ANTIDEPRESSANTS AND MONOAMINE RECEPTORS AND RESPONSES

抗抑郁药和单胺受体及反应

• 批准号: 2244212
• 负责人: ALAN FRAZER
• 金额: $ 15.52万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-09-15 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2244212
• 关键词: 6 hydroxydopamine; antidepressants; autoradiography; beta adrenergic agent; beta adrenergic receptor; brain mapping; desipramine; disease /disorder model; dopamine; dorsal raphe nucleus; electrostimulus; hippocampus; isoproterenol; laboratory rat; neurotoxins; norepinephrine; p chlorophenylalanine; serotonin

The goals of this project are to determine: (1) if different types of antidepressants alter the density and/or affinity of subtypes of either beta adrenoceptors (BARs) or 5-HT-1 receptors either throughout the brain or in localized areas; (2) how serotonergic nerves alter the ability of antidepressants to decrease the density of BARs; (3) factors involved in the regulation of central BARs in vivo; and (4) if alterations in central receptors for certain monamines occur in an animal model of depression. All experiments will use rats and receptors will be visualized and quantified using the technique of in vitro quantitative autoradiography. Many antidepressants decrease the density of BARs and this pharmacological effect has been speculated to be involved in their clinical effects. The experiments proposed will evaluate if a particular subtype of BAR is preferentially affected by antidepressants and whether changes are produced in common areas of the brain. In addition to affecting noradrenegic responsiveness, antidepressants change both electrophysiological and behavior responses elicited by serotonin (5-HT) agonists. The responses altered have been linked to subtypes of a receptor for 5-HT, termed the 5-HT-1 receptor. By using quantitative autoradiography, it will be possible to determine whether antidepressant-induced changes in these subtypes account for the alterations in responsiveness. In the experiments involving subtypes of BARs or 5-HT-1 receptors, rats will be given antidepressant of different types for 21 days. Antidepressants studied will be those that block selectively the uptake of norepinephrine or serotonin or inhibit selectively type A or type B monoamine oxidase. Serotonin neurons are involved in antidepressant-induced decreases in the density of BARs. To study this, the ability of either the antidepressant, desipramine, or the beta-agonist, isoproterenol (ISO), to decrease the density of BARs will be measured in intact rats or rats with lesions of central serotonergic neurons. Lesions will be made with the neurotoxin, 5,7-dihydroxytryptamine, given not only intraventricularly but also directly into areas containing noradrenegic cell bodies or nerve terminals. Lesions with a neurotoxin for catecholaminergic nerves, 6-hydroxydopamine, will be made in separate groups of rats to determine how central noradrenegic neurons influence the ability of ISO to decrease the density of beta-1 adrenoceptors. In these experiments, ISO will be given into the right lateral ventricle of rats through a permanently indwelling cannula connected to an Alzet minipump. This experiment will provide information about the feasibility of using beta agonists as antidepressants. The status pf central monoamine receptors will also be measured in rats exposed to uncontrolled shock, as this may be an animal model of depression.

该项目的目标是确定：（1）是否不同类型 抗抑郁药改变亚型的密度和/或亲和力 beta肾上腺素受体（杆）或5-HT-1受体的 在整个大脑或本地区域； （2）血清素能 神经会改变抗抑郁药降低密度的能力 酒吧（3）涉及的中央条调节的因素 体内（4）如果中央受体改变某些 孤儿发生在抑郁症的动物模型中。 所有实验 将使用大鼠和受体可视化和量化 体外定量自显影的技术。 许多 抗抑郁药降低了条的密度，这 据推测，药理学作用参与了 临床效应。 提出的实验将评估是否是 栏的特定亚型优先受到 抗抑郁药以及是否在公共区域产生变化 大脑。 除了影响北方 响应能力，抗抑郁药改变两个电生理学 以及5-羟色胺（5-HT）激动剂引起的行为反应。 这 改变的反应已与受体的亚型有关 5-HT称为5-HT-1受体。 通过使用定量 放射自显影，可以确定是否 抗抑郁药引起的这些子类型的变化说明了 响应能力的改变。 在涉及的实验中 将给予大鼠条形或5-HT-1受体的亚型 不同类型的抗抑郁药21天。 抗抑郁药 研究将是那些选择性地阻止的那些 去甲肾上腺素或5-羟色胺或抑制选择性型A或类型 B单胺氧化酶。 5-羟色胺神经元参与 抗抑郁药诱导的棒密度降低。 学习 这是抗抑郁剂，去甲胺或 β-激动剂，异丙肾上腺素（ISO），以降低条的密度 将在完整的大鼠或中央病变的完整大鼠或大鼠中测量 血清素能神经元。 病变将用神经毒素制成 5,7-二羟色胺，不仅静脉注射，而且给予 直接进入含有非二烯细胞体或神经的区域 终端。 具有神经毒素用于儿茶酚胺能神经的病变， 6-羟基胺，将以单独的大鼠组制成 确定中央方二烯神经元如何影响能力 ISO的降低β-1肾上腺素受体的密度。 在这些 实验，将ISO放入右侧心室 大鼠通过连接到Alzet的永久嵌入式套管 小型。 该实验将提供有关 使用β激动剂作为抗抑郁药的可行性。 状态 PF中央单胺受体也将在大鼠中进行测量 暴露于不受控制的电击，因为这可能是一个动物模型 沮丧。