The anhedonia hypothesis of drug addiction posits that drugs of abuse target the same neural systems as natural rewards such as food and sex. The most likely candidate brain region is the mesolimbic dopamine system. In animals, dopamine is released in the ventral striatum, or nucleus accumbens, in response to food, sexual mates, and to almost all drugs of abuse. There are several predictions one can make from the anhedonia hypothesis: (1) dopamine release in response to reinforcers will correlate with the degree of pleasure experienced; (2) natural reinforcers and drugs of abuse will release dopamine in the same brain areas; (3) aversive stimuli will not release dopamine. These predictions can be tested with PET experiments in human subjects. The method we use consists in comparing the binding potential of the D2 ligand [11C]raclopride in baseline and activation conditions. Studies in humans: Oral amphetamine and alcohol caused dopamine release in the ventral striatum in humans. The effect was greater in individuals with the novelty-seeking personality, a risk factor for addiction. The effect did not correlate with pleasure. However, while alcohol and amphetamine caused dopamine release in the ventral striatum, two natural rewards (money and food) targeted the main body and dorsal portion of the striatum. Thus there may be a dissociation between natural and drug rewards with respect to dopamine transmission. Another possibility is that conditioned rewarding stimuli target different brain regions than novel ones. We provided evidence for this second explanation by measuring dopamine release in response to smoking cigarettes in habitual smokers. Cigarette smoking caused dopamine release in the dorsal striatum. Finally, human and animal data suggest that hyper-responsiveness of the dopamine system may be a risk factor for addiction. How does dopamine hyper-responsiveness develop? We investigated this issue using two paradigms. We showed that poor parental bonding early in life was associated with a greater dopamine response to mental stress in adulthood. We also demonstrated sensitization in human subjects: we showed that repeated doses of oral amphetamine caused an enhanced response to subsequent amphetamine. This effect persisted after one year (See Figure 1).
