| Limitations in effectiveness of current antidepressants and their associated side effects, especially in treatment-resistant (or non-responsive) patients, call for development of new interventions. Ketamine, a common veterinarian anesthetic and an N-Methyl-D-aspartate (NMDA) antagonist that works on glutamatergic neurotransmitter could be such a compound. The most common antidepressants—including selective serotonin reuptake inhibitors (SSIRs), monoamine oxidase inhibitors (MAOI), and norepinephrine reuptake inhibitors—work to stabilize the level of key biogenic-amines in the brain of depressed individuals. The efficacy of these drugs are generally low (up to 30% of patients may not respond), and onset of effects can take 3-6 weeks. Recent clinical studies show that a single intravenous dose of ketamine produces a rapid and long lasting antidepressant effect. It is postulated that this effect is induced by ketamine inactivating NMDA receptors, which in turn enhances the function of postsynaptic AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid) receptors. This contention is based on observation that ketamine effect can be blocked by administration of AMPA antagonist, 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2, 3-dione (NBQX). Moreover, positive AMPA receptor modulators (AMPA-kines) have an antidepressant- like effect. Thus, we postulate that AMPA, a selective AMPA receptor agonist should also possess antidepressant-like effects and that its combination with ketamine should provide an additive or synergistic effect. Furthermore, we were interested in elucidating the central mechanisms that mediate the antidepressant effect of ketamine and/or AMPA. For this purpose we concentrated on the neurotrophic pathways that have been implicated in mood regulation. Our central hypothesis was that ketamine—alone or in combination with AMPA—alleviates depression by activating neurotrophic pathways through mediation of the functional interplay between AMPA and NMDA receptors.;The data provide evidence for dose-dependent antidepressant effects of AMPA and that combination of ineffective doses of AMPA and ketamine can result in significant antidepressant effects. Moreover, the antidepressant effect of such combination was associated with increases in AMPA/NMDA receptor density as well as in markers of neurogenesis and synaptogenesis in the hippocampus. These findings provide further support for effectiveness of glutamatergic based intervention in treatment of depression. |
