Regional and temporal expression of the peripheral benzodiazepine receptor in MPTP neurotoxicity.
We used the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to evaluate the sensitivity and specificity of the peripheral benzodiazepine receptor (PBR) as a biomarker of chemical-induced neurotoxicity. Receptor autoradiography of [3H]-PK11195, a PBR selective ligand, indicated dose-dependent increases throughout the nigrostriatal dopaminergic system as early as 24 h after MPTP administration (10-80 mg/kg), which persisted for at least 21 days. The binding of [3H]-PK11195 was increased as much as 98% in the corpus striatum and 114% in the substantia nigra, following MPTP exposure. The integrity of nigrostriatal dopaminergic terminals in the corpus striatum was assessed by measuring high affinity dopamine transporter (DAT) levels and dopamine content. DAT levels were measured by [3H]-WIN 35,428 autoradiography, and dopamine content decreased with increasing MPTP dose. Reductions of both indices of dopaminergic terminal integrity correlated with increased levels of [3H]-PK11195-binding in the striatum (r2 = 0.84 for DAT and 0.93 for dopamine content). Tyrosine hydroxylase (TH) immunohistochemistry demonstrated dose-dependent reductions of dopaminergic neurons in the substantia nigra pars compacta, with a 67% loss measured 7 days after treatment with 80 mg/kg MPTP. The loss of TH-positive neurons was correlated (r2 = 0.95) with increased levels of [3H]-PK11195 binding in the substantia nigra. These findings demonstrate that the PBR is both sensitive and specific for identifying brain regions involved in MPTP neurotoxicity.
D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism