Severe loss of noradrenergic (NA) neurons in the Locus Coeruleus/SubCoeruleus (LC/SubC) complex and of fiber terminals in the neocortical and hippocampal target regions occurs in Alzheimer's disease (AD), however, the exact role played by this system in the pathophysiology of AD is still unclear. In the present study, the NA contribution to cognitive functions was investigated following bilateral intracerebral administration of the selective immunotoxin anti-dopamine beta-hydroxylase (anti-DBH)-saporin, to adult or developing rats. Four or twelve weeks post-surgery, the animals underwent sequential tests to evaluate spatial learning and memory, followed by tissue analyses to assess the extent and selectivity of the lesion. When tested in the Morris Water Maze (MWM) task, lesioned animals, irrespective of their age at surgery, exhibited only very mild or no reference memory deficits, compared to Normal. By contrast, working memory (assessed by the Radial Arm Water Maze, RAWM task) was seen significantly impaired. DBH immunohistochemistry confirmed a massive loss of immunoreactive neurons in the LC/SubC complex, associated to a virtually complete denervation of target areas in the neocortex and hippocampus. The results point at the existence of a dissociation in the functional effects of the lesion, and suggest a role for ascending regulatory NA afferents in more complex aspects of cognitive performance. Data will be presented on the restoring effects of grafted neuroblasts.