Voluntary wheel running during adolescence prevents the increase in ethanol intake induced by social defeat in male mice

Abstract

Rationale: Exposure to social defeat (SD) induces a depressive phenotype, increased ethanol seeking and consumption, accompanied by activation of the neuroinflammatory response. However, a resilient response can be potentiated through physical exercise in the form of voluntary wheel running (VWR) during or after exposure to social stress. Therefore, the aim of this study was to test whether physical exercise during adolescence prior to being exposed to SD can enhance resilience to the increase in ethanol intake.

Methods: Male mice had access to VWR during adolescence and the effects of social defeat (4 sessions every 72 h) on oral ethanol self-administration (SA) was evaluated. Based on the social interaction test, mice were classified as resilient or susceptible to depressive-like behavior. Two weeks after the last encounter, mice were subjected to the drinking in the dark and oral ethanol SA paradigms. Mice were then sacrificed to measure brain-derived neurotrophic factor (BDNF) levels in the striatum and hippocampus.

Results: As expected, susceptible mice increased ethanol intake in the oral SA protocol. However, susceptible mice in the exercise condition did not increase ethanol intake, showing similar consumption and motivation for ethanol than the control and resilient groups. On the other hand, decreased BDNF levels were observed in susceptible mice in both experimental conditions compared to the control groups after ethanol SA.

Conclusions: The pre-exposure of VWR prevented the increase in consumption and motivation for ethanol induced by SD in susceptible mice. On the other hand, it appears that VWR did not exhibit any significant long-term effects on BDNF signaling, which is mainly affected in susceptible mice after ethanol intake.

Keywords: BDNF; Ethanol; Physical exercise; Resilience; Self-administration; Social stress; Wheel running.

Fig. 1

Experimental design

Fig. 2

Social defeat stress induces avoidance behavior in susceptible mice. a Time between no target and target sessions in the interaction zone. b Percentages of resilient and susceptible mice in both conditions (sedentarism and VWR-exposure). c Distribution of social interaction scores. d Repeated social defeat stress results in a spectrum of avoidance behavior, divided between susceptible and resilient phenotypes based on their social interaction ratio score. Error bars represent means ± SEM. ***p < 0.001, **p < 0.05 represent significant differences between no target vs. target session. ###p < 0.001 represent significant differences between sedentary vs VWR-exposed mice

Fig. 3

Effect of adolescent VWR on ethanol intake during DID. The dots represent means and the vertical lines ± SEM of the g/kg of ethanol at 20% consumed. *** p < 0.001, *p < 0.05 significant difference with Day 4; +  +  + p < 0.001 significant difference between VWR groups vs. non-VWR groups

Fig. 4

Effects of running wheel on the increase in oral ethanol self-administration induced by social stress in C57BL/6 J mice. The dots represent means and the vertical lines ± SEM of (a) the number of active responses and (b) the g/kg of ethanol at 20% consumed during FR1 schedule. The columns represent the mean and the vertical lines ± SEM of (c) the breaking point values, and (d) the g/kg of ethanol at 20% consumed during PR. ***p < 0.001, **p < 0.01, *p < 0.05 significant difference with SD-S group; +  + p < 0.01, + p < 0.05 significant difference between susceptible mice vs. controls; &&p < 0.01, &p < 0.05 significant difference between resilient mice vs. controls; ##p < 0.01, # p < 0.05 significant difference between groups with running wheel access vs. groups without access

Fig. 5

Comparison of the distributions and percentages of subpopulations a) according to SIT scores and b) according to ethanol consumption during the FR1 schedule of the SA

Fig. 6

Effects of long-term social defeat on BDNF protein levels in C57BL/6 J mice. The columns represent the mean and the vertical lines ± SEM of the BDNF protein levels (pg/100 mg of protein) in (a) the striatum and (b) the hippocampus. * p < 0.05 significant difference between susceptible mice (SD-S and VWR-SD-S groups) vs. controls mice (CTRL and VWR-CTRL groups)

Fig. 7

Regression plot for the Pearson correlation between striatal BDNF level and SIT ratio and between striatal BDNF level and average consumption of ethanol during FR1 schedule