α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: Update on animal and clinical studies and strategies for the future.
α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: Update on animal and clinical studies and strategies for the future.
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DOI：
10.1016/j.neuropharm.2020.108053
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发表时间：
2020-06-15
影响因子：
4.7
通讯作者：
Callahan PM
中科院分区：
文献类型：
--
作者：
Terry AV Jr;Callahan PM
精神分裂症是一种毁灭性的精神疾病，其有效治疗是精神病学中最具挑战性的问题之一。精神分裂症的症状是多种多样的，从阳性症状（如妄想、幻觉）到阴性症状（如快感缺乏、社交退缩）再到认知功能障碍。抗精神病药物可有效改善某些患者的阳性症状；然而，它们在改善阴性症状或认知障碍方面并不可靠有效。无法解决认知障碍是一个特别值得关注的问题，因为它们对功能结果有最大的长期影响。几十年来，人们一直致力于开发治疗精神分裂症的促认知药物，但迄今为止，还没有一种药物被批准用于临床。几年前，行为、神经生物学和遗传学的证据表明α7-烟碱乙酰胆碱受体（α7-nAChR）被确定为一种治疗靶点，现在有广泛的临床前证据表明α7-nAChR配体具有促进认知的作用和其他特性，应该对精神分裂症患者有益。然而，与其他促认知策略一样，迄今为止还没有α7-nAChR配体被批准用于精神分裂症的临床应用。在这篇综述中，讨论了几个可能影响α7-nAChR配体作为精神分裂症促认知药物的成功的主题，包括所使用的动物模型的翻译价值、临床试验设计的局限性、多药的混杂效应、剂量效应关系以及慢性与间歇性给药的考虑。确定α7-nAChRs的最佳药理学策略：激动剂，正变构调节剂，甚至受体拮抗剂也进行了讨论。
Schizophrenia is a devastating mental illness and its effective treatment is among the most challenging issues in psychiatry. The symptoms of schizophrenia are heterogeneous ranging from positive symptoms (e.g., delusions, hallucinations) to negative symptoms (e.g., anhedonia, social withdrawal) to cognitive dysfunction. Antipsychotics are effective at ameliorating positive symptoms in some patients; however, they are not reliably effective at improving the negative symptoms or cognitive impairments. The inability to address the cognitive impairments is a particular concern since they have the greatest long-term impact on functional outcomes. While decades of research have been devoted to the development of pro-cognitive agents for schizophrenia, to date, no drug has been approved for clinical use. Converging behavioral, neurobiological, and genetic evidence led to the identification of the α7-nicotinic acetylcholine receptor (α7-nAChR) as a therapeutic target several years ago and there is now extensive preclinical evidence that α7-nAChR ligands have pro-cognitive effects and other properties that should be beneficial to schizophrenia patients. However, like the other pro-cognitive strategies, no α7-nAChR ligand has been approved for clinical use in schizophrenia thus far. In this review, several topics are discussed that may impact the success of α7-nAChR ligands as pro-cognitive agents for schizophrenia including the translational value of the animal models used, clinical trial design limitations, confounding effects of polypharmacy, dose-effect relationships, and chronic versus intermittent dosing considerations. Determining the most optimal pharmacologic strategy at α7-nAChRs: agonist, positive allosteric modulator, or potentially even receptor antagonist is also discussed.
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影响因子：
6.6
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
Cortex; a journal devoted to the study of the nervous system and behavior
影响因子：
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作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
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