ATYPICAL ANTIPSYCHOTICS AND P50 GATING IN SCHIZOPHRENIA

描述：(改编自申请者摘要)：精神分裂症患者在听觉感觉信息的抑制性门控方面存在缺陷。这可以用P50 Auditorv诱发电位范式来证明。在这个范例中，精神分裂症患者无法降低两个紧密配对的听觉点击刺激中第二个的幅度。相反，与第一种声音相比，正常对照会降低第二种声音的幅度。这是抑制神经元处理的失败，或者是过滤或“选通”传入听觉刺激的能力失败。多种常规抗精神病药物的治疗未能使精神分裂症患者的门控缺陷正常化。相比之下，使用氯氮平治疗。作为一种典型的非典型抗精神病药物，已使抗精神病药物抵抗的精神分裂症患者的P50听觉门控正常化。在一些患者中，这种正常化持续了长达2年。相反，在类似的患者组中，利培酮治疗并未使P50门控正常化。虽然两种抗精神病药物都有很高的5HT2/D2亲和力，但只有氯氮平能阻断5HT3受体。P50听觉门控是由α-7烟碱受体介导的，而精神分裂症患者缺乏这种受体。尼古丁治疗只能短暂改善门控损害，因为α-7尼古丁受体是一种低亲和力、快速脱敏的受体。阻断5HT3受体会在海马区释放乙酰胆碱，这可能有助于改善门控损害。我们还假设，多巴胺能阻滞剂和5HT3阻滞剂的结合可能是最大的抗精神病作用所必需的。我们将通过研究4组25名精神分裂症患者的P50听觉门控和临床改善来验证这一假设，这些患者接受以下治疗之一：氯氮平(5HT3拮抗剂)、利培酮(无5HT3效应)、奥氮平(类似于氯氮平；5HT3拮抗剂)，以及另一组氟哌啶醇加恩丹西酮(一种5HT3特异性拮抗剂)。在上述每个实验中，我们还将研究失配负波(MMN)、声惊厥的预脉冲抑制(PPI)、P300和N400。这些指标的变化将与P50门控的变化相关。这个RSDA II将允许P.I.访问研究MMN、PPI、P300和N400的研究人员的实验室，并在植入电极的多单元记录实验中研究氯氮平的电生理学，这些电极被植入颞上回、丘脑网状核、海马体、内侧隔核和额叶皮质。他还将试验分析多单元数据所需的多变量统计技术。

DESCRIPTION: (adapted from applicant's abstract): Schizophrenic patients have a deficit in inhibitory gating of auditory sensory information. This can be demonstrated using a P50 auditorv evoked potential paradigm. In this paradigm, a schizophrenic patient fails to decrease the amplitude of the second of two closely paired auditory click stimuli. In contrast, normal controls decrease the amplitude of the second sound, compared to the first. This is a failure of inhibitory neuronal processing or of the ability to filter or "gate" incoming auditory stimuli. Treatment with multiple conventional neuroleptics fails to normalize the gating deficit in schizophrenic patients. In contrast, treatment with clozapine. a prototypical atypical antipsychotic, has normalized P50 auditory gating in neuroleptic-resistant schizophrenic patients. This normalization has lasted up to 2 years in some patients. In contrast, treatment with risperidone did not normalize P50 gating in a similar group of patients. Although both antipsychotics have a high 5HT2/D2 affinity, only clozapine blocks the 5HT3 receptor. P50 auditory gating is mediated by the alpha-7 nicotinic receptor, which is deficient in schizophrenic patients. Treatment with nicotine only briefly ameliorates the gating impairment because the alpha-7 nicotinic receptor is a low affinity, rapidly desensitizing receptor. Blockade of the 5HT3 receptor releases acetylcholine in the hippocampus that may help ameliorate the gating impairment. We also hypothesize that a combination of dopaminergic blockade and 5HT3 blockade may be necessary for maximal antipsychotic effect. We will test this hypothesis by studying P50 auditory gating and clinical improvement in 4 groups of 25 neuroleptic-resistant schizophrenic patients, treated with one of the following: clozapine (a 5HT3 antagonist), risperidone (no 5HT3 effect), olanzapine (similar to clozapine; 5HT3 antagonism), and another group treated with haloperidol supplemented by ondansetron (a specific 5HT3 antagonist). In each of the above experiments we will also study Mismatch Negativity (MMN), pre-pulse inhibition of acoustic startle (PPI), P300, and N400. Changes in these measures will be correlated with changes in P50 gating. This RSDA II will allow the P.I. to visit the labs of the researchers who have studied MMN, PPI, P300 and N400 with senior investigators in those measures, and to study clozapine's electrophysiology in multiunit recording experiments with electrodes implanted in superior temporal gyrus, reticular thalamic nucleus, hippocampus, medial septal nucleus, and frontal cortex. He will also experiment with the multivariate statistical techniques needed to analyze multiunit data.