1. ¹Bowles Center for Alcohol Studies, Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
2. ²Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
3. ³Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

Correspondence: Dr GR Breese, Bowles Center For Alcohol Studies, Department of Psychiatry, University of North Carolina School of Medicine, 3007 Thurston-Bowles Building, CB-7178, Chapel Hill, NC 27599-7178, USA. Tel: +1 919 966 3081; Fax: +1 919 966 5679; E-mail: george_breese@med.unc.edu

Received 15 September 2004; Revised 14 December 2004; Accepted 20 January 2005; Published online 23 February 2005.

Abstract

Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior ('anxiety'). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restraint stress 3, 7, or 14 days after rats were exposed to multiple withdrawals from a chronic 4.5% ethanol diet. Restraint stress reduced social interaction (ie anxiety-like behavior) at 3, but not at 7 or 14 days, after the multiple withdrawals. No anxiety response was observed in animals that received multiple withdrawals without stress or in animals that received stress when exposed only to control liquid diet. Drugs (ie a CRF₁-receptor antagonist, a benzodiazepine receptor antagonist, and a 5-HT_1A-receptor agonist) previously demonstrated to block the cumulative adaptation, when administered during repeated withdrawals, prevented stress-induced anxiety-like behavior during abstinence. Additionally, these drugs applied prior to stress in the rats previously exposed to the repeated withdrawal protocol, likewise, minimized stress-induced anxiety. The anxiety following stress during abstinence from previous chronic ethanol exposure is indicative of an interaction of stress with the persistent adaptive change caused by repeated withdrawals. Stress eliciting anxiety-like behavior during abstinence from previous ethanol exposures in rats is consistent with stress inducing anxiety during recovery (sobriety) in the alcoholic, a circumstance that can facilitate craving and relapse.