Atypical Antipsychotics and P50 Sensory Gating

描述(由申请人提供)：这是精神分裂症P50感觉门控研究的竞争性更新。与任何其他抗精神病药物相比，氯氮平改善受损的P50听觉门控的程度更大。这一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P50门控是由α-7尼古丁受体介导的，而不是直接作用于氯氮平。类似的非典型性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奎硫平更有效的5HT3拮抗剂。5HT3受体阻滞剂释放乙酰胆碱，激活参与P50门控的烟碱受体。我们的具体目标是在精神分裂症患者和DBA/2小鼠身上测试这一假设，这些小鼠的门控功能受损，α-7尼古丁受体缺乏。我们将：1)确定在服用奥氮平或奎硫平的精神分裂症患者中加入恩丹西酮(一种特异性的5HT3拮抗剂)是否会改善P50门控；2)确定每天增加一定剂量的恩丹西酮是否会增强服用奥氮平或奎硫平的稳定患者的P50门控；3)评估认知障碍是否随着P50门控的改善而改善；4)确定用恩丹西酮阻断5HT3受体是否会改善DBA/2、慢性可卡因治疗的C3H以及奎硫平、奥氮平或阿立哌唑治疗的C3H同源基因小鼠的门控；5)确定加入托烷司琼是否会在DBA/2、慢性可卡因治疗的C3H和C3H同源基因小鼠的门控方面产生更大的改善。托烷司琼在美国还不能用于人类使用，所以这个项目将‘评估是否值得获得IND用于患者测试。第二个假设是，必须添加多巴胺能拮抗剂或下调，以防止5HT3拮抗剂介导儿茶酚胺的释放干扰由于乙酰胆碱释放增加而引起的改善。我们将在人和动物身上测试阿立哌唑，一种D2和5HT1a受体的部分激动剂，与恩丹西酮一起使用，以评估这种组合是否也会改善听觉门控。阐明氯氮平缓解神经生理学缺陷的潜在机制可能有助于我们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.