No abstract

Addictive drugs act on brain reward systems, although the brain evolved to respond not to drugs but to natural rewards, such as food and sex. Appropriate responses to natural rewards were evolutionarily important for survival, reproduction, and fitness. In a quirk of evolutionary fate, humans discovered how to stimulate this system artificially with drugs. Many molecular features of neural systems instantiating reward, and of those systems affected by addictive drugs, are conserved across species from Drosophilae to rats to humans and include dopamine (DA), G-proteins, protein kinases, amine transporters, and transcription factors such as cAMP response element-binding protein (CREB). A better understanding of natural brain reward systems will therefore enhance understanding of the neural causation of addiction.

The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentive-sensitization theory of addiction", which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.

Amphetamine microinjection into the nucleus accumbens shell enhanced the ability of a Pavlovian reward cue to trigger increased instrumental performance for sucrose reward in a pure conditioned incentive paradigm. Rats were first trained to press one of two levers to obtain sucrose pellets. They were separately conditioned to associate a Pavlovian cue (30 sec light) with free sucrose pellets. On test days, the rats received bilateral microinjection of intra-accumbens vehicle or amphetamine (0.0, 2.0, 10.0, or 20.0 g/0.5 l), and lever pressing was tested in the absence of any reinforcement contingency, while the Pavlovian cue alone was freely presented at intervals throughout the session. Amphetamine microinjection selectively potentiated the cue-elicited increase in sucrose-associated lever pressing, although instrumental responding was not reinforced by either sucrose or the cue during the test. Intra-accumbens amphetamine can therefore potentiate cue-triggered incentive motivation for reward in the absence of primary or secondary reinforcement. Using the taste reactivity measure of hedonic impact, it was shown that intra-accumbens amphetamine failed to increase positive hedonic reaction patterns elicited by sucrose (i.e., sucrose "liking") at doses that effectively increase sucrose "wanting." We conclude that nucleus accumbens dopamine specifically mediates the ability of reward cues to trigger "wanting" (incentive salience) for their associated rewards, independent of both hedonic impact and response reinforcement.

The question of addiction speci cally concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentivesensitization theory of addiction", which we rst proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor suf cient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.