This grant application proposes to determine the role of age-related alterations in catecholamine (CA) metabolism in the initiation and maintenance of reproductive senescence in the rat. We would further extensively evaluate the consequences of the hormonal alterations associated with senescence on the rate of aging of CA neurons. All proposed experiments would utilize young (3 to 4 months), sexually mature, and middle-aged (11 to 12 months) and old (22 to 24 months) constant estrous (CE) rats of the Long Evans strain. For some experiments, the female Fischer 344 rat, which maintains a long reproductive life would be used for comparison. Based upon our observation that both norepinephrine (NE) and dopamine (DA) turnover decreases substantially in nuclei along the preoptico-tuberal pathway prior to the loss of luteinizing hormone (LH) secretory capacity at the onset of constant estrus, we would assess the effects of acutely and chronically administered alpha-adrenergic and dopaminergic receptor agonists on pulsatile LH release and steroid-induced surges of LH. The effects of these treatments on Luteinizing hormone-releasing hormone (LHRH) neurons would be evaluated by """"""""push-pull"""""""" cannulae methods. The role of chronic hyperprolactinemia (Hyp) in the aging of DA neurons would be evaluated by measuring the sequence of alteration in DA metabolism following the onset of hyperprolactinemia in animals which exhibit early (Long-Evans rats) or late reproductive senescence. Thus, the rate of DA neuronal dysfunction would be correlated with length and/or severity of the Hyp, rather than age per se. Parallel studies would evaluate the effects of chronic suppression of serum prolactin (PRL) on DA metabolism in middle-aged and old CE rats. The role of opioid neurons in reproductive would be evaluated (i) by estimating release rates of enkephalins and endorphins using """"""""push-pull"""""""" cannulae and (ii) assessing the effects on LH secretory capacity of chronic blockade of the opioid receptor through sustained release naloxone pellets. Finally, the effects of chronic Hyp on opioid neuronal function in aging rats would be evaluated using similar methods. These studies will (i) advance our knowledge of the neuronal system involved in the initiation and persistence of reproductive senescence (ii) provide an initial assessment of the role of chronic hormonal alteration, associated with reproductive senescence, in determining the rate of aging of CA neurons.
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