Abstract
N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.
Highlights
The N-Methyl-D-aspartate (NMDA) receptor (NMDAR) is an ionotropic glutamate receptor that possesses unique characteristics
The function of NMDARs usually declines with age, which most likely contributes to the reduced plasticity that leads to learning and memory impairment
The glutamate released would lead to the stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in pyramidal cells, which would result in the described state of hyperactivity
Summary
The N-Methyl-D-aspartate (NMDA) receptor (NMDAR) is an ionotropic glutamate receptor that possesses unique characteristics. Two different processes are necessary for activating NMDARs. First, the previous membrane depolarization removes Mg2+ ions, and second, the additional binding of co-agonists glycine and glutamate allows voltage-dependent inflow of Na+ and Ca2+ ions and the outflow of K+ ions. NMDARs are ionotropic glutamate receptors made up of four subunits. Copyright (1994), with permission regional expression in the rat brain and functional properties of four. GluN2C subunits are practically restricted cerebellum low levels of expression in retrosplenial cortex and thalamus [8,12]. GluN2A-containing receptors exclusively, to extrasynaptic compartment have may been have been reported to contribute to synaptic[14,15,16,17]. P.H. Seeburg, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors, Pages No 529-524, Copyright (1994), with permission from Elsevier”. Most clinical trials have failed to show significant efficacy, while exhibiting adverse effects [18,19]
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