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The Journal of Neuroscience, April 15, 2002, 22(8):3262-3268

cAMP Response Element-Binding Protein Is Essential for the Upregulation of Brain-Derived Neurotrophic Factor Transcription, But Not the Behavioral or Endocrine Responses to Antidepressant Drugs

Alana C. Conti¹, John F. Cryan², Ashutosh Dalvi², Irwin Lucki^{1, 2, 3}, and Julie A. Blendy^{1, 3}

Departments of ¹ Pharmacology and ² Psychiatry, and ³ Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084

Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment.

Key words: CREB; BDNF; antidepressant; gene expression; forced swimming test; tail suspension test; desipramine; fluoxetine

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2283262-07$05.00/0

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