Multidisciplinary Perspectives on Impaired Control over Substance Use Christopher S. Martin, Mark T. Fillmore, Tammy Chung, Craig M. Easdon, and Klaus A. Miczek This article presents the proceedings of a symposium held at the June 2005 meeting of the Research Society on Alcoholism in Santa Barbara, California. Impaired control over substance use has long been considered a central feature of alcohol and drug dependence. However, much remains to be learned about the nature of impaired control, the mechanisms by which acute and chronic substance use can lead to impaired control, and how this construct is best assessed in the laboratory and the clinic. The goal of this symposium was to describe current perspectives on impaired control over al- cohol and drug use from diverse research areas, to promote future multidisciplinary work in this area. Four speakers described their work on impaired control using human clinical samples (Dr. Chung), animal models (Dr. Miczek), experimental laboratory paradigms in humans (Dr. Fillmore), and neuroimaging studies (Dr. Easdon). Taken together, the talks highlighted the heterogeneous nature of constructs such as impaired inhibitory control, and patterns of impulsive and compulsive sub- stance use. Future clinical and experimental research should attempt to carefully define and measure particular aspects of impaired control and to seek insights from other disciplines. Key Words: Alcohol Dependence, Impaired Control, Inhibition, Impulsivity, Compulsivity. I MPAIRED CONTROL OVER substance use has long been considered an important clinical and diagnostic feature of alcohol and drug dependence. Difficulties in refraining from the initiation of a use episode and in self- regulating intake, even in the face of severe negative con- sequences, were termed ‘‘loss of control’’ by Jellinek (1960) and are described here as ‘‘impaired control’’ to emphasize the dimensional nature of the construct (Storm and Cutler, 1975). Much remains to be learned about the nature of impaired control, the mechanisms by which acute and chronic substance use can lead to impaired control, and how this construct is best assessed in the laboratory and the clinic. Definitions of alcohol and drug dependence have evolved over the years. Physiological dependence, described by neuroadaptation involved in substance toler- ance and withdrawal, is no longer seen as the defining fea- ture of dependence. Instead, descriptions of dependence by the World Health Organization (WHO), the Diagnostic and Statistical Manual (DSM), and the Alcohol Depend- ence Syndrome (Edwards and Gross, 1976) have long highlighted the importance of behavioral aspects of com- pulsive substance taking and seeking, difficulties in cessa- tion and the high probability of relapse. Many theories (e.g., Koob and Le Moal, 1997; Robinson and Berridge, 1993, 2003; Stewart et al., 1984; Wise and Bozarth, 1987) have emphasized the centrality of the brain’s reward cir- cuitry, which is involved in the appetitive motivation for natural rewards such as food, water, and sex and is a crit- ical pathway for drug-induced reward. Repeated sub- stance use can produce neuroadaptations in this system that ‘‘hijack’’ the brain’s reward system and sensitize the incentive salience of substances and related stimuli, lead- ing to strong drug craving that drives further drug seeking behavior. A sensitized reward system can deliver a strong motivational drive even after long-term abstinence has been achieved, helping explain high relapse rates. However, another aspect of dependence that has received far less attention in research and theory involves neuroadaptation and dysfunction within brain regions involving inhibitory control over behavior. Incentive sali- ence theories have trouble fully explaining why drug use persists even in the face of severe negative consequences and when persons are highly motivated to quit and cut From the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (CSM, TC); the Department of Psychology, University of Kentucky, Lexington, Kentucky (MTF); the Rotman Research Institute of the Baycrest Cen- tre, University of Toronto, Toronto, Ontario, Canada (CME); and the Departments of Psychology, Psychiatry, Pharmacology and Neurosci- ence, Tufts University, Medord, Massachusetts. (KAM). Received for publication September 9, 2005; accepted November 17, 2005. Supported by NIH Grants R01 AA13397 and K02 AA00249 (CM), R01 AA12895 and R01 DA14079 (MF), K01 AA00324 and R01 AA 14357 (TC) and R01 AA013983 and R01 DA02632 (KM) and grants from the McDonnell-Pew Foundation, the Alcoholic Beverage Medical Re- search Foundation, and the Ontario Mental Health Foundation (CE). Reprint requests: Christopher S. Martin, PhD, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213; E-mail: martincs@upmc.edu Copyright r 2006 by the Research Society on Alcoholism. DOI: 10.1111/j.1530-0277.2006.00035.x Alcohol Clin Exp Res, Vol 30, No 2, 2006: pp 265–271. 265 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 30, No. 2 February 2006