The
neuropeptide PACAP (
pituitary adenylate cyclase-activating polypeptide) is a cotransmitter of
acetylcholine at the adrenomedullary synapse, where autonomic regulation of
hormone secretion occurs. We have previously reported that survival of prolonged metabolic stress in mice requires
PACAP-dependent biosynthesis and secretion of adrenomedullary
catecholamines (CAs). In the present experiments, we show that CA secretion evoked by direct high-frequency stimulation of the splanchnic nerve is abolished in native adrenal slices from male
PACAP-deficient mice. Further, we demonstrate that
PACAP is both necessary and sufficient for CA secretion ex vivo during stimulation protocols designed to mimic stress. In vivo, up-regulation of transcripts encoding adrenomedullary CA-synthesizing
enzymes (
tyrosine hydroxylase,
phenylethanolamine N-methyltransferase) in response to both psychogenic and metabolic stressors (restraint and
hypoglycemia) is
PACAP-dependent. Stressor-induced alteration of the adrenomedullary secretory cocktail also appears to require
PACAP, because up-regulation of
galanin mRNA is abrogated in male
PACAP-deficient mice. We further show that
hypoglycemia-induced
corticosterone secretion is not
PACAP-dependent, ruling out the possibility that
glucocorticoids are the main mediators of the aforementioned effects. Instead, experiments with bovine chromaffin cells suggest that
PACAP acts directly at the level of the adrenal medulla. By integrating prolonged CA secretion, expression of biosynthetic
enzymes and production of modulatory
neuropeptides such as
galanin,
PACAP is crucial for adrenomedullary function. Importantly, our results show that
PACAP is the dominant adrenomedullary
neurotransmitter during conditions of enhanced secretory demand.