Author's personal copy CHAPTER 39 Incentive Salience and the Transition to Addiction Mike J.F. Robinson, Terry E. Robinson and Kent C. Berridge University of Michigan, Ann Arbor, MI, USA OUTLINE Drug Addiction, Recovery, and Relapse 391 Sensitization of Incentive Salience 395 The Incentive Sensitization Theory 393 Factors That Influence Sensitization 396 What Psychologically Is Sensitized? Incentive Salience Cross-sensitization 396 Features 394 Context and Craving 396 What Is Incentive Salience? 395 A Role for Pleasure? 397 Mesolimbic Dopamine as a Common Currency for Summary 398 Incentive Salience 395 DRUG ADDICTION, RECOVERY, disorder, and an even smaller proportion suffer from AND RELAPSE chronic drug addiction. Yet, the worldwide monetary and social costs associated with drug control measures, Most adults have used a potentially addictive drug at corruption, lost productivity, and treatment of drug least once in their lifetime, if caffeine, alcohol, and nico- addiction are enormous. tine are included in addition to illicit drugs. In some The chief problem in treating drug addiction is cases, contact with a substance is so frequent and chronic or repeated relapse by those who have become socially accepted that many in society fail to recognize addicted in the above sense. Even after prolonged it as a “drug.” However, relatively few people develop periods of withdrawal and abstinence, a high percentage sufficient problems with drug use to meet the formal of addicted individuals in treatment programs eventu- criteria for addiction, even for potent illegal drugs ally relapse to drug taking. For example, in the case of such as cocaine or heroin. Drug addiction is character- a study of heroin users, relapse rates to reuse after cessa- ized by compulsive drug seeking, an impairment of tion were approximately 60% within 3 months and at social and psychological functions and/or damage to least 75% within 12 months. For this reason, drug addic- one’s health. It typically involves overwhelming tion is characterized as a chronic relapsing disorder; involvement with drug procurement and intake, a loss relapse is the rule rather than the exception and often of control, and a narrowing of interests away from other occurs repeatedly. forms of reward besides the drug of choice. According to There are three reasons frequently suggested to a 2004 survey, less than 10% of the US population meet explain relapse: (1) drug euphoria – that addicts resume the criteria for alcohol abuse or any illegal drug abuse drug taking to experience the intense pleasure Biological Research on Addiction, Volume 2 http://dx.doi.org/10.1016/B978-0-12-398335-0.00039-X 391 Copyright Ó 2013 Elsevier Inc. All rights reserved. Biological Research on Addiction, First Edition, 2013, 391–399 Author's personal copy 392 39. INCENTIVE SALIENCE AND THE TRANSITION TO ADDICTION (euphoria) they remember the drug producing; (2) over- also often occurs much later and even in fully “detoxi- learning habits or predictions – drug taking becomes such fied” addicts who are no longer experiencing any strong a well-entrenched habit that relapse is almost inevitable negative symptoms of withdrawal. Even if one adds or that learning becomes distorted in other ways to conditioned withdrawal that sometimes occurs later – create false predictions about drug rewards; and finally symptoms resurrected by drug cues – to the category of (3) withdrawal escape – that the withdrawal syndrome withdrawal, long-term feelings of withdrawal remain that accompanies the cessation of drug intake is so relatively infrequent and weak as a cause of relapse. unpleasant that an addict would do anything to stop it For example, McAuliffe reported that only 11 of 40 and so relapse occurs as an escape from withdrawal. (27.5%) heroin addicts reported experiencing condi- All these explanations certainly play a role in relapse, tioned withdrawal feelings at all, and only 2 (5%) said yet several considerations suggest that they leave out that it led them to ever resume drug use. Other reasons many situations where relapse occurs. for relapse must be more potent to explain why a detoxi- First, drug pleasure or euphoria certainly accounts for fied addict decides to take drugs again. In addition, the initial pattern of drug use and abuse, but may have addicts will often voluntarily undergo the unpleasant more difficulty in accounting for relapse. Some individ- process of withdrawal in detoxification clinics, some- uals actually have been described to experience times again and again, to reduce tolerance and the mone- a decrease in drug pleasure after prolonged use, due tary cost of their addiction and to possibly regain some of to development of tolerance, yet experience a simulta- the euphoria that comes with taking the drug. In short, neous increase in drug craving. Thus, relapse may occur withdrawal is not always highly avoided or so bad as at a moment of reduced drug pleasure but elevated drug to be the chief cause of addictive drug taking, and the craving. Also, relapse happens even in situations when end of withdrawal does not signal the end of addiction. addicts know that their drug will fail to lead to intense In contrast to these suggestions, the incentive sensiti- pleasure but rather to more misery. zation theory proposes an alternative view – that It has also been suggested that the repeated use of relapse frequently occurs as a result of drug-induced drugs creates a learning disorder or makes drug taking brain changes that lead to intense incentive motivation an overly ritualized habitual act. This may be true of for drugs, or pulses of “wanting” often triggered by the act of drug taking, but perhaps less so regarding drug cues, which may control behavior implicitly or the preceding flexible acts of drug seeking or drug sometimes may be experienced as feelings of drug craving. Learned habits or mispredictions alone cannot craving. Craving is defined as pathologically intense account for the excessive motivational attraction that feelings of wanting, which can be produced when drugs and their cues develop through the course of incentive salience (or core “wanting”) is translated addiction. The idea that addiction is merely a rigid into conscious awareness. At its core, the motivation stimulus–response habit does not account for how to take drugs is due to the overattribution of incentive motivation imbues the act of drug taking with compul- salience to drug-related stimuli. It is important to note sive overtones that cannot readily be overridden by that incentive salience is a distinct psychological the resolution to abstain. Other extremely well-learned process from withdrawal and drug pleasure. habits such as tying one’s shoes and brushing one’s teeth In particular, the incentive sensitization theory are not compulsive in a motivational sense – those habits proposed by Robinson and Berridge (1993) suggests can easily be left undone or stopped midway if one that craving and relapse are governed by a sensitized wishes, without experiencing a compulsive urge to neural system (mesocorticolimbic dopamine and related continue. The learning account as a rigid habit also fails systems) that normally functions to attribute incentive to explain the flexibility and resourcefulness that addicts salience to reward cues. This system transforms ordi- display when procuring drugs. nary stimuli, such as cues associated with rewards, Finally, many addictive drugs surely do induce into incentive stimuli, making them attractive and able homeostatic responses that oppose the primary drug to trigger an urge to pursue and consume their reward. effects and produce the phenomena of tolerance (when Repeated drug use produces sensitization of this brain drug is present) and withdrawal (when drug is absent). system, which leads to increased “wanting,” which in Withdrawal, in particular, is typically described as an turn leads to excessive control of behavior by drug- intense negative emotional state accompanied by related incentive stimuli. Addiction can therefore be dysphoria, anxiety, and irritability. Withdrawal may described as an excessive “wanting” problem. Impor- indeed be a potent reason why many addicts relapse tantly, excessive “wanting” can occur even in the and take drugs, at least while the withdrawal lasts. Yet, absence of excessive liking for drugs. In fact, the withdrawal is a relatively short-lived phenomenon and increasing dissociation that addicts exhibit between decays substantially within days to weeks. By contrast, how much they “want” drugs and the pleasure drugs while relapse frequently occurs during withdrawal, it produce explains many of the irrational features of II. NEUROSCIENCE Biological Research on Addiction, First Edition, 2013, 391–399 Author's personal copy THE INCENTIVE SENSITIZATION THEORY 393 behavior behind their drug-taking and drug-seeking frenzied bursts of effort to obtain the reward in habits. Irrational “wanting” for addictive drugs can Pavlovian-to-instrumental transfer (PIT) experiments. lead to persistent taking of drugs again and again Yet, sensitization does not increase “liking” reactions despite the adverse consequences and even if the that reflect the hedonic impact of the reward when it euphoria of drug consumption declines. actually arrives. Similarly, in humans who are becoming The basic mechanisms of the excessive attribution of drug tolerant, incentive motivation to take the drug can incentive salience to drugs and drug-related stimuli can grow as they become addicted, so that a single dose of even occur as a mostly unconscious process, creating urges drug can provoke intense urges to take more, even if to take drugs whether or not a strong subjective feeling of the person reports that the dose of drug no longer gives craving is simultaneously present. Such dissociation as much pleasure as it did initially. between acted-on motivation and confusing subjective It may be important to note that some neuroscientists feelings is what often renders the compulsive quality of initially questioned, after the incentive sensitization an addict’s own behavior astonishing even to him or her.