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Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on retinal dopaminergic system in mice
W Ryan Hamilton1, William J Trickler, Bonnie L Robinson
1Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/USFDA, Jefferson, AR 72079, USA.
Abstract:
The neurotoxins methamphetamine (METH) and MPTP are well-known for their effects on the nigrostriatal dopaminergic system and use in modeling neurodegenerative disorders such as Parkinson's disease. It is not well-known though, how METH or MPTP affects the visual system and specifically the retinal dopaminergic system. This study was designed to examine acute effects of multiple doses of METH and MPTP on the retinal dopaminergic system. Mice were exposed to either low- (LD) 10 mg/kg total dose or high-dose (HD) 30 mg/kg total dose, of METH or MPTP and the retinal catecholaminergic system was analyzed by HPLC. METH produced no significant changes in dopamine (DA), its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) or DA usage in the retina. LD-MPTP produced no change in DA level, but significantly decreased DOPAC and HVA. LD-MPTP also significantly decreased DA usage as measured by the DOPAC/DA and HVA/DA ratios. HD-MPTP significantly decreased DA, DOPAC and HVA, but did not affect DA usage. Taken together these results suggest that inhibition of the DA metabolizing enzymes monoamine oxidase A (MAO) or catechol-O-methyl transferase (COMT) may take place at lower doses of MPTP treatment; conversely, higher doses of MPTP may cause decreases in DA, DOPAC and HVA through another mechanism.
Insights
MPTP, but not methamphetamine, impacts the retinal dopaminergic system. Low-dose MPTP reduced dopamine metabolites and usage, while high-dose MPTP decreased dopamine and its metabolites.
Area of Science:
- Neuroscience
- Toxicology
- Ophthalmology
Background:
- Methamphetamine (METH) and MPTP are known neurotoxins affecting the nigrostriatal dopaminergic system.
- Their impact on the visual system, particularly the retinal dopaminergic system, is less understood.
Purpose of the Study:
- To investigate the acute effects of varying doses of METH and MPTP on the retinal dopaminergic system.
- To analyze changes in dopamine (DA) and its metabolites in the retina following exposure.
Main Methods:
- Mice were administered low (10 mg/kg) or high (30 mg/kg) doses of METH or MPTP.
- Retinal catecholaminergic systems were analyzed using High-Performance Liquid Chromatography (HPLC).
- Dopamine usage was assessed via DOPAC/DA and HVA/DA ratios.
Main Results:
- METH exposure did not significantly alter retinal DA, DOPAC, HVA, or DA usage.
- Low-dose MPTP (LD-MPTP) did not change DA levels but significantly decreased DOPAC and HVA, indicating reduced DA metabolism and usage.
- High-dose MPTP (HD-MPTP) significantly decreased DA, DOPAC, and HVA, but did not affect DA usage ratios.
Conclusions:
- MPTP significantly affects the retinal dopaminergic system, unlike METH.
- Low-dose MPTP may inhibit dopamine-metabolizing enzymes (MAO, COMT), reducing DA metabolite levels and usage.
- High-dose MPTP appears to decrease overall DA levels and its metabolites through a different mechanism than enzyme inhibition.
