BIOLOGICAL STUDIES OF THE MAJOR PSYCHOSES

(根据申请者的摘要改编)梅尔策博士正在申请 更新他的RSA以进一步研究5-羟色胺的作用， 多巴胺(DA)及其在SCH、MD和OCD中的相互作用 多种精神药物，尤其是氯氮平的作用机制 (CLZ)和其他非典型抗精神病药物(APD)。根据这些规定 目标，提出了14个研究目标。这些是：(1)测试是否 美培酮(Mel)是一种与CLZ一样有效的治疗耐药的SCH；(2) 测试氨氯齐特(AMP)是否是有效的非典型动作电位；(3)测试 假设5-HT2-D-2拮抗剂比率可能有助于 (4)丁螺环酮作为一种5-氨基丁螺环酮 通过测试5-HT1ald拮抗剂吲哚洛尔对HT1a的作用 阻断丁螺环酮引起的血浆催乳素(PRL)和 皮质醇；(5)通过确定是否将MK-212作为5-HT2探针在MAN中验证MK-212 丹参对血浆催乳素、促肾上腺皮质激素和皮质醇的影响 可被5-HT2拮抗剂Ritanserin预先抑制，但 不是通过吲哚；(6)通过以下方法在人体内验证5-HTP作为特异性5-HT2探针 表明对5-HTP、ACTH和皮质醇的分泌没有影响 (7)用平阳霉素阻断；(7) 假设促肾上腺皮质激素、皮质醇和催乳素对丁螺环酮和 MK-212在SCH患者中被钝化；(8)检验假设 Sch对5-HTP或MK-212的ACTH、皮质醇或PRL反应被抑制 临床有效剂量的美拉帕米和环丙沙星治疗； (9)显示除CLZ外的非典型动作电位降低。 血浆ACTH、皮质醇和24小时尿游离皮质醇升高 淋巴细胞糖皮质激素受体结合部位；(10)检测 假设APDs而不是CLZ会增加5-HT2的血小板结合率 这一增幅将与它们的功效成正比； 验证非典型动作电位占用大脑D2和5-HT2部位的假说 通过成像研究；(12)检验非典型动作电位的假说 增加大鼠纹状体和伏隔核5-羟色胺的释放，不增加D2 释放；(13)检验5-HT2和5-HT2升高的假设。 在评估了暴力和自杀后自杀脑中的HT1A结合位点 通过心理尸检进行诊断；以及(14)检验假设 特定的5-羟色胺摄取阻滞剂增强对MK212和5-HTP的反应，但 强迫症患者和对照组均不存在mCPP。 人体研究包括抗精神病药物抵抗和抗精神病药物反应。 从四个不同的临床招募精神分裂症患者 研究中心，收治100多名这样的患者，治疗30名患者 每年以门诊为基础，以及正常志愿者。这些 受试者和/或患者将从申请人所在的医院招募 并为他们的参与买单。将获得知情同意，并 将抽取血样。 动物研究涉及每年约2300只SD大鼠，用于 透析和内分泌挑战实验。

(Adapted from the applicant's abstract) Dr. Meltzer is applying for renewal of his renewal of his RSA to further study the roles of 5-HT, dopamine (DA) and their interaction in SCH, MD, and OCD, as well as in the mechanism of action of various psychotropic drugs, especially clozapine (CLZ) and other atypical antipsychotic drugs (APD). Pursuant to these goals, 14 study aims are proposed. These are: (1) to test whether melperone (MEL) is a effective as CLZ in treatment-resistant SCH; (2) to test whether amperozide (AMP) is an effective atypical APD; (3) to test the hypothesis that the 5-HT2-D-2 antagonist ratio can contribute to the identification of atypical APD's; (4) to validate buspirone in man as a 5- HT1a probe by testing the ability of pindolol, a 5-HT1ald antagonist to block the buspirone-induced increases in plasma prolactin (PRL) and cortisol; (5) to validate MK-212 in man as a 5-HT2 probe by determining if its effects on plasma PRL, adrenocortiotropic hormone (ACTH) and cortisol can be inhibited by pretreatment with ritanserin, a 5-HT2 antagonist, but not by pindolol; (6) to validate 5-HTP in man as a specific 5-HT2 probe by demonstrating that the effect on 5-HTP, ACTH and cortisol secretion is not blocked by treatment with pinodol as it is by retanserin; (7) to test the hypothesis that ACTH, cortisol, and prolactin responses to buspirone and MK-212 are blunted in patients with SCH; (8) to test the hypothesis that ACTH, cortisol or PRL responses to 5-HTP or MK-212 in SCH are inhibited by treatment with clinically effective doses of MEL and AMP as it is by CLZ; (9) to demonstrate that atypical APD's other than CLZ decrease basal plasma ACTH, cortisol and 24 hour urinary free cortisol and increase lymphocyte glucocorticoid receptor binding sites; (10) to test the hypothesis that APD's other than CLZ will increase 5-HT2 platelet binding sites and this increase will be proportional to their efficacy; (11) to test the hypothesis that atypical APD's occupy brain D2 and 5-HT2 sites through imaging studies; (12) to test the hypothesis that atypical APD's increase 5-HT release in rat striatum and accumbens and do not increase D2 release; (13) to test the hypothesis that there is elevated 5-HT2 and 5- HT1a binding sites in suicide brains after assessing both violence and diagnosis by psychological autopsy; and (14) to test the hypothesis that specific 5-HT uptake blockers enhance the response to MK 212 and 5-HTP but not mCPP in both OCD patients and controls. The human studies involve neuroleptic resistant and neuroleptic responsive patients with schizophrenia recruited from four different Clinical Research Centers, which admit over 100 such patients and treat 30 patients per year on an out-patient basis, as well as normal volunteers. These subjects and/or patients will be recruited from the applicant's hospital and paid for their participation. Informed consent will be obtained and blood samples will be drawn. The animal studies involve about 2,300 Sprague-Dawley rats per year for dialysis and endocrine challenge experiments.