Long-term methamphetamine-induced decreases of [(11)C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey.
The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatment on methamphetamine (METH)-induced striatal dopamine system deficits in the vervet monkey were characterized with [(11)C]WIN 35,428 (WIN)-positron emission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine terminal integrity. In two subjects, GDNF (200 microg/40 microl) was injected into the caudate and putamen unilaterally vs. saline contralaterally. After 1-2 weeks, + and -GDNF striatal WIN-PET binding values were equivalent as calculated by multiple time graphic analysis, suggestive of an absence of unilateral DAT up-regulation. Three other subjects (n = 3) received GDNF injections into the caudate and putamen unilaterally and one week later, were administered METH HCl (2 x 2 mg/kg; i.m., 24 hours apart; a neurotoxic dosage for this species). At 1 week post-METH, WIN-PET studies showed that mean WIN binding was decreased by 72% in the +GDNF and by 92% in the -GDNF striatum relative to pre-drug assessment values. Thus, GDNF pretreatment reduced the extent of METH-induced decreases in WIN binding. Subsequent WIN-PET studies (1.5-9-month range) showed a protracted recovery of WIN binding in each striatum, indicative of long-term but partially reversible METH neurotoxicity. Further, at each time point, WIN binding remained relatively higher in the +GDNF vs. -GDNF striatum. These results provide further evidence that the adult non-human primate brain remains responsive to exogenously administered GDNF and that this pharmacotherapy approach can counteract aspects of neurotoxic actions associated with methamphetamine.
Melega
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WP
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles CA 90095-1735, USA. wmelega@mednet.ucla.edu
Lacan
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Desalles
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Phelps
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ME
D000818:Animals; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000633:toxicity*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D008694:Methamphetamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine