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吸烟率最高，尼古丁被认为可以减轻与精神分裂症相关的一些症状。慢性尼古丁暴露上调烟碱激动剂与脑烟碱乙酰胆碱受体（nAChR）的结合。在死后的研究中，有区域特异性增加高亲和力nAChR结合在健康的人类吸烟者，但不是在精神分裂症吸烟者。虽然这些数据表明精神分裂症吸烟者中的高亲和力nAChR失调，但没有体内数据显示精神分裂症中的nAChR失调或其如何与吸烟或与精神分裂症相关的症状（认知缺陷）相关。使用[123 I]5-IA-85380（5-IA）和SPECT成像，我们最近表明，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%。与我们的初步数据中的尸检研究一致，精神分裂症吸烟者（SS）（n=7; 6例用药和1例未用药）相对于健康吸烟者（HS）显示脑[123 I]5-IA摄取的区域特异性降低，而无论用药状态如何。这些发现可能反映了精神分裂症吸烟者未能上调22-nAChR。此外，与健康的从不吸烟者（HNS）相比，SS显示出更高的[123 I]5-IA摄取，而与HNS相比，精神分裂症不吸烟者（SNS）（n=4）显示出丘脑中更低的[123 I]5-IA摄取，但在顶叶、额叶和枕叶皮质中也是如此。记忆力和注意力被戒烟所破坏，并通过恢复吸烟而恢复。目的：使用SPECT和5-IA，该提案旨在确定1A）SS是否显示相对于HS的区域特异性22- nAChR可用性降低; 1B）未给药SS是否显示相对于HNS的区域特异性22-nAChR可用性降低; 1C）给药和未给药SS之间的22-nAChR可用性存在差异; 2）SNS是否显示相对于HNS的22-nAChR可用性较低。此外，我们计划探索1）药物治疗SS与药物治疗SNS之间区域22-nAChR可用性的差异; 2）认知测试性能与区域22-nAChR可用性之间的关系; 3）戒烟和恢复吸烟对认知测试性能的影响。研究方法：HS和SS（用药和未用药）将通过咨询和应急管理的组合策略实现5天的确认戒烟，并仅对精神分裂症吸烟者进行住院治疗。还将研究匹配的HNS和SNS。所有受试者将使用SPECT和5-IA进行研究，然后进行MRI配准。将在照常吸烟、戒烟后24小时、戒烟5天以及受试者是否恢复吸烟的情况下评估认知测试（言语记忆、注意力、工作记忆和选择性注意力）。认知数据将与局部脑[123 I]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）可以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导致精神分裂症及其某些症状的高吸烟率（成瘾）。这项拨款申请建议使用大脑成像来研究精神分裂症中的尼古丁受体系统。

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.