PYY(3-36) induces Fos in the arcuate nucleus and in both catecholaminergic and non-catecholaminergic neurons in the nucleus tractus solitarius of rats.

Peptide YY (3-36) [PYY(3-36)] inhibits feeding in rodents, nonhuman primates and humans, yet the neural circuits underlying this action remain to be determined. Here we assessed whether PYY(3-36) inhibits feeding by activating neurons in forebrain and hindbrain sites containing Y2 receptors and linked to control of food intake, or in hindbrain sites immediately downstream of vagal afferent neurons. Rats received an anorexigenic dose of PYY(3-36), and the number of neurons expressing Fos, an indicator of neuronal activation, was determined in anterior hypothalamus (AH), arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), lateral hypothalamus (LH), ventromedial hypothalamus (VMH), central nucleus of the amygdala (CeA), area postrema (AP), and caudal medial nucleus tractus solitarius (cmNTS), commissural NTS (cNTS), and gelatinosus NTS (gNTS). Expression of tyrosine hydroxylase (TH), an indicator of catecholamine synthesis, was also measured in the cmNTS. PYY(3-36) increased Fos in ARC, cmNTS, gNTS and AP. Approximately 10% of Fos+ neurons in the cmNTS were TH+. These results suggest that PYY(3-36) inhibits feeding through direct activation of ARC neurons, and direct and/or indirect activation via vagal afferent nerves of cmNTS, gNTS and AP, including some catecholaminergic neurons in the cmNTS.

Chronic low dose islet amyloid polypeptide infusion reduces food intake, but does not influence glucose metabolism, in unrestrained conscious rats: studies using a novel aortic catheterization technique.

Islet amyloid polypeptide (IAPP) is a 37-amino acid polypeptide coproduced with insulin in the beta-cells of the pancreatic islets. The physiological effects of IAPP have not been established. Although effects on glucose metabolism are seen only at pharmacological doses both in vitro and in vivo, effects on food intake have been shown at near-physiological concentrations. The aim of the present study was to investigate the effects of similar elevations of circulating plasma IAPP levels on glucose metabolism in rats and to evaluate the function of a novel aortic catheterization technique. In a cross-over design, two sets of experiments in which conscious unrestrained rats received chronic IAPP infusions at 0 and 2 or 0 and 7 pmol/kg min were performed. Peripheral glucose disposal was determined by means of the hyperinsulinemic euglycemic clamp technique. Chronic elevations of circulating IAPP at concentrations that reduced food intake [43.5 +/- 6.2 g (control) vs. 35.7 +/- 8.2 g (IAPP; P < 0.01) and 34.0 +/- 2.2 g (control) vs. 28.8 +/- 1.4 g (IAPP; P = 0.07) for the 7 and 2 pmol/kg x min experiments, respectively] had no effect on the glucose metabolic rate [GMR; 18.5 +/- 0.6 mmol/kg x h (control) vs. 18.7 +/- 0.9 mmol/kg x h (IAPP) and 14.4 +/- 0.7 mmol/kg x h (control) vs. 15.6 +/- 0.7 mmol/kg x h (IAPP) for the 7 and 2 pmol/kg x min experiments, respectively]. Thus, effects on glucose metabolism are unlikely to explain the anorectic effect of IAPP.

Beer-induced prolactin secretion: a clinical and laboratory study of the role of salsolinol.

Salsolinol is a tetrahydroisoquinoline compound with opiate agonist and dopamine antagonist properties. The role of salsolinol, a minor constituent of beer, in beer-induced PRL secretion was investigated in humans and rats. Beer-stimulated PRL release was greater in women than in men; the PRL-stimulating effect of beer was not blocked by naloxone pretreatment. Administration of a solution of salsolinol or cocoa (another salsolinol-containing beverage) did not stimulate PRL secretion in normal women. In rats, administration of large doses of salsolinol ip or iv was required to raise serum PRL levels, and high concentrations of salsolinol were needed to antagonize the PRL-suppressive effects of dopamine in vitro. We conclude that salsolinol is not responsible for PRL secretion induced by beer ingestion.

Accurate energy compensation for intragastric and oral nutrients in lean males.

Lean healthy males received either parenteral or enteral infusions of pure fat or carbohydrate (2092 kJ), or isotonic saline, to determine their influences on food intake and energy regulation in self-selected lunch and dinner meals. In the first study, six males received intravenous infusions for 3.5 h in the morning, followed by lunch 30 min after the infusion ended and dinner 6 h later. No compensation was seen for energy differences in intravenous infusions. In the second study, six males received intragastric infusions for 15 min or 3.5 h. Rapid intragastric infusions of fat or carbohydrate and slow infusions of fat significantly reduced intake at lunch, whereas slow carbohydrate infusions did not. In both studies, subjects reduced intake at lunch 30 min after 2092-kJ yogurt preloads varying in fat and carbohydrate, demonstrating their ability to respond to orally derived energy. These results support the existence of mechanisms in the gastrointestinal tract for the rapid detection of the energy content of ingested nutrients or foods in lean males.

Increased pancreatic acinar content and secretion of cationic trypsinogen following 30-day continuous ethanol intoxication in rats.

The effects of sustained, high blood alcohol levels (216 +/- 120 mg/100 ml, S.D.) for 30 days on cholecystokinin (CCK)-mediated pancreatic exocrine function were studied in a rat model that achieves both maximally controlled, optimal nutrition and high alcohol intake (approximately 40.5% of total calories). In alcohol-fed rats, basal plasma levels of immunoreactive cationic trypsinogen (ICT) were reduced by 50% (P less than 0.05), but intravenous doses (0-30 IDU/kg/hr; 1 IDU = approximately 62.5 ng CCK-8) of cholecystokinin octapeptide (CCK-8) resulted in a 3-fold greater maximal concentration of ICT and an 80% steeper slope of the dose-response curve compared to those of pair-fed control animals. Basal plasma levels of amylase were not different in the two groups at basal conditions and did not change significantly following CCK-8 administration. In vitro studies with isolated pancreatic acini have shown that basal secretion of ICT into the media was similar in the two groups. However, ICT secretion in response to CCK-8 (30-3000 pM) was 2-fold greater in alcohol-fed rats than in pair-fed controls, resulting in a CCK-8 EC50 which was about half that of controls. On the contrary, the basal and maximal amylase secretion from acini isolated from alcohol-fed rats was reduced by 67 and 43%, respectively, causing a reduction in the magnitude of the response curve with almost identical EC50 and slopes. Despite the marked alterations in CCK-stimulated enzyme secretion, radioiodinated CCK-33 binding to receptors on acini isolated from both control and alcohol-fed rats was similar. Cellular concentrations of ICT and amylase, however, revealed similar patterns of alterations: 2 to 3-fold increase in ICT and 70% reduction in amylase in alcoholic acini compared to controls. These results indicate that the inverse changes in amylase and ICT secretions following continuous ethanol administration are probably due to differential effects on enzyme synthesis.

Effects of selective cholecystokinin antagonists L364,718 and L365,260 on food intake in rats.

The selective type A and B cholecystokinin (CCK) receptor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12-13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 micrograms/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 micrograms/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 micrograms/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 micrograms/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-171) (0.16-5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-171 stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 micrograms/kg IV), administered 30 min before continuous infusion of G-171 (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 micrograms/kg; cumulative 60-min output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats.

Mechanism of bombesin-induced pancreatic secretion in unanesthetized rats.

It is unclear whether stimulation of pancreatic enzyme secretion by intravenously administered bombesin is a direct effect on acinar cells or is mediated by release of CCK; this distinction is important for defining the potential role of bombesin-like peptides as regulators of pancreatic secretion. The role of CCK in bombesin-induced pancreatic secretion was examined in rats using CCK radioimmunoassay and the CCK receptor antagonist L-364,718. A biphasic pancreatic response occurred to sequential doubling doses of bombesin (31 to 2000 pmol/kg/h, each for 30 min; n = 9 rats); amylase secretion increased to peak at 250 pmol/kg/h (11.5 +/- 1.7 kU/30 min; 4.2 +/- 0.6 kU/30 min, basal) and then declined to basal levels at 2000 pmol/kg/h. The ED50 dose of bombesin for stimulation was 31 pmol/kg/h, and the maximal response did not differ significantly from that to exogenous CCK-8 (10.6 +/- 1.5 kU/30 min) in the same rats. When single doses of bombesin were infused for 2 h (31, 62, 125, 250 pmol/kg/h; one dose per day; order randomized; n = 8), a similar dose-response relationship was seen, both for peak amylase response and cumulative output over basal. L-364,718 (0.5 mg/kg IV) had no effect on the pancreatic response to ED50 or maximal doses of bombesin. Neither dose of bombesin altered plasma CCK levels. In contrast, other stimulants of pancreatic secretion (food ingestion, soybean trypsin inhibitor) caused marked elevations in plasma CCK levels. These results indicate that the potent stimulation of pancreatic secretion by exogenous bombesin in rats is not mediated by CCK, similar to findings in humans.

Bombesin receptor subtype mediation of gastroenteropancreatic hormone secretion in rats.

Bombesin is a potent releaser of many gut and pancreatic hormones including gastrin, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP), cholecystokinin (CCK), enteroglucagon, and insulin. Three mammalian bombesin-like peptides, gastrin-releasing peptide (GRP), neuromedin C (NMC or GRP-10), and neuromedin B (NMB), and two bombesin receptor subtypes, GRP preferring and NMB preferring, have been characterized. We used a highly potent, selective antagonist of the GRP-preferring receptor, [D-Phe6]bombesine(6-13)-methylester ([D-Phe6]Bn(6-13)OMe), to determine the receptor subtype mediating bombesin-induced secretion of gastrin, GIP, PP, peptide YY (PYY), and insulin, as well as the importance of endogenous bombesin-like peptides in controlling basal secretion of these hormones. Unanesthetized rats received femoral vein infusion of saline, bombesin (10 nmol/kg/h), [D-Phe6]Bn(6-13)OMe (1000 nmol/kg/h), or bombesin plus [D-Phe6]Bn(6-13)OMe. Blood was withdrawn from jugular vein catheters before and 30 min after the start of infusions. Plasma gastrin, GIP, PP, PYY, and insulin were measured by specific radioimmunoassays. [D-Phe6]Bn(6-13)OMe alone reduced basal insulin levels by 28% (p < 0.05) but did not alter basal levels of plasma PP, GIP, PYY, or gastrin (p > 0.05 for each). Bombesin infusion significantly increased plasma levels of each hormone (p < 0.0001 for each). [D-Phe6]Bn(6-13)OMe completely blocked bombesin-induced increases in PP, insulin, and gastrin, and almost completely blocked increases in GIP and PYY (p < 0.01 for each). Our results suggest that (a) exogenous bombesin significantly stimulates PP, insulin, GIP, PYY, and gastrin secretion, (b) bombesin-induced secretion of these hormones is primarily mediated by the GRP-preferring receptor, and (c) an endogenous bombesin-like peptide acting at this receptor subtype plays an important physiological role in control of basal secretion of insulin but not PP, GIP, PYY, or gastrin.

Effects of potent bombesin antagonist on exocrine pancreatic secretion in rats.

Recent synthesis of specific, potent bombesin receptor antagonists allows examination of the role of bombesin-like peptides in physiological processes in vivo. We characterized effects of [D-Phe6]bombesin(6-13)-methyl-ester (BME) on pancreatic enzyme secretion stimulated by the C-terminal decapeptide of gastrin releasing peptide (GRP-10), food intake, and diversion of bile-pancreatic juice in rats. In isolated pancreatic acini, BME had no agonistic effects on amylase secretion but competitively inhibited responses to GRP-10, yielding a pA2 value of 8.89 +/- 0.19. In conscious rats with gastric, jugular vein, bile-pancreatic, and duodenal cannulas, basal enzyme secretion (bile-pancreatic juice recirculated) was not affected by the antagonist. Maximal amylase response to GRP-10 (0.5 nmol/kg/h) was inhibited dose dependently by BME, reaching 97% inhibition at a dose of 400 nmol/kg/h. The dose response curve of amylase secretion stimulated by GRP-10 was shifted to the right by 40 nmol/kg/h BME, but maximal amylase response was unaltered, suggesting competitive inhibition in vivo. Liquid food intake and bile-pancreatic juice diversion caused substantial increases in amylase secretion; neither response was altered during administration of 400 pmol/kg/h BME. These results demonstrate that BME is a potent, competitive antagonist of pancreatic responses to bombesin-like peptides in vitro and in vivo. Lack of effect of BME on basal pancreatic secretion or responses to liquid food intake or diversion of bile-pancreatic juice in rats suggests that endogenous bombesin-like peptides do not act either directly or indirectly to mediate these responses.

Development of cholecystokinin radioimmunoassay using synthetic CCK-10 as immunogen.

Using an antiserum generated against synthetic CCK-10, we have developed a radioimmunoassay specific for the carboxyl-terminus of cholecystokinin (CCK). Three rabbits were immunized with synthetic sulfated carboxy-terminal CCK decapeptide (CCK-10) conjugated to keyhole limpet hemocyanin. Using 125I-CCK-39 prepared by the Iodogen method as a tracer, we found that all immunized rabbits produced antibodies against the conjugate. Antiserum R016 had the highest titer (1:225,000 after four immunizations) and was studied most extensively. R016 recognizes all molecular forms of CCK, including unsulfated and oxidized forms, but has negligible cross-reactivity with gastrin and other peptides. Using CCK-8 as a standard, the assay has a minimum detection limit of 0.5 pM and an ED50 of 11.5 pM. Serial dilutions of water/acid extracts of canine intestine were parallel to serial dilutions of sulfated CCK-8, CCK-33 and CCK-39. The assay was used to measure CCK concentrations in canine plasma after C18 Sep-Pak extraction; the concentration of immunoreactive CCK increased from a basal value of 7.8 +/- 1.0 to 9.5 +/- 1.2 and 11.1 +/- 1.2 pM 30 and 60 min postprandially (P less than 0.05 by paired analysis). This sensitive and uniquely specific CCK radioimmunoassay should be useful in characterizing several aspects of CCK physiology and the method for generating CCK antisera should be of value to other investigators.

Dose-related involvement of CCK in bombesin-induced pancreatic growth.

We examined the role of CCK in bombesin-induced pancreatic growth in rats using the CCK receptor antagonist L-364,718. Rats (155 +/- 1 g, 8-10 per group) received subcutaneous injections every 8 h for 5 days with bombesin (0.6, 1.7 and 5 nmol/kg) or bombesin in combination with L-364,718 (1 mg/kg). After 5 days the pancreas was removed and pancreatic weight, protein content, DNA, amylase and chymotrypsin contents were determined. Bombesin produced a significant increase (48-475%) of pancreatic weight, tissue contents of protein, DNA, amylase and chymotrypsinogen (F = 82, P less than 0.001). When a large dose of bombesin (5 nmol/kg) was combined with L-364,718 a significant inhibition (up to 70%) of all tissue parameters was observed (P less than 0.001). L-364,718 did not affect the growth response to a small dose of bombesin (0.6 nmol/kg). Plasma CCK levels 15 min after a single injection of bombesin (0.6, 1.7 and 5 nmol/kg) were significantly increased in response to the 5 nmol/kg dose (2.0 +/- 0.7 to 3.4 +/- 0.8 pM, F = 6.9, P less than 0.01). No increases of CCK plasma levels were found in response to the 0.6 and 1.7 nmol/kg doses of bombesin, corresponding to the lack of effects of L-364,718 on growth parameters at these doses. Measuring the time-course of CCK plasma levels after a single injection of 5 nmol/kg bombesin revealed an increase from basal values of 1.4 +/- 0.3 pM to maximal levels of 3.5 +/- 0.5 pM after 15 min (F = 7.1, P less than 0.001). Values returned to basal after 60 min. These results suggest that low doses of bombesin act directly at the acinar cell or through release of non-CCK growth factors whereas high doses of bombesin act in part through CCK release.

Brain regions where cholecystokinin suppresses feeding in rats.

The gut-brain peptide, cholecystokinin (CCK), inhibits food intake when injected either systemically or within the brain. To determine whether CCK's effect in the brain is anatomically specific, CCK-8 (0. 8, 4, 20, 100, 500 pmol) was microinjected into one of 14 different brain sites of rats, and its impact on subsequent food intake was measured. CCK-8 at 500 pmol significantly suppressed intake during the first hour post-injection following administration into six hypothalamic sites (anterior hypothalamus, dorsomedial hypothalamus, lateral hypothalamus, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus) and two hindbrain sites (nucleus tractus solitarius, fourth ventricle). Although lower doses were sometimes effective (anterior hypothalamus, dorsomedial hypothalamus, nucleus tractus solitarius), there appeared to be no significant difference in potency among sites. Injections into the medial amygdala, nucleus accumbens, posterior hypothalamus, dorsal raphe, and ventral tegmental area were either ineffective or produced a delayed response. The higher doses required for most sites, as well as the widespread effectiveness of CCK-8 within the hypothalamus, suggest that spread of CCK-8 to adjacent brain sites, and (or) to the periphery, may have been required for anorexia to occur. Findings reported in an accompanying paper provide strong evidence that paraventricular nucleus injection of CCK-8 (500 pmol) did not increase plasma CCK-levels sufficiently to suppress feeding by a peripheral mechanism. Together, these results suggest that CCK may be acting as a neurotransmitter or neuromodulator within two different brain regions to produce satiety - one region which includes the nucleus tractus solitarius in the hindbrain, and another more distributed region within the medial-basal hypothalamus.

Effects of paraventricular nucleus injection of CCK-8 on plasma CCK-8 levels in rats.

The aim of the study was to determine whether paraventricular nucleus (PVN) injection of an anorexic 500-pmol dose of cholecystokinin (CCK)-8 could increase plasma CCK-8 levels sufficiently to suppress feeding by a peripheral mechanism. Rats received PVN injections of CCK-8 either alone or with 3H-labelled propionylated CCK-8 (3H-pCCK-8) and plasma samples were taken at various times from 3 to 120 min post-injection. Plasma CCK-8 levels were estimated from measurements of both total plasma CCK-like immunoreactivity (CCK-LI) and 3H-pCCK-8 activity. PVN injections of CCK-8 and 3H-pCCK-8 produced estimated peak increases in plasma CCK-8 of 15+/-11 and 22+/-3 pM, respectively. The i.v. infusion of CCK-8 doses (0.2 and 1 nmol/kg h) that bracketed the threshold dose for suppression of feeding, increased plasma CCK-LI from a basal level of 6+/-1 to 49+/-10 and 166+/-36 pM, respectively. The i.v. injections of 600 and 4800 pmol of CCK-8 did not suppress feeding. These results suggest that PVN injection of an anorexic 500-pmol dose of CCK-8 does not increase plasma CCK-8 levels sufficiently to suppress feeding by a peripheral mechanism.

Effects of long-term infusion of anorexic concentrations of islet amyloid polypeptide on neurotransmitters and neuropeptides in rat brain.

Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P<0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P<0.01) and 24% (P<0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P<0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P<0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P<0.01) and CCK increased in the hypothalmus and striatum (both P<0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.

Comparative effects of caerulein on food intake and pancreatic secretion in dogs.

We compared effects of the CCK analog caerulein on feeding and pancreatic secretion. Nine fasted mongrel dogs with gastric and pancreatic fistulas received scalar doses of caerulein (0, 6.25, 12.5, 25, 50, 100, 200, 400 pmol/kg-hr, each for 30 min). The D50 dose for stimulation of pancreatic secretion was 15 pmol/kg-hr. Effects of intravenous caerulein (0 to 800 pmol/kg-hr; 15 min before and during a 45 min test meal) on food intake were examined in 8 beagles under 4 feeding conditions: 1 meal/day (22 hr fast), 2 meals/day (4 hr fast), 2 meals/day (19 hr fast), and after ad lib access to food followed by a 4 hr fast. The lowest doses that inhibited feeding were: 400 pmol/kg-hr for feeding condition, 200 pmol/kg-hr for and, and 150 pmol/kg-hr for. We conclude: the potency of caerulein for inhibition of food intake is dependent upon feeding condition; these results do not support a role for CCK as a satiety hormone, since the lowest dose of caerulein for inhibition of feeding was 10 times larger than the D50 dose of caerulein for stimulation of pancreatic secretion.

Volumetric measure and lick count of liquid food intake of rats.

A simple and relatively inexpensive lick counter-volumeter is described which automatically records liquid intake and drinking behavior of rats. It counts lick contacts while accurately measuring the rate of volume intake in constant unit volumes. The unit volumes are adjustable over a wide range. For a unit volume on the order of 60 microliter, the precision was 1.2% over a range of withdrawal rates from 1 to 10 ml/min. The average lick volume of rats consuming a liquid food was systematically lower by 18% during the second meal following a 15 hr fast when compared to that of the first. This change in average lick volume appears to reflect a change in the rat's motivation to drink the liquid food.

Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats.

The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (Nalpha-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 microCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 microCi each). Rats were decapitated 12s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/l4C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean+/-s.e.m.) was 1.6+/-0.3 for [3H]mannitol (n=5), 90.6+/-4.1 for [3H]devazepide (n=7, P<0.001 compared with mannitol) and 3.5+/-0.7 for [3H]A-65186 (n=4, P > 0.05 compared with mannitol, P < 0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.

Abdominal vagal mediation of the satiety effects of exogenous and endogenous cholecystokinin in rats.

The hypothesis that peripherally administered cholecystokinin C-terminal octapeptide (CCK-8) and endogenous CCK act by the same abdominal vagal mechanism to produce satiety was tested by injecting rats with CCK-8 or the type A CCK receptor antagonist MK-329 after they had received bilateral subdiaphragmatic vagotomies. CCK-8 (8 nmol/kg ip) inhibited 1-h food intake by 60%; vagotomy and MK-329 (0.5 mg/kg sc) each completely blocked this effect. In contrast, vagotomy did not alter the stimulatory effect of MK-329 (0.5 mg/kg sc) on feeding; 3-h cumulative intake in control and vagotomized animals was increased by 25 and 34%, respectively. These results suggest that satiety is mediated in part by an endogenous CCK action that is independent of abdominal vagal innervation.