In this grant I, as a new investigator, will take advantage of local expertise on physiology and anatomy of the neurohypophysis to investigate the pathophysiology and functional anatomy which may be involved in disorders producing inappropriate secretion of vasopressin (SIADH). SIADH is a common clinical syndrome causing hyponatremia and leading to seizures, coma and increased hospital mortality; but, the specific mechanisms of excessive AVP secretion are not well understood. The applicant has been involved in the development of two new methods to study vasopressin secretion. A new and sensitive measure of vasopressin synthesis in the rat was developed and correlated with hypothalamic vasopressin mRNA levels. Localization of c-fos antigen in magnocellular neurons using standard immunohistologic techniques is a new method to investigate the functional anatomy of the magnocellular neurohypophysis. C-fos is a cellular protein which is thought to be involved in initiation of transcription, and in preliminary studies we found an excellent correlation between the expression of c-fos antigen and activation of magnocellular neurons. Studies of vasopressin synthesis in an animal model of hyponatremia documented for the first time that vasopressin synthesis and mRNA levels could be down regulated. This model provides a mechanism to investigate neurotransmitter input to the neurohypophysis to determine whether vasopressin synthesis rate reflects a balance between excitatory and inhibitory input. Emphasis will be on the role of GABA in down regulation. Results of these studies will be used to plan studies to determine whether several drugs in current clinical use which cause SIADH act as a primary stimulus to AVP synthesis or as inhibitors of the down regulation AVP synthesis which we found occurs with hyponatremia.l Localization of c-fos antigen within magnocellular neurons will allow mapping of neuron activation within the magnocellular system during application of a specific stimulus or pathophysiologic disorder. This will be the first opportunity to determine whether there is functional heterogeneity of subpopulations of neurohypophyseal neurons. Heterogeneity may be expressed in response to specific neurotransmitters and to the drugs which act on the neurohypophysis. Completion of the studies will provide a training vehicle to increase my understanding of functional hypothalamic neuroanatomy,l neurotransmitter physiology and the use of molecular biologic techniques in animals to investigate causes of clinical disorders which occur in humans. The results will give new information on the neurotransmitter dysfunction and functional neuroanatomy which is deranged in disorders of excessive vasopressin secretion.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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University of Pittsburgh
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Roberts, M M; Robinson, A G; Fitzsimmons, M D et al. (1993) c-fos expression in vasopressin and oxytocin neurons reveals functional heterogeneity within magnocellular neurons. Neuroendocrinology 57:388-400