Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor.
BACKGROUND
Animal models of alcohol dependence suggest that long-term alterations in brain corticotropin-releasing factor (CRF) systems, key mediators of the behavioral stress response, may be involved in the development and reinstatement of dependence on drugs of abuse. The objective of the present study was to investigate the role of CRF in the regulation of ethanol self-administration and to examine the behavioral stress response during acute withdrawal and protracted abstinence.


METHODS
Male Wistar rats were made dependent on ethanol via chronic exposure to ethanol vapor. Ethanol self-administration and exploratory behavior in the elevated plus maze were measured at 2 hr and 3 to 5 weeks after exposure. The role of CRF in ethanol self-administration was examined via central injection of the CRF receptor antagonist D-Phe-CRF(12-41).


RESULTS
Rats showed increased responding for ethanol 2 hr and 3 to 5 weeks after chronic ethanol exposure, which was attenuated by central injection of D-Phe-CRF(12-41). In addition, rats displayed a decrease in open-arm exploration in the elevated plus maze when tested 2 hr and 4 weeks after exposure.


CONCLUSIONS
These results indicate that chronic ethanol exposure leads to increased ethanol self-administration and decreased open-arm exploration in the elevated plus maze during acute withdrawal and protracted abstinence. Attenuation of ethanol self-administration via central injection of D-Phe-CRF(12-41) implicates CRF as an underlying mechanism regulating long-term motivational effects associated with alcohol dependence.
Valdez
Glenn R
GR
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA. gvaldez@scripps.edu
Roberts
Amanda J
AJ
Chan
Karen
K
Davis
Heather
H
Brennan
Molly
M
Zorrilla
Eric P
EP
Koob
George F
GF
D000428:Alcohol Drinking / Q000188:drug therapy / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology; D013695:Temperance / Q000523:psychology
C083591:H-R corticotropin-releasing factor (12-41), Phe(12)-Nle(21,38), C(alpha-MeLeu(37))-; D010446:Peptide Fragments; D018019:Receptors, Corticotropin-Releasing Hormone; C113202:phenylalanyl corticotropin-releasing factor (12-41); D000431:Ethanol; D003346:Corticotropin-Releasing Hormone