Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex

Background: Mounting evidence indicates that long-term treatment with antip sychotic medications can alter the morphology and connectivity of cellular processes in the cerebral cortex. The cytoskeleton plays an essential role in the maintenance of cellular morphology and is subject to regulation by i ntracellular pathways associated with neurotransmitter receptors targeted b y antipsychotic drugs, Methods: We have examined whether chronic treatment with the antipsychotic drug haloperidol interferes with phosphorylation state and tissue levels of a major dendritic cytoskeleton-stabilizing agent, microtubule-associated p rotein 2 (MAP2), as well as levels of the dendritic spine-associated protei n spinophilin and the synaptic vesicle-associated protein synaptophysin in various regions of the cerebral cortex of rhesus monkeys. Results: Among the cortical areas examined, the prefrontal, orbital, cingul ate, motor, and entorhinal cortices displayed significant decreases in leve ls of spinophilin, and with the exception of the motor cortex, each of thes e regions also exhibited increases in the phosphorylation of MAP2. No chang es were observed in either spinophilin levels or MAP2 phosphorylation in th e primary visual cortex. Also, no statistically significant changes were fo und in tissue levels of MAP2 or synaptophysin in any of the cortical region s examined Conclusions: Our findings demonstrate that long-term haloperidol exposure a lters neuronal cytoskeleton- and spine-associated proteins, particularly in dopamine-rich regions of the primate cerebral cortex, many of which have b een implicated in the psychopathology of schizophrenia. The ability of halo peridol to regulate cytoskeletal proteins should be considered in evaluatin g the mechanisms of both its palliative actions and its side effects. Biol Psychiatry 2001;49:1-12 (C) 2001 Society of Biological Psychiatry.