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Effects of a chronic administration of two benzodiazepines on food intake in rats given a highly palatable diet
Abstract
Chronic administration of benzodiazepines is known to increase food intake in numerous species. But this effect has been studied only after a unique daily injection and over a short part of the 24 hr cycle. In the present study, during 28 days, drugs were administered to rats receiving ordinary chow or a highly palatable diet (cafeteria diet): diazepam (DZ) (2.5 mg/kg IP) twice a day, or brotizolam (BR) (1 mg/kg IP), a longer acting compound, once a day. In the chow fed rats, DZ and BR provoked a post injection hyperphagia throughout the study, followed by a compensatory hypophagia resulting in 24 hr food intakes not different from those of controls; conversely neither body weight nor weight of fat pads were increased. The cafeteria diet provoked hyperphagia and overweight. DZ did not induce any supplementary hyperphagia. BR provoked a post injection hyperphagia, also compensated in time, resulting again in 24 hr food intakes, body weight gains and weight of fat pads not increased compared to those of cafeteria controls. Thus in the rat, benzodiazepine treatment increases food intake, but only acutely, and does not provoke any trend toward obesity.
... Wise and Dawson 1974), and free feeding in home cages (e.g. Seyrig et al. 1986) and after single or chronic treatment (e.g. Niki 1965;Cooper and Francis 1979). ...
... The absence of effect on the amount of chow ingested is surprising, since time chewing in test sessions was strongly affected by CDP injections. However, a recent study (Seyrig et al. 1986) has also failed to observe enhanced eating during a 24-h cycle in the rat. On the other hand, the lack of effect on body weight and water ingestion over 24 h is consistent with previous reports (e.g. ...
... On the other hand, the lack of effect on body weight and water ingestion over 24 h is consistent with previous reports (e.g. Wise and Dawson 1974;Cooper and Posadas-Andrews 1979;Hodges et al. 1981 ;Seyrig et al. 1986). ...
Chronic administration of chlordiazepoxide (CDP) is known to increase feeding in several species and under different procedures. Although this effect does not appear to result from antineophobic and anxiolytic effects of this benzodiazepine, very little is known about the possible contribution of stereotyped nibbling and chewing responses to enhanced feeding. The present study addressed this issue. Experiments 1 and 2 showed that rats injected with 5 and 10 mg/kg CDP spent more time chewing wood than either food-deprived or satiated rats. Experiment 3 showed that rats chronically injected with CDP spent more time chewing biscuits than wood in choice tests; with repeated choice testing chewing biscuits increased while chewing wood decreased. Experiment 4 replicated these results, and ruled out the possibility that increased time chewing resulted only from the self-rewarding effects of chewing. Finally, Experiments 3 and 4 also showed that despite these strong local effects on feeding time, body weight and the amount of food and water ingested every day for 10 days were not increased by 5 and 10 mg/kg CDP. It is unlikely that the effects of CDP on feeding results only from induction of stereotyped nibbling and chewing.
... Although it is well established that CDP and other benzodiazepines enhance food intake, the effect of these drugs on body weight has been little studied. There is evidence that benzodiazepine-induced increases in food intake do not necessarily result in increases in body weight in rats (e.g., Cooper & Francis, 1979;Hodges, Green, Crewes, & Mathers, 1981;Seyrig, Falcou, Betoulle, & Apfelbaum, 1986). For example, free-feeding rats treated daily with diazepam or brotizolam ate more in the period after the drug injection but compensated in later periods by eating less so that their total daily intake was not different from that of control rats given saline injections (Seyrig et al., 1986). ...
... There is evidence that benzodiazepine-induced increases in food intake do not necessarily result in increases in body weight in rats (e.g., Cooper & Francis, 1979;Hodges, Green, Crewes, & Mathers, 1981;Seyrig, Falcou, Betoulle, & Apfelbaum, 1986). For example, free-feeding rats treated daily with diazepam or brotizolam ate more in the period after the drug injection but compensated in later periods by eating less so that their total daily intake was not different from that of control rats given saline injections (Seyrig et al., 1986). Not surprisingly, the body weight of these rats was Bow Tong Lett. ...
... As noted earlier, Seyrig et al. (1986) found that repeated administrations of the benzodiazepines (diazepam or brotizolam) increased food intake acutely in free-feeding rats but did not produce weight gain because a compensatory decrease in eating occurred during time periods that were removed from the drug injections. In Experiment 2 of our study, however, the rats given CDP gained more weight than those treated with saline. ...
In Experiment 1, the effect of repeated injections of 2.5, 5.0, or 10.0 mg/kg of chlordiazepoxide (CDP) on food intake and body weight was studied in rats on an activity anorexia (AA) regimen. For several days before CDP testing began, rats lived in activity wheels and had one 60-min meal per day. During CDP testing, this regimen continued except that each rat was injected with an appropriate dose of CDP or saline 30 min before each meal. CDP enhanced food intake; 5.0 mg/kg seemed most effective. However, the CDP-induced increase in eating did not noticeably stem weight loss. In Experiment 2, after several days of AA training, CDP (5.0 mg/kg) was tested under less severe conditions; food remained restricted, but access to the wheels was discontinued. Rats given CDP ate more and gained more weight than controls. These findings suggest that benzodiazepines such as CDP may help in treating anorexia nervosa and other anorectic conditions in humans.
... Ce médicament est souvent utilisé comme molécule de référence pour tester de nouveaux produits anti-stress (Bernet et al., 2000;Ciccocioppo et al., 2002;Rex et al., 2002) ou de nouveaux modèles de stress Hegarty & Vogel, 1995;Ely et al., 1997). Le diazépam peut modifier la prise alimentaire puisqu'il induit une hyperphagie pour des doses supérieures à 2,5 mg/kg (Johnson, 1978;Cooper, 1980;Seyrig et al., 1986). A partir de 0,5 mg/kg, le diazépam a des effets anxiolytiques sur une variété de mesures comportementales de l'anxiété (Rex et al., 1996;Schmitt & Hiemke, 1998;Bert et al., 2001;Ballard et al., 2005). ...
Stress is a contemporary important issue both in humans and animals and finding new ways to fight undesirable aspects of stress is crucial. Exposure to stress is known to alter feeding behaviour. Our objective was to study the effect of stress on food intake in rats fed with a standard diet in order to apply these findings to study the effect of an anti-stress yeast extract. Stress paradigms used were acute restraint (RS), forced swimming (FSS) and social defeat stress as well as chronic variable stress (CVS). In a first part, we showed that acute FSS and RS induced a decrease of food intake due to an increase of satiation. Those mechanisms might be mediated by POMC hypothalamic neurons. Furthermore, we found that CVS induced a basal hyperactivation of the HPA axis and thus an enhanced hypothalamic CRF expression which caused a decrease of food intake probably through inhibitory effect of NPY orexigenic pathways. In a second part, we showed that the yeast extract had no effect on stress-induced food intake inhibition either in acute or chronic stress. However, chronic administration of the product during CVS reduced the hyperactivation of the HPA axis.Our results give further evidence concerning mechanisms underlying stress-induced food intake inhibition. Others studies are needed to conclude about the anti-stress effect of the yeast extract we tested.
... Prevention of cheek-pouching distinguished anxiety from appetite changes, but changes to the consummatory drive were a potential confound with diazepam. This benzodiazepine stimulates food appetite and consumption in rats and mice (Berridge and Pecina, 1995;File, 1986;Seyrig et al., 1986). It is one of a few orexigenic compounds reported to stimulate food intake in hamsters (Birk and Noble, 1982). ...
... However, this chronic series of injections was not administered in connection with a daily drinking session, so that when the fluid-intake test of tolerance was administered, it illustrated the probable lack of dispositional tolerance rather than an absence of behavioral tolerance. With repeated administration to rats, no tolerance to the hyperphagic response to chlordiaz-epoxide (Hunt, Poulos, & Cappell, 1990;Posadas-Andrews & Nieto, 1988) or diazepam (Seyrig, Falcou, Betoulle, & Apfelbaum, 1986) injections occurred. This picture of a general lack of tolerance to the fluid and food ingestional increases produced by anxiolytic agents contrasts with the present findings. ...
When rats adapted to a water-deprived schedule that allowed daily drinking of a single fluid, either water or 1.5% sodium chloride (NaCl) solution, they were injected with a benzodiazepine (BZ) during a 1-hr session and they drank more NaCl solution or water in a dose-related fashion. Chronic drug administration led to partial tolerance to intake increases. Serum drug and metabolite levels indicated that the partial tolerance was not due to drug dispositional changes. Drug discontinuation produced precipitous decreases in intake, indicating the accrual of physiological dependence. The fluid ingestional increases produced by BZs may correlate with their anxiolytic efficacies and may occur by attenuating the punishing effects of ingesting beyond the point of satiety. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Anaesthesia in food producing animals in the EU and UK is legally limited to a narrow choice of drugs; the only licensed benzodiazepine being brotizolam. The aim of this study was to investigate the effects of brotizolam as a co-agent with ketamine on the quality of induction, intubation, muscle relaxation and recovery from isoflurane anaesthesia. Seventeen calves were enrolled in this prospective, blinded, randomized experimental study. Calves were sedated with 0.05mg/kg xylazine and 0.1mg/kg butorphanol IV. After assessing the quality of sedation, anaesthesia was induced with 2mg/kg ketamine (group KETA) or 2mg/kg ketamine with 2 μg/kg brotizolam IV (group BROTI). An additional 1mg/kg ketamine was administered IV every 2min until intubation was possible. Anaesthesia was maintained with isoflurane in a mixture of oxygen and air. The amount of ketamine required, quality of induction, intubation, muscle relaxation, and recovery were scored and compared between groups using ordinal regression models (P <0.05 was considered statistically significant). Sedation scores did not differ significantly between groups but were positively associated with the quality of recovery (P = 0.0098). Group BROTI was associated with a lower quality of induction (P <0.0001), intubation (P = 0.0203) and muscle relaxation (P = 0.0043). The sedation score and treatment had no effect on the number of attempts of intubation, additional ketamine doses, time to extubation and recovery time. Brotizolam had a negative effect on the quality of induction, intubation, and muscle relaxation compared to ketamine alone. We do not recommend using brotizolam under these circumstances.
When rats adapted to a water-deprived schedule that allowed daily drinking of a single fluid, either water or 1.5% sodium chloride (NaCl) solution, they were injected with a benzodiazepine (BZ) during a 1-hr session and they drank more NaCl solution or water in a dose-related fashion. Chronic drug administration led to partial tolerance to intake increases. Serum drug and metabolite levels indicated that the partial tolerance was not due to drug dispositional changes. Drug discontinuation produced precipitous decreases in intake, indicating the accrual of physiological dependence. The fluid ingestional increases produced by BZs may correlate with their anxiolytic efficacies and may occur by attenuating the punishing effects of ingesting beyond the point of satiety.
Since their introduction in the early 1960s it has been known that benzodiazepines potently increase food intake in many animal species, including higher primates. Behavioural and pharmacological evidence shows that this hyperphagic effect of benzodiazepines is not secondary to their anxiolytic properties, and can also be dissociated from sedative and muscle-relaxant effects. The hyperphagic response appears to be due to a direct effect on appetite mechanisms, and certainly arises from interactions of drugs with specific benzodiazepines recognition sites in the brain. The discovery of so-called ‘inverse agonists’, which bind to benzodiazepine sites, has led to experiments which show that they reduce food consumption and can block benzodiazepine-induced hyperphagia. The most recent research in this area shows that benzodiazepines enhance the hedonic quality of taste stimuli, and indicates that this may determine their effects on food preferences and food consumption. This evidence is reviewed in this article. Attention is also drawn to recent experimental work in patients with eating disorders; anorexia nervosa and bulimia. Both groups show heightened taste responsiveness to sweet, palatable taste. Further study of benzodiazepine effects on appetite should throw new light on neurochemical determinants of taste palatability. Inverse agonists acting at benzodiazepine receptors may provide examples of drugs which could be used to attenuate taste responsiveness to highly palatable foods.
In dwarf goats fasted for 2 h, i.v. administration of the benzodiazepine (BZ) agonists diazepam (60 μg/kg), brotizolam (2 and 4 μg/kg) and climazolam (100 μg/kg) induced hyperphagic effects, whereas i.v. injections of the BZ-antagonist flumazenil (R°15–1788; 0.5 mg/kg), the anthelmintic ivermectin (0.1 mg/kg), the 5-HT2 antagonist ritanserine (0.1 mg/kg), ACTH (10 μg/kg) and prednisolone (1 mg/kg) were inactive in a 30-min feeding test. Both the BZ-antagonist R°15–3505 (≤ 0.1 mg/kg) and the opiate receptor antagonist naloxone (0.1 mg/kg) had anorectic effects in dwarf goats given 30 min access to a palatable pelleted concentrate. The hyperphagic effects of climazolam and brotizolam were not antagonized by flumazenil, whereas similar doses of this drug completely reversed muscle incoordination and ataxia induced by much higher doses of these BZ-agonists. In the combination experiments with naloxone and BZ-agonists, naloxone antagonized the hyperphagic effects of both diazepam and brotizolam. Similarly, in the diazepam–R°15–3505 study, there was a significant effect of diazepam and a significant inhibition of this effect by R° 15–3505 (50 μg/kg). In the diazepam–ivermectin combination experiment no evidence for drug potentiation was found. These results and the mode of action of the above mentioned drugs are discussed in relation to feeding behaviour.
The effect of 5 days of food deprivation followed by 5 days of refeeding on γ-aminobutyric acid (GABA) receptors, central benzodiazepine receptors (CBR), and peripheral benzodiazepine binding sites (PBzS) was studied in female Sprague-Dawley rats. Starvation induced a decrease in the density of PBzS in peripheral organs: adrenal (35%;P < 0.001), kidney (33%;P < 0.01), and heart (34%;P < 0.001). Restoration of [3H]PK 11195 binding to normal values was observed in all three organs after 5 days of refeeding. The density of PBzS in the ovary, pituitary, and hypothalamus was not affected by starvation. Food deprivation resulted in a 35% decrease in cerebellar GABA receptors (P < 0.01), while CBR in the hypothalamus and cerebral cortex remained unaltered. The changes in PBzS observed in the heart and kidney may be related to the long-term metabolic stress associated with starvation and to the functional changes occurring in these organs. The down-regulation of the adrenal PBzS is attributable to the suppressive effect of hypercortisolemia on pituitary ACTH release. The reduction in cerebellar GABA receptors may be an adaptive response to food deprivation stress and may be relevant to the proaggressive effect of hunger.
In the past decade, there has been considerable emphasis on developing and refining the measurement instruments used to assess the rewarding effect of brain stimulation. These efforts have given rise to quantitative methods aimed at revealing the underlying neurophysiology and neuroanatomy by tracing the trajectories of the relevant neurons. In this paper, we summarize some of the quantitative findings that have resulted from research at the University of Ottawa in the neurobiology of motivated behavior. These include studies using markers to reveal which structures are metabolically activated by rewarding brain stimulation, comprehensive mapping of brain areas for self-stimulation and other stimulation-induced behaviors, and examination of the effects of benzodiazepines on feeding and reward.
In dwarf goats fasted for 2 h, i.v. administration of the benzodiazepine (BZ) agonists diazepam (60 micrograms/kg), brotizolam (2 and 4 micrograms/kg) and climazolam (100 micrograms/kg) induced hyperphagic effects, whereas i.v. injections of the BZ-antagonist flumazenil (R degrees 15-1788; 0.5 mg/kg), the anthelmintic ivermectin (0.1 mg/kg), the 5-HT2 antagonist ritanserine (0.1 mg/kg), ACTH (10 micrograms/kg) and prednisolone (1 mg/kg) were inactive in a 30-min feeding test. Both the BZ-antagonist R degrees 15-3505 (greater than or equal to 0.1 mg/kg) and the opiate receptor antagonist naloxone (0.1 mg/kg) had anorectic effects in dwarf goats given 30 min access to a palatable pelleted concentrate. The hyperphagic effects of climazolam and brotizolam were not antagonized by flumazenil, whereas similar doses of this drug completely reversed muscle incoordination and ataxia induced by much higher doses of these BZ-agonists. In the combination experiments with naloxone and BZ-agonists, naloxone antagonized the hyperphagic effects of both diazepam and brotizolam. Similarly, in the diazepam-R degrees 15-3505 study, there was a significant effect of diazepam and a significant inhibition of this effect by R degrees 15-3505 (50 micrograms/kg). In the diazepam-ivermectin combination experiment no evidence for drug potentiation was found. These results and the mode of action of the above mentioned drugs are discussed in relation to feeding behaviour.
The effect of food palatability and duration of food deprivation on the modulation of food intake by two benzodiazepine receptor (BDZR) ligands, CGS 9896 and CGS 8216, were investigated. Three diets differing in palatability (high, medium, or standard) and three different periods of food deprivation (0, 16, or 24 h) were used in all combinations to compare the effect of these variations on the observed modulation of food consumption by both BDZR ligands. Increasing diet palatability and/or food deprivation increased the baseline food consumption and reduced the sensitivity of the test to the detection of the hyperphagic effect of CGS 9896 but increased the sensitivity to detect the anorexic effect of CGS 8216. Only for the intermediate conditions of food deprivation (16 h) and for a standard or medium palatable diet were both significant hyperphagic effect of CGS 9896 and anorexic effect of CGS 8216 detected. Neither increased palatability nor hunger enhanced the modulation of feeding, indicating that neither "taste preference" nor "hunger" is the key factor in the mechanism of BDZR ligand-induced feeding response.
Effects of repeated intravenous (i.v.) administration of diazepam on food intake were investigated in freely moving rats implanted with a chronic i.v. cannula. Diazepam (0.2 and 2 mg/kg) was automatically injected i.v. at 3-h intervals for 3 consecutive days. Food intake was measured twice daily, ie for the light phase (7 00-19 00) and dark phase (19 00-7 00). Food intake during the light phase was increased in a dose-dependent manner following diazepam. Each injection of diazepam provoked hyperphagia, followed by a compensatory hypophagia until the next diazepam injection. Body weight, however, was increased significantly in rats treated with diazepam. When diazepam (2 mg/kg) was automatically injected at 3-h intervals for 10 consecutive days, tolerance did not develop to the hyperphagia and body weight was increased significantly following diazepam injection. After cessation of diazepam injection, both food intake and body weight decreased. These findings suggest that such excessive i.v. treatment with diazepam induces hyperphagia showing no tolerance accompanied by an increase in body weight, thus resulting in a trend toward obesity in rats.
Rats were adapted to a water-deprivation regimen that allowed daily 1-hr drinking sessions of a single fluid, either 1.5% NaCl solution or water. Oral, presession, acute doses of triazolam (0.05-1.6 mg/kg) or alprazolam (0.4-6.4 mg/kg) produced dose-related increases in session NaCl solution ingestion. The relative potencies found for these two drugs approximated their relative Ki values reported in the literature. The increased ingestion produced in this and other experiments by anxiolytic agents is presented as an alternative way of evaluating punishment attenuation, and hence anxiolytic activity. Chronic oral dosing (every 2nd day) with triazolam (0.2 mg/kg) or alprazolam (1.2 mg/kg) led, after several weeks, to partial, but surmountable, tolerance to the increased NaCl solution ingestion produced by these drugs, which was confirmed by a rightward shift in the dose-effect relations. During chronic dosing, no corresponding declines in the independently evaluated increases in water intake produced by these drugs occurred. Abrupt drug discontinuation produced a precipitous decrease in NaCl solution intake, with subsequent recovery. For triazolam, the initial discontinuation decrease in intake to below the original base line suggested the possible accrual of a mild physiological dependence under this moderate chronic dose regimen.
The pharmacokinetics and plasma binding of diazepam were compared in man, dog, rabbit, guinea pig and rat. Diazepam (D) and its major metabolite, desmethyl-diazepam, were measured in blood and plasma by a specific and sensitive gas-liquid chromatography assay with an electron capture detector. After an intravenous bolus injection plasma levels of D declined biexponentially in all species examined and the data were analyzed according to the two-compartment open model. The binding of D and desmethyldiazepam has been determined at therapeutic concentrations by equilibrium dialysis in man (96.8 and 96.6%, respectively), dog (96.0 and 95.9%), rabbit (89.9 and 94.7%), guinea pig (91.3 and 78.6%) and rat (86.3 and 90.5%). In man, the elimination half-life, T1/2(beta), increased significantly (P less than .01) with decreasing total plasma clearance (Cl). Plasma binding affected Vd and Cl, but only Cl increased significantly (P less than .05), if more free D was available. This indicates that unbound drug is rate-determining for clearance by the liver, and that D fits into the restrictive elimination class in man. In the four animal species tested, Cl was a direct linear function of the body surface area. T1/2(beta) and the rates of drug clearance were characteristic figures for each species: from 1.1 hours and 81.6 ml/min/kg in the rat to 32.9 hours and 0.35 ml/min/kg in man, whereas T1/2(alpha), the half-life of distribution, varied only approximately 3-fold (0.3-1.0 hours) in the different species. A considerably higher extraction ratio than the unbound fraction of diazepam exists in these animal species, and blood clearance exceeds liver blood flow, giving reason to assume a much higher ability of the liver to metabolize D, and a species-dependent extrahepatic metabolism. The large variations described suggest that pharmacokinetic data or plasma binding results cannot simply be extrapolated to man.
Found in 8 experiments with male Wistar rats that diazepam (2.5 mg/kg) produced vigorous eating but not drinking in sated Ss. The effect was found with familiar food in both test box and home cage and during both day and night. Ss trained under food deprivation leverpressed for food but not water under diazepam; the rate of response was dose dependent. Diazepam motivated learning of leverpressing for food but not as well as did deprivation. Diazepam-induced eating lasted 25-30 min and was terminated by feedback from eating, rather than by catabolism of the drug. Stomach loads of food but not of water inhibited the eating. These data indicate that diazepam has specific actions on hunger or food-satiety mechanisms. (27 ref)
The effect of chlordiazepoxide on food intake in the rat was studied under a variety of conditions. Administration of chlordiazepoxide (5mg/kg) produced an increase in food intake during a 2 hr feeding period up to 5 hr intervention after an intraperitoneal injection. A marked increase in food intake was observed during 10 daily injections of 5mg/kg chlordiazepoxide. Under the satiated condition an elevation of food intake by chlordiazepoxide was also evident. Chlordiazepoxide resulted in a slight but significant elevation of food intake following the stomach preload. Chlordiazepoxide failed to show any effect on consumption of the quinine-adulterated food. It may be suggested that the increase in food intake following the injection of chlordiazepoxide would be attributable to a loss of satiation of food motivation.
After four days of administration, chlordiazepoxide (5 mg/kg) increased the weight gain of rats on ad libitum food and water, whereas chlordiazepoxide (7·5 mg/kg) and lorazepam (0·25 and 0·5 mg/kg) decreased it. After a period of food deprivation, chlordiazepoxide (7·5 mg/kg) and lorazepam (0·5 mg/kg) increased food consumption after ½, 2 and 6 h. In a food preference test chlordiazepoxide (5 mg/kg) enhanced consumption of chocolate chips, whereas lorazepam (0·25 and 0·5 mg/kg) enhanced consumption of familiar chow. Chlordiazepoxide (5 and 7·5 mg/kg) enhanced consumption of unfamiliar chow, whether this was preferred or not, whereas lorazepam (0·25 and 0·5 mg/kg) enhanced consumption of familiar chow. Naloxone (4 mg/kg) reduced food intake in the first ½ h after injection and reduced consumption of unfamiliar chow. Naloxone (2 and 4 mg/kg) abolished consumption of chocolate chips in the food preference test.
The purpose of the writer was to determine the possible relationship between emotional behavior (defecation) and the speed of ambulatory activity (distance travelled per unit time). Each of 50 rats was observed individually in a round enclosure two minutes a day for 28 days. The results demonstrate a negative correlation between individual differences in defecating (emotional) behavior and individual differences in defecating (emotional) behavior and individual differences in ambulatory activity. Emotional rats were less active than non-emotional. "This relationship suggests that whenever activity is of utility to the animal, emotionality will hinder adjustment; whenever activity is of disservice to the animal, emotionality will facilitate adjustment." (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Various minor tranquilizers (benzodiazepines, barbiturates and meprobamate) induced an increase in the food intake of rats or mice. Drugs were injected i.p. 30 min before testing and the amount of food consumed during 30 min was recorded. The enhanced food consumption occurred when the animals were in a novel situation, in a situation which they had previously experienced, or in their home cage, in which they were used to eating in the daytime within 30 min. Studies with two benzodiazepines showed this effect to be maximal between 10 to 30 min after injection and to disappear 4 hrs after injection. Moreover, minor tranquilizers reduce the latency before eating of rats and mice tested in a new situation. These results and the observation of anti-anxiety drugs-induced hyperphagia in satiated animals suggest that:1.
The enhanced food consumption of a non familiar food in a novel situation induced by the minor tranquilizers could hardly be related only to their anti-anxiety action.
2.
The existence of some inhibitory controls (endogenous satiety in daytime or satiety after recent absorption) is not essential for the action of the minor tranquilizers.
3.
An increased motivation and a disruption in the food related behavior could possibly be an explanation for all the observed effects.
Chlordiazepoxide (CDP) at 15 mg/kg produced two distinct actions in a food preference test firstly a general appetite-enhancing effect, and secondly an anti-neophobic effect. Following acute injection of CDP the rats changed from eating predominantly familiar food to a novel food. This may signify an anti-neophobic effect of CDP However, following 10 days of treatment with CDP, the anti-neophobic effect was abolished and the choice of familiar food was enhanced. This could be an indication of a more general appetite-enhancing effect. Hence some form of tolerance may develop to CDP's effects over 10 days of treatment which selectively abolishes anti-neophobic action whilst leaving the appetite effect further enhanced. There were no indications of tolerance developing to the actions of CDP in animals familiarized with all the test foods before the preference test was run. Hence the presence of food novelty may be critical to the observation of some form of selective tolerance.
The effects of acute or chronic administration of chlordiazepoxide on several feeding parameters were studied in the rat. Given acutely, chlordiazepoxide reduced the rate of feeding, at lower dose levels (5.0 or 10.0 mg kg-1) tended to prolong feeding duration, and at a higher dose (15.0 mg kg-1) reduced the amount of food intake. Food texture can influence feeding parameters too; but the effects of the drug did not interact with the effects of food texture. After 9 daily injections of the drug, there were several indications of the development of tolerance to the effects of the drug on the feeding parameters. A possible role of 5-HT mechanisms in the reduction of eating rate produced by the drug is considered.
Food and water intake were measured in non-deprived pigeons over a 4h period during daytime. Under control conditions, the ratio of food to water intake was approximately 1:1, and both intakes were a simple linear function of time. Chlordiazepoxide (10 mg/kg, i.m.) doubled the mean amount of food intake, whilst leaving water intake unchanged. This is a first indication that chlordiazepoxide can selectively stimulate appetite for food in an avian species. Some birds showed sedation following a first acute injection; its duration was shortened after repeated injections, and the hyperphagic response to the drug was revealed.
Diazepam significantly increased milk consumption in rats that had never been exposed to this food before but not in rats trained to drink milk. Diazepam failed to increase lever-pressing for food reward except when this behavior had been previously suppressed by the simultaneous administration of electric shock. These data suggest that diazepam does not alter appetite, but enhances the expression of motivation suppressed by instinct or training.
The effect of different benzodiazepines on food intake was studied in cats which had been trained to eat their daily food within 3 hours, under conditions in which emotional factors were not present. When benzodiazepines were administered (at a dose ranging from 0.1 to 3 mg/Kg) before feeding, they increased both the total amount of food eaten and also the rate at which food was injested. When they were administered at the end of the feeding period, these compounds made the animals resume eating voraciously. The order of decreasing potency of the benzodiazepines tested was: oxazepam, N-methyl-lorazepam, diazepam, chlordiazepoxide, pinazepam, medazepam. Oxazepam (3 mg/Kg) stimulated maximally the food intake, even when administered up to 12 hours before feeding. Finally, oxazepam antagonized the anorexigenic effect of d-amphetamine, but did not influence amphetamine-induced hyperactivity and stereotyped behavior.
In two adult horses doses of 0.02-0.03 mg/kg diazepam, intravenously, increased 1 hr intake 54-75% above control levels. Intake was stimulated when the diet was a high grain, calorically dense one and also when the diet was a high fiber, calorically dilute one. Two young rapidly growing weanling horses showed an even more pronounced stimulation of intake. Following diazepam 1 hr intake was increased 105-240% above control lelvels. Promazine at a dose of 0.5 mg/kg also stimulated intake in adult horses, but not as markedly as did diazepam. A transquilizer and a neuroleptic appear to have a stimulatory eff upon short-term intake in horses.
Triflubazam (ORF 8063), a benzodiazepine derivative with a unique structural modification, produced in animals pharmacologic effects that were similar to, and pharmacologic effects that were different from those of the psychotherapeutic agents, chlordiazepoxide and diazepam. The drug was generally intermediate in potency to chlordiazepoxide and diazepam in motor performance, anticonvulsant and antiaggressive behavior tests in mice and produced minimal cardiovascular and autonomic effects in dogs. However, it had a larger LD50 and a considerably longer duration of action than diazepam in mice and produced sedation without presedation excitation in cats. ORF 8063 did not stimulate appetite in dogs at a dose of 2.0 mg/kg administered for 14 consecutive days and produced a slight, nondose related antiemetic effect. While the significance of these effects remains to be shown in clinical studies, early clinical studies have shown an anxiolytic effect of ORF 8063.
Pyrazapon, a pyrazolodiazepinone, exerts strong disinhibitory effects on behavior in a variety of animal tests (ingestion of a novel food substance, conditioned conflict, hypothalamic self-stimulation). In tests for sedation, motor depression, and ataxia, weak effects were seen relative to chlordiazepoxide and diazepam. Pyrazapon also shows considerable ability to protect against pentylenetetrazol-induced convulsions in acute tests. However, much tolerance develops to this effect in the course of daily treatments. Tolerance does not develop, on the other hand, to the behavioral disinhibitory effect. No untoward pharmacodynamic effects were observed at doses several fold greater than those producing the principle pharmacologic effects. Pyrazapon may well be an effective antianxiety drug with very weak sedative side effects.
Naive, non-hungry, non-thirsty rats ingested inordinate amounts of a sweetened milk solution when given their first opportunity to drink the solution while under the influence of benzodiazepine drugs. Among many other drugs tested, only phenobarbital gave a similar, although clearly weaker, effect. The test provides a simple, rapid, sensitive, and specific screen for benzodiazepine-like drugs. The effects were interpreted in terms of these drugs overcoming (disinhibiting) a rat's natural aversion to an unfamiliar food substance without at the same time greatly sedating the animal.
Two experimental situations induce hyperphagia in the rat: the cafeteria model and the tail-pinching model. In non-deprived rats which are offered for one hour a choice of 3 liquid cafeteria items in addition to ordinary chow and water, mild tail-pinching results in a preferential sucrose hyperphagia; naltrexone (2.5 mg/kg IP) suppresses this stress-induced hyperphagia; beta-endorphin (3 micrograms ICV) has the same effect. This apparent discrepancy is discussed: the antagonist may suppress the hyperphagia because it suppresses the reward provoked by the sucrose, the agonist because it makes it unnecessary.
Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half-life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 0.05) was markedly prolonged in obese subjects. However, mean steady-state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single-dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half-life was greatly prolonged in the obese subjects (82 vs. 32 hours, P less than 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P less than 0.01) was the reason for prolongation of the elimination half-life. Similarly for desmethyldiazepam, elimination half-life was prolonged in obese subjects (130 vs. 56 hours, P less than 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P less than 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal-weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetic data for 12 anticonvulsant drugs was evaluated after administration to laboratory rats. In all cases the half-life and elimination rate constants were significantly different from clinically-determinant values which suggests that pharmacokinetic parameters should be treated as species specific.
Distribution, and excretion of [14C]-brotizolam were determined after oral and intravenous administration in the rat, dog, rhesus monkey, and, in part, in cattle. Main metabolites were identified. Brotizolam was rapidly and extensively absorbed. In the rat, dog, and monkey blood levels were analysed according to the time and height of maximum radioactivity concentration. Elimination half-lives ranged from 14.8 to 20.8 h. Whole body autoradiographic studies in the rat showed that [14C]-brotizolam and its metabolites were distributed throughout the organism. The placenta was crossed, and brotizolam was found in the milk of rats as well as in that of cows. In the rat, dog and monkey, brotizolam was almost completely metabolized into hydroxylated compounds which were rapidly eliminated as conjugates. After multiple-dose treatment, neither a tendency to accumulation of brotizolam and its metabolites nor enzyme induction were found in the rat or monkey.
Chlordiazepoxide (5 and 10 mg/kg) and diazepam (2.5 mg/kg) reduced the latency to eat and enhanced feeding response to familiar food in a food-preference test. The increased feeding response resulted from an increased frequency of individual eating episodes (bouts) without significant change in the episode duration. Experiment II indicated that this facilitatory action of the two drugs was not dependent on the presence of principal novelty cues in the food-preference test. Diazepam (5 mg/kg), in contrast, enhanced the feeding responses to novel food in the food preference test. Experiment III demonstrated that although diazepam can counteract induced food neophobia, its facilitory action on the response to novel foods may be mediated by a mechanism which can operate independently of food neophobia.
Chlordiazepoxide (CDP) given acutely has been found to have dose-related effects in rats given food preference tests. Low doses selectively increase consumption of familiar food, while high doses increase novel food consumption. The present study examined the effects of three doses of CDP given chronically. All doses (2.5, 5.0 and 10.0 mg/kg) selectively increased novel food eating. There was some evidence for a selective retardation of eating rate for familiar food and an enhanced taste preference for sweet food in CDP-treated rats. However, the overall results suggest that increased consumption of novel food represents an antineophobic action of CDP, which is potentiated by chronic treatment over a low to medium dose range.
A modified hyponeophagia test is described as an animal model of anxiety. The effects of 0, 0.3, 1.0, 3.0 and 10 mg/kg diazepam, given both acutely and for 7 days pretest, were assessed in rats. Acutely, diazepam reduced hyponeophagia over the dose range 0.3-3.0 mg/kg but 10.0 mg/kg produced sedation and large variability. Chronically, the dose-response relationships were monotonic and the maximal effect was increased, suggesting that differential tolerance occurs to the sedative, but not to the anxiolytic, effects of this drug. Increased food deprivation did not mimic benzodiazepine effects on hyponeophagia, and actually prolonged eating latency in rats treated with 5-methoxy-N,N-dimethyltryptamine (2.5 mg/kg), which does not support an interpretation of diazepam effects in terms of appetitive actions. An arousal hypothesis of hyponeophagia was proposed and supported by the antagonism of the sedative effects of 10.0 mg/kg diazepam by d-amphetamine (0.5 mg/kg). Although both male and female rats were used throughout, sex differences were few in these studies.
Bicuculline antagonizes diazepam induced feeding in Syrian hamsters in a dose dependent manner using doses which do not affect running wheel activity. These results suggest that diazepam-induced feeding can be completely and specifically blocked by antagonizing GABA.
A highly palatable diet (ordinary chow supplemented with 4 highly palatable items changes every day) (HPD) provokes hyperphagia and overweight in the rat. After 17 weeks of such a diet, naltrexone (0.5 or 2.5 mg/kg IP) and opiate antagonist, was injected at the beginning of the dark period, and a food intake test was performed during the 3 following hours. Naltrexone does not modify the energy intake in control rats receiving ordinary chow but suppresses HPD induced hyperphagia. The involvement of the beta-endorphin system in this type of hyperphagia is discussed.