The proposed studies will examine the role of brain monoaminergic and LHRH neurons, estradiol and prolactin in the age-related transition to irregular estrous cyclicity and eventual acyclicity. Experiments, using 6-17 mo. old rats as an experimental model, have been designed to determine which of the following working hypotheses is (are) the most likely explanation(s) for the onset of irregular cycles: (1) Phasic LH release (preovulatory and steroid-induced) is accompanied and presumably regulated by changes in norepinephrine (NE), dopamine (DA) and serotonin (5HT) activity. Aging may affect the pattern of neurotransmitter dynamics to inhibit LH release. (2) LH surges are regulated, in part, by the amount of LHRH released into pituitary portal blood and this release is accompanied by changes in tissue concentrations of LHRH in specific hypothalamic structures known to contain cell bodies, axons and terminal boutons of the neurosecretory neurons. Aging may affect the levels in one or more discrete hypothalamic areas, its releasability and/or concentrations in portal blood. (3) Estradiol action at the brain and pituitary are necessary for LH surges to occur. Aging may alter the responsiveness of these sites to estradiol positive feedback such that steroids become incapable of facilitating LH surges. (4) Hyperprolactinemia is often associated with acyclicity in young females. Prolactin may become elevated gradually in aging rats and feedback to alter the cyclic profile in monoamine-LHRH dynamics and cyclic LH release. These hypotheses will be tested using several methodological advances. Neuronal activity will be assessed by 4 indices: (1) turnover rates of NE, DA and 5HT and LHRH levels and (2) measurement of monoamine metabolites in microdissected brain structures thought to be important in neural control of LH and likely sites of synaptic and neurohumoral contact between NE, DA and 5HT and LHRH containing neurons, (3) measurement of LHRH and DA in portal blood and (4) use of median eminence synaptosome preparations to study compounds which modulate LHRH and DA release. Receptor assays for estradiol, progesterone and DA allow examination of changes in receptor binding in separate areas of the brain and pituitary to evaluate whether changes in responsiveness to these hormones can be correlated with changes in receptor biochemistry. These parameters will be correlated with the onset of irregular cycles in middle aged rats to evaluate the role that each plays in this age-related transition.
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