LOCUS-COERULEUS (LC) - TARGET INTERACTION AND CAMP IN CONTROL OF LC DEVELOPMENT

The epigenetic stimuli that regulate the development of noradrenergic LC neurons were studied in an Vitro system of LC primary cultures. Nor adrenergic cells were identified using immunocytochemical staining for tyrosine hydroxylase (TH). Maturation of noradrenergic neurons was as sessed by measuring the high affinity uptake of norepinephrine (NE). C oculturing target cells with LC neurons exerts both stimulatory and in hibitory effects on NE uptake, depending on the density of plated cell s. The target stimulatory effect may be mediated by glial soluble fact ors, whereas the inhibitory effect may be mediated by glial membranal molecules. In addition to target derived trophic factors, the effect o f elevated cAMP levels was examined. cAMP analogs and forskolin dramat ically increase the number of TH+ cells, possibly by supporting their survival. This phenomenon is not dependent on calcium or calcium requi ring processes and is not mediated by glial cells. The trophic activit y of cAMP appears to be exerted by protein phosphorylation via cAMP de pendent protein kinase. Norepinephrine is suggested to be one signal t hat triggers cAMP elevation through the P-adrenergic receptor and ther eby affects LC development. Morphine, which is known to inhibit adenyl ate cyclase, reduces NE uptake and number of TH+ neurons. Morphine als o inhibits the NT-3 induced increase in noradrenergic survival. We hyp othesize that morphine exerts these effects by modulating the cAMP cas cade.