Selective Lifelong Destruction of Brain Monoaminergic Nerves Through Perinatal DSP-4 Treatment.

Abstract

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a highly selective neurotoxin for noradrenergic projections originating from the locus coeruleus (LC). The outcome of the systemic DSP-4 treatment of newborn rats is an alteration in postnatal development of the noradrenergic system, involving the permanent denervation of distal noradrenergic projection areas (neocortex, hippocampus, spinal cord), accompanied by noradrenergic hyperinnervation in regions proximal to the LC cell bodies (cerebellum, pons-medulla). DSP-4 is well tolerated by developing rats and does not increase the mortality rate. Permanent noradrenergic denervation in the cerebral cortex and spinal cord is present at all developmental stages, although this effect is more pronounced in rats treated with DSP-4 at an early age, i.e., up to postnatal day 5 (PND 5). Notably, regional hyperinnervation is a hallmark of neonatal DSP-4 treatment, which is not observed after either prenatal or adult DSP-4 application. In contrast to robust biochemical changes in the brain, DSP-4 treatment of newborn rats has a marginal effect on arousal and cognition functions assessed in adulthood, and these processes are critically influenced by the action of the noradrenergic neurotransmitter, norepinephrine (NE). Conversely, neonatal DSP-4 does not significantly affect 5-hydroxytryptamine (serotonin; 5-HT), dopamine (DA), gamma-aminobutyric acid (GABA), and histamine levels in brain. However, as a consequence of altering the functional efficacy of 5-HT1A, 5-HT1B, DA, and GABA receptors, these neurotransmitter systems are profoundly affected in adulthood. Thus, the noradrenergic lesion obtained with neonatal DSP-4 treatment represents a unique neurobiological technique for exploring the interplay between various neuronal phenotypes and examining the pathomechanism of neurodevelopmental disorders.