The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food

Rationale The CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.Objective To investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.Methods Instrumental responding and pellet consumption following administration of SR141716A (0–3 mg/kg) were recorded under an FI5 min FR5(5:S) operant schedule that incorporates both a 5 min initial appetitive phase and a 25 min consummatory phase. We compared the drug-induced change in responding to that recorded following a reduction in motivational state induced by pre-feeding. In a second experiment we assessed the effects of SR141716A (0–3 mg/kg) on Pavlovian approach behaviour for a stimulus (lever) associated with food reward (CS+) and a neutral stimulus (lever) not associated with reward (CS–).Results SR141716A reduced pellet consumption and instrumental responding during both the appetitive and consummatory phases of the second order schedule. Pre-feeding had a similar effect on responding during the appetitive phase, suggesting an effect on incentive motivation. SR141716A also blocked an enhancement of responding that occurred during the consummatory phase in pre-fed animals. SR141716A and pre-feeding had no effect on responding in the Pavlovian autoshaping paradigm.Conclusions SR141716A impacts on motivational processes in both the appetitive and consummatory phases of feeding behaviour.     

Activity of SR141716 on post-reinforcement pauses in operant responding for sucrose reward in rats

Cannabinoids increase food intake, via CB1 receptors. The CB1 antagonist, SR141716, has been reported to decrease palatable food consumption in both operant and non-operant procedures. Similarly, CB1 receptor blockade diminished responding for normal food pellets under a fixed-ratio 15 (FR-15) schedule of reinforcement. The present experiment investigated whether the control of a continuous schedule of reinforcement (CRF) for sucrose pellets would be sensitive to the CB1 antagonist in mildly deprived rats. SR141716 dose-dependently reduced responding in a CRF procedure, by increasing post-reinforcement pauses. Together with formerly published conclusions, the data suggest that CB1 blockade reduces the rewarding efficacy of both palatable and non-palatable food.     

Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding

Previous reports have indicated that administration of the central cannabinoid receptor (CB(1)) antagonist SR141716A decreases intake of highly palatable food and drink. Disruption of normal food intake has been reported only at high doses known to disrupt spontaneous behaviors. The present study was designed to determine if rates of responding for normal food were sensitive to the effects of cannabinoid receptor blockade. Adult, male Sprague-Dawley rats were trained to lever press for normal food pellets under a fixed-ratio 15 (FR 15) schedule of reinforcement. SR141716A (0.3-3.0 mg/kg) produced dose-dependent reductions in response rate. WIN 55,212-2 (0. 3 mg/kg), a high efficacy cannabinoid agonist, given as a pre-treatment to SR141716A, significantly attenuated the rate-suppressing effects of SR141716A, suggesting a principal role of CB(1) receptors in mediating these behavioral effects. These data indicate that high palatability is not necessary to observe an anorectic effect of SR141716A.     

Effects of amphetamine on food and fruit drink self-administration

The effects of oral d-amphetamine (0.12-1.0 mg/kg) on the responding of adult baboons were examined during choice sessions. In Experiment 1, responding on 1 lever was reinforced with 1 food pellet, and responding on a 2nd lever was reinforced with 4 food pellets. The response requirement (fixed ratio [FR]) on the latter lever was 4 times the FR value; that is, the unit price (responses/g) was the same. Amphetamine decreased responding on both levers similarly under all conditions. In Experiment 2, responding on 1 lever was reinforced with 1 pellet, and responding on a 2nd lever was reinforced with a sweet fruit drink. Amphetamine decreased responding reinforced by food to the greatest extent when the FR value was large and fruit drink was available. Findings indicate that choice procedures can provide baselines that allow the evaluation of the specificity of a manipulation on intake of a commodity.     

SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset

SR 141716 (1 and 3 mg/kg p.o.), a selective central (CB1) cannabinoid receptor antagonist, selectively reduced feeding of a very highly palatable cane-sugar mixture in marmosets. In contrast, standard primate pellet intake was not modified at the lower dose, but was slightly increased (+29%;p < 0.01) by the higher dose of SR 141716. These results are in agreement with the hypothesis that endogenous cannabinoid systems are involved in the modulation of the appetitive value of food.     

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.     

CB1 cannabinoid receptor-mediated modulation of food intake in mice

1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.     

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

RATIONALE: Procedures for studying the effects of medications on satiation will assist the development of obesity medications. OBJECTIVES: Develop a procedure for measuring satiation during consumption of bland and highly palatable food and determine the effect of acute intramuscular administration of dexfenfluramine (DFEN), which increases serotonin levels, and memantine (MEM), which blocks N-methyl-D: -aspartate receptors. MATERIALS AND METHODS: A modified progressive ratio (PR) procedure was used to track changes in reinforcing strength when a food was consumed. The response requirement increased after each reinforcement, and reinforcing strength was estimated using the breakpoint (BP), which was the last completed response cost. There was one preferred food (sweet candy) and one chow pellet PR session per week. During each session, four male and four female adult baboons experienced three 1-h PR trials, separated by 30 min. Chow pellets were available at all other times. We examined the BP for one to 20 candies or chow pellets. Drug effects were examined when baboons had access to one and ten candies or chow pellets. RESULTS: BPs for candy were greater than for pellets. Varying the pellet/candy pieces per delivery produced an inverted U-shaped function on the first trial, i.e., maximal BP was observed for three items, and the BP for multiple items, but not a single item, decreased across trials, i.e., BP decreased with food intake and satiation. DFEN and MEM decreased responding with the greatest effects at ten deliveries, suggesting that DFEN and MEM enhanced satiation. CONCLUSION: Drugs that enhance satiation for several types of food may be particularly effective for decreasing food intake.     

The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats

Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.     

Evidence for an interaction between CB1 cannabinoid and oxytocin receptors in food and water intake

Oxytocin and CB(1) cannabinoid receptors independently modulate food intake. Although an interaction between oxytocin and cannabinoid systems has been demonstrated with respect to the cannabinoid withdrawal syndrome, the interaction between these systems in modulating food intake has not yet been examined. The present study had three primary purposes: (1) to determine whether oxytocin and a CB(1) receptor antagonist block food and fluid intake in a supra-additive manner, (2) to determine the relative position of the CB(1) receptors in the chain of control of food intake in relation to the oxytocin system, and (3) to determine whether the increase in fluid intake induced by an oxytocin antagonist is mediated via cannabinoid receptors. Rats were habituated to the test environment and injection procedure, and then received intracerebroventricular (ICV) injections of various combinations of the oxytocin receptor antagonist tocinoic acid, the cannabionid receptor agonist delta(9)-tetrahydrocannabinol (THC), oxytocin, or the cannabinoid receptor antagonist SR 141716. Food and water intake and locomotor activity were then measured for 120 min. When administrated alone, SR 141716 and oxytocin dose-dependently attenuated baseline food intake, while oxytocin but not SR 141716 reduced water intake. Sub-anorectic doses of SR 141716 and oxytocin attenuated baseline feeding beyond what would be expected by the sum of the individual drug effects without affecting baseline water intake. THC stimulated feeding but not water intake. THC-induced feeding was not blocked by oxytocin, however, the oxytocin did attenuate water intake during such feeding. SR 141716 dose-dependently reduced tocinoic-acid-stimulated food intake and partially attenuated water intake. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings reveal an interaction between cannabinoid and oxytocin systems in food intake. Results further reveal that the oxytocin system effects on water intake are partially mediated via CB(1) receptors, CB(1) receptors are located downstream from oxytocin receptors, and CB(1) receptor signalling is necessary to prevent oxytocin from altering food intake.     

Age-dependent effects of the cannabinoid CB1 antagonist SR141716A on food intake, body weight change, and pruritus in rats

Rationale  The cannabinoid CB1 selective antagonist SR141716A (Rimonabant) has been shown to decrease body weight in laboratory animals and humans. Furthermore, SR141716A can elicit scratching behavior in rodents, a behavior that has been hypothesized to contribute to SR141716A-induced decrease in food intake. Although childhood obesity is a rising health issue, it is unknown whether SR141716A is equipotent at modulating food intake and other CB1-mediated behaviors in younger subjects. Objective  To determine whether CB1 receptor blockade is equipotent at modulating food and water intake, body weight, and scratching behavior, the effect of a range of SR141716A doses on these behaviors in food-restricted postnatal day (P) 18, 28, and 60 male rats was investigated. Brain concentrations of SR141716A were determined in each age group. Results  SR141716A dose- and age-dependently suppressed food and water intake and body weight gain and elicited head scratching, with the most potent effects observed in P18 and P28 rats. Brain concentrations of SR141716A were significantly elevated in P18 rats relative to P28 and P60 rats. SR141716A-elicited head scratching was attenuated by the 5-HT_2A/2C antagonist ketanserin. Conclusions  SR141716A is more potent at modulating food intake and head scratching in very young animals; these differences can be attributed to an increase in brain penetration of SR141716A for P18 but not for P28 and P60 rats. In addition, SR141716-elicited head scratching is modulated by 5HT receptor antagonism and is not a contributing factor to SR141716A's anorectic effects.     

Evaluation of limited and unlimited food intake during withdrawal in triazolam-dependent baboons

Chronic administration of benzodiazepine (BZ) agonists in baboons typically increases food intake, in a dose-dependent manner, during drug administration and suppresses food intake after termination of drug dosing. To determine if suppressed food intake after termination of chronic BZ administration (i.e. withdrawal) was related to increased food consumption during drug administration, the effects of chronic triazolam (1.0 mg/kg/day, intragastrically, for 30-34 days) and subsequent triazolam withdrawal on food intake was studied under two conditions in each of four baboons: (1) when the number of pellets was unlimited; and (2) when the number of pellets was limited so that pellet intake could not increase above the mean number of pellets per day obtained during a preceding vehicle condition. Pellets were available during daily 20-h sessions under a fixed-ratio 10 schedule of reinforcement. All baboons completed both pellet conditions, and the order of exposure was counterbalanced across subjects. During the unlimited pellet condition, pellets per day were increased during triazolam administration and then were suppressed in a time-limited manner when triazolam was discontinued in all four baboons. When pellet intake was limited during triazolam administration, pellet intake after triazolam discontinuation was suppressed in three of four baboons, and the magnitude and duration of suppression was generally less than during the unlimited pellet condition. Other behavioral signs of withdrawal (e.g., tremor/jerk, vomit/retch) were observed in all four baboons under both pellet conditions. These data suggest that the hyperphagic effects of triazolam appear to contribute to the subsequent suppression of food intake during triazolam withdrawal. However, these hyperphagic effects do not account for the entire phenomenon of suppressed food intake during BZ withdrawal.     

The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF1 receptors.

The major problem in treating excessive eating is high rates of relapse to maladaptive eating habits during diet treatments; this relapse is often induced by stress or anxiety states. Preclinical studies have not explored this clinical problem. Here, we adapted a reinstatement model (commonly used to study relapse to abused drugs) to examine the role of stress and anxiety in relapse to palatable food seeking during dieting. Rats were placed on restricted diet (75-80% of daily standard food) and for 12 intermittent training days (9 h/day, every other day) lever-pressed for palatable food pellets (25% fat, 48% carbohydrate) under a fixed ratio 1 (20-s timeout) reinforcement schedule. Subsequently, the rats were given 10 daily extinction sessions during which lever presses were not reinforced, and were then injected with yohimbine (an alpha-2 adrenoceptor antagonist that induces stress and anxiety in humans and non-humans) or given a single food pellet to assess reinstatement of food seeking. The rats rapidly learned to lever press for the palatable pellets and across the training days the ratio of timeout nonreinforced lever presses to reinforced lever presses progressively increased more than three-fold, suggesting the development of compulsive eating behavior. After extinction, yohimbine injections and pellet priming reliably reinstated food seeking. The corticotropin-releasing factor1 (CRF1) receptor antagonist antalarmin attenuated the reinstatement induced by yohimbine, but not pellet priming. Antalarmin also reversed yohimbine's anxiogenic effects in the social interaction test. These data suggest that CRF is involved in stress-induced relapse to palatable food seeking, and that CRF1 antagonists should be considered for the treatment of maladaptive eating habits.     

Suppression of food intake and food-reinforced behavior produced by the novel CB1 receptor antagonist/inverse agonist AM 1387

Cannabinoid CB1 receptor antagonist/inverse agonists are becoming increasingly recognized for their potential therapeutic utility as appetite suppressants. In the current paper we characterize the biochemical and behavioral effects of AM 1387, which is a novel CB1 antagonist. AM 1387 exhibited binding affinity and selectivity for the CB1 over the CB2 receptor. Moreover, AM 1387 decreased GTPgammaS (EC50: 22.82 nM) and increased forskolin-stimulated cAMP (EC50: 274.6 nM), as did the CB1 inverse agonist AM 251 (GTPgammaS EC50: 25.82 nM; cAMP EC50: 363.8 nM), indicating that AM1387 also has inverse agonist properties in vitro. In the behavioral characterization in rats, AM 1387 suppressed lever pressing for food on two operant schedules (fixed-ratio 1 and 5). Timecourse of the effect on fixed-ratio 5 responding was then determined, and the half-life (t1/2=4.87 h) was found to be threefold shorter than what has been shown for SR 141716A, and fourfold shorter than AM 251. Finally, AM 1387 was found to suppress food intake using three diets of differing macronutrient composition and palatability. It was concluded that AM 1387 may be a useful tool for examining the effects of CB1 receptor antagonism or inverse agonism on food intake.     

Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats

RATIONALE: Recent studies have shown that the cannabinoid CB1 receptor antagonist, SR 141716, is capable of reducing voluntary ethanol intake in rodents, suggesting the involvement of the CB1 receptor in the neural circuitry mediating the positive reinforcing properties of ethanol. OBJECTIVES: The present study extended to the agonists the investigation on the pharmacological manipulation of ethanol intake by cannabinoid agents. METHODS: Selectively bred, Sardinian alcohol-preferring (sP) rats were offered ethanol and water under the two-bottle free choice procedure with unlimited access for 24 h/day. RESULTS: The acute administration of WIN 55,212-2 (0.5-2 mg/kg; IP) and CP 55,940 (3-30 microg/kg; IP) induced a significant, dose-dependent increase in ethanol intake. Conversely, water consumption and intake of regular food and a highly palatable sucrose solution were not affected by treatment with WIN 55,212-2 and CP 55,940. The stimulatory effect of WIN 55,212-2 and CP 55,940 on ethanol intake was completely prevented by administration of SR 141716 (0.3 mg/kg; IP) and the opioid receptor antagonist, naloxone (0.1 mg/kg; IP). CONCLUSIONS: Administration of WIN 55,212-2 and CP 55,940 promoted voluntary ethanol intake in sP rats. This effect was mediated by stimulation of the cannabinoid CB1 receptor and required the activation of the endogenous opioid system. The results of the present study add further support to the hypothesis that the cannabinoid CB1 receptor is part of the neural substrate regulating ethanol intake. These results are also discussed in terms of WIN 55,212-2 and CP 55,940 administration possibly fixing to a higher level the hedonic set-point mechanism regulating ethanol drinking behavior in sP rats.     

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.     

Endocannabinoid system and alcohol addiction: pharmacological studies

The present paper describes the results of recent pharmacological studies implicating the cannabinoid CB1 receptor in the neural circuitry regulating alcohol consumption and motivation to consume alcohol. Cannabinoid CB1 receptor agonists have been found to specifically stimulate alcohol intake and alcohol's motivational properties in rats. Conversely, the cannabinoid CB1 receptor antagonist, SR 141716, has been reported to specifically suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking and alcohol's motivational properties in rats. More recent data indicate that opioid receptor antagonists a) blocked the stimulatory effect of cannabinoids on alcohol intake, and b) synergistically potentiated the suppressing effect of SR 141716 on alcohol intake and alcohol's motivational properties. Consistently, SR 141716 blocked the stimulatory effect of morphine on alcohol intake. These results suggest a) the existence of a functional link between the cannabinoid and opioid receptor systems in the control of alcohol intake and motivation to consume alcohol, and b) that novel and potentially effective therapeutic strategies for alcoholism may come from the combination of cannabinoid and opioid receptor antagonists.     

Early tolerance to the hypophagic effect of the cannabinoid receptor antagonist SR141716 does not impede blockade of an orexigenic stimulus

The cannabinoid CB1 receptor antagonist SR141716 (Rimonabant) is known to reduce food intake by central and peripheral mechanisms. Recently, SR141716 has been reported to block the orexigenic effect of ghrelin, a potent orexigenic peptide produced by the stomach. This study investigated whether in rats, made tolerant to the hypophagic effect of SR141716, the drug was still capable to block the orexigenic activity of another non-natural (hypothalamic) peptide, i.e., the growth hormone releasing peptide (GHRP) hexarelin, a ghrelin mimetic. In the acute experiments, each dose of SR141716 (1, 5 and 10 mg/kg i.p.) reduced food intake with respect to vehicle-treated rats, whereas hexarelin (160 microg/kg s.c.) markedly stimulated feeding. All doses of SR141716 were capable to reduce the orexigenic effect of the GHRP. A 15-day administration of SR141716 (10 mg/kg i.p.) reduced both food intake and body weight. Tolerance to the hypophagic effect of SR141716 developed within 5 days, but in contrast, body weight remained markedly below that of vehicle-treated group throughout the entire treatment period. Interestingly, despite development of tolerance to its hypophagic effect, SR141716 was capable to suppress the orexigenic effect of repeated hexarelin challenge tests performed throughout the chronic experiments. In conclusion, the results of the present study confirm and broaden the existence of a functional relationship between ghrelin and endocannabinoids in the control of food intake, and bespeak the ability of a CB1 receptor antagonist to suppress orexia caused by stimuli alien to direct stimulation of the cannabinoid system.     

Food intake in baboons: effects of d-amphetamine and fenfluramine

Food intake of four adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22 hours. Food was available under a two-component operant schedule. Following completion of the first "procurement component" response requirement, access to food, i.e., a meal, became available under the second "consumption component" during which each response produced a one-g food pellet. After a 10-minute interval in which no response occurred, the consumption component was terminated. The effects of oral d-amphetamine (AMPH: 0.03-1.0 mg/kg) and fenfluramine (FEN: 0.25-2.0 mg/kg) were determined by having the baboons drink a dose on Tuesdays and Fridays 45 to 60 min before the daily session. Dose-dependent decreases in food intake were observed with AMPH being four times as potent as FEN. Although both drugs were equally efficacious in decreasing food intake, they had dissimilar effects on the topography of feeding behavior. AMPH decreased food intake by increasing the latency to the first meal, decreasing the size of the first meal, and decreasing the number of meals within a session. FEN, in contrast, had no significant effect on latency to the first meal or size of the first meal, but decreased the number of meals within a session. In addition, the drugs had different effects on the patterning of responding within the first meal. Finally, at the doses tested, there was no evidence of nonspecific motor deficits disrupting food intake. Although there are some differences between these results and the previously reported effects of these drugs, it is clear that AMPH and FEN influence feeding behavior in different ways.     

The role of CB1 receptors in sweet versus fat reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940)

It is well established that Cannabis sativa can increase appetite, particularly for sweet and palatable foods. In laboratory animals, cannabinoid CB1 receptor antagonism decreases motivation for palatable foods, and most recently, the CB1 receptor antagonist SR141716A, or rimonabant (Acomplia), was reported to produce weight loss in obese human subjects. Indeed, the endocannabinoid system plays a select role in the rewarding properties of palatable foods, and this is well characterized in laboratory animals with sweet sucrose solutions. In the present study, CB1 knockout mice (CB1 KO) and wild-type littermate mice (WT) were trained to respond for a complex sweet as well as a pure fat reinforcer under a progressive ratio (PR) schedule, to determine whether motivation to consume different palatable foods is tonically regulated by CB1 receptors. To assess sweet reinforcement, several concentrations of the liquid nutritional drink, Ensure, were presented under the PR schedule. For fat reinforcement, several concentrations of corn oil (emulsified in 3% xanthan gum) were made available. Additionally, to compare the result of genetic invalidation of the CB1 receptor to antagonism of the CB1 receptor system, the effect of SR141716A (3.0 mg/kg) on responding for Ensure and corn oil were also assessed using the PR schedule. We also assessed the effect of the CB1 agonist CP-55940 (30 microg/kg) on responding for Ensure and corn oil. CB1 KOs took significantly longer to acquire operant responding maintained by Ensure, and responding for Ensure under the PR schedule was significantly reduced in CB1 KOs as well as in WTs pretreated with SR141716A, as compared to WT controls. Additionally, pretreatment with the CB1 agonist CP-55940 increased responding for Ensure. In contrast, responding for corn oil during acquisition and under the PR schedule was not significantly different in CB1 KOs versus wild-type mice. However, SR141716A did reduce responding for corn oil in WTs, and CP-55940 significantly increased responding for corn oil. Taken together, these results suggest that CB1 receptors are preferentially involved in the reinforcing effects of a complex sweet, as compared to a pure fat, reinforcer. These data also suggest, however, that antagonism of CB1 receptors with SR141716A is sufficient to attenuate the reinforcing effect of Ensure and corn oil, while activation of the central CB1 system is sufficient to enhance Ensure and corn oil reinforcement.