title: Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress.
abstract: Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection.
  
  
  CONCLUSIONS
  The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN.
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and amatj@colorado.edu.
authors.forename: Jose
authors.initials: J
authors.lastname: Amat
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado 80305, and.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Dolzani
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Scott
authors.initials: S
authors.lastname: Tilden
authors.affiliation: Department of Psychology, Boston College, Chestnut Hill, Massachusetts 02467.
authors.forename: John P
authors.initials: JP
authors.lastname: Christianson
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kubala
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Kristi
authors.initials: K
authors.lastname: Bartholomay
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sperr
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ciancio
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Department of Psychology and Neuroscience and the Center for Neuroscience and.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
mesh_terms: D000778:Anesthetics, Dissociative / Q000008:administration & dosage; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects*; D002908:Chronic Disease; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D001523:Mental Disorders / Q000503:physiopathology* / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000503:physiopathology* / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000778:Anesthetics, Dissociative; D000928:Antidepressive Agents; D007649:Ketamine
keywords: anxiety; ketamine; serotonin; stress resilience