Ketamine

Ketamine binds noncompetitively within the ion channel of neuronal NMDA receptors, blocking calcium influx and interfering with glutamate-mediated excitatory neurotransmission and synaptic plasticity. At high doses in the central nervous system, integrated signaling between the cortex, thalamus, and limbic system is broadly suppressed, producing a dissociative state that alters consciousness, sensation, and emotional processing. Clinically, this appears as potent analgesia and loss of pain perception, although some brainstem and spinal reflexes may remain preserved. At subanesthetic doses, ketamine preferentially inhibits NMDA receptors on GABAergic interneurons in the prefrontal cortex, reducing inhibitory input and causing a transient increase in glutamate release from pyramidal neurons. This disinhibitory effect activates postsynaptic AMPA receptors, which in turn stimulates the mTOR signaling pathway, promotes synaptic protein synthesis and neural plasticity remodeling, and is thought to underlie its rapid antidepressant-related effects.