title: Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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  Both ethanol- and cocaine-withdrawn rats initially exhibited reduced CRF-LI content in the amygdala followed by a progressive increase culminating in elevated levels 6 weeks post-withdrawal. Ethanol-withdrawn rats also initially had reduced hippocampal, frontal cortical and hypothalamic CRF-LI levels and time-dependent reductions in basal CORT levels. Cocaine-withdrawn rats showed time-dependent elevations in frontal cortical CRF-LI and basal CORT levels.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.
authors.affiliation: CVN7, Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. ezorrilla@scripps.edu
authors.forename: E P
authors.initials: EP
authors.lastname: Zorrilla
authors.forename: G R
authors.initials: GR
authors.lastname: Valdez
authors.forename: F
authors.initials: F
authors.lastname: Weiss
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000032:analysis / Q000378:metabolism*; D000431:Ethanol / Q000009:adverse effects* / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration
chemical_list: D000431:Ethanol; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; D003345:Corticosterone