ANTIDEPRESSANT ACTIVITY OF NONCOMPETITIVE AND COMPETITIVE NMDA RECEPTOR ANTAGONISTS IN A CHRONIC MILD STRESS MODEL OF DEPRESSION

The antidepressant properties of the non-competitive NMDA receptor ant agonist, MK-801 (dizocilpine), and the competitive NMDA receptor antag onist, 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 str ess model of depression. In this model animals subjected to a variety of mild stressors for a prolonged period of time show a substantial de crease in the consumption of palatable sucrose solution (anhedonia). I t was previously demonstrated that the chronic mild stress-induced anh edonia can be reversed by chronic treatment with various antidepressan t drugs. In this study we found that the stress-induced deficit in suc rose intake was gradually reversed by chronic (4-5 weeks) treatment wi th 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 comparab le to those observed following similar administration of imipramine (1 0 mg/kg i.p. or p.o.). The increase in sucrose intake following chroni c administration of imipramine and NMDA receptor antagonists was speci fic to stressed animals; the behaviour of non-stressed controls was un changed by any of the drugs tested. These results confirm those of pre vious studies, carried out on 'normal' animals, suggesting that antago nists of NMDA receptors may have antidepressant properties.