The Development and Maintenance of Drug Addiction - BLOG NOW

The development and maintenance of drug addiction (Link to full-length article)

Author(s): Roy A Wise and George F Koob


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.


Our inaugural Circumspectives is entitled “The development and maintenance of drug addiction”, authored by Roy A. Wise and George F. Koob (2014).  The authors are eminent addiction researchers who have had a tremendous influence on the field, through both their research and generative spirits.  For decades they have had a rather famous scientific disagreement, centered on their opposing views about what motivates addictive behavior.  Dr. Wise is a proponent of the idea that the positive (rewarding) effects of abused drugs are most important, whereas Dr. Koob’s theory is that it is the aversive effects of drug withdrawal (the “Dark Side”) that are critical.
We welcome your thoughts on this debate and, if you wish to share them, your own ideas for experiments that would help to resolve this debate and push the field forward.
Bill Carlezon, Ph.D., on behalf of the Editors of NPP.
Perhaps the antagonists are describing two sides of the one coin. Is the alleviation of withdrawal rewarding? Does the "dark side" make reward de-escalate more rapidly? We see people totally detoxed but then relapse upon return to their usual haunts at the first cue. Is this driven by Koob's prolonged motivational withdrawal or is it an example of Wise's reinforced compulsive use. Or both.
Simon Holliday
Posted: Aug 03, 2014 7:57 AM
Thank you for taking the time to write. We are happy to take suggestions for future articles. I personally encourage ACNP members to take a more active role in their journal by taking the time to share their ideas of what types of articles they would like to see. Hopefully this is the first of many Circumspectives pieces that stimulate collegial discussion on matters of great importance to the college.
Bill Carlezon
Posted: Jan 25, 2014 9:51 AM
ACNP used to be, and should continue to be, the setting for translational research on psychiatric and addictive disorders. I am currently mentoring two neuroscience graduate students who are working in our clinical research laboratories in studies of recovery and relapse in alcohol dependent and opioid dependent patients in 90-120 day supervised extended care. While the patients do not have the types of addiction "careers" of Don Klein's Lexington patients, both students have commented how much more complex the issues of addiction recovery and risk of relapse are in patients compared with the rodent models with which they have become familiar. What is missing from your "debate" is the complexity that one finds in clinical research-and the failure of either "reward" or "the dark side" to fully account for risk of addiction or risk of relapse in real patients. As opposed to other areas of research in psychiatry, the addiction field does have robust animal models that enable researchers to examine addiction related phenomena in the brain-and at the level of epigenetic changes in relevant brain regions. What is missing from your debate is the opportunity to bring this back to the human condition and the clinical research laboratory. The animal models have not been especially robust in predicting the possible efficacy of medications in the treatment of various addictive disorders (see various putative predictors of medications to treat cocaine dependence that "worked" in animal models and failed in patients.) The stories of "drug reward" and "the dark side" as explanations of addiction are not new stories-nor even a debate. Both issues are important, but insufficient explanations of risk of addiction and risk of relapse. The addictions field should be leading the way to new frontiers of translational research-and ACNP and its journal should be the venue. Sadly, your "debate" lacks the insights or experience of many talented clinical investigators. And ACNP is increasingly losing its relevance to those with that kind of interest and experience. In a symbolic way, the absence of the clinical investigator from this "debate" is symptomatic of ACNP's descent into a mini (and less relevant) Society for Neuroscience. How unfortunate that the College and its Journal have voluntarily given up our roots in clinical research, especially when the rest of medicine is emphasizing the importance of translational research (a term that explicitly includes clinical investigation).
Roger Meyer
Posted: Jan 24, 2014 4:32 PM

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