Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure
- Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure
- 난신 리; 롱지언 류; 제이슨 드와이더; 모나 바나스; 이보영; 손 현; 샤오유엔 리; 죠지 아흐자니안; 로날드 듀먼
- Antidepressant; depression; ketamine; rapamycin; spines; synaptogenesis
- Issue Date
- Biological psychiatry
- VOL 69, NO 8, 754-761
- Background: Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartate
(NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require
chronic administration of antidepressants or the molecular mechanisms that could account for the rapid responses.
Methods: We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on
depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex neurons.
Results: The results demonstrate that acute treatment with the noncompetitive NMDA channel blocker ketamine or the selective NMDA
receptor 2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonic and anxiogenic behaviors.Wealso found that CUS exposure
decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (excitatory
postsynaptic currents) in layer V pyramidal neurons in the prefrontal cortex and that these deficits are rapidly reversed by ketamine.
Blockade of the mammalian target of rapamycin protein synthesis cascade abolishes both the behavioral and biochemical effects of
Conclusions: The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could
contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in a mammalian target of rapamycin
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