Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence.
BACKGROUND
Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.


METHODS
Using naive and ethanol-dependent rats, we compared electrophysiologic effects and interactions of CRF and ethanol on CeA GABAergic transmission, and we measured GABA dialyzate in CeA after injection of CRF(1) antagonists and ethanol. We also compared mRNA expression in CeA for CRF and CRF(1) using real-time polymerase chain reaction. We assessed effects of chronic treatment with a CRF(1) antagonist on withdrawal-induced increases in alcohol consumption in dependent rats.


RESULTS
CRF and ethanol augmented CeA GABAergic transmission in naive rats via increased GABA release. Three CRF1 receptor (CRF(1)) antagonists decreased basal GABAergic responses and abolished ethanol effects. Ethanol-dependent rats exhibited heightened sensitivity to CRF and CRF(1) antagonists on CeA GABA release. Intra-CeA CRF(1) antagonist administration reversed dependence-related elevations in GABA dialysate and blocked ethanol-induced increases in GABA dialyzate in both dependent and naive rats. Polymerase chain reaction studies indicate increased expression of CRF and CRF(1) in CeA of dependent rats. Chronic CRF(1) antagonist treatment blocked withdrawal-induced increases in alcohol drinking by dependent rats and tempered moderate increases in alcohol consumption by nondependent rats in intermittent testing.


CONCLUSIONS
These combined findings suggest a key role for specific presynaptic CRF-GABA interactions in CeA in the development and maintenance of ethanol dependence.
Roberto
Marisa
M
Committee on the Neurobiology of Addictive Disorders, Scripps Research Institute, La Jolla, California 92037, USA. mroberto@scripps.edu
Cruz
Maureen T
MT
Gilpin
Nicholas W
NW
Sabino
Valentina
V
Schweitzer
Paul
P
Bajo
Michal
M
Cottone
Pietro
P
Madamba
Samuel G
SG
Stouffer
David G
DG
Zorrilla
Eric P
EP
Koob
George F
GF
Siggins
George R
GR
Parsons
Loren H
LH
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000437:Alcoholism / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000494:pharmacology*; D021983:Cyclophilins / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D006727:Hormone Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D011743:Pyrimidines; C412383:R 121919; D012333:RNA, Messenger; C085075:CGP 55845A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D003346:Corticotropin-Releasing Hormone; D021983:Cyclophilins; D014633:Valine