Neurochemical Research, Vol. 7, No. 3, 1982
INHIBITION
OF FOOD INTAKE IN THE RAT
N. BLAVETAND F. V. DEFEUDIS Department of Pharmacology lnstitut Henri Beaufour 72 Avenue des Tropiques 91940 Les Ulis France
Accepted November 21, 1981
The effects of single oral administrations of tricyclic antidepressants (imipramine and desipramine), an atypical antidepressant (nomifensine), known anorexic agents, haloperidol, and diazepam on food intake were compared in SpragueDawley rats over a 4-day test period. The tricyclic antidepressants produced decreases in food intake during the total 4-day test period following their administration. In contrast, the anorexic agents (d-amphetamine, cocaine, mazindol, fenfluramine and quipazine), nomifensine, and haloperidol produced decreases in food intake only on the day of their administration. Diazepam produced an increase in food intake only on the day of its administration. In addition to revealing that high doses of antidepressants can decrease food intake, this model appears to show some specificity for tricyclic antidepressants.
INTRODUCTION Many animal models exist for testing antidepressant action. Models based mainly on the catecholamine hypothesis of affective disorders include: antagonism of reserpine- or tetrabenazine-induced hypothermia, ptosis or sedation in rats or mice (27, 42, 52), potentiation of L-DOPA-induced salivation, piloerection, or increased motor activity in mice pretreated with a monoamine oxidase inhibitor (MAOI) (14); disruption of responding in operant behavioral tasks such as electrical self-stimulation of brain or continuous avoidance in rats (27, 44), potentiation of yohimbine-induced toxicity in dogs or mice (36). Other models which do not depend on drugdrug interactions have also been employed: e.g., mouse-killing by rats (26, 46, 53), separation-induced depression-like syndromes (28, 48), or the "behavioral despair" test (2, 39). Since all of these models can provide
339 0364-3190/82/0300-0339503.00/0 9 1982 Plenum Publishing Corporation
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"false-negative" and/or "false-positive" responses, several test are generally required to detect antidepressant activity. Taking our lead from the findings that tricyclic antidepressants can potentiate amphetamine-induced anorexia and weight loss (11, 21,27, 30, 55), that classic anorexic agents, like tricyclic antidepressants, can act by blocking norepinephrine (NE) and/or serotonin (5-HT) uptake processes (47), and that the anorexic agent mazindol, a potent inhibitor of NE and DA uptake (15), was initially developed as an antidepressant (6), we have compared the actions of some classic anorexic agents with those of two tricyclic antidepressants and one atypical antidepressant on food intake in the rat. Haloperidol and diazepam were also studied.
EXPERIMENTAL PROCEDURE Animals. Food intake was determined using male Sprague-Dawley rats (Charles River) weighing about 200-250 g at the time experiments were initiated. Animals were housed singly in plastic cages (14 x 20 x 30 cm; Iffa Credo) containing litter. One week with food and water ad libitum was allowed for acclimatization of the animals to their new surroundings. A rhythm of 12 hours of darkness (19.00-7.00 hr) and 12 hr of light (7.00-19.00 hr) was maintained throughout the experiments. Testing procedure. The animals were trained to consume food between 11.00-15.00 hr while having free access to water; they received cups of food in plastic cages (8.5 x 13 • 27 cm; Iffa Credo). Food consisting of a mixture of 600 g of powdered standard rat chow (Union d'Alimentation Rationnelle; U.A.R.) and 250 ml of soybean oil was given to the rats daily. The amount of food consumed was determined by weighing the cups before and at 30 min, 1 hr, 2 hr, 3 hr and 4 hr after their presentation to the animals; spilled food was collected and put back into the food cups. Food intake was considered to have stabilized when the quantity consumed did not vary more than 3 g/day per animal (37). Determinations made on Monday were considered as "control" values, drugs were tested on Tuesday, and the persistence of drug effects was determined during Wednesday, Thursday and Friday. Cage litter was changed on Friday after all testing had been completed. Animals were tested in groups of six, and the experimenter was not aware of the drugs being tested. Single oral doses of each test substance or an equivalent volume of the vehicle
FIG. |. Effects of single oral administrations of known anorexic agents on food intake in the rat. Compared to "control" animals which received only the vehicle (water) on Day 2, animals that received these anorexic agents on Day 2 exhibited marked decreases in food intake which were evident only on the day of drug administration. "Day 1" indicates day before drug administration; "Day 2" indicates day of drug administration; "Days 3, 4 and 5" indicate days after drug administration. Drugs (or vehicle alone) were given 30 min before presentation of food to the animals. Means ___ SEM for 6 animals in all cases; all values for Day 2 differed significantly (p < 0.05 - p < 0.001, Student's t-test; two-tailed) from those of Day 1 and from those of control animals, except for the 4-hr value for d-amphetamine and the 3- and 4-hr values for cocaine. Some SEM are not indicated for the purpose of clarity.
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FiG. 2. Effects of single oral administrations of tricyclic antidepressants 0mipramirte and desipramine) and of an atypical antidepressant (nomifensine) on food intake in the rat. Means -+ SEM for 6 animals in all cases; all values for Day 2 (day of drug administration) differed significantly (p < 0.05 - p < 0.001) from those of Day 1 (day before drug administration) and from those of control animals (cf. Figure 1); in addition, significant differences (p < 0.05 - p < 0.001; Student's t-test; two-tailed) between values for Days 3, 4 and 5 and those for Day 1 existed for most of the data points for imipramine and desipramine, but not for those of nomifensine. Some SEM are not indicated for the purpose of clarity. See legend to Figure 1 for explanation of symbols. Drugs were administered 30 min before presentation of food to the animals. At the doses used, food intake was inhibited 99% by nomifensine and 75% by imipramine or desipramine. (water) were administered to each animal using intragastric tubes (1 ml/100 g body weight) 30 rain before presentation of food to the animals. At the doses chosen for this study, all drugs, except diazepam, inhibited food intake by 75-100% during the first hour of testing, commencing 30 minutes after their administration (see Figures 1-3 and refs. 3-5). Drugs. The following substances were used: d-amphetamine-SO4 (Cooperation Pharmaceutique Fran~aise; C.P.F.); cocaine-HC1 (C.P.F.); desipramine (Ciba-Geigy); diazepam
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(Hoffmann-LaRoche); fenfluramine-HC1 (Lab. Servier); haloperidol (Lab. Janssen); imipramine-HC1 (Sigma Chem. Co.); mazindol (Sandoz); nomifensine-hydrogen maleate (Lab. Hoechst); quipazine-maleate (Miles Labs).
RESULTS Under control conditions, the rats consumed 9.6 _+ 0.4 g of food during the first 30 min, 10.8 _+ 0.4 g during the first hr, 11.9 -+ 0.4 g during two hr, 12.6 _+ 0.4 g during three hr and 13.4 _+ 0.4 g during the total fourhr period of testing (means __ SEM; n = 72 values from 72 rats in all cases). Results provided in Figure 1 indicated that food intake under control (no drug) conditions was reproducible over the total 5-day testing period. Anorexic agents whose actions require intact catecholaminergic systems (d-amphetamine, mazindol, cocaine) as well as those requiring intact serotoninergic systems (fenfluramine, quipazine) (18, 22, 34, 45) all produced marked decreases in food intake on the day of their administration 25 Diazepam
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FIG. 3. Effects of single oral administrations of a major tranquillizer (haloperidol) and an anxiolytic agent (diazepam) on food intake in the rat. Means _+ SEM for 6 animals in all cases. Regarding haloperid01, all values for Day 2 (day of drug administration) differed significantly (t7 < 0.05 - p < 0.001) from those of Day 1 (day before drug administration) and from those of control animals (cf. Figure 1); diazepam produced a significant increase in food intake at the 3- and 4-hr test periods on Day 2 (p < 0.05); Student's t-test; twotailed. Some SEM are not indicated for the purpose of clarity. See legend to Figure 1 for explanation of symbols. Drugs were adialinistered 30 min before presentation of food to the animals.
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("Day 2" of Figure 1), but these anorexic responses did not occur on subsequent days of testing (i.e., "Days 3, 4 and 5" of Figure 1). In contrast, single high doses of the tricyclic antidepressants, imipramine and desipramine, produced anorexic responses during the total 4-day period following their administration (Figure 2). However, the anorexic action of a high dose of the atypical antidepressant nomifensine resembled (in terms of persistence of action) those of the classic anorexic agents (cf. Figure 1). Haloperidol also altered the pattern of food intake in a fashion similar to that of classic anorexic agents, whereas diazepam produced an increase in food intake which was limited to the day of its administration (Figure 3).
DISCUSSION In accord with previous reports (18, 22, 34, 45), acute treatments with the anorexic agents d-amphetamine, cocaine, mazindol, fenfluramine and quipazine all produced a transient inhibition of food intake in the rat (i.e., this anorexic action was evident only on the day of drug administration). Regarding the mechanisms of action of these anorexic agents, fenfluramine is considered to be an indirect, or direct, serotonin (5-HT)agonist (12, 16, 17, 19, 22), quipazine acts primarily as a direct 5-HTagonist (54), mazindol, like amphetamine, is believed to act mainly by releasing and/or blocking catecholamine re-uptake (9), cocaine is believed to act mainly by blocking the re-uptake of catecholamines (e.g., 49, 51), but might also release catecholamines (e.g., 7, 35). The striking difference observed between the actions of the classic anorexic agents and tricyclic antidepressants involved the persistence of anorexic action. Single oral doses of tricyclic antidepressants produced anorexic behavior on the day of their administration as well as on the three days which followed (Fig. 2). Therefore, if persistence of the anorexic response is used as the criterion, the tricyclic antidepressants can be separated from classic anorexics, as well as from at least one atypical antidepressant (nomifensine) using the test described herein. However, this method might not be specific to tricyclic antidepressants, since our preliminary experiments have revealed that oral administration of high doses of the MAOI tranylcypromine (10 and 30 mg/kg) produced a decrease in food intake which persisted for two days and since the tetracyclic antidepressant maprotiline has anorexic activity in this test (unpublished observations, 1981). In any case, this model might be useful for further examining the relationship between the neurobiological substrates for depression and food intake (or other consummatory behaviors). Recent reports have been conflicting with regard to the actions of tri-
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cyclic antidepressants on food intake. Although it has been shown that amphetamine-induced anorexia can be potentiated by acute administration of tricyclic antidepressants (21, 30, 55), other workers have found that clomipramine, an inhibitor of the active transport of 5-HT into serotoninergic neurones (8), effectively antagonized fenfluramine-induced anorexia (10, 12) and that subchronic treatment of rats with desipramine decreased anorexic responses to amphetamine for a period of weeks following cessation of desipramine treatment (55). Regarding the difference between the actions of nomifensine and the tricyclic antidepressants, it should be noted that nomifensine-hydrogen maleate is a new type of antidepressant which has pharmacological and biochemical properties that differ from those of tricyclic compounds or MAOIs (20, 23, 24, 29, 32, 43). The different anorexic responses shown herein might be explained by the findings that nomifensine, unlike imipramine, has no cardiovascular and/or anticholinergic effect (24), and that it might induce a release of dopamine (DA) while inhibiting both NE and DA re-uptake (20, 29). The similar effects of nomifensine, d-amphetamine, cocaine, mazindol, fenfluramine and quipazine on food intake shown herein indicates that nomifensine might have a mechanism of action that is more like that of the anorexic agents than like that of the tricyclic antidepressants. In this regard, Spencer (47) has suggested that nomifensine's pharmacological profile indicates that it might have properties intermediate between those of amphetamine and imipramine. Although chronic neuroleptic medication is often associated with considerable weight gain in psychoti c humans (25, 31), a high oral dose of haloperidol decreased food intake in the rat (Fig. 3). In line with our results, Uguru-Okorie (50) has recently shown that chronic intraperitoneal injection of haloperidol (1 or 10 mg/kg) also decreased food intake in the rat. The orectic response to acutely-administered diazepam (Figure 3) was, of course, expected, since this agent is known to stimulate food intake in rats (e.g., 41) and in other animals (1, 13, 40, 56). In sum, even though weight gain commonly results from chronic treatment with antidepressants (e.g., 33, 38) further development of the method based on the anorexic actions of a single administration of tricyclic antidepressants that is described herein (i.e., in terms of dose-response curves) might serve as a useful test system for further studies on these agents.
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