Effect of MPTP on Serotonergic Neuronal Systems and Mitochondrial Complex I Activity in the Living Brain: A PET Study...

The objective of the present PET study was to compare the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on serotonergic neuronal systems and mitochondrial complex I (MC-I) activity with that of dopamine in conscious rhesus monkeys (Macaca mulatta). Methods: A Parkinson disease monkey model was prepared by repeated administration of MPTP. For the PET measurements, normal and MPTP-treated conscious monkeys received an intravenous injection of ¹¹C-DASB for serotonin transporter, ¹⁸F-MPPF for serotonin 1A receptor, ¹¹C-PE2I for dopamine transporter, ¹¹C-6MemTyr for dopamine synthesis, ¹¹C-raclopride for dopamine D₂ receptor, or ¹⁸F-BCPP-EF for MC-I. Serotonin and dopamine parameters were calculated using time-activity curves in the cerebellum as the input function. The total distribution volume of ¹⁸F-BCPP-EF was assessed using Logan plot graphical analysis with metabolite-corrected plasma as the input function. Results: MPTP-induced diffuse reductions in MC-I activity were observed throughout the brain, except the cerebellum. Significant reductions in the presynaptic dopamine parameters-dopamine transporter and dopamine synthesis-were detected in the striatum and substantia nigra pars compacta of MPTP-treated monkeys, whereas no significant differences in postsynaptic dopamine D₂ receptor binding were observed. Serotonin transporter binding was reduced by MPTP not only in striatal regions but also in extrastriatal regions. In contrast, serotonin 1A receptor binding was unaffected by MPTP anywhere in the brain. In the cortex, the reduction of serotonin transporter binding correlated with that of MC-I. Conclusion: The results obtained by multiparametric PET measurements in a Parkinson disease monkey model demonstrated that chronic MPTP treatment induced reductions not only in the dopaminergic system in the nigrostriatal pathway but also in serotonin transporter in the cortical and subcortical regions. These results suggest that the neurotoxicity of MPTP is not exclusive to the nigrostriatal pathway, as predicted from MC-I damage in the extrastriatal regions of the brain.