Defeat In Mice Research Articles

P.4.046 Effect of cannabidiol on behavioural changes elicited by social defeat in mice

P.4.046 Effect of cannabidiol on behavioural changes elicited by social defeat in mice

A CRH1 Antagonist into the Amygdala of Mice Prevents Defeat‐Induced Defensive Behavior

Corticotropin-releasing hormone (CRH) is believed to play an important role in the regulation of behavioral responses to stress. CRH(1) receptor antagonists may reduce stress responsivity. Stress increases CRH in the amygdala, important in memory consolidation. We hypothesized that infusion of a CRH(1) antagonist into the amygdala following social defeat would prevent the development of generalized fear responses. Acute social defeat in mice increases defense towards intruders, even nonaggressive intruders, placed within their home cage. We infused the CRH(1) antagonist antalarmin (0.25 microg/125 nl) bilaterally into the amygdala of mice immediately after defeat and measured their response to a nonaggressive intruder stimulus mouse placed within their home cage 24 h after defeat. Defeated mice that received vehicle displayed high levels of crouch defensive posture and numerous flights from intruders, relative to nondefeated mice that received vehicle. Defeated mice that received antalarmin into the amygdala exhibited significantly less defensive posture than did vehicle-treated defeated mice. Display of defensive posture in antalarmin-treated mice approached that of vehicle-treated nondefeated mice. These findings support a role for CRH in the amygdala to promote consolidation of emotional memory and indicate that antagonism of CRH(1) receptors in the amygdala may prevent the development of exaggerated fear responses in stressed mice.

Felbamate reduces hormone release and locomotor hypoactivity induced by repeated stress of social defeat in mice

Glutamatergic neurotransmission plays a role in stress hormone release and the development of mood diseases. The aim of these studies was to verify the hypothesis that repeated treatment with felbamate, an antiepileptic drug modulating glutamatergic neurotransmission, affects hormone release in response to chronic stress. A mouse model of repeated social defeat (nonaggressive male mouse repeatedly defeated by aggressive counterparts) was used. The results showed that acute treatment with felbamate reduced hypolocomotion in an open field induced by repeated social conflict. The same stress procedure resulted in increased release of corticosterone and dopamine. Felbamate decreased noradrenaline concentrations and inhibited stress-induced rise in corticosterone and dopamine. It is suggested that modulation of stress hormone release may be induced by the action of felbamate on glutamate neurotransmission, and neuroendocrine changes could contribute to behavioural effects of the drug. Antidepressant action of this mood-stabilizing drug suggested by clinicians needs further verification.

Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice

Acute social defeat in mice activates the hypothalamic–pituitary–adrenal axis (HPA) and induces long-term behavioral changes, including exaggerated fear responses and inhibition of territorial behavior. Stress-induced hormonal and neurotransmitter release may contribute to disruption of expression of genes important for cell survival, neuronal plasticity, and neuronal remodeling. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor associated with structural cellular changes that occur during nervous system development and contributes to neural plasticity in the adult brain. In rats, acute (1–2 h) restraint stress transiently reduces BDNF mRNA expression in the hippocampus, a region important in the memory and in HPA regulation; restraint stress also decreases BDNF expression in the basolateral amygdala (BLA), a region important for fear consolidation and emotional memory. We hypothesized that a brief (10 min) exposure to intense social stress, a more naturalistic stressor than restraint stress, would also reduce BDNF mRNA in the hippocampus and BLA of mice. In the present study, we examined the time course of expression of BDNF mRNA expression in the hippocampus and amygdala, as well as other subcortical and cortical brain regions, following acute social stress. In situ hybridization analysis for BDNF mRNA expression showed that there was a significant decrease in BDNF mRNA expression in all regions studied in mice 24 h after social defeat when compared to control (naïve) mice ( P<0.05). These findings support our hypothesis that BDNF mRNA levels are reduced by social stress, and may have implications for brain plasticity and behavioral changes following social stress.

Cytokine Production by Spleen Cells after Social Defeat in Mice: Activation of T Cells and Reduced Inhibition by Glucocorticoids

Social disruption (SDR) is an effective model of social stress associated with an enhanced inflammatory reactivity of the immune system. The aim of the present study was to further describe SDR effects on cytokine production by spleen cells, testing selectively monocyte and T cell functions as a result of this stressor. For this purpose, splenocytes from control mice (C) and mice socially stressed for 7 days (SDR) were cultured in the presence of lipopolysaccharide (LPS) or concanavalin A (Con A). Splenocyte proliferation, cytokine production and sensitivity of spleen cells to corticosterone were assessed in vitro. The humoral response to keyhole limpet hemocyanin (KLH) immunization was assessed. SDR induced splenomegaly and enhanced splenocyte basal proliferation. The pro-inflammatory influence of SDR was confirmed by an increased release of interleukin-6 (IL-6) by LPS-stimulated cultures and by a reduced sensitivity of spleen cells to the anti-inflammatory effect of corticosterone. The mechanism increasing cytokine production in response to LPS was cytokine specific, since among inflammatory cytokines, IL-6 but not interferon-γ (IFN-γ) was enhanced by stress. In stressed mice, the increase in IL-6 and IFN-γ and the decrease in IL-10 release in Con A-stimulated cultures indicate that SDR did not modify the Th1/Th2 cytokine balance but globally activated T cells. Plasma anti-KLH antibody levels were similar in both groups. Wounded and non-wounded mice presented similar responses to stress. This study shows that social disruption stress enhances the reactivity of cells from both the acquired and innate immune systems.

Importance of fighting in the immune effects of social defeat

Social defeat involves a clear physical component in the form of fight-induced injuries. The impact of body injuries on the immune response is not yet well known. In this study we compared the endocrine and immune responses to two types of social defeat in mice, one limiting the occurrence of skin injuries (mild social stress, MSS), and the other not (social disruption stress, SDR). In the two situations, six defeats were applied within 1 week. Plasma corticosterone and IL-6 levels were measured in blood samples taken after social defeat. Reactivity to LPS and sensitivity to corticosterone (CS) of spleen cells was assessed by measuring the in vitro production of cytokines (IL-6, IFN-γ and IL-10) in response to LPS under a range of increasing concentrations of CS. The two types of stressors induced a similar plasma corticosterone response, but SDR mice showed significantly higher plasma IL-6 than MSS mice. Splenocytes from SDR but not from MSS mice produced more IL-6 and IL-10 in response to LPS and presented an altered responsiveness to CS in comparison to control mice. We conclude that the procedure involving fights and skin injuries was able to modulate the immune response in the spleen, whereas the procedure preventing the occurrence of fights did not. The increased immune reactivity observed in the fight-associated procedure could result from either a stronger psychological stress or a direct immune activation through the wounds.

FMRFamide, a putative endogenous opiate antagonist: Evidence from suppression of defeat-induced analgesia and feeding in mice

Social conflict and defeat in mice leads to an activation of endogenous opiate systems. The effects of intracerebroventricular administration of the peptide FMRFamide (Phe-Met-Arg-Phe-NH 2) and the opiate antagonist naloxone, on agrressive encounters, defeat-induced analgesia and defeat-induced feeding were examined in male mice. Both substances reduced the number of bites required to cause defeat in subordinate mice during aggressive encounters, as well as suppressing the subsequent defeat-induced analgesia. Administration of FMRFamide or naloxone also reduced defeat-induced feeding. These results indicate that FMRFamide (or FMRFamide-like neuropeptides) may function as endogenous opioid antagonists.

PLG and FMRFamide — Endogenous peptides with marked inhibitory effects on opioid-induced feeding

1. Social conflict and defeat in mice leads to an activation of endogenous opiate systems and the display of marked feeding behavior. 2. Intraperitoneal administrations of prolyl-leucyl-glycinamide (PLG 0.01–10 mg/kg) leads to a dose-dependent inhibition of defeat-induced feeding that is analogous to that obtained after treatment with either the endogenous peptide FMRFamide (Phe-Met-Arg-Phe-NH 2), or the prototypic opiate antagonist, naloxone. 3. These results suggest that PLG, and FMRFamide, or related small peptides may function as endogenous antagonists of opioid-induced feeding.