CHOLINERGIC MECHANISMS OF SENSORY GATING--SCHIZOPHRENIA

本项目旨在评估毒蕈碱和烟碱的作用， 调节P50听觉感觉门控的胆碱能机制 精神分裂症 我们之前已经记录了P50波形 听觉诱发电位（AEP）的条件测试 用于评估抑制性神经元通路的强度的范例。 正常对照组的AEP P50波形显著降低， 对两个紧密配对的点击中的第二个的反应。 两人都未服药 和药物治疗的精神分裂症受试者表现出较少的减量，表明， P50听觉门控缺陷。 大约一半的一级亲属 精神分裂症患者的P50有类似的缺陷， 听觉感觉门控 通过研究P50听觉感觉门控， 在确定的患者的一级亲属的缺陷，我们可以 阐明遗传性P50听觉缺陷的机制 感觉门控而不必控制神经抑制剂的作用 和抗胆碱能药物通常用于治疗 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 的 毒蕈碱与烟碱对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，在这方面， 阐明这两种机制的相对重要性， 增强我们对与以下疾病相关的感觉门控缺陷的理解 精神分裂症，也许指向新的药理学 精神分裂症的治疗方法 在本研究中，我们将研究3 受试者组-无精神疾病家族史的正常对照组 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和中等的影响， 在P50听觉门控前给予东莨菪碱， 和治疗后。 格隆溴铵，它不会进入 大脑，将作为安慰剂对照。 第二个实验将研究 6 mg口服尼古丁对感觉门控的影响，氨甲酰甲胆碱 模拟外周胆碱能作用的外周胆碱能剂 无中枢神经系统（CNS）影响。 第三项研究将使用 美卡拉明，一种神经节阻滞剂和CNS烟碱阻滞剂， 评估阻断CNS烟碱胆碱能传递对 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.