Suppression by the cannabinoid CB1 receptor antagonist, rimonabant, of the reinforcing and motivational properties of a chocolate-flavoured beverage in rats

Pharmacological blockade of the cannabinoid CB1 receptor has been repeatedly reported to suppress intake of food, including highly palatable foods, in laboratory animals. This study was designed to investigate whether treatment with the cannabinoid CB1 receptor antagonist, rimonabant, would reduce the reinforcing and motivational properties of a chocolate-flavoured beverage [containing 5% (w/v) chocolate powder] in nonfood-deprived and nonwater-deprived Wistar rats trained to self-administer this beverage under an operant conditioning procedure. This study was also aimed at assessing to what degree self-administration behaviour could be manipulated environmentally. After a period of training and maintenance of the self-administration behaviour, separate groups of rats were exposed to different experimental conditions [session length varying from 20 to 120 min; fixed ratio (FR) schedule of reinforcement varying from FR10 to FR40; reinforcer presentation varying from 2.5 to 10 s; concentration of the chocolate powder varying from 5% (w/v) to 0%]; other rat groups were used to test the effect of acute and repeated treatment with rimonabant (1-5.6 mg/kg, intraperitoneally) on two schedules of reinforcement (FR10 and progressive ratio) and extinction responding. All rats rapidly acquired and steadily maintained high levels of self-administration of the chocolate-flavoured beverage. Changes in experimental conditions modified the rats' self-administration behaviour; these changes seemed to be the result of the rats' attempt to adjust their behaviour so as to consume as much of the chocolate-flavoured beverage as possible when it was presented at its most palatable 5% concentration. Treatment with rimonabant dose-dependently suppressed self-administration of the chocolate-flavoured beverage. When rimonabant was administered repeatedly, only a modest degree of tolerance developed to its reducing effect. Finally, treatment with rimonabant resulted in a dose-dependent reduction of the motivational properties of the chocolate-flavoured beverage, measured by the progressive ratio schedule of reinforcement and extinction-responding procedure. These results suggest that self-administration of a chocolate-flavoured beverage can be rapidly and reliably established in rats and that this behaviour is environmentally manipulable. These results also suggest that the cannabinoid CB1 receptor is a crucial component of the neural substrate mediating the reinforcing and motivational properties of a highly palatable food such as a chocolate-flavoured beverage.     

Rimonabant’s reductive effects on high densities of food reinforcement,but not palatability,in lean and obese Zucker rats

Rationale

Cannabinoid antagonists purportedly have greater effects in reducing the intake of highly palatable food compared to less palatable food. However, this assertion is based on free-feeding studies in which the amount of palatable food eaten under baseline conditions is often confounded with other variables, such as unequal access to both food options and differences in qualitative features of the foods.

Objective

We attempted to reduce these confounds by using a model of choice that programmed the delivery rates of sucrose and carrot-flavored pellets.

Methods

Lever pressing of ten lean (Fa/Fa or Fa/fa) and ten obese (fa/fa) Zucker rats was placed under three conditions in which programmed ratios for food pellets on two levers were 5:1, 1:1, and 1:5. In phase 1, responses on the two levers produced one type of pellet (sucrose or carrot); in phase 2, responses on one lever produced sucrose pellets and on the other lever produced carrot pellets. After responses stabilized under each food ratio, acute doses of rimonabant (0, 3, and 10 mg/kg) were administered before experimental sessions. The number of reinforcers and responses earned per session under each ratio and from each lever was compared.

Results and conclusions

Rimonabant reduced reinforcers in 1:5 and 5:1 food ratios in phase 1, and across all ratios in phase 2. Rimonabant reduced sucrose and carrot-flavored pellet consumption similarly; rimonabant did not affect bias toward sucrose, but increased sensitivity to amount differences in lean rats. This suggests that relative amount of food, not palatability, may be an important behavioral mechanism in the effects of rimonabant.     

MK801 increases feeding and decreases drinking in nondeprived, freely feeding rats

The noncompetitive NMDA receptor antagonist MK801 has been reported to increase food intake in rats during scheduled test meals of palatable foods or after food deprivation, but not in nondeprived rats given rodent chow. To determine if MK801 has an effect on spontaneous meals, MK801 (100 microg/kg) was administered 15 min prior to dark onset to nondeprived rats maintained on powdered rodent chow, and spontaneous food and water access was measured. MK801 increased the length of the first meal and the amount of time spent feeding within the meal. Conversely, MK801 decreased the length and size of the first drinking bout. MK801 did not alter the latency to the first meal or drinking bout, nor the intervals between successive meals or bouts. The effects of MK801 on feeding and drinking bouts were partially confirmed by measuring total chow and water intake over the first 2 h of the dark period. Thus, acute MK801 can significantly alter spontaneous chow feeding and drinking in nondeprived rats when administered prior to dark onset.     

Inhibition of Opioid Transmission at the ��-Opioid Receptor Prevents Both Food Seeking and Binge-Like Eating

Endogenous opioids, and in particular μ-opioid receptors, have been linked to hedonic and rewarding mechanisms engaged during palatable food intake. The aim of this study was to investigate the effects of GSK1521498, a novel μ-opioid receptor antagonist, on food-seeking behavior and on binge-like eating of a highly preferred chocolate diet. Food seeking was measured in rats trained to respond for chocolate under a second-order schedule of reinforcement, in which prolonged periods of food-seeking behavior were maintained by contingent presentation of a reward-associated conditioned reinforcer. After reaching a stable baseline in both procedures, animals were treated with GSK1521498 (0.1, 1, and 3 mg/kg; IP) or naltrexone (NTX, 0.1, 1, and 3 mg/kg; SC). The binge eating model was characterized by four temporally contiguous phases: 1-h chow access, 2-h food deprivation, 10-min chow access, and 10-min access to either chocolate-flavoured food or standard chow. During training the rats developed binge-like hyperphagia of palatable food and anticipatory chow hypophagia (anticipatory negative contrast). Both compounds reduced binge-like palatable food hyperphagia. However, GSK1521498 reduced the impact of high hedonic value on ingestion more specifically than NTX, abolishing anticipatory chow hypophagia. GSK1521498 also dose-dependently reduced food seeking both before and after food ingestion, whereas NTX reduced food seeking only after food ingestion. Thus, while both drugs affected the hedonic value of the preferred food, GSK1521498 also directly decreased incentive motivation for chocolate. Selective μ-opioid receptor antagonism by GSK1521498 may have utility as a treatment for reducing maladaptive, palatability-driven eating behavior by reducing the motivational properties of stimuli that elicit the binge eating commonly associated with obesity.     

CRF–CRF1 Receptor System in the Central and Basolateral Nuclei of the Amygdala Differentially Mediates Excessive Eating of Palatable Food

Highly palatable foods and dieting are major contributing factors for the development of compulsive eating in obesity and eating disorders. We previously demonstrated that intermittent access to palatable food results in corticotropin-releasing factor-1 (CRF₁) receptor antagonist-reversible behaviors, which include excessive palatable food intake, hypophagia of regular chow, and anxiety-like behavior. However, the brain areas mediating these effects are still unknown. Male Wistar rats were either fed chow continuously for 7 days/week (Chow/Chow group), or fed chow intermittently 5 days/week, followed by a sucrose, palatable diet 2 days/week (Chow/Palatable group). Following chronic diet alternation, the effects of microinfusing the CRF₁ receptor antagonist R121919 (0, 0.5, 1.5 μg/side) in the central nucleus of the amygdala (CeA), the basolateral nucleus of the amygdala (BlA), or the bed nucleus of the stria terminalis (BNST) were evaluated on excessive intake of the palatable diet, chow hypophagia, and anxiety-like behavior. Furthermore, CRF immunostaining was evaluated in the brain of diet cycled rats. Intra-CeA R121919 blocked both excessive palatable food intake and anxiety-like behavior in Chow/Palatable rats, without affecting chow hypophagia. Conversely, intra-BlA R121919 reduced the chow hypophagia in Chow/Palatable rats, without affecting excessive palatable food intake or anxiety-like behavior. Intra-BNST treatment had no effect. The treatments did not modify the behavior of Chow/Chow rats. Immunohistochemistry revealed an increased number of CRF-positive cells in CeA—but not in BlA or BNST—of Chow/Palatable rats, during both withdrawal and renewed access to the palatable diet, compared with controls. These results provide functional evidence that the CRF–CRF₁ receptor system in CeA and BlA has a differential role in mediating maladaptive behaviors resulting from palatable diet cycling.     

Blockade by the cannabinoid CB1 receptor antagonist, rimonabant (SR141716), of the potentiation by quinelorane of food-primed reinstatement of food-seeking behavior.

It has been shown previously that the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716), reduced the intake of palatable food as well as the self-administration of several drugs of abuse, suggesting that endocannabinoid systems play a role in brain reward function. The present study investigated whether a cannabinoid step was involved in food-seeking behavior induced by explicit stimuli, using an operant reinstatement procedure in rats. Experimental sessions consisted of a 15-min food rewarded period, followed by a 45-min extinction period. Rimonabant did not affect the response reinstatement induced by noncontingent delivery of food pellets, but prevented (0.03-0.3 mg/kg) the potentiation by quinelorane, a dopamine D3 receptor-preferring agonist, of food-seeking behavior. A possible link between cannabinoid processes and D3- and/or D2-mediated dopaminergic transmission was further investigated by studying Fos protein expression in cortico-limbic structures in D3 (D3-/-) and D2 (D2-/-) knockout mice. Rimonabant (10 mg/kg) increased Fos immunoreactivity in the prefrontal cortex (pFCortex) and in the shell but not the core of the nucleus accumbens (NAcc). Fos induction by this dose of rimonabant was not seen in mice lacking CB1 receptors, providing clear evidence for the involvement of CB1 receptors. In the NAcc shell, the effect of rimonabant was suppressed in D3-/-, but remained unchanged in D2-/- mice. In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion. In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes. Overall, these results are consistent with the notion that endocannabinoid functions control brain reward processes and in particular the capacity of explicit stimuli to precipitate food-seeking behavior.     

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB₁) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB₁ receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB₁ receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB₁ receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB₁ receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.     

Selection of a palatable dietary option is not preferentially reduced by cannabinoid CB1 receptor antagonist AM251 in female C57Bl/6J mice

We previously showed in female rats that administration of the cannabinoid CB1 receptor antagonist AM251 reduced energy intake by selectively decreasing consumption of a palatable dietary option in comparison to a standard maintenance chow. In the present study we sought to generalize these findings to mice. We presented 6 week old female C57Bl/6J mice with daily 8 h access to a sugar fat whip dietary option along with ad libitum access to moist chow. Mice were injected daily with either vehicle (equal parts polyethylene glycol and saline, 2 ml/kg) or one of three doses of AM251 (1, 3, or 10 mg/kg). Food intake and body weight were measured daily for 21 days. Although 8 h access to sugar fat whip did not induce overconsumption in female mice, AM251 reduced their energy intake and body weight in a dose-dependent manner. The decrease in energy intake occurred for both chow and sugar fat whip. This difference from results in rats suggests that the effect of AM251 on palatable food intake may only be evident in models that induce overconsumption and/or that rats and mice may react differently to CB1 receptor antagonists.     

Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats

RATIONALE: Recent studies in animals have implicated endogenous cannabinoids in the regulation of palatable food intake, but it is not yet clear to what extent pharmacological agents acting on this system may have sustained actions and applicability to different feeding protocols. OBJECTIVES: In the present study, we examine the effects of the cannabinoid CB1 receptor antagonist SR 141716 on food intake of rats, and its behavioral specificity. We examine whether tolerance develops to the anorectic actions of SR 141716, and whether it has either additive or synergistic actions with dexfenfluramine or naloxone. METHODS: Undeprived rats were trained to eat a daily sweet milk dessert and on test days were administered single or combination drugs and intakes were recorded. In other studies, rats were deprived for 24 h of either food or water and intakes recorded after drug administration at the end of this time. In one study, rats were fed ad libitum chow with SR 141716 added. RESULTS: SR 141716 (1-3 mg/kg) suppressed both palatable food intake in undeprived rats and food, but not water, intake after deprivation. Using an isobolographic analysis, SR 141716 had an additive anorectic effect with dexfenfluramine. In contrast, SR 141716 in combination with naloxone had a significantly supra-additive anorectic action. SR 141716 was also effective orally and no tolerance to its anorectic effect developed over 3 days. CONCLUSIONS: These data show that SR 141716 is an effective anorectic agent using both palatable foods and bland chow, and is selective because water intake was unaffected. SR 141716 is also effective orally and has an effect sustained for at least several days. There appears to be a synergistic interaction between opioid and cannabinoid systems in the regulation of feeding, whereas the combination of a serotonin releasing agent and the CB1 antagonist is additive.     

Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats

The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.     

Accurate caloric compensation in rats for electively consumed ethanol-beer or ethanol-polycose mixtures

High elective intake of ethanol was achieved in rats by presenting ethanol in palatable vehicles. We simultaneously measured intake of food (chow) to assess the accuracy of caloric compensation for the energy in the alcoholic commodity. In the first study, we used beer; nonalcoholic beer was consumed in large amounts, and when 5% or 10% ethanol was added, intake amounted to approximately 10% of daily calories. In the second study, Polycose in either solution or a gel matrix was used as the palatable vehicle for ethanol. The intake of ethanol was even higher than in the beer study, particularly in the gel preparation. In all cases, both male and female rats showed accurate caloric compensation by a reduction in chow intake. In a final study, we showed that restricted time access to the Polycose-alcohol gel produced high elective intakes and substantial blood alcohol levels. Over 24 h, caloric compensation was again accurate. Thus, unlike some reports in humans, rats seem able to compensate accurately for alcohol calories and in particular when, as with most alcohol consumption by humans, these are presented in palatable vehicles.     

Effects of liraglutide and sibutramine on food intake,palatability, body weight and glucose tolerance in the gubra DIO-rats

Aim:

To validate the gubra DIO-rats as a useful animal model of human obesity.

Methods:

The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.

Results:

Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.

Conclusion:

This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.     

Preference for palatable food is reduced by the gamma-hydroxybutyrate analogue GET73, in rats.

Palatability and variety of foods are major reasons for "hedonic" eating, and hence for overeating and obesity. Palatable food and drugs of abuse share a common reward mechanism, and compounds that block the reinforcing effect of drugs of abuse preferentially suppress the intake of palatable foods. This research was aimed at studying the influence of the gamma-hydroxybutyrate analogue N-(4-trifluoromethylbenzyl)-4-methoxybutanamide (GET73) - that inhibits alcohol consumption - on consumption and reinforcing effect of palatable food. Adult male rats were used. For place preference conditioning, sweetened corn flakes were used as the reinforcer, and GET73 (50, 100 and 200mgkg(-1)) or vehicle were orally (p.o.) administered either 30min before each training session and the test session, or only before the test session. To study the influence on consumption, GET73 was given p.o. at the same doses once daily for 12 days to rats given free access to both palatable and varied food (cafeteria diet) or to standard chow. Both acquisition and expression of palatable food-induced conditioned place preference were inhibited by GET73, either administered throughout the conditioning period or only before the test session. GET73 reduced also the consumption of cafeteria food, while that of standard chow was increased. At these doses, GET73 had no detrimental effect on open-field behaviour. GET73 seems to specifically attenuate the gratification produced by varied and palatable food, without affecting the consumption of not particularly palatable chow. Since, overweight and obesity are mostly due to the overeating of palatable and varied foods, drugs like GET73 could represent a somewhat ideal and rational approach to obesity treatment.     

Rimonabant,Gastrointestinal Motility and Obesity

Background:

Obesity and overweight affect more than half of the US population and are associated with a number of diseases. Rimonabant, a cannabinoid receptor 1 blocker in the endocannabinoid (EC) system, was indicated in Europe for the treatment of obesity and overweight patients with associated risk factors but withdrawn on Jan, 2009 because of side effects. Many studies have reported the effects of rimonabant on gastrointestinal (GI) motility and food intake.

The aims of this review are:

1. to review the relationship of EC system with GI motility and food intake;
2. to review the studies of rimonabant on GI motility, food intake and obesity;
3. and to report the tolerance and side effects of rimonabant.

Methods:

the literature (Pubmed database) was searched using keywords: rimonabant, obesity and GI motility.

Results:

GI motility is related with appetite, food intake and nutrients absorption. The EC system inhibits GI motility, reduces emesis and increases food intake; Rimonabant accelerates gastric emptying and intestinal transition but decreases energy metabolism and food intake. There is rapid onset of tolerance to the prokinetic effect of rimonabant. The main side effects of rimonabant are depression and GI symptoms.

Conclusions:

Rimonabant has significant effects on energy metabolism and food intake, probably mediated via its effects on GI motility.     

7-OH-DPAT selectively reduces intake of both chow and high fat diets in different food intake regimens

Mesolimbic dopaminergic system activation correlates with ingestive behavior in numerous feeding regimens. DA release is enhanced by food intake following deprivation, amount of food consumed, and the palatability of the food consumed. The dopamine-3 receptor (D3-R) has a limited expression pattern that is restricted largely to the mesolimbic dopaminergic system. The D3-R has been hypothesized to inhibit DA-mediated reward, locomotion and motivation. To test the potential for an inhibitory role of the D3-R on food intake, we administered the D3-R agonist 7-OH-DPAT (5, 10 and 50 microg/kg ip) to rats that had ad libitum access to standard rodent chow (3.41 kcal/gm, 0.51 kcal/gm from fat) or a preferable, high fat (HF) (4.4 kcal/gm, 1.71 kcal/gm from fat). In the second set of experiments we administered 7-OH-DPAT (10, 50 and 100 microg/kg) to rats that had access to chow or HF diet for only 3 h per day (meal fed). In the third set of experiments we administered 7-OH-DPAT (10 and 50 microg/kg) to rats that had access to chow or HF diet after a 21-h food restriction. The 10 and 50 microg/kg doses significantly, but equally reduced intake of chow and HF diet in animals that were ad libitum fed. In animals that were meal-fed the dose response was effectively shifted to the right and the 10 microg/kg dose was ineffective at reducing intake. The 50 and 100 microg/kg doses significantly but equally reduced intake of both diets. In animals that were 21-h restricted and had access to chow both the 10 and 50 microg/kg doses were ineffective at reducing intake. However, in animals that had access to HF diet, 7-OH-DPAT dose-dependently reduced intake. These results support a potential role for the D3-R in ingestive behavior particularly in situations that involve a significant learned component.     

Chronic administration of the antiretroviral nevirapine increases body weight, food, and water intake in albino Wistar rats

Abstract Background: Nevirapine (NVP) is an antiretroviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in the blood. This study was undertaken to investigate the effect of chronic administration of NVP on body weight, food, and water intake using apparently healthy albino Wistar rats. Methods: Twenty adult albino Wistar rats (50-125 g body weight) were used for the study. Rats in the control group (n=10) were fed normal rodent chow, whereas the NVP group (n=10) were fed by gavage NVP (0.4 mg/kg body weight) two times daily (07.00 h and 18.00 h) in addition to normal rodent chow for 12 weeks. All animals were allowed free access to clean drinking water. Results: Results showed that the mean daily food and water intake in the NVP group were significantly higher (p<0.001) when compared with the control group, respectively. The mean change in body weight in the NVP group was significantly higher (p<0.001) than the control group. Conclusions: These results suggest that chronic administration of NVP may increase body weight in rats, probably due to its stimulatory effects on food and water intake.     

Effects of naltrexone on food preference and concurrent behavioral responses in food-deprived rats

Naltrexone (0.05-5.0 mg/kg, SC) was administered to food-deprived rats prior to a 15-min food-preference test. Total food intake and feeding duration was reduced following administration of the opiate antagonist. However, while naltrexone reduced the consumption of the initially-preferred chocolate-coated cookies, the ingestion of the nonpreferred standard laboratory chow pellets was significantly enhanced. These data cannot be explained in terms of a general anorexic effect and nonspecific suppression of feeding responses. Instead, they indicate that naltrexone reduced preference for the highly palatable cookies, so that a feeding response to the chow pellets emerged. Under the conditions of test-familiarity, naltrexone did not reduce grooming, locomotion or rearing duration. An increase in locomotion may have been secondary to the reduction in feeding. The results agree with previous data from animal and human studies in suggesting that endogenous opioid peptide activity is involved in the palatability of preferred foods.     

Effects of the cannabinoid antagonist SR141716 (rimonabant) and d-amphetamine on palatable food and food pellet intake in non-human primates

The purpose of this study was to determine if a cannabinoid CB(1) receptor antagonist would selectively decrease consumption of highly palatable food in non-human primates. The CB(1) receptor antagonist SR141716 (rimonabant; 0.12-1.0 mg/kg, i.m.) and the stimulant anorectic drug d-amphetamine (0.12-1.0 mg/kg, i.m.) were administered to non-food deprived baboons for the purpose of measuring the effect of each drug on consumption of the normal diet, and a large single meal of a high-carbohydrate candy. Four male and four female baboons had access to food 24 h each day, but they had to complete a two phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Three days a week baboons received a jelly sugar-coated candy (Skittles) during the first meal and then pellets were available in subsequent meals. All baboons ate as many individual candies in one meal as they did pellets throughout the entire day. Acute d-amphetamine and, to a lesser extent, SR141716 decreased both candy intake in a single meal and pellet intake in a single meal and over 24 h. d-Amphetamine, but not SR141716, increased latency to the candy meal and the first pellet meal indicating that the two drugs differentially altered feeding topography. Although males ate more food pellets than females, few other sex differences were observed. Thus, although effective in decreasing food intake, there was no evidence of a specific effect of CB(1) receptor antagonism on consumption of a large meal or a palatable food.     

Chronic prevention of μ-opioid receptor (MOR) G-protein coupling in the pontine parabrachial nucleus persistently decreases consumption of standard but not palatable food

Rationale Acute pharmacological studies implicate μ-opioid receptors (MORs) in the parabrachial nucleus (PBN) of the brainstem in modulating eating. The long-term effects of preventing the cellular function of parabrachial MORs on food consumption remain to be elucidated.Objectives To determine whether (1) chronic inhibition of MOR-mediated G-protein coupling in the PBN of rats would persistently reduce eating and (2) food properties dictate the effects of MOR blockade.Materials and methods We microinfused the irreversible MOR antagonist, β-funaltrexamine (β-FNA) into the lateral PBN and measured the intake of standard and calorically dense palatable chow for 1 week. First, rats were given standard chow for 20 h daily and a calorically dense palatable chow for 4 h during the day. We infused the agonist, [d-Ala², N-Me-Phe⁴, Glycinol⁵]-Enkephalin (DAMGO), 1 week after β-FNA to probe the acute effects of exogenous stimulation of MORs on palatable food intake. [³⁵S]GTPγS autoradiography quantified regional loss of MOR cellular function. Next, we measured the actions of β-FNA on food intake in rats given only standard or palatable chow for 1 week.Results One infusion of β-FNA persistently decreased consumption of standard but not palatable chow, regardless of feeding regimen. β-FNA also blocked DAMGO-stimulated palatable chow intake, prevented DAMGO-stimulated G-protein coupling in the central and external lateral subnuclei of the PBN, and decreased coupling in the medial PBN. β-FNA did not affect κ-opioid receptors.Conclusions MORs in the lateral PBN serve a physiological role in stimulating consumption of standard food. Properties of the diet, such as high palatability or caloric density, may override the influence of inhibiting MOR function.