PHARMACOLOGY OF FOREBRAIN SEROTONIN RECEPTORS

前脑血清素受体的药理学

• 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
• 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/2267878
• 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（5-HT）受体的药理学，但其功能 意义不确定。 总体目标是使用选择性 在体内评估前脑5-HT受体亚型的药理学剂。 假设是选择性激活5-HT受体的封锁 离散大脑区域中的亚型将引起独特的模式 对影响的自主，血液动力学和神经内分泌反应 心血管功能。 具体的目的是将微型药物纳入 前下丘脑，旁腔核，内侧前核 区域和中央杏仁核中有意识，不受约束的大鼠：1）描述 前脑5-HT1A，5-HT2和5-HT3受体的角色 功能，2）确定神经AN/或激素介体 回答。 主要使用的5-HT激动剂是8-OH-DPAT [8- 羟基-2-di-nu-丙基氨基）四丁素]，用于5-HT1A受体，doi [（加/减）-1-（2-5-二甲氧基-4-偶氮基）-2-氨基丙烷HC1]，用于5- 5-HT3受体的HT2/1C受体和2-甲基5-HT。 其他激动剂 提供更详细的受体特征可能包括 氟替诺甘和5-羧酰胺丁胺（5-HT1A），dob [（（plus/minus）-1-（2-） 5-二甲氧基-4-溴苯基）-2-氨基丙烷HBR]（5-HT2/1C）和 苯基硫酰胺（5-HT3）。 主要使用的拮抗剂是 用于5-HT1A受体的尖龙，用于5-HT2受体的酮素和ICS 5-HT3受体的205-930。 同样，更详细的特征可能 包括使用（ - ）Pindolol，（+）Pindolol和Methiothepin（5-HT1A）， LY 53857和尖峰（5-HT2/1C和MDL 72222和Ondansetron（5-HT3）。 这些药物的适当使用以及描述 使用自显影技术的扩散距离以及 自主和激素拮抗剂改变反应的能力将 允许对5-HT的机制进行定量的体内评估 前脑中的受体亚型调节动脉压，心脏 速率，心输出和肾脏，肠肠系和肠系膜上血 流。 将反射与血清素能药物的直接反应分开 将在慢性手术压力感受之后进行微注射 停用。 总体而言，实验将提供详细的 有关大脑区域，受体亚型和神经肿瘤的信息 5-HT受体调节心血管稳态的机制。 这些研究将为有关 离散前脑区域中5-HT受体亚型的功能 体外生化，细胞和分子的延伸 药理。