In the earliest version of the hypothesis described in this chapter, mesolimbic dopamine was believed to be the neurochemical correlate of pleasure and reward. However, during the past decade, experimental evidence has led to several revisions. Pha-sic dopamine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneering observations in monkeys that dopamine neurons in the ventral tegmental area (VTA) are most efficiently activated by a reward (eg, a few drops of fruit juice) that is not anticipated. When the animal learns to predict the occurrence of a reward (eg, by pairing it with a stimulus such as a sound), dopamine neurons stop responding to the reward itself (juice), but increase their firing rate when the conditioned stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons are inhibited below their baseline activity and become silent. In other words, the mesolimbic system continuously scans the reward situation. It increases its activity when reward is larger than expected and shuts down in the opposite case, thus coding for the prediction error of reward. Under physiologic conditions the mesolimbic dopamine signal could represent a learning signal responsible for reinforc-ing constructive behavioral adaptation (eg, learning to press a lever for food). Addictive drugs, by directly increasing dopamine, would generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforce-ment. As a consequence, behavior becomes compulsive; that is, decisions are no longer planned and under control, but auto-matic, which is the hallmark of addiction. This appealing hypothesis has been challenged based on the observation that some reward and drug-related learning is still possible in the absence of dopamine. Another intriguing observation is that mice genetically modified to lack the primary molecular target of cocaine, the dopamine transporter DAT, still self-administer the drug. Only when transporters of other biogenic amines are also knocked out does cocaine completely lose its rewarding properties. However, in DAT –/– mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive monoamine transporters (NET, SERT) are able to clear some dopamine. When cocaine is given, these transporters are also inhibited and dopamine is again increased. As a conse-quence of this substitution among monoamine transporters, fluoxetine (a selective serotonin reuptake inhibitor, see Chapter 30) becomes addictive in DAT –/– mice. This concept is supported by newer evidence showing that deletion of the cocaine-binding site on DAT leaves basal dopamine levels unchanged but abol-ishes the rewarding effect of cocaine. The dopamine hypothesis of addiction has also been chal-lenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore nega-tive reinforcers) also activate a subpopulation of dopamine neu-rons in the VTA. The neurons that are activated by aversive stimuli preferentially project to the prefrontal cortex, while the dopamine neurons inhibited by aversive stimuli are those that mostly tar-get the nucleus accumbens. These recent findings suggest that in parallel to the reward system, a system for aversion-learning originates in the VTA, which may be at the origin of the negative affective state seen during drug withdrawal. Regardless of the many roles of dopamine under physi-ologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic projection. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction, a concept that is now supported by novel tech-niques that allow controlling the activity of dopamine neurons in vivo. In fact manipulations that drive sustained activity of VTA dopamine neurons cause the same cellular adaptations and behavioral changes typically observed with addictive drug exposure, including late-stage symptoms such as persistence of self-stimulation during punishment.