The purpose of the present study was to determine whether central administration of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a selective metabotropic glutamate receptor agonist, would stimulate glucose metabolism, activate the hypothalamic-pituitary-adrenal axis, or influence pancreatic endocrine secretion. Intracerebroventricular injection of ACPD increased arterial glucose levels by 60% within 15 min, which were sustained throughout the 3-h experimental protocol. This hyperglycemia resulted from an early increase in hepatic glucose production (HGP, 88%) that exceeded the increase in glucose uptake by peripheral tissues (66%). Stimulation of glucose metabolism was associated with transient elevations in plasma insulin (145%) and glucagon (3-fold) levels and more sustained elevations in corticosterone (141%), epinephrine (3- to 5-fold), and norepinephrine (32-110%). Intravenous infusion of alpha- and beta-adrenergic antagonists prevented the ACPD-induced increase in glucose metabolism. Arterial blood pressure, cardiac index, and total peripheral resistance were not altered after ACPD. Overall, the changes in regional blood flow were unremarkable, although ACPD did increase blood flow to the liver (2-fold) and heart (48%) and decrease flow to the stomach (33%). These results indicate that central administration of ACPD 1) enhances HGP, which is primarily mediated by adrenergic stimulation; 2) increases glucose uptake by peripheral tissues, which appears to be mediated by both hyperinsulinemia and hyperglycemia; 3) stimulates pancreatic and adrenal hormone secretion independent of adrenergic activation; and 4) produces minimal changes in regional blood flow that cannot explain the glucose metabolic response produced by ACPD.(ABSTRACT TRUNCATED AT 250 WORDS)