Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression.

The antidepressant properties of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the competitive NMDA receptor antagonist, CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentonoic acid) and its (R)-enantiomer CGP 40116, were studied in a chronic mild stress model of depression. In this model, animals subjected to a variety of mild stressors for a prolonged period of time show a substantial decrease in the consumption of palatable sucrose solution (anhedonia). It was previously demonstrated that the chronic mild stress-induced anhedonia can be reversed by chronic treatment with various antidepressant drugs. In this study we found that the stress-induced deficit in sucrose intake was gradually reversed by chronic (4-5 weeks) treatment with MK-801 (0.3 mg/kg i.p.), CGP 37849 (5 mg/kg i.p.) and CGP (25 mg/kg p.o.). The magnitude of this effect and its time course were comparable to those observed following similar administration of imipramine (10 mg/kg i.p. or p.o.). The increase in sucrose intake following chronic administration of imipramine and NMDA receptor antagonists was specific to stressed animals; the behaviour of non-stressed controls was unchanged by any of the drugs tested. These results confirm those of previous studies, carried out on 'normal' animals, suggesting that antagonists of NMDA receptors may have antidepressant properties.