Atypical Antipsychotics and P50 Sensory Gating

描述（由申请人提供）：这是精神分裂症中P50感觉门控研究的竞争性更新。氯氮平改善受损的P50听觉门控的程度比任何其他抗精神病药都要大。这种改善与临床改善相关。为什么氯氮平比其他非典型药物更有效尚不清楚，特别是因为P50门控是由α -7烟碱受体介导的，而不是由氯氮平直接作用。类似的非典型药物不能有效改善受损的P50门控。然而，氯氮平是一种比奥氮平或喹硫平更有效的5HT3拮抗剂。5HT3阻断释放乙酰胆碱，刺激。7个尼古丁受体负责介导P50门控。我们的具体目标是在精神分裂症患者和DBA/2小鼠中验证这一假设，这些小鼠的α -7尼古丁受体受损和缺陷。我们将：1)确定服用奥氮平或喹硫平的精神分裂症患者急性加入昂丹司琼（一种特异性5HT3拮抗剂）是否能改善P50门控制；2)确定在奥氮平或喹硫平稳定的患者中，增加日剂量的昂丹司琼是否会增强P50门控制；3)评估认知缺陷是否随着P50门控的改善而改善；4)确定用昂丹西酮阻断5HT3受体是否会改善DBA/2、慢性可卡因治疗的C3H和用喹硫平、奥氮平或阿立哌唑治疗的C3H基因小鼠的门通；5)确定是否加入托司司琼，一种5HT3拮抗剂。在DBA/2、慢性可卡因处理的C3H和C3H基因小鼠中，激动剂活性将产生更大的门控改善。在美国，托哌司琼尚未可用于人类，因此该项目将评估是否值得获得IND用于患者试验。第二种假设是，必须加入多巴胺能拮抗剂或下调，以防止5HT3拮抗剂介导的儿茶酚胺释放干扰由于乙酰胆碱释放增加而导致的改善。我们将对D2和5HT1A受体的部分激动剂阿吡拉唑与昂丹西琼在人和动物身上进行测试，以评估这种组合是否也能改善听觉门控制。阐明氯氮平减轻神经生理缺陷的潜在机制可能有助于我们在未来设计更好的药物。

DESCRIPTION (provided by applicant): This is a competing renewal of studies of P50 sensory gating in schizophrenia. Clozapine improves impaired P50 auditory gating to a greater extent than any other antipsychotic. This improvement correlates with clinical improvement. Why clozapine is more effective than other atypicals is not clear, especially since P50 gating is mediated by the alpha-7 nicotinic receptor, not directly acted on by clozapine. Similar atypicals do not effectively improve impaired P50 gating. However, clozapine is a more effective 5HT3 antagonist than either olanzapine or quetiapine. 5HT3 blockade releases acetylcholine, which would stimulate .7 nicotinic receptors responsible for the mediation of P50 gating. Our specific aims test this hypothesis in schizophrenic patients and in DBA/2 mice, which have impaired gating and deficits in alpha-7 nicotinic receptors. We will: 1) Determine whether adding ondansetron (a specific 5HT3 antagonist) acutety to schizophrenic patients taking olanzapine or quetiapine improves P50 gating; 2) Determine whether adding a daily dose of ondansetron will enhance P50 gating in patients stable on olanzapine or quetiapine; 3) Assess if improvement in cognitive deficits occurs with improvement in P50 gating; 4) Determine if blockade of 5HT3 receptors with ondansetron will improve gating in DBA/2, chronic-cocaine-treated C3H, and C3H congenic mice treated with quetiapine, olanzapine, or aripiprizole; and 5) Determine if adding tropisetron, a 5HT3 antagonist with documented .7 agonist activity, will produce greater improvement in gating in DBA/2, chronic-cocaine-treated C3H, and C3H congenic mice. Tropisetron is not yet available for human use In the United States, so this project will' assess whether it will be worthwhile to obtain an IND for testing in patients. A second hypothosis is that dopaminergic antagonism or downregulation must be added to prevent the 5HT3 antagonist-mediated release of catecholamines from interfering with the improvement due to the increased acetylcholine release. We will test adpiprazole, a partial agonist at the D2 and 5HT1A receptors, with ondansetron in human and animals to assess whether this combination will also improve auditory gating. Elucidating a potential mechanism by which clozapine alleviates a neurophysiological deficit may help us design better medications in the future.