Vicarious defeat stress induces increased alcohol consumption in female mice: Role of neurokinin-1 receptor and interleukin-6

Abstract

There is a high frequency of comorbidity of alcohol use disorder (AUD) and depression in human populations. We have studied this relationship in our lab using the social defeat stress (SDS) model, which results in both depression-like behaviours and increased alcohol consumption in male mice. However, standard SDS procedures are difficult to use in female mice due to a lack of territorial aggression. In the experiments presented here, we used vicarious defeat stress (VDS) to assess social withdrawal and alcohol consumption in female C57BL6/J mice. We also assessed the expression of interleukin-6 (IL6), which is a proinflammatory cytokine that is associated with depression in humans and sensitivity to SDS in mice. In these experiments, C57BL/6 female mice underwent 10 days of VDS where they witnessed the physical defeat of a male conspecific by an aggressive CD1 mouse. After the end of VDS, mice were either given access to alcohol or sacrificed for the measurement of IL6 expression. We found that VDS increased alcohol consumption and IL6 expression in the frontal cortex and hippocampus. Given that the neurokinin-1 receptor (NK1R) can mediate both stress-induced alcohol consumption and IL6 expression, we tested the ability of NK1R antagonism to reduce VDS-induced alcohol consumption and found that this treatment reduced alcohol intake in both VDS-exposed mice and in unstressed controls. The observed increase in alcohol consumption suggests that VDS is a model that can be utilized to study stress-induced alcohol consumption in female mice, and that this is sensitive to NK1R antagonism.

Keywords: alcohol; neurokinin; stress.

FIGURE 1

Timeline of experiments.

FIGURE 2

Vicarious defeat stress (VDS) decreases social interaction (SI). Time (in seconds) spent in the interaction zone was measured in the SI test. A t‐test revealed that the VDS‐stressed mice spent significantly less time in the interaction zone compared to the control counterparts (t(27) = 2.4, p = 0.02). *p < 0.05.

FIGURE 3

Changes in interleukin‐6 (IL6) expression following vicarious defeat stress (VDS). Expression of the proinflammatory cytokine IL6 in the amygdala (AMG), hippocampus (HPC), prefrontal cortex (PFC), dorsal striatum (DS) and ventral striatum (VS). A significant effect of stress was found for the HPC (t(10) = 4.27, p = 0.002) and PFC (t(10) = 5.11, p = 0.0005). ^** p < 0.01, ^*** p < 0.001.

FIGURE 4

Alcohol consumption following vicarious defeat stress (VDS). (A) The alcohol consumption monitored daily revealed a significant main effect of stress (p = 0.002). (B) Average of the final 3 days of alcohol consumption prior to neurokinin‐1 receptor (NK1R) antagonist treatment indicated a significant effect of VDS on alcohol consumption (t(27) = 2.70, p = 0.01). (C) Alcohol preference was also affected by VDS exposure t(27) = 3.4, p = 0.002. (D) The change in alcohol consumption following VDS negatively correlated with social interaction time (R² = 0.2, p = 0.02). *p < 0.05, ^** p < 0.01.

FIGURE 5

Effect of neurokinin‐1 receptor (NK1R) antagonist treatment. Alcohol consumption following L‐733060 treatment was assessed and a main effect of antagonist was observed at both 2 h (F(1,27) = 38.8, p < 0.0001) and 24 h (F(1,27) = 0.044, p = 0.0001) time points, suggesting that NK1R antagonism attenuates alcohol consumption in stressed and unstressed mice. Antagonist administration unexpectedly reduced water consumption at 2 h (F(1,26) = 5.1, p = 0.03), but this effect was no longer present at 24 h (F(1,27) = 0.05, p = 0.83). *p < 0.05, ^*** p < 0.001, ^**** p < 0.0001.