PHARMACOLOGY OF FOREBRAIN SEROTONIN RECEPTORS

前脑血清素受体的药理学

• 批准号: 3416648
• 负责人: RICHARD H ALPER
• 金额: $ 13.89万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/3416648
• 关键词: amygdala; autoradiography; baroreceptors; blood pressure; brain mapping; cardiovascular function; cardiovascular pharmacology; consciousness; heart rate; hemodynamics; homeostasis; hormone regulation /control mechanism; hypothalamus; kidney circulation; laboratory rat; mesenteric artery; microinjections; neuroendocrine system; neuropharmacology; paraventricular nucleus; preoptic areas; prosencephalon; receptor sensitivity; serotonin; serotonin inhibitor; serotonin receptor; stimulant /agonist

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、细胞和生化方面取得了进展 5-羟色胺受体的药理作用及其功能 重要性是不确定的。总体目标是使用选择性 在体内评估前脑5-羟色胺受体亚型的药理药物。 假说是选择性激活阻断5-羟色胺受体 大脑离散区域中的亚型将导致独特的模式 自主神经、血流动力学和神经内分泌反应的影响 心血管功能。具体目标是将药物微量注射到 下丘脑前核、室旁核、视前内侧核 清醒的无拘束大鼠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AN/或激素介质 回应。主要使用的5-羟色胺激动剂是8-羟基-DPAT[8- 羟基-2-二正丙氨基)四氢萘]对5-HT1a受体，DOI [(plus/minus)-1-(2-5-dimethoxy-4-iodophenyl)-2-aminopropane hc1]用于5- HT2/1C受体和2-甲基5-羟色胺为5-HT3受体。其他激动剂 为了提供更详细的受体特性，可能包括 5-羟色胺(5-HT1a)，道布[(正/负)-1-(2- 5-二甲氧基-4-溴苯基-2-氨基丙烷[5-HT2/1C]和 苯双胍(5-HT3)。主要使用的拮抗剂是 螺环酮用于5-HT1a受体，酮色林用于5-HT2受体，ICS 205-930为5-HT3受体。同样，更详细的描述可能 包括(-)吲哚、(+)吲哚和甲硫平(5-HT1a)的使用， LY 53857和螺环酮(5-HT2/1C)，MDL 72222和恩丹西酮(5-HT3)。 这些药物的适当用法与对 使用放射自显影技术的扩散距离以及 自主神经和激素拮抗剂改变反应的能力将 允许在体内定量评估5-羟色胺的作用机制 前脑受体亚型调节动脉压、心脏 心率、心输出量与肾、髂动脉和肠系膜上动脉血 流动。将5-羟色胺能药物的反射和直接反应分开 将在慢性外科压力感受器之后进行显微注射 去感觉神经。总体而言，这些实验将提供详细的 关于脑区、受体亚型和神经体液的信息 5-羟色胺受体调节心血管内稳态的机制。 这些研究将提供重要的体内数据，关于 前脑离散区域5-羟色胺受体亚型的功能 体外生化、细胞和分子生物学研究进展 药理学。