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. article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

中文翻译：

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α7烟碱乙酰胆碱受体作为精神分裂症的治疗靶标：动物和临床研究的最新进展以及未来的策略。

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异质的，从阳性症状（例如妄想，幻觉）到阴性症状（例如快感，社交退缩）到认知功能障碍。抗精神病药可有效缓解某些患者的阳性症状。但是，它们不能有效改善不良症状或认知障碍。无法解决认知障碍特别令人关注，因为它们对功能结局具有最大的长期影响。尽管数十年来的研究致力于精神分裂症的前认知剂的开发，但至今尚未批准任何药物用于临床。融合行为，神经生物学，遗传证据已导致几年前将α7-烟碱乙酰胆碱受体（α7-nAChR）鉴定为治疗靶标，并且现在有大量的临床前证据表明α7-nAChR配体具有促认知作用和其他有益的特性精神分裂症患者。但是，与其他前认知策略一样，迄今为止，尚无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，讨论了可能会影响α7-nAChR配体作为精神分裂症前认知剂的成功的几个主题，包括所用动物模型的翻译价值，临床试验设计局限性，多药店的混杂效应，剂量效应关系，以及长期与间歇给药的注意事项。还讨论了确定α7-nAChRs的最佳最佳药理策略：激动剂，正构构调节剂，甚至可能是受体拮抗剂。这篇文章是“尼古丁神经药理学的当代进展”专刊的一部分。