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G P Smith

Publications and source records attributed to G P Smith.

At least 19 recordsLinked to original sources
PubMed1992

Enkephalin is a competitive antagonist of cholecystokinin in the gastrointestinal tract, as predicted from prior conformational analysis.

Prior calculations based on ECEPP (Empirical Conformational Energies for Peptides Program) of the low energy minima for cholecystokinin (CCK) and Met-enkephalin have demonstrated that significant structural features of these two peptides are identical. This result suggested the possibility that Met-enkephalin, as well as other enkephalin analogues of similar structure, could associate with receptors for CCK. To test this theoretical result, we examined the ability of Met-enkephalin and its analogues to bind to peripheral CCK receptors in the rat gastrointestinal tract; in particular, we measured the ability of the opiate peptide to inhibit the effects of CCK in a physiological assay system which we have previously characterized: CCK-induced contraction of the isolated rat pyloric sphincter. We find that Met-enkephalin is an antagonist of the CCK-8-induced contraction, with a IC50 of 110 nM. Furthermore, antibodies against CCK were found to cross-react with Met-enkephalin and its analogues in a manner which suggests a distinct structure-activity relationship. These experimental results strongly support the theoretical results of conformational analysis showing structural similarity between enkephalin and CCK. They further suggest that enkephalins could modulate the response of CCK systems under physiological conditions.

Amino Acid Sequence↗
PubMed1992

Postprandial sleep and thermogenesis in normal men.

Twelve normal male subjects were given low- (16.77 kj/kg) and high- (54.49 kj/kg) calorie liquid carbohydrate lunch meals on 4 days, during which measures of sleep EEG, thermogenesis (heat production), core body temperature, and skin surface temperature were obtained. On 2 days subjects were required to remain awake, and on 2 days sleep was allowed. Both meals were administered in each condition. On the days that subjects were instructed to remain awake, thermogenesis was significantly greater following high-calorie meals than low-calorie meals, and both meal conditions produced levels of thermogenesis that were greater than those observed when sleep was allowed. When given the opportunity, 11 of 12 subjects slept following both low- and high-calorie meals. There was no difference between meal conditions in the total minutes or percent of stages 1, 2, 3/4, or rapid eye movement (REM) sleep following meals. However, the onset of postprandial sleep episodes was associated with the peak of the postprandial rise in thermogenesis, and the occurrence of sleep was followed by precipitous and statistically significant declines in thermogenesis and core body temperature, as well as increases in skin surface temperature. These data suggest that postprandial sleep is associated with rises in thermogenesis, and that its occurrence decreases postprandial heat production and body temperature.

Adult↗
PubMed1992

The 5-HT1A agonist 8-OH-DPAT attenuates the satiating action of cholecystokinin.

To investigate the dependence of the satiating action of cholecystokinin (CCK) on serotonergic action at central 5-HT receptors, we examined the effect of systemic pretreatment with 8-OH-DPAT (a 5-HT1A agonist that decreases central 5-HT synthesis and release via an action at somatodendritic autoreceptors in the brainstem raphe) on the suppression of food intake induced by systemic administration of cholecystokinin octapeptide (CKK-8). 8-OH-DPAT significantly attenuated the satiating action of CKK-8. This result is consistent with the hypothesis that peripherally acting CCK recruits central serotonergic processes to elicit normal satiety.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Raclopride decreases sucrose intake of rat pups in independent ingestion tests.

To investigate the role of dopaminergic activity at D2 receptors in the mediation of the positive reinforcing effect of sucrose on ingestion in preweanling rats, we tested the effects of the D2 antagonist, raclopride, on the intake of 10% sucrose of rats on postnatal days (PN) 7, 14, and 21. Intake was measured during independent ingestion tests in which pups licked sucrose from the floor of a beaker and during oral catheter tests in which sucrose was continuously infused through an anterior, sublingual, oral catheter. Rats were tested once to eliminate the possibility that repeated test experience would affect the response to raclopride. Pretreatment with raclopride resulted in decreased intake in independent ingestion (II) tests, but not in oral catheter (OC) tests on PN 7, 14, and 21. The inhibition of intake was not due to a generalized motor deficit because raclopride did not affect latency to eat, time-sampled activity scores, or latency to withdraw the hindlimb from a raised position. These results demonstrate that dopaminergic activity at D2 receptors is necessary for the positive reinforcing effect of sucrose that maintains ingestion in the II test but not in the OC test.

Animals↗
PubMed1992

Devazepide antagonizes the inhibitory effect of cholecystokinin on intake in sham-feeding rats.

3S(-)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl) -1H-indole-2-carboxamide (devazepide), a potent and selective cholecystokininA (CCKA) antagonist, has been shown to reverse the inhibitory effect of exogenously administered CCK-8 on food intake. In all tests, however, the inhibition of food intake could have been due not only to the CCK-8 administered but also to synergistic interactions between administered CCK-8 and endogenous satiety signals, such as glucagon or CCK released from the small intestine, elicited by the postingestive effects of the test diet. To eliminate these possible interactions, we investigated the effect of devazepide on the inhibitory effect of CCK-8 on the intake of a milk diet during 30 min of sham feeding, a procedure that minimizes or eliminates the postingestive satiating effect of food. Under these conditions, devazepide was a potent antagonist of the inhibitory effect of CCK-8 (16 mumol/kg, IP): The approximate ED50 was 625 ng/kg (1.3 nmol/kg) and the threshold dose was between 62.5 and 625 ng/kg.

Animals↗
PubMed1992

Are gut peptides a new class of anorectic agents?

In the past 20 years, the mechanisms of the satiating effect of food that terminate a meal have been investigated intensively in rodents and in humans. This research has revealed that three peptides, cholecystokinin, pancreatic glucagon, and bombesin, released by ingested food from the gastrointestinal tract decrease meal size in a specific, dose-related manner without signs of acute toxicity or tolerance. In humans, the three peptides decrease meal size without decreasing the reported pleasure or satisfaction of the meal. Although their chemical structure and specific effect justify calling these peptides a new class of anorectic agents, not enough work has been done to evaluate their efficacy for weight loss in obese humans or their safety when administered for months.

Animals↗
PubMed1992

Intravenous infusion of CCKA-receptor antagonist increases food intake in rats.

To test the hypothesis that endogenous cholecystokinin (CCK) released from the small intestine by ingested food produces a satiating effect by acting at CCKA-receptors, we measured the effect of slow continuous intravenous infusions of three doses of MK-329, a potent and selective CCKA-antagonist, on food intake during 2.5-h tests in 13 Sprague-Dawley male rats after 1 h of food deprivation. MK-329 increased food intake significantly and the lowest dose tested (0.5 mg.kg-1.h-1) produced the most consistent effect on cumulative intake. Part of the increased food intake under these conditions was due to a decrease in the satiating effect of food ingested at the first meal on the postprandial intermeal interval. These results are consistent with, but do not prove, the hypothesis that the satiating effect of endogenous CCK released from the small intestine by ingested food is mediated by CCKA-receptors.

Animals↗
PubMed1992

Intake of different concentrations of sucrose and corn oil in preweanling rats.

To investigate the orosensory control of ingestion in preweanling rats, we infused one of the following liquids continuously through anterior sublingual intraoral catheters for 20 min: sucrose solutions (5, 10, 20, and 40%) and corn oil emulsions (6.25, 12.5, 25, 50, and 100%). Pups were tested at 7, 14, 21, and 28 days of age. Each pup was tested only once. Intake of sucrose and of corn oil became increasingly correlated with concentration from 7 to 21 days. Sucrose elicited more intake than water by day 7, whereas corn oil did not until day 14. Low concentrations of sucrose had differential effects on intake by day 14, but low concentrations of corn oil emulsions did not have differential effects on intake until day 21. At all ages, the peak intake of sucrose was significantly larger than the peak intake of corn oil. These differences are probably not based on prior experience because each test of ingestion represented a first exposure to the stimulus. Thus we suggest that the differences are due to the maturation of the orosensory control of ingestion by sucrose and corn oil.

Aging↗
PubMed1992

Analysis of the microstructure of the rhythmic tongue movements of rats ingesting maltose and sucrose solutions.

The interlick interval distribution of rats while ingesting maltose under real and sham feeding conditions and while ingesting seven concentrations of sucrose under real feeding conditions was analyzed. The analysis revealed that the licking behavior of rats is organized into bursts of licking at a high rate. These bursts occurred in clusters that were separated by brief (250-500 ms) interruptions. The clusters were separated by intervals that ranged from 500 ms to many hundreds of seconds. Sham feeding increased the length of the meal by increasing the number but not the size of the clusters. Increasing the concentration of sucrose increased monotonically the size of the clusters but varied the number of clusters as an inverted-V-shaped function. This analysis revealed the details of the central nervous system's control over ingestive behavior.

Animals↗
PubMed1991

Characterization of axonally transported [125I]PYY binding sites in rat vagus nerve.

Quantitative receptor autoradiography was used to characterize [125I]PYY binding to slide-mounted sections of rat cervical vagus nerve which had been ligated 24 h prior to extraction. Saturation and competitive binding characteristics were determined for the accumulation of binding sites detected in the segment of the nerve proximal to the ligature. High and low affinity binding components were resolved (Kd = 93 pM and 2.1 nM). The rank order of potency for competing ligands was PYY greater than NPY much greater than PYY13-36 much greater than [Pro34]NPY suggesting that vagal PYY/NPY binding sites are PYY-preferring and of the Y2 type.

Animals↗
PubMed1991

Infra-additivity of combined treatments with selective D1 and D2 receptor antagonists for inhibiting sucrose reinforcement.

Selective antagonists of either the D1 receptor (SCH 23390) or of the D2 receptor (raclopride) produce a dose-related inhibition of sucrose sham feeding in the rat. We investigated the effect of combined treatments with these antagonists on sucrose sham feeding and observed infra-additivity of inhibition across a range of doses. On the basis of this observed occlusive relationship, we conclude that the relevant D1 and D2 receptor mechanisms mediating sweet taste reward do not function independently.

Animals↗
PubMed1991

Increased food intake after type A but not type B cholecystokinin receptor blockade.

To assess the role of cholecystokinin (CCK) receptors in mediating the satiating effect of an oral preload, overnight food-deprived rats (n = 7) were given access to a high-carbohydrate liquid diet for 40 min. At the end of 40 min, food was removed and rats were injected subcutaneously (SC) with devazepide (DVZ; 1 ng/kg-1 mg/kg), an antagonist selective for the CCK-A receptor, or its vehicle, 0.5% carboxymethylcellulose (CMC). Thirty min after injection, rats were given access to the same liquid food for 60 min. DVZ increased food intake significantly. Furthermore, the effectiveness of a very low dose of DVZ (10 ng/kg) is strong evidence that the effect of DVZ was specific for CCK-A receptors. Three of the rats that increased food intake after DVZ were also tested with L-365,260, an antagonist selective for the CCK-B receptor (10 ng/kg-100 micrograms/kg). L365,260 did not increase food intake significantly. These results confirm and extend previous reports that CCK-A receptor blockade increases food intake after an oral preload. They do not, however, demonstrate a role for the CCK-B receptor in mediating the satiating effect of ingested food under the same experimental conditions.

Animals↗
PubMed1991

Potency of SCH 23390 for decreasing sucrose intake in rat pups depends on mode of ingestion.

To investigate the role of dopaminergic mediation of the positive reinforcing effect of sucrose during development, we tested the effects of the D-1 antagonist, SCH 23390, on the intake of 10% sucrose in 7-, 14-, and 21-day-old rats during independent ingestion (pups lick sucrose from the floor of a beaker) or during continuous intraoral infusion of sucrose. SCH 23390 inhibited intake more in independent ingestion tests than in intraoral catheter tests. At 7 and 14 days this difference was qualitative--SCH 23390 was efficacious in independent ingestion tests, but not in intraoral catheter tests. At 21 days the difference was quantitative--SCH 23390 decreased intake in both tests, but was more potent in independent ingestion tests. SCH 23390 decreased intake during independent ingestion tests without changing latency to eat or time-sampled activity scores at 7 and 14 days, but not at 21 days; thus the inhibition of intake is not accounted for by a generalized motor deficit at 7 and 14 days. Possible explanations for the differential potency include density of reinforcement, pattern of central dopamine metabolism, and interference with the appetitive movements required to maintain contact with the sucrose in the independent ingestion test.

Aging↗
PubMed1991

Failure to detect increases in brain dopamine metabolism in rats sham feeding sucrose and corn oil.

In a recent study we found that when rats sham fed 6% sucrose, 10% sucrose, and 100% corn oil, the rank order of inhibitory potency for D-1 and D-2 receptor antagonists was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a complementary study, sham-feeding rats preferred 100% corn oil greater than 10% sucrose greater than 6% sucrose as measured by two-bottle preference tests. The preferences are evidence for the rank order of reward value of these solutions. In the present study we tested the hypothesis that the relative antagonist potencies were due to differential release of DA, dependent on the reward value of the sham-fed solution. Dopamine metabolism, estimated by the ratio of dihydroxphenylacetic acid (DOPAC) to DA, was measured in forebrain-DA terminal fields during sham feeding of 100% corn oil, 6% sucrose, and 10% sucrose. The results did not support our hypothesis: no increase in DA metabolism was observed after the sham feeding of any solution.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Type-A CCK receptors mediate the inhibition of food intake and activity by CCK-8 in 9- to 12-day-old rat pups.

To determine the type of cholecystokinin (CCK) receptor that mediates the inhibitory effects of peripherally administered CCK-8 on food intake and activity in 9- to 12-day-old rat pups, we gave injections of a type-A CCK receptor antagonist, MK-329, or of the type-B CCK receptor antagonist, L-365,260, prior to CCK-8 (IP). MK-329 reversed the inhibitory effects of CCK-8, but L-365,260 did not. This demonstrates that the inhibitory effects of CCK-8 (IP) are mediated by type-A, but not type-B, CCK receptors in pups of this age.

Animals↗