Category: receptor_pharmacology
Glutamate is the major excitatory neurotransmitter. Ionotropic receptors: NMDA (Mg²⁺-blocked at rest, Ca²⁺-permeable on coincident depolarization + glutamate binding — Hebbian "coincidence detector" for LTP), AMPA (fast Na⁺/K⁺ current, primary EPSP carrier), kainate (presynaptic modulation + epileptogenesis). Metabotropic mGlu (Gq or Gi) modulate. Therapeutic targets: NMDA antagonists for depression (ketamine, esketamine — rapid antidepressant via glutamate-burst/BDNF mechanism), Alzheimer's (memantine — moderate-affinity uncompetitive NMDA blocker), and dextromethorphan (low-affinity NMDA antagonist + sigma-1 — DXM/quinidine combo for pseudobulbar affect). ALS: riluzole reduces presynaptic glutamate release + blocks Na⁺ channels. AMPA negative allosteric: perampanel for partial-onset epilepsy. Phencyclidine + ketamine share the NMDA-channel-pore binding site (dissociative phenotype). Glycine + D-serine are NMDA co-agonists at the glycine-B site.