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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.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2006 Apr; Vol. 69 (4), pp. 1366-72. Date of Electronic Publication: 2006 Jan 03. - Publication Year :
- 2006
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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.
- Subjects :
- Animals
Benzodiazepines pharmacology
Blotting, Western
Male
Olanzapine
Phosphorylation
Prefrontal Cortex enzymology
Rats
Rats, Sprague-Dawley
Subcellular Fractions enzymology
Antipsychotic Agents pharmacology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Prefrontal Cortex drug effects
Subcellular Fractions drug effects
Up-Regulation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 69
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 16391238
- Full Text :
- https://doi.org/10.1124/mol.105.019828