Alcohol Withdrawal and Conditioning Hilary J. Little, David N. Stephens, Tamzon L. Ripley, Gilyana Borlikova, Theodora Duka, Manja Schubert, Doris Albrecht, Howard C. Becker, Marcello F. Lopez, Friedbert Weiss, Colin Drummond, Michelle Peoples, and Christopher Cunningham This review contains the proceedings from a symposium held at the RSA conference in 2003 on “Alcohol Withdrawal and Conditioning.” The presentations covered a range of interactions between conditioning and alcohol withdrawal, in both animal behavior and the clinic. Dr. D.N. Stephens first described his studies exploring the consequences of alcohol dependence and repeated experience of withdrawal on the condi- tioning process. His data suggested that repeated withdrawal from moderate alcohol intake impairs amygdala-dependent mechanisms for learning about aversive events. Dr. H. Becker then detailed studies examining the consequences of repeated ethanol withdrawal experience on subsequent ethanol drinking behavior in mice, and conditions in which motivational properties of odor cues that are associated with different phases of ethanol withdrawal influence such relapse behavior. The data suggested that cues associated with acute withdrawal or “recovery” from withdrawal may serve as modulating factors in influ- encing subsequent ethanol drinking behavior, and that the timing of the cues determines their conse- quences. Dr. F. Weiss described recent findings from animal models of relapse that suggested the efficacy of alcohol-associated contextual stimuli in eliciting alcohol-seeking behavior resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans. The interactive effects of stress and ethanol-related environmental stimuli were found to be dependent on concurrent activation of endogenous opioid and corticotropin-releasing factor systems. Conditioning factors (i.e., exposure to drug-associated stimuli) and stress could therefore interact to augment vulnerability to relapse. Dr. C. Drummond then addressed the clinical aspects of conditioning during alcohol withdrawal and described studies showing exposure of alcoholics to alcohol-related cues elicited greater subjective and physiological responses than exposure to neutral cues. The former responsivity showed a relationship with a measure of motivation to drink alcohol. Finally, Dr. C. Cunningham provided a summary of the concepts involved in the presenta- tions and discussed the conditioning processes that affect behavior during and after alcohol withdrawal. Key Words: Alcohol Withdrawal, Conditioning, Learning. L EARNING HAS LONG been recognized to play an important role in alcohol abuse and alcoholism, but the effects of chronic alcohol consumption on conditioning processes have only recently been studied. Conditioning and prior experience are crucially important in determining whether and when alcohol consumption takes place and there is increasing evidence that the processes involved in conditioning are altered by prior alcohol dependence and withdrawal. Such factors interface with neuroadaptive changes that play a significant role in perpetuating drink- ing, as well as underlying the ability of environmental cues to trigger relapse after periods of abstinence. The contri- butions to this symposium highlight the recent discoveries made on the influences of alcohol withdrawal on condition- ing and the importance of such data in relation to the alcohol dependence process and relapse drinking. THE EFFECTS OF ALCOHOL DEPENDENCE AND WITHDRAWAL ON AVERSIVE CONDITIONING D.N. Stephens, T.L. Ripley, G. Borlikova, T. Duka, M. Schubert, and D. Albrecht Alcohol-seeking and other aspects of alcoholics’ behav- ior may be mediated by simple conditioning processes. To what extent are these influenced by the patient’s previous history of taking alcohol? Clinical, as well as animal labo- ratory experimental studies, indicates that repeated expe- rience of detoxification results in profound behavioral changes, associated with neurobiological changes in several brain regions. The best documented of such changes is the increased propensity to seizures experience following mul- Departments of Pharmacology and Addictive Behaviour, George’s Hospi- tal Medical School, Cranmer Terrace, London, SW17 ORE, U.K. (HJL, CD, MP); Department of Psychology, University of Sussex, Brighton, UK (DNS, TLR, TD); Institute of Physiology (Charité), Humboldt University, Berlin, Germany, Charleston Alcohol Research Center (MS, DA); Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina (HCB, MFL); Department of Veterans Affairs, Charleston, South Carolina 29425 (HCB); Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (FW); De- partment of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health and Science University, Portland, OR, 97239 (CC). December 23, 2004; January 11, 2005. Reprint requests: Hilary J. Little, Departments of Pharmacology and Addictive Behaviour, St. George’s Hospital Medical School, Cranmer Terrace, London, SW17 ORE, U.K.; Fax: +44-208-725-2675. E-mail: hilary.little@sghms.ac.uk Copyright © 2005 by the Research Society on Alcoholism. DOI: 10.1097/01.ALC.0000156737.56425.E3 0145-6008/05/2903-0453$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 29, No. 3 March 2005 Alcohol Clin Exp Res, Vol 29, No 3, 2005: pp 453–464 453