ADAPTIVE-CHANGES IN THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX AFTER CHRONIC TREATMENT WITH IMIPRAMINE AND 1-AMINOCYCLOPROPANECARBOXYLIC ACID

Chronic (14 daily injections) treatment of mice with the prototypic tr icyclic antidepressant imipramine significantly alters ligand binding to the N-methyl-D-aspartate (NMDA) receptor complex. These effects wer e compared to a chronic regimen of 1-amino-cyclopropanecarboxylic acid , a high-affinity partial agonist at strychnine-insensitive glycine re ceptors which mimics the effects of imipramine in preclinical models p redictive of antidepressant action. Changes in the NMDA receptor compl ex after chronic, but not acute treatment with imipramine were manifes ted as: 1) a reduction in the potency of glycine to inhibit [H-3]5,7-d ichlorokynurenic acid binding to strychnine-insensitive glycine recept ors; 2) a decrease in the proportion of high-affinity glycine sites in hibiting [H-3]CGP 39653 binding to NMDA receptors; and 3) a decrease i n basal [H-3]MK-801 binding (under nonequilibrium conditions) to sites within NMDA receptor-coupled cation channels which was reversible by the addition of glutamate. These effects were observed in cerebral cor tex, but not in hippocampus, striatum or basal forebrain. Chronic trea tment with 1-aminocyclopropanecarboxylic acid resulted in changes whic h parallelled those of imipramine on ligand binding to the NMDA recept or complex, but the reduction in basal [H-3]MK-801 binding did not ach ieve statistical significance. These findings indicate that adaptive c hanges in the NMDA receptor complex could be a feature common to chron ic treatment with structurally unrelated antidepressants.