CORTICOSTEROID NEUROMODULATION OF SEROTONIN SYSTEM AGING

皮质类固醇对血清素系统衰老的神经调节

• 批准号: 6761990
• 负责人: JOAN M LAKOSKI
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761990
• 关键词: G protein; adrenalectomy; aging; biological signal transduction; clinical depression; corticosteroids; electrophysiology; female; gene expression; hippocampus; hormone regulation /control mechanism; hormone therapy; hypothalamic pituitary adrenal axis; in situ hybridization; laboratory rat; memory disorders; neuroimmunomodulation; nonhuman therapy evaluation; northern blottings; receptor coupling; receptor expression; serotonin receptor; western blottings

Depressive disorders are linked to impairments in the regulation of glucocorticoid and serotonin (5-HT) systems. Examination of depression in the elderly patient has revealed a role for the interaction of the adrenal hormone corticosterone and 5-HT receptors and may also underlie deficits in memory, learning and losses in ability to adapt to stress with aging. Our long term goal is to understand corticosterone and 5-HT receptor interaction in the aging hippocampus and provide new clinical approaches for improving the treatment of depression and memory loss in geriatric patients. Using a corticosterone treatment paradigm, we will test the hypothesis that the cellular pharmacological characteristics of the 5-HT1A receptor subtype, as modulated by corticosteroids in the hippocampus, change with aging and loose responsiveness to this hormone, including losses in signal transduction. Electrophysiological, neurochemical and molecular biological approaches will be utilized in the female Fischer 344 rat (3, 12 and 18 mo) under several conditions of corticosterone hormone exposure (adrenalectomy plus low, moderate and high concentrations of hormone replacement) sham adrenalectomy or intact treatment. Aim 1 will utilize in vivo extracellular recording techniques in the chloral hydrate anesthetized rat chronically treated with corticosterone and evaluate neuronal responses to selective 5-HT1A receptor agonists with aging. Aim 2 will establish the effect of chronic corticosterone exposure on binding and gene expression characteristics of the 5-HT1A receptor in the aging hippocampus using radioligand binding, quantitative autoradiography and in situ hybridization techniques. Aim 3 will address signal transduction in the aging hippocampus mediating corticosterone and 5-HT receptor interactions. Chronic corticosterone administration effects on G protein levels will be examined by Western blot techniques and compared with assessment of age- associated declines in 5-HT1A receptor-mediated G protein- coupling. The results of these studies may lead to an indication that specific glucocorticoid antagonists may facilitate the onset of therapeutic efficacy for antidepressants in the elderly via actions at the serotonergic system.

抑郁症与糖皮质激素和5-羟色胺（5-HT）系统的调节受损有关。 老年患者抑郁症的检查揭示了肾上腺激素皮质酮和5-羟色胺受体相互作用的作用，也可能是记忆力、学习能力和适应衰老压力能力丧失的基础。 我们的长期目标是了解衰老海马中皮质酮和5-HT受体的相互作用，并为改善老年患者抑郁症和记忆丧失的治疗提供新的临床方法。 使用皮质酮治疗范例，我们将测试的假设，即5-HT 1A受体亚型的细胞药理学特征，在海马皮质类固醇调制，随着年龄的增长和松散的反应，这种激素，包括信号转导的损失。 在皮质酮激素暴露（肾上腺切除术加低、中和高浓度激素替代）、假肾上腺切除术或完整处理的几种条件下，将在雌性Fischer 344大鼠（3、12和18月龄）中使用电生理学、神经化学和分子生物学方法。 目的1将利用在体细胞外记录技术在水合氯醛麻醉大鼠慢性皮质酮治疗和评估神经元的反应，选择性5-HT 1A受体激动剂与衰老。 目的2应用放射配基结合、定量放射自显影和原位杂交技术，研究慢性皮质酮暴露对衰老海马5-HT 1A受体结合和基因表达特征的影响。 目的3探讨衰老海马中皮质酮与5-HT受体相互作用的信号转导机制。 将通过蛋白质印迹技术检查长期皮质酮给药对G蛋白水平的影响，并与5-HT 1A受体介导的G蛋白偶联中年龄相关下降的评估进行比较。 这些研究的结果可能表明，特异性糖皮质激素拮抗剂可能通过对肾上腺素能系统的作用促进老年人抗抑郁药的疗效。