title: Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors.
abstract: Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between drug-induced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [(11)C]raclopride, a dopamine D(2) receptor radioligand that competes with endogenous dopamine for occupancy of the D(2) receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for self-reports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the "high" induced by methylphenidate was significantly correlated with the levels of released dopamine (r = 0.78, p <.001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D(2) receptor occupancy by dopamine and the intensity of the high.
authors.affiliation: Brookhaven National Laboratory, Upton, New York, USA. volkow@bnl.gov
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
authors.forename: G J
authors.initials: GJ
authors.lastname: Wang
authors.forename: J S
authors.initials: JS
authors.lastname: Fowler
authors.forename: J
authors.initials: J
authors.lastname: Logan
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: C
authors.initials: C
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Hitzemann
authors.forename: N R
authors.initials: NR
authors.lastname: Pappas
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D011877:Radionuclide Imaging; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012054:Reinforcement, Psychology
chemical_list: D000697:Central Nervous System Stimulants; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D004298:Dopamine