Regionally Specific Regulation of ERK MAP Kinase in a Model of Antidepressant-Sensitive Chronic Depression
Received 11 December 2006; received in revised form 23 July 2007; accepted 24 July 2007. published online 24 September 2007.
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.
aInterdepartmental Neuroscience Program, Yale University, New Haven, Connecticut
bDepartment of Psychiatry, Division of Molecular Psychiatry, Yale University, New Haven, Connecticut
cDepartment of Psychology, Yale University, New Haven, Connecticut
dDepartment of Pharmacology, Yale University, New Haven, Connecticut.
Address reprint requests to Jane R. Taylor, Ph.D., Yale University, Department of Psychiatry, Division of Molecular Psychiatry, Connecticut Mental Health Center, Ribicoff Labs, 34 Park Street, New Haven, CT 06508
ABSTRACT