Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia

Current antipsychotic drugs (APDs) act on D2 receptors, and preclinical studies demonstrate that repeated D2 antagonist administration downregulates spontaneously active DA neurons by producing overexcitation-induced inactivation of firing (depolarization block). Animal models of schizophrenia based on the gestational MAM administration produces offspring with adult phenotypes consistent with schizophrenia, including ventral hippocampal hyperactivity and a DA neuron overactivity. The MAM model reveals that APDs act differently in a hyperdopamineregic system compared to a normal one, including rapid onset of depolarization block in response to acute D2 antagonist administration and downregulation of DA neuron population activity following acute and repeated D2 partial agonist administration, none of which are observed in normal rats. Novel target compounds have been developed based on the theory that glutamatergic dysfunction is central to schizophrenia pathology. Despite showing promise in preclinical research, none of the novel drugs succeeded in clinical trials. However, preclinical research is generally performed in normal, drug-naive rats, whereas models with disease-relevant pathology and prior APD exposure may improve the predictive validity of preclinical research. Indeed, in MAM rats, chronic D2 antagonist treatment leads to persistent DA supersensitivity that interferes with the response to drugs that target upstream pathology. Moreover, MAM rats revealed that the peri-pubertal period is a stress-sensitive window that can be targeted to prevent the development of MAM pathology in adulthood. Neurodevelopmental models, such as the MAM model, can thus be used to test potential pharmacotherapies that may be able to treat schizophrenia in early stages of the disease. This article is part of the issue entitled 'Special Issue on Antipsychotics'.