Abstract
NMDA antagonists mimic the effects of clinically effective antidepressants in both
preclinical tests predictive of antidepressant action and procedures designed to model
aspects of depressive symptomatology. These findings led to experiments demonstrating
that chronic administration of NMDA antagonists to rodents results in a downregulation
of cortical β-adrenoceptors, a phenomenon also observed following chronic treatment
with many antidepressants. These neurochemical and behavioral similarities between
antidepressants and NMDA antagonists prompted us to examine the impact of chronic
antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day)
administration of seventeen different antidepressants to mice produced adaptive changes
in radioligand binding to NMDA receptors. Detailed studies with three antidepressants
(imipramine, citalopram, and electroconvulsive shock) show that these changes develop
slowly, persist for some time after cessation of treatment, and (for imipramine and
citalopram) are dose dependent. Moreover, following chronic treatment with imipramine,
these changes in radioligand binding to NMDA receptors appear restricted to the cerebral
cortex. Based on the consistency of these effects across antidepressant treatments,
we propose that adaptive changes in NMDA receptors may be the final common pathway
for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand
binding to NMDA receptors is altered in frontal cortex of suicide victims (compared
to age and post-mortem interval matched controls) is consistent with the hypothesis
(Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved
in the pathophysiology of depression.
