CHOLINERGIC MECHANISMS OF SENSORY GATING IN SCHIZO.

该项目旨在评估毒碱和尼古丁的作用。 P50听觉门控的胆碱能调节机制 精神分裂症。我们之前已经组合记录了P50波形 听觉诱发电位(AEP)的条件性测试 用于评估抑制性神经元通路强度的范式。 正常对照组的AEP P50波形显著降低。 对两个紧密配对的单击中的第二个的响应。两人均未服药 而服用药物的精神分裂症患者表现出较少的减少，这表明， P50听觉门控缺陷。大约一半的一级亲属 作为一个特征，精神分裂症患者在P50中有类似的缺陷 听觉感觉门控。通过对P50听觉感觉门控的研究 在确诊患者的一级亲属中存在缺陷，我们可以 阐明P50听觉遗传性缺陷的机制 感觉门控，无需控制抗神经药的效果 以及通常用于治疗的抗胆碱能药物 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。这个 毒扁豆碱与烟碱对P50调节的相对重要性 人类受试者的听觉门控尚未建立。然而， 阐明这两种机制的相对重要性将大大 增强我们对感觉门控缺陷的理解 精神分裂症，也许为新的药理学指明了方向 精神分裂症的治疗方法。在这项研究中，我们将研究3 受试者分组--无家族精神病史的正常对照 疾病，非精神分裂症患者的一级亲属，以及 感觉正常的精神分裂症患者的一级亲属 门控。第一个实验将研究低水平和中等水平的影响。 M受体拮抗剂东莨菪碱对P50听性门控的影响 并在治疗后。格列吡酯，它不会进入 大脑，将安慰剂作为对照。第二个实验将研究 口服6毫克尼古丁对感觉门控的影响。比其他人更重要 模拟外周胆碱能效应的外周胆碱能药 没有中枢神经系统(CNS)的影响。第三项研究将使用 甲戊胺，神经节阻滞剂和中枢尼古丁阻滞剂 评价阻断中枢尼古丁胆碱能传递对大鼠脑血管紧张素转换酶的影响 P50门控。

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 of the auditory evoked potential (AEP) with a conditioning-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 P50 auditory gating. About half of all first-degree 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 deficit in P50 auditory sensory gating without having to control for the effects of neuroleptics and anticholinergic medications that arc commonly used to treat schizophrenic patients. In an animal model, blocking 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-degree relatives with impaired P50 gating. The relative importance of muscarinic versus nicotinic modulation of P50 auditory gating in human subjects has not been established. However, elucidating the relative importance of the two mechanisms would greatly enhance our understanding of a sensory gating deficit associated with schizophrenia, and perhaps point the way toward new pharmacologic approaches in treating schizophrenia. In this study we will study 3 groups of subjects- normal controls with no family history of mental illness, nongating first-degree relatives of schizophrenic patients, and first-degree relatives of schizophrenic patients with normal sensory gating. The first experiment will study the effects of low and moderate dose scopolamine, a muscarinic antagonist, on P50 auditory gating before and after treatment. Glycopyrrolate, which does not cross into the brain, will be the placebo control. The second experiment will study the effects of 6 mg of oral nicotine on sensory gating, with. bethanechol as a peripheral cholinergic agent to mimic peripheral cholinergic effects without central nervous system (CNS) effects. The third study will use mecamylamine, a ganglionic blocking agent and CNS nicotinic blocker to assess the effect of blocking CNS nicotinic cholinergic transmission on P50 gating.