Effects of catecholamines on water intake in rats.

It is known that intraperitoneally (IP) injected adrenaline (A) inhibits food intake in otherwise hungry animals. In a recent work, Hinton et al. (6) showed that IP A also inhibits water intake in thirsty rats, concluding that A's effect is unspecific. We administered A IP or intramuscularly (IM) in different doses in rats made thirsty either by 18-h water deprivation or by subcutaneous injection of hypertonic saline or polyethylene glycol. IP A reduced water intake in all experimental conditions. A dose-related inhibition was observed in water-deprived animals. On the other hand, IM A showed a small effect only at the highest dose (50 micrograms/100 g body weight). When some of these experiments were repeated using noradrenaline (NA) and isoproterenol (IS), IM administration of either substance showed no effect. IP administration reduced water intake significantly only at the highest dose of NA (50 micrograms/100 g). It is concluded that water intake inhibition by catecholamines in rats made thirsty either by osmotic or by volumetric challenges is of porto-hepatic origin and, in contrast with food intake inhibition, has no beta-adrenergic component.

Dissociation of intake adjustments to sustained and day-to-day changes in food caloric density.

Rats were subjected to day-to-day changes in food caloric density superimposed on a sustained (average) change above or below the basal value. This was done by giving them a different diet every day, so that caloric density gradually increased from a basal value. By repeating this procedure the caloric density varied in a sinusoidal pattern above or below the basal value. Short-term compensatory changes in food intake followed a reversed and delayed sinusoidal pattern (compared to that of caloric density), and achieved only an incomplete compensation of caloric intake. On the other hand, long-term changes in the average food intake led to a complete compensation of the average caloric intake for the high-calorie diets. The low-calorie diets produced a marked body weight loss, although these rats maintained the partly compensatory responses to the day-to-day changes in caloric density; that is, food intake decreased when the caloric density of the diet increased to the basal value, overriding any effect of body weight loss. It is concluded that short-term and long-term controls of food intake are relatively independent of each other and that the short-term control determines the daily caloric intake, with a delay that probably indicates learning processes, while the long-term control is determining the average caloric intake over a period of several days, accounting for a more or less complete compensation of caloric density changes.

Ontogeny of the endorphinergic and dopaminergic modulation on the immobility reflex elicited by clamping in rats.

The effects of some dopaminergic and endorphinergic agonists and antagonists on the immobility reflex (IR) elicited by clamping the neck of the rat were investigated. We found that both morphine and haloperidol produce a significant increase in the duration of this IR at all ages tested (10, 20 and 300 days). The effect of apomorphine depends on the age of the rat, showing an increase in the duration of the immobility reflex only at the age of 10 days which was not counteracted by haloperidol. Naloxone alone showed a slight non-significant tendency to increase the duration of the IR but blocked morphine effects at all ages tested. When naloxone was added to apomorphine there was a peculiar effect: the duration of the immobility reflex was increased significantly in rats of 20 days and adults, but not in 10-day-old rats. The combination of morphine plus haloperidol showed the most marked potentiation of the immobility reflex at all ages tested. These results are discussed with respect to the development of dopaminergic and endorphinergic systems to control posture and movement during the IR, and its possible relation to the catatonia of schizophrenics. A hypothetical model explaining an interaction between the dopaminergic and endorphinergic systems in developing and adult rats is presented.

Adrenaline anorexia blocked by alpha and beta adrenergic antagonists in 24-h fasted rats.

The effect of alpha and beta adrenergic blockers, phentolamine (PH) and propranolol (PR), on the anorexia induced by intraperitoneal (i.p.) adrenaline (A) was studied in 24 h-fasting male and female adult Wistar rats. I.p. PH elicited a small but significant increase in food intake in both males and females. The combination of PH + PR completely blocked the anorexia elicited by i.p. A in both males and females. In females, PH and PR alone partially blocked A-induced anorexia. In males, PH had no significant effect on A-induced anorexia but PR blocked it completely. It was concluded that the relative participation of alpha and beta adrenergic receptors in A-induced anorexia seems to depend on the sex of the rat, at least for the doses used in the present study: in females, alpha and beta actions seem to be approximately equal, while in males the beta is predominant.

Ontogeny of alpha- and beta-adrenergic anorexia in rats.

The anorectic action of alpha- (phenylephrine) and beta- (isoproterenol) adrenergic agonists was studied in mildly deprived neonatal, weanling, prepubescent, and adult rats. Intraperitoneal phenylephrine produced a reduction of food intake at all ages but with reduced potency and with a maximum of 50% in neonates. Contrary to intramuscular epinephrine that has no effect on feeding at any age, intramuscular phenylephrine was as effective as intraperitoneal in neonates, probably because it is not as rapidly destroyed in tissues as epinephrine. However, in weanlings and adults intramuscular phenylephrine was much less anorectic than intraperitoneal, suggesting that this effect is exerted via the liver. Isoproterenol did not reduce milk intake at any age before adulthood. Lactate had no effect on milk intake before the age of 40 days. Thus catecholamine anorexia is a purely alpha-adrenergic effect in young rats and appears before the metabolic effect of lactate. beta-Adrenergic anorexia, on the other hand, can be obtained only after puberty, suggesting that the mechanism mediating it matures after the preparatory action of the sexual hormones.

Adrenaline-induced anorexia acts on tail-pinch feeding in the rat.

Non-injurious tail-pinching of rats induced much more milk intake than water intake, whether the fluids were offered singly or in a choice. In both the single item and choice situations i.p. injection of adrenaline in doses of 2.5 to 15 micrograms/100 g elicited a marked, dose-related inhibition of tail-pinch-induced (TPI) milk intake, but had no consistent effect on the small amount of TPI water intake. The same doses of adrenaline injected i.m. has no inhibitory effect on TPI milk intake; on the contrary, they elicited increases (although these were not statistically significant). Thus, the effects of adrenaline (probably of hepatic origin because they are produced only by i.p. injections) which inhibit feeding caused by food deprivation are also capable of inhibiting non-homeostatic feeding induced by tail-pinch in a satiated rat.

Anorexia elicited by different catecholamines in rats.

Adrenaline (A) produces a strong anorexic effect, possibly by acting on hepatic receptors (nerve endings on hepatocytes). To study whether this is mediated by alpha- or beta-adrenergic mechanisms, or both, the anorexigenic effects of intraperitoneal injections of A, noradrenaline (NA) and isoproterenol (I) were studied under four different experimental conditions: (I) at the beginning of the dark period in rats fed ad libitum, or (II) on a 24 h-feeding/24 h-fasting schedule; (III) during the light period, under the same feeding schedule; (IV) after an acute 24 h fast. In condition I, the three catecholamines produced a marked decrease in feeding, slightly larger for A. In condition II (dark), they elicited a decrease in food intake about double that in condition III (light), their relative potencies also differed: A greater than I greater than NA in II and A greater than I = NA in III. In IV, the same relative potencies were obtained as in III. A mixture of half-doses of NA and I had the same effect in III and IV as either NA or I alone, suggesting that the alpha and beta effects are additive. However, even a mixture of the full doses of NA and I was not as effective as A in condition IV. This suggests that A is more potent than NA or I at stimulating hepatic adrenergic receptors that cannot be classified as either alpha or beta.

Ontogeny of immobility reactions elicited by clamping, bandaging, and maternal transports in rats.

Wistar neonate rats assume a characteristic posture when being transported by the mother. This carrying posture is normally elicited by the pressure given by the mother's teeth on the pup's neck. By clamping or bandaging the neck and head an immobility reflex with flexion of body and limbs resembling the carrying posture is elicited when pups are in a supine position. On the contrary, by bandaging or by lightly clamping the pups in a prone position, a dorsiflexion with extension of forelimbs is elicited. Both clamping or bandaging inhibits contact and air righting. After a period of immobility bursts of activity follow. The characteristics of all the reactions described above depend on the age of the developing pups. It seems that the immobility reflex with ventroflexion of the body is a behavior used initially by pups to facilitate carrying by the mother, and by both pups and adults as a defense against predators. The posture adopted by the pups bandaged in the neck in a prone position is very similar to the posture they adopt while suckling from the mother. It is postulated that the weight of the mother when lying over the pups plus the pressure on the paws caused by their prone position, could be the stimulus that normally produces the suckling posture.

Correlation between immobility reflex and electrocortical afterdischarges in rabbits.

Correlation between immobility reflex and electrocortical after-discharges in rabbits. In each experimental session, the immobility reflex was elicited by inversion of the rabbit and afterward three electroshocks were applied at 15-min intervals. A significant negative semilogarithmic correlation between the duration of the immobility reflex and the average duration of the electrocortical afterdischarges was observed during the first two experimental sessions. In subsequent sessions such correlation disappeared. It was postulated that the inhibitory processes responsible for the immobility reflex, and those responsible for postepileptic extinction, could initially share some neural mechanisms, but with repetition, they become independent of each other.

Ontogeny of epinephrine-induced anorexia in rats.

Intraperitoneal or intraportal epinephrine elicits a strong inhibition of food intake in adult rats and dogs but has no effect when injected intramuscularly or intrajugularly, in spite of production of larger hyperglycemia and cardiovascular changes. These facts suggest that the effect of epinephrine on feeding is elicited via the liver. Ontogeny of this adrenergic control of food intake was studied in newborn and weanling rats. Anorexic effect of intraperitoneal epinephrine was clearly observed in dam-deprived 3-day-old neonatal rats (youngest in which it was tested), both when they were offered enriched milk through an anterior oral cannula while they were isolated from their dam and when they were allowed to suckle from her. However, anorectic effect was less in neonatal rats (day 3-13) than in adults. Weanling rats, 21-26 days old, were as sensitive to intraperitoneal epinephrine as adults. In 3- to 4-day-old rats it also reduced water intake, but this effect disappeared by day 12 and was not observed in mildly water-deprived adults. Peripheral adrenergic control of intake appears very early in ontogeny of rats. First, it affects food and water intake equally, but by day 12 it affects only food intake. Increase in sensitivity to epinephrine after weaning is probably due to an increase in number of hepatocytic adrenergic receptors and/or increase in enzymes necessary for hepatic effects of epinephrine.

Glycogenolytic substances, hepatic and systemic lactate, and food intake in rats.

Changes in hepatic lactate and glucose and systemic blood lactate produced by intraperitoneal injections of epinephrine, isoproterenol, glucagon, and insulin showed a high correlation (r = 0.9) with the changes in food intake elicited by the same substances. The changes in systemic blood glucose showed no correlation with the changes in feeding, which suggests that central glucoreceptors are not playing an important role in the observed changes in feeding. The intramuscular epinephrine had no significant effect on food intake, in spite of changes in systemic and hepatic lactate and glucose similar to those elicited by intraperitoneal epinephrine. However, intramuscular epinephrine had no hepatic glycogenolytic effect. This suggests that the changes in glucose and lactate elicited by intraperitoneal epinephrine result from hepatic glycogenolysis, whereas the changes elicited by intramuscular epinephrine result from muscular glycogenolysis and inhibition of insulin. Thus hepatic glucose and lactate are good predictors of feeding only when they are produced endogenously by hepatic glycogenolysis. It was concluded that hepatic lactate cannot be the substance sensed by hepatic metabolic receptors. However, due to a possible change in the hepatic lactate-to-pyruvate ratio elicited by intraperitoneal epinephrine, hepatic pyruvate may still be correlated with feeding during the action of both intramuscular and intraperitoneal epinephrine. Therefore the hypothesis that pyruvate is the substance monitored by hepatic metabolic receptors should be tested.

Effect of adrenergic blockers and depleters on food intake in rats.

In rats kept at a constant temperature (24 +/- 1.5 degrees C) and on a reversed day/night cycle (light from 11 p.m. to 11 a.m.), the amount of food eaten during the first 2 h of darkness and during 24 h was measured every day. When reserpine or guanethidine were injected 5 min before the beginning of the dark period on four consecutive days, there was no significant change in the 0.5-, 1-, or 24-h food intake on the injection days, but there was a significant increase in the 0.5-, 1- and 2-h food intake during the next five to eight days, without any change in the 24-h intake. A single injection of dichloroisoproterenol produced no change on the day of injection but it induced a significant increase in the 0.5-, 1- and 2-h intake on the following 15 days, without any change in the 24-h intake. The increase in the early night-time feeding without any change in the 24-h intake was interpreted as an increase in meal size (diminished preabsorptive satiation) compensated by a decrease in meal frequency. Both reserpine and guanethidine are catecholamine depleters but the latter does not penetrate into the brain. Dichloroisoproterenol is a beta-blocker acting on the glycogenolytic effects of catecholamines. The results thus agree with the hypothesis that glycogenolysis elicited by the liberation of intrahepatic catecholamines from the sympathetic nerve endings and chromaffin cells plays a role in preabsorptive satiation.

Effects of hepatic denervation on the anorexic response to epinephrine, amphetamine, and lithium chloride: a behavioral identification of glucostatic afferents.

Intraperitoneal injections of epinephrine (20, 40, 80, and 160 microgram/kg) and amphetamine (.1, .2, and .4 mg/kg) were administered to rats with various forms of hepatic denervation. In Experiment 1, destruction of the esophageal trunks of the vagus attenuated epinephrine and amphetamine anorexia, but destruction of the hepatic vagus did not. In Experiment 2, rats with celiac ganglionectomy, subdiaphragmatic vagotomy, or the combined operation all exhibited decreased epinephrine anorexia to the same extent. However, ganglionectomized rats were less responsive to amphetamine anorexia than were vagotomized ones. Vagotomized rats were significantly more reactive to lithium chloride (10, 20, and 30 mg/kg) than were controls. These results suggest that the major component of hepatic metabolic afferent fibers travels from the liver, through the celiac ganglion, and into the esophageal vagal trunks where they ascend to the brain. The anorexic action of amphetamine appears to result from a centrally induced sympathetic action on the liver.

Dissociation between behavioral and electrocortical manifestations of electroshock convulsions during the action of an anticonvulsive drug.

It was shown that 5-OH-5-ethyl-5-phenyl-butyramide (formerly called 5-ethyl-5-phenyl-2-pyrrolidinone) significantly reduces convulsions induced by electroshock in rats, and by drugs in mice. We are reporting a dissociation between the effects of this drug on the behavioral manifestations of electroshock and on the electrocortical afterdischarges. At 50 mg/kg, the drug reduced greatly the duration of the tonic phase of muscular convulsions, but had little or no effect on their total duration or on the electrocortical afterdischarges. At 100-150 mg/kg, the effect on the tonic phase was only slightly larger, but the total duration of behavioral convulsions and the intensity of electrocortical afterdischarges were substantially reduced, while the duration of the latter was either slightly reduce or increased. Only 200 mg/kg, which had clear depressant effects, produced a complete disappearance of all manifestations of electroshock convulsions. It can be concluded that this drug acts more strongly on subcortical structures that transmit cortical convulsions to the muscles, than on the cortical mechanisms that generate electrocortical afterdischarges.