title: Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]WIN-35,428 positron emission tomography studies and direct in vitro determinations.
abstract: The present study sought to determine whether doses of methamphetamine in the range of those used recreationally by humans produce brain dopamine (DA) neurotoxicity in baboons and to ascertain whether positron emission tomography (PET) imaging with the DA transporter (DAT) ligand [11C]WIN-35,428 ([11C]2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane) could be used to detect methamphetamine-induced DAT loss in living primates. Baboons were treated with saline (n = 3) or one of three doses of methamphetamine [0.5 mg/kg (n = 2); 1 mg/kg (n = 2); and 2 mg/kg (n = 3)], each of which was given intramuscularly four times at 2 hr intervals. PET studies were performed before and 2-3 weeks after methamphetamine treatment. After the final PET studies, animals were killed for direct neurochemical determination of brain DA axonal markers. PET-derived binding potential values, used to index striatal DAT density, were significantly decreased after methamphetamine, with larger decreases occurring after higher methamphetamine doses. Reductions in striatal DAT documented by PET were associated with decreases in DA, dihydroxyphenylacetic acid, and specific [3H]WIN-35,428 and [3H]DTBZ binding determined in vitro. Decreases in DAT detected with PET were highly correlated with decreases in specific [3H]WIN-35,428 binding determined in vitro in the caudate of the same animal (r = 0.77; p = 0.042). These results indicate that methamphetamine, at doses used by some humans, produces long-term reductions in brain DA axonal markers in baboons, and that it is possible to detect methamphetamine-induced DAT loss in living nonhuman primates by means of PET.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: V
authors.initials: V
authors.lastname: Villemagne
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: D F
authors.initials: DF
authors.lastname: Wong
authors.forename: R F
authors.initials: RF
authors.lastname: Dannals
authors.forename: G
authors.initials: G
authors.lastname: Hatzidimitriou
authors.forename: W B
authors.initials: WB
authors.lastname: Mathews
authors.forename: H T
authors.initials: HT
authors.lastname: Ravert
authors.forename: J
authors.initials: J
authors.lastname: Musachio
authors.forename: U D
authors.initials: UD
authors.lastname: McCann
authors.forename: G A
authors.initials: GA
authors.lastname: Ricaurte
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008454:Mazindol; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology*; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000378:metabolism; D010215:Papio / Q000502:physiology*; D019966:Substance-Related Disorders / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D014055:Tomography, Emission-Computed; D014316:Tritium
chemical_list: 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; D009498:Neurotoxins; C493214:SLC6A3 protein, human; D014316:Tritium; D008694:Methamphetamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D008454:Mazindol; D003042:Cocaine; D004298:Dopamine