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The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high‐affinity dopamine D2 receptor partial agonist. Atypical antipsychotics, all of which have dopamine D2 receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)‐γ‐induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti‐inflammatory effect on IFN‐γ‐induced microglial activation. Not quinpirole, dopamine D2 full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)‐α from IFN‐γ‐activated microglia and suppressed the IFN‐γ‐induced elevation of intracellular Ca2+ concentrations ([Ca2+]i) in murine microglial cells. Increased [Ca2+]i has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN‐γ‐induced microglial activation through the suppression of IFN‐γ‐induced elevation of [Ca2+]i in microglia. Our results demonstrated that not only antipsychotics which have dopamine D2 receptor antagonism but also aripiprazole have anti‐inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions.

Schizophrenia is one of the most severe psychiatric diseases noted for its chronic and often debilitating processes; affecting approximately 1% of the world's population, while its etiology and therapeutic strategies still remain elusive. In the 1950s, the discovery of antipsychotic effects of haloperidol and chlorpromazine shifted the paradigm of schizophrenia. These drugs proved to be antagonists of dopamine D2 receptor (D2R), thus dopamine system dysfunction came to be hypothesized in the pathophysiology of schizophrenia, and D2R antagonism against dopamine neurons has been considered as the primary therapeutic target for schizophrenia. In addition, abnormalities of glutamatergic neurons have been indicated in the pathophysiology of schizophrenia. On the other hand, recent neuroimaging studies have shown that not only dementia but also schizophrenic patients have a significant volume reduction of some specific regions in the brain, which indicates that schizophrenia may involve some neurodegenerative process. Microglia, major sources of various inflammatory cytokines and free radicals such as superoxide and nitric oxide (NO) in the CNS, play a crucial role in a variety of neurodegenerative diseases such as dementia. Recent postmortem and positron emission computed tomography (PET) studies have indicated that activated microglia may be present in schizophrenic patients. Recent in vitro studies have suggested the anti-inflammatory effects of antipsychotics on microglial activation. In this article, we review the anti-inflammatory effects of antipsychotics on microglia, and propose a novel therapeutic hypothesis of schizophrenia from the perspective of microglial modulation.

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Background: BDNF and Ca 2ϩ mobilization is important for microglial function. Results: We showed BDNF elevates intracellular Ca 2ϩ through TRPC3 channels. Conclusion: TRPC3 is important for BDNF suppression of microglial activation. Significance: TRPC3 might be important for the treatment of psychiatric disorders.