Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization.
In abstinent alcoholics, stress induces negative affect-a response linked to craving and relapse. In rats, repeated stresses at weekly intervals before 5-day ethanol diet sensitize withdrawal-induced anxiety-like behavior ("anxiety") that is blocked by a corticotrophin-releasing factor 1 (CRF-1)-receptor antagonist. Current experiments were performed to identify brain sites that support CRF involvement in stress sensitization of ethanol withdrawal-induced anxiety-like behavior. First, different doses of CRF microinjected weekly into the central amygdala (CeA) before ethanol exposure produced a dose-related sensitization of anxiety during ethanol withdrawal. Subsequently, CRF microinjection into the basolateral amygdala, dorsal raphe nucleus (DRN), or dorsal bed nucleus of the stria terminalis (d-BNST) also sensitized ethanol withdrawal-induced anxiety. In contrast, sensitization of ethanol withdrawal-induced anxiety was not observed after weekly CRF administration into the ventral-BNST, CA1-hippocampal region, or hypothalamic-paraventricular nucleus. Then, experiments documented the CRF receptor subtype responsible for CRF and stress sensitization of withdrawal-induced anxiety. Systemic administration of a CRF-1 receptor antagonist before CRF microinjection into the CeA, DRN, or d-BNST prevented CRF-induced sensitization of anxiety during ethanol withdrawal. Furthermore, repeated microinjections of urocortin-3, a CRF-2 receptor agonist, into the CRF-positive sites did not sensitize anxiety after withdrawal from ethanol. Finally, microinjection of a CRF-1 receptor antagonist into the CeA, DRN, or d-BNST before stress blocked sensitization of anxiety-like behavior induced by the repeated stress/ethanol withdrawal protocol. These results indicate that CRF released by stress acts on CRF-1 receptors within specific brain regions to produce a cumulative adaptation that sensitizes anxiety-like behavior during withdrawal from chronic ethanol exposure.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7178, USA.
Mae M
MM
Huang
David H
DH
Overstreet
Darin J
DJ
Knapp
Robert
R
Angel
Tiffany A
TA
Wills
Montserrat
M
Navarro
Jean
J
Rivier
Wylie
W
Vale
George R
GR
Breese
D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D001931:Brain Mapping; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D054832:Urocortins / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone