Thesis

Behavioral interactions of NMDA receptors and antidepressants

Research over the past decade has implicated the N-methyl-D-aspartate (NMDA) receptors in the therapeutic effects of antidepressants. Even though there is a strong body of evidence supporting a role for NMDA receptors more research is needed to better understand if and how these receptors may be involved in the actions of antidepressants. The general aim of these studies, was to explore the acute interaction of NMDA receptor antagonists and antidepressants. More specifically, these studies explored the interaction of pharmacologically diverse NMDA receptor antagonists, MK-801 (a noncompetitive antagonists), PCP (a noncompetitive antagonists), dextrorphan (a noncompetitive antagonist), memantine (a non competitive antagonist), LY235959 (a competitive antagonist) and ifenprodil (a polyamine antagonist) with the tricyclic antidepressant desipramine in behavior. Based on the current literature, it is hypothesized that the coadministration of NMDA antagonists and desipramine will lead to a synergistic behavioral effect. The results from these studies supported our hypothesis. When desipramine was combined with the noncompetitive antagonists, MK-801, PCP, dextrorphan or memantine there was a synergistic behavioral effect. Along these same lines when desipramine was combined with the competitive antagonist, L Y235959 there was increase in L Y235959 induced behavior. When the polyamine antagonist, ifenprodil, was combined with desipramine there was a trend in the right direction, however it did not reach statistical significance. The results of these studies are consistent with the suggestion that antidepressants act at least in part by modifying NMDA receptor function. Knowledge of the role of NMDA receptor in antidepressant effects may lead to a better understanding of the mechanism involved in the actions of antidepressants, which could potentially help in discovering newer antidepressants with fewer problematic side effects.

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