Stress-induced Anorexia Research Articles

CRH-deficient mice have a normal anorectic response to chronic stress

Many studies have implicated corticotropin-releasing hormone (CRH) as a mediator of stress-induced decreases in food intake. However, urocortin, sauvagine, and urotensin, other members of the family of CRH-like molecules, have also been shown to be potent inhibitors of food intake. This raises the possibility that a CRH-related molecule might also be responsible for stress-induced anorexia. We therefore examined the effects of three chronic stressors, repetitive daily restraint, turpentine abscess, and surgical stress, upon food intake in wildtype and CRH-deficient mice created by targeted inactivation of the CRH gene. We have found that both genotypes have similar basal food intake which initially decreases to the same degree following initiation of each stress paradigm. Food intake also recovers following the same time course and to the same degree in both genotypes. Therefore, CRH is not necessary for decreases in food-intake induced by the chronic stressors examined in this study.

Decreased Type 2 Corticotropin-Releasing Hormone Receptor mRNA Expression in the Ventromedial Hypothalamus during Repeated Immobilization Stress

Chronic or repeated stress results in reduction of food intake and body weight in rats. Stress-induced anorexia has been attributed to increased corticotropin-releasing hormone (CRH) function in the central nervous system. To explore possible roles of other neuropeptides and peripheral hormones involved in food intake and energy utilization during continuing stress, we examined the impact of repeated immobilization stress on expression of mRNAs coding for CRH, neuropeptide Y (NPY), galanin and pro-opiomelanocortin (POMC) mRNAs in such hypothalamic nuclei as the paraventricular nucleus (PVN), arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH), as well as plasma insulin and leptin concentrations. Changes in type 2 CRH receptor (CRHR-2) mRNA in the ventromedial hypothalamus (VMH), a possible target of anorectic CRH effect, were also examined. Rats were immobilized for 2 h daily for 6 days and sacrificed 24 h after the last immobilization. Immobilized rats had lower food intake and body weight and higher levels of PVN CRH mRNA than controls. Repeated immobiliza tion also lowered plasma insulin and leptin concentrations and VMH CRHR-2 mRNA levels. These results provide additional evidence linking VMH CRHR-2 mRNA levels to plasma leptin concentration. ARC NPY and DMH galanin mRNAs increased following repeated immobilization, while ARC POMC mRNA decreased. DMH NPY mRNA and ARC galanin mRNA were unaltered by immobilization. Since NPY and galanin are considered orexigenic, while the POMC-melanocortin-4 receptor system is apparently anorexigenic, the changes in neuropeptide mRNAs and VMH CRHR-2 mRNA may play counterregulatory roles against anorectic CRH effects.

Selective melanocortin MC 4 receptor blockage reduces immobilization stress-induced anorexia in rats

We investigated the effects of selective melanocortin MC 4 receptor blockage on immobilization stress-induced anorexia. Male rats were subjected to immobilization once a day for 4 days. Prior to each of the stress treatments, the rats were injected i.c.v. (intracerebroventricularly) with either saline or the melanocortin MC 4 receptor antagonist HS014 (cyclic [AcCys 11, d-Nal 14, Cys 18, Asp-NH 2 22]β-MSH-(11–22) (melanocyte-stimulating hormone). Rats subjected to neither stress nor i.c.v. injections served as controls. The results showed that the cumulative food intake and body weight gain in the stressed group treated with HS014 was significantly higher than in the stressed group and significantly lower than in the control group. Repeated injections of the melanocortin MC 4 receptor antagonist were effective and there were no signs of tachyphylaxis. This is the first report showing that melanocortin MC 4 receptor blockage can relieve an anorectic condition, which may indicate that melanocortin MC 4 receptor blockage is an effective way to treat anorectic disorders.

Taste and emotionality in rats selectively bred for high versus low saccharin intake

Rats were selectively bred for high versus low saccharin ingestion, a putative measure of enhanced stress and emotionality (Dess, 1991). In Experiment 1, third-generation Occidental high-saccharin (HiS) and low-saccharin (LoS) rats were tested for saccharin ingestion and emotionality. The saccharin test confirmed that the lines differed on the selection phenotype. In addition, LoS rats were more emotional, as evidenced by longer emergence latencies and more defecation in a modified open-field test. In Experiment 2, LoS rats had lower quinine preference scores and drank saccharin-adulterated glucose less avidly. These outcomes are reminiscent of the behavior shown by inescapably shocked rats. Unlike helpless rats, however, LoS rats drank less avidly during a dilute sucrose test, an effect more reminiscent of chronic mild stress. The lines did not differ reliably on intake of concentrated glucose or Polycose, even when the latter was mixed with saccharin. In Experiment 3, LoS rats preferred saccharin less strongly than did HiS rats at concentrations of 0.05% to 0.7% and had an aversion to a 1.0% solution. In Experiment 4, LoS rats were affected more by shock, as assessed by stress-induced anorexia. These and other recent findings support the notion of shared mechanisms for taste, emotionality, and stress vulnerability.

Neurochemical studies of stress-induced anorexia mediated by serotonergic mechanism in the hypothalamus

Neurochemical studies of stress-induced anorexia mediated by serotonergic mechanism in the hypothalamus

Mechanisms of vasopressin's anorectic effect

The present experiments investigated the effect of vasopressin (VP) on food intake in rats under various conditions. VP (1.25–10 μg/kg body weight = b.wt.) injected intraperitoneally (IP) at the onset of the dark phase of the lighting cycle inhibited feeding in a dose-dependent manner. The suppression of feeding induced by VP was primarily due to a delayed onset of the first meal after injection and was reversed by a V 1-receptor antagonist (7 μg/kg b.wt., IP), by the Ca ++-channel blocker verapamil (5 mg/kg b.wt., IP) and by the α-adrenergic receptor antagonist phentolamine (500 μg/kg b.wt.), but not by dissection of the hepatic branch of the vagus. In further experiments VP inhibited gastric emptying. This effect was not reversed by phentolamine. VP had also an aversive effect, but this effect was weaker than that of LiCl and probably not involved in VP-induced hypophagia. The results suggest that VP reduces feeding through a V 1-receptor-mediated activation of an α-adrenergic mechanism. The inhibition of gastric emptying or a possible stimulation of hepatic oxidative metabolism by VP seems to be not essential for VP's effect on feeding. The results are consistent with a role of VP in stress-induced anorexia in rats.

The effects of chronic central administration of corticortrop in-releasing factor on food intake, body weight, and hypothalamic-pituitary-adrenocortical hormones

The effects of chronic central administration of corticotropin-releasing factor (CRF) on food intake, body weight, and hypothalamic-pituitary-adrenocortical hormones were investigated in rats. The infusion of ovine CRF at doses of 0.3 and 1.0 μg/h continuously induced decrease in food intake and a suppression of body-weight gain for 7 days. The inhibition of body weight gain induced by CRF could not be accounted for solely by a decreased food intake since the suppression of body-weight gain in CRF-infused rats was significantly greater than that observed in rats which received the same amount of food as the CRF-infused rats. The content of proopiomelanocortine (POMC) -derived peptides in the anterior lobe of the pituitary as well as the plasma levels of ACTH and corticosterone (B) were significantly elevated in CRF-treated rats, and the CRF content in the hypothalamus was significantly decreased. These results suggest that chronic intracerebroventricular (icv) administration of CRF stimulates the synthesis and secretion of POMC-related peptides in the pituitary and suppresses food intake accompanied by inhibition of body weight gain. The results are similar to clinical and laboratory findings observed in patients with stress-induced anorexia.

Stress-induced anorexia and hypothalamic serotonin release in rats

Stress-induced anorexia and hypothalamic serotonin release in rats

Inhibition of feeding by ACTH-(1-24): behavioral and pharmacological aspects

The time course of the behavior of rats fasted for 24 h was analyzed with observation starting either 10 or 60 min after the i.c.v. administration of ACTH-(1-24) (4 μg/animal). The anorectic effect of this peptide was direct and specific because it could be dissociated in time from the grooming-inducing effect. The effect is a central one, not linked either to an interaction with the peripheral feeding-regulatory system, or to the release of adrenal steroids. ACTH-(1-24), like corticotropin-releasing factor (CRF), is capable of antagonizing the stimulation of feeding seen during starvation, insulin (10 IU/kg s.c.)-induced hypoglycemia, stimulation of GABAergic (muscimol, 250 ng/rat i.c.v.), noradrenergic (norepinephrine, 20 μg/rat i.c.v.) or opioidergic systems. The data suggest that both CRF and ACTH may be considered as putative mediators in the production of stress-induced anorexia.

Stress-induced anorexia in rats mediated by serotonergic mechanisms in the hypothalamus

The effects of stress on food intake and on neural activity in the lateral hypothalamic area (LHA) were investigated. Significant reduction of daily food intake was observed after 2 hr immobilization. The reduction of body weight was also significant during experimental days. Duplicate injections of methysergide (5 mg/kg, IP) antagonized the immobilization-induced anorexia for 3 hr and injection of naloxone had no effect. Single neuron activity was recorded from a chronically implanted electrode. Activity of 80% of LHA neurons was significantly decreased by immobilization stress. Methysergide significantly attenuated the suppressive effect of immobilization. Further, direct effects of 5-HT on LHA neurons were examined in anesthetized rats. Of 43 LHA neurons tested, the activity of 35 was inhibited by electrophoretic application of 5-HT. These results suggest that immobilization-induced anorexia is mediated at least in part through serotonergic mechanisms in the LHA.

Involvement of corticotropin-releasing factor in restraint stress-induced anorexia and reversion of the anorexia by somatostatin in the rat

The mechanism by which restraint stress induces suppression of food intake and the influence of intracerebroventricular (icv) administration of somatostatin on the anorexia induced by restraint stress were examined in the rat. Ninety minutes of restraint stress reduced food intake of rats to approximately 60% that of control. Anorexia induced by 90 min restraint stress was partially reversed by icv administration of α-helical CRF (9–41), a corticotropin-releasing factor (CRF) antagonist, and completely reversed by anti-CRF γ-globulin. These results provide further evidence in support of the theory that CRF is involved in the inhibitory mechanism of food intake in restraint stress. ICV administration of somatostatin 14 and SMS 201–995, an analog of somatostatin, also reversed restraint stress-induced anorexia. It is, therefore, suggested that somatostatin may counteract the suppressive action of CRF on food intake in stress.

The influence of cyproheptadine on immobilization and oestradiol benzoate induced anorexia in ovariectomized rats.

Repeated bodily immobilization significantly reduced the food intake of ovariectomized rats. Additionally, immobilization and oestradiol benzoate were found to produce additive effects in depressing feeding. To determine whether serotonergic mechanisms are involved in the stress- and oestrogen-induced anorexia, the 5-HT antagonist cyproheptadine was given to ovariectomized rats that were immobilized and treated with oestradiol benzoate. Cyproheptadine had no effect on the anorexia produced by oestradiol. The food intake of immobilized rats treated with cyproheptadine was similar to control values, suggesting 5-HT involvement in the stress-induced anorexia. However, cyproheptadine had no ameliorating effects on the changes in body weight following immobilization treatment. The implications of these findings are discussed in relation to a possible neuroendocrine basis for anorexia.

Immobilisation stress-induced anorexia is not due to gastric ulceration

The relationship between the anorexia following immobilisation and the associated gastric pathology in male and female rats was investigated. Male rats were injected with saline or the histamine-H 2. antagonist, ranitidine, which inhibits gastric acid secretion but does not readily enter the brain. Thirty minutes later, the animals were immobilised for 2 hours. Ranitidine pretreatment reduced the number of gastric lesions but had no effect on the degree of stress-induced anorexia. The number of gastric lesions did not correlate significantly with the degree of anorexia or weight loss. Previous studies have reported that female rats (unlike males) exhibit anorexia after repeated daily immobilisations and have greater gastric pathology following stress. Therefore, in a second experiment, female rats were pretreated with saline or ranitidine and immobilised for 2 hours/day for 4 days. The drug did not decrease the number of lesions observed after this treatment. However, as in the first experiment, the number of lesions did not correlate significantly with anorexia or weight loss. It is therefore unlikely that immobilisation stress-induced anorexia in either male or female rats is merely a consequence of gastric ulceration.

The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats

The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors.

CRF antagonist partially reverses CRF- and stress-induced effects on feeding

Exogenous corticotropin releasing factor (CRF) causes centrally mediated behavioral changes including decreased feeding and increased grooming. These behavioral changes are also seen in response to some stressors. However, the role of endogenous CRF in the behavioral response to stressors has not been investigated fully. We report below our findings on the behavioral effects of alpha-helical CRF (9–41), a recently discovered competitive antagonist of CRF-induced ACTH release. Alpha-helical CRF (9–41) partially reversed the decrement in feeding induced by CRF. Furthermore, the reduction in food intake due to restraint stress was partially reversed by alpha-helical CRF (9–41). These results indicate that changes in endogenous CRF release induced by the restraint Stressor may play a role in stress-induced anorexia.

Stress-induced anorexia: Implications for anorexia nervosa

Recent studies have suggested that stress may be a precipitating factor in the etiology of anorexia nervosa. The present paper examines the possible mechanisms involved in stress-induced anorexia and suggests how stress-induced changes in opiate systems, the hypothalamic-pituitary-adrenal axis and serotonergic systems may provide an explanation of many of the physiological and behavioral responses observed in anorexia nervosa. The present paper suggests that certain psychosocial and endocrinological factors may interact to provide the setting conditions for the syndrome. Finally, it is suggested that a dual therapeutic approach is required in that the syndrome needs to be treated both physiologically and psychologically to prevent relapse.

The role of peptides in feeding

Morley, Gosnell and Levine discuss the variety of peptides that have been demonstrated to play a role in the modulation of food intake. In particular, the endogenousopioid peptide, dynorphin, represents one of the major neurotransmitters involved in the initiation of feeding. Corticotropin releasing factor is important in the pathogenesis of stress-induced anorexia and may have an etiological role in anorexia nervosa. Calcitonin gene related peptide is also a potent central satiety factor. A number of gastrointestinal peptides including cholecystokinin, bombesin, glucagon, and somatostatin have been shown to provide important input as satiety signals from the gut. The integrative action of many of the neurotransmitters involved in appetite regulation can be conceived as a satiety cascade similar to the classical cascade systems regulating blood clotting and complement fixation. But the authors stress that our increased knowledge of satiety mechanisms has not simplified concepts of pharmacological appetite suppressants.

Effect of centrally administered corticotropin releasing factor (CRF) on multiple feeding paradigms

Recently, a 41-residue corticotropin-releasing factor (CRF) has been characterized from the hypothalamus. In the present study, it was found that this stress-related peptide suppressed feeding induced by a variety of substances including muscimol, norepinephrine, dynorphin and insulin. These data suggest that the corticotropin-releasing factor may represent an important agent in stress-induced anorexia.

The comparative efficacy of buspirone and diazepam in the treatment of anxiety

In this double-blind study, 56 adult psychoneurotic outpatients with a primary diagnosis of anxiety neurosis were randomly assigned to receive buspirone (N = 18), diazepam (N = 20), or placebo (N = 18) over a four-week period. A battery of tests administered weekly indicated that buspirone, a new agent not chemically related to any currently marketed drugs, was as effective an antianxiety agent as diazepam and produced no more and perhaps fewer side effects. Buspirone showed excellent antidepressant effects as well. If further studies confirm the authors' findings and determine that buspirone does not result in tolerance and addiction, it would be more advantageous than the benzodiazepines in the treatment of anxiety.