Elsevier

Biological Psychiatry

Volume 76, Issue 7, 1 October 2014, Pages 550-558
Biological Psychiatry

Archival Report
Effects of Striatal ΔFosB Overexpression and Ketamine on Social Defeat Stress–Induced Anhedonia in Mice

https://doi.org/10.1016/j.biopsych.2013.12.014Get rights and content

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.

Section snippets

Animals and Drugs

Male C57BL/6J mice (6–8 weeks old) were purchased from Jackson Laboratories (Bar Harbor, Maine), and male CD-1 mice (retired breeders) were purchased from Charles River Laboratories (Wilmington, Massachusetts). Inducible bitransgenic male mice that overexpress ΔFosB were generated from crosses of NSE-tTA (line A) and TetOP-ΔFosB (line A11) mice and fully backcrossed to a C57BL/6J background, using a tetracycline-regulated gene expression system (55). The ΔFosB mice were raised on water

Results

The effects of social defeat on ICSS thresholds were evaluated after each episode of defeat, enabling tracking of changes in responsiveness across the entire CSDS regimen (Figure 1A,B). To facilitate a side-by-side comparison of interval duration effects on ICSS thresholds, LInt and ShInt data are presented together (Figure 1B,C). The effects of CSDS on ICSS thresholds depended on group [F2,22 = 13.53, p < .001] and day [F15,330 = 2.98, p < .001], with a marginal group × day interaction (p =

Discussion

In the ICSS paradigm in mice, CSDS produces anhedonia. Specifically, the present study shows that CSDS decreases the rewarding impact of lateral hypothalamic stimulation, as measured by elevations in ICSS thresholds (19), with effects persisting 5 days following CSDS. These results are broadly consistent with the results of previous studies in rats (59) and hamsters (60), which used other methodologies to quantify brain stimulation reward strength. As expected on the basis of previous work (54)

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