Studies are focused primarily on the cellular and subcellular mechanisms regulating the release of luteinizing hormone- releasing hormone (LHRH) and other hypothalamic peptides that participate in the modulation of pituitary hormone release. Specific studies were conducted to elucidate the role of monoaminergic neurotransmitters in the release of LHRH from nerve terminals, the nature of the specific aminergic receptors involved in the neuronal activation that precedes LHRH release, the clarification of the post-receptor events that participate in the peptide-release process, the involvement of arachidonate metabolites in amplifying or modifying the response to key neurotransmitters, and the additional role played by intracellular messengers such as Ca+2, protein kinase C, and other putative intracellular messengers derived from the metabolism of membrane phospholipids. Other parts of the project were directed to perform an in-depth analysis in vivo of the changes in LHRH prohormone levels and processing in discrete brain nuclei that are known to be involved in regulation of gonadal function. Different experimental paradigms were employed to re-create situations calling for an enhanced (or altered) function of the hypothalamic-pituitary-gonadal axis, such as steroid-feedback manipulations, pregnancy, lactation, estrous cycle, stress, ablation of selected endocrine glands or brain areas, etc. Finally, a group of experiments were directed to evaluate the mechanisms underlying the effects of neonatal neurotoxin treatment on the reproductive sphere, as well as the developmental changes and the role of steroids on certain sexually dimorphic patterns of gonadotropin secretion. The results are integrated to provide a comprehensive hypothesis of the complex, multi-level regulatory mechanisms modulating gonadal function.
