CORTICOSTEROID NEUROMODULATION OF SEROTONIN SYSTEM AGING

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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.