Stress symptoms induced by repeated morphine withdrawal in comparison to other chronic stress models in mice.

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.

Behavioral sensitization to intermittent morphine in mice is accompanied by reduced adrenocorticotropine but not corticosterone responses.

The present study was aimed to test the hypothesis that behavioral sensitization to intermittent administration of morphine is accompanied by sensitization of adrenocorticotropine (ACTH) and corticosterone responses and with signs of hyperactivity of the hypothalamic-pituitary-adrenocortical function in mice. Male mice were injected subcutaneously with 40 mg/kg morphine or saline every 72 h for 16 days (in total, six injections were performed) and the effects were compared to those after single drug injection. Hormones were investigated 60 min after the last (6th) morphine or saline injection, i.e. 3 days after the 5th injection of intermittent treatments. Locomotor sensitization was confirmed in a separate series. ACTH levels in response to the last morphine injection of the repeated dosage regimen were found to be lower compared to those in acutely morphine-treated mice. Morphine administration was followed by increases in plasma corticosterone, but no significant differences between the acutely and repeatedly treated groups were observed. The body weight of morphine-treated mice showed a characteristic pattern with decreases measured the day after morphine administration. No statistically significant differences in adrenal and thymus weights were found. In conclusion, behavioral sensitization to morphine in mice is accompanied by a blunted rather than an enhanced ACTH response to drug injection. Unchanged levels of plasma corticosterone demonstrate an absence of tolerance and possible involvement of ACTH unrelated mechanisms needs further verification. Intermittent administration of morphine for 2 weeks failed to induce marked signs of glucocorticoid overexposure.

Enriched environment influences adrenocortical response to immune challenge and glutamate receptor gene expression in rat hippocampus.

Housing of animals in an enriched environment (EE) has many positive effects on brain structure and function and can facilitate recovery from various brain injuries. The purpose of this study was to evaluate whether enriched rearing could alter the stress response induced by repeated immune challenge and to investigate the influence of EE and immune challenge on glutamate receptor gene expression in the hippocampus. Male 2-mo-old Wistar rats were kept under standard conditions (SC) or in an EE for 5 weeks. Immune challenge was performed by Escherichia coli lipopolysaccharide (LPS) injected repeatedly (ip) in increasing doses (10, 20, and 40 microg/kg/mL) once daily for five consecutive days. The animals were decapitated 2 h after the last injection. Blood samples, adrenals, and hippocampi were collected. LPS induced an increase in plasma and adrenal levels of corticosterone and a transient decrease in body weight of animals kept under SC, but not in an EE. Enriched housing resulted in an increase in adrenal weights and enhanced gene expression of hippocampal AMPA GluR1 receptor subunit. Concerning the LPS treatment, no effects on adrenal and thymus weights and glutamate receptor mRNA levels in the hippocampus were noticed. Thus, vulnerability to some negative effects of repeated immune challenge may be modified by environmental conditions associated with changes in brain plasticity. The fact that differences in housing conditions change stress response has to be considered in biomedical research.