ADAPTATION OF THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX FOLLOWING CHRONIC ANTIDEPRESSANT TREATMENTS

Chronic (14 day) but not acute (1 day) treatment of mice with clinical ly active antidepressants produces a significant (similar to 1.8-4.3 f old) reduction in the potency of glycine to inhibit [H-3]-5,7-dichlork ynurenic acid (5,7-DCKA) binding to strychnine-insensitive glycine rec eptors in neocortical membranes. Moreover, these effects were not obse rved following chronic treatment with a variety of nonantidepressant d rugs such as D-deprenyl, chlorpromazine, salbutamol, scopolamine and c hlordiazepoxide. The time course and dose-response relationships for t his effect were examined after treatment with two representative antid epressant drugs (imipramine and citalopram) and electriconvulsive shoc k (ECS). Increases in the IC50 of glycine to inhibit [H-3]-5,7-DCKA bi nding were observed after treatment for 7 days with ECS, 10 days with citalopram and 14 days with imipramine, respectively, and were no long er apparent by the 10th day after cessation of treatment. These findin gs indicate that the antidepressant-induced reduction in the IC50 of g lycine to inhibit [H-3]-5,7-DCKA binding is: 1) a slowly developing, a daptive phenomenon; 2) remarkably persistent after cessation of treatm ent; and 3) a significantly better predictor of antidepressant activit y (22 of 23 drugs) than either beta adrenoceptor down-regulation (15 o f 23 drugs) or efficacy in the forced swim test (13 of 23 drugs) [P < .01 vs. each measure, Fisher's Exact Test]. The ability of antidepress ants drawn from every principal therapeutic class to effect adaptive c hanges in the N-methyl-D-aspartate receptor complex is consistent with the hypothesis that this ligand-gated ion channel serves as a final c ommon pathway of antidepressant action and indicates that glutamatergi c pathways may be involved in the pathophysiology of depression.