Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats

Neuropsychopharmacology. 2007 Apr;32(4):955-63. doi: 10.1038/sj.npp.1301192. Epub 2006 Aug 30.


Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF((12-41)) prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF((12-41)) on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF((12-41)) 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Corticotropin-Releasing Hormone / analogs & derivatives*
  • Corticotropin-Releasing Hormone / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Male
  • Nicotine / administration & dosage*
  • Nicotinic Agonists / administration & dosage*
  • Rats
  • Rats, Wistar
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Reward*
  • Self Administration / methods
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / prevention & control*


  • Nicotinic Agonists
  • Receptors, Corticotropin-Releasing Hormone
  • phenylalanyl corticotropin-releasing factor (12-41)
  • Nicotine
  • Corticotropin-Releasing Hormone