FG 7142 specifically reduces meal size and the rate and regularity of sustained feeding in female rats: evidence that benzodiazepine inverse agonists reduce food palatability.

Benzodiazepine receptor inverse agonists reduce food intake in males, but their actions in females, in whom stress-related eating disorders are more common, as well as their behavioral mode of action remain unclear. The consummatory effects of benzodiazepine receptor ligands have alternately been hypothesized to reflect changes in the hedonic evaluation of food or secondary effects of anxiety-related or cognitive properties. To test the anorectic mode of action of benzodiazepine inverse agonists, the effects of FG 7142 on feeding microstructure were studied in nondeprived female Wistar rats (n=32). Microstructure analysis used a novel meal definition that recognizes prandial drinking. On pharmacologically synchronized diestrus I, rats were pretreated (-30 min dark onset) with the benzodiazepine partial inverse agonist FG 7142 (i.p. 0, 3.75, 7.5, 15 mg/kg) in a between-subjects design. FG 7142 delayed the onset of (16-541%), decreased the amount eaten (36-52%) and drunk (63-87%), and reduced the time spent drinking (59-87%) within the first nocturnal meal. Dose-dependent incremental anorexia continued 6 h into the dark cycle, whereas FG 7142 did not suppress the quantity, duration or rate of drinking past the first meal. Treated rats ate smaller meals (17-42%) of normal duration. This reflected that FG 7142 slowed feeding within meals (9-38%) by decreasing the regularity and maintenance of feeding from pellet-to-pellet. FG 7142 did not influence postprandial satiety; meal frequency and inter-meal intervals were unaffected. FG 7142 anorexia was blocked by the benzodiazepine receptor antagonist flumazenil in a 2:1 molar ratio (n=17 rats). The very early, nonspecific (+10 min), but not subsequent (2.5, 4.5 h) feeding-specific phase, of FG 7142 anorexia was mirrored by anxiogenic-like behavior in FG 7142-treated (7.5 mg/kg) female rats (n=48) in the elevated plus-maze. Thus, benzodiazepine receptor inverse agonists preferentially lessen the maintenance of feeding in female rats, effects opposite to those of palatable food.     

The effect of fenfluramine on the microstructure of feeding and drinking in the rat.

1. The effects of three doses of fenfluramine on feeding and drinking in the rat were examined. 2. Feeding and drinking were subdivided into meals and bouts, and the changes in feeding/drinking were expressed in terms of meal/bout frequency, meal/bout size, meal/bout length, and eating/drinking rate. 3. The changes in these parameters were examined over different time periods after the injection. 4. Significant changes in the distribution of inter-response intervals within meals were found in time period 1 with 5 mg/kg and 10 mg/kg doses of fenfluramine. Videotape and computer analysis showed that the changes in inter-response interval histograms differed significantly from those seen in normal animals approaching satiety. Drinking parameters also changed. 5. Compensatory increases in feeding were observed in time period 4 with the 10 mg/kg dose. 6. The difficulties in designing and interpreting experiments in feeding are discussed, and the action of fenfluramine as an anorectic drug is considered.     

GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding

A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC).     

Naloxone suppresses feeding and drinking but not wheel running in rats

The effects of naloxone hydrochloride on food and water intake and number of wheel revolutions were measured in male rats. The administration of 10 mg/kg naloxone but not 1 mg/kg suppressed the 3-hr food and water intake in nondeprived rats. Naloxone injections (1 mg/kg or 10 mg/kg) were ineffective in altering the number of wheel revolutions in nondeprived or food deprived rats. These results support the interpretation that the suppressive effects of naloxone previously reported with deprived rats are evident in nondeprived rats and are specific to feeding and drinking.     

Norepinephrine uptake by hypothalamic tissue from the rat related to feeding.

Norepinephrine (NE) uptake by rat hypothalamus in vitro was studied in relation to food intake. Significant daily variations in NE uptake were observed in caudal hypothalamus from freely feeding rats. A maximal elevation occurred at the beginning of the night when food intake is also increasing to a maximum. NE uptake by caudal hypothalamus from relatively hungry rats previously adjusted to restricted feeding during the daytime was enhanced in afternoon and evening when compared with uptake by tissue from ad lib feeding animals. Determination of NE uptake by caudal hypothalamus from freely feeding individual rats and registration of individual meals taken by these rats revealed a relation between hypothalamic neuronal activity and the feeding pattern of the rat. A positive correlation was observed between NE uptake in vitro and feeding rate during a 2- to 4-hr interval. It also appeared that NE uptake by caudal hypothalamus is dependent on the time elapsed after the last meal. The data were evaluated in view of physiological studies concerning the onset of feeding and the hypothesis of hypothalamic adrenergic control of food intake.     

Stimulation and inhibition of food intake by the selective dopamine D2 agonist, N-0437: a meal pattern analysis

Feeding and drinking responses were recorded in home-caged rats over 24-hour periods, and the data were analysed in terms of meal patterns. The highly selective dopamine D2 receptor agonist, N-0437, was injected IP at the start of the night phase. At the smallest dose (0.3 mg/kg), N-0437 increased food intake as a result of increases in meal size and duration. The rate of feeding during meals was not increased. This effect lasted 1-2 hours in the night phase. At higher doses (1.0 and 3.0 mg/kg), N-0437 inhibited food intake for 3-6 hours. The inhibition was due to a substantial reduction in meal size, with no change in meal frequency. Rate of feeding during meals tended to be reduced. A biphasic dose-effect relationship was not apparent in the drinking data, and there was not a significant effect of N-0437 on drinking responses. The meal pattern analysis results indicate the stimulation of D2 receptors produces increases and decreases in food intake and meal size. These results are discussed in terms of dose-dependent stimulation of presynaptic (autoreceptor) and postsynaptic D2 receptors, and the relationship to satiety within meals.     

Effect of lead exposure on patterns of food intake in weanling rats

The reduction in growth resulting from lead (Pb) exposure in weanling rats is consistent with a lowering of the biological set-point for food intake. In this study the effects of lead on the patterns of food intake were examined. For 10 days (from ages 26 to 36 days), female rats were provided with drinking water containing 250 ppm lead as the acetate (n = 6) or equivalent acetate as sodium acetate (n = 6). A computerized system was used to monitor daily food intake at 5-min intervals over 10 successive 23-h periods (each period consisting of 12 h dark, 11 h light). Control rats consumed approximately 75% to 85% of their food intake during the dark phase. Exposure to lead resulted in decreased body weight, tail length, and cumulative food intake. Decreased food intake associated with lead during the first 6 days of exposure was due to a decrease in the size of each meal during the dark phase, which reflected a decrease in the duration of each meal. These results suggest that lead, at least initially, was affecting food-satiety signals to produce a premature termination of food intake during a meal. After 6 days, the lead-exposed rats appear to have adjusted their meal size and meal duration to approximately control values. However, this compensation appears to have occurred at the expense of the daily (nocturnal) number of meals, which decreased slightly (although not significantly) in lead-exposed animals. Thus, the total daily intake of food in lead-treated animals remained depressed relative to control animals.     

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.     

The selective dopamine D1 receptor agonist SK&F 38393: its effects on palatability- and deprivation-induced feeding, and operant responding for food

A series of experiments investigated the involvement of the dopamine D1 receptor subtype in relation to feeding responses. The selective D1 agonists, SK&F 38393 (1.0-20 mg/kg) and SK&F 75760 (5 mg/kg), significantly reduced palatable food consumption in nondeprived rats. The anorectic effect of SK&F 38393 (10 mg/kg) was additive with that of the selective D2 receptor agonist, N-0437 (0.3 mg/kg). In nondeprived mice, SK&F 38393 had a stereoselective effect to reduce palatable food intake. At a peripherally-selective dose (3.0 mg/kg), the peripheral dopamine D1 receptor agonist, fenoldopam, had no effect on food intake. At 10 mg/kg, however, it exhibited anorectic properties, although this may have been due to some penetration of the blood-brain barrier. In rats adapted to a food-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) produced significant dose-dependent reductions in consumption of powdered chow and in lever-pressing for food pellets on a FR8 schedule of reinforcement. In rats adapted to a water-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) was substantially less effective in reducing water intake. The results are discussed in terms of a possible selective effect of D1 agonist activity on feeding behaviour.     

Delayed satiety-like actions and altered feeding microstructure by a selective type 2 corticotropin-releasing factor agonist in rats: intra-hypothalamic urocortin 3 administration reduces food intake by prolonging the post-meal interval.

Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n=176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF(2) receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin(2)-B, a selective CRF(2) antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF(2) control of food intake.     

Olanzapine affects locomotor activity and meal size in male rats

Olanzapine is an antipsychotic drug that frequently induces weight gain accompanied by increased fat deposition as a side effect. To investigate how olanzapine affects different aspects of energy balance, we used male rats to determine effects on meal patterns, food preference, locomotor activity and body temperature. In two short-term experiments olanzapine was administered via osmotic minipumps. In the first experiment, we offered rats standard lab chow only. In the second experiment, we offered rats free choice between chow, sucrose and saturated fat. In a third experiment, olanzapine was chronically administered via the drinking water to determine effects on body composition. In each experiment olanzapine decreased locomotor activity and altered meal patterns. Olanzapine caused an increase in average meal size accompanied by reduced meal frequency, without clearly affecting food preference. In the chronic experiment body composition was altered, favoring adipose tissue over lean muscle mass, despite reductions in overall body weight gain. The increase in average meal size implies that the primary effect of olanzapine on feeding is an impairment of the normal satiation process. Furthermore, energy balance is clearly affected by a reduction in locomotor activity. Thus, the effects of olanzapine on adiposity do not depend solely on the presence of hyperphagia.     

The anorectic effect of the selective dopamine D1-receptor agonist A-77636 determined by meal pattern analysis in free-feeding rats

Free-feeding rats meet much of their daily energy requirements by consuming food in meals during the nocturnal phase of the night/day cycle. Meal pattern analysis methodology has been developed to record the patterns of meal taken over a 24-h period, and to provide detailed information on a number of meal-related parameters. Previous work indicates that selective dopamine D1-receptor agonists reduce food intake in short-term feeding tests under the control of homeostatic or hedonic factors. In the present study, our aim was to investigate the effects of the dopamine D1-receptor agonist, A-77636 (0.1-1.0 mg/kg, s.c.), administered just prior to the start of the night period, on the free-feeding and drinking patterns of rats maintained on a standard ad libitum diet. The results indicate that A-77636 exerted a suppressant effect on food intake, due principally to a reduction in meal size and duration. We conclude that there is a dopamine D1-receptor involvement in the normal controls of meal size, and that selective D1-receptor agonists may act to limit meal size.     

Influence of diet palatability on the noradrenergic feeding response in the rat

Adult male rats which displayed a reliable feeding response to intrahypothalamic injections of norepinephrine (NE) on a chow diet were subsequently tested on one of three diets: an unpalatable quinine-adulterated meal, a palatable fat-adulterated meal, or a “neutral” unadulterated meal. The quinine diet completely blocked the NE feeding response, while the fat diet produced a small and unreliable reduction in the feeding response. When food deprived all groups increased their food intake, although the fat diet group tended to overeat, and the quinine diet group tended to undereat relative to the unadulterated diet group. The failure of the palatable fat diet to potentiate the NE feeding response does not support the hypothesis that this response mimics the ventromedial hypothalamic hyperphagia syndrome. The blocking effect of the quinine diet on NE feeding is consistent with other evidence which suggests that NE mediates the eating behavior induced by glucoprivation.     

Influence of taste and food texture on the feeding responses induced by 8-OH-DPAT and gepirone

Previously it has been shown that 5-hydroxytryptamine (5-HT)_1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats. These experiments were conducted to examine the possible influence of taste and textural factors on the feeding responses induced by these two drugs. Separate groups of non-water-deprived rats were given access to one of a variety of different solutions of saccharin (0.02, 0.04, 0.20 and 2.0% w/v) or water for 2 h each day. Rats were then treated with different doses of 8-OH-DPAT (10, 60 or 100 µg/kg) or gepirone (1 or 2.5 mg/kg) in a repeated measures design. Under saline injection an inverted-U shaped concentration-response curve was obtained, with the highest level of intake occurring in rats drinking from the 0.20% saccharin solution. The highest doses of 8-OH-DPAT and gepirone suppressed drinking of saccharin, particularly over the first 30 min of the test period, leading to a flattening of the concentration response curve. At 2 h post-injection 60 µg/kg 8-OH-DPAT enhanced the consumption of the 0.04% saccharin solution only. In a second experiment, 8-OH-DPAT or gepirone was administered to rats eating either standard pelleted chow or the same food presented in powdered form. Both drugs stimulated feeding. However, interactions with food type were found. At 60 and 100 µg/kg 8-OH-DPAT increased eating of both food types equally, but with 500 µg/kg rats are significantly more of the pelleted food. Gepirone at 1 and 2.5 mg/kg also significantly increased pelleted food intake compared to powdered food intake. These results suggest that taste factors alone are unlikely to be a major determinant of 8-OH-DPAT's effects on food intake. On the other hand, food texture may play a significant role in the capacity to elicit feeding after high doses of both 8-OH-DPAT and gepirone.     

Cannabinol and cannabidiol exert opposing effects on rat feeding patterns

Rationale

Increased food consumption following ?⁹-tetrahydrocannabinol-induced cannabinoid type 1 receptor agonism is well documented. However, possible non-?⁹-tetrahydrocannabinol phytocannabinoid-induced feeding effects have yet to be fully investigated. Therefore, we have assessed the effects of the individual phytocannabinoids, cannabigerol, cannabidiol and cannabinol, upon feeding behaviors.

Methods

Adult male rats were treated (p.o.) with cannabigerol, cannabidiol, cannabinol or cannabinol plus the CB₁R antagonist, SR141716A. Prior to treatment, rats were satiated and food intake recorded following drug administration. Data were analyzed for hourly intake and meal microstructure.

Results

Cannabinol induced a CB₁R-mediated increase in appetitive behaviors via significant reductions in the latency to feed and increases in consummatory behaviors via increases in meal 1 size and duration. Cannabinol also significantly increased the intake during hour 1 and total chow consumed during the test. Conversely, cannabidiol significantly reduced total chow consumption over the test period. Cannabigerol administration induced no changes to feeding behavior.

Conclusion

This is the first time cannabinol has been shown to increase feeding. Therefore, cannabinol could, in the future, provide an alternative to the currently used and psychotropic ?⁹-tetrahydrocannabinol-based medicines since cannabinol is currently considered to be non-psychotropic. Furthermore, cannabidiol reduced food intake in line with some existing reports, supporting the need for further mechanistic and behavioral work examining possible anti-obesity effects of cannabidiol.     

Sulpiride injections in the lateral hypothalamus induce feeding and drinking in rats

Amphetamine injections into the lateral hypothalamus inhibit feeding. This effect is blocked by local administration of neuroleptics, suggesting a role for dopamine in feeding inhibition. However, the type of dopamine receptor involved in satiety is not known. Therefore, we tested the effect of intrahypothalamic injections of sulpiride, a specific D₂ receptor blocker, on amphetamine anorexia in food-deprived rats, and on spontaneous feeding and drinking in satiated rats. Sulpiride attenuated by 36% the anorexia produced by intrahypothalamic injections of amphetamine. In satiated rats, sulpiride (8 μg/0.5 μl) elicited feeding (mean food intake after sulpiride: 5.4 g, and after vehicle 1.6 g, p<0.001), and drinking (mean water intake after sulpiride: 12.3 ml, and after vehicle: 0.9 ml, p<0.001). A dose response relationship was found between sulpiride dose and feeding or drinking. Sulpiride-induced drinking was observed in the absence of food, showing that it is not a postprandial phenomenon. These results suggest that hypothalamic D₂ receptors might be involved in feeding and drinking regulation.     

Serotonergic influences on food intake: effect of 5-hydroxytryptophan on parameters of feeding behaviour in deprived and free-feeding rats.

Three experiments were carried out to examine the effect of the serotonin precursor, 5-hydroxytryptophan, upon food intake and the micro-structure of eating in deprived rats, and on the pattern of meal taking in free-feeding animals. The study also investigated the capacity of a peripheral decarboxylase inhibitor (MK-486) to antagonise the effect of 5-HTP in order to identify a central or peripheral mode of action. In deprived rats 5-HTP brought about a dose related inhibition of food intake which was midly antagonised by MK-486. A detailed analysis of the behavioural changes occurring during eating showed that the inhibition of food intake by 5-HTP was reflected in a reduced number of eating bouts and a slower rate of eating. MK-486 did not antagonise the effect of 5-HTP on eating rate. In free-feeding rats whose food comsumption was continuously monitored for 24-hr periods, 5-HTP gave rise to reduction in meal size and a slowing of the intra-meal rate of eating. These findings are in keeping with the effects of other serotonergic manipulations on the patterns of feeding in rats.     

Microstructural analysis of the anorectic action of peripherally administered 5-HT

The anorectic action of systemically administered 5-HT (1, 2 and 4 mg/kg SC) was investigated in food deprived rats using the technique of microstructural analysis; small food pellets were delivered to a food hopper, and the time and occurrence of each pellet removal was recorded. Log-survivor analysis of inter-pellet intervals was used to define feeding bouts, and this was then used to compute measures of bout frequency, bout size, bout duration and eating rate. The 5-HT reduced food intake by selectively decreasing bout size and bout duration. No effects of 5-HT were observed on any of the other parameters measured. These effects of 5-HT are robust over a range of bout criteria, and replicable. Methysergide (3 mg/kg IP) attenuated the anorectic action of 5-HT by a significant increase in bout frequency and an attenuation of the effects of 5-HT on bout size, and bout duration. The results are discussed in terms of a possible role for peripheral 5-HT in the control of satiety, and implications for the mode of action of serotonergic anorectic agents such as fenfluramine.     

Effects of atropine methyl nitrate on sham feeding in the rat

The purpose of this experiment was to clarify the effects of administration of peripheral cholinergic blocking agents on sham feeding. Rats were implanted with chronically indwelling gastric cannulae and allowed to sham feed sucrose solutions varying in their degree of diet palatibility. Prior to the sham feeding tests, rats received an intraperitoneal injection of either atropine methyl nitrate (250 μg/kg) or a control substance, physiological (0.9%) saline. The results indicated that atropine methyl nitrate inhibited sham feeding at all levels of diet palatability tested. This reduction in food intake level following drug administration was apparent from the initiation of the sham feeding bout and did not result from a more rapid cessation of feeding under the drug condition. Further, similar doses of AMN did not reduce sham drinking of water in water-deprived animals. The implications of these findings to a cholinergic involvement in food intake control systems are discussed.     

Feeding pattern studies suggest that d-fenfluramine and sertraline specifically enhance the state of satiety in rats.

The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.