Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance

Abstract

Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24 days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-induced social avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24 days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24 days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.

Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression

“…Altered morphological changes in microglia after RSD, foot shock, and chronic unpredictable stress were all associated with augmented mRNA expression of pro-inflammatory molecules and exaggerated pro-inflammatory responses to mitogen-stimulation ( [9,19,46]). For instance, brain microglia from socially defeated mice show high levels of IL1-β, IL-6, TNF-α mRNA expression and reduced levels of GC responsive genes (GC-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)) [19].…”

“…Furthermore, isolated brain microglia from RSD mice and cultured ex vivo produced increased levels of IL-6, TNF-α, and CCL-2 following stimulation with lipopolysaccharide (LPS) compared to microglia from the brain of home cage control mice [19], even 24 days after stress cessation [46]. Neuroinflammatory mediators such as IL1-β, TNF-α, and IL-6, are involved in the neurobiological changes that reinforce fear/anxiety and threat circuitry [42], promoting the development and maintenance of prolonged depressive-and anxietylike behavior [42,46].…”

“…Recent literature has identified structural and functional impairments within the brain's reward circuitry, specifically in the ventral tegmental (VTA) area to the NAc pathway, that were associated with anhedonia (decreased sucrose preference), a depressive-like symptom in rodents [28]. Recently, increasing attention has focused on the relationship between neuroinflammation and mood disorders [7,17,19,42,46]. As stated previously, bouts of repeated stress induce immune-enhancement and cause a pro-inflammatory phenotype by promoting a state of GC-insensitivity to develop in innate immune cells [8,47].…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…Microglia isolated from mice 24 days after repeated social defeat stress also had higher IL-1β, IL-6 and TNF-α mRNA expression, and IL-1-β protein production in response to ex vivo LPS stimulation relative to non-stressed controls. 27 This upregulation in microglial proinflammatory function was accompanied by an increase in social avoidance behavior in repeated social defeat stress mice. Whether, specifically, stress-induced release of DAMPs resulted in microglial training was not investigated however.…”

“…26 Recent studies suggest that innate immune cells also retain longterm memory for non-infectious immunostimulatory challenges, such as stress. 27 Despite the widespread interest in immune function and psychiatric illness, there has been no exhaustive discussion relating to the implications of trained innate immunity on mental health pathology. Considering that trained innate immunity represents a paradigm shift in our understanding of immune function, 28 the theoretical contributions of trained innate immunity to illnesses such as depression are potentially marked and worth of a comprehensive analysis.…”