Sklair-Tavron L, Nestler E J, Segal M
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
Brain Res Bull. 1994;35(5-6):397-402. doi: 10.1016/0361-9230(94)90150-3.
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.
在蓝斑核（LC）原代培养的体外系统中，研究了调节去甲肾上腺素能LC神经元发育的表观遗传刺激因素。使用酪氨酸羟化酶（TH）免疫细胞化学染色来鉴定去甲肾上腺素能细胞。通过测量去甲肾上腺素（NE）的高亲和力摄取来评估去甲肾上腺素能神经元的成熟度。将靶细胞与LC神经元共培养，根据接种细胞的密度，对NE摄取产生刺激和抑制作用。靶刺激作用可能由神经胶质可溶性因子介导，而抑制作用可能由神经胶质膜分子介导。除了靶源性营养因子外，还研究了cAMP水平升高的影响。cAMP类似物和福斯高林可显著增加TH+细胞的数量，可能是通过支持它们的存活。这种现象不依赖于钙或需要钙的过程，也不是由神经胶质细胞介导的。cAMP的营养活性似乎是通过依赖cAMP的蛋白激酶进行蛋白磷酸化来发挥作用的。去甲肾上腺素被认为是一种通过β-肾上腺素能受体触发cAMP升高从而影响LC发育的信号。已知吗啡可抑制腺苷酸环化酶，它会降低NE摄取和TH+神经元的数量。吗啡还会抑制NT-3诱导的去甲肾上腺素能神经元存活增加。我们假设吗啡通过调节cAMP级联反应发挥这些作用。
