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. Noradrenergic cells were identified using immunocytochemical staining for tyrosine hydroxylase (TH). Maturation of noradrenergic neurons was assessed by measuring the high affinity uptake of norepinephrine (NE). Coculturing target cells with LC neurons exerts both stimulatory and inhibitory effects on NE uptake, depending on the density of plated cells. The target stimulatory effect may be mediated by glial soluble factors, whereas the inhibitory effect may be mediated by glial membranal molecules. In addition to target derived trophic factors, the effect of elevated cAMP levels was examined. cAMP analogs and forskolin dramatically increase the number of TH+ cells, possibly by supporting their survival. This phenomenon is not dependent on calcium or calcium requiring processes and is not mediated by glial cells. The trophic activity of cAMP appears to be exerted by protein phosphorylation via cAMP dependent protein kinase. Norepinephrine is suggested to be one signal that triggers cAMP elevation through the beta-adrenergic receptor and thereby affects LC development. Morphine, which is known to inhibit adenylate cyclase, reduces NE uptake and number of TH+ neurons. Morphine also inhibits the NT-3 induced increase in noradrenergic survival. We hypothesize that morphine exerts these effects by modulating the cAMP cascade.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
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Sklair-Tavron
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Nestler
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D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003470:Culture Media; D000242:Cyclic AMP / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008125:Locus Coeruleus / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D009020:Morphine / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D020933:Neurotrophin 3; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003470:Culture Media; D007328:Insulin; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase; D007545:Isoproterenol; D009638:Norepinephrine