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

• Published in: The Journal of pharmacology and experimental therapeutics 2010-01, Vol.332 (1), p.298-307
• Main Authors: Huang, Mae M., Overstreet, David H., Knapp, Darin J., Angel, Robert, Wills, Tiffany A., Navarro, Montserrat, Rivier, Jean, Vale, Wylie, Breese, George R.
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - chemically induced; Anxiety - metabolism; Anxiety - physiopathology; Anxiety - psychology; Behavior, Animal - drug effects; Body Weight - drug effects; Brain - drug effects; Brain Mapping; Corticotropin-Releasing Hormone - metabolism; Corticotropin-Releasing Hormone - pharmacology; Ethanol - administration & dosage; Ethanol - adverse effects; Male; Microinjections; Motor Activity - drug effects; Neuropharmacology; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - metabolism; Stress, Psychological - metabolism; Stress, Psychological - physiopathology; Stress, Psychological - psychology; Substance Withdrawal Syndrome - metabolism; Substance Withdrawal Syndrome - physiopathology; Substance Withdrawal Syndrome - psychology; Urocortins - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.159186

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.