Increased carbohydrate consumption by rats as a function of 2-deoxy-D-glucose administration

Dietary self-selection was examined following the administration of the glucoprivic agent, 2-deoxy-D-glucose (2-DG), in adult male rats given access to separate sources of the three macronutrients, protein, fat and carbohydrate. All animals received injections (IP) of saline, 250, 500 and 750 mg/kg 2-DG with nutrient intakes measured at 2, 4, 6 and 24 hrs following injections. Animals consumed significantly more carbohydrate at 4, 6 and 24 hrs after injections of 500 and 750 mg/kg 2-DG than after saline injections. In contrast, fat intake was significantly suppressed by all three doses of 2-DG at 2 hr, by 250 and 750 mg/kg 2-DG at 4 and 6 hrs, and by 750 mg/kg 2-DG at 24 hr after injections. Protein intake was significantly decreased by all three doses of 2-DG at 2 hr after injections. As a result of the increase in carbohydrate intake and complimentary decrease in fat intake following 2-DG injections, total caloric intake of animals given the self-selection regime was not modified as a function of drug administration. In comparison, rats given a single nutritionally complete diet (ground Purina Laboratory Chow) consumed significantly more calories following 2-DG administration than following saline injections. The ability of animals to make appropriate modifications in nutrient selection following regulatory challenges is discussed.     

Morphine selectively influences macronutrient intake in the rat

Dietary self-selection of the three macronutrients, protein, carbohydrate and fat, was examined in male rats following the administration of three doses of morphine sulphate: 10 mg, 15 mg, and 30 mg/kg body weight. Intakes of all three macronutrients were suppressed in a dose-dependent manner for a two-hour period following morphine administration. Both protein and carbohydrate intakes remained suppressed for a six-hour feeding period after morphine injections. In contrast, animals increased fat intake during the final four hours of the six-hour feeding period resulting in an overall increase in fat intake.     

Cholecystokinin and bombesin suppress operant responding for food reward

The effects of intraperitoneal injections of cholecystokinin (CCK) and bombesin (BBS) on food-rewarded operant responding were investigated. Response rates were significantly suppressed following administrations of CCK (0.7, 1.4, and 2.9 micrograms/kg). The effects appeared to be dose dependent. Responding was also suppressed following injections of BBS (6 and 16 micrograms/kg). These results confirm and extend previous findings concerning the possible function of these peptides.     

Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic fluoxetine in female rats.

Fluoxetine hydrochloride, a selective serotonin reuptake inhibitor, leads to reductions in food intake and body weight and is under investigation as a possible treatment for obesity. Additionally, it has been suggested that fluoxetine administration could lead to a selective suppression in carbohydrate consumption. Because women more often than men seek weight reduction treatment, the present study examined the acute and chronic effects of fluoxetine on food intake, macronutrient selection, body weight, estrous cycle, and motor activity in female rats. Female Long-Evans rats were provided with separate sources of protein, fat and carbohydrate, and nutrient intakes were recorded following single (5.0, 10.0, and 20.0 mg/kg, IP) and chronic daily (10 mg/kg for 28 days) injections of fluoxetine. Acute and chronic administration of fluoxetine significantly reduced total caloric intake when compared to vehicle treatment. Moreover, fluoxetine significantly suppressed fat and protein intakes, but not carbohydrate intake following both acute and chronic drug administration. Animals chronically treated with fluoxetine gained significantly less weight than animals treated with vehicle. Chronic fluoxetine treatment did not significantly alter estrous cycle. However, in both fluoxetine- and vehicle-treated animals, total caloric intake, and carbohydrate and protein intakes were reduced and fat intake was increased when estrogen levels were high. Fluoxetine significantly reduced motor activity up to 4 h postinjection, and increased motor activity 24 h postinjection.     

Effect of intraventricular adenosine on food intake in rats

Previous studies have shown that peripherally administered purines suppress food intake in rats. In this study we show that central administration of adenosine, adenine and AMP potently suppressed food intake in rats. Intraperitoneal adenosine suppressed feeding at the 100 and 50 mg/kg dose whereas 100, 50 and 10 micrograms of intraventricular adenosine suppressed feeding after intracerebroventricular injection at 30 minutes and up to 120 minutes at the high doses. Inosine, 2-deoxyinosine, 7-methyl-inosine and 2-deoxyguanosine all failed to suppress food intake when given intraventricularly at the same doses used for adenosine, adenine and AMP. Adenosine, 10 micrograms ICV, also decreases water uptake. The effect of adenosine was specific for ingestive behaviors as it did not significantly decrease spontaneous movement or grooming. These results suggest that adenosine suppresses feeding via a central mechanism and that this suppressive effect is not dependent on deamination of adenosine to inosine. The central adenosine effect appears to work by a different mechanism to the satiety effect of peripherally administered inosine.     

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 for 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 experiment are contrasted with patterns of dietary self-selection observed following morphine administration.     

Differential effects of amphetamine and fenfluramine on dietary self-selection in rats

Daily caloric intakes and dietary self-selection of the three macronutrients, protein, fat and carbohydrate were examined in female rats following administration of d-amphetamine sulfate (0.0, 0.5, 1.0 and 2.0 mg/kg, IP) or fenfluramine hydrochloride (0.0, 1.5, 3.0 and 6.0 mg/kg, IP). Animals were maintained on ground Purina Chow or one of two self-selection regimes, one with a high-caloric fat ration (7.85 kcal/g) and the other with a fat ration isocaloric to the carbohydrate and protein rations (3.76 kcal/g). Animals received drug injections at the beginning of a daily 8-hour feeding period with nutrient intakes measured at 2, 4 and 8 hrs following injections. While both amphetamine and fenfluramine led to dose-related decreases in total caloric intakes, the two drugs resulted in different temporal patterns of feeding. Amphetamine produced its greatest effect on caloric intake during the first 2 hours of the feeding period, whereas fenfluramine suppressed caloric intake equivalently across the 8-hour feeding period. The two anorectic drugs also led to different patterns of nutrient choice. When animals were given the high-caloric fat ration, amphetamine selectively decreased fat intake while fenfluramine produced decreases in both protein and fat intakes, sparing carbohydrate intake. In contrast, when animals were given the isocaloric fat ration, amphetamine resulted in a general suppression of nutrient intakes while fenfluramine led to a sustained decrease in fat intake with a relative sparing of protein and carbohydrate consumption.     

Diet selection following a chronic morphine and naloxone regimen

Total caloric intake and patterns of dietary self-selection of the three macronutrients, protein, carbohydrate and fat, were examined in adult male rats maintained on a 6-hr feeding schedule following daily injections of morphine (10 mg/kg), naloxone (1 mg/kg), the two drugs together, and saline. Animals received drug injections for 10 consecutive days. All animals received saline injections for the 5 days preceding and 5 days following the experimental period. Naloxone injections led to a significant reduction in total caloric intake. Neither morphine nor morphine and naloxone together significantly affected total caloric intake. Each of the drugs had a distinct effect on macronutrient selection. Morphine produced a significant increase in fat intake and decrease in carbohydrate intake, while naloxone led to a slight reduction in fat intake. When the two drugs were given together, a significant elevation in carbohydrate intake and reduction in fat intake were observed. Protein intake was not affected by any of the drugs. These results are discussed with respect to the hypothesized role of the endogenous opioid system in the regulation of energy balance.     

Peripheral serotonin administration selectively reduces fat intake in rats

Recent research has led to the hypothesis that serotonergic mechanisms may be involved in both the control of energy intake and appetites for specific nutrients. Most of this research has focused on serotonin (5-HT) within the central nervous system. However, there is evidence which suggests that peripheral 5-HT also may be involved in the control of energy intake and nutrient selection. To further assess this suggestion, the effects of peripheral 5-HT administration on energy consumption and nutrient intakes were examined in adult male Sprague-Dawley rats given separate sources of protein, fat and carbohydrate. Administration of 5-HT (doses ranging from 2-6 mg/kg) led to significant dose-related decreases in total energy intake in both freely feeding and food-restricted rats. Examination of individual nutrient intakes revealed that following 5-HT, fat intake was more suppressed than either carbohydrate or protein intakes. Administration of the 5-HT antagonist, methysergide, blocked the suppressive effects of 5-HT on both total energy intake and fat intake. The present data support the proposal that peripheral serotonergic mechanisms play a role in ingestive behaviors.     

Effect of (+)- or (-)-enantiomers of fenfluramine or norfenfluramine on nutrient selection by rats

The effects of the (+)- and (-)-enantiomers of fenfluramine and norfenfluramine on food choice and total food consumption by rats, have been examined. Animals were trained to select their food during an 8-h daily interval from two isocaloric-isocarbohydrate (40%) diets differing in protein contents (5 or 45% casein). Low doses of (+)-fenfluramine (1.25 or 1.65 mg kg-1) selectively reduced consumption of the 5%-protein diet during the hour after administration, thereby also reducing carbohydrate intake by a greater proportion than protein intake. Higher doses (2.5 or 4.0 mg kg-1) diminished consumption of both test diets to an equivalent extent. (+)-Norfenfluramine, although anorectic, did not modify the relative consumptions of carbohydrate and protein at any dose tested. These observations affirm that nutrient selection as well as total food consumption can be altered by drugs affecting particular neurotransmitters.     

Effect of 5-HT agonists on rats fed single diets with varying proportions of carbohydrate and protein

Low doses of 5-HT agonists have been shown to selectively suppress carbohydrate intake in rats given dietary choices. To investigate further the relationship between dietary macronutrient composition and 5-HT-induced anorexia, the present study examined the effects of three 5-HT agonists on rats fed single isocaloric diets containing varying proportions of carbohydrate (CHO) and protein (PRO). Rats were habituated to eat one of the three diets (73.5% CHO - 10% PRO, 58.5% CHO - 25% PRO or 43.5% CHO - 40% PRO) during the dark period (1900–0700 h). Saline or 5-HT agonists (fluoxetine, RU 24969 and dexfenfluramine) were administered intraperitoneally at 1845 hours, 15 min prior to food access. At the doses used, food intake was significantly affected only during the first hour of eating. All 5-HT agonists caused dose-dependent decreases in food intake (P < 0.01). The magnitude of decrease, however, was significantly influenced by diet composition. Reduction in intake was greatest in rats fed the 73.5% CHO - 10% PRO diet. Thus, rats chronically fed a diet high in carbohydrate content were more sensitive to the anorectic effect of 5-HT agonists than rats fed diets containing moderate to low levels of carbohydrate.     

Enhanced amphetamine anorexia, but not drinking suppression in obese Zucker rats

The effects of d-amphetamine on ad libitum consummatory behavior of genetically obese Zucker rats and their lean littermates were examined in two experiments. In Experiment 1 food intake was measured every two hours for six hours following intraperitoneal injections of 0.0, 0.5, and 1.0 mg/kg of d-amphetamine sulfate. Both lean and obese animals significantly suppressed food intake for the first two hours after injection of 0.5 and 1.0 mg/kg doses. Lean animals displayed no suppression of food intake at four or six hours after injection. In contrast to lean animals, obese rats continued to show a suppression of feeding at four hours after injection of 1.0 mg/kg. Total six-hour food intake of obese animals was significantly suppressed from baseline after 0.5 and 1.0 mg/kg of amphetamine, but only after the 1.0 mg/kg injection with lean animals. Experiment 2 examined the effects of these same doses on both food and water intake of different groups of obese and lean Zucker rats. The enhanced anorexia with the 1.0 mg/kg injection of amphetamine was replicated. Water intake, however, was suppressed only during the first two hours after both the 0.5 and 1.0 mg/kg injection in obese and lean rats. Results of the present experiments are discussed in light of previous studies of the effects of amphetamine on hypothalamically obese animals.     

Increased fat consumption induced by morphine administration in rats

Patterns of caloric intakes and dietary self-selection of the three macronutrients, protein, fat and carbohydrate were examined in male rats following the administration of morphine sulfate (0.0, 1.0, 10.0 and 20.0 mg/kg, IP). Animals were given access to either ground Purina Chow or one of two dietary self-selection regimes, one with a high-fat ration (7.8 kcal/g) and the other with a fat ration isocaloric to the carbohydrate and protein rations (3.8 kcal/g). Animals received morphine injections at the beginning of a six-hour feeding period and nutrient intakes were measured at 1,2,4 and 6 hours postinjection. Similar patterns of macronutrient choice were observed for both animals maintained on the high-fat regime and animals with access to the isocaloric components following morphine injections. As a function of morphine injections, animals on both self-selection regimes increased fat intake while suppressing carbohydrate intake and exhibiting little modifications in protein intake.     

In rats, the behavioral profile of CCK-8 related peptides resembles that of antipsychotic agents

The action of some CCK-8 related peptides, desulphated CCK-8 (CCK-DS), the sulphated form of CCK-8 (CCK-8-S) and ceruletide was explored in a number of test procedures with rats, in which antipsychotic agents are active. Following injection into the nucleus accumbens, all three peptides antagonized the hypolocomotion induced by low doses of apomorphine (10 ng). Ceruletide appeared to be the most potent in this respect (ED50: approximately 5 pg). The increased locomotion observed following injection of relatively high doses of apomorphine (10 micrograms) into the nucleus accumbens was antagonized by local pretreatment with CCK-8-S, but not with CCK-8-DS or ceruletide. None of these CCK-8 related peptides affected the stereotyped sniffing response elicited by treatment with apomorphine or amphetamine (10 micrograms) given into the nucleus caudatus. Passive avoidance behavior was facilitated following subcutaneous administration of 10 micrograms of CCK-8-related peptides 1 h before the retention test. The same periods given into the nucleus accumbens (0.3 pg) however attenuated passive avoidance behavior. intraventricular injection with CCK-8-DS and CCK-8-S induced a positive effect in various 'grip tests'. Given subcutaneously, the CCK-8-related peptides decreased the rate of ambulation and rearing especially in the middle of the open field. These results indicate that CCK-8 related peptides, especially CCK-8-DS and ceruletide, exhibit behavioral effects that are similar to those observed following treatment with gamma-type endorphins and that resemble the effects of antipsychotic agents. Very low doses of CCK-8 related peptides exert behavioral effects following injection into the nucleus accumbens, indicating that this brain area is extremely sensitive to the action of these peptides. It is postulated that certain peptides which are either present in neurons (like CCK-8-related peptides) or generated by brain endorphin systems (like gamma-type endorphins) control the activity of specific neurons of the mesolimbic dopaminergic pathways. This may be of relevance for the purported antipsychotic action of these peptides.     

Food intake suppression by histidine

Following injection of histidine (as 1-histidine monohydrochloride, 500 mg/kg, IP) rats showed a suppression of total food intake within the first 2 hours of a 12 hour daily feeding period but not if the rats were adapted to a 4 hour daily feeding period. Furthermore, rats adapted to a nocturnal as compared to a diurnal 12 hour feeding period showed a greater response (50% vs. 20% suppression of feeding) to histidine. Overall, within an experiment, food intake suppression correlated with the histidine dose (0, 125, 250, 375 and 500 mg/kg; for mean response r(3) = 0.90, p less than 0.05) although the lowest dose measured to be effective in a cross-over design experiment was 375 mg/kg. No differential effect upon protein or carbohydrate intake was observed in any of the studies. The effects of injections of 250 and 500 mg/kg histidine on food intake were associated with significant elevations of brain histidine and histamine. We conclude that histidine, possibly by changes in brain histidine, influences total food intake but not macronutrient selection.     

Role of medial preoptic area (MPOA) in the reproductive function and feeding behavior in rats

Adult female rats were given ad lib access to two pairs of specially prepared diets containing the three macro-nutrients, protein, fat and carbohydrate, in such proportion that both pairs were isocaloric but one pair varied in protein content (45% and 5%) and the other pair in carbohydrate content (70% and 25%). Body weights, food intake and selectivity were noted daily. Following lesions of Medial Preoptic Area (MPOA), there was an increase in the total food and protein intake and disruption of the regular estrus cycles. In the second series, the total food intake increased after ovariectomy and decreased following intracranial estrogen instillation in the MPOA. A change in the selectivity of the diets was also noted. The observations are suggestive of the role of MPOA in the food intake and selectivity and this is probably effected through the estrogen receptors situated therein.     

Cholecystokinin antagonizes morphine induced hypoactivity and hyperactivity in hamsters

Three experimental replications were used to test the effects of three doses (25, 50 or 75 micrograms/kg) of cholecystokinin octapeptide (CCK-8) on morphine induced changes in activity. For each dose of CCK-8, running wheel activity of golden Syrian hamsters was monitored for three hours following a series of two injections. The first injection consisted of either saline or CCK-8, the second of either saline or morphine sulfate (15 mg/kg). Thus, in each replication four groups were created: Group SAL/SAL (n = 8) received two saline injections, Group CCK/SAL (n = 8) an injection of CCK-8 followed by an injection of saline, Group SAL/MS (n = 8) an injection of saline followed by an injection of morphine and Group CCK/MS (n = 8) an injection of CCK-8 followed by an injection of morphine. Results indicated that a 25 micrograms/kg dose of CCK-8 blocked the hypoactivity elicited by morphine 40-60 min after opiate injection, whereas a 75 micrograms/kg dose of CCK-8 blocked the hyperactivity elicited by morphine 80-100 min after opiate injection. These findings are consistent with previous reports that CCK-8 antagonizes the effects of opiate agonists on a variety of behaviors and is supportive of the hypothesis that endogenous CCK-8 may antagonize endogenous opioid peptides in the control of behavior.     

Satietin: route of injection, dose response, effect on food and water intake and on running-wheel activity in the rat

Semipurified satietin significantly (p less than 0.05) reduced food intake when injected subcutaneously at 10, 15, 20 mg/kg into 48 hr fasted rats with no indication of a dose response. When infused intracerebroventricularly (ICV) at 12.5, 25 and 50 micrograms/rat (10 microliter vol) into ad lib fed rats at the end of the light period there was no effect on food intake for the first hour but 24 hr food intake was (p less than 0.001) reduced at all doses. The ICV dose response curve was shallow, with similar suppression at both 12.5 and 25 micrograms doses, but a (p less than 0.05) greater suppression with the 50 micrograms dose. An ICV threshold between 6.25 micrograms and 12.5 micrograms appears to exist since no suppression occurred after a dose of 6.25 micrograms. Four consecutive daily ICV infusions of satietin (25 micrograms/rat) in two rats progressively suppressed food intake to low levels, suggesting a cumulative effect. Following termination of satietin treatment daily food intake slowly returned towards normal without evidence of rebound feeding. In other ad lib fed rats, four ICV infusions of semipurified satietin, on days alternated with no infusion, reduced food intake (p less than 0.001), water intake (p less than 0.003) and running wheel activity (p less than 0.001) on the first day of injection but not on subsequent injection days. Suppression of activity approached significance on the second injection day. Highly purified satietin infused ICV produced similar responses. These findings may indicate a general disruption of behavior by satietin, thus, it may not play a physiological role in feeding behavior because of its apparent non-specificity.     

Changes in brain monoamine levels of rats during cholecystokinin octapeptide-induced suppression of feeding

Cholecystokinin octapeptide (CCK-8) in doses of 5 or 10 micrograms/kg was injected intraperitoneally to 24 hr food-deprived rats before a 30 min feeding period, and the dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT) contents of the hypothalamus, mesencephalon, amygdala, hippocampus and striatum were measured thereafter. The experimental procedure (deprivation + food intake) alone could induce changes in the brain monoamine contents of saline-treated animals as compared to the nondeprived control group. The most striking effect was observed in the hypothalamus, in which the contents of all three monoamines decreased. In the deprived control group there was a significant positive correlation calculated by linear regression analysis between the amount of food eaten and the DA contents of the amygdala. Injection of CCK-8 before food intake testing decreased the DA contents of the hypothalamus. In the CCK-8-treated animals the correlation between food intake and amygdaloid DA contents disappeared. The CCK-8 treatment specifically gave rise to a significant positive correlation between the amount of food eaten and the NE content of the hypothalamus; such a relation could not be observed in the saline-treated group. The hypothalamic NE contents altered in parallel with the effectiveness of both doses of CCK-8 in inhibiting food intake. The results indicate the importance of the hypothalamic NE system in the food intake-suppressing effect of CCK-8.     

Effects of adrenalectomy on macronutrient selection patterns in the rat

The present studies examined the effects of adrenalectomy (ADX) on nutrient selection of rats over the 24-h period, as well as during the first 2 h of the nocturnal feeding cycle. Results indicate that ADX, in rats showing generally similar preferences for carbohydrate and fat, equally suppresses intake of both of these nutrients over the 24-h period. The relative impact of ADX on carbohydrate and fat intake may shift depending upon baseline, with carbohydrate-preferring rats showing a stronger decrease in intake of this diet after ADX and fat-preferring rats exhibiting a greater decline in fat intake after ADX. Acute injections of corticosterone (CORT) and aldosterone (ALDO) are both found to restore carbohydrate as well as fat intake to ADX rats over the 24-h period. However, in the first 2 h of the dark feeding cycle, carbohydrate intake is found to be selectively suppressed after ADX, and CORT injection (0.5 and 2.0 mg/kg, SC) restores carbohydrate intake during this early dark period, while producing a small increase in fat intake only at the higher dose. This is in contrast to ALDO administration at dark onset, which has a stronger stimulatory effect on fat intake in the ADX rat but does not fully restore carbohydrate intake. These findings indicate that CORT and ALDO have differential effects on nutrient intake in ADX rats particularly at the onset of the dark cycle, and it is suggested that these are mediated, respectively, by the type I and type II steroid receptor systems in the brain.