Selective lesion of the developing central noradrenergic system: short- and long-term effects and reinnervation by noradrenergic-rich tissue grafts

P>The possibility to selectively remove noradrenergic neurons in the locus coeruleus/subcoeruleus (LC/SubC) complex by the immunotoxin anti-dopamine-beta-hydroxylase (DBH)-saporin has offered a powerful tool to study the functional role of this projection system. In the present study, the anatomical consequences of selective lesions of the LC/SubC on descending noradrenergic projections during early postnatal development have been investigated following bilateral intraventricular injections of anti-DBH-saporin or 6-hydroxydopamine to immature (4 day old) rats. Administration of increasing doses (0.25-1.0 mu g) of the immunotoxin produced, about 5 weeks later, a dose-dependent loss of DBH-immunoreactive neurons in the LC/SubC complex (approximate to 45-90%) paralleled by a similar reduction of noradrenergic innervation in the terminal territories in the lumbar spinal cord. Even at the highest dose used (1.0 mu g) the immunotoxin did not produce any detectable effects on dopaminergic, adrenergic, serotonergic or cholinergic neuronal populations, which, by contrast, were markedly reduced after administration of 6-hydroxydopamine. The approximate to 90% noradrenergic depletion induced by 0.5 and 1.0 mu g of anti-DBH-saporin remained virtually unchanged at 40 weeks post-lesion. Conversely, the approximate to 45% reduction of spinal innervation density estimated at 5 weeks in animals injected with the lowest dose (0.25 mu g) of the immunotoxin was seen recovered up to near-normal levels at 40 weeks, possibly as a result of the intrinsic plasticity of the developing noradrenergic system. A similar reinnervation in the lumbar spinal cord was also seen promoted by grafts of fetal LC tissue implanted at the postnatal day 8 (i.e. 4 days after the lesion with 0.5 mu g of anti-DBH-saporin). In these animals, the number of surviving neurons in the grafts and the magnitude of the reinnervation, with fibers extending in both the grey and white matter for considerable distances, were seen higher than those reported in previous studies using adult recipients. This would suggest that the functional interactions between the grafted tissue and the host may recapitulate the events normally occurring during the ontogenesis of the coeruleo-spinal projection system, and can therefore be developmentally regulated. Thus, the neonatal anti-DBH-saporin lesion model, with the possibility to produce graded noradrenergic depletions, holds promises as a most valuable tool to address issues of compensatory reinnervation and functional recovery in the severed CNS as well as to elucidate the mechanisms governing long-distance axon growth from transplanted neural precursors.