The mechanism of antidepressant action of ketamine is uncertain. It is not clear whether NMDA receptor is solely responsible for this action or interactions with other receptors are also necessary. It is not clear whether ketamine alone is sufficient for the antidepressive action or its metabolites are also important. In any case, it has been elucidated that acute blockade of NMDA receptors in the brain results in an activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate a variety of downstream signaling pathways to influence neurotransmission in the limbic system and mediate antidepressant effects of NMDA receptor antagonists like ketamine. Such downstream actions of this activation of AMPA receptors include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, deactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase. In addition to blockade of the NMDA receptor, the active metabolite of ketamine hydroxynorketamine, which does not interact importantly with the NMDA receptor but nonetheless indirectly activates AMPA receptors similarly, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine. Recent research has elucidated that an acute inhibition of the lateral habenula, a part of the brain in the limbic system that has been referred to as the "anti-reward center" (projecting to and inhibiting the mesolimbic reward pathway and modulating other limbic areas), may be involved in the antidepressant effects of ketamine.