title: Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression.
abstract: BACKGROUND
  Elevated phosphorylation of neurotrophin-regulated transcription factors, such as cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), in the hippocampus has been proposed as a common mediator of antidepressant (ADT) efficacy in otherwise naive rodents. The intracellular factors by which ADTs and glucocorticoids, causal factors in depression, regulate depression-like behavior remain unclear, but extracellular signal-regulated kinase 1/2 (ERK1/2), upstream of CREB, is a likely candidate.
  
  
  METHODS
  We explored the long-term consequences of glucocorticoid exposure and subsequent ADT treatment in a novel model of chronic depression. Motivated behaviors, immobility during tail suspension, and ERK1/2, known to be required for behavioral response to ADTs, were quantified.
  
  
  RESULTS
  Chronic corticosterone (CORT) increased immobility, decreased responding in an operant conditioning task of motivation, and selectively reduced phosphorylated ERK1/2 (pERK1/2) in the dentate gyrus. Behavioral and biochemical measures were restored to baseline by amitriptyline (AMI) treatment. Corticosterone regulated pERK1/2 on a time course that paralleled increases in heat shock proteins associated with depression and decreased tyrosine kinase receptor B (trkB) phosphorylation. Chronic AMI also produced regionally dissociable effects on pERK1/2 in CA1/CA3, amygdala, and striatum, but not prefrontal cortex.
  
  
  CONCLUSIONS
  Antidepressant efficacy in a motivational task and behavioral despair assay are associated with altered limbic pERK1/2, including restored pERK1/2 in the dentate gyrus after stress-related insult.
authors: Interdepartmental Neuroscience Program, Department of Psychiatry, Yale University, New Haven, Connecticut 06508, USA.
authors: Shannon L
authors: SL
authors: Gourley
authors: Florence J
authors: FJ
authors: Wu
authors: Drew D
authors: DD
authors: Kiraly
authors: Jonathan E
authors: JE
authors: Ploski
authors: Alexia T
authors: AT
authors: Kedves
authors: Ronald S
authors: RS
authors: Duman
authors: Jane R
authors: JR
authors: Taylor
mesh_terms: D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D050882:CREB-Binding Protein / Q000187:drug effects / Q000235:genetics; D002908:Chronic Disease; D003216:Conditioning, Operant / Q000187:drug effects; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D005473:Fluoxetine / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics; D009042:Motivation; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D000639:Amitriptyline; D000893:Anti-Inflammatory Agents; D000929:Antidepressive Agents, Tricyclic; D050882:CREB-Binding Protein; D003345:Corticosterone; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases; D005473:Fluoxetine; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D017367:Selective Serotonin Reuptake Inhibitors