Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats.
BACKGROUND
Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF(1) receptor antagonists on excessive ethanol self-administration in dependent rats.


METHODS
Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF(1) antagonists) and ethanol self-administration was measured.


RESULTS
The nonpeptide, small molecule CRF(1) antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats.


CONCLUSIONS
These data demonstrate that CRF(1) receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF(1) antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.
Funk
Cindy K
CK
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA. creiter@scripps.edu
Zorrilla
Eric P
EP
Lee
Mei-Jing
MJ
Rice
Kenner C
KC
Koob
George F
GF
D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D006727:Hormone Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000379:methods; D014227:Triazines / Q000627:therapeutic use
D002492:Central Nervous System Depressants; D006727:Hormone Antagonists; C476980:MJL 1-109-2; D011743:Pyrimidines; D011758:Pyrroles; C412383:R 121919; D014227:Triazines; C103016:antalarmin; D000431:Ethanol; D003346:Corticotropin-Releasing Hormone