The authors postulated that certain pharmacological properties of cocaine would trigger the pathological activation of a cerebral circuit that enabled the maintenance of behaviors required to achieve a targeted biological goal. The PET imaging technique was used to measure the concentration of positron emitter labeled compounds in the living brain. Two approaches were employed: (1) characterize cocaine binding in the baboon brain and investigate its pharmacokinetics in the human brain; and (2) compare cocaine behavior with that of methylphenidate, a drug which inhibits the dopamine transporter like cocaine but which is abused in humans much less frequently than cocaine. Results showed that the very fast uptake and clearance of cocaine from the brain contrasted with that of methylphenidate. Methylphenidate cleared from the brain at a much slower rate and was less addictive than cocaine. The authors believe periodic and frequent stimulation of the dopaminergic system secondary to chronic cocaine use favors activation of a circuit that involves the orbitofrontal cortex, cingulate gyrus, thalamus, and striatum. This circuit is abnormal in cocaine abusers, perpetuates compulsive cocaine administration, and is perceived by the cocaine abuser as a more intense desire resulting in the loss of control over the drive to use more cocaine. 49 references, 1 table, and 6 figures