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Attenuation of MPTP-induced dopaminergic neurotoxicity by a serotonin uptake blocker
W J Brooks1, M F Jarvis, G C Wagner
1Department of Psychology, Rutgers State University, New Brunswick, New Jersey.
Abstract:
Monoamine oxidase-B (MAO-B) has been determined to be the enzyme responsible for the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into its toxic metabolite 1-methyl-4-phenylpyridine ion (MPP+). Since this enzyme has been localized primarily in astrocytes and serotonergic neurons, it would appear that MPP+ is being produced outside the dopaminergic neurons. To investigate this possibility, the administration of MPTP was preceded by systemically administered fluoxetine. In keeping with its demonstrated ability to inhibit uptake into serotonergic neurons and serotonin uptake into astrocytes, fluoxetine pretreatment resulted in a significant attenuation of MPTP-induced depletions of striatal dopamine and serotonin concentration. These results support the extra-dopaminergic production of MPP+.
Insights
Monoamine oxidase-B (MAO-B) converts MPTP into a toxic metabolite. Fluoxetine pretreatment prevented MPTP-induced dopamine and serotonin depletions, supporting extra-dopaminergic production of MPP+.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Monoamine oxidase-B (MAO-B) is implicated in converting MPTP to its toxic metabolite MPP+.
- MAO-B is primarily localized in astrocytes and serotonergic neurons, suggesting extra-dopaminergic MPP+ production.
Purpose of the Study:
- To investigate the site of MPP+ production following MPTP administration.
- To determine if fluoxetine pretreatment affects MPTP-induced neurotoxicity.
Main Methods:
- Systemic administration of MPTP.
- Pretreatment with fluoxetine, a selective serotonin reuptake inhibitor.
- Measurement of striatal dopamine and serotonin concentrations.
Main Results:
- Fluoxetine pretreatment significantly attenuated MPTP-induced depletions of striatal dopamine.
- Fluoxetine pretreatment also attenuated MPTP-induced depletions of striatal serotonin.
- These findings support the hypothesis that MPP+ is produced outside dopaminergic neurons.
Conclusions:
- MPP+ production occurs outside of dopaminergic neurons.
- Astrocyte and serotonergic neuron MAO-B activity contributes to MPTP neurotoxicity.
- Targeting extra-dopaminergic pathways may be a strategy for mitigating MPTP-induced damage.