The GABA- and dopaminergic (DA) neurons of the tubero-hypothalamic area and their target cells, the pituitary intermediate lobe (IL) melanotropes, will be used as a model system for the ontogeny of the mechanisms for neuronal co-transmitter control of endocrine cells. The concept of co- localization of multiple neurotransmitters within one neuron has become established through recent research. Co-localization adds a level of increased complexity to synaptic communication which is important to study to better comprehend neuronal regulation. Ontogenic studies unfold the processes by which a developing system forms and can explain the basis of the complexity of the mature system. The overall objective of this project is to link pre- and postsynaptic events during the ontogeny of the tubero-hypophysial system. The specific aims are: (1) to establish the chronology of the development of the co- localization of GABA and DA in neurons of the tubero-hypothalamic area; (2) to define the time-sequence and spatial pattern of the GABA and DAergic innervation of the IL; (3) to establish the ontogeny of dopamine (d 2) and GABA receptors; and, (4) to study the impact of the event of innervation on IL melanotrope mitotic rate, pro-opiomelanocortin (POMC) gene expression, and secretory vesicle population. The techniques to be used include immunohistochemistry, immunocytochemistry, electron microscopic morphometry, in situ hybridization histochemistry, [3H]thymidine incorporation, and receptor binding assays. The significance of these studies relates to how co-localized neurotransmitters regulate their target cells. Understanding these regulatory mechanisms, which are unlikely to be unique to GABA/DA regulation of melanotropes, will allow the elucidation of more complex cellular communication systems. Comprehension of the mechanisms for co- transmitter action is a necessary step toward the design of therapeutic interventions to treat neurological disorders without adverse drug effects.
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