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Handbook of Neurotoxicity pp 219–236Cite as

Nature of DSP-4-Induced Neurotoxicity

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Abstract

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a noradrenergic neurotoxin which selectively damages noradrenergic projections originating from the locus coeruleus (LC) and transiently alters sympathetic neurons in the periphery. DSP-4 accumulates intraneuronally and produces nerve terminal degeneration via alkylation of diverse neuronal structures. DSP-4 inhibits norepinephrine (NE) reuptake, stimulates NE release, and increases turnover rate of NE. Systemic administration of DSP-4 has a rapid dose-dependent depleting effect on the endogenous NE level. The effect of DSP-4 is largely restricted to noradrenergic neurons; however, DSP-4 slightly reduces the level of 5-hydroxytryptamine and dopamine. The rat age at the time of DSP-4 injection is important in determining the nature of the long-term changes in the noradrenergic system. Thus, DSP-4 treatment of adult rats produces morphological changes of NE neurons with a pronounced decrease in NE levels in the cerebral cortex, hippocampus, spinal cord, and cerebellum. Less affected are the hypothalamus and pons-medulla. This process is not long lasting and after several months a regeneration of NE nerve terminals is observed. DSP-4 injected to newborn rats induces an alteration of the postnatal development of noradrenergic system with a permanent NE denervation in brain areas distal to LC cell bodies (cortex and hippocampus) and a hyperinnervation in regions proximal to LC (brainstem, cerebellum, and pons-medulla). This type of hyperinnervation does not exist after DSP-4 treatment of adult animals. The noradrenergic lesion obtained with DSP-4 is highly reproducible; therefore, DSP-4 may represent a suitable tool to discern LC neuron degeneration and recovery and to investigate the projections of non-coerulean NE neurons.

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Abbreviations

5-HIAA:

5-hydroxyindoleacetic acid

5-HT:

Serotonin

AD:

Aldehyde dehydrogenase

AR:

Aldehyde reductase

CNS:

Central nervous system

COMT:

Catechol-O-methyl transferase

DA:

Dopamine

DAT:

Dopamine transporter

DBH:

Dopamine-β-hydroxylase

DHPG:

3,4-dihydroxyphenylethylene glycol

DOPAC:

3,4-dihydroxyphenylacetic acid

DSP-4:

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

GABA:

γ-aminobutyric acid

i.p.:

Intraperitoneal injection

i.v.:

Intravenous injection

LC:

Locus coeruleus

MAO:

Monoamine oxidase

MHPG:

3-methoxy-4-hydroxyphenylethylene glycol

NE:

Norepinephrine

NET:

Norepinephrine transporter

OCTs:

Organic cation transporters

s.c.:

Subcutaneous injection

SERT:

Serotonin transporter

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  1. Departments of Neurology, Neurosurgery, and Biomedical Engineering, Montreal Neurological Institute, McGill University, 3801 University Street, room 753, Montreal, QC, Canada

    Aleksandra Bortel

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

    Richard M. Kostrzewa

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Bortel, A. (2014). Nature of DSP-4-Induced Neurotoxicity. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_75

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