ANTIDEPRESSANT EFFECTS ON LOCUS COERULEUS ACTIVITY

抗抑郁药对蓝斑活动的影响

• 批准号: 2245537
• 负责人: RITA VALENTINO
• 金额: $ 11.15万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2245537
• 关键词: MAO inhibitors; action potentials; antidepressants; auditory stimulus; brain electrical activity; clinical depression; corticotropin releasing factor; deprenyl; dopamine agonists; drug administration rate /duration; drug interactions; electroconvulsive therapy; electroencephalography; electrophysiology; excitatory aminoacid; fluoxetine; laboratory rat; locus coeruleus; neural transmission; neuroendocrine system; neuropharmacology; neurotransmitters; pharmacokinetics; psychopharmacology; secretion; stress; stressor

Results from this laboratory suggest that the stress-related neurohormone, corticotropin-releasing factor (CRF) serves as a neurotransmitter in the noradrenergic nucleus locus coeruleus (LC). Clinical studies suggest that CRF is hypersecreted in depression. Because depression is characterized by both neuroendocrine and biogenic amine dysfunctions, the effects of CRF hypersecretion on biogenic amine dysfunctions, the effects of CRF hypersecretion on biogenic amine nuclei (i.e., the LC) may be a link between these dysfunctions in depression and may be a common target of action for the mechanism of antidepressants. The hypotheses of this proposal are that CRF hypersecretion in depression results in altered LC discharge characteristics and that antidepressant treatments prevent this by interfering with CRF neurotransmission in the LC. This could occur by: 1) Pharmacologic antagonism of CRF; 2) Functional antagonism of CRF; or 3) Attenuation of CRF release. Supporting this, progress made during the previous funding period demonstrated that 4 pharmacologically distinct antidepressants share the potential to interfere with CRF neurotransmission in the LC after chronic administration. Sertraline and phenelzine altered LC sensory-evoked discharge in a manner opposite to CRF, suggesting that they could functionally antagonize CRF. Desmethylimipramine and mianserin attenuated stress-elicited CRF-dependent LC activation, suggesting that they attenuate CRF release. The proposed Aims will further test the hypotheses: 1) Determine whether other antidepressant treatments interfere with CRF neurotransmission in the LC in anesthetized rats. Previous studies of acute and chronic antidepressant effects on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by CRF, and LC activation by a stressor which requires CRF release will be extended to include other antidepressants and electroconvulsive shock; 2) Extend previous studies of the acute and chronic effects of antidepressants on LC spontaneous discharge, sensory-evoked discharge, activation by CRF and activation by stress to unanesthetized rats. LC spontaneous discharge, auditory-evoked discharge, activation by CRF and activation by hemodynamic or noise stress will be recorded and compared in unanesthetized rats administered antidepressants or vehicle; 3) Characterize LC discharge and the effects of antidepressants in models of CRF hypersecretion. CRF hypersecretion will be mimicked by adrenalectomy, chronic stress, and chronic i.c.v. administration of CRF. The effects of these manipulations on LC spontaneous and sensory- evoked discharge, and the ability of antidepressants to reverse these effects will be determined; and 4) Investigate possible mechanisms by which antidepressants interfere with CRF neurotransmission in the LC by elucidating their site of action. It will be determined whether antidepressants act within the LC or on LC afferents to produce effects that interfere with CRF function in the LC. The proposed studies will help elucidate neurotransmitter pathology in depression, mechanisms of action of antidepressant treatments, and interactions between neuroendocrine and catecholamine systems.

该实验室的结果表明与压力有关 神经激素，皮质激素释放因子（CRF）用作A 去甲肾上腺核基因座（LC）中的神经递质。 临床研究表明，CRF在抑郁症中已超出分泌。 因为抑郁症的特征是神经内分泌和生物源性 胺功能障碍，CRF过度分泌对生物胺的影响 功能障碍，CRF过度分泌对生物胺的影响 核（即LC）可能是这些功能障碍之间的联系 抑郁症，可能是行动的常见目标 抗抑郁药。 该提议的假设是CRF 抑郁症的高分泌导致LC排出改变 特征和抗抑郁药的治疗阻止了这种特征 在LC中干扰CRF神经传递。 这可能是通过： 1）CRF的药理学拮抗作用； 2）CRF的功能拮抗作用； 或3）CRF释放的衰减。 支持这一点，进步取得了 在上一个资金期间证明了4 药理学上不同的抗抑郁药具有 慢性后，干扰LC的CRF神经传递 行政。 舍曲林和苯嗪改变了LC感觉诱发的 以与CRF相对的方式排放，表明他们可以 在功能上对抗CRF。 脱甲基氨基胺和米亚梅林 减弱应力引起的CRF依赖性LC激活，表明 他们减弱了CRF的发布。 拟议的目标将进一步测试 假设：1）确定是否其他抗抑郁药治疗 在麻醉大鼠的LC中干扰CRF神经传递。 先前关于急性和慢性抗抑郁作用对LC的研究 自发放电，LC感官诱发的放电，LC激活 CRF和需要CRF释放的压力源激活LC 扩展到包括其他抗抑郁药和电击剂 震惊; 2）扩展了先前对急性和慢性影响的研究 LC自发放电，感官诱发的放电上的抗抑郁药， CRF的激活和应力激活对未经麻醉的大鼠。 LC 自发放电，听觉诱发的放电，CRF激活和 血液动力或噪声应力的激活将被记录并比较 在未经麻醉的大鼠中，施用抗抑郁药或媒介物； 3） 表征LC放电和抗抑郁药在模型中的影响 CRF高度分泌。 CRF超级分泌会被模仿 肾上腺切除术，慢性应激和慢性I.C.V.管理 CRF。 这些操作对LC自发和感觉的影响 诱发的排放，以及抗抑郁药逆转这些的能力 将确定效果； 4）通过 哪种抗抑郁药干扰LC中的CRF神经传递 通过阐明其行动地点。 将确定是否 抗抑郁药作用于LC或LC传统，以产生效果 该干扰LC中的CRF功能。 拟议的研究将 有助于阐明抑郁症的神经递质病理学， 抗抑郁治疗的作用和之间的相互作用 神经内分泌和儿茶酚胺系统。