Regionally Specific Regulation of ERK MAP Kinase in a Model of Antidepressant-Sensitive Chronic Depression

Shannon L. Gourley, Florence J. Wu, Drew D. Kiraly, Jonathan E. Ploski, Alexia T. Kedves, Ronald S. Duman, Jane R. Taylor

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249 Scopus citations


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 naïve 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.

Original languageEnglish (US)
Pages (from-to)353-359
Number of pages7
JournalBiological Psychiatry
Issue number4
StatePublished - Feb 15 2008

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry


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