Differential time courses of exogenous 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine and its metabolite MPP+ in the rat striatum and nucleus accumbens measured using in vivo voltammetry.
The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) has been shown to affect nigrostriatal projection neurons to a greater extent than substantia nigra neurons that project to the nucleus accumbens. To investigate this preferential vulnerability, the intracerebral pharmacokinetics of locally-applied MPTP was investigated using in vivo voltammetry. First, we examined whether MPTP and MPP+ were measurable in vitro. At the most efficient oxidation potential for MPTP (850 mV), its metabolite MPP+ was also partly oxidized, whereas at that for MPP+ (650 mV), MPTP was not oxidized. Then, in vivo measurements were taken less than 1 mm from the site of infusion of MPTP. MPTP and endogenously produced MPP+ peaked later and took longer to return to baseline in the nucleus accumbens than in the striatum. Systemic monoamine oxidase-B inhibitor pargyline delayed the peak and return to baseline of endogenously produced MPP+ in the nucleus accumbens. Exogenously applied MPP+ also took longer to peak and return to baseline in the nucleus accumbens. These results indicate that the difference in the pharmacokinetics of exogenously applied MPTP in the striatum and nucleus accumbens may be due to a difference in uptake in these regions, and that the difference in pharmacokinetics of endogenously produced MPP+ may be due to differences in both uptake and monoamine oxidase-B activity.
Nakazato
T
T
Department of Physiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. nakazato@med.juntendo.ac.jp
Akiyama
A
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004563:Electrochemistry; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism*; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium