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Selective decrease in extracellular DOPAC concentrations in rat striatum following in vivo dialysis with low
E J Caliguri1, J N Johannessen
1National Institute of Mental Health, Laboratory of Clinical Science, Bethesda, MD 20892.
Abstract:
Using the technique of in vivo dialysis, 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was applied to the rat striatum and the effects of this treatment on the efflux of striatal dopamine (DA) and metabolites were monitored. The inclusion of low concentrations of MPP+ (1 and 10 microM) in the dialysis solution caused a progressive decrease in the efflux of dihydroxyphenylacetic acid (DOPAC), the major deamination product of DA, while homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) remained unchanged. Unlike the effects of dialysis with millimolar concentrations of MPP+, a large increase in the efflux of striatal DA was not observed. The effect of dialysis with 1 microM MPP+ was blocked if 1 microM GBR 12909, a specific DA reuptake blocker, was included in the dialysis fluid, suggesting uptake of MPP+ into striatal DA terminals mediated this effect.
Insights
Low concentrations of 1-methyl-4-phenylpyridinium (MPP+) reduced dopamine metabolite efflux in rat striatum. This effect was blocked by a dopamine reuptake inhibitor, suggesting MPP+ uptake into dopamine terminals mediates its impact.
Area of Science:
- Neuroscience
- Neuropharmacology
- Toxicology
Background:
- 1-methyl-4-phenylpyridinium (MPP+) is the neurotoxic metabolite of MPTP.
- MPTP is implicated in Parkinsonism.
- Understanding MPP+ neurotoxicity mechanisms is crucial.
Purpose of the Study:
- To investigate the effects of low MPP+ concentrations on dopamine (DA) and its metabolites in the rat striatum.
- To elucidate the mechanism of MPP+ action on striatal neurotransmitter efflux.
Main Methods:
- In vivo dialysis technique was used to perfuse the rat striatum with MPP+.
- Efflux of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) was monitored.
- The effect of a dopamine reuptake blocker (GBR 12909) on MPP+ action was assessed.
Main Results:
- Low MPP+ concentrations (1 and 10 microM) progressively decreased DOPAC efflux.
- Homovanillic acid and 5-hydroxyindoleacetic acid efflux remained unchanged.
- A significant increase in striatal DA efflux was not observed with low MPP+ concentrations.
- The reduction in DOPAC efflux by 1 microM MPP+ was blocked by GBR 12909.
Conclusions:
- MPP+ uptake into striatal dopamine terminals, mediated by the dopamine transporter, appears to be responsible for its effects on dopamine metabolism.
- This suggests a specific mechanism of neurotoxicity distinct from high-concentration effects.
- Findings contribute to understanding the neurotoxic pathways relevant to MPTP-induced neurodegeneration.