Lippincott's Illustrated Reviews: Biochemistry

Despite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge.We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as Bdnf, Arc and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of Bdnf expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization.Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology.