CHOLINERGICS AND SENSORY GATING IN SCHIZOPHRENIA

这是对以前申请的重新提交。 这个项目是 旨在评估毒蕈碱和烟碱胆碱能的作用 调节精神分裂症P50听觉感觉门控的机制。 我们以前记录的P50波的听觉和 诱发电位（AEP）与条件测试范式用于评估 抑制性神经通路的强度。 正常对照显示 AEP P50波形响应于第二次 两个紧密配对的咔嗒声 不管是未用药的还是用药的 精神分裂症受试者表现出较少的减量，表明， P50听觉门控的抑制机制。 大约一半的 精神分裂症患者的一级亲属有一个特征， 在P50听觉感觉门控中存在类似缺陷。 通过研究P50 确定的一级亲属中的听觉感觉门控缺陷 患者，我们可以阐明遗传的潜在机制， 缺陷的P50听觉感觉门控干扰的影响 神经安定剂和抗胆碱能冥想，通常用于 治疗精神分裂症患者 在动物模型中，阻断烟碱 胆碱能神经元向海马的传递损害听觉 感觉门控 尼古丁治疗可逆转这一缺陷。 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3组受试者-正常对照， 无精神病家族史，无直系亲属 一个精神分裂症患者。 第一 实验将研究6毫克口服尼古丁对感觉的影响， 门控 第二个实验将研究0.0006 mg/kg的 东莨菪碱对P50听觉门控的影响 治疗后 第三项研究将使用美加明，以评估 高亲和力烟碱受体对P50门控的拮抗作用。 在每项研究中，听觉诱发电位使用P50条件反射- 测试范例将在治疗前和30分钟，1 治疗后1小时和2小时。 在第四项研究中，我们会问， 精神分裂症患者一级亲属与正常对照组 患者佩戴尼古丁贴片。 他们将记录他们的P50 在贴敷贴剂之前，此后每周一次，持续4周， 评估CNS尼古丁受体可能的长期脱敏作用。 将通过MANOVA和单独的组分析进行统计分析 *tx* 时间相互作用效应。 在第五项研究中，我们将给予正常 对照组和精神分裂症患者的非一级亲属 在两小时内连续服用两剂尼古丁， 烟碱受体的短期脱敏。 个体效应 将通过单独分析 TX* 时间 * 导联效应。

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.