Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression

Biol Psychiatry. 2008 Feb 15;63(4):353-9. doi: 10.1016/j.biopsych.2007.07.016. Epub 2007 Sep 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacology
  • Antidepressive Agents, Tricyclic / therapeutic use*
  • CREB-Binding Protein / drug effects
  • CREB-Binding Protein / genetics
  • Chronic Disease
  • Conditioning, Operant / drug effects
  • Corticosterone / administration & dosage
  • Corticosterone / pharmacology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Major* / genetics
  • Depressive Disorder, Major* / physiopathology
  • Disease Models, Animal
  • Endoplasmic Reticulum Chaperone BiP
  • Extracellular Signal-Regulated MAP Kinases / genetics*
  • Fluoxetine / therapeutic use*
  • Heat-Shock Proteins / genetics
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Locomotion / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones / genetics
  • Motivation
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*


  • Anti-Inflammatory Agents
  • Antidepressive Agents, Tricyclic
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Amitriptyline
  • CREB-Binding Protein
  • Extracellular Signal-Regulated MAP Kinases
  • Corticosterone