NORADRENERGIC MECHANISMS OF ANTIDEPRESSANT ACTIVITY

抗抑郁活性的去甲肾上腺素能机制

• 批准号: 2460282
• 负责人: JAMES M O'DONNELL
• 金额: $ 9.72万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460282
• 关键词: CHO cells; adenylate cyclase; antidepressants; antisense nucleic acid; behavior; beta adrenergic receptor; centrally acting drug; desipramine; drug interactions; enzyme activity; laboratory rat; microdialysis; neurochemistry; neuropharmacology; norepinephrine; phosphodiesterases; receptor expression; transfection

The focus of the research is on elucidating noradrenergic mechanisms involved in antidepressant activity. The research plan describes experiments to test two overall hypotheses. First, it is hypothesized that beta-2 adrenergic autoreceptors are present on noradrenergic terminals in the central nervous system and that these receptors are involved in mediating the antidepressant-like behavioral effects of centrally acting beta adrenergic agonists. Second, it is hypothesized that atypical/beta-3 adrenergic receptors are present in the central nervous system and that stimulation of these receptors produces antidepressant-like effects on behavior. These hypotheses will be tested using both behavioral and neuropharmacological techniques. The specific procedures to be employed include examination of drug effects on behavior maintained under a differential-reinforcement-of-low-rate operant schedule, measurement of drug-receptor interactions using receptor and adenylyl cyclase assays, and assessment of norepinephrine release in vitro using superfusion and in vivo using microdialysis. The second, related area of research, which is not a formal component of the research plan, involves the examination of the antidepressant potential of inhibitors of Type IV phosphodiesterase and the study of how the activity of this enzyme and its sensitivity to pharmacological inhibition are regulated by central noradrenergic neurons.

研究重点是阐明去甲肾上腺素能机制 参与抗抑郁活性。研究计划描述了 测试两个总体假设的实验。首先，假设 β2 肾上腺素能自身受体存在于去甲肾上腺素能末端 中枢神经系统以及这些受体参与 介导中枢作用的抗抑郁样行为效应 β肾上腺素能激动剂。 其次，假设非典型/β-3 肾上腺素能受体存在于中枢神经系统中，并且 刺激这些受体会产生抗抑郁样作用 行为。这些假设将通过行为和 神经药理学技术。采取的具体程序 包括检查药物对行为的影响 低速率操作计划的差异强化，测量 使用受体和腺苷酸环化酶测定进行药物-受体相互作用，以及 使用灌注和体内去甲肾上腺素体外释放评估 体内使用微透析。第二个相关研究领域是 不是研究计划的正式组成部分，涉及检查 IV 型磷酸二酯酶抑制剂的抗抑郁潜力 以及该酶的活性及其敏感性的研究 药理学抑制作用由中枢去甲肾上腺素能神经元调节。