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2′-NH2-MPTP: A Serotonin and Norepinephrine Neurotoxin

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Handbook of Neurotoxicity

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Abstract

Altered serotonin and norepinephrine neurotransmission has been implicated in a variety of psychiatric and neurodegenerative diseases. Selective ablation of these systems represents one avenue for studying their roles in normal behavior, disease processes, and therapeutic interventions. 2′-NH2-MPTP, an amine-substituted analog of the dopaminergic neurotoxin MPTP, can be used to degenerate serotonin and/or norepinephrine forebrain innervation to investigate pathophysiological and behavioral consequences in several strains of mice, rats, and nonhuman primates. 2′-NH2-MPTP is converted to a toxic metabolite by monoamine oxidase type-A and type-B. This metabolite, a presumed pyridinium, is a substrate for serotonin and norepinephrine transporters. Acute effects immediately following 2′-NH2-MPTP administration are characteristic of serotonin syndrome. Genetic, biochemical, and immunocytochemical evidence indicates that neurodegeneration caused by 2′-NH2-MPTP is selective, long lasting, and occurs by an oxyradical mechanism.

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Abbreviations

2′-NH2-MPP+ :

1-Methyl-4-(2′-aminophenyl)-phenylpyridinium

2′-NH2-MPTP:

1-Methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine

5-HIAA:

5-Hydroxyindoleacetic acid

5-HT:

5-Hydroxytryptamine serotonin

5,6-DHT:

5,6-Dihydroxytryptamine

5,7-DHT:

5,7-Dihydroxytryptamine

BDNF:

Brain-derived neurotrophic factor

CSF:

Cerebrospinal fluid

DA:

Dopamine

DAT:

Dopamine transporter

DOPAC:

3,4Dihydroxyphenylacetic acid

DSP-4 N:

(2-Chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride

GFAP:

Glial fibrillary acidic protein

HVA:

Homovanillic acid

Ip:

Intraperitoneal

Iv:

Intravenous

LD50 :

Median lethal dose

MAO-A:

Monoamine oxidase type-A

MAO-B:

Monoamine oxidase type-B

MHPG:

3-Methoxy-4-hydroxyphenylglycol

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NE:

Norepinephrine

NET:

Norepinephrine transporter

PET:

Positron emission tomography

Ro 4–1284:

2-Hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,5,6,7-hexahydrobenzo[a]chinolizine

SERT:

Serotonin transporter

VMAT2:

Vesicular monoamine transporter type-2

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Authors and Affiliations

  1. David Geffen School of Medicine, Department of Chemistry and Biochemistry, Semel Institute for Neuroscience and Human Behavior, and Hatos Center for Neuropharmacology, University of California, Los Angeles, CA, 90095, USA

    Jason B. Ochroch, Amanda J. Bressler, Hongyan Yang, Stefanie C. Altieri & Anne M. Andrews

  2. Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA

    Dennis L. Murphy

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  1. Jason B. Ochroch
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  2. Amanda J. Bressler
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  3. Hongyan Yang
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  4. Dennis L. Murphy
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  5. Stefanie C. Altieri
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  6. Anne M. Andrews
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Correspondence to Jason B. Ochroch .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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© 2014 Springer Science+Business Media New York

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Ochroch, J.B., Bressler, A.J., Yang, H., Murphy, D.L., Altieri, S.C., Andrews, A.M. (2014). 2′-NH2-MPTP: A Serotonin and Norepinephrine Neurotoxin. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_77

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