Ketamine’s Mechanism of Action
Ketamine operates by blocking the N-methyl-D-aspartate (NMDA) glutamate receptor Ca2+ channel to reduce the presynaptic release of glutamate; however, the exact mode of action is not known. Some researchers speculate that increasing free glutamate in turn stimulates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which then mediate fast, excitatory neurotransmission. Ketamine’s antidepressant actions might instead be the result of AMPA stimulation rather than only an NMDA receptor blockade. The rapid antidepressant effects of ketamine are associated with fast induction of synaptogenesis and the reversal of atrophy caused by chronic stress.(9) In other words, ketamine seems to actually rebuild synapses. The effectiveness of ketamine in treating pain has been tied to its effects on the NMDA receptor, the AMPA receptors, as well as on the m-opioid receptors; however, some researchers have also pointed to the restoration of balance in the glutamate/ γ-Aminobutyric acid (GABA) system.