NMDA receptor antagonism requires serotonin and noradrenaline to induce antidepressant-like effects in a treatment-resistant depression rat model.

Abstract

Non-competitive NMDA receptor antagonists like MK-801 have shown rapid antidepressant-like effects in animal models. However, research on their ability to enhance classical antidepressants in treatment-resistant depression, and the involvement of monoaminergic systems, is limited. This study investigated MK-801's antidepressant effects in male and female rats, focusing on serotonergic and noradrenergic mechanisms, and whether low doses of MK-801 could boost the effects of traditional antidepressants. Thus, independent groups of Wistar Kyoto Rats were administered MK-801 alone or with desipramine or sertraline, and then evaluated in the open field and the forced swimming test (FST). Finally, the participation of the serotonergic and noradrenergic systems in the mechanism of action of MK-801 was analyzed using specific neurotoxins (pCPA and DSP4). MK-801 had an antidepressant-like effect in both male and female rats, but the effect was more conspicuous in males. When combined with sertraline or desipramine, MK-801 produced a synergistic effect. Serotonin depletion did not cancel the antidepressant-like effect of MK-801 but shifted the behavioral response from swimming to climbing. In contrast, noradrenaline depletion partially attenuated the effect of MK-801, resulting in a complete block of both active behaviors. The combined depletion of serotonin and noradrenaline abolished the effect of MK-801, suggesting that the presence of both neurotransmitters is necessary for its antidepressant-like actions. In conclusion, MK-801 may enhance the effect of classical antidepressants in treatment-resistant models. Moreover, NMDA receptor antagonism relies on the integrity of the serotonergic and noradrenergic systems to exert antidepressant-like effects.