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Biol Psychiatry. 2014 Oct 1;76(7):550-8. doi: 10.1016/j.biopsych.2013.12.014. Epub 2014 Jan 8.

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

Author information

1
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
2
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
3
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. Electronic address: bcarlezon@mclean.harvard.edu.

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

PMID:
24495460
PMCID:
PMC4087093
DOI:
10.1016/j.biopsych.2013.12.014
[Indexed for MEDLINE]
Free PMC Article

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