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
alpha-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.