Hypophagia after long-term administration of sulpiride in adult female rats: a model of D2 dopamine receptors supersensitivity?

Sulpiride (20 mg/kg/ip for 21 days) induced in female rats a significant body weight increase and hyperphagia. After drug withdrawal a significant hypophagia was observed. It is hypothesised that this hypophagia might be a spontaneous manifestation of D2 dopamine receptors supersensitivity, either in the perifornical region of the lateral hypothalamus or in the pituitary.     

Meal patterns and glucoprivic feeding in the guanethidine-sympathectomized, adrenodemedullated rat

The feeding behavior of rats sympathectomized by neonatal administration of guanethidine (GUA) and/or adult adrenal demedullation (MDL) was investigated. GUA treatment tended to decrease body weight gain and food intake, chiefly by decreasing meal size and increasing satiety ratios. It also attenuated the increase in food intake caused by 2-deoxy-D-glucose (2DG; 150, 300, 450 mg/kg, IP) but not by insulin (3, 6, 9 U/kg, IP). MDL altered meal patterns in the same manner as GUA treatment but the effects were of smaller magnitude. It did not influence the response to either glucoprivic challenge. Combined GUA treatment and MDL generally produced additive effects. These results suggest that the major sympathetic influence on feeding is through adrenergic innervation and not circulating catecholamines. The hypothesis that the alteration in feeding patterns produced by ventromedial hypothalamic lesions is due to decreased sympathetic activity was not supported.     

Synchronized release of dopamine and serotonin in the medial and lateral hypothalamus of rats

A positive linear correlation between dopamine and serotonin release was found in the ventromedial hypothalamus and in the lateral hypothalamic area in fasting rats and in fed rats during intermeal intervals. Dopamine release in the ventromedial hypothalamus positively correlated with dopamine and serotonin release in the lateral hypothalamic area, which occurred only during intermeal intervals and was non-significant during the meal consumption periods or during fasting. Meal size correlated significantly only with a decrease in serotonin release in the lateral hypothalamic area. The study was designed to evaluate the relationship between dopamine and serotonin release in these hypothalamic areas and their dependence on feeding status. Microdialysis was performed simultaneously via two probes, one in the ventromedial hypothalamus and the other in the contralateral lateral hypothalamic area, of freely moving male lean Zucker rats over 24h with preserved light and dark phase, either with ad libitum access to food and water, or when no food was available. Dopamine and serotonin concentrations were measured by high-performance liquid chromatography with electrochemical detection in 20-min dialysis samples. Time-series analysis was applied to determine linear correlations between monoamines and in relation to food intake. Data showed that release of dopamine and serotonin is synchronized within the ventromedial hypothalamus and lateral hypothalamic area, particularly in the dark phase and when no food was ingested. However, synchronized release of monoamines between these nuclei occurred only during intermeal intervals: the periods of satiety.These findings suggest a tight relationship between dopaminergic and serotonergic systems of the lateral hypothalamic area and ventromedial hypothalamus, which is influenced by the feeding state and which may be involved in maintaining the balance within and between the centers of the parasympathetic and sympathetic nervous systems. The data also illustate that food intake is coupled unequivocally to the release of dopamine and serotonin in the hypothalamus, suggesting it as a mechanism of activation of postsynaptic neurons associated with new metabolic status.     

Response to glucoprivic and hydrational challenges by normal and hypothalamic hyperphagic rats

Obese VMH-lesioned rats displayed normal, but delayed, increases in food intake to 350 mg/kg 2-deoxy-D-glucose (2-DG) and were hyperresponsive to 4 and 8 U of insulin. Lesioned rats maintained at preoperative body weight responded normally to insulin, but did not increase food consumption to 350 mg/kg 2-DG. Both lean and obese lesioned rats decreased feeding following 750 mg/kg 2-DG. The lesioned animals displayed either no change or an increase in water/food ratios. Those with normal water/food ratios showed a loss in circadian control of water intake and drank less than controls during food deprivation. VMH-lesioned rats responded normally to polyethylene glycol and were hyperresponsive to hypertonic saline regardless of differences in body weight or water/food ratios. The possibility of ventromedial hypothalamic damage producing a general increase in responding, or numerous more specific effects, is discussed.     

Meal-stimulated increased concentrations of CCK in the hypothalamus of Zucker obese and lean rats

CCK is a putative satiety peptide found to be active when administered peripherally and centrally. Concentrations of CCK have been measured in the brains of fed and fasted animals, but as yet no clear correlation with feeding has been found. In the present experiment rats were sacrificed after a 6-hr fast or 5 min after a meal. Areas of the hypothalamus were removed from these rats and assayed for CCK content. The relationship between obesity and CCK content in specific areas of the brain was also investigated by using Zucker obese and lean rats. In fed rats the CCK concentrations were higher than in fasted rats in the ventromedial hypothalamus (VMH) (56 vs. 42 pg/mg tissue, p less than 0.005), lateral hypothalamus (38 vs. 27 pg/mg, p less than 0.01) and supraoptic nucleus (48 vs. 39 pg/mg, p less than 0.01). In obese rats the concentrations were higher than in lean rats in the VMH (56 vs. 41 pg/mg, p less than 0.003), dorsal medial hypothalamus (37 vs. 30 pg/mg, p less than 0.04) and anterior hypothalamus (61 vs. 37 pg/mg, p less than 0.001). Average concentrations of CCK in all hypothalamic areas were higher in females than males (50 vs. 40 pg/mg, p less than 0.001). Thus, CCK concentrations in specific areas of the hypothalamus increased with feeding, supporting the potential role of CCK in the central nervous system as a satiety peptide. Further, although the concentrations of CCK in obese rats were higher than those in lean rats, the changes in CCK concentration with feeding were the same, showing that obesity is not a consequence of decreased concentrations or concentration changes of CCK in brain.     

Effects of insulin and 2-deoxy-D-glucose on plasma glucose level and lateral hypothalamic eating threshold in the rat

Thresholds for elicited eating through monopolar electrodes in the perifornical region of the lateral hypothalamus and plasma glucose concentration were determined over periods of several hours, while blood glucose levels and cellular glucose utilization were altered by means of forced feeding through hypothalamic stimulation, subcutaneous insulin injections and/or intraperitonneal 2-deoxy-D-glucose injections. Forced feeding resulted in increased thresholds for elicited eating, whereby the plasma glucose concentration in the tail vein was positively correlated to these thresholds. A subsequent, long-lasting, severe insulin-hypoglycemia was not sufficient to normalize such elevated thresholds. However, 2-deoxy-D-glucose in doses of 100–250 mg/kg, after an initial increase, decreased thresholds 90 min after injection. When insulin and 2-deoxy-D-glucose were combined so as to balance the contrary glycemic effects, the insulin effect dominated, resulting in slightly increasing thesholds. The results are discussed in terms of the recently suggested hypothesis that insulin regulates glucose entry into glucosensitive systems of the ventromedial hypothalamus, and thus generates satiety signals rather than hunger.     

Trypsin inhibitor effects on food intake and weight gain in Zucker rats

Decreased body weight and increased pancreas weight which occur in rats fed raw soybeans are thought to be due to the presence of trypsin inhibitors in the soybeans (SBTI). Since trypsin is postulated to be a negative feedback signal for cholecystokinin (CCK) secretion, SBTI may have these effects by increasing secretion of CCK. CCK is a putative satiety signal; thus, increased secretion of CCK could decrease food intake, and, if maintained over a period of time, body weight. In these experiments the effects of a trypsin inhibitor [N,N-dimethyl-carbamoyl 4-(4-guanidino-benzylyloxy)-phenyl acetate methane-sulfate (DGPM)]on feeding pattern were investigated in Zucker obese and lean rats. Administration of 25-200 mg/kg DGPM to 6-hr fasted rats decreased daily food intake by dose-dependently decreasing average meal size in both obese and lean rats, but the response was greater in obese rats. Administration of 100 mg/kg DGPM twice daily for 7 days decreased food intake and body weight in obese but not lean rats. Thus, these results suggest that decreased body weight associated with SBTI is due to decreased food intake partly as a result of increased secretion of the putative satiety peptide CCK.     

2-Buten-4-Olide (2-B4O) suppresses feeding in neonate and developing rat pups

The factors that control the satiety behavior and consequently the milk intake in neonates are complex. Mechanical stimulus of gastric filling and emptying are understood to be critical players, though not exclusive. Recently, sugar acid namely, 2-Buten-4-Olide (2-B4O) has been suggested as an endogenous satiety substance in studies conducted on adult rats and monkeys. However, the role of 2-B4O in neonate and suckling rat pups is not well elucidated and this study investigates the same. 2-B4O (50, 75 mg/kg, ip) was injected in rat pups on post-natal days (0-2, 4-6 and 12-14) and the mean difference in body weight at 0.5, 1.2 and 24 h following treatment was recorded. A dose dependent effect on body weight that correlated with the age of the pups was recorded. In another set of experiment, 2-B4O was micro-infused bilaterally into lateral hypothalamus of 12-14 days old pups (1 µl of 10 µg/µl). Within 30 min of micro-infusion, 2-B4O initiated a significant reduction of body weight that lasted up to 24 h following treatment. The results of the present study implicate a critical role of 2-B4O as an endogenous feeding suppressant even in neonate and suckling rat pups.     

Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens

The hypothesis that the dopaminergic system plays a role in feeding behavior was tested in three experiments. First, microdialysis was performed in the nucleus accumbens (NAC) at 20 min intervals during free feeding in rats at 80% of normal body weight. Extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) increased significantly during eating indicating an increase in DA turnover. Second, microdialysis samples were collected from the NAC during bar pressing with a) a signal light on and food available, b) the light on but no food available, c) neither light nor food. Only when food was available did extracellular DA, DOPAC and HVA increase significantly. This increase in DA turnover occurred in the accumbens but not in the ventral striatum. Third, electrical stimulation of the perifornical lateral hypothalamus (LH) that was capable of inducing feeding increased extracellular DA, DOPAC and HVA in the NAC. This occurred whether the animal had food to eat or not. The effect of LH stimulation on DA turnover resembled the effects of free feeding and operant feeding in Experiments 1 and 2. Perifornical LH stimulation did not increase dopamine turnover in the ventral striatum. The results show that perifornical LH stimulation activates the mesolimbic dopamine system and that dopamine release in the accumbens is involved in feeding. The increase in dopamine turnover outlasted the consummatory act. This suggests that accumbens dopamine may be related to sensory input, feeding reflexes, food reward or memory processes and not just to the consummatory act itself.     

Changes in brain CCK concentrations with peripheral CCK injections in Zucker rats

Evidence suggests that the satiety responses to peripherally administered CCK are mediated by a CNS component(s). Since CCK concentrations in the hypothalamus can change with degree of hunger, they may also be involved in the feeding response to peripherally administered CCK. Six-hr fasted rats were administered saline or 2 micrograms/kg CCK-8 and half were allowed to eat a meal. They were sacrificed after a meal or after the fast and hypothalamic content of CCK was measured by RIA. In rats injected with CCK, compared with those injected with saline, CCK concentrations were decreased in the ventromedial hypothalamus (VMH, 39 vs. 47 pg/mg tissue, p less than 0.004) and dorsomedial hypothalamus (17 vs. 21 pg/mg, p less than 0.009) and increased in the lateral hypothalamus (28 vs. 19 pg/mg, p less than 0.01). CCK concentrations in fed compared with fasted rats were higher in the VMH (47 vs. 39 pg/mg, p less than 0.002) and in obese compared with lean rats CCK concentrations were higher in the paraventricular nucleus (48 vs. 38 pg/mg, p less than 0.05), suprachiasmatic nucleus (46 vs. 34 pg/mg, p less than 0.008) and VMH (52 vs. 34 pg/mg, p less than 0.001). Since peripheral injections of CCK influenced concentrations of CCK in hypothalamic areas associated with feeding, these results provide evidence that the feeding response to peripherally injected CCK may be mediated by changes in CCK content of specific brain areas.     

The Role of Neurochemical Mechanisms of Ventromedial Hypothalamus in Various Models of Anxiety in Rats

Microinjections of glutamic acid, serotonin, and sulpiride in the ventromedial hypothalamus reduced anxiety in an illuminated platform avoidance task in rats, while dopamine, apomorphine, picrotoxin, and memantine increased it. Similar injections of phenylephrine and yohimbine reduced anxiety in threatening situation task only, while GABA reduced it in both tasks. It is suggested that various emotional and stress phenotypes are realized through functionally different neurochemical mechanisms of ventromedial hypothalamus.     

Acute and repeated administration of sulpiride alters Met-and Leu-enkephalin content of rat brain

Following acute administration of sulpiride (100 mg/kg, i.p.), Met-enkephalin levels were increased in striatum but decreased in substantia nigra and nucleus accumbens. No effect was observed in hypothalamus or frontal cortex. In contrast, Leu-enkephalin content was decreased in the nucleus accumbens but not elsewhere. Administration of sulpiride (10 or 100 mg/kg, i.p.) for 21 days, followed by 2 days drug withdrawal, caused a dose-dependent increase in Met-enkephalin in nucleus accumbens but decreases in hypothalamus and frontal cortex. No change was observed in the striatum or substantia nigra. Repeated sulpiride administration caused a decrease in Leu-enkephalin content of the hypothalamus and cortex but not elsewhere.     

Effects of ventromedial hypothalamic lesions on rat ethanol intake

The consumption of food, water and ethanol solutions, in free choice condition, was studied in 9 rats with electrolitic lesion of ventromedial hypothalamus, before and after the operation and compared with 2 controls submitted to sham operation. Changes in body weight were studied between 20 and 30 days after the operation. In all the experimental rats there was an increase in food, water consumption and body weight while ethanol intake decreased significantly.     

On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals

The influence of sulpiride on the in vivo release of dopamine and DOPAC from the rat striatum was investigated by microdialysis. Racemic sulpiride was administered systemically (i.p.) to control rats and to rats in which a striatum was pretreated by kainic acid. In addition various concentrations (10(-8) to 10(-5) M) of the two enantiomers of sulpiride were infused into the striatum and the effects on the release of dopamine were recorded. Infusion as well as systemic administration of sulpiride caused a maximal increase in the release of dopamine of about 180-190% of basal values. A similar increase was seen in kainic acid-pretreated rats. The rises in dopamine seen after systemic administration or infusion of sulpiride were not additive, suggesting that similar mechanisms were involved. DOPAC dialysate levels also increased during infusion of the neuroleptic but the rise was significantly less when sulpiride was administered i.p. to kainic acid pretreated rats. It is concluded that the rise in dopamine release seen after neuroleptics is mediated by autoreceptors localized on nerve terminals. This implies that the well-known increase in electrical activity of dopaminergic neurons during neuroleptic treatment, is not responsible for the increased release of the transmitter.     

CCK as a central satiety factor: behavioral and electrophysiological evidence

CCK and its derivatives potently inhibit feeding, even after vagotomy. This effect is thus considered to be peripheral. Recently, however, the vagal gastric branch was reported to essentially bring feeding inhibition into full play. In the present study, it was found that CCK-8, administered into the third cerebroventricle (III-cv), or into the lateral hypothalamus (LHA), significantly and dose-dependently inhibited feeding induced by electrical stimulation of the contralateral LHA (LHA-ESIF) in the chronic rat. This inhibition by CCK-8 was not affected by systemic pretreatment with proglumide (1 mg), a selective antagonist, while CCK (250 ng) simultaneously microinjected into the III-cv with 5 micrograms proglumide almost completely eliminated the CCK effect on LHA-ESIF. Neuronal activity of the ventromedial hypothalamus (VMH) was enhanced, and that of the LHA was suppressed by electrophoretic direct application of CCK on neurons in urethane-chloralose-anesthetized rats. CCK also markedly decreased the threshold of VMH glucose responding neurons. These results indicate that the satiety effect is not only peripheral, but might also be central, especially through feeding-related hypothalamic neurons, which are probably important in feeding inhibition.     

Hypothalamic monoamines measured by microdialysis in rats treated with 2-deoxy-glucose or d-fenfluramine

The effects on brain monoamines (norepinephrine, serotonin and the metabolite of dopamine) following administration of d-fenfluramine (10 mg/kg IP) and 2-deoxy-d-glucose (500 mg/kg IP) have been measured by microdialysis from the ventromedial hypothalamus, lateral hypothalamic area and dorsomedial hypothalamus of conscious, unrestrained rats. Following administration of d-fenfluramine there was a significant increase in the concentration of serotonin in the ventromedial hypothalamus and lateral hypothalamic area, but no significant increase in the DMH. 5-HIAA (5-hydroxy-3-indoleacetic acid), the metabolite of serotonin, was increased in the DMH, but not in the other two regions. DOPAC (3,4-dihydroxyphenylacetic acid) was increased following fenfluramine treatment in all three regions examined. An increase in norepinephrine was observed in the VMH, but not in the other two regions, while the concentration of the 3-methoxy-4-hydroxyphenylglycol (MHPG) was increased in both areas. Treatment with 2-deoxy-D-glucose (2DG) was associated with fewer changes. In the lateral hypothalamic area there was a decrease in 5-HIAA and an increase in DOPAC. In the VMH there was an increase in norepinephrine and a decrease in MHPG in the DMH, but otherwise no significant alterations were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pancreatic glucagon and postprandial satiety in the rat

The hypothesis that administration of pancreatic glucagon inhibits feeding by eliciting satiety for food was tested against several behavioral and physiological criteria of specificity. The effects of intraperitoneal glucagon injections on intake of a palatable milk diet were tested in rats maintained with ad lib access to pelleted diet. Injections of 25–800 μg/kg glucagon administered at meal onset inhibited meal size by 17–36%, but did not affect the normal postprandial behavioral satiety sequence or elicit any behavioral signs of toxicity. Latency to rest and intermeal interval were not affected. Glucagon decreased meal size by specifically inhibiting feeding during the terminal phase of the meal without affecting feeding earlier in the meal. This was also the case when glucagon was injected 4 min prior to meal onset. This range of glucagon doses did not affect water intake in water deprived rats consuming fluid volumes comparable to the milk intakes. They also did not affect body temperature. Finally, injection of 400 μg/kg glucagon after the initial exposure to a novel drinking fluid was not sufficient to form a conditioned taste aversion in a two bottle preference test. These data, together with reports that circulating pancreatic glucagon levels increase during meals, strongly suggest that pancreatic glucagon is involved in the production of postprandial satiety.     

Manipulation of D2 receptors with quinpirole and sulpiride affects locomotor activity before spatial behavior of rats in an active place avoidance task

Dopamine-mediated neurotransmission is widely studied with respect to motivation, motor activity and cognitive processes. The aim of the present study was to evaluate the role of D2 receptors in the behavior of rats in the active allothetic place avoidance (AAPA) task. D2 receptor agonist quinpirole and antagonist sulpiride were administered intraperitoneally 20min prior to behavioral testing. Administration of quinpirole led to dose-dependent increase of locomotion; the spatial efficiency was spared across the dose range studied (0.05-1.0mg/kg). In contrast, sulpiride decreased locomotor activity at a dose not influencing spatial efficiency (60mg/kg); the highest dose of sulpiride (100mg/kg) caused a deficit in both locomotor and spatial behaviors. The results suggest a relatively lesser importance of D2 receptors for spatial efficiency in the AAPA task, with a predominant influence of D2 receptor ligands on motor activity.     

The effects of chronic ventromedial hypothalamic stimulation on weight gain in rats

The effects of chronic stimulation of the ventromedial hypothalamus and adjacent structures on body weight, food intake, and epididymal fat pad weight were examined in normophagic rats. Three hours of intermittent low level electrical stimulation were delivered threetimes per week for four weeks; body weight and food intake were monitored for an additional ten days after stimulation trials had ceased. Animals receiving ventromedial hypothalamic stimulation had the shallowest growth curves while stimulation of other structures produced a rate of growth that fell between that of the ventromedial hypothalamic and the implanted control group. This pattern persisted during the poststimulation phase. Food intake, while initially depressed in the stimulated groups, began to approach control levels by the third week of stimulation. Efficiency of food utilization (weight gain/consumption) was significantly reduced during the first week of stimulation in the ventromedial hypothalamic stimulated group. Fat pad weight was slightly decreased in this group as well. These findings suggest that chronic stimulation of the ventromedial hypothalamus causes a persistent shift in metabolic rate that results in a long-term inhibition of weight gain.     

Pathogenesis of cardiac hypertrophy in iron deficiency anaemia: the role of noradrenaline.

This study examined the effect of long-term administration of reserpine, an adrenergic blocking agent, on cardiac hypertrophy in animals with severe iron deficiency anaemia. This condition was induced by feeding rats on an iron-deficient diet for 30 days from the time of weaning. Anaemia was indicated by lowering of blood haemoglobin levels. Reserpine was administered i.p. (0.15 mg/kg body wt) every day during the experiment. Marked cardiac hypertrophy, as indicated by increase heart weight and increased size of cardiac muscle cells, was evidenced in iron-deficient rats, while the heart weights and myocardial cell size of drug-treated anaemic rats were in the normal range. The successful prevention of cardiac hypertrophy in anaemic iron-deficient rats by reserpine administration supports the hypothesis that noradrenaline plays a key role in the cardiac-hypertrophy process in iron deficiency anaemia.