Activity-stress ulcer in the rat: Frequency and chronicity

Rats were housed in activity cages and fed 1 hr each day. Characteristic changes in daily food consumption, running activity and body weight indicated the presence of a disease state in which stomach lesions were a major feature. If rats upon entering the disease state were removed from the activity-stress procedure, stomach lesions were always observed even after 4 recovery days of ad lib feedings and no running. The value of this ulcerogenic technique as a model for studying therapeutic procedures is discussed.     

Effects of divided feeding on activity-stress ulcer and the thymus weight in the rat

Rats housed in running-wheel activity cages and fed 1 hr or 2 hr daily exhibited excessive running and subsequently died revealing large stomach ulcers, reduced absolute thymus weight, and an increase in relative weight of adrenal glands. However, two 0.5-hr or two 1-hr daily feedings did significantly reduce ulcer incidence. Control rats for the four feeding schedules did not die, were ulcer free, and did not exhibit the changes in thymus and adrenal weight observed in exprimental rats. These results suggest that the divided daily feeding schedule ameliorates the ulcerogenic and immune processes in activity-stress rats.     

Patterns of weaning and adult response to stress

We have previously shown that excitation of certain neurons in the ventromedial nucleus of the hypothalamus (VMH) of rats induces hyperrunning activity. The present study investigated the involvement of these VMH neurons in inducing excessive running under the activity-stress paradigm. The VMH of 6-week-old male rats was bilaterally lesioned by administration of kainic acid. Control animals received saline in the VMH. They were housed in running-wheel activity cages with free access to food for 6 days of the recovering period, and then fed 1 h each day for 6 days. Control animals exhibited marked increases in both running activity and its light/dark ratio, and developed stomach ulcers. In contrast, animals with bilateral VMH lesions showed a significantly attenuated increase in running activity and no change in light/dark ratio. VMH lesions also suppressed stomach ulceration. These results suggest that VMH neurons play a crucial role in inducing excessive running and stomach ulceration during exposure to the activity-stress paradigm.     

Early weaning predisposes rats to exacerbated activity-stress ulcer formation

Rats were weaned early (Day 15), normally (Day 21) or late (Day 27). When they reached 200 g (+/- 10) they were placed into the activity-stress paradigm. Half the rats in each weaning group were housed in activity-wheel cages and fed only 1 hr each day. The remaining rats served as food-yoked home cage controls and were fed only that amount of food eaten by their wheel-housed partners. Early weaned rats ran more than normally or late weaned animals. Early weaned rats also died at a faster rate and exhibited a significantly greater cumulative ulcer length than did normally or late weaned rats, although ulcer incidence did not differ between the groups. No ulcers occurred in home cage control rats. Early maternal deprivation may generally predispose rats to stress-induced gastrointestinal disease, whether or not such disease has an acid etiology.     

Feeding regime affects activity-stress ulcer production

Rats were divided into either an active group housed in activity wheels or a control group housed in stationary laboratory cages. Both active and control groups were further divided into groups receiving 1, 2, 3, or 4 meals daily for a total feeding time of 1 hr. Control rats were food-yoked to active animals. Results indicated that active rats fed 1 meal daily developed significantly more ulceration, lost more weight, and consumed less food and water than other groups. The number of daily meals had no effect on the amount of activity. No control animals developed ulcers, although they received the same amount of food. These results suggest that frequent feedings mitigate gastric peptic ulcer formation in rats placed in the activity-stress ulcer paradigm.     

Daily feeding schedule and housing on incidence of activity-stress ulcer

In Experiment 1 the number and size of ulcers resulting from exposure to an activity-stress procedure were inversely related to the length of the pre-stress experience with either 1 hr or 2 hr daily feeding schedules. In Experiment 2, rats housed in group cages during the pre-stress period were more vulnerable to the ulcerogenic effects of the activity-stress procedure. A pellet food or powdered food treatment condition failed to provide significant group differences. Vulnerability to stress-ulcer is discussed in terms of the disparity of the environmental conditions between the acclimation period and the activity-stress period.     

Influence of activity-stress on thymus,spleen and adrenal weights of rats: Possibility for an immunodeficiency model

Rats were housed in standard activity cages under normal LD cycle (lights on 7:00–19:00) and fed 1 hr each day for 2 weeks. Control rats which were fed 1 hr each day in laboratory cages or fed freely in activity cages did not die and were ulcer-free. Incidence of rats with ulcer was higher in the group fed 1 hr in the nighttime than in the daytime group fed 1 hr in the morning, whereas the mortality was similar for both groups. The daytime group died sooner than the nighttime group. Thymus and spleen weights of rats exposed to activity-stress decreased considerably, while adrenal weights increased. The victims always revealed pulmonary infection, and the microscopic pathology of the thymus and spleen disclosed the lack of immunologically competent cells. Accordingly, these results suggest that rats exposed to activity-stress reveal, not only ulceration, but also immunosuppression. Stress factors and the possibility of utilizing the activity-stress rat for an immunodeficiency model are discussed.     

Pimozide mitigates excessive running in the activity-stress paradigm.

The present study investigated the role of dopamine in the maintenance of behaviors observed in the activity-stress paradigm. In Experiment 1, several doses (0, 0.125, 0.25, 0.50, and 1.0 mg/kg) of the dopamine D2-receptor blocker, pimozide, were administered to rats maintained on an ad lib feeding schedule. Results indicated that 0.25 mg/kg pimozide did not disrupt running activity when compared to control animals. In Experiment 2, injections of either 0, 0.25, or 0.50 mg/kg pimozide were given every 12 hours to rats subjected to the activity-stress paradigm. Although 0.25 mg/kg pimozide had no effect on dark-phase activity, it significantly suppressed light-phase activity and subsequently increased the number of survivors in the paradigm. It was concluded that dopamine plays a role in maintaining high running levels in the activity-stress paradigm.     

Lipid peroxidation and antioxidant status in rat: effect of food restriction and wheel running

Using the activity-based anorexia model, the aim of this investigation was to explore antioxidant enzyme activity (catalase, superoxide dismutase), total antioxidant status (TAS), and alpha-tocopherol in blood, liver, and gastrocnemius muscle associated with the food restriction and voluntary wheel running during 8 days. In addition, lipid peroxidation was measured by measurements of malondialdehyde (MDA). Wistars rats (n = 56) were randomly assigned to one of four groups: an ad lib sedentary group, a control wheel activity group, a food restriction-induced hyperactivity group (1 h/day ad lib food, 23 h/day ad lib wheel access), and a food-restricted sedentary group. The animals were killed when the rats in the food-restricted group had lost 25% of their free feeding weight. Antioxidant enzyme activities and TAS in blood, liver, and gastrocnemius muscle were unaffected by voluntary wheel running. A wheel activity effect (P < 0.05) was obtained for the MDA concentrations in plasma, with lower concentrations in trained animals. Food restriction effects were obtained for antioxidant capacity in liver, as well as for CAT activity in the gastrocnemius muscle and plasma MDA concentrations with lower values in the restricted animals. On the other hand, the food-restricted rats showed higher plasma TAS concentrations (P < 0.05) and higher alpha-tocopherol concentrations in the liver (P < 0.05) when compared to animals fed ad libitum. Our results also showed that food restriction coupled to wheel running decreased antioxidant parameters in liver, and plasmatic MDA concentrations and increased TAS plasma concentrations when compared to the ad libitum sedentary situation.     

Effects of food restriction on glucose tolerance, insulin secretion, and islet-cell proliferation in pregnant rats

Pregnancy is associated with increased glucose-stimulated insulin secretion and increased pancreatic islet-cell proliferation. In the present study it was investigated whether increased food intake, as occurs during pregnancy, is involved in the regulation of these phenomena. From Day 0 of pregnancy, rats received each day the mean amount of food they consumed daily during the estrous cycle prior to conception. This food restriction regime resulted in lower maternal body weight, and in lower fetal weight on Day 20 of gestation, but did not affect fetal survival. Food-restricted rats showed decreased insulin responses to an i.v. glucose challenge on Day 13, and lower islet-cell replication rates on Day 14 of pregnancy than pregnant rats fed ad lib. Plasma lactogenic activity in food-restricted animals was increased on Days 11 and 13; plasma progesterone levels were unchanged, but plasma leptin concentrations declined progressively during food restriction. Glucose tolerance was normal, suggesting that food restriction improved insulin action. On Day 20 of pregnancy, insulin responses were similar in food restricted and ad lib-fed rats; glucose tolerance was still unchanged. It thus seems that the improved insulin action as present on Day 13 had disappeared on Day 20. Also on Day 20, lactogenic activity as well as progesterone concentrations were similar in food-restricted and ad lib-fed rats. It was concluded that increased food intake plays an important role in the stimulation of islet-cell proliferation and insulin secretion, as well as in the diminished insulin action during the second week of rat pregnancy.     

Feeding conditions and estrous cycle of female rats under the activity-stress procedure from aspects of anorexia nervosa.

The present study investigated the application of female rats with activity stress as an animal model for anorexia nervosa. Young female rats were singly housed in activity-wheel cages with food-restricted schedule (2, 3, or 4 h of food availability per day) for 3 weeks. Estrous cycle, body weight, food intake, and wheel revolution were recorded daily. Gastric pathology was also observed using the endoscopic technique. Rats that were subjected to either a 3- or 4-h feeding schedule exhibited the cessation of estrous cycle, loss of body weight, and suppression of food intake. These animals also showed a remarkable increase in running activity. However, they had no gastric lesions throughout the experimental period. On the contrary, the 2-h feeding schedule elicited severe gastric lesions and high mortality. The results suggest that behavioral and physiological changes of the young female rats with 3 or 4 h feeding share some symptoms of anorexia nervosa, although their anorexia is not self starvation.     

Food restriction neither improves nor exacerbates reproduction in obese female Zucker rats.

Obese female Zucker rats have several reproductive abnormalities, including delayed puberty, abnormal estrous cyclicity, and behavioral hyporesponsiveness to ovarian steroid hormones. To ascertain whether excessive body weight per se causes these reproductive abnormalities, obese Zucker female rats were fed ad lib or were food restricted to match their body weights to those of lean counterparts. Food restriction neither accelerated vaginal opening nor normalized estrous cyclicity in obese female rats. Following ovariectomy, an injection of estradiol benzoate (EB, 15 microg/kg, s.c.) induced extremely low sexual receptivity in all rats, and proceptive behaviors were never observed. After treatment with EB plus progesterone (P, 2 mg/kg, s.c.), lean rats were very receptive (lordosis quotient, LQ = 94 +/- 2%) and proceptive (PRO = 12.5 +/- 2 events/min) while both ad lib-fed and food-restricted obese rats were only marginally receptive and proceptive (LQ= 19 +/- 9%, PRO = 1.8 +/- 0.7 events/min; LQ = 31 +/- 15%, PRO = 4.7 +/- 3 events/min, respectively). A higher progesterone dose (20 mg/kg) elicited vigorous sexual receptivity (LQ = 88-99%) and proceptivity (PRO = 16.5-20.4 events/min) in all EB-treated rats. Adiposity was significantly lower in food-restricted obese rats as compared to ad lib-fed obese rats (36.5 +/- 1.7% vs. 69.4 +/- 2.7%), but greater than that observed in lean rats (24.4 +/- 1.1%). These data suggest that excessive body weight per se does not underlie reproductive abnormalities in obese Zucker rats, but do not rule out the possibility that excessive adiposity may contribute to their infertility.     

Hyperactivity aggravates semistarvation-induced changes in corticosterone and triiodothyronine concentrations in plasma but not luteinizing hormone and testosterone levels

Semistarvation over a ten-day period resulted in a weight loss of 30% in male Wistar rats, which had continuous access to a running wheel. The animals increased their activity up to 20 km per day. Controls fed ad lib increased activity only slightly (up to 2.3 km on day ten). Groups of semistarved and ad lib-fed sedentary rats were studied as controls. The circadian pattern of corticosterone (B), triiodothyronine (T3), luteinizing hormone (LH) and testosterone (T) was studied. Corticosterone was synergistically increased by semistarvation and exercise. The reduction of triiodothyronine by semistarvation was significantly greater in the running wheel group. Both luteinizing hormone and testosterone were significantly decreased by semistarvation. Hyperactivity did not result in additional suppression of LH and testosterone.     

Long term effects of quinine on food intake and body weight in the rat

Adulteration of a chow diet with 0.75% quinine sulfate produces a short-lived decrement in food intake in both ad lib-fed and previously food-restricted adult female rats. In contrast, quinine produces a long-lasting depression in body weight; ad lib access to quinine-treated chow results in a plateauing of body weight at a lower level until quinine is removed from the diet, despite recovery of food intake.     

The influence of semistarvation-induced hyperactivity on hypothalamic serotonin metabolism.

Male rats kept in a running wheel developed hyperactivity when food was restricted. Highest activity occurred around noon when food was given. Semistarved sedentary and ad lib fed sedentary and running rats served as controls. Five-hydroxyindole-acetic acid (5-HIAA) in the medial basal hypothalamus was lowest in the sedentary ad lib fed group. Running significantly increased 5-HIAA. Starvation likewise increased 5-HIAA. This effect was further enhanced by hyperactivity. When the circadian rhythm of serotonin (5-HT) and 5-HIAA was studied in the hypothalamus, a minimum of 5-HT as seen in semistarved sedentary and running rats around feeding time (noon). At this time 5-HIAA reached a maximum in the semistarved running rats while semistarved sedentary and ad lib fed rats showed no circadian pattern of 5-HIAA. These data indicate that serotonin turnover in the medial basal hypothalamus is increased as a consequence of semistarvation and hyperactivity.     

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.     

Monoamine metabolism and its responses to food deprivation in the brain of Zucker rats

Monoamines and their metabolites levels were simultaneously measured by high-performance liquid chromatography in brain regions of lean and fatty Zucker rats when fed ad lib and deprived of food for 72 hr to evaluate each monoamine metabolism. Metabolite/monoamine ratios were shown for brevity to represent its metabolism. 3-Methoxy-4-hydroxyphenylethyleneglycol/noradrenaline ratios were not affected by the phenotype factor but increased in the cortex of fatty rats and reduced in the midbrain of both phenotypes after fasting; the interaction between phenotype and feeding factors was observed in the cortex and hippocampus. 3,4-Dihydroxyphenylacetic acid/dopamine ratios were increased in the cortex of deprived fatty rats and in the medulla-pons of ad lib-fed fatties compared with lean counterparts and also increased in the striatum of lean rats after food deprivation; the interaction was observed in the cortex, midbrain and medulla-pons. Homovanillic acid/dopamine ratios were decreased in the striatum of deprived fatty rats and in the midbrain and medulla-pons of fatty rats whether deprived or not, but the ratios were not significantly changed by fasting; the interaction was observed in the striatum. 5-Hydroxyindoleacetic acid/5-hydroxytryptamine ratios were reduced in the cortex, striatum and medulla-pons of fatty rats in both feeding states and in the midbrain of deprived fatties, and after food deprivation increased in the cortex and midbrain of lean rats and in the hippocampus of both phenotypes; the interaction was observed in the midbrain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Somatic, metabolic and endocrine correlates of set point recovery in food-restricted and ad lib-fed weanling rats with dorsomedial hypothalamic lesions

Male Sprague-Dawley rats received either electrolytic lesions in the dorsomedial hypothalamic nuclei (DMNL rats) or sham-operations (CON), and were fed lab chow ad lib for 41 post-operative (POP) days. Subsequently one lesioned (DNML-AL) and one control group (CON-AL) continued to receive lab chow ad lib until the end of the experiment (POP day 78). A second lesioned (DMNL-RE) and control group (CON-RE) were given 80% of the amount of food eaten by their ad lib-fed counterparts for 28 days. At this time several rats from each group were killed. The remaining animals were then given lab chow ad lib for nine days and then also killed. Both DMNL-RE and CON-RE recovered their lowered body weight, food intake and feeding efficiency and showed the same pattern and relative magnitude as their ad lib-fed counterparts. Similarly, carcass lipid, epididymal fat pad lipid, incorporation of glucose-U-C14 into fat pad saponifiable lipid, total lipid, total glycogen (DPM/protein), liver protein, incorporation of glucose into liver CO2 and concentrations of plasma glucose, glycerol, triglycerides and free fatty acids normalized on refeeding to the same extent and in the same pattern in DMNL-RE as in CON-RE. In contrast to previous studies, plasma insulin was lower in DMNL-AL than in CON-AL but DMNL-RE and CON-RE had similar levels on refeeding. Also on refeeding, both DMNL-RE and CON-RE showed the same enhanced glucose incorporation into liver total lipid. The data show that DMNL rats, although smaller in size and hypophagic in absolute terms, recovered lost body weight--at least under our relative mild reduction of 80% of their ad lib-fed controls--with the same competence and in the same time interval as sham-operated controls. It is quite possible that a more severe restriction of body weight would have uncovered some deficits in DMNL rats, however. Under the constraints of the present experimental arrangement, the data strengthen previous evidence for the existence in DMNL rats of an "organismic" set point that makes for a "scaled-down" but homeostatically normal animal.     

Fixed interval feeding does not entrain the circadian pacemaker in blind rats.

Male and female rats were blinded by orbital enucleation at 1 or 21 days of age and were housed along with intact controls in a temperature- and light-controlled room (22 +/- 2 degrees C, LD 12:12). At 40 days of age the rats were transferred to running wheel cages connected to an event recorder and their activity patterns were monitored for the next 11--16 wk. After 4--6 wk in the running wheels, the rats were subjected to a fixed interval feeding (FIF) schedule lasting 23 days followed by 4--6 wk of ad libitum feeding and watering. Of 19 blind rats with interpretable activity records, 14 showed no change in their activity patterns associated with the FIF other than the addition of a large component of activity before and after the feeding period every day. It was concluded that, in contrast to the squirrel monkey, FIF is not an important zeitgeber for blind rats.     

Food-restriction interacts with vasopressin modulation of activity

The effects of peripheral injection of various doses of lysine-vasopressin (LVP), administered 30 min before a 5-min session in a hole-board apparatus, were compared as a function of food restriction. Comparison of performance for various indices of general activity clearly showed that the food-restricted rats were more active and exhibited less photophobia than normally fed ones. The differences between the two groups were maintained in a second session 24 hours later. There was no sign of behavioral habituation to the apparatus among restricted animals. Different doses (0.2, 1, 2 micrograms of LVP) affected food-restricted animals differently from the rats fed ad lib. Only the highest dose reduced activity in both groups. A posttest injection of the smallest dose (0.2 micrograms) had an opposite effect on the activity in the hole-board, measured 24 hours after the injection. A second experiment showed that plasma and adrenal corticosterone were higher in deprived rats. The administration of 0.2 micrograms of LVP was followed by an increase in corticosterone. In food-restricted rats this increase was bigger and was still observed 24 hours after the injection. There is an interaction between feeding conditions and LVP injections which affects both the internal hormonal state and spontaneous reactivity to environment. These findings are of relevance to the effect of vasopressin on behavior.