Dopaminergic modulation of frontal activity: involvement in cocaine addiction

Using positron emission tomography (PET) and a multiple tracer approach, we have documented disruption of brain dopamine activity in chronic cocaine abusers that is associated with decreased metabolic activity in frontal cortex which we postulate accounts in part for the loss of control and the compulsive intake of cocaine in the cocaine addict. To further investigate the relationship between dopamine activity and frontal metabolism observed in the cocaine abusers, we have used a drug challenge paradigm with methylphenidate (MP; 0.5 mg/kg, i.v.) to increase brain dopamine. We have evaluated its effects on frontal glucose metabolism and on [11C]raclopride binding in normal control individuals and in cocaine abusers. Because [11C]raclopride binding has a relatively low affinity, it competes with endogenous dopamine for binding to the receptor and has been used successfully in the human brain to assess relative changes in dopamine concentration. Thus, this dual tracer strategy allows us to assess relative changes in dopamine induced by MP and to compare these with the effects on brain glucose metabolism. These studies have shown that: (1) the effects of MP on regional brain glucose metabolism are different when administered in one single dose than when administered in repeated sequential doses; (2) the MP-induced changes in regional brain glucose metabolism are different in individuals who have never been exposed to stimulants than in chronic cocaine abusers; (3) the rate of change in dopamine concentration secondary to MP is significantly correlated with the changes in metabolism in prefrontal and cingulate cortices.