Both 2-deoxy-D-glucose (2-DG) and insulin, administered systemically, evoke spontaneous feeding in the satiated animal. To determine whether hypothalamic norepinephrine (NE) could be involved in this eating response, we examined the effect of the two compounds on the kinetics of NE release from this structure in the unrestrained rat. An individual site in the hypothalamus of the rat was radiolabeled by 1.0-2.0 microCi of [14C]NE microinjected in a volume of 0.5-1.0 microliters through a permanently implanted guide cannula. Then 30 min later, the NE-labeled tissue was perfused, by means of push-pull cannulas, with an artificial cerebrospinal fluid at a rate of 25 microliters/min. The duration of each perfusion was 5.0 min with a 5.0-min interval between successive perfusions. After two base-line samples were collected, a saline control injection or either 40 mg/kg 2-DG or 20 U/kg insulin was given intraperitoneally; then the perfusion sequence was continued for an additional 1-h period. Aliquots of the collected samples of perfusate were analyzed by combined scintillation spectrometry and high-pressure liquid chromatography. 2-DG enhanced the release of NE at sites in the medial hypothalamus, whereas insulin generally caused a suppression of catecholamine efflux particularly at sites within the lateral hypothalamic area. The changes in NE efflux were morphologically specific. Taken together with the differences in amine release, these results suggest that 2-DG and insulin modify feeding by independent neurochemical mechanisms that may involve noradrenergic neurons at the hypothalamic level.