A competitive antagonist of NMDA receptors CGP 40116 attenuates experimental symptoms of schizophrenia evoked by MK-801.

In the present study, the interaction between a noncompetitive [(+)-MK-801] and a competitive (CGP 40116) NMDA receptor antagonists was tested in two different behavioral paradigms: locomotor activity test and prepulse inhibition of the acoustic startle reflex. Additionally, their effects on working memory and selective attention were evaluated in the delayed alternation task. All above paradigms served to model the symptoms of schizophrenia. It was found that locomotor stimulatory effect of (+)-MK-801 (0.4 mg/kg) was antagonized by prior administration of CGP 40116 (5 mg/kg). Lower doses of CGP 40116 (1.25 and 2.5 mg/kg) were ineffective. CGP 40116 given alone did not influence locomotor activity in rats. It was also shown that CGP 40116 antagonized the disruption of the process of sensorimotor gating evoked by (+)-MK-801. On the contrary, both CGP 40116 and (+)-MK-801 increased a number of errors in the delayed alternation test revealing detrimental effect of CGP 40116 on spatial working memory and selective attention even at a lower dose than that required to antagonize the effects of (+)-MK-801. The presented results indicate that noncompetitive and competitive NMDA receptor antagonists, when used at relatively low doses, may produce qualitatively different behavioral effects, as evidenced by the experiments with locomotor activity and prepulse inhibition. Moreover, the competitive NMDA receptor antagonists may even inhibit some psychotomimetic effects related to the noncompetitive blockade of this receptor. However, therapeutic potential of CGP 40116, a competitive NMDA receptor antagonist, should be considered with caution since in the range of doses effective against the psychotomimetic effects of (+)-MK-801, it impairs rats' performance in the delayed alternation paradigm, i.e. it worsens efficacy of working memory.