Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats

Psychopharmacology (Berl). 2001 Dec;158(4):374-81. doi: 10.1007/s002130100773. Epub 2001 Jun 13.


Rationale: Despite prolonged abstinence, prior drug dependence is accompanied by lasting changes in physiology, psychosocial functioning and vulnerability to relapse. One proposed mechanism for these alterations is dysregulation of corticotropin-releasing factor (CRF) neurocircuitry.

Objectives: To determine regional brain CRF content and HPA-axis activity during protracted cocaine and ethanol withdrawal in dependent rats.

Methods: To study protracted ethanol withdrawal, rats ( n=22) were fed a nutritionally complete, ethanol (10% v/v) liquid diet for 3-4 weeks. Controls ( n=12) were pair-fed an isocaloric, ethanol-free formulation. To study protracted cocaine withdrawal, rats ( n=23) self-administered cocaine (0.25 mg/infusion; FR-5) daily for 3 weeks during 3-h sessions and subsequently were allowed to self-administer cocaine during two 12-h "binge" sessions. Controls ( n=6) received yoked saline infusions. Regional brain CRF-like-immunoreactivity (CRF-LI), plasma ACTH-LI and CORT-LI levels were determined from 1 day to 6 weeks post-withdrawal.

Results: Both ethanol- and cocaine-withdrawn rats initially exhibited reduced CRF-LI content in the amygdala followed by a progressive increase culminating in elevated levels 6 weeks post-withdrawal. Ethanol-withdrawn rats also initially had reduced hippocampal, frontal cortical and hypothalamic CRF-LI levels and time-dependent reductions in basal CORT levels. Cocaine-withdrawn rats showed time-dependent elevations in frontal cortical CRF-LI and basal CORT levels.

Conclusions: Protracted withdrawal from ethanol or cocaine is associated with altered limbic CRF-LI and circulating CORT levels beyond the detoxification stage. The delayed nature of some changes suggests that they may not represent residual effects of acute withdrawal, but rather emerging manifestations of a separate process, such as allostatic load.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Brain / metabolism*
  • Cocaine / administration & dosage
  • Cocaine / adverse effects*
  • Corticosterone / blood
  • Corticosterone / metabolism*
  • Corticotropin-Releasing Hormone / analysis
  • Corticotropin-Releasing Hormone / metabolism*
  • Ethanol / adverse effects*
  • Ethanol / blood
  • Hypothalamo-Hypophyseal System / metabolism
  • Male
  • Pituitary-Adrenal System / metabolism
  • Radioimmunoassay
  • Rats
  • Rats, Wistar
  • Self Administration


  • Ethanol
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Cocaine
  • Corticosterone