Chronic effects of a nonpeptide corticotropin-releasing hormone type I receptor antagonist on pituitary-adrenal function, body weight, and metabolic regulation

CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of i.p. antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean +/- SD, 2.62 +/- 0.063 pg/ml) and corticosterone concentrations (10.21 +/- 1.80 microg/dl) compared with those in vehicle-treated rats [respectively, 5.3 +/- 2.0 (P < 0.05) and 57.02 +/- 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 +/- 3.58%) compared with that in placebo-treated controls (6.8 +/- 0.91%). We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic.     

Long-term effects of nutrition with fat-reduced foods on energy consumption and body weight

In a 3-month intervention study 70 women (40 < age < 60; 24 < BMI < 29), randomized into two groups, were supplied ad libitum and free of charge with 1) customary fat-reduced foods (D group) or 2) products with normal fat content (K group). After 6 months without any contact to the volunteers food intake and body weight were controlled. Results: During the intervention period fat intake (by 22 g/d) and total energy intake (by 266 kcal/d) of the volunteers in the D group were significantly lower than in the K group. Fat reduction was not accompanied by a compensative increase in the intake of other nutrients. The weight loss was significant in the D group (1.5 kg) and not significant in the K group (0.7 kg). Between the two groups the difference in weight reduction was not significant. In the follow-up a lowered fat and energy intake had been voluntarily retained in the D group and adopted by most of the individuals in the K group. Conclusion: The consumption of low-fat products lowers the energy and fat intake and may be useful for a long-term weight control and health support.     

Evaluation of behavioural effects of neural melanocortin receptor antagonists injected ICV and in VTA in rats

The purpose of this study was to examine intratester, intertester, and interdevice reliability of range of motion measurements of the elbow and forearm. Elbow flexion and extension and forearm pronation and supination were measured on 38 subjects with elbow, forearm, or wrist disease by 5 testers. Standardized test methods and a randomized order of testing were used to test groups of patients with universal standard goniometers, a computerized goniometer, and a mechanical rotation measuring device. Intratester reliability was high for all 3 measuring devices. Meaningful changes in intratester range of motion measurements taken with a universal goniometer occur with 95% confidence if they are greater than 6 degrees for flexion, 7 degrees for extension, 8 degrees for pronation, and 8 degrees for supination. Intertester reliability was high for flexion and extension measurements with the computerized goniometer and moderate for flexion and extension measurements with the universal goniometer. Meaningful change in interobserver range of motion measurements was expected if the change was greater than 4 degrees for flexion and 6 degrees for extension with the computerized goniometer compared with 10 degrees and 10 degrees, respectively, if the universal goniometer was used. Intertester reliability was high for pronation and supination with all 3 devices. Meaningful change in forearm rotation is characterized by a minimum of 10 degrees for pronation and 11 degrees for supination with the universal goniometer. Reliable measurements of elbow and forearm arm movement are obtainable regardless of the level of experience when standardized methods are used. Measurement error was least for repeated measurements taken by the same tester with the same instrument and most when different instruments were used.     

Posterodorsal amygdaloid lesions in rats: long-term effects on body weight

Bilateral lesions in the most posterodorsal aspects of the amygdala in female rats resulted in immediate and dramatic weight gains on a standard lab chow diet. The rate of weight gain returned to normal by Day 20, but the difference in body weight between animals with amygdaloid lesions and those with sham lesions was maintained for the duration of the study (60 days). Because rats with posterodorsal amygdaloid lesions have also been found to be hyperinsulinemic, it is hypothesized that the lesions result in a similar, though smaller, version of the syndrome that follows lesions of the ventromedial hypothalamus.     

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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some effects of ovarian hormones on food intake and body weight in female rats.

Conducted 3 experiments with a total of 63 ovariectomized and 41 ovariectomized-adrenalectomized Sprague-Dawley rats in which ovarian steroids affected food intake and body weight. These effects were probably mediated by estradiol and progesterone, since these 2 hormones were more effective than their principal metabolites (estrone 5a-pregnane-3,20-dione, 5ai0regnane-3,20-dione, respectively) in altering the food intake and body weight of ovariectomized Ss. Estradiol seemed to affect food intake by lowering the set point about which body weight is regulated in a dose-dependent fashion. These actions of estradiol could be attenuated or completely blocked by concurrent injections of progesterone. Estradiol-treated ovariectomized Ss were far more responsive to the weight- and appetite-promoting actions of progesterone than were ovariectomized-adrenalectomized Ss, suggesting that the principal action of progesterone on energy balance may be to interfere with the effects of estradiol. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of caging variables on body weight and weight gain in mice

The effects on body weight of mixing litters to attain constant density of mice per cage, as opposed to housing litters in separate cages, was studied. Mixing litters resulted in a decreased weight gain between 21 and 42 da of age and a decreased adult body weight at 63 da of age compared to housing litters in separate cages, whether the separately housed litters were allowed to vary in density or not. Mixed litter housing also increased the variance of the body weight measures among males. Housing litters separately, even if it entails variable density of housing, appears to be the preferred method for studies involving inheritance of body weight.     

Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats

We injected i.c.v. the natural agonist alpha-MSH (melanocyte-stimulating hormone) and the first selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11, D-Nal14, Cys18, Asp-NH(2)22]-beta-MSH(11-22) in rats and scored a number of behavioral effects which have been related to the melanocortic peptides. The results showed that HS014 (5 microg/rat) completely blocked alpha-MSH (3 and 5 microg/rat)-induced grooming, yawning and stretching. Penile erections induced by alpha-MSH were, however, only partially blocked by HS014. Injections of alpha-MSH decreased food intake in food-deprived rats, whereas HS014 increased food intake. When the peptides were given together, the food intake was similar to that of saline treated controls. Locomotion/exploration and resting were not influenced by either peptide. Our data show that exogenous beta-MSH decreases food intake, and that an endogenous central melanocortinergic inhibitory tone on feeding prevails which can be blocked with HS014, leading to an increase in food intake. Our data also provide evidence that grooming, stretching and yawning in rats may be mediated by the melanocortin MC4 receptor, whereas penile erections might perhaps be mediated by some other melanocortin receptor.     

General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats.

In an earlier work (S. E. Swithers & T. L. Davidson, 2008), rats provided with a fixed amount of a yogurt diet mixed with saccharin gained more weight and showed impaired caloric compensation relative to rats given the same amount of yogurt mixed with glucose. The present 4 experiments examined the generality of these findings and demonstrated that increased body weight gain was also demonstrated when animals consumed a yogurt diet sweetened with an alternative high-intensity sweetener (acesulfame potassium; AceK) as well as in animals given a saccharin-sweetened base diet (refried beans) that was calorically similar but nutritionally distinct from low-fat yogurt. These studies also extended earlier findings by showing that body weight differences persist after saccharin-sweetened diets are discontinued and following a shift to a diet sweetened with glucose. In addition, rats first exposed to a diet sweetened with glucose still gain additional weight when subsequently exposed to a saccharin-sweetened diet. The results of these experiments add support to the hypothesis that exposure to weak or nonpredictive relationships between sweet tastes and caloric consequences may lead to positive energy balance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Naloxone-induced opiate withdrawal produces long-lasting and context-independent changes in aggressive and social behaviors of postdependent male mice.

The purpose of this study was to determine whether an environment associated with naloxone-induced morphine withdrawal affects aggressive or social behaviors in postdependent mice. Morphine-dependent or saline-treated mice received 3 naloxone injections in 1 of 2 different environments (A or B); 15 days afterward, when the mice were completely drug free, an aggression test was carried out in Environment A. All the mice suffering morphine withdrawal showed a significant increase in aggression, irrespective of the environment in which the withdrawal took place. In these conditions, the impact of morphine dependence and the 3 induced withdrawals was so profound that the environment could not be discriminative. In addition, modifications in the behavioral profile of postdependent mice that suffered only spontaneous withdrawal were long-lasting, with the mice carrying out more attacks during social investigation without presenting threat postures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of chromium on body composition and weight loss

Chromium is an essential nutrient involved in the regulation of carbohydrate and lipid metabolism. Normal dietary intake of chromium in humans and farm animals is often suboptimal. In addition to its effects on glucose, insulin, and lipid metabolism, chromium has been reported to increase lean body mass and decrease percentage body fat, which may lead to weight loss in humans. The effects of chromium on body composition are controversial but are supported by animal studies, which increase their validity. A subject's response to chromium depends on his or her chromium status, diet consumed, type and amount of supplemental chromium, and study duration. There have been no confirmed negative effects of chromium in nutritional studies. Chromium is only a small part of the puzzle in the control of weight loss and body composition, and its effects, if present, will be small compared with those of exercise and a well-balanced diet.     

Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.     

Effect of chronic administration of fenfluramine and quipazine on body weight gain after ovariectomy and on brain serotonin receptor binding.

In Exp I, chronic fenfluramine administration prevented excess weight gain following ovariectomy in 24 female Long-Evans rats but did not alter weight gain in 27 sham-operated controls. Chronic quipazine treatment had no long-term effect on body weight. Fenfluramine treatment for 28 days produced a 13% decrease in [–3H]-serotonin binding to hypothalamic membranes and no change in [–3H]-spiroperidol binding to striatum. In Exp II with 10 female Sprague-Dawley rats, chronic fenfluramine had no effect on [–3H]-serotonin binding to diencephalon. Results are discussed in terms of central and peripheral mechanisms of action and tolerance to fenfluramine. (10 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of diet on feeding and body weight regulation during pregnancy and lactation in the golden hamster (Mesocricetus auratus).

Conducted 3 experiments with 90 female golden hamsters to test the hypothesis that the weight loss shown by lactating hamsters constitutes a regulated weight loss. Results support the hypothesis, showing that prefattened overweight Ss lost more weight from the time of mating to the end of lactation than did unmanipulated controls. However, the weight loss during lactation was reduced by giving Ss access to a high-fat diet, a result indicating that a portion of the lactational weight loss may also be regulated by the diet provided. When lactating Ss were given access to a fractionated diet consisting of pure fat, pure carbohydrate, or 45% protein, they increased their proportional intake of both protein and fat but not of carbohydrate. Studies show that hamsters differ from rats in their pattern of energy regulation during pregnancy, lactation, and the postsuckling period. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Restraint, weight loss, and variability of body weight.

Restrained and unrestrained Ss (n?=?24) were weighed daily for a 6-wk period and again 6 mo later in order to determine whether dietary restraint or relative body weight is the better predictor of weight variability. Restraint was a significantly better predictor of naturally occurring weight fluctuations than was relative body weight. Furthermore, the 2 factors of the Restraint Scale, Concern for Dieting and Weight Fluctuations, were both significant predictors of weight variability. We propose that exaggerated weight fluctuations are not a natural concomitant of higher body weight but possibly the consequence of a cycle of dieting and overeating, which seems to preclude actual weight loss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Leptin and the regulation of body weight

Leptin has received considerable attention as a newly recognized metabolic hormone and for its potential for therapeutic use in the treatment of human obesity. Furthermore, defects in the leptin signal pathway that result in obesity in animal models have raised the possibility of a similar etiology for obesity in humans. This review will summarize the current findings on leptin in both humans and rodents. These findings will be discussed with respect to our view of the physiology and potential for pathophysiology in leptin-mediated regulation of body weight and composition.     

Sigma receptor ligands and imidazoline secretagogues mediate their insulin secretory effects by activating distinct receptor systems in isolated islets

The effects of two potent sigma receptor agonists (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine) and DTG (N,N'-di-(o-tolyl)guanidine) on the insulin secretory responses in rat islets of Langerhans were investigated. Both sigma receptor ligands were able to potentiate the insulin secretory response of islets incubated at 6 mM glucose, in a dose-dependent manner and were also able to reverse the effects of diazoxide on insulin release. When islets were treated with efaroxan, a well-characterised imidazoline insulin secretagogue, and either (+)-3-PPP or DTG together, there was an unexpected and profound absence of stimulation of insulin release as compared to when islets were incubated with each compound alone. Experiments performed with islets where there was desensitization of DTG/sigma receptor or efaroxan/imidazoline binding site mediated responses suggest that at least two distinct receptor systems appear to be involved. The complex interactions of these two classes of drug require further investigation.     

Central noradrenergic neurons: Differential effects on body weight of electrolytic and 6-hydroxydopamine lesions in rats.

Compared the effects of bilateral electrolytic and 6-hydroxydopamine (6-OHDA) lesions of the ventral noradrenergic bundle (VB) in 2 experiments with a total of 67 female albino rats. When Ss were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. Exp II, in which both types of lesions were placed at a rostral ventromedial hypothalamic site, yielded the same pattern of results. Diet-dependent increased in body weight were attributed to the destruction of a non-noradrenergic system, which was spared by the relatively selective 6-OHDA lesion but damaged by the nonselective electrolytic lesion. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor

BACKGROUND: Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function. METHODS: The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined. RESULTS: BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA. CONCLUSION: NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.