Implications of an animal model of sugar addiction, withdrawal and relapse for human health.

The effect of intermittent glucose administration on the circadian rhythm of body temperature was studied in rats to provide evidence of sugar addiction, withdrawal and relapse. Metabolic and behavioral phenomena were also observed. Biotelemetry transmitters recorded body temperature for the duration of the 4-week experiment. Rats were divided into an experimental and a control group, which were maintained on the same habituation conditions for the duration of the experiment, with the exception of weeks 2 and 4, when the experimental group was presented with a 25% glucose solution. Experimental animals displayed a precipitous drop in body temperature and behavioral changes associated with withdrawal during week 3, when sugar was removed. There was an increase in kilocalories (kcal) consumed during weeks 2 and 4 by experimental animals and, by the end of the experiment, these animals showed a greater percent increase in body weight. Elevated blood glucose levels were found in experimental animals. The study demonstrates that the effects of sugar addiction, withdrawal and relapse are similar to those of drugs of abuse. Implications of the rewarding and addicting effects of sugar are related to weight gain, obesity and Type II diabetes. Furthermore, pitfalls related to dieting are elucidated.

Vasopressin deficiency provides evidence for separate circadian oscillators of activity and temperature.

Vasopressin-containing Long-Evans and vasopressin-deficient Brattleboro rats were maintained in individual cages while telemetered activity (AC) and body temperature (BT) data were collected. Rats were initially exposed to a 12 h/12-h light/dark cycle (photic zeitgeber) and were allowed ad-libitum access to food and water. Daily feeding, care, and handling (nonphotic zeitgebers) occurred at the beginning of the second hour of the dark cycle. After a 14-day habituation period, rats were subjected to continuous light (LL) or dark (DD) and nonphotic cues were presented irregularly. During the habituation period, both strains exhibited clear 24-h circadian rhythms of AC and BT. In LL or DD, photic cues were removed and nonphotic cues were presented irregularly. There was a shift in the rhythm for Long-Evans animals to 26 h for both AC and BT in LL and 24.6 h in DD. Feeding, care, and handling were seen as minor artifact. In Brattleboro rats, although there were robust 26-h and 24.6-h circadian rhythms of AC in the LL and DD, respectively, BT data were inconsistent and showed sporadic fluctuations. In the BT rhythm of Brattleboro animals, strong peaks were associated with feeding, care, and handling times and trough periods were characterized by a dramatic drop in temperature. This experiment demonstrates that AC and BT are controlled by separate oscillators. In addition, the importance of vasopressinergic fibers in the control of circadian rhythms of BT is evidenced by the loss of circadian rhythms in animals lacking these functional fibers when exposed to free-running paradigms where there is no entrainment of photic or nonphotic oscillators.

Interaction of Vasopressin and Splenda on Glucose Metabolism and Long-term Preferences under Ad-libitum and Food-restricted Conditions.

Previous research has demonstrated that vasopressin-containing rats are capable of adapting to the stress of food restriction; whereas, vasopressin-deficient rats cannot adapt to this stressor. In the present study, the value of using a low-calorie (Splenda) or no-calorie (Equal) artificial sweetener to reverse the deleterious effects of food restriction in vasopressin-deficient rats was examined. In association with this effect, the role of vasopressin in long-term preferences for the two artificial sweeteners was studied. Vasopressin-deficient, Brattleboro (DI) rats and vasopressin-containing, Long-Evans (LE) rats underwent an habituation phase during which they had ad-libitum access to food. This was followed by an experimental phase during which the rats were divided into four groups. (1) DI rats continued with ad-libitum feeding, (2) LE rats continued with ad-libitum feeding, (3) DI rats subjected to 23 h of food restriction, and (4) LE rats subjected to 23 h of food restriction. All rats had ad-libitum access to an 8% Splenda solution, a 1% Equal solution, and water throughout both phases of the experiment. The deleterious effects of food restriction were completely reversed in DI rats, including survival, no stomach pathology, and normal plasma levels of glucose and urea nitrogen.

The role of vasopressin in modulating circadian rhythm responses to phase shifts.

Telemetered body temperature (BT), heart rate (HR), and motor activity (AC) data were collected in vasopressin-containing, Long-Evans (LE) and vasopressin-deficient, Brattleboro (DI) rats. In Experiment 1, the rats were initially exposed to a 12 h/12 h light/dark cycle under ad-libitum feeding and were then subjected to either a phase-advance or phase-delay shift of 6 h. After the phase-advance shift, neither strain adapted; however, after the phase-delay shift, both strains adapted rapidly. In Experiment 2, the animals were subjected to either a nocturnal or a diurnal restricted-feeding paradigm and were then exposed to either a phase-advance or phase-delay shift with synchronized feeding. In the nocturnal restricted-feeding paradigms, both strains rapidly adapted to both shifts. Concerning diurnal restricted-feeding, DI animals readily entrained to the presentation of food in both shifts; whereas, LE animals exhibited a confused rhythmicity. In Experiment 3, animals were subjected to a phase-advance shift, while the time of feeding was held constant. Following the shift, LE animals responded to the onset of the dark at the new time; yet, were still influenced by the presentation of food. The DI animals maintained the preshift circadian pattern and continued to be dominated by the presentation of food. These experiments indicate that circadian rhythms of LE animals are dominated by the light entrainable oscillator (LEO) in ad-libitum feeding and by both the LEO and food entrainable oscillator (FEO) in restricted-feeding. On the other hand, the circadian rhythms of DI animals are dominated by the FEO unless food is provided ad-libitum. The demonstrated role of vasopressin in synchronizing circadian rhythms to the LEO may be of significance in understanding human circadian rhythm disturbances, such as jet lag.

Role of vasopressin in long-term preferences of sucrose and polycose under ad-libitum and food-restricted conditions.

Vasopressin-deficient (DI) and vasopressin-containing (LE) rats were given continuous access to 32% sucrose and 32% polycose solutions under ad-libitum and food-restricted conditions in a long-term preference test. Although all animals preferred Polycose to sucrose in both conditions, food restriction introduced a stress that significantly increased the consumption of Polycose in DI rats. Considering total caloric intake, Polycose was preferred by both strains only under food restriction and the effect was greatly exacerbated in DI animals compared to LE animals. The differences observed between DI and LE animals in response to ad-libitum feeding and food-restriction stress indicate that vasopressin, directly and/or indirectly, influences the physical and metabolic functions and processes of the animals, which, in turn, affect their intake of Polycose.

Interactions between vasopressin and food restriction on stress-induced analgesia.

To investigate the role of the hormone vasopressin (VP) in mediating the response of an organism to food restriction stress-induced analgesia, tail flick latencies and scored qualitative behavioral responses were recorded in VP-containing (LE) rats and VP-deficient (DI) rats. These variables were measured under nonstressed (ad lib) and stressed (food restriction) conditions. In the ad lib condition, DI and LE rats had a similar tail flick latency and scored qualitative behavioral response to the stimulus eliciting the tail flick. During the food restriction condition, however, LE animals developed significant food restriction stress-induced analgesia, as measured by tail flick latency. On the other hand, DI animals did not develop significant analgesia. In addition, DI animals exhibited a significantly greater scored qualitative behavioral response to the stimulus eliciting the tail flick than LE animals. These results demonstrate that VP plays an important role in the regulation of food restriction stress-induced analgesia, as well as the scored qualitative behavioral response elicited by the tail flick stimulus.

The interaction of vasopressin and the photic oscillator in circadian rhythms.

Telemetered body temperature (BT), heart rate (HR), and activity (AC) data were collected in vasopressin-containing Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. The rats were exposed to a 12/12 h light/dark cycle under three conditions: 1) ad lib feeding throughout the 24-h cycle, 2) two scheduled-feeding periods during the diurnal component of the light/dark cycle, and 3) two scheduled-feeding periods during the nocturnal component of the light/dark cycle. With ad lib feeding, natural nocturnal cycles of BT, HR, and AC were maintained in both strains. Marked changes were observed under the condition of scheduled feeding during the diurnal component of the light/dark cycle. In DI animals the influence of the photic oscillator was lost and BT, HR, and AC shifted from nocturnal to diurnal patterns. Circadian rhythms in DI animals were now synchronized by the nonphotic zeitgeber of scheduled food presentation. On the other hand, LE animals lost a well-defined circadian rhythmicity resulting from adherence to the photic oscillator, while at the same time being influenced by the nonphotic oscillator. Under the condition of scheduled feeding during the nocturnal component of the light/dark cycle, the circadian rhythms were similar in DI and LE rats. Results show that vasopressin has a significant interaction with the photic oscillator, which is obvious only when the photic and nonphotic oscillators are uncoupled. In addition, the results demonstrate that the strength of the photic oscillator is decreased or that the effect of this oscillator is masked or lost in DI rats compared to LE rats.

Vasopressin, immobilization, and the dexamethasone suppression test in rats.

To investigate the role of the hormone vasopressin (VP) in mediating the response of the body to stress, corticosterone levels of VP-containing (LE) rats and VP-deficient (DI) rats were compared following administration of the dexamethasone suppression test (DST) under stressed and nonstressed conditions. The stressor utilized was immobilization, an acute physical stressor. Dexamethasone (DEX), a synthetic glucocorticoid, was injected subcutaneously at a dose of 0.025 mg/kg. This dose of DEX was found to significantly suppress plasma corticosterone in the nonstressed animals (both DI and LE) via feedback inhibition of the hypothalamic-pituitary-adrenocortical (HPA) axis. In the stressed situation, however, LE animals exhibited "escape" from DEX suppression, whereas DI animals did not. Escape indicates a resistance of the HPA axis to the suppressive action of DEX. Thus, in the absence of corticotropin-releasing factor, which is inhibited by DEX, VP alone appears to be sufficient to elicit significant corticosterone release. These results support the hypothesis that VP plays an important role in the regulation of glucocorticoid release in acute stress via the HPA axis.

Vasopressin deficiency and blood glucose interactions on passive avoidance behavior.

The performance of a passive avoidance task (measured for two trials based upon number of complete step-downs and latency to respond) and blood glucose levels were examined in five groups of animals. The groups included vasopressin-deficient (DI) and vasopressin-containing (LE) rats under ad lib (AL) and food-restricted (FR) conditions, as well as DI-FR animals provided with access to an 8% sucrose solution (SUC). In the AL condition, no significant differences were found between DI and LE animals in either step-down occurrences or blood glucose levels. However, the DI animals were significantly slower in latency to respond in trial 1. With FR, the LE animals resembled the LE-AL animals in both passive avoidance behavior and blood glucose levels. The DI-FR animals that were not provided with SUC showed an impairment in passive avoidance behavior and low blood glucose levels, whereas DI-FR animals provided with SUC showed an amelioration of passive avoidance deficiencies and had blood glucose levels comparable to AL animals and LE-FR animals. On trial 2, a significant negative correlation was found between number of step-down occurrences and blood glucose levels, and a significant positive correlation was found between latency to respond and blood glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin deficiency and circadian rhythms during food-restriction stress.

Vasopressin-containing, Long-Evans (LE) rats and vasopressin-deficient, Brattleboro (DI) rats were monitored for activity and core body temperature via telemetry. Rats were exposed to a 12-12 light-dark cycle and allowed to habituate with ad lib access to food and water. The habituation period was followed by an experimental period of 23 h of food-restriction stress in which a 1-h feeding period was provided during the light cycle. Although both strains of animals showed nocturnal activity and temperature rhythms during the habituation period, DI rats were more active than LE rats. The DI rats also had a lower body temperature in the dark. During the experimental period, both strains exhibited a phase shift of activity and body temperature correlating with the presentation of food. The DI rats developed a diurnal shift more rapidly than LE rats. The DI animals showed a dramatic increase in activity during the light phase and a marked decrease in body temperature during the dark phase. The LE animals showed a significant attenuation of activity, but maintained both nocturnal and diurnal temperature peaks throughout the food-restricted condition.

Modulatory effects of vasopressin on glucose and protein metabolism during food-restriction stress.

Plasma levels of glucose and urea nitrogen were compared in vasopressin-containing (LE) and vasopressin-deficient (DI) rats under ad lib and food-restricted conditions. In the ad lib situation, DI and LE rats had similar levels of glucose and urea nitrogen. Variations in this pattern were observed under food-restricted conditions. The DI animals exhibited lower levels of glucose and higher levels of urea nitrogen than their LE counterparts. During food restriction, the glucose levels of LE animals were not different from that observed under ad lib conditions. A significant decrease, however, was observed in the glucose levels in DI animals during food restriction. Urea nitrogen levels in LE animals decreased during food restriction as compared to the ad lib situation, whereas urea nitrogen levels of DI animals increased during food restriction. These observations indicate that vasopressin has a modulatory role on glucose and protein metabolism during the stress of food restriction.

Vasopressin, corticosterone levels, and gastric ulcers during food-restriction stress.

Corticosterone levels and ulcers were compared in vasopressin-containing (LE) and vasopressin-deficient (DI) rats under ad lib and food-restricted conditions. In the ad lib situation, DI and LE rats had similar corticosterone levels and no ulcers. After 1 day of food restriction, the corticosterone levels were elevated in DI and LE rats, with a significantly higher level in LE rats. No ulcers were present in either strain. After 2 days of food restriction, the corticosterone levels were similar in DI and LE rats. The level in DI rats was comparable to that of the preceding day, but the level in LE animals dropped significantly from the previous day. Significant ulceration was evident in DI rats, but absent in LE rats. Following 3 days of food restriction, the corticosterone level in LE rats had returned to the ad lib level, whereas, for DI rats, an elevated level was maintained. There were no ulcers in LE rats, but they were present in DI rats. Thus LE and DI rats responded differently to the stress of food restriction. The mechanism underlying the response is most likely related to changes in the hypothalamic-pituitary-adrenocortical axis and its reaction to stress.

Effects of vasopressin replacement during food-restriction stress.

The effects of subcutaneous injections of vasopressin in vasopressin-deficient (Brattleboro or DI) rats were observed during nonstress (habituation) and stress (food-restriction) conditions as compared to other rats. Four groups of animals were employed: 1) Long-Evans (LE) rats that were food restricted with no injections (normal control animals), 2) DI rats that were food restricted with no injections, 3) DI rats injected with vasopressin, and 4) DI rats injected with peanut oil (vehicle). The parameters studied were: body weight, food intake, water intake, and gastric ulcer formation. With respect to body weight, water intake, and ulcer formation, two sets of animals emerged. The vasopressin-injected DI rats resembled the LE control rats, whereas the peanut oil-injected DI rats were similar to the DI rats with no injections. The former set of animals showed a higher body weight, reduced water intake, and fewer gastric ulcers than the latter set of animals. Thus the vasopressin-injected DI rats and the LE control rats could cope with the stress of food restriction, but the peanut oil-injected DI rats and the DI rats with no injections could not.

Vasopressin deficiency and the modulation of consummatory behavior.

This study examined patterns of consummatory behavior in normal and vasopressin-deficient rats under ad lib and food-restricted conditions. Differing patterns of intake of food, water, sucrose, and saccharin were found in the two groups. During the ad lib period, the normal rats gained more weight and ate significantly more food than vasopressin-deficient rats. The vasopressin-deficient animals consumed significantly more sucrose than normal animals during this period. No significant differences in body weight, food intake, sucrose intake, or saccharin intake were noted during the food-restricted period between the two groups. During the food-restricted condition the normal animals showed a cyclic pattern of food, sucrose, and saccharin intake. This cyclic pattern of intake was absent in vasopressin-deficient animals. A vasopressin-serotonin interaction is hypothesized as a possible mechanism producing the differences in the two strains of animals. In addition, the data support the position that food consumption is regulated primarily by caloric and/or nutritional factors.

Effects of vasopressin deficiency, age, and stress on stomach ulcer induction in rats.

Susceptibility to ulceration induced by restraint, restraint plus intermittent shock, and activity stress was studied in 6 week and 18 week old Brattleboro and Long-Evans rats. Older animals developed more glandular ulcers than younger animals with Brattleboro rats having significantly greater ulceration than Long-Evans rats in both conditions. With activity stress, younger subjects developed significantly more glandular ulcers than older subjects; whereas, older subjects developed significantly more nonglandular ulcers than younger subjects. In both instances, the ulceration was significantly greater in Brattleboro rats than in Long-Evans rats. There were significantly high correlations among running behavior, survival time, and the development of glandular ulcers in younger animals exposed to activity stress. The presence of vasopressin, as well as the age of the subject and the nature of the stress, influences the type and degree of stomach pathology induced.

Effects of TRH injection on hippocampal-hypothalamic-pituitary-thyroid interactions.

The first experiment was conducted in an attempt to ascertain the effects of hippocampal lesions on plasma levels of total T4, total T3, free T4, and TSH. Animals with hippocampal lesions had significantly lower levels of total T4, free T4 and TSH than cortical control and normal animals. There were no significant differences in total T3 among the three groups. Since these results indicated that animals with hippocampal lesions manifested a dysfunction in the hypothalamic-pituitary-thyroid axis, a second experiment was undertaken to determine the site of mediation. A TRH injection test demonstrated that the dysfunction occurs at the level of the hypothalamus. It is hypothesized that in the normal animal the hippocampus exerts a facilitating effect on the hypothalamic-pituitary-thyroid axis.