Proceedings of the National Academy of Sciences Vol. 67, No. 2, pp. 1063-1070, October 1970 Reciprocal Hunger-Regulating Circuits Involving Alpha- and Beta-Adrenergic Receptors Located, Respectively, in the Ventromedial and Lateral Hypothalamus* Sarah Fryer Leibowitz THE ROCKEFELLER UNIVERSITY, NEW YORK, N.Y. 10021 Communicated by Neal E. Miller, July 30, 1970 Abstract. The injection of adrenergic and adrenolytic drugs directly into the brain through permanently implanted cannulas has yielded results showing that food consumption in the rat is regulated by a hypothalamic alpha-adrenergic "hunger" system and a hypothalamic beta-adrenergic "satiety" system. The rats' differential responses to alpha-adrenergic and beta-adrenergic drugs in- jected into different hypothalamic sites indicate the following: (1) the lateral hypothalamic "feeding" center contains beta receptors, the activation of which produces satiation, presumably by inhibition of the lateral "feeding" cells; (2) the ventromedial hypothalamic "satiety" center contains alpha receptors, the activation of which produces eating, presumably by inhibition of the ventro- medial "satiety" cells; and (3) the medio-lateral perifornical area of the hypo- thalamus contains both alpha and beta receptors, which lead to inhibition of the ventromedial or lateral hypothalamic centers respectively. It is suggested that the ventromedial and lateral hypothalamus are connected by reciprocal circuits, so that activation of the ventromedial center results in stimulation of the lateral beta receptors which inhibit the lateral "feeding" cells, and activation of the lateral center results in stimulation of the ventromedial alpha receptors which inhibit the ventromedial "satiety" cells. In the rat hypothalamus there appears to exist an adrenergic mechanism con- sisting of both alpha and beta receptors which function antagonistically in the regulation of hunger in rats.'-' This antagonistic relationship exists between an alpha-adrenergic "hunger" system, which elicits eating behavior, and a beta- adrenergic "satiety" system, which suppresses eating behavior. A great deal of pharmacological evidence has accumulated in this laboratory to support the concept of a hypothalamic alpha- and beta-adrenergic hunger- regulating system. Grossman4 first showed that norepinephrine, when injected directly into the hypothalamus, induced an eating response in satiated rats. This norepinephrine eating response was found to be blocked by an alpha, but not a beta, antagonist. 6 In a recent series of studies," 3 I have tested other al- pha-adrenergic agonists in the rat hypothalamus and have found that these drugs, like norepinephrine, enhance food consumption, both in satiated and food-de- prived rats. However, when beta-adrenergic agonists were injected into the same hypothalamic site, they were found to suppress food consumption. The 1063 Downloaded by guest on September 26, 2021 1064 PHYSIOLOGY: S. F. LEIBOWITZ PRoc. N. A. S. hunger-stimulating effect of the alpha agonists was found to be blocked by a hypothalamically-injected alpha-adrenergic antagonist and enhanced by a hypo- thalamically-injected beta-adrenergic antagonist, and the hunger-suppressing effect of the beta agonists was found to be blocked by the beta-adrenergic an- tagonist and enhanced by the alpha-adrenergic antagonist. Further evidence in support of these opposing alpha and beta hunger-regulat- ing systems was obtained when the alpha- and beta-adrenergic antagonists were injected alone into the rat hypothalamus in relatively high doses, and they were found to affect food consumption in the expected direction.' The alpha antag- onist suppressed food intake, presumably by blocking the hypothalamic alpha "hunger" system, and the beta antagonist enhanced food intake, presumably by blocking the hypothalamic beta "satiety" system. Problem. In the above studies, which demonstrated a neurochemical dif- ferentiation between a hypothalamic "hunger" system and a hypothalamic "satiety" system, all drugs were injected into the same anatomical site, namely, the perifornical region of the hypothalamus at the level of the anterior portion of the ventromedial nucleus. However, a great deal of both lesion and electrical stimulation work has shown that hunger and satiety in the rat are anatomically differentiated in other parts of the hypothalamus, with the ventromedial hypo- thalamus as a "satiety center" and the lateral hypothalamus as a "hunger cen- ter."7 The question arises as to whether there is a functional association be- tween the hunger/satiety systems found to be differentiated anatomically and the hunger/satiety systems found to be differentiated neurochemically. It is suggested here that the two hypothalamic areas, lateral and ventromedial, which have been associated with hunger and satiety, respectively, are neurochemically different, and that the interaction that occurs between these hypothalamic hunger-regulating areas is mediated by alpha- and beta-adrenergic nerve con- nections. In an attempt to localize the alpha and beta hunger-regulating systems within specific areas of the hypothalamus, a study was carried out which varied the anatomical site of injection of several different alpha- and beta-adrenergic drugs. This localization study, in addition to providing information concerning the neurochemistry of the receptors in these areas, may answer questions concerning the location of the central site of action of particular hunger-regulating drugs, such as amphetamine, which are normally administered peripherally; the physio- logical role that the perifornical region plays in hunger regulation; and the signifi- cance and extent of drug spread after central injection. Five hypothalamic injection sites were chosen for the study, in which a series of alpha- and beta- adrenergic agonists and antagonists were tested. These sites, which were approximately at the same anterior-posterior level, were the ventro- medial area, the dorsomedial area, the medio-lateral perifornical area, and two areas in the lateral hypothalamus. The results clearly demonstrated a neuro- chemical-anatomical relationship. Briefly, we found that the medial hypo- thalamus was sensitive only to the alpha drugs; that the lateral hypothalamus was sensitive only to the beta drugs; and, confirming our previous findings, that the perifornical region was sensitive to both the alpha and beta drugs. Downloaded by guest on September 26, 2021 VOL. 67, 1970 HYPOTHALAMIC HUNGER-REGULATING CIRCUITS 1065 Materials and Methods. Placement of cannulas: A total of 73 male albino Sprague-Dawley rats (approx 320 g) were used in these experiments. They were all stereotaxically implanted with unilateral chronic cannulas under Nembutal anesthesia according to the procedure described by Slangen and Miller.' All placements were aimed at one of five areas in the hypothalamus: two in the medial hypothalamus, two in the lateral hypothalamus, and one in between. Coordinates for the five placements were as follows. (1) The ventromedial hypothalamus (n = 21), with skull flat, was 2.7 mm behind bregma, 0.4 mm lateral, and 9.5 mm vertical. (2) The dorsomedial hypo- thalamus (n = 5), with skull flat, was 2.9 mm behind bregma, 0.7 mm lateral, and 8.7 mm vertical. (3) The medio-lateral perifornical area (n = 20), with the teeth bar 3.1 mm above the intra-aural line, was 0.0 mm (bregma), 1.3 mm lateral, and 8.2 mm ver- tical. (4) The first lateral hypothalamic placement (n = 21), with skull flat, was 2.8 mm behind bregma, 1.5 mm lateral, and 8.5 mm vertical. This placement has been found to be effective in experiments on self-stimulation and stimulus-bound eating. (5) The second lateral hypothalamic placement (n = 6), which is slightly more posterior, had DeGroot coordinates of 5.4 mm anterior, 1.8 mm lateral, and -2.7 vertical. All five placements, which were histologically verified at the completion of the experiments, were found to be at roughly the same anterior-posterior level. General procedure: All rats were maintained and tested on Purina lab chow pellets. The first series of tests was carried out on the rats while they were food- and water-satiated. The test, which was given in the morning every 2-3 days, con- sisted of measuring the rats' food intake during the first 90 min immediately after drug injection. After an interval of several days, the second series of tests was begun. These tests were carried out on the rats while they were food-deprived. The deprivation period, which lasted for 18 hr, extended from 4:00 p.m. on the day before the test day until 10:00 a.m. the next morning, when they were tested. These tests were given every 3-4 days and also consisted of measuring the rats' food intake during the first 90 min im- mediately after drug injection. Upon completion of each test, the rats received food and water ad lib. until their next period of deprivation. Drugs: The following drugs were used in these experiments. (1) l-Norepinephrine bitartrate (0.01, 0.02, and 0.04,mol). Peripheral experiments show this drug to have primarily alpha-adrenergic activity except with respect to the heart, where it acts as a beta-adrenergic agonist.8 In the central nervous system, norepinephrine also appears to be primarily alpha-adrenergic, although under special circumstances, such as in the pres- ence of an alpha antagonist and at higher doses, some beta-adrenergic activity has been identified.3 Because of the relatively low doses used here, the present study is concerned only with norepinephrine's alpha-adrenergic action. (2) l-Epinephrine bitartrate (0.02 and 0.04 pmol). In the periphery, this drug is known to have both alpha- and beta- adrenergic activity.8 In the brain, it also appears to have both alpha and beta activity, depending upon dose.',3 In the present study, epinephrine is injected at the relatively low doses which were found to have primarily alpha-adrenergic effects. (3) l-Isopro- terenol bitartrate (0.10 and 0.05 umol), which, in the periphery as well as in the central nervous system, appears-to have only beta-adrenergic activity." 8 (4) d-Amphetamine sulfate (0.1 and 0.2 gmol).