Differential effects of classical neuroleptics and a newer generation antipsychotics on the MK-801 induced...

Cognitive dysfunction plays an important role in mental disorders like schizophrenia and may involve inadequate glutamatergic signalling in different regions of the brain, mediated by e.g. glutamatergic N-methyl-D-aspartate (NMDA) receptors. In rodents, NMDA receptor antagonists often increase motor activity; in addition they induce a more primitive and undifferentiated behavioural pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia. In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 in conjunction with six antipsychotic agents, some with reported clinical effects on cognition, was characterised and quantified. The classical neuroleptic drugs chlorpromazine and trifluoperazine, the atypical antipsychotic agents ziprasidone and olanzapine, the gamma-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor potentiator CX516 and the serotonin (5-HT)2A-antagonist M100907 were tested. In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioural pattern dominated by forward locomotion; spatial movements, the number of switches between the states moving and stationary, and rearing frequency were reduced. All test substances counteracted MK-801-induced hyperactivity, but differed in their ability to improve behavioural quality. Chlorpromazine and trifluoperazine were unable to restore behavioural diversity while ziprasidone, olanzapine, CX516 and M100907 restored it to varying degrees. A striking similarity in movement pattern was seen between the hypoglutamatergic mice treated with the AMPA-receptor agonist CX516, and those receiving the 5HT2A-antagonist M100907.