Alcohol aversion in the rat: behavioral assessment of noxious drug effects.

Injections of p-chlorophenylalanine or n-butyraldoxime given after rats were first given a 10-minute drinking test with saccharin or ethanol solutions produced a learned aversion to these solutions. These findings suggest that the reduced self-selection of alcohol (preference) resulting from the administration of these drugs, reported by others, is not specifically alcohol-related. The technique described offers a sensitive procedure for the assessment of unpleasant effects of drugs.

My scientific life: 40 years at the College de France.

This article presents a translation into English from an autobiographical document written in French by Jacques Le Magnen. The text contains a full translation of Le Magnen's account of the progression of scientific studies in his laboratory, as well as selected biographical data illustrated by quotes from Le Magnen's text. A complete scientific bibliography is included.

Is regulation of body weight elucidated.

A new perspective on mechanisms involved in the regulation of a constant fat body mass and its relation to body energy balance is presented on the basis of a series of experiments. A study of the neuroendocrine conditions underlying the daily weight gain-weight loss cycle in rat and man and experimentally induced over and underweight, leads to the notion that lipogenesis and lipolysis above and below a range of physiological fluctuations of body fat develop a counter-regulatory tendency to correcting lipolysis and lipogenesis respectively. This development is attributed to a chronic central action of plasma insulin concentration on hypothalamic insulin receptors. This liporegulatory system which controls and regulates the filling and emptying of fat stores modulates the feeding system which controls and regulates the filling of a gastrointestinal store by eating and its emptying by metabolic food utilization.

Fall in blood glucose level precedes meal onset in free-feeding rats.

It has been suggested for a long time that the metabolic stimulation to eat or the hunger arousal of eating, originated from a fall in the blood glucose level induced by the periodic failure of hepatic glucose production to match the peripheral glucose uptake. However, this suggestion has not been substantiated directly by the results of periodic blood glucose evaluations performed during intermeal intervals in free-fed rats. In this experiment, a technique involving a continuous blood glucose determination over several hours was used in free-feeding, undisturbed rats. It was shown that all nocturnal and diurnal meals were preceded by a 6 to 8% fall of blood level, starting 5 to 6 min prior to meal onset. The overall consequences of these findings are discussed.

Aspects of the neuroendocrine bases of the diurnal metabolic cycle in rats.

The difference between nocturnal and diurnal glucose disappearance rate, glucose stimulated insulin release and insulin sensitivity has been studied in normal adult female rats. The glucose clearance rate measured after an IV injection of glucose (1 g/kg) was found to be slower during the day than at night. However, due to the non-physiological level of hyperglycemia induced, the insulinogenic index failed to reveal a difference in glucose stimulated insulin release. On the contrary, the hypoglycemic response to an IV injection of 0.5 IU/kg of insulin indicated a higher insulin sensitivity and tissue glucose uptake at night compared to the day. The results are discussed with respect to the role of the neuroendocrine diurnal pattern underlying the diurnal periodicity of feeding.

Palatability and preabsorptive insulin release.

The purpose of these experiments was to determine whether the level of orally-triggered and vagally-mediated preabsorptive insulin release was related to the degree of food palatability as measured by the amount of food necessary to produce satiation. Rats were habituated to a feeding schedule of five meals per day. During a test meal they were presented with one of 3 forms of their regular diet: unaltered, sweetened with Sucaryl sodium or adulterated with quinine hydrochloride. From 1.5 min preceding the meal to 19.5 min later, blood was continuously drawn via a chronic intravenous catheter. Blood was collected for regular intervals and immunoreactive insulin levels were determined. During the test meals, the rats ate 3, 4.9 and 1.5 g of the three diets, respectively. Within the first 3 min following meal onset, they exhibited a peak insulin release of 47, 65 and 25 microU/ml, respectively. Since this early insulin response disappeared long before the end of the meal, it was suggested that the palatability-dependent amount eaten could be affected by the palatability-modulated preabsorptive insulin release.

Behavioral regulation of the blood glucose level in rats.

Rats bearing one or two intravenous (IV) or one intravenous and one intragastric (IG) chronic catheters, were allowed to press one or two levers controlling the IV injection of either insulin or glucagon alone, or insulin paired with glucagon or with a glucose solution IV or IG. It was shown that rats readily learned to press for the various solutions and exhibited a sustained pattern of self-injection specific to these solutions and to their combinations. The rats self-injected insulin, glucagon and glucose preferentially during the 20 min preceding and following meals. Alone, or in combination with other solutions, glucose and glucagon were self-injected preferentially before meals and insulin after meals. Consequently, glucose or glucagon to insulin self-injection ratios were inversed from the pre-meal to the post-meal periods. In addition, rapid alternations from one lever to the other were observed in the coupled self-injections of insulin and glucose or insulin and glucagon. No effects of the self-injections on the free feeding pattern were observed. The results are interpreted as evidence for the reinforcing effects of a correction of both hypoglycemia and hyperglycemia and for a role of these systemic primary reinforcements in the normal post-ingestive modulation of oral feeding responses.

Parameters of the meal pattern in rats: their assessment and physiological significance.

Parameters of the meal pattern in rats were assessed and their physiological significance investigated through a detailed study of continuous graphic recordings over 20 consecutive days in ten rats. Both prandial and diurnal periodicities were examined. The definition of meals, by a criterion of 40 min of non-eating before and after a feeding episode, was validated statistically. The two superimposed periodicities were substantiated by studying night and daytime differences in meal sizes, meal-to-meal intervals, meal size/interval ratios, and post prandial correlations. The results provide new evidence for the role of metabolic and neuroendocrine factors in determining the relationships between meal size and post-meal intervals and their differences during the two parts of the diurnal cycle.

Changes of meal patterns induced by food deprivation: metabolic correlates.

Six hour food intake following 0 to 6 hours of food deprivation was compared during the light and dark cycle in rats. Changes in the size of the first meal and the length of the first post-meal interval, as a function of deprivation, were related to plasma glucose and free fatty acid levels immediately prior to and 90 minutes following the first meal. It was determined that at night the size of the first meal increased and the relative duration of the post-meal interval decreased as a function of previous fast duration. The shortening of post-meal satiety was associated with the food deprivation induced decrease of blood glucose level and rise of free fatty acids which were observed prior to the meal. The fast induced changes of the meal pattern observed at night and the resulting 6 hour hyperphagia support the conclusion that the duration of post-meal satiety is determined by the meal-to-meal balance between energy intake and utilization.

Variations of meal-to-meal liver glycogen in rats.

Liver glycogen content was determined in free feeding rats sacrificed at the beginning of nocturnal meals or 60 min later. It was found that the glycogen content at the beginning of meals and 60 min later was highly correlated with the cumulative food intake since the beginning of the dark cycle, and therefore, increased from meal to meal. The comparison of these correlations between the cumulative food intake and the liver glycogen at the beginning of the meal and 60 min after ruled out the possibility that a constant decrement of glycogen might be involved in both meal onset and prandial periodicity of feeding. Rather the results are consistent with the view that the glycogen load during the night is a minute carbohydrate store which, like the fat store, is involved in the diurnal 12/12 hr feeding periodicity.

Differential effects of 2-deoxy-D-glucose on plasma glucose, free fatty acids and feeding during the light and dark cycle in rats.

The effects of 2-deoxy-D-glucose (2-DG) combined with 0 to 6 hr of food deprivation on plasma glucose (PG), plasma free fatty acid (PFFA) levels and feeding were compared during the 2 parts of the diurnal cycle. In one group, PG and PFFA were measured prior to the injection of either 2-DG or saline and 90 min after injections without restoration of access to food. In a second group, food was reintroduced following injection and intake was measured. At night, PG and PFFA measured prior to injections decreased and increased with respect to the length of food deprivation. Ninety minutes after 2-DG, PG and PFFA were elevated above control levels as a function of previous deprivation. During the day, fasting time did not affect PG and PFFA 90 min after a saline injection; but, after 2-DG, PG increased and PFFA decreased irrespective of the previous deprivation period. At night, food intake increased after saline and 2-DG as a function of fast duration, but increases were significantly lower after 2-DG. During the day, the duration of food deprivation did not affect food intake after 2-DG and saline; but irrespective of previous food deprivation, the cumulative intake of the first 2 hr was higher after 2-DG. Results are discussed in relation to the dual activation by 2-DG of facilitatory and inhibitory mechanisms of food intake.

Recovery of body weight following starvation or food restriction in rats.

Recovery of body weight and food intake have been studied and compared after a 25% weight loss produced by total starvation in one group of rats or by food restriction in a second group. It was shown that rats in both groups returned to their initial body weight within the same time on the average, but the hyperphagia observed during the recovery phase was significantly higher in restricted than in starved rats. In the former, the increase of food intake fully accounted for the weight gain. On the contrary, the recovery of body weight in previously starved rats involved both hyperphagia and a long lasting persistence of the fasting hypometabolism. In addition, it was shown that in those rats the higher the contribution of hypometabolism the longer the recovery. Starvation diabetes was higher in starved than in restricted rats and might be one factor which impairs weight regulation through hyperphagia after a weight loss induced by food deprivation.

Food deprivation induced parallel changes in blood glucose, plasma free fatty acids and feeding during two parts of the diurnal cycle in rats.

The changes in plasma glucose and free fatty acid levels and in subsequent feeding induced by 4 to 10 hr of food deprivation were investigated in rats and compared for the two parts of the diurnal cycle. It was found that increasing fast duration at night induced a more rapid fall of plasma glucose and elevation of plasma free fatty acids than in the day. However, a similar increment of the first post fast meal was elicited by an identical decrement of blood glucose level for the two periods except after a 10 hr fast during the day. The acute effect of darkness and light per se being experimentally excluded, it was concluded that the size of the first meal following short term food deprivation was dependent throughout the diurnal cycle on the fast induced glucoprivic condition.

Chewing and swallowing as indices of the stimulation to eat during meals in humans: effects revealed by the edogram method and video recordings.

Patterns of chewing and swallowing were recorded during standardized meals in humans. Cocktail size (3 cm2) open sandwiches were served in one of five different flavors. An oscillographic recording of chewing and swallowing showed that chewing activity varied with the palatability and variety of foods. Chewing time was shorter and fewer chews were observed as palatability increased. Swallowing did not change as a function of stimulus flavor. Pause duration between two successive food pieces became shorter as palatability increased. The effects of sensory factors were most evident at the beginning of meals and decreased until the end of meals. A later study which compared eating parameters in sandwich, semi-solid, and traditional French meals (different courses ingested in succession: appetizer, main course, cheese and dessert), as assessed from video recordings, found that different microstructure parameters responded to palatability manipulation in different meal types. Strength of mastication and prandial drinking might be other important parameters to look at in order to understand the motivation to eat and its fluctuations during the meal.

Feeding rate and responses to food deprivation as a function of fasting-induced hypoglycemia.

The relation between hypoglycemia induced by 3 hr of food removal at various times throughout the day and the amount eaten during the corresponding ad-lib periods was examined in rats. It was found that the 3-hr-deprivation fall in blood glucose was different between the night and the daytime and also between the beginning and the end of the daytime. A highly significant correlation existed between the 3-hr ad-lib intake and this time-dependent fall in blood glucose. Moreover, the correlation between the same fall in blood glucose and increases in subsequent intakes after 3-hr deprivation was also significant. The conclusion is drawn that rats eat at a rate just required to prevent hypoglycemia under ad-lib conditions and that after food deprivation they transiently increase this rate to correct the fall in blood glucose and to reestablish the required supply of glucose to tissues.

Failure of naloxone to affect initial and acquired tolerance to ethanol in rats.

The effects of naloxone on the initial sensitivity to ethanol and the subsequent changes in tolerance induced by prior ethanol treatment were studied in rats by using the drinking test for assessing behavioral effects. Naloxone (N) was administered concurrently with ethanol (E) in either 5 successive single doses spaced at 2-day intervals (Experiment 1) or during 4 days of chronic i.v. infusion (E: 9 g/kg, N: 9 mg/kg in 6 injections per day, Experiment 2). Both treatments produced an increase in nervous tolerance toward ethanol. However naloxone was found to exert no effect on either initial or acquired tolerance toward ethanol. The results are discussed in terms of possible relations between the CNS mechanisms involved in tolerance to morphine and ethanol.

Daily body energy balance in rats.

The aim of the present study was to examine the balance between caloric intake and expenditures in successive 12 and 24 hour periods, for several consecutive days in rats. The simultaneous and continuous measurements of respiratory exchanges and of the spontaneous feeding pattern were performed in 6 rats during 38 days, in periods of 2 to 4 successive days. At night, caloric intake exceeded caloric expenditures by 32% on the average. In individual rats, the excess was positively correlated to meal size but not to meal number. During the daytime, caloric intake was 24% lower on the average than the concomitant energy expenditures. In individual subjects, these deficits were correlated to meal number but not to meal size. A nocturnal excess and the subsequent daytime deficit, and the diurnal deficit and the excess during the subsequent night were highly positively correlated. In fact, the 24 hour energy balance was either slightly positive (12% excess) or negative (4% deficit). The daily weight gain or loss was highly correlated to the residual excess and/or deficit with a mean caloric cost of 4.8 kcal per g of body weight. The absence of correlation between balances on successive days indicates that the body energy balance is regulated within 24 hr through 12/12 hr compensations and that no compensatory mechanisms are involved beyond 24 hr.

Dual effects of 2-deoxy-D-glucose on food intake in the rat: inhibition at night and stimulation in the day-time.

The effect of 2-deoxy-D-glucose on food intake in rats has been reexamined. The effects were compared following administration of 2-DG IP (250, 500, 750 mg/kg and saline) either at the beginning of a 12-hr dark or 12-hr light period. Ad lib food intake was recorded during the subsequent 24 hours. In the day-time 2-DG enhanced food intake. The increase was not dose-dependent. It was apparent only during the first four hours and was compensated during the following eight hours. At night, an inhibition in food intake was observed. This inhibition was mainly manifested during the first four hours and was not dose-dependent. However, a dose related compensation during the subsequent hours resulted in a dose-dependent inhibition of the nocturnal intake. A second expermient indicated that after an overnight fast 2-DG also inhibited the high food intake induced in the day-time. In a third experiment, insulin 10 IV SC combined to 2-DG was shown to further increase food intake in the day-time. At night the combined administration of insulin and 2-DG cancelled their respective opposite effects and no change of food consumption was observed. The results are interpreted in terms of the contrasted neuroendocrine and metabolic patterns prevailing in the two parts of the diurnal cycle.

Fast-induced changes in plasma glucose, insulin and free fatty acid concentration compared in rats during the night and day.

Changes in PG, PI and PFFA were examined and compared in fed rats or after 0 to 12 hours of fasting, during the night or during the day. At night, a progressive decrease in PG and PI and an increase in PFFA were induced by 0 to 12 hours of food deprivation. During the light period a decrease in PG occurred only from the 6th hour of fasting. A slight, progressive increase in PFFA levels was induced from 0 to 12 hours of fasting, while no significant variation of PI levels was observed. The results are discussed in terms of relationships between blood glucose, PFFA levels, and food intake in control rats over the circadian cycle.

Meal related effects of IV glucose, glucagon and insulin on blood glucose level: role in glucoregulation exhibited by self-injecting rats.

In previous works, it was demonstrated that rats self-injected with (IV) glucose, insulin and/or glucagon and that the self-administration pattern was related to the meal. It was suggested that the different preprandial or postprandial blood glucose level (B.G.L) determined the meal and were dependent on it. Previously self-injected amounts of glucose, glucagon and insulin were here injected by an automatic device and their effect on B.G.L. were compared in the post and preprandial conditions. Results indicated that the effects of insulin, glucagon and glucose on B.G.L., which were different during the postprandial hyperglycemia compared to the preprandial normoglycemia, accounted for the different self-injection patterns. Furthermore successive injection of glucose and insulin or glucagon and insulin suggest that rats, by pressing alternatively two levers performed a regulatory correction of variations of their B.G.L. It is concluded that rats may learn to perform a behavioral regulation of their B.G.L. by IV self-injections of glucose and glucoregulatory hormones.