The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight.

Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor-/- mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor-/- mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor-/- mice maintained normal body weight well into adult life. In addition, each of the two receptor-/- strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.

Determinants of dietary self-selection in experimental animals.

During the past 10 yr, renewed interest has been expressed in the mechanisms controlling the intake of specific dietary components. In particular, this interest has focused on research examining the role of the central nervous system in regulating intake of the three macronutrients protein, fat, and carbohydrate. Several hypotheses relating specific neurotransmitter systems to nutrient selection have developed from this research. However, conflicting data make the acceptance of any one hypothesis about diet selection untenable. As an attempt to reconcile some of the conflicting data, the present paper describes a variety of factors which can influence patterns of nutrient choice. The effects of diet composition, the experimental environment, the animals' background, and nutritional history on diet selection are examined.

Modifications of nutrient selection induced by naloxone in rats.

Total caloric intake and dietary self-selection of the three macronutrients protein, fat, and carbohydrate were examined in male rats maintained on a 6-h feeding schedule following the administration of the opioid antagonist naloxone HCl (0.1, 1.0, and 10.0 mg/kg IP). Total caloric intake (calculated as the sum of caloric intakes from each of the macronutrients) was decreased for up to 2 h following naloxone administration. By the end of the 6-h feeding period, however, no differences in total caloric intakes were observed as a function of naloxone injections. Examination of intakes of the individual macronutrients revealed that naloxone differentially affected fat, carbohydrate, and protein consumption. Across the 6-h feeding period, animals consumed less calories from the fat ration following all three doses of naloxone than after saline injections. Carbohydrate intake was decreased up to 2 h following naloxone injections, but returned to control values by the end of the 6-h feeding period. Protein intake, in contrast to fat and carbohydrate intakes, did not vary as a function of naloxone administration. Results of the present examination are contrasted with patterns of dietary self-selection observed following morphine administration.

Central and peripheral contributions of endogenous opioid systems to nutrient selection in rats.

The contribution of central and peripheral sites to opioid mediation of energy intake and dietary self-selection of the three macronutrients, protein, fat, and carbohydrate, was examined in male rats. Animals given access to either Purina Chow or a self-selection regime were injected with either the opioid antagonist, naltrexone (0.0, 0.1, 1.0, and 5.0 mg/kg, IP), or quarternary naltrexone (0.0, 0.1, 1.0, and 5.0 mg/kg, IP), an opioid antagonist that does not readily enter the central nervous system. Animals received injections at the beginning of an 8-h feeding period, and nutrient intakes were measured at 1, 2, 4, and 8 h postinjection. Naltrexone and its quarternary analogue differed in their effects both on total energy intake and macronutrient selection. Naltrexone led to significant decreases in total energy intake in animals on both dietary regimes, whereas quarternary naltrexone did not modify energy intake of animals given access to either diet. Naltrexone produced a sustained reduction in fat intake and initial decreases in carbohydrate and protein intakes. Quarternary naltrexone did not modify overall energy intake but did lead to modifications in nutrient choice. In contrast to naltrexone, quarternary naltrexone resulted in increased fat intake, decreased carbohydrate intake, and a small reduction in protein intake. These data suggest that both peripheral and central sites contribute to opioid effects on patterns of nutrient choice.

Does sucrose or aspartame cause hyperactivity in children?

Anecdotal evidence has led to the hypothesis that there is a relationship between sugar intake and hyperactive behavior. To assess this hypothesis, a recent study using a range of behavioral and cognitive measures evaluated the effects of diets high in sucrose, aspartame, and saccharin on the performance of school-aged children believed to be sensitive to sugar, and preschool children. Although intakes exceeded average dietary levels, neither sucrose nor aspartame negatively affected behavior. Taken together with previous work, these results indicate that sugar is not a major cause of hyperactivity.

Chronic sucrose intake augments antinociception induced by injections of mu but not kappa opioid receptor agonists into the periaqueductal gray matter in male and female rats.

Chronic intake of a palatable sucrose solution enhances the antinociceptive potency of systemically administered mu, and kappa opioid receptor agonists. To investigate whether the effects of sucrose on the actions of opioid drugs are mediated within the central nervous system (CNS), antinociception was examined following the administration of mu and kappa opioid receptor agonists into the periaqueductal gray area (PAG). Male and female Long-Evans rats consumed either water and ground chow, or water, chow and a 32% (w/v) sucrose solution. After adaptation to the dietary conditions, a guide cannula was stereotaxically implanted into the PAG. Injections of the mu agonist, morphine (0.0, 2.5, 5.0, 10.0 and 20.0 microg), into the PAG led to dose-related increases in antinociceptive responses on a tail flick test in both male and female rats. Rats which had consumed sucrose displayed significantly greater levels of antinociception than rats not given the sugar. Antinociceptive responses to morphine did not differ as a function of sex. Injections of the kappa agonist, spiradoline (0, 100, 300, 600 microg), into the PAG increased tail flick latencies in male and female rats. However, antinociceptive responses did not vary as a function of diet in rats injected with spiradoline. In both diet conditions, spiradoline led to greater levels of antinociception in female rats than in male rats. These results support the hypothesis that intake of palatable foods and fluids act within the CNS to moderate the behavioral actions of opioid drugs.

Dietary modulation of oral amphetamine intake in rats.

The interaction of sucrose availability and oral self-administration of amphetamine was examined in 23 male Sprague-Dawley rats. Fourteen rats were given a 0.075 mg/ml amphetamine sulfate solution as their sole source of fluid and 9 rats were given water. Feeding conditions were alternated between weeks with both granulated sucrose and chow available and weeks with only chow present. Rats drank significantly less of the amphetamine solution when consuming sucrose and chow than when eating chow alone. Sucrose intake had a slight effect on water intake. Rats drinking the amphetamine solution consumed significantly less food, gained significantly less weight, and were significantly less efficient at using calories for weight gain than rats drinking water. However, when given access to sucrose, rats drinking the amphetamine solution chose a significantly greater proportion of their daily caloric intake as sucrose (60%) than rats drinking water (42.5%). The present results demonstrate that 1) amphetamine intake alters nutrient choice and 2) that dietary variables can profoundly affect drug self-administration.

Patterns of nutrient selection in rats with streptozotocin-induced diabetes.

The effects of experimental diabetes on energy intake, patterns of nutrient selection, water intake, body weight and body composition were examined in male Sprague-Dawley rats given ground Purina Chow or a dietary self-selection regime. Following adaptation to dietary conditions, a portion of the animals in each diet group were made diabetic by the administration of 45 mg/kg streptozotocin (STZ). The remaining animals in each group served as vehicle-injected controls. STZ reliably produced diabetes in rats on both dietary regimes. Immediately after the induction of diabetes, rats on the self-selection regime increased carbohydrate and protein intakes and decreased fat intake. Approximately three weeks after STZ administration, diabetic rats reduced carbohydrate intake and increased fat intake. Diabetic animals in both diet groups were hyperphagic and polydipsic relative to non-diabetic controls. During the first three weeks following STZ injections, energy and water intakes of diabetic animals in the two dietary conditions were similar. However, after this initial period, energy and water intakes of diabetic rats given the self-selection regime were significantly lower than those of diabetic animals given Purina Chow.

2-DG-induced glucopenia does elicit feeding in rats with lesions of the zona incerta.

Rats with lesions of the rostral zona incerta (ZI) were maintained on either a palatable liquid diet or Purina Laboratory Chow and tested for their ability to respond to acute cellular glucoprivation. Food intake was measured at two-hour intervals during a six-hour feeding test following the administration of either 2-deoxy-D-glucose (2-DG) (200, 400 and 600 mg/kg) or insulin (4 U/rat). ZI-lesioned rats maintained on the liquid diet responded vigorously both to 2-DG and insulin-induced glucopenia. In contrast, ZI-lesioned animals consuming chow failed to augment feeding following 2-DG administration, although they did increase food intake as a function of insulin administration. These data suggest that dietary factors play an important role in the feeding responses of ZI-lesioned animals and must be considered when drawing conclusions about feeding behavior in brain-damaged animals.

Self-starvation: a problem of overriding the satiety signal?

Rats housed in either activity wheels or standard laboratory cages received access to food either ad lib or for one 60-min, two 30-min, or four 15-min periods per day. Imposition of restricted feeding schedules led to reductions in food intake and body weight which were greater for animals with access to activity wheels. Increases in activity reflected the percent of body weight loss, which varied directly with frequency of food access. Subsequent recovery of intake was facilitated by partitioning total feeding time into briefer but more frequent periods. In the most extreme frequency-of-access condition, animals with access to running wheels failed to recover from the reduction of intake incurred by imposition of the restricted feeding schedule, even though their total feeding time was the same as that of animals that did recover. These data indicate that self-starvation is not induced by activity per se but results from a general failure to recover intake which, in turn, results from a failure to override the satiety signal within a meal.

Patterns of eating as a function of the cost of the meal.

Rats were required to complete fixed ratio schedules (FR 20-FR 2560) of wheel turns to obtain access to food. By decreasing meal frequency and increasing meal size directly as functions of the fixed ratio requirement, animals controlled total daily food intake and body weight relatively constant until the highest ratio requirement was introduced. These functional changes in feeding patterns provide experimental support for theoretical models of optimal feeding strategies. At the highest ratio requirement, as animals lost weight, they increased running and therefore opportunities to feed, however, food intake continued to decrease with increasing exposure to this schedule. As rats on this schedule initiated feeding each time food became available, but did not eat large enough to this schedule. As rats on this schedule initiated feeding each time food became available, but did not eat large enough meals to maintain body weight, it is suggested that activity may interest with satiety mechanisms to produce termination of meals.

Preoperative experience with insulin enhances glucoprivic feeding in rats with lateral hypothalamic lesions.

Adult male Sprague-Dawley rats received either one injection per week of regular insulin (IP, 5 Units) or saline for 4 weeks prior to destruction of the LH or sham-operations. During this preoperative period, animals given insulin consumed significantly more food in a 6-hr test period than animals given saline. Following surgery, animals were given 3 weeks to recover from the acute effects of LH lesions and then tested for responsiveness to glucoprivic challenges. Sham-operated animals from both pre-operative injection groups consumed significantly more food during a 6-hour period when injected with either insulin (5 and 7.5 Units) or 2-DG (400 mg/kg) than when given saline injections. Similarly, LH-lesioned rats with preoperative experience with insulin significantly increased food intake when given insulin or 2-DG. In contrast, LH-lesioned rats without preoperative experience with insulin failed to increase feeding in response to the administration of either insulin or 2-DG. Differences in feeding responses following glucoprivation between LH-lesioned rats with and without preoperative exposure to insulin were not a function of differences in the extent of central nervous system damage. The present data indicate that experimental conditions play an important role in determining the presence or absence of regulatory deficits following brain damage.

Selection of protein and fat by diabetic rats following separate dilution of the dietary sources.

Diabetic and normal rats were allowed to select their diets from separate sources of protein, carbohydrate and fat. Following the determination of baseline intakes, diabetic and normal rats received dietary components in which either the protein (Experiment 1) or fat source (Experiment 2) was diluted by 25% or 50% by the addition of cellulose. Diabetic rats failed to maintain protein intake at both dilution levels, but made up for the loss of protein-derived calories by consuming more fat. Diabetic rats maintained fat intake at both dilution levels. Dietary dilutions had no effect on total caloric intakes or body weight gain of diabetic rats. Diabetic status, measured by fasting plasma glucose levels and urinary glucose excretion rates, also was unaffected by diet dilutions. These data suggest that diabetic rats maintain total caloric intake following dilution of either the protein or fat source of their diets, but defend intake of fat-derived calories more readily than protein-derived calories. Normal rats maintained both protein and fat intake at the 25% but not at the 50% dilution level. These findings are discussed in terms of the ability of diabetic rats to solve the metabolic problems associated with their diabetic condition.

Wheel running attenuates the antinociceptive properties of morphine and its metabolite, morphine-6-glucuronide, in rats.

Recent work has shown that chronic exercise is associated with a reduction in the pain-relieving actions of opioid drugs in experimental animals. To determine whether this reduction represents an interaction between exogenously administered opioids and the endogenous opioid system, or is the result of altered drug pharmacokinetics, the antinociceptive actions of morphine and its metabolite, morphine-6-glucuronide (M6G), were compared in active and inactive female Long-Evans rats. Active animals were housed in running wheels and inactive animals in standard laboratory cages for 3 weeks preceding determinations of antinociception using the tail-flick test. At the end of the 3-week period, active rats were running the equivalent of 9-11 km a day. Antinociceptive responses, determined following subcutaneous injections of either morphine (0.625-20 mg/kg) or M6G (0.3-10.0 mg/kg), were significantly reduced in active rats relative to inactive rats. This reduction was manifested by both a lower magnitude of antinociception, and a shorter duration of antinociception after drug administration in active compared to inactive rats. This reduction was not associated with alterations in the estrous cycle or with differences in body weight between the active and inactive animals. The present results support the hypothesis that cross-tolerance develops between endogenous opioid peptides released in response to exercise and exogenously administered opioid drugs.

Developmental aspects of sucrose-induced obesity in rats.

Daily caloric intakes and body weights were measured from weaning to 70 days of age in male Sprague-Dawley rats given access to either a standard laboratory diet and water, or the standard diet, a 32% sucrose solution and water. Lee index of obesity (3 square root body weight/naso-anal length) and fasting blood glucose levels were determined at 46, 57, and 70 days of age. Animals were sacrificed at 70 days, and body composition analyses were performed. Aniamls given access to the sucrose solution consumed significantly more calories per day than animals given only the standard diet. Sucrose animals took approximately 50 to 60% of their daily caloric intake from the sugar solution. Despite the greater caloric intakes of the sucrose animals, sucrose and control animals did not differ in body weight. While there were no differences in body weights between the two groups, the Lee Index of obesity was significantly greater in the sucrose animals than in controls as early as 46 days of age. Fasting blood glucose levels were significantly lower in sucrose animals than in controls at both 46 and 57 days of age. Direct determinations of body compositions when animals were 70 days of age revealed that animals with access to sucrose had significantly greater percentages of body fat and lower percentages of body protein than controls.

Preferences for foods with varying levels of salt and fat differ as a function of dietary restraint and exercise but not menstrual cycle.

Women commonly report increased cravings for foods high in sugar, fat, and/or salt premenstrually relative to other times during the menstrual cycle. To determine if elevated cravings for foods high in salt and/or fat were related to alterations in food preferences across the menstrual cycle, preference and sensory ratings for air-popped popcorn with varying levels of salt (0.0, 1.5, and 4.0 g) and butter (3.3, 10, and 30 g) added to 30 g of popcorn were assessed in 34 normal-weight, college-aged women for 4 consecutive weeks. Additionally, using the Profile of Mood Scale (POMS), mood states were determined across the menstrual cycle. Dietary restraint, disinhibition, and hunger were assessed using the Three Factor Eating Questionnaire (TFEQ). Neither preference ratings nor ratings of the saltiness or fatness of the popcorn samples varied as a function of the menstrual cycle. Moreover, no differences in mood states were observed across the menstrual cycle. However, preference ratings for the popcorn samples were significantly greater for restrained than unrestrained eaters. Restrained eaters also rated the samples as significantly more salty, and had significantly higher scores on the tension-anxiety and depression-dejection subscale of the POMS than unrestrained eaters. Additionally, preference ratings of women who reported exercising more than 3 h a week were significantly greater than those of women who reported exercising less than 3 h a week. It is hypothesized that the variations in preference ratings observed as a function of dietary restraint and exercise are the result of differences in cognitive beliefs about food, rather than differences in physiological factors.

Maternal malnutrition in the rat: effects on food intake and body weight.

The effects of dietary protein level on food intake and body weight were examined in adult female rats during a 35-day pre-mating period and during gestation and lactation. During the pre-mating period, no differences in daily food intake were observed among rats fed a 6% casein, 8% casein or 25% casein diet. However, during this period, rats fed the 6% casein diet gained significantly less weight than those with ad lib access to the 8% or 25% casein diets or than rats pair-fed the 25% casein diet in amounts equivalent to that consumed by rats in the 6% or 8% casein groups. Additionally, rats fed the 6% casein diet displayed decreased efficiency of energy utilization, calculated as weight gain per 100 kilocalories consumed, relative to rats fed the 8% or 25% casein diets. No differences in food intake were observed among the groups during gestation. However, rats fed the 6% casein diet gained less weight than rats fed the 8% or 25% casein diets. During lactation rats fed either the 6% or 8% casein diet consumed significantly less food than animals given the 25% casein diet ad lib. During the second week of lactation, rats receiving ad lib access to the 25% casein diet gained weight while those receiving the 6% or 8% casein diets continued to lose weight. At parturition, body weights of pups did not differ as a function of dietary condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary influences on the acute effects of anorectic drugs.

The effects of acute administration of d-amphetamine sulfate (0.0, 0.5, 1.0 and 2.0 mg/kg) and dl-fenfluramine hydrochloride (0.0, 1.5, 3.0 and 6.0 mg/kg) on food intake were examined in male Sprague-Dawley rats fed either a high-carbohydrate diet (carbohydrate equaled 65% of total calories) or a high-fat diet (fat equaled 65% of total calories). Animals were given ad lib access to the diets throughout the experiment. Drug injections were given at 0900 on experimental days and food intakes were measured at 1, 3 and 6 h postinjection. Amphetamine led to dose-related decreases in food intake for animals on both diets. The effects of amphetamine were most noticeable at 1 and 3 h postinjection. No differences in amphetamine's effects on food intake were found as a function of diet. Fenfluramine injections also led to dose-related reductions in food intake for animals in both dietary conditions. In contrast to amphetamine, however, fenfluramine led to greater reductions in food intake for rats fed the high-fat diet than for rats fed the high-carbohydrate diet. These data demonstrate that dietary variables must be considered when evaluating the anorectic actions of psychopharmacological agents.

Menstrual cycle and dietary restraint influence taste preferences in young women.

Previous reports indicate that some women increase their consumption of sugar and fat premenstrually. To ascertain whether this is due to differences in taste acuity for sweetness and fatness and/or preference across the menstrual cycle, 25 female and 12 male undergraduates rated the pleasantness, sweetness, and fatness of 16 taste stimuli made of dairy products with varied fat contents (0%, 3.5%, 10%, 36%) and sucrose (0%, 5%, 10%, 20%) over 4 consecutive weeks. There was a marked decline in ratings over the 4 weeks of testing. Taste preferences of women were not uniform across the menstrual cycle. Those who began testing during the luteal and menstrual weeks had increased preference ratings compared to those who began during the follicular or ovulatory weeks. Preference ratings for taste stimuli containing 0% and 5% sucrose were lower in women with higher scores on a restraint of eating scale, than for women with lower scores. No differences in sweetness or fatness ratings were observed across the menstrual cycle, or as a function of dietary restraint. Men had increased preference for taste stimuli containing 10% and 20% sucrose compared to women; however, no differences in ratings of either sweetness or fatness were found as a function of gender. These data indicate that taste preference in women is not homogeneous across the cycle. Instead, many factors, including the menstrual cycle and degree of eating restraint, influence preference ratings.

Mineral content of the diet alters sucrose-induced obesity in rats.

The effects of dietary mineral levels on caloric intake, nutrient choice, body weight, adipose tissue weight, interscapular brown adipose tissue (IBAT) weight, and thermogenic capacity, and plasma insulin and glucose levels were examined in adult male Sprague-Dawley rats. In Experiments 1 and 2, rats were fed a purified diet with zinc (Zn), chromium (Cr), and selenium (Se) added, or the same diet without the addition of these minerals. In Experiment 3, the effects of Zn and Cr were examined separately. In all experiments, half of the rats in each diet group were given a 32% sucrose solution in addition to their standard diet and water. Rats given sucrose consumed more calories and gained more weight than rats not given sucrose. However, mineral levels altered the effects of sucrose on these measures. Added minerals increased percent sucrose intake, reduced weight gain and feed efficiency, increased GDP binding in IBAT mitochondria, improved glucose tolerance, and reduced plasma insulin levels. The reduction in weight gain and increased feed efficiency found when Zn alone was added to the diet was independent of sucrose condition. In comparison, the alterations observed in these measures when Cr alone was added to the diet varied as a function of sucrose availability.