The ability of certain anorexic drugs to suppress food consumption depends on the nutrient composition of the test diet
Abstract
The effects of five anorexic agents on food consumption were tested in rats offered single, isocaloric, isonitrogenous diets differing in carbohydrate content. Three of the test agents, damphetamine, benzphetamine and chlorphentermine, are sympathomimetic and cause CNS stimulation; the others, MK-212 and d-fenfluramine, are thought to facilitate serotonin-mediated neurotransmission. At ED50 doses, the sympathomimetic drugs reduced food consumption whether the test diet was rich (75% dextrin) or poor (25% dextrin) in carbohydrate. In contrast, MK-212 and d-fenfluramine failed to reduce consumption of the 25% dextrin test diet. These observations suggest that anorexic drugs like d-amphetamine and d-fenfluramine do not act via a common “amphetamine receptor,” and are compatible with earlier observations, made on rats given diet pairs simultaneously, that enhanced serotoninergic neurotransmission selectively suppresses appetite for carbohydrates.
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Cited by (39)
Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry
2000, Brain ResearchCitation Excerpt :The anorexic effect of dexfenfluramine decreased over the next three days of treatment, but fluoxetine-treated animals remained anorexic. This observation supports the theory that SSRIs in general, and fluoxetine in particular, have anorexic properties [9, 38, 53]. The magnitude of the anorexic effect of fluoxetine in rats was surprising.
We compared the effects of treatment with high doses of fluoxetine, sibutramine, sertraline, and dexfenfluramine for 4 days on brain serotonergic nerve terminals in rats. Methylenedioxymethamphetamine (MDMA) and 5,7-dihydroxytryptamine (5,7-DHT) were used as positive controls because both compounds deplete brain serotonin. Food intake and body weight changes were also monitored and yoked, pair-fed animals were used to control for possible changes in morphology due to nutritional deficits. Fluoxetine, sibutramine, sertraline and dexfenfluramine all produced a significant reduction in body weight. Fluoxetine, sibutramine and sertraline treatment resulted in no depletion of brain serotonin but produced morphological abnormalities in the serotonergic immunoreactive nerve network. In contrast, dexfenfluramine and MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network. These results indicate that even though fluoxetine, sibutramine and sertraline do not deplete brain serotonin, they do produce morphological changes in several brain regions (as identified by serotonin immunohistochemistry). Dexfenfluramine and MDMA, on the other hand, markedly deplete brain serotonin and also produce morphological changes. Collectively, these results lend support to the concept that all compounds acting on brain serotonin systems, whether capable of producing serotonin depletion or not, could produce similar effects on the morphology of cerebral serotonin systems.
Reduction of fat and protein intakes but not carbohydrate intake following acute and chronic Fluoxetine in female rats
1999, Pharmacology Biochemistry and BehaviorFluoxetine hydrochloride, a selective serotonin reuptake inhibitor, leads to reductions in food intake and body weight and is under investigation as a possible treatment for obesity. Additionally, it has been suggested that fluoxetine administration could lead to a selective suppression in carbohydrate consumption. Because women more often than men seek weight reduction treatment, the present study examined the acute and chronic effects of fluoxetine on food intake, macronutrient selection, body weight, estrous cycle, and motor activity in female rats. Female Long–Evans rats were provided with separate sources of protein, fat and carbohydrate, and nutrient intakes were recorded following single (5.0, 10.0, and 20.0 mg/kg, IP) and chronic daily (10 mg/kg for 28 days) injections of fluoxetine. Acute and chronic administration of fluoxetine significantly reduced total caloric intake when compared to vehicle treatment. Moreover, fluoxetine significantly suppressed fat and protein intakes, but not carbohydrate intake following both acute and chronic drug administration. Animals chronically treated with fluoxetine gained significantly less weight than animals treated with vehicle. Chronic fluoxetine treatment did not significantly alter estrous cycle. However, in both fluoxetine- and vehicle-treated animals, total caloric intake, and carbohydrate and protein intakes were reduced and fat intake was increased when estrogen levels were high. Fluoxetine significantly reduced motor activity up to 4 h postinjection, and increased motor activity 24 h postinjection.
Macronutrient-specific dietary selection in rodents and its neural bases
1999, Neuroscience and Biobehavioral ReviewsThe only evidence for nutrient selection comes from baseline or treatment effects on nutrient intakes that are qualitatively similar when sensorily contrasting forms of each macronutrient are investigated and/or dietary compositions and strains of rat or mouse are different within or between laboratories. By that criterion the only potential case of a treatment reliably altering macronutrient selection identified in the present review of the literature is d-norfenfluramine, fluoxetine and paraventricular serotonin (5-HT) reducing the intake of dextrin-containing diets at early dark. The only clear example of reverse effects of an agonist and an antagonist on dietary intake was found with serotonergic agents. Claims for catecholaminergic or opioid involvement in protein intake and peptidergic involvement in carbohydrate intake were not substantiated. There remain the issues of which learnt macronutrient-specific postgastric actions and sensory cues from the affected diet rely on the neural pathway(s) on which the drug is acting to alter dietary selection. Until experiments address these questions, the neural bases of nutrient-specific appetites will remain unknown. Drug effects must be consistent across differently textured and flavoured versions of each macronutrient tested.
Food Composition
1994, Handbook of Behavioral NeuroscienceThis chapter describes the effect of food composition on animal health in experimental studies. The health status of animals is highly dependent on the amount and quality of the consumed food. About 50 essential nutrients must be present in the food in proper amounts for an optimal growth and reproduction capacity. Extensive investigations have been performed with the rat to establish its requirements of various nutrients, especially in regard to micronutrients like vitamins and trace elements. Diets fed to laboratory animals vary markedly in nutrient composition and in the level of contaminants. Differences in this regard exist among brands of various manufacturers, but such differences may also occur between batches of a single commercial diet. The significance of these variations for experiments will vary with the topic that is studied. It is desirable that the investigator is continuously informed about the quality of the diet consumed by the animals. Where possible, quality control must be organized in consultation with the manufacturer.
Starvation or dietary restriction are known to modify post-fasting dietary self-selection. We have examined the effects of activation of the serotoninergic system and food deprivation on macronutrient self-selection following a period of starvation. Rats were starved for 4 days and either treated or not with dl-fenfluramine or fluoxetine. Starved untreated animals showed a post-fasting anorexia and an increased preference for carbohydrate intake, even though lipids remained the preferred source of calories. Treatment with fenfluramine or fluoxetine increased post-fasting anorexia, abolished the preference for carbohydrates and decreased lipid intake. Fluoxetine, but not fenfluramine, resulted in decreased protein intake as well. Following a 2-day refeeding period ad libitum, during which the animals were not treated with drugs, the anorectic effect of fenfluramine disappeared but that of fluoxetine remained unchanged. In addition, we noted that at an equimolar dose to dl-fenfluramine (100 μmol/kg/day) fluoxetine treatment resulted in the death of all the animals in the group by the second day of refeeding; no deaths were observed in any of the other groups. In conclusion, we confirm a post-starvation anorexia and increased carbohydrate intake following long-term fasting. In addition we show that activation of the serotoninergic system abolishes the increase in carbohydrate intake and potentiates post-starving anorexia.
Reversible, short-lasting, and dose-dependent effect of (+)-fenfluramine on neocortical serotonergic axons
1991, Brain ResearchDextrofenfluramine ((+)-fenfluramine) is the dextro-optical isomer of the racemic compound (±)-fenfluramine. This compound stimulates the release of serotonin (5-HT) and blocks its re-uptake in serotonergic nerve terminals. (+)-Fenfluramine and its nor metabolite which have been localized in significant amounts in the rat brain are useful anorectic agents in animals. In humans, (+)-fenfluramine is used as an anti-obesity agent when administered orally in doses of 0.25 mg/kg/twice a day. Studies in some animal species (such as the rat and monkey, but not mice) using high doses of (+)-fenfluramine (administered subcutaneously) have shown long-term neurochemical and immunocytochemical effects in selected brain regions. In the present study we used the rat to determine the mechanism underlying the anorectic effect of orally administered (+)-fenfluramine. The rat was selected because long-term effects of (+)-fenfluramine have been previously described in this species. In addition, a variety of other aspects of orally administered (+)-fenfluramine have been addressed in this study. For example, how long does the depletion of 5-HT in the nerve terminals last following cessation of the drug treatment? i.e. is the effect reversible? Is this depletion of 5-HT and the resultant abnormal morphology of 5-HT-immunoreactive nerve terminals seen at high doses dose-dependent? Since some of these questions relate to morphological evaluation of this drug in brain 5-HT systems, we have examined this system as part of our ongoing effort to examine brain monoaminergic systems under perturbed conditions. We have used a morphological (immunocytochemical) approach to answer these questions. The primary function of this study was to evaluate the effects of short-term exposure (4 days) to varying doses of orally administered (+)-fenfluramine on 5-HT-immunoreactive nerve terminals in the frontal cortex of the rat. The frontal cortex was selected because it contains a homogeneous population of nerve fibers and terminals unlike other cortical regions, the hippocampus, striatum and the hypothalamus where a mixed population of coarse and fine fibers has been described. Since the previously reported effect of fenfluramine on 5-HT nerve terminals was the appearance of coarse fibers, the region of cortex selected for this study showed no coarse fibers in the pair-fed control. This essential feature of control regions has not been used in previous studies on this subject. The present study demonstrates that (+)-fenfluramine produces a dose-dependent reduction in 5-HT immunoreactivity of 5-HT nerve terminals in the neocortex of adult rats. Repeated oral administration of a (+)-fenfluramine ‘loading dose’ for 4 days resulted in a progressive, dose-dependent decrease in 5-HT immunoreactivity in the frontal cortex as well as in other cortical areas. This phenomenon is completely reversible, with complete return to normal of 5-HT immunoreactivity at 15 days post-treatment. Furthermore, repeated administration of this drug produced no behavioral responses in the animals. In addition to reduction in 5-HT immunoreactivity, earlier reports using massive doses of (±)-fenfluramine administered parenterally into rats, describe thick 5-HT-immunoreactive axons in the neocortex. At the outset of our study we repeated this study with (±)- and (+)-fenfluramine (24 and 48 mg/kg/day) administered subcutaneously for 4 days in the rat ((+)-fenfluramine is twice as potent as (±)-fenfluramine) in order to examine these thick 5-HT-immunoreactive profiles. In most of the experiments in this study we used oral doses ranging from 2 mg/kg/day to 48 mg/kg/day. The lowest dose at which the thick profiles were first observed with oral administration was 16 mg/kg/day (which is far in excess of the anorectic dose of 0.06–1.25 mg/kg/day). Although it is not possible to compare the doses between rats and humans because of marked differences in the metabolism in these two species, it is unlikely that the human therapeutic dose of 0.2–0.4 mg/kg of (+)-fenfluramine would produce these thick profiles. Furthermore, the rapid and complete return of 5-HT immunoreactivity in the frontal cortex of the rats within 15 days after treatment indicates that the effect of this drug is merely to deplete the nerve terminals of 5-HT resulting in their inability to be 5-HT-immunoreactive, and once the drug has been discontinued the mechanisms for synthesizing 5-HT are able to re-accumulate this putative neurotransmitter (5-HT) in the nerve terminals resulting in the return of 5-HT immunoreactivity. Loading with (+)-fenfluramine and its response in 5-HT-immunoreactive terminals in the brain represents an example of a robust, chemically, specific change in the immunoreactivity of a specific population of nerve terminals that is labile and reversible.