Tolerance to amphetamine hypophagia: a real-time depiction of learning to suppress stereotyped movements in the rat

To analyze how tolerance develops to amphetamine-induced hypophagia, the authors recorded real-time licking responses in rats given chronic injections of the drug and access to milk for 30 min. Initially, licking was greatly reduced and occurred only late in the session. The acquisition of tolerance was characterized by a decrease in the latency to initiate licking, a gradual increase in the number of licks, and a reorganization of the temporal licking pattern such that licks were distributed throughout the session, interspersed with pauses. On post-tolerance dose-response tests, licking was directly proportional to drug dose in some rats. The results support the view that tolerance to amphetamine hypophagia involves a behavioral adaptation to the motor effects of the drug.     

Hypothalamic function as related to body weight and body fat in anorexia nervosa.

Percentage body fat is predictive of the onset of menstruation at puberty. In anorexia nervosa a relationship between luteinizing hormone (LH) levels and percentage weight loss has been reported. In the current study the relationship of percentage body fat and of percentage weight loss to LH and LH reactivity was examined in anorexia nervosa. Fifteen women with anorexia nervosa were studied. The resting levels of LH were measured, and in seven of the subjects LH response to luteinizing hormone releasing hormone (LHRH) and clomiphene was tested. The increment in plasma LH was measured in response to a 100 microgram dose of LHRH, and also to a 5-day course of clomiphene 100 mg. The resting LH levels were found to correlate with percentage fat, body weight, and percentage weight loss. Correlations were also found between the response to either LHRH or clomiphene and percentage weight loss, percentage fat, and absolute body weight. Other pituitary hormones measured did not show a relationship to body fat or weight. It is concluded that in addition to being predictive of the onset of menstruation, percentage body fat is significantly related to resting LH and LH reactivity in anorexia nervosa. Although percentage body fat, percentage weight loss, and absolute body weight are all significant correlates of LH reactivity, we cannot at this time conclude that any one in particular is the superior.     

Lipectomy, body weight, and body weight set point in rats.

Adult, Wistar male rats were lipectomized or sham lipectomized. The food-hoarding behavior was measured repeatedly and plotted against the animals' body weights. Body weight set point was estimated as the intercept of regression line of hoarding with the X axis. Body fat content was measured with a TOBEC body composition analyzer. Body weight set point, fat content, and girth were obtained initially, after surgery, and after recovery. The hoarding threshold was lowered for 2 weeks after surgery, from 561 +/- 20 to 512 +/- 19 g (lipectomized), and from 582 +/- 15 to 558 +/- 14 g (sham lipectomized). After a 4-week recovery, all rats reached their prelipectomy body weight set point and regained their initial body fat. Five weeks after surgery, no significant difference was found between the body weight set points of lipectomized and sham-lipectomized rats. This indicates that the body weight set point was not mainly modulated by fat depots. The transient lowering of the set point is thought to be due to surgical stress.     

The effects of amphetamine on body weight and energy expenditure.

Although there is evidence suggesting that, in addition to suppressing food consumption, amphetamine reduces body weight by increasing energy expenditure, there is little consistency among the few studies examining that factor. In this experiment, the effect of amphetamine on daily energy consumption, within-day body weights, and hourly measures of metabolic rate (MR) and respiration quotient (RQ) were assessed. Daytime drug injections decreased total energy consumption, produced biphasic changes over time in MR, and persistently lowered RQ values. In contrast, nighttime injections of drug had little effect on energy consumption and MR but did reduce RQ for the first 4 postinjection hours. These effects show that amphetamine effects interact with the circadian organization of behavior and suggest that rodent studies of anorectic agents have more relevance for humans if drugs are given during the night, when rats are normally awake and eating. From this study, it seems clear that amphetamine reduces body weight by altering metabolic rate and fat metabolism in rats when the drug is given during the day.     

Set points, settling points, and the control of body weight

Recently a number of investigators have suggested that body weight may be controlled by a neural system which contains a reference or set point. The finding that the body weight level which animals will defend can be altered by lesions of the lateral and ventromedial hypothalamus has been taken to provide support for this claim. In this paper we describe a simple feedback control model which contains no set point, and yet is able to account in full for these and other data which have been cited in support of the existence of a body weight set point. Since such a model exists it appears to be unnecessary and unparsimonious to introduce the concept of a neural set point to explain the fact that body weight maintains a relatively constant value which is defended against certain types of challenges. Constancy and defense of body weight are at best only prima facie evidence for the existence of a neural set point controlling body weight.     

Tolerance to amphetamine: contingent suppression of stereotypy mediates recovery of feeding

In this article, the effect of chronic injections of amphetamine on feeding and behavioral activation was analyzed. Rats were given milk either through an intraoral cannula or in a standard drinking tube, and the level of their behavioral activation was monitored before, during, and after access to the milk. Cannula- and bottle-fed rats given saline showed similar patterns of intake and activity. Bottle-fed rats given amphetamine (2 mg/kg) showed substantially greater suppression of intake than did cannula-fed rats, but recovered more rapidly, confirming earlier findings (Salisbury & Wolgin, 1985). Such recovery was accompanied by a suppression of stereotyped head scanning movements during access to milk, but not before and after milk access. In contrast, cannula-fed rats given amphetamine showed stereotyped head scans throughout the session for the duration of the experiment. These results suggest that tolerance to the suppression of intake by amphetamine involves learning to suppress stereotyped head movements. The constraints on such learning are briefly discussed.     

Amphetamine tolerance and body weight set point: a dose-response analysis

The theory that amphetamine anorexia and tolerance reflect the lowering of a set point for body weight regulation was evaluated. In the first experiment, rats given either 2 or 4 mg/kg d-amphetamine and access to milk ultimately achieved comparable levels of tolerance and maintained their weight at 94%-96% of control levels. Thus, the level of maintained body weight was not dose-dependent. In the second experiment, increasing the doses resulted in renewed anorexia and weight loss, and the appearance of behavioral stereotypies. Whereas mean intake then recovered, body weight remained at 79%-82% of control levels. However, milk intake for individual rats was extremely variable. Such variability is inconsistent with the notion that body weight was actively regulated by caloric intake. Drug withdrawal had little further effect on intake, and it led to weight "rebound" in only one group. When subsequently retested with the original doses, both groups were again anorexic and showed more intense stereotypy. This finding suggests that drug withdrawal caused a general increase in sensitivity to amphetamine, rather than a set-point-related change in feeding. Taken together, the data do not support the set point theory of amphetamine tolerance.     

Effects of guanethidine sympathectomy on feeding, drinking, weight gain and amphetamine anorexia in the rat

Adult female rats that underwent sympathectomy induced by guanethidine treatment (10, 20 or 40 mg/kg) exhibited markedly increased water intake, but did not display significant alterations of either food intake, body weight, or the Lee Index of obesity. Guanethidine treatment did not attenuate amphetamine anorexia as evidenced by comparable dose-dependent reductions in food intake to d-amphetamine sulfate (0.25, 0.50, 1.0, and 2.0 mg/kg) in sympathectomized and control rats. These data are not consistent with the hypothesis that amphetamine anorexia is partially mediated via enhanced BAT thermogenesis.     

Evidence that transient nicotine lowers the body weight set point

OBJECTIVE: Smokers usually gain weight when they quit smoking. The present work explores the hypothesis according to which such a rise is a behavioral response to a raised body weight set point taking place when nicotine is eliminated from the body. RESEARCH METHODS AND PROCEDURES: The human body weight set point was assessed with classical behavioral and psychophysical methods, from the delay to experience negative alliesthesia when repeatedly ingesting sweet stimuli. Seven habitual smokers were tested once before lunch, after smoking (nonabstinent) as usual and once again after refraining from smoking (abstinent). Three additional nicotine-naive subjects were tested under the same procedure after receiving at 0730 h in the morning a transdermal nicotine patch (14 mg) or a placebo patch. Two of the subjects also received nicotine (7 mg) for a third session. RESULTS: Oral and transdermal administration of nicotine did not decrease the initial pleasure or modify the initial palatability of eating sweet stimuli, but significantly accelerated the following onset of self-reported displeasure (negative alliesthesia) aroused by repeated ingestion of sweet stimuli. DISCUSSION: These results are understood as an acute lowering of the body weight set point by nicotine. The body weight gain taking place after quitting smoking may, therefore, be explained by the removal of the lowering of the body weight set point induced by nicotine.     

Tolerance to amphetamine hypophagia: a microstructural analysis of licking behavior in the rat

The development of tolerance to amphetamine-induced hypophagia was assessed by recording changes in lick parameters in rats given chronic administration of the drug (2 mg/kg) and access to sweetened milk. Although licking and milk intake gradually recovered, the volume of milk ingested per lick remained suppressed. Amphetamine had no effect on the interlick interval or the force per lick. In contrast, the drug caused a sustained increase in the number of lick bursts (defined by pause criteria of 0.5-2.0 s) and a decrease in the number of licks per burst (but only at pause criteria of 0.5 and 1.0 s). These results suggest that tolerant rats frequently interrupt licking, resulting in less efficient capture of milk.     

Effects of dexamethasone on the body weight set point of rats

Adult Wistar male rats were given dexamethasone in their drinking water. Food-hoarding behavior was measured repeatedly, and plotted against the animals' body weights. Body weight set point was estimated as the intersection of the regression line of hoarding with the X axis, i.e. as the threshold at which hoarding appears when body weight drops, and disappears when body weight returns to its initial value. Body weight set point was obtained before and during dexamethasone treatment. Control rats underwent the same sequence without dexamethasone in their drinking water. The hoarding threshold was raised when rats ingested low doses of dexamethasone, and was lowered when they ingested high doses. These results are discussed in the light of CRH as the main signal for the body weight set point.     

Effects of testosterone on body weight and adipose tissue: role of aromatization

Treatment of castrated male rats with low doses of testosterone propionate (TP; 0.2 mg/day) increases food intake and body weight gain, but long-term treatment with a higher dose of TP (1 mg/day) reduces body weight gain and carcass fat content. Concurrent treatment with androsta-1,4,6-triene-3, 17-dione (ATD), which blocks the aromatization of androgens to estrogens, prevents the weight-reducing effects of high doses of TP. Long-term treatment with 1 mg TP/day also depletes cytoplasmic estrogen receptors and reduces lipoprotein lipase activity in epididymal fat pads. Both of these effects are blocked by concurrent treatment with ATD. These findings suggest that in male rats given high doses of TP, estrogenic metabolites of the androgen may reduce body weight gain by direct effects on adipose tissue metabolism, including lipoprotein lipase activity. These mechanisms may underlie the reductions in body weight and carcass fat content seen in gondadally-intact, sexually-active male rats.     

A role for affect in context-dependent sensitization to amphetamine

Repeated exposure to stimulant drugs, such as amphetamine, induces sensitization to their behavioral activating effects. It is commonly assumed that behavioral sensitization is expressed in the environment explicitly paired with the drug but not in a different environment explicitly unpaired with the drug. The experiments reported here show that this assumption is incorrect. It was found that sensitization was expressed in an environment explicitly unpaired with amphetamine, but imbued with positive affective valence by its association with a natural reward, oral sucrose. These results suggest that the affective valence of the environment in which the drug is administered plays a decisive role in the expression of drug effects, regardless of any previous association of that environment with the drug.     

Amphetamine's effects on food consumption and body weight: the role of adaptive processes

Three experiments were conducted to characterize the time course of amphetamine's effects on food consumption using procedures that would allow both decreases and increases in eating to be evident relative to control levels. In Experiment 1 we measured eating over 12 postinjection hr in rats. Orderly changes in within-day temporal patterns of eating over the 12 days of amphetamine administration suggest the role of conditioned adaptive processes. In Experiment 2, animals were not presented food until 2 hr after drug administration. Initial anorexia and subsequent hyperphagia were produced by repeated administration of amphetamine. Experiment 3 assessed both within-day and over-day changes in body weight and food consumption and showed that in addition to the drug's anorectic effect, amphetamine also reduces body weight via other mechanisms. In interpreting tolerance to anorectic drugs, it is necessary to evaluate such changes in body weight that indicate shifts in hunger that occur over days as well as shifts in within-day temporal patterns of eating that indicate the presence of conditioned adaptive changes. It is proposed that these two adaptive mechanisms account for pharmacodynamic tolerance.     

Estimation of body dimensions in anorexia nervosa

The estimation of body dimensions in a group of 31 patients with anorexia nervosa and a control group of 20 psychoneurotic females has been studied with different techniques, including a visual size estimation apparatus and the marking of indicated body points on a paper attached to the wall. The results confirm the previously described tendency by patients with anorexia nervosa to overestimate body size in the stage before their treatment in hospital. Various differences between the two groups were found and the anorexic patients were more inconsistent in the estimation of the different body measures. On the basis of correlations with the results of an internal-external control questionnaire, it is suggested that overestimation and variability in visual size estimation could be promoted by an orientation towards external control.     

Amenorrhoea, body weight and serum hormone concentrations, with particular reference to prolactin and thyroid hormones in anorexia nervosa.

Twenty women with anorexia nervosa were investigated at varying stages during weight gain. Basal prolactin and TSH and prolactin responses to TRH were normal and unrelated to body weight. LH, FSH and 17 beta oestradiol were low in emaciated patients and rose with weight gain. There was no correlation between serum gonadotrophin and prolactin concentrations. T3 and T4 concentrations were low but T3 rose with weight gain during refeeding over 4-6 weeks, whereas T4 remained low. A positive correlation was found between the TSH response to TRH and body weight. The abnormalities in the hypothalamic-pituitary-thyroid axis were similar to those seen in a variety of chronic illnesses and appear to be unrelated to the amenorrhoea. The failure of restoration of normal function at least after short-term refeeding requires further investigation. It was concluded that the amenorrhoea in anorexia nervosa is not associated with changes in prolactin secretion but is determined primarily by changes in the hypothalamic-pituitary-gonadal axis. These changes are induced largely by nutritional factors but psychological factors may also be involved.     

Effect of increased growth rate during the suckling period on subsequent body weight and muscle weight to body weight ratio

The effect of increased growth rate during the suckling period on subsequent body growth rate and muscle weight to body weight (MW/BW) ratio was examined in inbred and outbred male and female mice. Growth rate during the suckling period was increased by reducing litter size to 4 pups within six hours of birth. Body weight, MW/BW ratio, and dry weight to wet weight (DW/WW) ratio for the soleus, tibialis anterior, extensor digitorum longus, biceps brachii, and heart muscles were measured at 4, 8, 16, and 24 weeks of age. The results indicate that increasing growth rate during the suckling period results in an increased body weight at 24 weeks of age in outbred male and female mice; whereas, in inbred male and female mice body weight is greater at 4 weeks of age but by 8 weeks of age the mice raised in normal litters have "caught up" with those raised in small litters. MW/BW ratio is increased in several muscles during the suckling period but returns to normal during the post weaning period.