Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats

Psychopharmacology (Berl). 2008 Jan;195(4):591-603. doi: 10.1007/s00213-007-0950-5. Epub 2007 Sep 26.


Rationale: Stressful events during periods of drug abstinence likely contribute to relapse in cocaine-dependent individuals. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) responsiveness.

Objectives: This study examined stressor- and CRF-induced cocaine seeking and other stress-related behaviors in rats with different histories of cocaine self-administration (SA).

Materials and methods: Rats self-administered cocaine under short-access (ShA; 2 h daily) or long-access (LgA; 6 h daily) conditions for 14 days or were provided access to saline and were tested for reinstatement by a stressor (electric footshock), cocaine or an icv injection of CRF and for behavioral responsiveness on the elevated plus maze, in a novel environment and in the light-dark box after a 14- to 17-day extinction/withdrawal period.

Results: LgA rats showed escalating patterns of cocaine SA and were more susceptible to reinstatement by cocaine, EFS, or icv CRF than ShA rats. Overall, cocaine SA increased activity in the center field of a novel environment, on the open arms of the elevated plus maze, and in the light compartment of a light-dark box. In most cases, the effects of cocaine SA were dependent on the pattern/amount of cocaine intake with statistically significant differences from saline self-administering controls only observed in LgA rats.

Conclusions: When examined after several weeks of extinction/withdrawal, cocaine SA promotes a more active pattern of behavior during times of stress that is associated with a heightened susceptibility to stressor-induced cocaine-seeking behavior and may be the consequence of augmented CRF regulation of addiction-related neurocircuitry.

Publication types

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

MeSH terms

  • Animals
  • Anxiety / physiopathology
  • Arousal / physiology*
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / physiopathology*
  • Corticotropin-Releasing Hormone / physiology*
  • Extinction, Psychological / physiology
  • Fear / physiology
  • Male
  • Maze Learning / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Recurrence
  • Self Administration
  • Social Environment
  • Stress, Psychological / complications*
  • Stress, Psychological / physiopathology


  • Corticotropin-Releasing Hormone
  • Cocaine