Stress-induced potentiation of cocaine reward: a role for CRF R1 and CREB

Neuropsychopharmacology. 2009 Nov;34(12):2609-17. doi: 10.1038/npp.2009.91. Epub 2009 Aug 12.


Both clinical and preclinical research have shown that stress can potentiate drug use; however, the underlying mechanisms of this interaction are unknown. Previously, we have shown that a single exposure to forced swim (FS) reinstates extinguished conditioned place preference (CPP) to cocaine and that cAMP response element binding protein (CREB) is necessary for this response. CREB can be activated by corticotropin releasing factor (CRF) receptor type 1 (CRF(R1)) binding, which mediates neuroendocrine and behavioral responses to stress as well as to drugs of abuse. The present experiments investigate whether changes in cocaine reward elicited by previous exposure to stress are mediated by CREB and/or CRF(R1). Chronic exposure to FS in advance of conditioning enhances cocaine CPP in wild-type mice, but this is blocked in CREB-deficient mice. In addition, pretreatment with the CRF(R1) antagonist, antalarmin, before FS exposure blocks this stress-induced enhancement of cocaine CPP. Furthermore, FS-induced increase in phosphorylated CREB (pCREB), specifically in the lateral septum (LS) and nucleus accumbens (NAc) is also blocked by antalarmin. Taken together, these studies suggest that both CREB and CRF(R1) activation are necessary for stress-induced potentiation of drug reward.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Mice
  • Mice, Knockout
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiopathology
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacology
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Reward*
  • Septum of Brain / drug effects
  • Septum of Brain / physiopathology
  • Space Perception / drug effects
  • Space Perception / physiology
  • Stress, Psychological / physiopathology*
  • Swimming
  • Time Factors


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Dopamine Uptake Inhibitors
  • Pyrimidines
  • Pyrroles
  • Receptors, Corticotropin-Releasing Hormone
  • antalarmin
  • CRF receptor type 1
  • Cocaine