title: Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.
abstract: 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. We also 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 ketamine.
  
  
  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 dependent manner.
authors.affiliation: Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Liu
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Mounira
authors.initials: M
authors.lastname: Banasr
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Hyeon
authors.initials: H
authors.lastname: Son
authors.forename: Xiao-Yuan
authors.initials: XY
authors.lastname: Li
authors.forename: George
authors.initials: G
authors.lastname: Aghajanian
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D007649:Ketamine; D020123:Sirolimus