CORTICOSTEROID NEUROMODULATION OF SEROTONIN SYSTEM AGING

抑郁障碍与糖皮质激素和5-羟色胺(5-羟色胺)系统的调节受损有关。对老年患者的抑郁症检查揭示了肾上腺激素皮质酮和5-羟色胺受体的相互作用，也可能是记忆、学习和适应压力能力随年龄增长而丧失的原因。我们的长期目标是了解老化海马区皮质酮和5-羟色胺受体的相互作用，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，我们将检验这一假设，即5-HT1A受体亚型的细胞药理学特征受海马区皮质类固醇的调节，随着年龄的增长和对这种激素的松散反应而改变，包括信号转导的丧失。在雌性Fischer 344大鼠(3、12和18mo)上，采用电生理、神经化学和分子生物学的方法，在皮质酮激素暴露(肾上腺切除加低、中、高浓度激素替代)、假肾上腺切除或完整治疗的几种条件下进行。目的1利用水合氯醛麻醉大鼠体内细胞外记录技术，长期给予皮质酮治疗，评估神经元对选择性5-HT1A受体激动剂的增龄反应。目的利用放射配基结合、放射自显影和原位杂交技术，研究慢性皮质酮暴露对衰老大鼠海马区5-HT1a受体结合和基因表达特征的影响。目标3将阐述老化的海马区中的信号转导，介导皮质酮和5-羟色胺受体的相互作用。长期服用皮质酮对G蛋白水平的影响将通过Western印迹技术来检测，并与5-HT1A受体介导的G蛋白偶联的年龄相关下降的评估相比较。这些研究的结果可能导致一种迹象，即特定的糖皮质激素拮抗剂可能通过作用于5-羟色胺能系统而促进老年人抗抑郁药物的疗效。

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.