Imaging Nicotinic Acetylcholine Receptors in Schizophrenia

描述（由申请人提供）：精神分裂症中的尼古丁乙酰胆碱受体精神分裂症患者的吸烟率最高，尼古丁被认为可以缓解精神分裂症相关的一些症状。慢性尼古丁暴露向上调节尼古丁激动剂与脑尼古丁乙酰胆碱受体（nAChR）的结合。在死后研究中，在健康人类吸烟者中存在高亲和力nAChR结合的区域特异性增加，但在精神分裂症吸烟者中没有。虽然这些数据表明在精神分裂症吸烟者中存在高亲和力的nAChR失调，但没有体内数据显示精神分裂症中nAChR失调或其与吸烟或与精神分裂症相关的症状（认知缺陷）之间的关系。我们最近使用[123I]5-IA-85380 （5-IA）和SPECT成像显示，与死后数据一致，健康吸烟者的22-nAChR可用性比从不吸烟者高30%。与我们的前期研究数据相一致，精神分裂症吸烟者（n=7； 6人接受药物治疗，1人未接受药物治疗）与健康吸烟者（HS）相比，大脑[123I]5-IA摄取的区域特异性减少，无论药物状况如何。这些发现可能反映了精神分裂症吸烟者无法上调22-nAChR。此外，与健康的从不吸烟者（HNS）相比，SS显示出更高的[123I]5-IA摄取，而精神分裂症不吸烟者（SNS） （n=4）在丘脑、顶叶、额叶和枕叶皮层的[123I]5-IA摄取也比HNS低。记忆力和注意力会因戒烟而受到干扰，并通过重新吸烟而恢复。目的：使用SPECT和5-IA，本提案旨在确定1A) SS相对于HS是否显示降低的区域特异性22- nAChR可用性；1B)与HNS相比，未给药的SS显示区域特异性22-nAChR可用性降低；1C)用药组和未用药组的22-nAChR可用性存在差异；2) SNS的22-nAChR利用率低于HNS。此外，我们计划探索1)用药SS与用药SNS之间区域22 nAChR可用性的差异；2)认知测试成绩与区域22-nAChR可用性的关系；3)戒烟和复吸对认知测试成绩的影响。方法：HS和SS（服药和未服药）将通过咨询和应急管理相结合的策略实现5天的确认戒断，并仅对精神分裂症吸烟者进行住院治疗。匹配的HNS和SNS也将被研究。所有受试者将使用SPECT和5-IA进行研究，随后进行MRI共配准。认知测试（言语记忆、注意力、工作记忆和选择性注意）将在正常吸烟、戒烟后24小时、戒烟5天以及重新吸烟时进行评估。认知数据将与区域脑[123I]5-IA摄取（VT和VT'）相关。精神分裂症患者的吸烟率很高，吸烟（尼古丁）可能减轻精神分裂症的某些症状。这导致了尼古丁受体系统的改变可能是精神分裂症患者吸烟率高（成瘾）及其某些症状的原因。这项拨款申请建议使用脑成像来研究精神分裂症的尼古丁受体系统。

DESCRIPTION (provided by applicant): Nicotinic Acetylcholine Receptors in Schizophrenia Schizophrenic patients have among the highest rates of tobacco smoking and nicotine is thought to alleviate some of the symptoms associated with schizophrenia. Chronic nicotine exposure up regulates nicotinic agonist binding to brain nicotinic acetyl choline receptors (nAChR). In postmortem studies, there are region-specific increases in high affinity nAChR binding in healthy human tobacco smokers but not in schizophrenic smokers. While these data suggest high affinity nAChR dysregulation in schizophrenic smokers, there are no in vivo data showing nAChR dysregulation in schizophrenia or how it might relate to smoking or the symptoms (cognitive deficits) associated with schizophrenia. Using [123I]5-IA-85380 (5-IA) and SPECT imaging we have recently shown that consistent with post mortem data, healthy smokers have 30% higher 22-nAChR availability vs. never smokers. Consistent with post-mortem studies in our pilot data schizophrenic smokers (SS) (n=7; 6 medicated and 1 unmedicated) show region specific reductions in brain [123I]5-IA uptake relative to healthy smokers (HS) regardless of medication status. These findings may reflect a failure to upregulate 22-nAChR in schizophrenic smokers. Further, SS show higher [123I]5-IA uptake compared to healthy never smokers (HNS) while schizophrenic nonsmokers (SNS) (n=4) show lower [123I]5-IA uptake in the thalamus, but also in the parietal, frontal, and occipital cortices compared to HNS. Memory and attention were disrupted by smoking abstinence and restored by the resumption of smoking. Aims: Using SPECT and 5-IA, this proposal aims to determine if 1A) SS show reduced region specific 22- nAChR availability relative to HS; 1B) unmedicated SS show reduced region specific 22-nAChR availability relative to HNS; 1C) there are differences in 22-nAChR availability between medicated and unmedicated SS; 2) SNS show lower 22-nAChR availability compared to HNS. In addition we plan to explore 1) differences in regional 22 nAChR availability between medicated SS vs. medicated SNS; 2) the relationship between cognitive test performance and regional 22-nAChR availability; and 3) the effects of smoking abstinence and smoking resumption on cognitive test performance. Methods: HS and SS (medicated and unmedicated) will achieve 5 days of confirmed abstinence with a combined strategy of counseling and contingency management, and hospitalization for only the schizophrenic smokers. Matched HNS and SNS will also be studied. All subjects will be studied using SPECT and 5-IA followed by an MRI for coregistration. Cognitive testing (verbal memory, attention, working memory and selective attention) will be assessed while smoking as usual, 24 hours after quitting, 5 days abstinence and if subjects resume smoking. Cognitive data will be correlated with regional brain [123I]5-IA uptake (VT and VT'). PUBLIC HEALTH RELEVANCE There are high rates of smoking in individuals with schizophrenia and smoking (nicotine) may alleviate certain symptoms of schizophrenia. This has led to the suggestion that alterations in the nicotine receptor system may contribute to the high rates of smoking (addiction) in schizophrenia and some of its symptoms. This grant application proposes to use brain imaging to study the nicotine receptor system in schizophrenia.