Abstract
In abstinent alcoholics, stress induces negative affect-a response linked to craving and relapse. In rats, repeated stresses at weekly intervals prior to 5-day ethanol diet sensitize withdrawal-induced anxiety-like behavior ("anxiety") that is blocked by a CRF1-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) prior to 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 following 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 prior to CRF microinjection into the CeA, DRN or d-BNST prevented CRF-induced sensitization of anxiety during ethanol withdrawal. Further, 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 prior to 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.
- Central amygdala
- Corticotropin Releasing Hormone (CRF)
- Ethanol-Sensitization
- Raphe
- Stress
- d-Bed-Nucleus-Stria-Terminalis
Footnotes
- Received July 31, 2009.
- Revision received October 14, 2009.
- Accepted October 15, 2009.
- The American Society for Pharmacology and Experimental Therapeutics