BIOLOGICAL STUDIES OF THE MAJOR PSYCHOSES

（摘自申请人摘要）Meltzer博士正在申请 更新他的RSA以进一步研究5-HT的作用， 多巴胺（DA）及其在SCH，MD和OCD中的相互作用，以及在 各种精神药物，特别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 目标，提出了14个研究目标。 （1）测试是否 美哌隆（MEL）是一种有效的CLZ治疗耐药SCH;（2）， 测试安吡嗪（AMP）是否是一种有效的非典型APD;（3）测试 假设5-HT 2-D-2拮抗剂比例可以有助于 非典型APD鉴别;（4）验证丁螺环酮在人体中作为5- HT 1a探针，通过测试吲哚洛尔，一种5-HT 1ald拮抗剂， 阻断丁螺环酮诱导的血浆催乳素（PRL）增加， 皮质醇;（5）通过确定MK-212是否可作为5-HT 2探针， 对血浆PRL、促肾上腺皮质激素（ACTH）和皮质醇的影响 可通过5-HT 2拮抗剂利坦色林预处理抑制，但 而不是吲哚洛尔;（6）通过以下方法验证5-HTP在人体中作为特异性5-HT 2探针： 证明对5-HTP、ACTH和皮质醇分泌的影响不是 用皮诺醇治疗阻断，因为它是由retanserin;（7）测试 假设ACTH、皮质醇和催乳素对丁螺环酮反应， MK-212在SCH患者中变钝;（8）为了检验以下假设， SCH中ACTH、皮质醇或PRL对5-HTP或MK-212的反应被抑制， 用临床有效剂量的MEL和AMP按CLZ治疗; (9)证明CLZ以外的非典型APD降低了基础 血浆促肾上腺皮质激素、皮质醇和24小时尿游离皮质醇， 淋巴细胞糖皮质激素受体结合位点;（10）检测 假设APD而不是CLZ会增加5-HT 2血小板结合 （11）增加的数量将与其功效成比例; 检验非典型APD占据脑D2和5-HT 2位点的假设 通过影像学研究;（12）检验非典型APD的假设， 增加大鼠纹状体和纹状体5-HT释放，不增加D2 （13）为了检验存在升高的5-HT 2和5-HT 3的假设， 在评估暴力和自杀后，自杀者大脑中的HT 1a结合位点 通过心理解剖进行诊断;（14）检验假设， 特异性5-HT摄取阻断剂增强对MK 212和5-HTP的反应， 而在强迫症患者和对照组中均无mCPP。 人类研究包括抗精神病药和抗精神病药反应 精神分裂症患者招募从四个不同的临床 研究中心，收治100多名此类患者，治疗30名患者 在门诊的基础上，以及正常的志愿者。 这些 受试者和/或患者将从申请人的医院招募 并为他们的参与付费。 将获得知情同意书， 将抽取血液样本。 动物研究涉及每年约2，300只Sprague-Dawley大鼠， 透析和内分泌激发实验。

(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.