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      Stress Symptoms Induced by Repeated Morphine Withdrawal in Comparison to Other Chronic Stress Models in Mice

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          The present study was aimed at evaluating chronic stress models in mice with special attention to morphine treatment. We hypothesized that repeated periods of drug withdrawal induce chronic stress. To verify this hypothesis, mice were made dependent on morphine and then subjected to several types of repeated withdrawal. Body weight reduction, thymus involution, adrenal gland enlargement and activation of the hypothalamo-pituitary-adrenal axis were used as signs of chronic stress. The changes were compared to those induced by ‘laboratory’ models of chronic stress (2 weeks of repeated restraint or rat exposure) and to a disease model of streptozotocin-induced diabetes mellitus (STZ-DM). Mice were made dependent using increasing doses of morphine three times a day for 3 days (10–20–40 mg/kg s.c.). Thereafter, withdrawal was induced either spontaneously (morphine 40 mg/kg injected at 24- or 72-hour time intervals for 2 weeks) or repeatedly precipitated by naloxone (10 mg/kg s.c.) injected daily 3 h after morphine. The results show that repeated periods of spontaneous drug withdrawal (24 or 72 h) in morphine-dependent mice represent a mild stress load. Repeated withdrawal precipitated by naloxone induced clear chronic stress-like changes. Changes observed in the naloxone-precipitated withdrawal model were even more pronounced than those found in laboratory models, namely repeated restraint or exposure to the rat. The most severe chronic stress state developed in mice during untreated STZ-DM. Thus, naloxone-precipitated withdrawal in mice seems to be an appropriate model of chronic stress.

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          Most cited references 36

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          Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.

           Paul Willner (1997)
          This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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            Regulation of pituitary ACTH secretion during chronic stress.

            Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.
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              Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis.

              We studied the effects of long-term (i.e. 4 wk) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice. Voluntary exercise was provided by giving mice access to a running wheel, in which they indeed ran for about 4 km/d. Exercising mice showed similar body weights as control animals but presented less abdominal fat, lighter thymuses, and heavier adrenal glands. Exercise resulted in asymmetric structural changes in the adrenal glands. Whereas control mice had larger left than right adrenals, this condition was abolished in exercising animals, mainly because of enlargement of the right adrenal cortex. Tyrosine hydroxylase mRNA expression in the adrenal medullas of exercising mice was increased. In exercising mice, early-morning baseline plasma ACTH levels were decreased, whereas plasma corticosterone levels at the start of the dark phase were twice as high as those in control animals. To forced swimming and restraint stress, exercising mice responded with higher corticosterone levels than those of the control animals but with similar ACTH levels. However, if exposed to a novel environment, then exercising mice presented decreased ACTH responses. Interestingly, exercising mice showed a decreased corticosterone response to novelty only when the novel environment contained a functioning running wheel. Glucocorticoid receptor levels were unchanged, whereas mineralocorticoid receptor levels were decreased, in hippocampus of exercising animals. Corticotropin-releasing factor mRNA levels in the paraventricular nucleus were lower in exercising mice. Thus, voluntary exercise results in complex, adaptive changes at various levels within the HPA axis as well as in sympathoadrenomedullary and limbic/neocortical afferent control mechanisms. These changes seem to underlie the differential responsiveness of the HPA axis to physical vs. emotional challenges.

                Author and article information

                S. Karger AG
                July 2005
                29 July 2005
                : 81
                : 3
                : 205-215
                aInstitute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; bInstitute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia; cMinority/Remedial Coaching Centre, Sagar, India
                87034 Neuroendocrinology 2005;81:205–215
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 6, Tables: 1, References: 49, Pages: 11
                Original Paper


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