long-term olanzapine administration.

  • Received October 12, 2005.
  • Accepted January 3, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (4)
Molecular Pharmacology
Vol. 69, Issue 4
1 Apr 2006
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Research ArticleArticle

Long-Term Exposure to the Atypical Antipsychotic Olanzapine Differently Up-Regulates Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylation in Subcellular Compartments of Rat Prefrontal Cortex

Fabio Fumagalli, Angelisa Frasca, Maria Spartà, Filippo Drago, Giorgio Racagni and Marco Andrea Riva
Molecular Pharmacology April 1, 2006, 69 (4) 1366-1372; DOI: https://doi.org/10.1124/mol.105.019828

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Research ArticleArticle

Long-Term Exposure to the Atypical Antipsychotic Olanzapine Differently Up-Regulates Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylation in Subcellular Compartments of Rat Prefrontal Cortex

Fabio Fumagalli, Angelisa Frasca, Maria Spartà, Filippo Drago, Giorgio Racagni and Marco Andrea Riva
Molecular Pharmacology April 1, 2006, 69 (4) 1366-1372; DOI: https://doi.org/10.1124/mol.105.019828
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