new england journal
mechanisms of disease
Jordi Camí, M.D., Ph.D., and Magí Farré, M.D., Ph.D.
rug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences. Addictive substances induce pleasant states (euphoria in the initiation phase)or relieve distress. Continued use induces adaptive changes in the central nervous system that lead to tolerance, physical dependence, sensitization, craving, and relapse (Table 1). The addictive drugs discussed here are opioids, cannabinoids, ethanol, cocaine, amphetamines, and nicotine. The World Health Organization1 and the American Psychiatric Association2 use the term “substance dependence”rather than “drug addiction.” “Drug addiction,” however, emphasizes the behavioral connotation of the term and is less likely to be confused with physical dependence.3 We use both terms interchangeably in this review. The American Psychiatric Association’s definition of substance dependence2 requires a patient to meet at least three of the seven criteria listed in Table 1. Tolerance and physicaldependence reflect physiological adaptation to the effects of a drug, whereas the remaining criteria define uncontrollable drug consumption. However, tolerance and physical dependence are neither necessary nor sufficient for a diagnosis of substance dependence. Substance abuse2 or harmful use,1 a less severe disorder, may result in dependence. Theories of addiction have mainly been developed fromneurobiologic evidence and data from studies of learning behavior and memory mechanisms. They overlap in some aspects and are not mutually exclusive. None of them alone can explain all aspects of addiction. It is not our purpose to present a detailed assessment of these theories, especially because of the complexity of the problem. Generally, addictive drugs can act as positive reinforcers(producing euphoria) or as negative reinforcers (alleviating symptoms of withdrawal or dysphoria). Environmental stimuli (cues) associated with drug use itself can also induce a conditioned response (withdrawal or craving) in the absence of the drug.4,5 Koob and Le Moal6,7 have proposed that the organism tries to counteract the effects of a given drug through a vicious circle in which the hedonic setpoint (the point at which pleasure is achieved) continually changes in response to the administration of the substance. They argue that drug addiction results from dysregulation of the reward mechanism and subsequent allostasis, the ability to achieve stability through change. Robinson and Berridge8,9 emphasize the dissociation between the incentive value of the drug (“wanting”) and its pleasurable orhedonic effects (“liking”), so that the brain system involved in the reward mechanism becomes hypersensitized to both the direct effects of the drug and associated stimuli that are not directly attributable to the drug. This hypersensitization causes pathologic wanting, or craving, independently of the presence of withdrawal symptoms and leads to compulsive drug-seeking and drug-taking behavior.Although liking progressively decreases, drugs become pathologically wanted (craving). Complementary to this incentive–sensitization theory,8,9 compulsive drug-seeking and drug-taking behavior is facilitated by difficulties in decision making and the ability to judge the consequences of one’s own actions. These cognitive difficulties have been linked to deficits in the activation of areas in theprefrontal cortex.10,11 An overlap in
n engl j med 349;10 september 4, 2003
From the Institut Municipal d’Investigació Mèdica (J.C., M.F.), Universitat Pompeu Fabra (J.C.), and Universitat Autònoma de Barcelona (M.F.) — all in Barcelona, Spain. Address reprint requests to Dr. Camí at Institut Municipal d’Investigació Mèdica, Doctor Aiguader 80, E-08003 Barcelona, Spain, or at email@example.com. N...
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