Experiments are proposed to investigate the control mechanisms of the onset of puberty in the female rhesus monkey. The goals set for this proposal are 1) to test further the hypothesis that an increase in episodic release of luteinizing hormone releasing hormone (LHRH), due to maturation of the hypothalamus, is the key factor controlling the onset of puberty, 2) to investigate the inhibitory nature of the hypothalamus before puberty, and 3) to determine the role of norepinephrine (NE) as a neurotransmitter that stimulates LHRH release at the onset of puberty. First, the release pattern of LHRH and gonadotropin-associated peptide (GAP) from the stalk-median eminence (S-ME) during maturation will be determined using a push-pull perfusion method. Although we have already found that an increased release of pulsatile LHRH begins before menarche and continues through the mid-pubertal period in intact females, further experiments are planned in ovariectomized females to examine the """"""""gonadostat"""""""" theory. Second, the profile of LHRH release in precocious puberty induced by posterior hypothalamic lesions will be compared to that seen in physiological puberty. Posterior hypothalamic lesions may enhance the pulsatile release of LHRH, thereby resulting in precocious puberty. Moreover, a possible inhibitory neural system before puberty will be investigated by applying electrical stimulation to the hypothalamus or by administering nalmefene, an endogenous opiate antagonist. Third, developmental changes in catecholamine (NE, dopamine and their metabolites) release will be monitored in association with pubertal increase in LHRH output in the S-ME. Catecholamines, especially NE, may be a stimulatory neurotransmitter for pulsatile LHRH release at the onset of puberty. To test this possibility, 1) we will examine the effects of various drugs which stimulate or block catecholamine neural transmission on LHRH release in the S-ME, and 2) the effects of grafting adrenal chromaffin cells to the basal hypothalamus on precocious puberty. In the latter, adrenal chromaffin cells prior to transplantation, will be primed with nerve growth factor in vitro in order to acquire the properties of catecholamine neurons. Fourth, morphological changes in LHRH/GAP neurosecretory neurons during development will be investigated. Results from these projects will not only provide evidence to support the proposed hypothesis, but also clarify the mechanism of the onset of puberty controlled by the hypothalamus.
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