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: 6028102
• 负责人: JOAN M LAKOSKI
• 金额: $ 19.78万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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/6028102
• 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血清素 (5-HT) 系统调节受损有关。 对老年患者抑郁症的检查揭示了肾上腺激素皮质酮和 5-HT 受体相互作用的作用，也可能是记忆、学习缺陷和随着年龄增长而适应压力能力丧失的原因。 我们的长期目标是了解衰老海马体中皮质酮和 5-HT 受体的相互作用，并为改善老年患者抑郁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，我们将检验以下假设：5-HT1A 受体亚型的细胞药理学特征（由海马皮质类固醇调节）会随着年龄的增长和对该激素的反应迟缓而变化，包括信号转导的损失。 电生理学、神经化学和分子生物学方法将在雌性 Fischer 344 大鼠（3、12 和 18 个月）中在多种皮质酮激素暴露条件（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治疗下使用。 目标 1 将在长期接受皮质酮治疗的水合氯醛麻醉的大鼠中利用体内细胞外记录技术，并评估神经元对选择性 5-HT1A 受体激动剂随衰老的反应。 目标 2 将利用放射性配体结合、定量放射自显影和原位杂交技术确定慢性皮质酮暴露对衰老海马中 5-HT1A 受体结合和基因表达特征的影响。 目标 3 将解决衰老海马体中介导皮质酮和 5-HT 受体相互作用的信号转导问题。 将通过蛋白质印迹技术检查慢性皮质酮施用对G蛋白水平的影响，并与5-HT1A受体介导的G蛋白偶联的年龄相关下降的评估进行比较。 这些研究的结果可能表明，特定的糖皮质激素拮抗剂可能通过作用于血清素能系统，促进老年人抗抑郁药物发挥治疗功效。