PT  - JOURNAL ARTICLE
AU  - Fabio Fumagalli
AU  - Angelisa Frasca
AU  - Maria Spartà
AU  - Filippo Drago
AU  - Giorgio Racagni
AU  - Marco Andrea Riva
TI  - 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
AID  - 10.1124/mol.105.019828
DP  - 2006 Apr 01
TA  - Molecular Pharmacology
PG  - 1366--1372
VI  - 69
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/69/4/1366.short
4100  - http://molpharm.aspetjournals.org/content/69/4/1366.full
SO  - Mol Pharmacol2006 Apr 01; 69
AB  - 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.