Julie Kneip

Flavor enhances the antidipsogenic effect of naloxone

Naloxone suppressed ingestion of tap water following a 15 hour deprivation at doses of 20, 10 and 5 mg/kg. Addition of saccharine (0.2%), saline (0.8%), sucrose (2%) and HCl (0.1 M) to tap water resulted in an increased sensitivity to naloxone-induced suppression of water intake following the 15 hour deprivation. The volume of quinine solution (0.1%) consumed was not altered by administration of naloxone. We suggest that naloxone suppresses drinking behavior due to alterations in taste perception.

Effect of centrally administered corticotropin releasing factor (CRF) on multiple feeding paradigms

Recently, a 41-residue corticotropin-releasing factor (CRF) has been characterized from the hypothalamus. In the present study, it was found that this stress-related peptide suppressed feeding induced by a variety of substances including muscimol, norepinephrine, dynorphin and insulin. These data suggest that the corticotropin-releasing factor may represent an important agent in stress-induced anorexia.

Peptide YY (PYY), a poteny orexigenic agent

Peptide YY (PYY) enhances feeding and drinking more potently than does neuropeptide Y after central administration. Chronic administration of PYY every 6 h for 48 h causes massive food ingestion. Tolerance to this effect of PYY does not appear to develop. This data suggests that PYY is one of the most potent orexigenic substances yet to be identified. PYY may play a role in the pathogenesis of bulimic syndromes.

The effect of vagotomy on the satiety effects of neuropeptides and naloxone

As abdominal vagotomy blocks the satiety effect of cholecystokinin-octapeptide, we felt it would be worthwhile to examine whether the satiety effect of any of the other putative satiety neuropeptides was mediated through the vagus. We confirmed that the satiety effect of peripherally administered cholecystokinin (10 micrograms/kg) was mediated through the vagus. In addition, the satiety effect of peripherally administered TRH (8 mg/kg) also was not present in vagotomized animals. Vagotomy had no effect on the satiety effects of peripherally administered bombesin, calcitonin and naloxone. Nor did vagotomy alter the satiety effect produced by central administration of bombesin, TRH, calcitonin nor naloxone.

Dynorphin-(1–13), dopamine and feeding in rats

Intraventricular administration of the dopamine agonist, bromergocryptine, reliably induces feeding over a narrow dose range with a bell-shaped curve. Bromergocryptine (80 micrograms) induced feeding is inhibited by the dopamine antagonist, haloperidol (0.5 mg/kg) and the opiate antagonist, naloxone (10 and 1 mg/kg). The leucine-enkephalin containing opioid peptide, dynorphin-(1-13) induces feeding which is inhibited by haloperidol (0.5 and 0.1 mg/kg) and by naloxone (1 mg/kg). Of the common satiety factors tested only bombesin (10 micrograms/kg subcutaneously) inhibited both dynorphin-(1-13) and bromergocryptine induced feeding. Cholecystokinin-octapeptide (10 and 20 micrograms/kg, subcutaneously), thyrotropin-releasing hormone (10 and 20 micrograms), ICV) and calcitonin (1 unit, ICV) all failed to inhibit dynorphin-(1-13)-induced feeding. Calcitonin and CCK-8 but not TRH inhibited bromergocryptine-induced feeding. These studies have demonstrated the close interaction between dopaminergic an dopiate systems in the regulation of food intake. The concept of dopamine being primarily responsible for the initiation of chewing behavior and the opiates regulating food ingestion is compatible with the observations reported here.

Muscimol induced feeding: A model to study the hypothalamic regulation of appetite

Abstract Intraventricular administration of the GABA agonist, muscimol, reliably induces feeding in sated rats in a dose dependent manner over a range from 50 to 500 ng. We used this pharmacological stimulant of appetite to examine the interrelationships of the peptides and monoamines involved in the hypothalamic regulation of appetite. Eating induced by muscimol (500 ng ICV) was suppressed by the opiate antagonist, naloxone; the dopamine antagonist, haloperidol; the cholinergic antagonist, atropine and by calcitonin. We could demonstrate no effect of thyrotropin releasing hormone or its metabolite histidyl-proline diketopiperazine or cholecystokinin-octapeptide, bombesin, isoproterenol, or phentolamine in doses known to suppress appetite. Based on these experimental results we propose a model of intrahypothalamic appetite regulation.

Effect of centrally administered neurotensin on multiple feeding paradigms.

Recent studies have suggested that the tridecapeptide, neurotensin, may be an endogenous satiety factor. The present study was undertaken to examine the effects of neurotensin on multiple paradigms known to stimulate feeding. Following a 30 hour starvation period, neurotensin suppressed feeding at the 20 microgram and 10 microgram dose, but not at the 1 microgram dose when compared to saline controls. Norepinephrine (20 micrograms ICV) induced feeding was suppressed at the 20 microgram neurotensin dose but not at the 10 microgram or 1 microgram dose. In contrast, neurotensin did not suppress muscimol induced feeding at any of the doses. Insulin induced feeding (10 units SC) also was not suppressed by neurotensin. Neurotensin suppressed dynorphin induced feeding at the 20 microgram and 10 microgram but not at the 1 microgram dose. Neurotensin suppressed spontaneous feeding (p less than 0.01) in vagotomized rats (2.5 +/- 0.3 g/2 hr) when compared with saline controls (4.2 +/- 0.5 g/2 hr) suggesting that an intact vagus is not necessary for neurotensins anorectic effect. We conclude that neurotensin may play a role in short-term appetite regulation by a complex interaction with monoamines and neuropeptides, particularly norepinephrine and the kappa opiate agonist, dynorphin.

Peptidergic regulation of norepinephrine induced feeding

The inhibitory effect of a variety of substances on feeding induced by norepinephrine (20 micrograms ICV) was studied. Subcutaneous administration of 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 micrograms/kg; subcutaneously) and cholecystokinin octapeptide (10 micrograms/kg; subcutaneously) also reduced norepinephrine induced eating, as did ICV administration of calcitonin (2 units). Neither thyrotropin-releasing hormone (1 microgram ICV) nor its metabolits, histidyl-proline diketopiperazine (1 microgram ICV) altered norepinephrine-induced feeding. The studies reported here suggest a neuromodulatory role of peptides in the central regulation of norepinephrine-induced feeding.

Neuropeptides and thermoregulation: The interactions of bombesin, neurotensin, TRH, somatostatin, naloxone and prostaglandins

In this study we have examined the interactions of bombesin (1 microgram ICV), neurotensin (1 microgram ICV), TRH (10 micrograms ICV), somatostatin (10 micrograms ICV), PGE2 (10 micrograms ICV) and naloxone (10 mg/kg SC) on thermoregulation in the rat at room temperature (20 +/- 1 degree C). Given alone, bombesin, neurotensin, somatostatin and naloxone all produced hypothermia (bombesin greater than neurotensin greater than somatostatin congruent to naloxone). PGE2 was hyperthermic, and TRH had no effect. Bombesin and PGE2 neutralized one anothers effects. Neurotensin had no effect on PGE2-induced hyperthermia. Naloxone enhanced the hypothermic effect of bombesin and somatostatin enhanced the rate of onset of hypothermia after bombesin. TRH had no effect on bombesin-induced hypothermia. TRH, somatostatin and naloxone had no effect on neurotensin-induced hypothermia. TRH antagonized the hypothermia due to naloxone and somatostatin.

The κ opioid receptor and food intake

Abstract Many studies have suggested a role of opioid receptors in the modulation of food intake. Several distinct classes of opioid receptors have been postulated. In an attempt to establish which opioid receptor(s) modulate feeding we studied the effect of the κ agonist, bremazocine, on feeding and compared its effects to the preferential μ agonist, morphine, and the mixed κ-σ agonist, butorphanol and the κ agonist, ethylketocyclazocine. Bremazocine increased feeding to the same extent as morphine and was less potent than mixed agonist/antagonists. The bremazocine effect demonstrated a bell-shaped dose response curve. Daily admiistration of bremazocine or morphine enhances the effect on increasing food intake. However, this effect of daily injections on enhancing food intake is not present when animals receiving morphine are crossed over to bremazocine and vice versa. The bremazocine effect is enhanced by diprenorphine and not inhibited by naloxone. Low doses of the dopamine antagonist, haloperidol, enhance the bremazocine effect and higher doses inhibit it. Finally, using another κ agonist, tifluadom, we showed that the effect on food intake is stereospecific. Our studies provided further evidence for a role for the κ opiod receptor in feeding. However, they also suggest that more than one subpopulation of opioid receptors is involved in feeding modulation.