Response of central monoamine neurons following an early neurotoxic lesion.

Abstract

Systemic treatment with the selective monoamine neurotoxins 6-hydroxydopamine (6-OH-DA), N-(2-chloroethyl)N-ethyl-2-bromobenzylamine (DSP4) or 5,7-dihydroxytryptamine (5,7-HT) in the neonatal stage produces marked and permanent alterations of the postnatal development of central noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons. 6-OH-DA and DSP4 act preferentially on NA neurons, in particular on the locus coeruleus system, whereas 5,7-HT acts on 5-HT neurons. The neurotoxin treatment leads to pronounced denervations of distant nerve terminal projections while innervation areas close to the cell bodies become hyperinnervated. The total number of monoamine nerve terminals developed in the CNS after the neurotoxin treatment is approximately unchanged. A surgical lesion of NA and 5-HT axons in the neonatal stage causes similar changes compared to a neonatal neurotoxin treatment. The postsynaptic monoamine receptors appear to develop independently of the presynaptic nerve terminals, although the transmitter availability at the receptors is able to regulate the number of receptors (up and down regulation). The transmitter turnover is increased in terminals spared by the neurotoxin in denervated areas, while decreased in hyperinnervated regions. The alterations in receptor density and transmitter turnover may represent compensatory mechanisms. Substance P has a counteracting effect while morphine has a potentiating effect on the 6-OH-DA-induced NA denervation and hyperinnervation, indicating that the functional state of the neuron may modulate the final outcome of a neonatal 6-OH-DA treatment. The results indicate that the altered development of central monoamine neurons following a neonatal monoamine neurotoxin treatment or axotomy is mainly related to a 'pruning effect', i.e. the prevention of the development of one axonal branch leads to a proliferative growth response in intact branches.