Role of Prefrontal Cortex in Pharmacological Models of Schizophrenia and Antipsychotic Action the European Journal of Psychiatry

NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models due to their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Likewise, 5-HT2A receptor agonists display hallucinogen actions resembling psychotic symptoms. Overall, these drugs are useful models of schizophrenia for the screening of new antipsychotic drugs. However, the cellular and network elements involved in these actions are poorly known. Data obtained by several groups in recent years indicate that the prefrontal cortex (PFC) and anatomically related areas play a major role in these actions. This paper summarizes data obtained by the authors supporting that a) NMDA-R antagonists (phencyclidine –PCP–, dizocilpine –MK–801–) and 5-HT2A agonists (DOI) alter the function of PFC in a similar fashion, and b) antipsychotic drugs exert their therapeutic action, at least in part, by normalizing hyperactivity states in PFC. While the actions of NMDA-R antagonists may involve blockade of these receptors in PFC and subcortical areas, that of antipsychotic drugs, in particular atypical drugs like clozapine, appear to be mediated essentially by a local action in PFC. These results help to better understand the neurobiological basis of the action of pharmacological models of schizophrenia and the mode of action of antipsychotic drugs. Received 15 May 2009 Revised 28 May 2009 Accepted 28 May 2009