Imaging Nicotinic Acetylcholine Receptors in Schizophrenia

描述(申请人提供)：精神分裂症患者的尼古丁乙酰胆碱受体吸烟率是最高的，尼古丁被认为可以缓解与精神分裂症有关的一些症状。慢性尼古丁暴露可上调尼古丁激动剂与脑烟碱型乙酰胆碱受体(NAChR)的结合。在尸检研究中，在健康的吸烟者中，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。虽然这些数据表明精神分裂症吸烟者中存在高亲和力的nAChR异常，但没有体内数据显示精神分裂症中的nAChR异常，或它可能与吸烟或与精神分裂症相关的症状(认知缺陷)之间的关系。使用[123I]5-IA-85380(5-IA)和SPECT显像，我们最近发现，与尸检数据一致，健康吸烟者的22-nAChR利用率比从不吸烟者高30%。与我们试点数据中的尸检研究一致，精神分裂症吸烟者(SS)(n=7；6人服用药物，1人未服用药物)显示，与健康吸烟者(HS)相比，与健康吸烟者(HS)相比，大脑特定区域的[123I]5-IA摄取减少，无论药物状态如何。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显示更高的[123I]5-IA摄取，而精神分裂症非吸烟者(SNS)(n=4)丘脑的[123I]5-IA摄取比HNS低，但在顶叶、额叶和枕叶皮质也比HNS低。戒烟会扰乱记忆力和注意力，而恢复吸烟则会使记忆力和注意力恢复。目的：使用SPECT和5-IA，该建议旨在确定是否1)SS相对于HS显示区域特异性22-AChR可用性降低；1B)非药物SS相对于HNS显示区域特异性22-nAChR可用性降低；1C)用药和未用药SS之间22-nAChR可用性存在差异；2)与HNS相比，SNS显示更低的22-nAChR可用性。此外，我们计划探索1)用药SS和用药SNS之间的区域性22-nAChR可用性的差异；2)认知测试表现和区域性22-nAChR可用性之间的关系；以及3)戒烟和戒烟对认知测试表现的影响。方法：HS和SS(药物和非药物)将实现5天的确认戒断，并采取咨询和应急管理相结合的策略，仅对精神分裂症吸烟者住院。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，然后进行磁共振成像以进行联合配准。认知测试(言语记忆、注意力、工作记忆和选择性注意)将在正常吸烟时、戒烟24小时后、戒烟5天后以及受试者是否重新吸烟时进行评估。认知数据将与大脑区域[123I]5-IA摄取(VT和VT‘)相关。公共卫生相关性精神分裂症患者的吸烟率很高，吸烟(尼古丁)可以缓解精神分裂症的某些症状。这导致了尼古丁受体系统的变化可能导致精神分裂症的高吸烟率(成瘾)及其一些症状。这项拨款申请建议使用大脑成像来研究精神分裂症患者的尼古丁受体系统。

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.