Novel pharmacokinetic model to estimate dopamine dynamics in humans using PET

Abstract Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine enhancing medication widely used to treat attention-deficit/hyperactivity disorder, has rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster when injected than when taken orally, we hypothesized that the amplitude and the speed of dopamine release in striatum would underly drug reward. To test this hypothesis we developed a non-invasive method to assess methylphenidate-related extracellular dopamine increases at 1-minute temporal resolution using positron emission tomography, which we validated in preclinical microdialysis data. Using a placebo-controlled double-blind within-subjects design, we show in 20 healthy controls that striatal dopamine increases induced by intravenous methylphenidate (0.25 mg/kg) were significantly faster than those induced by oral methylphenidate (60 mg) and that the time-to-peak of dopamine release was strongly associated with the intensity of self-reports of feeling “high”. With this novel approach we show for the first time in humans that stronger drug reward is associated with shorter dopamine time-to-peak after methylphenidate administration.