An evaluation of immune function and effects of fluoxetine in rodent models of depressive and sickness behavior

Several lines of research have identified similarities between behaviors associated with major depressive disorder (MDD) and those associated with immune activation, referred to as sickness behaviors. Reports of altered immune parameters in MDD patients further point to a shared mechanism underlying depressive and sickness behaviors. Most reliable of these immune changes are suppressed natural killer cell activity (NKCA) and alterations in leukocyte subsets. Further, some studies have demonstrated that treatment of MDD with the selective serotonergic reuptake inhibitors (SSRIs) increase NKCA in a subset of depressed patients. In light of these findings the following questions were posed: (1) Is sickness behavior induced by animal models of depressive states? (2) Is NKCA suppression observed in rodent models of MDD, and is this reduction reversible by SSRI administration? (3) Does repeated immune activation induce depressive behaviors and the immune alterations observed in MDD patients, and does SSRI administration restore these alterations? Behavioral similarities between depressive and sickness behaviors, and immune alterations associated with MDD suggest that immune activation leads to depressive behaviors. The immune alterations found with MDD are also associated with the release of proinflammatory cytokines from activated macrophages which have been implicated in sickness behavior and hypothalamic-pituitary-adrenal (HPA) axis activation. Administration of proinflammatory mediators to non-depressed patients induces depressive symptoms and increases HPA axis activity. HPA axis activation is associated with MDD and is modulated by SSRIs. Further, SSRIs have been shown to suppress macrophage function. Chronic mild stress (CMS) in rodents is used to model MDD, and elicits depressive behaviors and increases HPA axis activity. With the questions above, the following hypotheses were tested: (1) CMS and repeated immune activation with zymosan (yeast cell wall mannoprotein) will have similar and parallel effects on depressive behaviors measured in Porsolt\u27s forced swim test and on sickness behaviors defined by the social investigation task; (2) Both CMS and repeated immune activation will activate the HPA axis evidenced by elevated circulating corticosterone; (3) Both CMS and repeated immune activation will disrupt innate immune function measured by decreased NKCA and macrophage activation evidenced by increased intracellular ROS; and (4) chronic fluoxetine will normalize behavior, endocrine, and immune responses. CMS suppressed NKCA, and consistent with findings in MDD patients, chronic fluoxetine abrogated CMS-induced suppression of NKCA. Furthermore, CMS stimulated macrophage activity as evidenced by increased ROS, which was not altered by fluoxetine. Taken together these findings suggest that the CMS model is an appropriate model to further explore the relationship between depressive behaviors and related immune function. In contrast, chronic zymosan did not alter immune measures. Both CMS and chronic zymosan induced depressive behaviors, however neither manipulation induced sickness behavior. While previous studies have evaluated acute pathogen administration, given the chronic nature of MDD, the current study used repeated administration of pathogen. This may account for the differences with previous research. FLX did not reverse behavior alterations induced by chronic zymosan

An evaluation of immune function and effects of fluoxetine in rodent models of depressive and sickness behavior

Several lines of research have identified similarities between behaviors associated with major depressive disorder (MDD) and those associated with immune activation, referred to as sickness behaviors. Reports of altered immune parameters in MDD patients further point to a shared mechanism underlying depressive and sickness behaviors. Most reliable of these immune changes are suppressed natural killer cell activity (NKCA) and alterations in leukocyte subsets. Further, some studies have demonstrated that treatment of MDD with the selective serotonergic reuptake inhibitors (SSRIs) increase NKCA in a subset of depressed patients. In light of these findings the following questions were posed: (1) Is sickness behavior induced by animal models of depressive states? (2) Is NKCA suppression observed in rodent models of MDD, and is this reduction reversible by SSRI administration? (3) Does repeated immune activation induce depressive behaviors and the immune alterations observed in MDD patients, and does SSRI administration restore these alterations? Behavioral similarities between depressive and sickness behaviors, and immune alterations associated with MDD suggest that immune activation leads to depressive behaviors. The immune alterations found with MDD are also associated with the release of proinflammatory cytokines from activated macrophages which have been implicated in sickness behavior and hypothalamic-pituitary-adrenal (HPA) axis activation. Administration of proinflammatory mediators to non-depressed patients induces depressive symptoms and increases HPA axis activity. HPA axis activation is associated with MDD and is modulated by SSRIs. Further, SSRIs have been shown to suppress macrophage function. Chronic mild stress (CMS) in rodents is used to model MDD, and elicits depressive behaviors and increases HPA axis activity. With the questions above, the following hypotheses were tested: (1) CMS and repeated immune activation with zymosan (yeast cell wall mannoprotein) will have similar and parallel effects on depressive behaviors measured in Porsolt\u27s forced swim test and on sickness behaviors defined by the social investigation task; (2) Both CMS and repeated immune activation will activate the HPA axis evidenced by elevated circulating corticosterone; (3) Both CMS and repeated immune activation will disrupt innate immune function measured by decreased NKCA and macrophage activation evidenced by increased intracellular ROS; and (4) chronic fluoxetine will normalize behavior, endocrine, and immune responses. CMS suppressed NKCA, and consistent with findings in MDD patients, chronic fluoxetine abrogated CMS-induced suppression of NKCA. Furthermore, CMS stimulated macrophage activity as evidenced by increased ROS, which was not altered by fluoxetine. Taken together these findings suggest that the CMS model is an appropriate model to further explore the relationship between depressive behaviors and related immune function. In contrast, chronic zymosan did not alter immune measures. Both CMS and chronic zymosan induced depressive behaviors, however neither manipulation induced sickness behavior. While previous studies have evaluated acute pathogen administration, given the chronic nature of MDD, the current study used repeated administration of pathogen. This may account for the differences with previous research. FLX did not reverse behavior alterations induced by chronic zymosan