Dopamine transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans

Objectives: Recent studies using positron emission tomography (PET) have es tablished the relationship between an intravenous dose of cocaine and the p ercentage occupancy of the dopamine transporter in humans, and have documen ted the requirement of more than 50% occupancy for perception of the "high" . The present experiments were conducted to examine dose-occupancy and dose -effect relationships in mice for cocaine and also for methylphenidate, a d opamine uptake blocker used in pediatric psychiatry, Methods: Percentage oc cupancies of the dopamine transporter by cocaine and methylphenidate were e stimated after intravenous injection in mice from the displacement of in vi vo binding of [H-3]cocaine from the striatum. Locomotor activity was measur ed in a photocell apparatus. Results. The relationship between drug doses ( milligrams of hydrochloride salt per kilogram body weight) and percentage o ccupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dos e and transporter occupancy, previously measured in human and baboons using [C-11]cocaine or [C-11]D-threo-methylphenidate and PET. Methylphenidate in creased locomotor activity in the mice substantially more than cocaine at t he same dose and the same degree of dopamine-transporter receptor occupancy . Conclusions: The range of dopamine-transporter occupancy required for beh avioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced "high" in human su bjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were fo und to have Very similar psychopharmacological properties.