Catecholamine and second messenger lnfluences on prefrontal cortical networks of "representational knowledge": A rational bridge between genetics and the symptoms of mental illness
Catecholamine and second messenger lnfluences on prefrontal cortical networks of "representational knowledge": A rational bridge between genetics and the symptoms of mental illness
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DOI：
10.1093/cercor/bhm033
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发表时间：
2007-09-01
期刊：
影响因子：
3.7
通讯作者：
Arnsten, Amy F. T.
中科院分区：
文献类型：
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作者：
Arnsten, Amy F. T.
多巴胺(DA)和去甲肾上腺素(NE)对前额叶皮质(PFC)的认知功能都有强大的、倒U形的影响。最佳的去甲肾上腺素水平通过抑制首选输入附近的cAMP-HCN(cAMP超极化激活的环核苷酸门控阳离子通道)信号而增加“信号”，而最佳的去甲肾上腺素受体刺激水平通过增加非首选输入附近的cAMP信号来减少“噪音”。在应激过程中，过量的儿茶酚胺释放会损害工作记忆：1)cAMP-HCN信号的水平非常高，减少首选和非首选输入；2)高水平的去甲肾上腺素(NE)参与所有磷脂酰肌醇(PI)信号的刺激，从而抑制细胞放电。常见的精神疾病与这些途径中的细胞外变化有关：注意缺陷多动障碍与基因变化有关，这种基因变化将儿茶酚胺的传递减少到次优水平，并使用增加儿茶酚胺传递的药物进行治疗；而创伤后应激障碍(PTSD)与去甲肾上腺素的传递放大有关，去甲肾上腺素的传递受损，但杏仁核功能增强。创伤后应激障碍现在用阻断α1或β肾上腺素受体的药物治疗。相比之下，更严重的精神疾病，如精神分裂症和双相情感障碍，与调节压力激活的细胞内信号通路的分子的遗传变化有关。具体地说，DISC1抑制cAMP信号转导，而G蛋白信号转导调节因子4抑制PI信号转导。这些基因的功能丧失可能使患者容易出现严重的应激诱导的PFC功能障碍，包括思维障碍的症状。
Both dopamine (DA) and norepinephrine (NE) have powerful, inverted U influences on prefrontal cortical (PFC) cognitive function. Optimal NE levels engage alpha 2A-adrenoceptors and increase "signals" via inhibition of cAMP-HCN (cAMP-hyperpolarizationactivated cyclic nucleotide-gated cation channel) signaling near preferred inputs, whereas optimal levels of DA D1 receptor stimulation decrease "noise" by increasing cAMP signaling near nonpreferred inputs. Excessive levels of catecholamine release during stress impair working memory 1) by very high levels of cAMP-HCN signaling diminishing preferred as well as nonpreferred inputs and 2) by high levels of NE engaging all stimulation of phosphotidyl inositol (PI) signaling that suppresses cell firing. Common mental illnesses are associated with extracellular changes in these pathways: Attention Deficit Hyperactivity Disorder is linked to genetic changes that reduce catecholamine transmission to suboptimal levels and is treated with agents that increase catecholamine transmission, whereas Post-Traumatic Stress Disorder (PTSD) is associated with amplified noradrenergic transmission that impairs PFC but strengthens amygdala function. PTSD is now treated with agents that block alpha 1 or beta adrenoceptors. In contrast, the more severe mental illnesses, schizophrenia and bipolar disorder, are associated with genetic changes in molecules regulating intracellular signaling pathways activated by stress. Specifically, DISC1 inhibits cAMP signaling whereas regulator of G-protein signaling 4 inhibits PI signaling. Loss of function in these genes may render patients vulnerable to profound stress-induced PFC dysfunction including symptoms of thought disorder.