Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice

Abstract

Background: Chronic social defeat stress (CSDS) produces persistent behavioral adaptations in mice. In many behavioral assays, it can be difficult to determine if these adaptations reflect core signs of depression. We designed studies to characterize the effects of CSDS on sensitivity to reward because anhedonia (reduced sensitivity to reward) is a defining characteristic of depressive disorders in humans. We also examined the effects of striatal ΔFosB overexpression and the N-methyl-D-aspartate receptor antagonist ketamine, both of which promote resilience, on CSDS-induced alterations in reward function and social interaction.

Methods: Intracranial self-stimulation (ICSS) was used to quantify CSDS-induced changes in reward function. Mice were implanted with lateral hypothalamic electrodes, and ICSS thresholds were measured after each of 10 daily CSDS sessions and during a 5-day recovery period. We also examined if acute intraperitoneal administration of ketamine (2.5-20 mg/kg) reverses CSDS-induced effects on reward or, in separate mice, social interaction.

Results: ICSS thresholds were increased by CSDS, indicating decreases in the rewarding impact of lateral hypothalamic stimulation (anhedonia). This effect was attenuated in mice overexpressing ∆FosB in striatum, consistent with pro-resilient actions of this transcription factor. High, but not low, doses of ketamine administered after completion of the CSDS regimen attenuated social avoidance in defeated mice, although this effect was transient. Ketamine did not block CSDS-induced anhedonia in the ICSS test.

Conclusions: This study found that CSDS triggers persistent anhedonia and confirms that ΔFosB overexpression produces stress resilience. The findings of this study also indicate that acute administration of ketamine fails to attenuate CSDS-induced anhedonia despite reducing other depression-related behavioral abnormalities.

Keywords: Anhedonia; antidepressant; defeat; intracranial self-stimulation (ICSS); ketamine; social interaction; stress.

Figure 1

Chronic social defeat stress (CSDS) increases reward thresholds in the intracranial self-stimulation (ICSS) test. (A) Experimental design; LInt=long interval (16 hr) between a defeat bout and ICSS testing, ShInt=short interval (6 hr). (B) CSDS increases reward thresholds in the LInt (n=10) and ShInt (n=6) groups compared to controls by the second day of defeat. Controls in the LInt group (n=6) and ShInt group (n=3) were not significantly different and were pooled. Data are expressed as mean (± SEM) % change from the average baseline threshold. Gray background represents days in which mice were defeated (D1-10). (C) Average thresholds for baseline (BL1-5), defeat (D1-10), and post-defeat (P1-5) for each group expressed as % change from average baseline threshold (BL1-5). CSDS increases reward thresholds in the LInt and ShInt groups on D1-10 and P1-5 compared to within-group baseline threshold (BL1-5) and compared to controls (D) Rate-frequency functions for individual control and defeated representative mice demonstrate that CSDS causes parallel rightward shifts. *p<0.05, **p<0.01, ***p<0.001 for within-group comparisons to baseline (BL1-5); ^p<0.05, ^^p<0.01, ^^^p<0.001 for between-group comparisons to controls; ^#p<0.05 for comparisons between ShInt and LInt groups; ns=not significant.

Figure 2

Inducible ΔFosB overexpression in striatum blocks the anhedonic effects of CSDS in the ICSS test. ΔFosB-Control mice (n=3), but not ΔFosB-ON mice (n=3) tested 8 weeks after DOX discontinuation, show increases in ICSS thresholds on D1-10 and P1-5 compared to BL1-5. ***p<0.001 for within-group comparisons to baseline (BL1-5); ^p<0.05, ^^^p<0.001 for between-group comparisons.

Figure 3

Ketamine attenuates CSDS-induced social avoidance. (A) A high (20 mg/kg) but not low (2.5 mg/kg) dose of ketamine given 1 hr after the final defeat bout (Day 10) attenuates social avoidance in defeated mice. Inset: Individual SI scores in defeated mice from each dose group. (B–C) There were no effects of group (control, defeat) or treatment (vehicle, 20 mg/kg ketamine) on distance traveled (B) or velocity (C) during the SI test. (D) Mice in the vehicle and ketamine (20 mg/kg) groups exhibit comparable degrees of social avoidance compared to controls when retested 1 week later (Day 18). (E) Ketamine (20 mg/kg) administered 24 hrs before the first day of defeat does not attenuate social avoidance measured at the end of the CSDS procedure. *p<0.05 compared to controls within each dose, n=6–12 mice/group.

Figure 4

(A) Ketamine, at the effective dose (20 mg/kg) used in the SI test, does not interfere with fear memory retention in the passive avoidance test. All mice, regardless of treatment with vehicle or ketamine 1 hr after the training day, avoid entering the dark compartment on the testing day. (B) Ketamine treatment (20 mg/kg) 24 hrs prior to testing does not affect behavior in the elevated plus maze (EPM). *p<0.05 for within-group comparisons, n=8–11 mice/group.

Figure 5

Ketamine (20 mg/kg) administered 1 hr after the final defeat bout does not block the anhedonic effects of CSDS in the ICSS test on D10 or P1-5. Gray background represents the thresholds obtained post-treatment. Mice were defeated for 10 days (LInt schedule) and matched into saline and ketamine groups. Ketamine had no effect in control mice. *p<0.05 for between-treatment group comparisons to controls, n=4–6 mice/group.