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Dynamic Regulation of Glutamatergic Postsynaptic Activity in Rat Prefrontal Cortex by Repeated Administration of Antipsychotic Drugs

Center of Neuropharmacology, Department of Pharmacological Sciences University of Milan, Milan, Italy (F.F., A.F., G.R., M.A.R.); and Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni di Dio-Fatebenefratelli, Brescia, Italy (G.P.)

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. Because glutamatergic dysfunction plays a role in the pathophysiology of schizophrenia, we focused our analysis on glutamatergic neurotransmission after 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 N-methyl-D-aspartate (NMDA) subunit NR1, the regulatory NMDA subunit NR2A, and its scaffolding protein postsynaptic density 95 as well as the trafficking of subunit 1 of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor to the membrane. In addition, haloperidol alters total as well as phosphorylated levels of calcium calmodulin kinase type II at synaptic sites and its interaction with the 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 patients treated with haloperidol.

Address correspondence to: M.A. Riva, Center of Neuropharmacology, Department of Pharmacological Sciences, Via Balzaretti 9, 20133 Milan, Italy. E-mail: m.riva{at}unimi.it

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