6.03.7.1.3.1 NMDA receptors
Several types of antidepressants can alter the expression of mRNA for the NMDA receptor while glutamate levels are elevated in the occipital cortex of medication-free subjects with unipolar major depression.63 Direct NMDA receptor antagonists have antidepressant effects in animal models including behavioral despair and chronic mild stress paradigms. Two drugs with putative glutamatergic properties, lamotrigine (43) and riluzole, have been reported to have antidepressant activity in the clinic trials while a preliminary study using the noncompetitive NMDA receptor antagonist, ketamine (84), showed rapid and short-lived antidepressant actions. A more recent study in 18 subjects64 showed that ketamine (0.5mgkg_ 1 i.v.) significantly improved depressive symptoms (HAMD-21 score) within 2h of administration to the same extent as seen with bupropion, SSRIs, and venlafaxine at 8 weeks. This effect remained significant through the following week after treatment. These data suggest that NMDA antagonists, like ketamine which acts at the PCP site on the receptor, may be beneficial in the treatment of depression.
6.03.7.1.3.2 Group 1 glutamate receptors (mGlu 1-8)
Metabotropic glutamate (mGlu) receptors (mGlu 1-8) are a heterogeneous family of GPCRs that modulate brain excitability via presynaptic, postsynaptic, and glial mechanisms. Glutamate receptors regulate brain glutamate activity and may play an important role in the pathophysiology of depression. NMDA receptor antagonists, mGluR1 and mGluR5 antagonists, and positive modulators of AMPA receptors have antidepressant-like activity in a variety of preclinical models. A single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms.65
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