Doses of GBR12909 that suppress cocaine self-administration in non-human primates substantially occupy dopamine transporters as measured by [C-11] WIN35,428 PET scans

GBR12909 (GBR) is a high-affinity, selective, and long-acting inhibitor of dopamine (DA) uptake that produces a persistent and noncompetitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular DA in the nucleus accumbens of rats. Prior studies showed tha t intravenous infusion of CBR to Rhesus monkeys selectively reduced (1 mg/k g) and eliminated (3 mg/kg) cocaine self-administration, This study tested the hypothesis that doses of GBR, that reduce cocaine self-administration i n nonhuman primates produce significant occupation of DA transporters. DA t ransporters were quantitated in two baboons using [C-11]WIN35,428 and posit ron emission tomography (PET). Each baboon underwent paired control/ blocke d PET scans (performed on three separate study days, 3-4 weeks apart). On t he first scan the baboon received saline (3 ml/kg) 90 minutes before the in jection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes befor e the second [C-11]WIN 35,428 study. The same experimental design was repea ted with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 m g/kg (n = 2), and 10 mg/kg (n = 2) reduced binding potential by 26, 53, and 72%, respectively. GBR was well tolerated in all baboons. These results de monstrate that doses of GBR that suppress cocaine self-administration in no nhuman primates also produce high occupancy of the DA transporter. These da ta strongly suggest that occupancy for the DA transporter by GBR explains i ts ability to attenuate cocaine-induced increases in extracellular DA and t o suppress cocaine self-administration. Moreover, these data suggest that e xperimental human studies of orally administered GBR to test the DA hypothe sis of cocaine addiction should use doses that produce at least 70% occupan cy of the DA transporter. Synapse 32:44-50, 1999. (C) 1999 Wiley-Liss, Inc.