Neural control of pancreatic polypeptide (PP) release has not been previously investigated in the mouse. In addition, it is not known to what extent increased glucagon secretion during hypoglycemia in mice is neurally mediated vs. an effect of hypoglycemia to directly stimulate glucagon secretion at the level of the islet. Feeding or the cholinergic agonist carbachol increased plasma PP levels in conscious mice (+74 +/- 18 pg/ml vs. fasted mice and +141 +/- 17 pg/ml vs. control, respectively). Neuroglucopenia induced by 2-deoxy-D-glucose or insulin-induced hypoglycemia also increased plasma PP (+79 +/- 18 and +89 +/- 11 pg/ml vs. control, respectively). These increases were abolished by hexamethonium and reduced by atropine methylnitrate (atropine). Hypoglycemia-induced hyperglucagonemia (+1,243 +/- 275 pg/ml) was reduced to 31 +/- 7% of control by atropine (+382 +/- 85 pg/ml), to 48 +/- 9% of control by combined adrenergic blockade (+601 +/- 112 pg/ml), and nearly abolished by atropine plus combined blockade (+143 +/- 41 pg/ml; 11 +/- 3% of control) or hexamethonium (+151 +/- 38 pg/ml; 12 +/- 3% of control). We conclude the following in the mouse. 1) Feeding or cholinergic agonists increase plasma PP. 2) During neuroglucopenia or hypoglycemia, plasma PP is increased via nicotinic and muscarinic mechanisms. 3) The glucagon response to hypoglycemia is predominantly the result of autonomic activation and is mediated by both muscarinic and adrenergic mechanisms.