Adrenergic targets for the treatment of cognitive deficits in schizophrenia
Adrenergic targets for the treatment of cognitive deficits in schizophrenia
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DOI：
10.1007/s00213-003-1724-3
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发表时间：
2004-06-01
影响因子：
3.4
通讯作者：
Arnsten, AFT
中科院分区：
文献类型：
--
作者：
Arnsten, AFT
理由。精神分裂症患者的前额皮质（PFC）认知功能严重受损。尽管多巴胺一直是精神分裂症研究的主要焦点，但去甲肾上腺素 (NE) 对 PFC 认知功能也有显着影响。客观的。本综述旨在确定肾上腺素能受体，它们可能是精神分裂症治疗作用的适当靶标。方法。对影响动物和人类 PFC 功能的肾上腺素能机制的研究进行了综述。结果。适度水平的 NE 会参与突触后 α(2A) 肾上腺素能受体并增强工作记忆。这些有益效果已在动物的行为和细胞水平上观察到，并已转化为 PFC 损伤患者的临床效果。因此，α(2A)-肾上腺素能受体是经过验证的分子靶点。相比之下，应激过程中释放的高水平 NE 通过激活蛋白激酶 C 细胞内信号传导损害 PFC 认知功能，该信号通路与精神分裂症的病因学越来越相关。阻断 α(1) 肾上腺素受体或抑制蛋白激酶 C 有助于保护动物 PFC 认知功能，并且可能对人类具有类似的治疗作用。阻断 α(2C) 受体也可能有助于增强儿茶酚胺释放，同时阻断纹状体中有害的 DA 作用。结论。高选择性肾上腺素能药物可能有助于增强精神分裂症患者的 PFC 功能。
Rationale. The cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in schizophrenic patients. Although dopamine has been the major focus of schizophrenia research, norepinephrine (NE) also has marked influences on PFC cognitive functioning. Objective. This review aims to identify the adrenergic receptors which may be appropriate targets for therapeutic actions in schizophrenia. Methods. Studies of adrenergic mechanisms influencing PFC function in animals and humans were reviewed. Results. Modest levels of NE engage postsynaptic alpha(2A)-adrenergic receptors and strengthen working memory. These beneficial effects have been observed at both the behavioral and cellular levels in animals, and have translated to the clinic in patients with PFC impairments. Thus, the alpha(2A)-adrenergic receptor is a proven molecular target. In contrast, high levels of NE released during stress impair PFC cognitive function via activation of protein kinase C intracellular signaling, a pathway increasingly associated with the etiology of schizophrenia. Blockade of alpha(1) adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive function in animals, and may have similar therapeutic actions in humans. Blockade of the alpha(2C) receptor may also be helpful in enhancing catecholamine release while blocking detrimental DA actions in striatum. Conclusion. Highly selective adrenergic agents may be useful for enhancing PFC function in schizophrenic patients.