Abstract

The vast preclinical literature indicates an anti-anxiety like profile of action of both competitive and non-competitive NMDA receptor complex antagonists. To clarify further the role of NMDA-related mechanisms in emotional control, it was of special interest to compare the effects of intraperitoneally injected different NMDA antagonists with diazepam, in two animal models of anxiety: the open field exploratory behaviour and the Vogel conflict test. Next, the results of repeated administration of diazepam, (+)-MK-801 (non-competitive NMDA antagonist) and CGP-37849 (competitive NMDA antagonist) were evaluated and compared with modifications in monoamine levels, in the striatum and limbic forebrain. The role of limbic structures i.e., the hippocampus and nucleus accumbens septi in the anxiolytic-like effects of (+)-MK-801 and AP7 (competitive NMDA antagonist) was also characterised. Overall, different NMDA antagonists appeared to showed an anxiolytic-like profile, similar to diazepam. Of all drugs examined, CGP-37849 seems to possess the best pharmacological profile and the largest distinction between the doses showing an anxiolytic-like action in the open field test, and changing rat motor behaviour. On repeated administration this drug not only retained its anxiolytic-like potency in the Vogel test, but even enhanced rat exploratory behaviour in a new environment. Nevertheless, positive clinical data need to support clear-cut preclinical results obtained with NMDA receptor complex antagonists.

Keywords: Anxiety, NMDA receptor complex antagonists, Diazepam, open field test, Vogel conflict test