Cognitive dysfunction plays an important role in mental disorders like schizophrenia, autism and ADHD, 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 behavioral pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia, childhood autism and ADHD.

In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 was characterised and quantified, in conjunction with currently used or potential antipsychotic agents (some of which have reported clinical effects on cognition). The video-tracking software EthoVision 1.95 was used for this purpose. After 30 minutes of drug pre-treatment, mice were individually introduced into a diffusely illuminated open field arena and videotaped from above for 30 minutes. The videotapes were then analysed using EthoVision. Variables calculated included: distance moved, number of stops, rearing frequency, spatial movements and variation in body area. Data were evaluated with Partial Least Square (PLS) Discriminant Analysis.

In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioral pattern, dominated by forward locomotion: spatial movements, switches between the moving and stationary states, and rearing frequency were all reduced compared to controls. Most test substances reduced MK-801-induced hyperactivity, but differed in their ability to restore behavioral diversity. A striking similarity in movement pattern was seen between hypoglutamatergic mice treated with the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor potentiator, CX516, and hypoglutamatergic mice receiving the 5HT2A-antagonist, M100907.

In both preclinical and clinical studies, CX516 has been observed to improve a number of cognitive functions: for instance, in schizophrenic patients, CX516 improved attention and memory. The similarity in movement pattern produced by the AMPA receptor potentiator CX516, with observed positive effects on cognition, and the 5HT2A-antagonist M100907, might indicate that 5HT2A-receptor blockade is beneficial for some aspects of cognitive functions. In line with this theory, the combined dopamine D2/5HT2A-antagonist risperidone has been reported to have favourable effects on working memory, executive functioning and attention in schizophrenia.

Paper presented at Measuring Behavior 2002 , 4^th International Conference on Methods and Techniques in Behavioral Research, 27-30 August 2002, Amsterdam, The Netherlands

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