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5,6- and 5,7-Dihydroxytryptamines as Serotoninergic Neurotoxins

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Handbook of Neurotoxicity

Abstract

Dihydroxytryptamines are able to selectively destroy central serotonin neurons when catecholaminergic neurons are protected. Compared to serotonin, 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) are indole derivatives that acquire their neurotoxicity due to additional hydroxyl groups on the indole ring. Factors influencing the action of dihydroxytryptamines include the site of injection, the speed and volume of injection, the amount and type of antioxidant used, the type of anesthesia, and the dose and type of catecholamine uptake blocker. Two major hypotheses have been proposed to explain the molecular mechanism that underlies the toxicity of 5,6- and 5,7-DHT. The first suggests that highly reactive (electrophilic) quinonoid intermediates, created as a result of 5,6- and 5,7-DHT auto-oxidation, bind covalently to molecules indispensable for neuronal function. The second hypothesis states that during the auto-oxidation of dihydroxylated tryptamines, reactive oxygen species such as superoxide radical anion (O2 –), hydrogen peroxide (H2O2), and the hydroxyl radical (HO·) are generated as toxic by-products. The use of 5,6- and 5,7-DHT in both adult and neonatal animals enables the recognition the role of 5-HT in locomotor activity (LMA), prepulse inhibition, seizure susceptibility, sleeping behavior, feeding and drinking behavior, sexual and aggressive behavior, the regulation of body temperature, the response to novel and noxious stimuli, learning and memory, the antinociceptive action of drugs, neuroendocrine regulatory mechanisms, and developmental plasticity.

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Abbreviations

5-HT:

5-hydroxytryptamine, serotonin

5-HTP:

5-hydroxytryptophan

5,6-DHT:

5,6-dihydroxytryptamine

5,7-DHT:

5,7-dihydroxytryptamine

6-OHDA:

6-hydroxydopamine

CNS:

Central nervous system

DA:

Dopamine

DRN:

Dorsal raphe nuclei

DTPA:

Diethylene triamine pentaacetic acid

FSH:

Follicle-stimulating hormone

GH:

Growth hormone

GSH:

Glutathione

H2O2 :

Hydrogen peroxide

HO:

Hydroxyl radical

L-5-HTP:

5-hydroxy-L-tryptophan

LMA:

Locomotor activity

MAO:

Monoamine oxidase

MAOI:

Monoamine oxidase inhibitor

MRN:

Median raphe nuclei

NA:

Noradrenaline

NGF:

Nerve growth factor

O2 – :

Superoxide radical anion

PPI:

Prepulse inhibition

PTZ:

Pentylenetetrazol

REM:

Rapid eye movements

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

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  1. Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, ul. Sobieskiego 9, 02-957, Warsaw, Poland

    Justyna Paterak & Roman Stefański

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  1. Justyna Paterak
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  2. Roman Stefański
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Correspondence to Roman Stefański .

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

    Richard M. Kostrzewa

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Paterak, J., Stefański, R. (2014). 5,6- and 5,7-Dihydroxytryptamines as Serotoninergic Neurotoxins. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_76

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