Nature of DSP-4-induced neurotoxicity

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.