Pharmacology Biochemistry&Behavior, Vol. 16, pp. 225-228, 1982. Printed in the U.S.A. Peptidergic Regulation of Norepinephrine Induced Feeding JOHN E. MORLEY, ALLEN S. LEVINE, SAMUEL S. MURRAY AND JULIE KNEIP Neuroendocrine Research Laboratory, Minneapolis VA medical Center, Minneapolis, MN 55417 and The Division of Endocrinology and the Departments of Medicine and Food Science and Nutrition University of Minnesota, Minneapolis-St. Paul, MN Received 30 March 1981 MORLEY, J. E., A. S. LEVINE, S. S. MURRAY AND J. KNEIP. Peptidergic regulation of norepinephrine induced feeding. PHARMAC, BIOCHEM. BEHAV. 16(2) 225-228, 1982.--The inhibitory effect of a variety of substances on feeding induced by norepinephrine (20 /~g ICV) was studied. Subcutaneous administration of the opiate antagonist, naloxone, inhibited norepinephrine-induced eating at 10 and 5 mg/kg, but not a 1 mg/kg. Intraventricular administration of the GABA antagonist, bicuculline, produced a dose related decrease in food ingestion. The putative satiety hormones, bombesin (10/zg/kg; subcutaneously) and cholecystokinin octapeptide ( 10/zg,/kg; subcutaneously) also reduced norepi- nephrine induced eating, as did ICV administration of calcitonin (2 units). Neither thyrotropin-releasing hormone (1 tzg ICV) nor its metabolits, histidyl-proline diketopiperazine (1/xg ICV) altered norepinephrine-induced feeding. The studies reported here suggest a neuromodulatory role of peptides in the central regulation of norepinephrine-induced feeding. Norepinephrine Bombesin Opiates Cholecystokinin Naloxone TRH GABA Histidyl-proline diketopiperazine Bicuculline Appetite WE HAVE previously proposed an integrated hypothesis to explain the monoaminergic-peptidergic regulation of appetite [12]. We suggested that the hypothalamus acts as a neuroen- docrine transducer with the control of food intake involving a delicate balance between a number of neuropeptides and monoamines. It was suggested that food intake is initiated by a tonic signal produced by a dopamine-enkephalinergic mechanism in the area of the lateral hypothalamus and that this signal is governed by inhibitory inputs from the medial hypothalamic area including a serotonergic-cholecystokinin (CCK) and a nor-adrenergic-thyrotropin releasing hormone (TRH) system. Historically, norepinephrine (NE) has been implicated as an important hypothalamic factor in the activation of feeding [8,21] although it has been demonstrated that its function after injection into some areas of the lateral hypothalamus can produce the opposite effect [8]. In this report we have used norepinephrine induced feeding as a pharmacological model to examine the interrelationships of the monoaminer- gic and peptidergic substances involved in the hypothalamic regulation of appetite. METHOD Male Sprague-Dawley rats (200--250 g) kept under stand- ard lighting conditions (12 hr/day artificial light--6 am to 6 pm) and given free access to a standard rat diet and water, were used for all experiments. Cannulas were implanted into the lateral ventricle as previously described [14]. The animals were allowed a minimum of 5 days postoperative recovery before experiments were commenced. Norepi- nephrine (Sigma Chemical Co., St. Louis MO) was freshly dissolved in slightly acidified saline and administered in a 5 /zl volume ICV. All other drugs and peptides were dissolved in saline and administered in a 5/zl volume ICV or in a 0.5 cc volume subcutaneously. All feeding antagonists were ad- ministered immediately before norepinephrine was given. Substances were obtained from the following sources: histidyl-proline diketopiperazine (Dr. Chandan Prasad, Louisiana State University, School of Medicine, New Or- leans); naloxone (Endo Products, Garden City, New York); phentolamine (Ciba Pharmaceutical, Summit New Jersey); cholecystokinin-octapeptide (Peninsula Labs, Inc., San Car- los, CA); bombesin (Sigma Chemical Co., St. Louis MO); TRH (Calbiochem-Behring Corporation, LaJolla, CA); cal- citonin (Armour Pharmaceuticals, Phoenix, AZ) and bicuculline methiodide (Vega Biochemicals, Tucson, AZ). All animals had free access to food and water until the experiments were performed. All tests were performed be- tween 1300 to 1500 hours. Immediately after drug adminis- tration animals were put in a new cage together with 2 pellets of pre-weighed Purina rat chow (7-10 g). In all studies, food intake is expressed as grams eaten (to the nearest 0.1 g/30 minutes. For each experiment a new batch of animals was used. Concurrent controls demonstrating the effect of norepi- nephrine on eating were used for each experiment. No rat was used more than three times, with a minimum of 48 hours between each time the animal was tested. Controls and each of the treatments used in a particular experiment were run concurrently with a cross-over design so that approximately equal numbers of animals received norepinephrine alone or 225