Factors influencing active avoidance behavior in rats with ventromedial hypothalamic lesions

Ventromedial hypothalamic lesioned rats maintained at preoperative body weight received an equal number of shocks while emitting significantly fewer responses than controls in a lever-pressing free-operant avoidance paradigm, and performed as well as unoperated animals in lever-pressing and shuttle box (both 1- and 2-way) discriminated avoidance tasks. The failure of VMH lesions to facilitate performance in the 2-way avoidance paradigm was probably the result of a ceiling effect. With the exception of the simple one-way avoidance task, obese lesioned rats were markedly impaired in the acquisition of all active avoidance behavior, but escape behavior was not affected. When tested in a free-operant paradigm, the avoidance performance of well trained lesioned animals varied inversely with body weight. As obese rats displayed lower flinch thresholds to shock than controls and similar levels of activity and responding as lean lesioned animals, it was concluded that their impaired avoidance behavior was not due to changes in sensitivity or mobility. The possible relation to other VMH lesion- and/or obesity-induced deficits is discussed.     

Body weight and body composition of male rats following hypothalamic lesions.

Carcass analyses were performed on 160 male rats maintaining reduced, normal, or elevated levels of body weight following lateral hypothalamic (LH), sham (control), or ventromedial hypothalamic (VMH) lesions, respectively. Extracted body lipid (ranging from 26 to 738% of the control mean) correlated highly (r = +0.95) with the level of maintained body weight (which ranged from 67 to 191% of control). Neither the nonfat solids (which ranged from 60 to 123% of control) contributed significantly to the variance in body weight (r = +0.01 and +0.06, respectively). Fat thus accounted for approximately 90% of the overall variance in body weight among LH, control, and VMH animals. Consideration of only the LH data, however, revealed a breakdown of this close covariance of body fat and weight. Fat mass correlated significantly with body weight in LH rats maintaining weight 0-12% below normal; but, at maintained body weights below 88%, the correlation between weight and fat in LH rats was only +0.07. Variation in lean body mass then better accounted for differences in body weight. The implications of these observations for existing lipostatic theories of weight regulation are discussed.     

Sex differences in the effects of high-fat feeding on behavior and carcass composition

Male and female Sprague-Dawley rats were fed a high-fat diet (40% by weight) for 11 weeks beginning at 70–80 days of age. At the end of the 11th week, high-fat fed rats of both sexes were significantly heavier than chow-fed controls. All rats were then food deprived and were trained to bar-press in an operant chamber for Noyes pellets. Testing on fixed ratio (FR) schedules started when their body weights reached 85% of pre-deprivation levels and they pressed bar steadily. At the end of operant testing, all rats were refed their previous diet until body weights returned to pre-deprivation levels. The animals were then sacrificed. Fat pads from retroperitoneal, inguinal and gonadal regions were dissected out and cellularity determined. Carcass composition was analyzed by chemical methods. On the operant apparatus, the high-fat fed female rats (F-HF) behaved more like VMH lesioned obese rats, i.e. decreased bar pressing responses when compared with controls. No difference in operant responding was found between males fed high-fat diet and chow. Fat cell number and size were increased in retroperitoneal and inguinal fat pad for rats fed high-fat diet. In gonadal pads, only cell size was increased. Females on the high-fat diet had higher percentages of body fat than males on the high-fat diet. The behavioral difference in F-HF rats could be attributed to their higher adiposity. The results support previously reported findings on the behavior and adipose tissue cellularity of dietary obese rats.     

Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose

The present study tested whether rats release more accumbens dopamine (DA) during a sugar binge when they are underweight vs. normal weight. Since acetylcholine (ACh) in the nucleus accumbens (NAc) normally increases as a meal progresses and satiety ensues, we also tested whether ACh release is altered when an animal has lost weight. Rats were maintained on daily 8-h access to chow, with 10% sucrose solution available for the first 2 h. Microdialysis performed on day 21, at normal body weight, revealed an increase in extracellular DA to 122% of baseline in response to drinking sucrose. Extracellular ACh peaked at the end of the meal. Next, the rats were food and sucrose restricted so that by day 28 they were at 85% body weight. When retested, these animals released significantly more DA when drinking sucrose (179%), but ACh release failed to rise. A control group was tested in the same manner but given sugar only on days 1, 21 and 28. At normal body weight, control animals showed a non-significant rise in DA when drinking sucrose on day 21. On day 28, at 85% body weight, the controls showed a small increase (124%) in DA release; however, this was significantly lower than the 179% observed in the underweight rats with daily sugar access. These findings suggest that when an animal binges on sugar and then loses weight, the binge releases significantly more DA and less ACh than when animals are at a normal body weight.     

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.     

Effects of VMH lesions on schedule induced and schedule dependent behaviors

Ten male hooded rats were exposed to an FI 1 min food reinforcement generator schedule at 80% body weight and schedule dependent lever pressing and schedule induced licking and drinking were recorded. When lever pressing, licking, and drinking stabilized the 10 rats were divided into two groups. One group was composed of 4 animals subjected to sham lesion procedures plus one animal with asymmetrical ventromedial hypothalamic (VMH) lesions. The other group was composed of 5 animals with bilateral symmetrical VMH destruction. Results demonstrate that VMH destruction produces a slight transient decrease only in water intake when on schedule at 80% body weight. When animals are returned to ad lib eating and body weight increased and they are returned to the test chamber, the VMH lesion animals display increased licking and drinking. Although VMH lesion animals ate and drank more than controls, they did not eat more in response to food deprivation and did not drink more in response to water deprivation and the intraperitoneal administration of hypertonic saline. The presence or absence of food or water was the determining factor in the overeating or excessive drinking of the VMH lesion animals. Results are discussed in terms of gastrointestinal influences on the hypothalamic mechanisms involved in the production of schedule induced behaviors.     

Responses to dietary adulterations in rats with zona incerta lesions

Large lesions of the rostral zona incerta (ZI) permanently reduced food and water intake and body weight to about 75% of control levels. When quinine hydrochloride was added to the water supply, the experimental animals exhibited a somewhat greater initial decrease in fluid consumption, but otherwise responded much like control rats to quinine adulteration of both food and water. The ZI animals reduced their fluid intake when water was added to the food supply, in the form of wet mash, while the controls showed no compensation for the auxiliary water. When presented with sucrose solutions, the ZI animals increased their fluid intake, but reduced their mash consumption, to a greater degree than control rats. The experimental animals also showed an exaggerated response in both food and caloric intake to the addition of sucrose to the wet mash.     

Deafferentation affects short-term but not long-term control of food intake

Deafferentation affects short-term but not long-term control of food intake (PHYSIOL BEHAV XX(X) 000-000, 2005). Rats were treated neonatally with capsaicin (CAP) to investigate the involvement of vagal afferents in food intake control and body weight regulation. In the first set of experiments, rats were offered increasing concentrations of sucrose (10-15-20-40%) in short-term feeding tests of 1 h. At the end, 10% was offered again to see whether CAP rats modified their intake after repeated exposure to different concentrations of sucrose solution. Results demonstrated that CAP animals overconsume persistently compared to vehicle (VEH) controls. This overconsumption is most pronounced and variable at 10% trials. Hypertonic 40% sucrose solution resulted in a small but significant drop in intake in CAP rats. Overall, if the concentration of sucrose solution is more than 10%, sucrose ingestion of CAP and VEH rats does not depend on the concentration of sucrose solution and remains relatively constant during all trials. In another experiment, rats were exposed to a high-fat condensed milk suspension (CMS) for 5 days. CAP rats initially overconsumed from this CMS compared to VEH. This was accompanied by a decreased intake in chow. However, over the 5 day period CAP animals adjusted their CMS and chow intake to control levels. During both experiments there were no differences in body weight gain between CAP and VEH. Together, these results suggest that capsaicin-sensitive vagal C-fibers are involved in the control of volume ingestion and short-term food intake control but are not required for long-term control of energy intake.     

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.     

Developmental aspects of sucrose-induced obesity in rats

Daily caloric intakes and body weights were measured from weaning to 70 days of age in male Sprague-Dawley rats given access to either a standard laboratory diet and water, or the standard diet, a 32% sucrose solution and water. Lee index of obesity (3 square root body weight/naso-anal length) and fasting blood glucose levels were determined at 46, 57, and 70 days of age. Animals were sacrificed at 70 days, and body composition analyses were performed. Aniamls given access to the sucrose solution consumed significantly more calories per day than animals given only the standard diet. Sucrose animals took approximately 50 to 60% of their daily caloric intake from the sugar solution. Despite the greater caloric intakes of the sucrose animals, sucrose and control animals did not differ in body weight. While there were no differences in body weights between the two groups, the Lee Index of obesity was significantly greater in the sucrose animals than in controls as early as 46 days of age. Fasting blood glucose levels were significantly lower in sucrose animals than in controls at both 46 and 57 days of age. Direct determinations of body compositions when animals were 70 days of age revealed that animals with access to sucrose had significantly greater percentages of body fat and lower percentages of body protein than controls.     

Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions

The effects of adrenalectomy in rats with ventromedial or paraventricular hypothalamic lesions have been studied in two experiments. Rats with ventromedial hypothalamic lesions or lesions in the paraventricular nucleus were allowed to gain weight for fourteen days at which time they were adrenalectomized. Before adrenalectomy, animals with VMH lesions ate more, gained significantly more weight than animals with lesions in the paraventricular nucleus, and both were significantly heavier and consumed more food than sham-operated controls. Following adrenalectomy, food intake decreased and both groups of lesioned animals lost weight. The animals with VMH lesions stabilized at weights above the control animals. Implantation of corticosterone enhanced weight gain and food intake in animals with lesions in either the paraventricular nucleus or the ventromedial hypothalamus. In the second experiment, one subgroup of rats with VMH lesions was adrenalectomized, and allowed to eat ad lib. Two other groups of sham-operated rats with VMH lesions served as controls. One group ate ad lib and one group was pair fed to the food intake of the adrenalectomized VMH-lesioned rats. Weight gain in the adrenalectomized VMH-lesioned rats and the pair-fed VMH-lesioned controls was similar and less than the VMH-lesioned rats eating ad lib. GDP binding to interscapular brown adipose tissue was related to the degree of weight gain, not to the presence of the VMH lesion. These data show that corticosterone is essential for the expression of obesity in both PVH- and VMH-lesioned rats. They also argue that the reduction in the activity of the sympathetic nervous system of VMH-lesioned rats as estimated by the GDP binding to mitochondria from brown adipose tissue is associated with hyperphagia.     

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.     

Sex differences in the effects of voluntary activity on sucrose-induced obesity

Sedentary, adult rats of both sexes fed Purina chow and a 32% sucrose solution overate, gained excess weight and had higher Lee Indexes of obesity than control animals fed only Purina chow. The magnitude of these effects was similar in the males and females. Animals of both sexes fed the sucrose diet showed a slower rate of weight loss during food deprivation than the chow controls. Access to an activity wheel led to a reduction in caloric intake and the elimination of obesity in male rats. In the chow fed male rats activity led to a smaller, transient suppression in caloric intake and a slightly lower level of body weight than the sedentary chow controls. Access to activity did not affect body weight in the female rats in either dietary condition. Rather, both active groups of female rats appeared to compensate for the energy cost of voluntary activity by a small increase in food consumption. Long-term exposure to activity was associated with more rapid weight loss during food deprivation in both males and females. These data reveal that high levels of activity and obesity can co-exist when normal female rats are fed a palatable diet but that activity eliminates this form of obesity in the male rat.     

Decreased NaCl sensitivity in zinc-deprived rats.

NaCl thresholds and ability to discriminate between NaCl and sucrose were assessed in rats using an operant discrimination conditioning procedure before and during moderate and severe zinc deprivation and during zinc supplementation. NaCl thresholds were approximately 1 mM before dietary zinc manipulation. They increased in all zinc-deprived rats tested 10 and 17 days after initiation of deprivation but did not change in pair-fed controls maintained on supplemental zinc. Threshold changes were greater for those rats severely zinc deprived than for those only moderately deprived and were greater as the period of deprivation lengthened. Plasma zinc concentrations decreased significantly in deprived rats from values obtained at baseline, values in severely deprived rats being significantly lower than in those only moderately deprived. Although zinc-deprived rats discriminated NaCl from sucrose, they made more discrimination errors than controls. Following 24 days of zinc supplementation, previously deprived rats exhibited no significant improvement in gustatory performance, although their body weight increased and plasma zinc concentrations increased; but these later changes were not significant. These results demonstrate that zinc deprivation induces decreased gustatory sensitivity and confirm a role for zinc in taste.     

Effect of VMH lesion on sucrose-fed analgesia in formalin pain

The ingestion of sucrose (ad libitum) produces an immediate analgesic response to phasic noxious stimuli. The underlying mechanism for the analgesic effect of sucrose is attributed to its palatability, which mediates analgesia probably by the release of beta-endorphin in the hypothalamus. The present study was designed to explore the role of ventromedial hypothalamus in the mediation of sucrose-fed analgesia. Adult male albino rats each received (20%) sucrose solution orally through a separate bottle until they had ingested 4-5 ml. Their behavioral responses to tonic noxious stimulus in a formalin test were studied in pre- and postsucrose-fed rats of control and in the VMH lesion groups. The average pain rating of a 60-min session significantly (p < 0.01) decreased after sucrose feeding in control rats, from 1.94 +/- 0.13 to 1.45 +/- 0.14, but sucrose feeding by the VMH lesion rats did not alter their tonic nociceptive response from a 1.70 +/- 0.07 presucrose-fed state to a 1.71 +/- 0.08 postsucrose-fed state. VMH lesion per se did not alter the nociceptive response in comparison with controls. The results suggest that sucrose feeding produces analgesia to tonic noxious stimulus, which is abolished by lesion of the VMH, thereby indicating a significant role of VMH in sucrose-fed analgesia.     

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.     

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.     

Schedule-induced polydipsia in desalivate rats as a function of percent free-feeding weight

Desalivate and control rats maintained at 80% of free-feeding weight were delivered 45 mg pellets on a fixed-time 1-min schedule for 14 sessions of polydipsia testing. Desalivate rats showed polydipsia immediately, but had lower asymptotic intakes than controls. Over the 14 polydipsia sessions postpellet bout size and frequency increased gradually in controls but remained stable in desalivates. Body weight increases to 105% of free-feeding weight over 21 additional sessions resulted in decreased intakes which were similar for desalivates and controls. In controls both bout size and frequency decreased as a function of body weight increases, while in desalivates only bout size decreased. The immediate acquisition of polydipsia in the desalivates was attributed to the prandial drinking pattern learned during postoperative recovery, whereas the attenuated levels of polydipsia were attributed to overhydration and consequent precise control of drinking bout size.     

Transplantation of pancreatic beta-cells prevents development of hypothalamic obesity in rats.

The present experiments have tested the hypothesis that ventromedial hypothalamic (VMH) lesions enhance insulin secretion by neural mechanisms. Rats were made diabetic by injecting streptozotocin to destroy their own pancreatic beta-cells. Subsequently, transplants of fetal pancreatic tissue were placed under the renal capsule. VMH lesions were placed in rats whose diabetes was cured with transplants as well as sham-transplanted animals. The animals were followed for 4 wk. The lesioned rats with pancreatic transplants gained no more weight than the sham-operated controls. There was no significant rise in insulin in the transplanted rats after VMH lesioning, but the VMH lesioned rats with intact pancreatic tissue showed the expected rise in insulin. Food intake rose 71% in the VMH lesioned rats with intact beta-cells, but only 23% in the VMH lesioned rats with transplants. Hypertrophy of the pancreatic islets was also observed in the VMH lesioned rats with an intact pancreas, but was not found in the VMH lesioned rats with a transplanted pancreas. Thus, transplantation of pancreatic tissue beneath the renal capsule of diabetic rats prevented the characteristic hyperphagia, hyperinsulinemia, and obesity in VMH lesioned rats whose pancreas was free from intact innervation. The results support the hypothesis that neural mediation of the rise in insulin is the primary factor in the development of hypothalamic obesity.     

Effects of amphetamine and phenylpropanolamine on food intake in rats with ventromedial hypothalamic or dorsolateral tegmental damage

Female rats with sham lesions or lesions of the ventromedial hypothalamus (VMH) or the dorsolateral tegmentum (DLT) were maintained at 80% normal body weight to minimize possible group differences in hunger motivation. VMH rats displayed attenuated amphetamine (0.5, 1.0, and 2.0 mg/kg) anorexia when fed a high-fat test diet but normal anorexia when fed a pellet test diet whereas DLT rats displayed attenuated amphetamine anorexia when fed either test diet. Neither VMH nor DLT rats displayed attenuated anorexia to phenylpropanolamine (5.0, 10.0, and 20.0 mg/kg), an analogue of amphetamine. These results are discussed in terms of an amphetamine-activated arousal mechanism within the DLT.