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Functional antagonists at the NMDA receptor complex exhibit antidepressant actions
1Laboratory of Neuroscience, National Institutes of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
European Journal of Pharmacology
|August 21, 1990
Summary
Inescapable stress impairs memory formation by affecting N-methyl-D-aspartate (NMDA) receptors. Antagonists of these NMDA receptors show antidepressant effects in animal models, suggesting a new therapeutic approach.
Area of Science:
- Neuroscience
- Psychopharmacology
- Behavioral Science
Background:
- Inescapable stress induces behavioral depression and impairs hippocampal Long Term Potentiation (LTP).
- LTP induction in the CA1 hippocampus is dependent on N-methyl-D-aspartate (NMDA) receptor activation.
- Clinically effective antidepressants alleviate stress-induced behavioral depression.
Purpose of the Study:
- To investigate the role of the NMDA receptor complex in stress-induced behavioral deficits.
- To evaluate NMDA receptor antagonists as potential antidepressants.
Main Methods:
- Utilized animal models for antidepressant evaluation.
- Administered NMDA receptor antagonists: AP-7 (competitive), MK-801 (non-competitive), and ACPC (glycine receptor partial agonist).
Main Results:
- AP-7, MK-801, and ACPC mimicked the effects of clinically effective antidepressants in animal models.
- NMDA receptor antagonists demonstrated efficacy in models of behavioral depression.
Conclusions:
- The NMDA receptor complex is implicated in the behavioral deficits caused by inescapable stress.
- Substances reducing NMDA receptor neurotransmission may constitute a novel class of antidepressants.
- The hypothesis linking NMDA receptor pathways to affective disorder pathophysiology warrants further investigation.