CORTICOSTEROID NEUROMODULATION OF SEROTONIN SYSTEM AGING

抑郁症与糖皮质激素和血清素（5-HT）系统的调节受损有关。老年抑郁症患者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、学习缺陷和适应压力能力丧失的基础。我们的长期目标是了解皮质酮和5-羟色胺受体在衰老海马中的相互作用，为改善老年抑郁症和记忆丧失患者的治疗提供新的临床方法。使用皮质酮治疗模式，我们将验证这样的假设，即5-HT1A受体亚型的细胞药理学特征，由海马皮质类固醇调节，随着年龄的增长和对这种激素的反应性减弱而改变，包括信号转导的丧失。在皮质酮激素暴露（肾上腺切除术加低、中、高浓度激素替代）、假肾上腺切除术或完整治疗的几种条件下，雌性Fischer 344大鼠（3,12和18个月）将采用电生理、神经化学和分子生物学方法。目的1将利用体内细胞外记录技术，对长期接受皮质酮治疗的水合氯醛麻醉大鼠进行研究，评估神经元对选择性5-HT1A受体激动剂的反应。目的2将利用放射配体结合、定量放射自显影和原位杂交技术，建立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。目的3将解决信号转导在老化海马介导皮质酮和5-羟色胺受体的相互作用。慢性皮质酮给药对G蛋白水平的影响将通过Western blot技术进行检测，并与5-HT1A受体介导的G蛋白偶联的年龄相关下降进行比较。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对血清素能系统的作用促进老年人抗抑郁药的治疗效果。

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.