Substance P modifies the 6-hydroxydopamine induced alteration of postnatal development of central noradrenaline neurons

Abstract

Systemic treatment of new-born rats with the catecholamine neurotoxin 6-hydroxydopamine leads to a permanent and selective alteration of the postnatal development of the central noradrenaline neurons, in particular of the locus coeruleus system. The changes involve a pronounced and permanent degeneration of distant nerve terminal projections (e.g. in the cerebral cortex and spinal cord) and a hyperinnervation of regions close to the noradrenaline perikarya (e.g. in the cerebellum and ponsmedulla). Substance P administered intracisternally was found to counteract significantly both the 6-hydroxydopamine-induced denervation and hyperinnervation, as monitored by measuring endogenous noradrenaline levels and [ 3H]noradrenaline uptake in vitro. The counteracting effect of substance P disclosed a clear dose-response relationship and was most effective when injected on postnatal days one and two, while practically no effects were observed after injection on postnatal days three and four. Substance P treatment alone of new-born rats had no effect on the postnatal development of the regional monoamine levels. Binding studies employing radioligand technique showed substance P treatment to abolish the 6-hydroxydopamine-induced increase in β-receptor binding in the frontal cortex, suggesting the ‘spared’ noradrenaline terminals to be functionally active. Substance P was shown to increase the utilization of noradrenaline in the neonatal stage. The results indicate that the counteracting effect of substance P may be due to a prevention of degeneration, growth stimulation and/or trophic influences on central noradrenaline neurons, possibly related to an excitatory effect of substance P on noradrenaline neurons.