The goal of the proposed studies is to localize and to characterize the intracerebral sites of action of gonadotropin releasing hormone (GnRH) and to identify the neurotransmitters which regulate the intracerebral GnRH system. We propose to examine whether: 1. the intracerebral GnRH system can be divided into an """"""""endocrine"""""""" GnRH system which acts at the anterior pituitary to regulate gonadotropin release, and into a non- endocrine,""""""""GnRH system which acts in the brain only. We have shown in previous studies that only one subgroup of the GnRH neurons releases the peptide into the blood stream while the other subgroup releases the peptide at presynaptic terminals within the central nervous system. We plan to further characterize these two GnRH systems and to identify the neurotransmitters which innervate the different subsets. 2. GnRH acts in the brain through specific membrane receptors. We have described the distribution of specific GnRH binding sites in the central nervous system. The results of """"""""in vitro"""""""" autoradiographic and biochemical (radioreceptor assays) studies suggest that the binding of the GnRH agonist Buserelin to brain membranes is specific, reversible, saturable and of high affinity. We propose to characterize the brain GnRH binding sites in detail with morphological (autoradiography), biochemical (radio-receptor assay) and immunological (monoclonal anti-idiotypic antibodies) procedures in order to determine their distribution, structure-binding requirements and affinities. 3. the expression of the brain GnRH receptors varies with the endocrine status of the animal. Behavioral studies have suggested that GnRH injections into the central gray facilitate lordosis behavior only under certain endocrine conditions. In analogy to the anterior pituitary where the number of GnRH receptor varies with the stage of the estrous cycle, we propose to study changes in the characteristics of the brain GnRH receptors with quantitative autoradiography and radioreceptor assays. The proposed combination of morphological and biochemical approaches will provide detailed information on how the intracerebral- neuromodulatory GnRH system is regulated, where in the brain GnRH acts, and which dynamic changes occur during various endocrine conditions. The results will be important for our basic understanding of how the brain participates in the regulation of hormonal homeostasis and may provide clues for treatment of disorders caused by central failure to maintain an adequate GnRH release.
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