烟碱型乙酰胆碱受体在精神分裂症认知功能损伤机制中的作用

Increasing evidence shows that schizophrenia is associated with multi-faceted deficits in neurocognitive function. However, the pathophysiological mechanisms underlying these cognitive deficits are unclear. Lack of effective treatment by currently available medications for cognitive deficits remains a major unmet need. The previous studies by our research group have shown that schizophrenia has a higher rate of cigarette smoking than patients with other psychiatric diagnoses and the general population. Moreover, the memory functions are better in the schizophrenic smokers than nonsmokers. These results suggest that cigarette smoking or nicotine serves as a form of self-medication, and nicotinic acetylcholine receptors (nAChRs) play a critical role in this activity. The main purposes of this project are: 1) to examine the effects of smoking on cognitive deficits of schizophrenia using the case-control desgin; 2) to explore the possible biomedical mechanisms for the effects of nicotine on cognitive improvement of the patients using the electroneurophysiological tests such as P50 auditory inhibitory gating and neurobiochemical measures; 3) to examine the associations of nAChR gene polymorphisms and smoking status or cognitive function in schizophrenia using the pharmacogenetic approach; 4) to investigate the the effects of tropisetron, a partial agonist at the α7 nicotinic acetylcholine receptor (CHRNA7) as an add-on therapy to antipsychotic medications on cognitive deficits in schizophrenia using a randomized double-blind and placebo-controlled design, and further to determine whether the genetic variants of CHRNA7 gene may modulate the therapeutic efficacies of tropisetron treatment. The main goal of this study is to elucidate the neurobiological mechanisms of cognitive deficits in schizophrenia, and provide the reliable evidences for the developmnt of new drugs in the treatment of cognitive deficits and for the new pattern of the cominbed treatment in the clinical services.

诸多证据表明，精神分裂症存在广泛认知功能损伤，但机制尚未阐明，缺乏有效干预手段。课题组前期研究提示，精神分裂症患者吸烟率显著高于其它精神障碍和健康对照，且吸烟患者记忆功能显著优于非吸烟患者；由此推测，吸烟可能是患者的"自我治疗"行为，而烟碱型乙酰胆碱受体（nCHR）作用关键。本项目采用病例对照研究，大样本验证吸烟和非吸烟患者认知损伤的差别，运用神经电生理、神经生化的方法，探索尼古丁影响患者认知功能可能的神经生物学机制；以nCHR基因为靶基因，采用分子遗传学方法，探讨该基因多态性对患者吸烟、认知状况的调节作用；采用随机、双盲、安慰剂对照试验，加用nCHRα7部分激动剂（托烷司琼）对患者进行治疗，以验证nCHR与认知损伤的关系，分析CHRNA7基因多态性对脱烷司琼疗效的调控作用。本项目旨在探索精神分裂症认知损伤可能的生物学机制，为药物开发和建立可供临床参考的联合治疗新模式提供可靠依据。

研究背景：精神分裂症存在广泛认知功能损伤，但机制尚未阐明，缺乏有效干预手段。课题组前期研究提示，精神分裂症患者吸烟率显著高于其它精神障碍和健康对照，且吸烟患者记忆功能显著优于非吸烟患者；由此推测，吸烟可能是患者的“自我治疗”行为，而尼古丁乙酰胆碱受体（nCHR）作用关键。.研究内容：本项目分两部分：1）采用病例对照研究，大样本验证吸烟和非吸烟患者认知损伤的差别，运用神经电生理、神经生化的方法，探索尼古丁影响患者认知功能可能的神经生物学机制；2）采用随机、双盲、安慰剂对照试验，加用nCHRα7部分激动剂（托烷司琼）对患者进行治疗，治疗前后检测临床症状、认知功能和P50， 以及检测CHRNA7基因多态性。.重要结果: 1）精神分裂症病人认知功能存在广泛损伤，表现在认知功能检测RBANS的总分和5个分量表中的4个均表现为显著性降低；2）精神分裂症病人血清BDNF水平比正常对照组显著性降低；3）与正常组相比，病人组P50 （S2/S1）显著性增高；4）在病人组，BDNF水平与认知功能的近期和远期记忆存在显著性相关；5）病人组与正常组的尼古丁受体alpha7的两个多态性D15S1360和L76630之间无显著性差异; 6)与单纯的利培酮相比，托烷司琼合并利培酮对阴性症状和认知损伤改善更显著；7）与单纯的利培酮相比，托烷司琼合并利培酮降低P50(S2/S1)比率更显著，而且P50(S2/S1)比率的降低值与近期记忆和远期记忆的改善显著性正相关。8）治疗后，单纯利培酮和托烷司琼合并利培酮两组均使BDNF水平显著增加，但后者增加更加显著，而且BDNF水平增加与认知功能近期记忆的改善正相关。9）尼古丁受体alpha7的两个多态性D15S1360和L76630与临床疗效、认知功能和P50的变化均无无显著性相关。.科学意义：本项目探索精神分裂症认知损伤与尼古丁alpha-7受体的关系，并通过此受体的部分激动剂改善认知功能指标，为开发治疗精神分裂症病人认知功能损伤的药物和建立可供临床参考的联合治疗新模式提供可靠依据。