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First published on January 3, 2006; DOI: 10.1124/mol.105.019828

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Received for publication October 12, 2005.
Revised December 22, 2005.
Accepted for publication January 3, 2006.

Chronic exposure to the atypical antipsychotic olanzapine differently up-regulates ERK 1/2 phosphorylation in subcellular compartments of rat prefrontal cortex

Fabio Fumagalli 1, Angelisa Frasca 2, Maria Sparta 3, Filippo Drago 3, Giorgio Racagni 4, Marco Andrea Riva 1*

1 Center of Neuropharmacology, Department of Pharmacological Sciences University of Milan 2 IRCCS, San Giovanni di Dio-Fatebenefratelli, Brescia, Italy 3 Department of Experimental and Clinical Pharmacology, University of Catania, Italy 4 Dept. Pharm. Sciences Univ. Milan, Italy; IRCCS, San Giovanni di Dio-Fatebenefratelli, Brescia, IT

* Address correspondence to: E-mail: m.riva{at}unimi.it

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 employed to investigate the effect of chronic administration (14 days) with the typical antipsychotic haloperidol and the atypical olanzapine on the expression and phosphorylation state of ERK1 and ERK2, proteins involved in the regulation of multiple intracellular signaling cascades. A single injection of both drugs produced an overall decrease in ERK 1/2 phosphorylation, in different subcellular compartments. Conversely chronic treatment with olanzapine, but not haloperidol, increased ERK 1/2 phosphorylation in the prefrontal cortex, in a compartment-specific and time-dependent fashion. In fact, ERK 1/2 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 sacrificed 24 h following the last injection. This effect might be the result of an activation of the MAP kinase pathway, since the phosphorylation of MEK 1/2 was also increased by chronic olanzapine. Our data demonstrate that chronic olanzapine exposure 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 following chronic olanzapine administration.


Key words: MAP Kinase, Anti-psychotics, Synaptic plasticity


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