PT  - JOURNAL ARTICLE
AU  - Mae M. Huang
AU  - David H. Overstreet
AU  - Darin J. Knapp
AU  - Robert Angel
AU  - Tiffany A. Wills
AU  - Montserrat Navarro
AU  - Jean Rivier
AU  - Wylie Vale
AU  - George R. Breese
TI  - 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
AID  - 10.1124/jpet.109.159186
DP  - 2010 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 298--307
VI  - 332
IP  - 1
4099  - http://jpet.aspetjournals.org/content/332/1/298.short
4100  - http://jpet.aspetjournals.org/content/332/1/298.full
SO  - J Pharmacol Exp Ther2010 Jan 01; 332
AB  - 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.© 2010 by The American Society for Pharmacology and Experimental Therapeutics