Tolerance and withdrawal after chronic lorazepam treatment in rats

The purpose of the study was to develop an animal model for benzodiazepine tolerance and dependence on the basis of oral administration, using lorazepam as the test drug. We have used the continuous measurement of locomotor activity in home cages to obtain a narrow estimation of the time course of withdrawal related hyperactivity as an observer-independent symptom.

Acute administration of lorazepam (9.5–37.5 mg/kg body weight/day) resulted in the first week in a dose-dependent muscle relaxation on the accelerod and sedation in the open field. The most striking manifestation of sedation, however, was the decrease of nocturnal locomotor activity in home cages. After 5 weeks of administration tolerance to the sedative effect had developed. In a second study , using a lower dose range (2.5–9.5 mg/kg body weight/day), a decrease of nocturnal locomotor activity was also observed as was the development of tolerance. The latter can be partly explained by dispositional tolerance, i.e., decreased serum concentrations after administration of lorazepam for more than 2- weeks. Withdrawal of lorazepam in the experiment using high doses led to three symptoms, i.e., a decrease in food intake, loss of body weight and an increase in daytime locomotor activity. The decrease in food intake and the loss of body weight were maximal on the first day of withdrawal. The increase in the daytime locomotor activity was present in the high dose experiment only, with a maximum on days 2–3 and a duration of at least 1 week. The increase however, was not dependent on the dose previously administered.

The symptoms ‘loss of body weight’ and ‘decrease in food intake’ appeared to be more sensitive in benzodiazepine withdrawal: they were dose dependently present over the whole dosage range (2.5–37.5 mg/kg body weight/day).

It is concluded that the model represents a sensitive model to measure lorazepam tolerance and dependence in animals. Comparative studies with other benzodiazepines are in progress.     

Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats.

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.     

A comparison of the effects of a subtype selective and non-selective benzodiazepine receptor agonist in two CO(2) models of experimental human anxiety

Studies in human volunteers that can demonstrate proof of concept are attractive in that possible mechanisms and potential new drug treatments can be examined. We have been developing models of anxiety disorders using the inhalation of 7.5% CO(2) for 20 min to model generalised anxiety disorder, as well as using the previously reported 35% CO(2) as a model for panic anxiety. In a double-blind, placebo-controlled, three-way crossover study in 12 healthy volunteer subjects, we compared a full agonist at the benzodiazepine receptor that binds to four alpha-subtypes of the receptor (alpha-1,-2,-3,-5) (alprazolam 1 mg), with zolpidem (5 mg), an agonist selective for the alpha-1 subtype of the gamma amino butyric acid-receptor subtype A (GABA-A) receptor, which is a widely used hypnotic drug. Compared with placebo, both drugs significantly attenuated peak CO(2)-induced changes in subjective feelings after the inhalation of 7.5% CO(2) for 20 min. However, there were fewer significant differences after a single vital capacity inhalation of 35% CO(2), where zolpidem was less efficacious than alprazolam at reducing CO(2)-induced symptoms. In conclusion, our results show that zolpidem shows some anxiolytic efficacy in the 7.5% CO(2) model, similar to alprazolam, and this is the first report of such an effect of zolpidem in a model of anxiety. These and other studies of benzodiazepines in clinical and volunteer studies suggest a definite role of the GABA-A receptor in CO(2)-induced anxiety, and it would be of interest to examine other GABA-A receptor subtype selective drugs, which are now in early phase clinical studies and are showing selective efficacy in pharmacodynamic studies.     

Differential effect of a polyherbal formulation-OB-200G in male and female mice subjected to forced swim stress

The antistress effect of a polyherbal formulation-OB-200G (500 mg/kg. p.o.) was studied in both male and female mice subjected to forced swim stress. Fluoxetine (10 mg/kg, i.p.) was chosen as standard drug for comparison. Exposure of mice to chronic stress regime resulted in decreased body weight in both male and female mice, increased sweetened food intake, anxiety, depression and locomotor activity in stressed female mice as compared to unstressed control (normal) mice. Treatment with OB-200G resulted in a further decrease in body weight, increased food intake and locomotor activity in both stressed male and female mice. It also reduced immobility time, decreased latency to enter and increased number of entries and time spent in mirror chamber in stressed female mice. Administration of fluoxetine (10 mg/kg, i.p.) decreased body weight and food intake in both stressed male and female mice. Fluoxetine treatment also increased time spent in mirror chamber and decreased immobility time in stressed female mice. Thus, like fluoxetine, OB-200G decreased body weight and produced antianxiety and antidepressant effects in stressed female mice and may prove beneficial in obese patients reported to be more susceptible to stress-related psychological disorders.     

The effects of long-term nicotine treatment on locomotion,exploration and memory in young and old rats

To assess the effects of long-term treatment with nicotine on several behavioral measures (locomotor activity, exploratory efficiency, habituation, short-term and long-term memory) of young (5 months) and old (22 months) rats in a hexagonal tunnel maze, nicotine was added to the drinking water (0, 20 or 50 mg/l) for up to 131 experimental days. With the exception of effects on exploratory efficiency, young and old rats did not differ in their response to the drug. Nicotine decreased body weight throughout the experiment. Nicotine treatment reduced water intake during the first 30 min of the daily 4.5 h access to drinking water. Nicotine increased locomotor activity throughout the experiment. When nicotine treatment was discontinued during a 7-day withdrawal period, locomotor activity immediately dropped to control values. Intertrial habituation was not affected by nicotine. Long-term nicotine treatment had an attenuating effect on exploratory efficiency in young rats; however, the drug did not influence performance in tasks measuring spatial memory. Finally, age increased weight, decreased locomotor activity and impaired exploratory efficiency and short-term memory. Age, however, did not affect the performance of the long-term memory task.     

Fenfluramine-induced suppression of food intake and locomotor activity is differentially altered by the selective type A monoamine oxidase inhibitor clorgyline

Administration of fenfluramine to rats produced decreases in 1-h food intake and locomotor activity. Short-term (2–6 days) or long-term (21–25 days) treatment with the monoamine oxidase (MAO) type A inhibiting antidepressant clorgyline potentiated fenfluramine-induced suppression of food intake but did not affect fenfluramine-induced suppression of locomotor activity. Although daily (4 h) food intake was not significantly less in clorgyline-treated animals relative to saline-treated controls, body weight gain was significantly less in clorgyline-treated animals relative to controls. These findings demonstrate a differential effect of clorgyline treatment on fenfluramine-induced suppression of food intake and locomotor activity. Offprint requests to: C. S. Aulakh     

Changes in locomotor-activity patterns as a measure of spontaneous morphine withdrawal: no effect of clonidine

The anti-withdrawal action of clonidine was studied in a model of spontaneous morphine withdrawal in rats. After withdrawal the behaviour of the animals was registered continuously for several days. In the initial phase of induction of dependence the locomotor activity was enhanced during daytime. Partial tolerance to this increase developed in the course of 3 weeks. In morphine withdrawn animals the activity decreased strongly at night, and this effect was maximal on the second night after removal of morphine. After four nights the nightly activity was restored. Treatment with clonidine (100 micrograms/kg s.c. twice daily) changed neither the observed decrease in nightly locomotor activity nor other withdrawal symptoms such as a decrease in food intake and loss of body weight. In non-dependent animals clonidine induced a biphasic effect in locomotor activity, i.e. a decrease in the first few hours of the night and an increase in the second part of the night. The latter can be interpreted as a rebound phenomenon occurring after only three injections. It was concluded that clonidine was not effective as an anti-withdrawal compound in a model for spontaneous morphine abstinence. The low incidence of symptoms relating to a hyperactive sympathetic system during spontaneous withdrawal may be an explanation for the absence of an effect of clonidine.     

Chronic administration of nalmefene leads to increased food intake and body weight gain in mice

Nalmefene is an orally available opioid receptor antagonist that has been shown to suppress appetite in humans, but its effects on chronic food intake and body weight remain unclear. Here, we report that chronic (21-day) oral administration of nalmefene at 2 or 10 mg/kg/day in diet-induced obese (DIO) mice led to significant increases (9-11%) in cumulative food intake. Mice in the nalmefene-treated groups also gained body weight at a rate faster than the control. Body composition analysis showed that the extra body weight gains in the treated animals were mostly due to increased fat accumulation. Since acute nalmefene treatment showed a trend toward a decrease rather than an increase in food intake, it is possible that the orexigenic effect of chronic oral administration of nalmefene was caused by pharmacologically active metabolites rather than the drug itself. Our results argue against the potential use of nalmefene for treating human obesity.     

Behavioural consequences of cocaine withdrawal in rats

Abstract— This study was designed to examine the impact of cocaine withdrawal on several behavioural parameters in rats. After 1 and 3 day withdrawal from continuous cocaine administration (50 mg kg^?1 for 28 days, subcutaneous infusion via osmotic minipumps), rats showed significant changes in spontaneous locomotor activity, conditioned avoidance response and increased levels of anxiety. However, cocaine withdrawal did not alter the motor co-ordination, body weight, food and water consumption of these animals. The neurochemical effects of cocaine on central dopaminergic neuronal systems may account for locomotor deficit observed in these cocaine-withdrawal animals.     

Long-term imipramine treatment differentially affects fenfluramine-induced suppression of food intake and locomotor activity

Administration of fenfluramine to rats produced decreases in one-hour food intake and locomotor activity. Short-term (2-6 days) or long-term (21-25 days) treatment with the tricyclic antidepressant, imipramine, did not affect daily food intake, body weight gain or baseline locomotor activity when compared to saline treatment. However, long-term but not short-term imipramine treatment attenuated fenfluramine-induced decreases in one-hour food intake. On the other hand, neither short-term nor long-term imipramine treatment affected fenfluramine-induced decreases in locomotor activity. These findings demonstrate a differential effect of long-term imipramine treatment on fenfluramine-induced suppression of food intake and locomotor activity.     

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.     

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.     

Opioid-dependent anticipatory negative contrast and binge-like eating in rats with limited access to highly preferred food.

Binge eating and an increased role for palatability in determining food intake are abnormal adaptations in feeding behavior linked to eating disorders and body weight dysregulation. The present study tested the hypothesis that rats with limited access to highly preferred food would develop analogous opioid-dependent learned adaptations in feeding behavior, with associated changes in metabolism and anxiety-like behavior. For this purpose, adolescent female Wistar rats were daily food deprived (2 h) and then offered 10-min access to a feeder containing chow followed sequentially by 10-min access to a different feeder containing either chow (chow/chow; n=7) or a highly preferred, but macronutrient-comparable, sucrose-rich diet (chow/preferred; n=8). Chow/preferred-fed rats developed binge-like hyperphagia of preferred diet from the second feeder and anticipatory chow hypophagia from the first feeder with a time course suggesting associative learning. The feeding adaptations were dissociable in onset, across individuals, and in their dose-response to the opioid-receptor antagonist nalmefene, suggesting that they represent distinct palatability-motivated processes. Chow/preferred-fed rats showed increased anxiety-like behavior in relation to their propensity to binge as well as increased feed efficiency, body weight, and visceral adiposity. Chow/preferred-fed rats also had increased circulating leptin levels and decreased growth hormone and 'active' ghrelin levels. Thus, the short-term control of food intake in rats with restricted access to highly preferred foods comes to rely more on hedonic, rather than nutritional, properties of food, through associative learning mechanisms. Such rats show changes in ingestive, metabolic, endocrine, and anxiety-related measures, which resemble features of binge eating disorders or obesity.     

Effects of chronic imipramine and clomipramine oral administration on maternal behavior and litter development

The effects of the oral administration of imipramine (IM) or clomipramine (CIM) in adult female rats before pregnancy or during nursing were evaluated. IM caused a significant decrease of body weight in both groups of animals and affected the body weight of litters when administered during nursing. CIM reduced the increase of weight in the mothers throughout the experiment. Both IM and CIM decreased water and food intake and locomotor activity of the adult rats. Rats treated during nursing with IM showed decreased maternal behavior at various times of treatment. The milk intake of pups from drug-treated mothers also decreased. Pup eyeopening was delayed by CIM both before pregnancy and during nursing and by IM treatment during nursing. Vaginal opening was retarded in female litters from mothers treated during nursing. Openfield behavior showed modifications at 60 days of age in male pups from mothers exposed to IM during nursing.Results indicate that the two tricyclic drugs were able to produce general and behavioral modifications in both mothers and their litters. These modifications seem to depend on whether the drug is given before pregnancy or during nursing. Control experiments in dams fed with a restricted diet suggest that the observed alterations in maternal behavior and litter development is not due to the undernourishment caused by drug administration.     

Comparative effects of continuous infusion of mCPP, Ro 60-0175 and d-fenfluramine on food intake, water intake, body weight and locomotor activity in rats

1. The aim of the study was to compare the effects of 14 day subcutaneous infusion of the 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP, 12 mg kg(-1) day(-1)) and Ro 60-0175 (36 mg kg(-1) day(-1)) and the 5-HT releasing agent and re-uptake inhibitor, d-fenfluramine (6 mg kg(-1) day(-1)), on food and water intake, body weight gain and locomotion in lean male Lister hooded rats. 2. Chronic infusion of all three drugs significantly reduced food intake and attenuated body weight gain. In contrast, drug infusion did not lead to significant reductions in locomotor activity in animals assessed 2 and 13 days after pump implantation. 3. In a subsequent 14 day study that was designed to identify possible tolerance during days 7 - 14, animals were given a subcutaneous infusion of mCPP (12 mg kg(-1) day(-1)) or d-fenfluramine (6 mg kg(-1) day(-1)) for either 7 or 14 days. During the first 7 days both drugs significantly reduced body weight gain compared to saline-infused controls; however, from day 7 onwards animals withdrawn from drug treatment exhibited an increase in body weight such that by day 14 they were significantly heavier than their 14-day drug-treated counterparts. 4. Both mCPP and d-fenfluramine reduced daily food intake throughout the infusion periods. For 14-day treated animals this hypophagia was marked during the initial week of the study but only minor during the second week. In light of the sustained drug effect on body weight, the data suggest that weight loss by 5-HT(2C) receptor stimulation may be only partly dependent on changes in food consumption and that 5-HT(2C) receptor agonists may have effects on thermogenesis. 5. These data suggest tolerance does not develop to the effects of d-fenfluramine, mCPP and Ro 60-0175 on rat body weight gain.     

Melanin-concentrating hormone-1 receptor antagonism decreases feeding by reducing meal size

Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (-)enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4 carboxamide). Food intake was continuously monitored for 24 h using a BioDAQ food intake monitoring system. A total of 10 mg/kg T-226296 significantly decreased body weight and 24-h food intake, and had no effect on locomotor activity. The decrease in food intake was due to a reduction in meal size, not meal frequency. We conclude that MCH-1 receptor antagonism with T-226296 decreases food intake in DIO rats by selectively reducing meal size, and that the reduced food intake is not due to a generalized behavioral malaise.     

Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics

The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.     

Olanzapine causes hypothermia, inactivity, a deranged feeding pattern and weight gain in female Wistar rats

Olanzapine is an a-typical antipsychotic drug antagonizing predominantly 5-HT and dopamine, but also histamine, muscarin, and α-adrenergic receptors. In humans, Olanzapine induces weight gain and increases the risk of type 2 diabetes. The underlying mechanisms of Olanzapine-induced weight gain are unclear. To study this we administered Olanzapine (5 mg/kg) in female Wistar rats on a medium fat diet for 14 days via a permanent gastric catheter twice a day, just prior to the onset and at the middle of dark phase. Food and water intake, locomotor activity and body temperature were measured. Olanzapine acutely induced hypothermia, markedly decreased locomotor activity and increased body weight during 14 days of treatment. Olanzapine treatment did not result in an alteration of 24 h food intake, but diurnal patterns of feeding behavior and body temperature were dramatically changed. We conclude that in female Wistar rats Olanzapine has an acute hypothermic effect, that the effect of Olanzapine on feeding behavior is secondary to the effect on activity, and that Olanzapine-induced weight gain is primarily the result of reduction in locomotor activity.     

Reduction of Food Intake by Fenofibrate is Associated with Cholecystokinin Release in Long-Evans Tokushima Rats

Fenofibrate is a selective peroxisome proliferator-activated receptor α (PPARα) activator and is prescribed to treat hyperlipidemia. The mechanism through which PPARα agonists reduce food intake, body weight, and adiposity remains unclear. One explanation for the reduction of food intake is that fenofibrate promotes fatty acid oxidation and increases the production of ketone bodies upon a standard experimental dose of the drug (100~300 mg/kg/day). We observed that low-dose treatment of fenofibrate (30 mg/kg/day), which does not cause significant changes in ketone body synthesis, reduced food intake in Long-Evans Tokushima (LETO) rats. LETO rats are the physiologically normal controls for Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are obese and cholecystokinin (CCK)-A receptor deficient. We hypothesized that the reduced food intake by fenofibrate-treated LETO rats may be associated with CCK production. To investigate the anorexic effects of fenofibrate in vivo and to determine whether CCK production may be involved, we examined the amount of food intake and CCK production. Fenofibrate-treated OLETF rats did not significantly change their food intake while LETO rats decreased their food intake. Treatment of fenofibrate increased CCK synthesis in the duodenal epithelial cells of both LETO and OLETF rats. The absence of a change in the food intake of OLETF rats, despite the increase in CCK production, may be explained by the absence of CCK-A receptors. Contrary to the OLETF rats, LETO rats, which have normal CCK receptors, presented a decrease in food intake and an increase in CCK production. These results suggest that reduced food intake by fenofibrate treatment may be associated with CCK production.     

Oral administration of the 5-HT<Subscript>2C</Subscript> receptor agonist,<Emphasis Type="Italic"> m</Emphasis>CPP,reduces body weight gain in rats over 28 days as a result of maintained hypophagia

Rationale. The 5-HT_2C receptor subtype has been implicated extensively in the regulation of ingestive behaviour. Objective. To assess whether chronic administration of the preferential 5-HT_2C receptor agonist, mCPP, reduces rat body weight gain and to determine if this effect is wholly or partially attributable to the effect of the drug on daily food intake. Methods. Animals were orally dosed with mCPP (10 mg/kg P.O., b.i.d.) or d-fenfluramine (2.5 mg/kg P.O., b.i.d.) for 28 days. Further groups of animals received drug treatments for the first 14 days and then received vehicle for the remainder of the experiment. Locomotor activity was assessed on days 2, 14, and 28. In a second study, animals received mCPP or d-fenfluramine for a 14-day period (dose and route were identical to the previous study). A group of pair-fed controls were included to determine whether the effects on body weight gain were attributable entirely to drug-induced hypophagia. Results. Both mCPP and d-fenfluramine reduced body weight relative to vehicle-treated controls over the 28-day period. Withdrawal of the drugs on day 14 resulted in a significant rebound weight gain. Neither mCPP nor d-fenfluramine induced significant changes in locomotor activity compared to controls on any of the days tested (2, 14 or 28). In the second, 14-day study, changes in the body weights of pair-fed controls closely paralleled those of their drug-treated counterparts. Conclusion. These data indicate that chronic oral treatment with mCPP and d-fenfluramine significantly reduces rat body weight gain, an effect that is reversible upon withdrawal and wholly attributable to maintained hypophagia. Electronic Publication