Regulation of catecholamine neurotransmitterlevels in the extracellular fluid by cyclic AMP

我们发现，在嗜铬细胞瘤PC12细胞培养中，环AMP （cAMP）抑制儿茶酚胺运输并增加细胞外多巴胺水平，这是单胺能神经元模型。本研究的目的是阐明cAMP是否调节CNS和PNS中的单胺转运和细胞外单胺神经递质。采用脑微透析技术，研究了cAMP对自由活动大鼠纹状体区胞外多巴胺水平的影响。在培养的PC12细胞中也检测了cAMP对单胺转运的作用机制。大鼠纹状体透析输注二丁基cAMP （dBcAMP）导致细胞外多巴胺水平升高，在细胞外液低Ca^<2+>浓度下可检测到dBcAMP的作用，而在高K^+ (50mM)的纹状体输注时未观察到多巴胺的增加。比较dBcAMP与单胺转运抑制剂诺非芬和利血平对细胞外多巴胺的影响，也支持了cAMP通过抑制纹状体多巴胺能神经元的胺转运而增加细胞外多巴胺的观点。dBcAMP对多巴胺衍生代谢物二羟基苯基乙酸（DOPAC）水平的影响也被检测，并与单胺转运抑制剂进行了比较。dBcAMP表现出与利血平相似的作用，提示dBcAMP可抑制单胺通过分泌囊膜的转运。在PC12细胞中，我们证实了cAMP通过下调单胺转运抑制儿茶酚胺再摄取和增加细胞外多巴胺。

We had found that cyclic AMP (cAMP) inhibited catecholamine transport and increased the extracellular dopamine level in pheochromocytoma PC12 cell culture, a model for monoaminergic neurons. An aim of the present study is to clarify whether cAMP regulates the monoamine transport and extracellular monoamine neurotransmitter in the CNS and PNS.With using a brain microdialysis technique, we examined cAMP effect on extracellular dopamine level in striatum regions of freely moving rat. Mechanisms of this cAMP action on the monoamine transport was also examined with PC12 cells in culture.Dialytic infusion of dibutyryl cAMP (dBcAMP) into rat striatum resulted in an increase in extracellular dopamine level and this dBcAMP effect was detectable under the low Ca^<2+> concentration in the extracellular fluid where the dopamine increase was not observed by the infusion of striatum with high K^+ (50mM). Comparison of the dBcAMP effect on extracellular dopamine with monoamine transport inhibiors, nomifensine and reserpine, also supported the idea that cAMP increases extracellular dopamine by inhibiting the amine transport in dopaminergic neurons in the striatum. Effect of dBcAMP on a level of dihydroxyphenylacetic acid (DOPAC), a dopamine-derived metabolite, was also examined and was compared with those of the monoamine transport inhibitors. dBcAMP showed an effect similar to that of reserpine, suggesting the inhibition of monoamine transport through secretory vesicular membrane by dBcAMP.With PC12 cells, we confirmed that cAMP inhibited catecholamine reuptake and increased extracellular dopamine by down-regulating the vesicular monoamine transport.