Brain imaging studies have shown that reductions in striatal D2R in addicted subjects are associated with decreases in the activity of several prefrontal regions (Figure 3). These include the orbitofrontal cortex (involved in salience attribution and goal-directed behaviors), ACC (involved in inhibitory control and awareness), and the dorsolateral PFC (involved in higher cognitive operations and decision making) (35, 36, 48). Thus, improper DA modulation of these prefrontal regions in addicted subjects could underlie the enhanced incentive motivational value of drugs and the users’ loss of control over drug intake (41). Because impairments in the orbitofrontal cortex and ACC are associated with compulsive behaviors and impulsivity, we also postulate that DA’s impaired modulation of these regions could underlie the compulsive and impulsive drug taking in addiction (49, 50). Indeed, preclinical and clinical studies have shown that low striatal D2R levels are associated with impulsivity (51, 52), and in rodents, impulsivity predicts compulsive cocaine administration. In turn, overexpression of D2R in the striatum interferes with compulsive alcohol (53) and cocaine (54) intake. Imaging studies have also documented that in addicted subjects there
