PHARMACOLOGY OF FOREBRAIN SEROTONIN RECEPTORS

前脑血清素受体的药理学

基本信息

批准号：
2267878
负责人：
RICHARD H ALPER
金额：
$ 12.62万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-04-01 至 1996-03-31
项目状态：
已结题

项目摘要

Progress has been made in molecular, cellular and biochemical pharmacology of serotonin (5-HT) receptors yet their functional significance is uncertain. The GENERAL OBJECTIVE is to use selective pharmacologic agents to assess forebrain 5-HT receptor subtypes in vivo. The HYPOTHESIS is that selective activation of blockade of 5-HT receptor subtypes in discrete brain regions will elicit unique patterns of autonomic, hemodynamic and neuroendocrine responses to affect cardiovascular function. The SPECIFIC AIMS are to microinject drugs into the anterior hypothalamus, paraventricular nucleus, the medial preoptic area and central amygdala in conscious, unrestrained rats to: 1) DESCRIBE ROLES FOR FOREBRAIN 5-HT1A,5-HT2, and 5-HT3 RECEPTORS IN CARDIOVASCULAR FUNCTION, AND 2) DETERMINE NEURAL AN/OR HORMONAL MEDIATORS OF THE RESPONSES. The 5-HT agonists to be used primarily are 8-OH-DPAT [8- hydroxy-2-di-nu-propylamino) tetralin] for 5-HT1A receptors, DOI [(plus/minus)-1-(2-5-dimethoxy-4-iodophenyl)-2-aminopropane HC1] for 5- HT2/1C receptors and 2-methyl 5-HT for 5-HT3 receptors. Other agonists to provide more detailed receptor characterizations may include flesinoxan and 5-carboxamidotryptamine (5-HT1A), DOB [(plus/minus)-1-(2- 5-dimethoxy-4-bromophenyl)-2-aminopropane HBr] (5-HT2/1C) and phenylbiguanide(5-HT3). The antagonists to be used primarily are spiperone for 5-HT1A receptors, ketanserin for 5-HT2 receptors, and ICS 205-930 for 5-HT3 receptors. Again, more detailed characterizations may include the use of (-)pindolol, (+) pindolol, and methiothepin (5-HT1A), LY 53857 and spiperone (5-HT2/1C, and MDL 72222 and ondansetron (5-HT3). The appropriate use of these drugs in conjunction with a description of diffusional distances using autoradiographic techniques as well as the ability of autonomic and hormone antagonists to alter responses will allow an quantitative in vivo assessment of mechanisms by which 5-HT receptor subtypes in the forebrain regulate arterial pressure, heart rate, cardiac output and renal, iliac and superior mesenteric blood flows. To separate reflex from direct responses the serotonergic drugs will be microinjected following chronic surgical baroreceptor deafferentation. Overall, the experiments will provide detailed information on brain regions, receptor subtypes and neurohumoral mechanisms by which 5-HT receptors regulate cardiovascular homeostasis. These studies will provide significant in vivo data regarding the function of 5-HT receptor subtypes in discrete forebrain areas as an extension of the in vitro biochemical, cellular and molecular pharmacology.

在分子、细胞和生物化学方面取得了进展血清素 (5-HT) 受体的药理学及其功能意义是不确定的。一般目标是有选择地使用体内评估前脑 5-HT 受体亚型的药物制剂。假设是选择性激活 5-HT 受体阻断离散大脑区域的亚型将引发独特的模式自主神经、血流动力学和神经内分泌反应影响心血管功能。具体目标是将药物显微注射到下丘脑前部、室旁核、内侧视前核清醒、不受约束的大鼠中的杏仁核区域和中央：1) 描述前脑 5-HT1A、5-HT2 和 5-HT3 受体在心血管中的作用功能，以及 2) 确定神经和/或激素介质回应。主要使用的 5-HT 激动剂是 8-OH-DPAT [8- 羟基-2-二-正丙氨基）四氢化萘]用于5-HT1A受体，DOI [(加/减)-1-(2-5-二甲氧基-4-碘苯基)-2-氨基丙烷HCl] 为 5- HT2/1C 受体和 5-HT3 受体为 2-甲基 5-HT。其他激动剂提供更详细的受体特征可能包括氟辛克生和 5-甲酰胺色胺 (5-HT1A)，DOB [（加/减）-1-(2- 5-二甲氧基-4-溴苯基)-2-氨基丙烷HBr](5-HT2/1C)和苯基双胍(5-HT3)。主要使用的拮抗剂有用于 5-HT1A 受体的螺哌隆、用于 5-HT2 受体的酮色林和 ICS 205-930 为 5-HT3 受体。同样，更详细的特征可能包括使用 (-) 吲哚洛尔、(+) 吲哚洛尔和甲硫替平 (5-HT1A)， LY 53857 和螺哌隆 (5-HT2/1C)，以及 MDL 72222 和昂丹司琼 (5-HT3)。这些药物的正确使用与描述相结合使用放射自显影技术以及自主神经和激素拮抗剂改变反应的能力将允许对 5-HT 的机制进行定量体内评估前脑中的受体亚型调节动脉压、心脏心率、心输出量以及肾血、髂血和肠系膜上血流动。将血清素药物的反射与直接反应分开将在慢性手术压力感受器后进行显微注射传入神经阻滞。总的来说，实验将提供详细的有关大脑区域、受体亚型和神经体液的信息 5-HT 受体调节心血管稳态的机制。这些研究将提供有关以下方面的重要体内数据：离散前脑区域 5-HT 受体亚型的功能体外生化、细胞和分子的扩展药理。