Fig. 5. Antiglutamatergic agents as putative treatments for mood disorders.

Activation of the AMPA receptor (AMPA R) by glutamate depolarizes the membrane. When glutamate and glycine are present, depolarization results in the release of magnesium from the NMDA receptor (NMDA R) channel. Calcium also enters through the NMDA R pore. In addition, interchange of cations occurs via NMDA R and kainate receptors (KA R). Activation of group I metabotropic glutamate receptors (mGlu I), which are couped to a G protein (Gq/11), activates phospholipase C-β (PLC-β). Activation of group II metabotropic glutamate receptors (mGlu II), which are coupled to either Gi or Go, inhibit adenylate cyclase (AC) and opening of potassium channels (not shown), respectively. Glutamate is synthesized in neuron from α-ketoglutarate through the tricarboxylic acid cycle (TCA). After release, glutamate is sequestered by glutamate transporters (EAAT1/2/3), shown in glia and a presynaptic neuron (EAAT 3). In glia, the enzyme glutamine synthetase catabolizes glutamate to glutamine, which diffuses to neurons and is metabolized to glutamate through the enzyme glutaminase. The different glutamate receptors and the presumed antiglutamatergic drug site of action is presented. Memantine is a non-competitive antagonist at the NMDA receptor. Felbamate is an anticonvulsant, a non-competitive NMDA receptor antagonist (NR1/NR2B-specific), and inhibits the release of glutamate (acting through blockade of Ca²⁺ and Na⁺ voltage-dependant channels). Riluzole inhibits glutamate release through blockade of Ca²⁺ and Na⁺ voltage-dependant channels. Zinc is an endogenous modulator of ligand- and voltage-gated ion channels. The second generation of mGlu group II and III receptors agonist is also depicted.