Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans.

We summarize our studies with positron emission tomography investigating the role of dopamine (DA) in the reinforcing effects of cocaine and methylphenidate in humans and its involvement in cocaine addiction. These studies have shown that the rate at which cocaine and methylphenidate enter the brain and block the dopamine transporters (DAT) is the variable associated with the 'high', rather than the presence per se of the drug in the brain. Our studies also show that, while the level of DAT blockade is important in predicting the intensity of the 'high' induced by these drugs (DAT blockade > 50% is required for these drugs to induce a 'high'), the rate at which DAT are blocked determines whether the 'high' is perceived or not. Thus, oral methylphenidate, which leads to slow DAT blockade, does not induce a 'high', even at doses which block DAT more than 60%. In cocaine abusers, we have shown significant reductions in DA D2 receptors that are associated with decreased metabolism in cingulate gyrus and in orbitofrontal cortex. We suggest that this is one of the mechanisms by which DA disruption leads to compulsive drug administration in cocaine addiction. Cocaine abusers also show significant decreases in DA release, which coupled with the reduction in D2 receptors may result in decreased activation of reward circuits by physiological reinforcers and may perpetuate cocaine use as a means to compensate for this deficit. Thus, strategies to enhance DA brain function in ways that mimic physiological DA activity may be of help in overcoming cocaine addiction.