Neuropsychopharmacology (2014) 39, 254–262; doi:10.1038/npp.2013.261; published online 6 November 2013


The Development and Maintenance of Drug Addiction

Roy A Wise1 and George F Koob2

  1. 1Department of Behavioral Neuroscience, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
  2. 2Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA

Correspondence: Dr RA Wise, Behavioral Neuroscience, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, 5500 Nathan Shock Dr, Suite 2000, Baltimore, MD 21224, USA, Tel: +443 740 2460, Fax: +443 740 2728, E-mail:

Received 29 July 2013; Revised 11 September 2013; Accepted 12 September 2013
Accepted article preview online 11 October 2013; Advance online publication 6 November 2013



What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of ‘addiction’ should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents.


substance abuse; dependence; motivation; incentive

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