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

      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.

      Key Words

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      • Chronic Social Defeat and Intracranial Self-Stimulation: Unmasking the Many Faces of Depression?
        Biological PsychiatryVol. 76Issue 7
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          Depression is a highly complex psychiatric disorder owing in part to the great variability in patient symptoms; treatment response; and, presumably, underlying biological mechanisms (1). This complexity as well as the inherent difficulty in studying mental symptoms in rodents has made depression very difficult to model in the laboratory. Chronic social defeat stress (CSDS) offers construct, face, and predictive validity; it induces many of the core symptoms of depression that are measurable in rodents.
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