Release properties and functional integration of noradrenergic-rich tissuegrafted to the denervated spinal cord of the adult rat

Noradrenaline- (NA-) containing grafts of central (embryonic locus coeruleu s, LC) or peripheral (juvenile adrenal medullary, AM, autologous superior c ervical ganglionic, SCG) tissue were implanted unilaterally into rat lumbar spinal cord previously depleted of its NA content by 6-hydroxydopamine (6- OHDA) intraventricularly. A microdialysis probe was implanted in the spinal cord 3-4 months after transplantation, and extracellular levels of noradre naline were monitored in freely moving animals during basal conditions and following administration of pharmacological or behavioural stimuli. Age-mat ched normal and lesioned animals both served as controls. Morphometric anal yses were carried out on horizontal spinal sections processed for dopamine- beta-hydroxylase (DBH) immunocitochemistry, in order to assess lesion- or g raft-induced changes in the density of spinal noradrenergic innervation, re lative to the normal patterns. In lesioned animals, the entire spinal cord was virtually devoid of DBH-positive fibers, resulting in a dramatic 88% re duction in baseline NA, compared with that in controls, which did not chang e in response to the various stimuli. LC and SCG grafts reinstated approxim ate to 80% and 50% of normal innervation density, respectively, but they di ffered strikingly in their release ability. Thus, LC grafts restored baseli ne NA levels up to 60% of those in controls, and responded with significant ly increased NA release to KCI-induced depolarization, neuronal uptake bloc kade and handling. In contrast, very low NA levels and only poor and incons istent responses to the various stimuli were observed in the SCG-grafted an imals. In AM-grafted animals, spinal extracellular NA levels were restored up to 45% of those in controls; probably as a result of nonsynaptic, endocr ine-like release, as grafted AM cells retained the chromaffine phenotype, s howed no detectable fibre outgrowth and did not respond to any of the pharm acological or behavioural challenges. Thus, both a regulated, impulse-depen dent, and a diffuse, paracrine-like, NA outflow may play roles in the recov ery of lesion-induced sensory and/or motor impairments previously reported with these types of grafts following transplantation into the severed spina l cord.