The NMDA receptor is a protein on the surface of nerve cells that responds to glutamate, the most abundant excitatory chemical messenger in the brain. Its full name is N-methyl-D-aspartate receptor, after the laboratory compound first used to study it. When glutamate binds to it and the cell is already partly activated, the receptor opens a channel that lets calcium flow in. That calcium signal is central to learning and memory because it triggers changes that make connections between neurons stronger or weaker, a process called synaptic plasticity.
The NMDA receptor matters in psychiatry because ketamine and esketamine work by blocking it. When the receptor is blocked briefly, the brain responds with a surge of glutamate release and increased activity at a related receptor type called AMPA. That cascade activates growth signals, including BDNF, and within hours leads to the formation of new synapses in the prefrontal cortex and hippocampus. Chronic stress and depression are associated with loss of these synapses, so restoring them may be part of why esketamine lifts mood quickly. The same receptor is involved in dissociation, which is why esketamine can make you feel detached from your surroundings during a session. Research into other NMDA-targeting medications continues, including the oral combination of dextromethorphan and bupropion approved in 2022 for major depression.