The Dopamine Hypothesis of Addiction
In the earliest version of the hypothesis described, mesolimbic dopamine was believed to be the neurochemical cor-relate of pleasure and reward. However, during the past decade, experimental evidence has led to several revisions. Phasic dop-amine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneer-ing 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 situ-ation. It increases its activity when reward is larger than expected, and shuts down in the opposite case, thus coding for the predic-tion error of reward.
Under physiologic conditions the mesolimbic dopamine sig-nal could represent a learning signal responsible for reinforcing 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 observa-tion is that mice genetically modified to lack the primary molecu-lar target of cocaine, the dopamine transporter DAT, stillself-administer the drug. Only when transporters of other bio-genic 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 dop-amine. When cocaine is given, these transporters are also inhib-ited and dopamine is again increased. As a consequence of this substitution among monoamine transporters, fluoxetine (a selec-tive serotonin reuptake inhibitor,) 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 abolishes 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 negative reinforcers) also activate a subpopulation of dopamine neurons in the VTA. Some of the neurons that are activated by aversive stimuli do in fact release dopamine, while the majority of dopamine neurons are actually inhibited by aversive stimuli. These recent findings suggest that in parallel to the reward sys-tem, a system for aversion-learning originates in the VTA.
Regardless of the many roles of dopamine under physiologic conditions, all addictive drugs significantly increase its concen-tration 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 techniques that allow controlling the activity of dopamine neurons in vivo. In fact manipulations that drive sustained activity of VTA dop-amine neurons cause the same cellular adaptations and behav-ioral changes typically observed with addictive drug exposure.