Effects of chronic mild stress (CMS) and imipramine administration, on spleen mononuclear cell proliferative response, serum corticosterone level and brain norepinephrine content in male mice.

There is increasing evidence that stress and emotional reactions produce changes in various immune processes. These changes may be due to alterations of the stress responses endocrine and for autonomic mediating mechanisms. In order to study such effects, the impact of chronic mild stress (CMS) application, and of subsequent imipramine administration were studied on the spleen mononuclear cell proliferative response period. OFI strain male mice were subjected to 4 or 7 weeks of CMS. The effects of these treatments on serum corticosterone levels and hypothalamic and hippocampal norepinephrine (NE) contents were also assessed. Subjects submitted to CMS had a higher spleen mononuclear cell proliferative response after either treatment duration. Imipramine treatment diminished this response enhancement in CMS exposed animals, but did not alter the proliferative responses of control subjects. Serum corticosterone levels, as well as hypothalamic and hippocampal nonrepinephrine contents did not significantly vary between groups. Taken together, these results suggest that CMSs effects on immune reactivity are not related to serum glucocorticoids or NE changes in these locations associated with the hypothalamic-pituitary- adrenocortical (HPA) axis.

Behavioral and neurochemical responses in mice bearing tumors submitted to social stress.

Through the proinflammatory cytokines secreted in response to inflammation or injury, the immune system produces physiological and behavioral alterations. This study analyzes the effects on behavior, mononuclear proliferative response and central monoamine activity in response to the inoculation of tumor cells in mice submitted to social stress. Two groups of male OF1 mice were used, one of which was inoculated with B16 melanoma cells. Both groups were subdivided into two new groups, with one being submitted to social stress through sensory contact model with a selected aggressive subject, and the other being handled without social interaction. Subjects were exposed to social stress for a 24-h period, with three 5 min intervals of direct physical interaction, where the behavior was recorded and assessed. One hour after the stress and/or handling, they were put down and samples taken for physiological assessment. Significant behavioral changes were found in subjects with implanted tumors, mainly characterized by an increase in avoidance behavior and a decrease in immobility, defense-submission and non-social exploration behavior, coupled with an increase in the spleen mononuclear cell proliferative response. Similarly, an increase was observed in the density of dopamine(2) (D(2))-receptors in the striatum (SRT) and an increase in dopaminergic (DOPAC/DA) and serotonergic (5HIAA/5HT) turnover in the hypothalamus. The increase in the density of D(2)-receptors in the SRT coincides with the decrease in some behaviors with a predominant motor component. The results indicate significant changes in the defensive strategy used to cope with situations of intense social stress in mice bearing tumors.

Social stress paradigms in male mice: Variations in behavior, stress and immunology.

Male OF1 strain mice were allocated, after 2 weeks of individual housing, to cohabitating (6 or 16 days), fixed dyadic interaction pairs (6 or 16 daily encounters) or control groups (6 or 16 days). These different social stress situations were assessed for their effects on splenic contents of NE, IL-1 and IL-2 and serum levels of corticosterone. Spleen NE contents showed no significant variations, but serum corticosterone titers were generally higher in interacting pairs and subordinates. Splenic IL-2 did not respond in the same way to the treatments as IL-1. The differences in splenic interleukin contents could not be simply related to observed changes in serum corticosterone levels. Different mechanisms appear to regulate changes in glucocorticoids and the measured cytokines. These physiological phenomena do not simply reflect in the animal's social status (dominant or submissive). The intensity and duration of the agonistic behavior displayed as well as the interaction experience accumulated may account for the observed differences between the paradigms.

Effects of antalarmin and nadolol on the relationship between social stress and pulmonary metastasis development in male OF1 mice.

It has been found that acute social stress in male OF1 mice produced a general immunosuppression and increased B16F10 tumor development. This study examined the effects of blocking either the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic adrenomedullary (SAM) system on the impact of such stress on tumor development. Naive male OF1 mice were individually housed for 12 days before being inoculated with tumor cells or vehicle. Six days later, tumor-bearing mice were inoculated with antalarmin (a corticotropin-releasing factor receptor antagonist), nadolol (a beta-adrenergic antagonist) or vehicle. All these mice were subjected to social stress by pairing them for 24h with counterparts selected for their high and homogeneous levels of aggressiveness. The pairs were only in physical contact for three 5-min periods, being in sensory contact for the rest of this period. One hour after social stress, serum corticosterone and IFN-gamma levels were analyzed in each experimental group. Fifteen days later, lungs were removed to determine the number of metastatic foci with their areas, and blood samples were taken to assess serum titers of corticosterone and IFN-gamma. Both antalarmin and nadolol-treated mice developed significantly fewer metastatic foci with smaller areas than vehicle-treated subjects although only the group treated with antalarmin had reduced corticosterone levels. This study confirms that social stress has complex effects on immune system and tumor development that are not simply linked to corticosterone titers.

Time-dependent behavioral, neurochemical, and immune consequences of repeated experiences of social defeat stress in male mice and the ameliorative effects of fluoxetine.

This study attempted to determine whether differing numbers of days of repeated defeat experience altered behavior, immune measures, and neuroendocrine mediators in mice. OF1 male mice were socially stressed by repeated experiences of defeat in a sensorial contact model. Subjects exposed to nine defeats showed more stretch-attend postures and fewer active defense elements than counterparts exposed to 23 defeats. Submissive subjects with nine experiences of defeat also had a lower splenocyte proliferative response than unmanipulated controls. The proliferation index progressively increased but at a higher rate in manipulated controls than in socially stressed subjects, resulting in a significant immunosuppressive effect after 23 days of exposure to social stressors. Nine days of such exposure resulted in higher hypothalamic ratios of serotonin and dopamine to their major metabolites than in unmanipulated or manipulated controls and subjects socially stressed for 23 days. The data generally indicate that the acute social stressors (such as nine defeats) produce a profile of behavioral and physiological variables characteristic of a state of anxiety. The proliferation index was also lower after 52 days of social stress than in manipulated controls. Fluoxetine treatment appeared to have an anxiolytic effect, reducing immobility, and even seemed to protect subjects from the immune impairment and endocrine alteration caused by social stressors. The results generally provide clues that improve our knowledge of the consequences of social stressors and their possible treatment.