Effects of dopamine-depleting brain lesions on experimental hyperphagia in rats

Dopamine (DA)-depleting brain lesions of various sizes were produced in rats either by intracerebroventricular injections of 6-hydroxydopamine (6-HDA) or by electrolytic lesions of the lateral hypothalamic (LH) area. Among 30 animals that became aphagic and adipsic for at least four days after large LH or 6-HDA-induced brain lesions, only three developed hyperphagia after electrolytic lesions of the ventromedial hypothalamus (VMH) or daily injections of long-acting protamine-zinc insulin (PZI). In 20 rats with smaller LH or 6-HDA-induced lesions, which had not shown marked initial behavioral dysfunctions, only three gained as much weight after VMH lesions as the control animals. Similarly, 6 of 10 rats with smaller LH lesions could not tolerate a 15-day series of PZI treatments, although 14 of 17 rats with smaller 6-HDA-induced lesions increased their food intake and gained weight during the PZI treatments as did control animals. These results indicate that hypothalamic hyperphagia can be blocked by DA-depleting brain lesions that neither produce an initial period of aphagia and adipsia nor involve hypothalamic tissue. They further indicate that even small LH lesions may prevent the development of hyperphagia elicited by PZI, whereas only very large 6-HDA-induced lesions consistently have this effect.     

Reappearance of dynamic hyperphagia during the static phase in medial hypothalamic lesioned rats

Female rats overate and became obese following electrolytic lesions of the medial hypothalamus. While every animal displayed the characteristic dynamic-static hyperphagic syndrome, not all of them maintained a permanent static phase. After many weeks or months of maintaining body weight at an elevated obese plateau with near-normal food consumption, several of the rats which had at least doubled their preoperative body weight displayed a spontaneous renewal of hyperphagia that was longer lasting and nearly equal in amplitude to the initial dynamic phase. Only one of the less obese animals displayed the phenomenon. The sudden increases in food intake and body weight were not due to a change in diet or any of the other variables which are known to influence the eating habits of obese lesioned rats.     

Hyperphagia and obesity following ventromedial hypothalamic lesions in rats with subdiaphragmatic vagotomy

Bilateral subdiaphragmatic vagotomy chronically reduced body weight to 85–90% of sham vagotomy weight levels in female rats maintained on a standard pellet diet (observed for 114 days). Ventromedial hypothalamic lesions 70 days after vagotomy resulted in marked hyperphagia and obesity, although the increases were not as great as those following lesions in nonvagotomized animals. When the order of surgery was reversed, vagotomy reduced the body weight of obese VMH-lesioned rats to vagotomized control levels, with no evidence of recovery after 90 days. These results suggest that while enhanced vagal activity and/or vagally mediated hyperinsulinemia contribute to VMH lesion-induced overeating and weight gains, they are not necessary for the manifestation of either the hyperphagia or obesity. The importance of adaptation to the effects of vagal transections for the appearance of hypothalamic hyperphagia and obesity is discussed.     

Reinforcement frequency and body weight as determinants of motivated performance in hypothalamic hyperphagic rats

Non-Obese and Obese VMH lesioned rats were tested on a series of increasing VI schedules (from 0.25 to 4.0 min). Response rates decreased as a function of increases in interreinforcement interval for all groups, and the functions did not differ in form or in slope between the groups. Respone rates for the Non-Obese VMH, Lesion Control, and Normal Control groups were similar, while response rates for the Obese VMH group were significantly less than those of the other groups. This reduction in work output by the Obese VMH rats was attributed solely to their increased weight at the time of testing.     

Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia

The relation of hyperinsulinemia to hyperphagia was examined in rats with lesions of the ventromedial hypothalamus (VMH). Plasma insulin and glucose levels were assayed after a 4-hr fast and 17 min after the initiation of a meal (6 ml of sweetened milk in 7 min) in animals with sham lesions, VMH animals maintained at preoperative body weight by food restriction, and VMH animals fed ad lib. Both VMH groups displayed basal and postabsorptive hyperinsulinemia, compared with the sham-operated control group, but insulin levels were greatest under the ad lib feeding condition. It is suggested that VMH hyperinsulinemia is due both to a primary effect of the lesion and to hyperphagia and that marked obesity can result in the absence of basal hyperinsulinemia as a result of hyperphagia with consequent postabsorptive hyperinsulinemia.     

Relationship between plasma corticosterone and insulin levels in rats with ventromedial hypothalamic lesions

The effects of ventromedial hypothalamic (VMH) lesions on plasma corticosterone, insulin, and glucose levels were studied in food-restricted and ad lib fed female rats. VMH lesions resulted in significant elevations of corticosterone and insulin levels compared to control values during the first 25 days after surgery. However, unlike insulin values which were generally greater in VMH rats fed ad lib than in food-restricted animals, plasma corticosterone levels were unaffected by level of food intake. Corticosterone and insulin levels were unrelated preoperatively and in sham-operated animals, but were positively correlated (r = .82) by Day 25 in ad lib fed VMH rats. It is concluded that the elevation in plasma glucocorticoids observed in VMH rats is a primary effect of the lesion that is independent of food intake or initial weight gain.     

Characteristics of insulin-induced hyperphagia in the golden hamster

Two experiments were performed to investigate in some detail the behavioural and metabolic effects of the administration of regular insulin to golden hamsters. In Experiment 1 dose-response curves describing the effects of insulin upon both food intake and plasma glucose (PG) were generated. Dosages of less than 20 units/kg did not cause increases in food intake, while dosages of 10 units/kg or greater produced significant hypoglycemia at +6 hr post-injection. There was also a significant inverse linear relationship (r=?.528) between individual hamsters' food intakes and PG levels over the range of insulin dosages. It Experiment 2, insulin (30 units/kg) caused increases in meal frequency but not in meal size, and hyperphagia developed within +3 hr of insulin administration. When food was not available, insulin caused PG levels to fall below control levels at +1 hr and to remain depressed until at least +6 hr post-injection. However when hamsters were allowed to eat, PG did not fall significantly below control levels until +3 hr and began to recover at +5 hr post-injection. Results are discussed in relation to several apparent peculiarities in the hamster's behavioural response to regular insulin, specifically the small magnitude and the slow development of insulin-induced hyperphagia, and the hamster's relative insensitivity to the hyperphagic effect of insulin.     

Hypothalamic hyperphagia prevented by prior subdiaphragmatic vagotomy: Insulin hyperphagia is unaffected

Male rats were given bilateral subdiaphragmatic vagotomy or a sham operation. Both groups of animals showed equivalent hyperphagia and weight gain during a ten day treatment with long-acting insulin. Despite this ability to increase feeding, the vagotomized rats did not overeat and become obese after VMH lesions.     

Pituitary-adrenocortical response to shock-induced stress in normal and hypothalamic hyperphagic rats.

Several previous experiments have reported that mediobasal hypothalamic lesions that include the ventromedial nuclei result in decreased adrenal weights and impaired pituitary-adrenocortical responses to stress. In the present experiment, lean and obese rats with lesions of the ventromedial hypothalamus that spared the median eminence were found to have normal adrenal weights and normal elevations in plasma corticosterone to shock-induced stress. The previous results were attributed to incidental damage to adjacent structures, particularly the median eminence. Lean but not obese VMH-lesioned rats were found to have higher baseline corticosterone levels.     

Impaired free-operant avoidance behavior following ventromedial hypothalamic lesions in rats

Under each of 3 shock intensities, ventromedial hypothalamic lesioned rats emitted fewer responses and received more shocks than control animals in a lever-pressing free-operant avoidance paradigm. While the performance of the control animals improved across 10 days of testing and within each session, the between- and within-session performance of the lesioned rats, after improving moderately during the first few days of testing, deteriorated as training progressed. Although the response rates of the lesioned animals were relatively unrelated to the different current levels, their shock rates varied inversely with intensity. This resulted from an increase in the frequency of long interresponse times and a reduction in the number of consecutive shocks. Preoperative training substantially improved the avoidance behavior of lesioned animals, but their postoperative performance was nevertheless inferior to their preoperative levels.     

The effects of pretraining on the bar-pressing performance of VMH-lesioned rats

Ventromedial hypothalamic lesioned rats preoperatively trained on an FR-128 schedule displayed postoperative improvements in performance which were a direct function of the degree of hyperphagia. The postoperative performance by the pretrained VMH-lesioned animals did not significantly differ from that of control animals during short test sessions following periods of deprivation, but substantially exceeded that of controls with continuous opportunity to respond. The increase in the number of pellets obtained was achieved by increases in both the meal size and the rate of bar-pressing. Previous attempts to account for the deficit in performance by nonpretrained VMH-lesioned animals in terms of decreased motivation or lowered activity are rejected in favor of an explanation based on a modification of affective response following such lesions.     

Changes in 24-hour fluctuations of feeding behavior during hypothalamic hyperphagia in rats

Lesions were electrolytically placed in the ventromedial hypothalamic area in rats. Bilateral lesions appear to be more effective in producing hyperphagia than unilateral lesions. Changes in the circadian pattern during the hyperphagic phase are mainly brought about by a variable degree of increase in eating during the light periods. The fact whether or not a rhythm is present is determined by the localization of the lesion. Symmetrically placed lesions result in loss of rhythmicity in most cases but this does not correlate with the degree of hyperphagia. A possible role of connections between the suprachiasmatic nucleus and the ventromedial hypothalamic area is suggested.     

Effects of chronic quinine-adulteration of the water supply on food and fluid intake and body weight in lean and obese hypothalamic hyperphagic rats.

Obese rats with lesions of the ventromedial hypothamamus (VMH) consumed little or no food or fluid for 8–20 days when their water supply was chronically adulterated with 0.03% quinine hydrochloride. Three of the obese animals consumed significant amounts of food and fluid after the first week, five others continued to lose weight (at the rate of approx. 10 g./day) throughout the experiment. The experiment was terminated after 20 days when two animals died, and three others were so emaciated that death appeared imminent. Lean VMH rats that had been maintained at pre-operative body weights by restricted feeding prior to the quinine adulteration reduced their liquid and food intake only briefly after the quinine was introduced. After 4 or 5 days these animals were hyperphagic and hyperdipsic and displayed a substantial and sustained increase in body weight during the remaining 15 days of the experiment. The control animals curtailed both food and fluid intake sharply during the first 24–48 hours after the introduction of the quinine adulteration. Fluid intake subsequently recovered to approx. 60% of baseline and food intake returned to essentially normal levels. Body weight remained stable although slightly below baseline throughout the 20-day test period. The different response to quinine-adulterated water by lean and obese VMH-lesioned rats is similar to previously reported reactions to adulterated food. It is therefore concluded that explanations of VMH finickiness in terms of dysfunctions in appetite or hunger (terms appropriate only for food intake) are too limited. A more general deficit is proposed.     

Local administration of l-DOPA in the chicken ventromedial hypothalamus increases dopamine release in a dose-dependent manner

l-DOPA induced extracellular dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the ventromedial hypothalamus (VMH) of chickens were measured by in vivo microdialysis. Several doses of 3,4-dihydroxy-l-phenylalanine (l-DOPA) were administered locally through the microdialysis probe into the VMH of chickens for 10 min. Local perfusion of l-DOPA increased the extracellular levels of DA. The increased DA was dose-related and was significantly higher compared to the baseline and control group. The maximal level of DA was 212% and 254%, respectively, of the baseline following administration of 1 and 2 μg/ml l-DOPA. There were no changes in NE and 5-HT levels from baseline after l-DOPA perfusion. l-DOPA (1 μg/ml) was mixed with Ca²⁺-free Ringer, tetrodotoxin (TTX) (2 μM) and high K⁺ and was perfused for 30 min into the chicken VMH. TTX and Ca²⁺-free Ringer's solution inhibited the effectiveness of l-DOPA in increasing DA release. The NE and 5-HT levels were significantly lower than the baseline. After administration of K⁺ a significant increase of DA, NE and 5-HT was observed. The microdialysis results are consistent with our objective that l-DOPA induced extracellular DA increases in the VMH in a dose-dependent manner and the released DA, NE and 5-HT within the dialysate were related to neuronal activity.     

Passive avoidance behavior in lean and obese rats with ventromedial hypothalamic lesions

Lean and obese rats with ventromedial hypothalamic lesions performed reliably worse than control animals in the acquisition of a step-down passive avoidance task. However, obese rats performed significantly better than lean VMH animals, which consistently leaped off the platform on the second and succeeding trials. While there were no significant differences between groups in the acquisition of a step-through passive avoidance task, lean and obese rats with VMH lesions took reliably longer than control animals to reach criterion when an identical step-through response had previously been reinforced (punishment-extinction of a one-way conditioned avoidance response). Both lean and obese VMH-damaged rats made more punished approach responses to water than control animals following water-deprivation to 88% of body weight, but only lean VMH rats made a significantly greater number of punished approach responses to liquid food than unoperated animals following food-deprivation to 88% of body weight. The number of punished consummatory responses appeared to be influenced by baseline intake. Among the animals tested in more than one paradigm, there was a significant positive correlation between the number of punished consummatory responses and the number of shocks received during punishment-extinction of the one-way CAR, but no relationship was observed between the performances in either of these and the step-down avoidance paradigm. The impaired passive avoidance behavior by rats with VMH lesions is attributed to both an inability to inhibit a previously reinforced response and a change in response tendencies to aversive stimuli.     

Insulin-induced hyperphagia in alloxan-diabetic rats fed a high-fat diet.

Alloxan-diabetic rats fed a standard, low-fat diet lost body weight and were hyperphagic; those fed a high-fat diet lost comparable amounts of weight, but did not overeat compared to normal animals. When given injections of protamine-zinc insulin, all diabetic rats gained weight; however, while those fed the low-fat reduced food intake from elevated levels, diabetics fed the high-fat diet became hyperphagic. Diabetic rats maintained on a high-fat diet increased food intake during long-term insulin treatment sooner and to a greater extent than normal controls. These findings are interpreted in light of the effects of insulin on storage and supply of metabolic fuels.     

Impaired and enhanced shuttle box avoidance behavior following ventromedial hypothalamic lesions in rats

VMH-lesioned female Long-Evans hooded rats held to preoperative body weight acquired a shuttle box avoidance response only as rapidly as control animals at both a moderate and high shock level when intertrial interval crossings were not punished, and at a moderate shock intensity with punished ITI crossings. Both groups displayed 90–95% asymptotic avoidance behavior under all three conditions. Obese rats with VMH lesions displayed impaired avoidance behavior under these conditions, displaying only 55–60% asymptotic avoidance behavior after 110 trials. The impaired avoidance behavior by obese rats was not due to immobility, for they emitted as many unpunished ITI crossings as control animals. Both lean and obese rats with VMH lesions avoided a significantly greater number of shocks than control animals at a high shock intensity when ITI crossings were punished, with control animals averaging only 20% avoidance responding after 110 trials. Lean VMH rats again performed better than obese rats, displaying 85% and 60% asymptotic avoidance behavior, respectively. Lean VMH rats made more punished ITI crossings than control animals at the high shock intensity, but there was no difference between the unoperated and obese VMH-lesioned animals. Previous discrepant results with shuttle box avoidance experiments are attributed to different testing conditions, although strain differences are also possible.     

Reduced salivation in rats following ventromedial hypothalamic lesions

Salivation was assessed in normal rats and rats with bilateral lesions of the ventromedial hypothalamus (VMH). VMH lesioned rats demonstrated a reliable reduction of salivation. This hyposalivation occurred during a one month period that animals were maintained on dry rat chow and for a 16 day period that animals were maintained on a palatable liquid diet. VMH rats did not differ from control rats in the amount of saliva secreted in response to Prostigmin or wintergreen solution. Thus, while the VMH rat shows a reduced basal salivation level, such animals salivate normally in response to a strong taste substance.     

Medial hypothalamic lesions and play fighting in juvenile rats

The effects of medial preoptic area (MPOA), anterior hypothalamic (AH) and ventromedial hypothalamic (VMH) lesions on play fighting were studied in juvenile rats that were housed and observed in heterosexual groups of 6-8 animals. Overall males engaged in play fighting more frequently than females and none of the lesions reliably affected this measure. Males also initiated more play fights. AH and VMH lesions reduced the frequency of play initiation in both sexes, but MPOA lesions had no reliable effect in either sex.     

Studies of ventromedial hypothalamic afferents in the rat using three methods of HRP application

Summary The afferent neural connections of the ventromedial nucleus of the rat hypothalamus (VMH) have been studied in detail using three horseradish peroxidase (HRP) application methods: HRP crystal implants, HRP-gel implants, and iontophoretic deposition of the enzyme. Examination of the cases in which the retrograde tracer was best confined to various subdivisions of the nucleus revealed that the septal area projects only to the ventrolateral VMH, and that the medial preoptic area, rostral lateral hypothalamus, and the ventral subiculum project mainly to the ventrolateral VMH. Thus, the subdivision of the VMH that contains the highest density of estradiol-concentrating neurons (Morrell et al. 1986) receives a larger set of inputs than the rostral and central parts of the nucleus. The central subdivision receives a more restricted set of projections than either the medial or the lateral regions. These studies suggest that there may be partial anatomical segregation of neural inputs to the various subdivisions of the VMH.