RT Journal Article
SR Electronic
T1 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
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1366
OP 1372
DO 10.1124/mol.105.019828
VO 69
IS 4
A1 Fabio Fumagalli
A1 Angelisa Frasca
A1 Maria Spartà
A1 Filippo Drago
A1 Giorgio Racagni
A1 Marco Andrea Riva
YR 2006
UL http://molpharm.aspetjournals.org/content/69/4/1366.abstract
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.