title: Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist.
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-HT1A-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.
authors.affiliation: Bowles Center for Alcohol Studies, Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7178, USA. george_breese@med.unc.edu
authors.forename: George R
authors.initials: GR
authors.lastname: Breese
authors.forename: David H
authors.initials: DH
authors.lastname: Overstreet
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Knapp
authors.forename: Montserrat
authors.initials: M
authors.lastname: Navarro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects; D002065:Buspirone / Q000008:administration & dosage; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects*; D005442:Flumazenil / Q000008:administration & dosage; D005526:Food, Formulated; D018757:GABA Modulators / Q000008:administration & dosage; D007398:Interpersonal Relations; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012149:Restraint, Physical / Q000379:methods; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D013315:Stress, Psychological / Q000150:complications; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; C101628:CP 154526; D002492:Central Nervous System Depressants; D018757:GABA Modulators; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D017366:Serotonin Receptor Agonists; D000431:Ethanol; D005442:Flumazenil; D002065:Buspirone
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