Doses of GBR12909 that suppress cocaine self-administration in non-human primates substantially occupy dopamine transporters as measured by [11C] 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 that intravenous infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self-administration. This study tested the hypothesis that doses of GBR that reduce cocaine self-administration in nonhuman primates produce significant occupation of DA transporters. DA transporters were quantitated in two baboons using [11C]WIN35,428 and positron emission tomography (PET). Each baboon underwent paired control/blocked PET scans (performed on three separate study days, 3-4 weeks apart). On the first scan the baboon received saline (3 ml/kg) 90 minutes before the injection of the radiotracer. GBR (1 mg/kg i.v.) was infused 90 minutes before the second [11C]WIN 35,428 study. The same experimental design was repeated with GBR doses of 3 and 10 mg/kg, respectively. Doses of 1 (n = 2), 3 mg/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 demonstrate that doses of GBR that suppress cocaine self-administration in nonhuman primates also produce high occupancy of the DA transporter. These data strongly suggest that occupancy for the DA transporter by GBR explains its ability to attenuate cocaine-induced increases in extracellular DA and to suppress cocaine self-administration. Moreover, these data suggest that experimental human studies of orally administered GBR to test the DA hypothesis of cocaine addiction should use doses that produce at least 70% occupancy of the DA transporter.
Villemagne
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VL
Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-0807, USA.
Rothman
R B
RB
Yokoi
F
F
Rice
K C
KC
Matecka
D
D
Dannals
R F
RF
Wong
D F
DF
D000818:Animals; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D003864:Depression, Chemical; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010215:Papio; D010879:Piperazines / Q000494:pharmacology*; D012646:Self Administration; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine