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First published on February 4, 2008; DOI: 10.1124/mol.107.043786

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Received for publication November 26, 2007.
Revised February 4, 2008.
Accepted for publication February 4, 2008.

Dynamic regulation of glutamatergic post-synaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs

Fabio Fumagalli 1, Angelisa Frasca 1, Giorgio Racagni 1, Marco Andrea Riva 1*

1 University of Milan

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

Abstract

Antipsychotics are the mainstay for the treatment of schizophrenia. Although these drugs act at several neurotransmitter receptors, they are expected to elicit different neuroadaptive changes at structures relevant for schizophrenia. Since glutamatergic dysfunction plays a role in the pathophysiology of schizophrenia, we focused our analysis on glutamatergic neurotransmission following repeated treatment with antipsychotic drugs. Rats were exposed to a 2 week pharmacological treatment with the first generation antipsychotic haloperidol and the second generation antipsychotic olanzapine. By using western blot and immunoprecipitation techniques, we investigated the expression, trafficking and interaction of essential components of glutamatergic synapse in rat prefrontal cortex. Prolonged treatment with haloperidol, but not olanzapine, dynamically affects glutamatergic synapse by selectively reducing the synaptic level of the obligatory NMDA subunit NR1, the regulatory NMDA subunit NR2A and its scaffolding protein PSD95 as well as the trafficking of GluR1 to the membrane. Additionally, haloperidol alters total as well as phosphorylated levels of CaMKII at synaptic sites and its interaction with regulatory NMDA subunit NR2B. Our data suggest that the glutamatergic synapse is a vulnerable target for prolonged haloperidol treatment. The global attenuation of glutamatergic function in prefrontal cortex might explain, at least in part, the cognitive deterioration observed in haloperidol-treated patients.


Key words: Glutamate, Anti-psychotics, Synaptic plasticity


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