CHOLINERGICS AND SENSORY GATING IN SCHIZOPHRENIA

这是对先前申请的重新提交。这个项目是 旨在评估毒扁豆碱和烟碱胆碱能 精神分裂症患者P50听觉感觉门控的调节机制。 我们之前已经联合记录了听觉的P50波形 诱发电位(AEP)和条件测试范式用于评估 抑制性神经元通路的强度。正常对照显示 AEP P50波形对第二次刺激的显著减退 两个紧密配对的滴答声。未用药和已用药 精神分裂症受试者表现出较少的减少，这表明， 抑制机制与P50听觉门控有关。约占总数的一半 精神分裂症患者的一级亲属有一个特征，即 类似的P50听觉感觉门控缺陷。通过研究P50 已确定的一级亲属的听觉感觉门控缺陷 患者，我们可以阐明遗传的潜在机制 P50听觉感觉门控干扰的缺陷 抗精神病药和抗胆碱能冥想，通常用于 治疗精神分裂症患者。在动物模型中，阻断尼古丁 胆碱能神经元向海马区的传递损害听觉 感官门控。这种缺陷被尼古丁治疗所逆转。 在一项初步研究中，我们发现口服尼古丁会短暂地增强 P50门控受损的一级亲属的P50门控。 在这项研究中，我们将研究三组受试者-正常对照组和 无精神疾病家族史，无一级亲属 精神分裂症患者中，有一种精神分裂症患者。第一 实验将研究6毫克口服尼古丁对感官的影响 门控。第二个实验将研究0.0006毫克/公斤的 M受体拮抗剂东莨菪碱对P50听性门控的影响 治疗后。第三项研究将使用甲基胺，以评估 高亲和力烟碱受体拮抗对P50门控的影响 在每项研究中，听觉诱发电位使用P50条件反射- 测试范式将在治疗前和30分钟内记录，1 1小时，治疗后2小时。在第四项研究中，我们将询问 正常对照和精神分裂症患者的非一级亲属 患者必须佩戴尼古丁贴片。他们会把他们的P50记录下来 在佩戴贴片之前和之后每周进行4周，按顺序 评估中枢尼古丁受体长期脱敏的可能性。 统计分析将由Manova进行，并对组进行单独分析 *TX*时间交互效应。在第五项研究中，我们将给出正常值 精神分裂症患者一级亲属的对照与非配对 两个剂量的尼古丁在两小时内互相研究可能 烟碱受体的短期脱敏。个体效应 将通过单独的分析来评估不同的脑电导联 TX*时间*领先效应。

This is a resubmission of a previous application. This project is designed to assess the roles of muscarinic and nicotinic cholinergic mechanisms that modulate P50 auditory sensory gating in schizophrenia. We have previously combined recording the P50 waveform oft he auditory evoked potential (AEP) with a condition-testing paradigm used to assess the strength of inhibitory neuronal pathways. Normal controls show a significant decrement of the AEP P50 waveform in response to the second of two closely paired clicks. Both unmedicated and medicated schizophrenic subjects show less decrement, indicating, a deficit in inhibitory mechanisms involved in P50 auditory gating. About half of all first-degrees relatives of schizophrenic patients have as a trait, a similar deficit in P50 auditory sensory gating. By studying the P50 auditory sensory gating deficit in first degree relatives of identified patients, we can elucidate the mechanisms underlying the inherited deficits in P50 auditory sensory gating interference from the effects of neuroleptic and anticholinergic meditations that are commonly used to treat schizophrenic patients. In an animal model, blockade of nicotinic cholinergic neuronal transmission to the hippocampus impaired auditory sensory gating. This deficit was reversed by treatment with nicotine. In a preliminary study, we found that oral nicotine transiently enhanced P50 gating in first-degrees relatives with impaired P50 gating. In this study we will study 3 groups of subjects- normal controls with no family history of mental illness, nongating first-degrees relatives of schizophrenic patients, an schizophrenic patients. The first experiments will study the effects of 6 mg of oral nicotine on sensory gating. The second experiment will study the effects of 0.0006 mg/kg of scopolamine, a muscarinic antagonist, on P50 auditory gating before and after treatment. The third study will use mecamylamine, to assess the effect of antagonism of high affinity nicotinic receptors on P50 gating. In each study, auditory evoked potentials using the P50 conditioning- testing paradigm will be recorded prior to treatment and 30 minutes, 1 hour, and two hours after treatment. In the fourth study, we will ask normal controls and nongating first-degree relatives of schizophrenic patients to wear a nicotine patch. They will have their P50s recorded prior to wearing the patch and weekly thereafter for 4 weeks, in order to assess possible long-term desensitization of CNS nicotine receptors. Statistical analysis will be by MANOVA and separate analyses of group *tx*time interaction effects. In the fifth study, we will give normal controls and nongating first-degrees relatives of schizophrenic patients two doses of nicotine within two hours of each other to study possible short-term desensitization of nicotinic receptors. Individual effects on different EEG leads will be assessed by separate analyses of tx*time*lead effects.