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

Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia. Neuropharmacology. 2019 May 08;: Authors: Sonnenschein SF, Grace AA Abstract 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-naïve rats, whereas models with disease-relevant pathology and prior APD exposure may improve the predictive validity of preclinical rese...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research