The long term goals of this project are to elucidate the role of peripheral dopamine receptors on adrenal chromaffin cells and the mechanisms by which they alter neurotransmitter release. Although dopamine containing cells (SIF cells) are known to be present in sympathetic ganglia, the site of action and role of dopamine in ganglionic function remains obscure. Adrenal chromaffin cells resemble postganglionic, sympathetic neurons in their synthesis, storage and release of catecholamines. It has recently been reported that dopamine receptor agonists inhibit adrenal catecholamine release. We have obtained preliminary evidence for the presence of D2 dopamine receptors on adrenal chromaffin cells, their interaction with GTP binding proteins, and for their inhibition of calcium channels and catecholamine release. We plan to characterize the dopamine receptors on chromaffin cells by radioligand binding techniques, using 3H-N- methylspiperone, a D2 dopamine receptor antagonist, and 3H-N- propylapomorphine, a D2 receptor agonist. The role of dopamine receptors in adrenal medullary function will be determined by measuring the effects of dopaminergic ligands on calcium translocation, cytosolic calcium levels and catecholamine release. The possible role of GTP-binding proteins in the receptor transduction mechanism will be examined by determining the effects of pertussis toxin and cholera toxin and of guanyl nucleotide derivatives on radioligand binding, calcium movements and catecholamine release. In a general sense it is anticipated that new insights into the function of peripheral dopamine receptors and their mechanisms of modulating neurohormone release will result from this project. The specific role of D2 dopamine receptors in regulating adrenal chromaffin cell calcium movements and catecholamine secretion should be clarified. An improved understanding of the pharmacology and cellular regulation of catecholamine release will be relevant to the management of the adrenal medullary tumor, pheochromocytoma. Since adrenaline release is central to the neurochemistry of the acute stress response, there will also be direct relevance to the associated effects on cardiovascular and pulmonary function and hypertension.
