What value do NMDA receptor antagonist models of schizophrenia have for novel drug discovery?

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine can induce schizophrenic features in healthy volunteers and exacerbate the symptoms in schizophrenic patients. Furthermore, the administration of NMDA receptor antagonists to rodents produces hyperlocomotion. The ability of drugs to attenuate this hyperlocomotion correlates with clinical efficacy on positive symptoms. Similarly, social withdrawal is taken as a surrogate of unsociability in schizophrenia. Furthermore, first episode psychosis and chronic schizophrenia can be modeled by acute and subchronic administration of NMDA receptor blockers, respectively. Therefore, the NMDA hypofunction model provides a powerful tool to develop new therapeutic strategies in drug discovery to treat schizophrenia.

This perspective describes the similitudes between schizophrenia in humans and the traits demonstrated by rodent models based upon the hypofunction of NMDA receptors. Comparisons are made in terms of behavioral, neurochemical, neuroimaging and neurophysiological studies. Different therapeutic responses are also discussed.

Both schizophrenic patients and developed rodent models exhibit many similitudes such as decreased expression of NMDA receptors, enhanced dopaminergic and serotonergic transmission as well as altered gamma oscillations and deficits in cognitive paradigms. The NMDA receptor antagonism model can thus represent an excellent strategy to study the neurobiological underpinnings of schizophrenia and the potential therapeutic role of new antipsychotic drugs.