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.
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
Rachel J
RJ
Donahue
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
John W
JW
Muschamp
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Scott J
SJ
Russo
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Eric J
EJ
Nestler
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. Electronic address: bcarlezon@mclean.harvard.edu.
William A
WA
Carlezon
D059445:Anhedonia / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D004558:Electric Stimulation; D007031:Hypothalamus / Q000503:physiopathology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012201:Reward; D012653:Self Stimulation; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*
D000928:Antidepressive Agents; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D007649:Ketamine
Anhedonia; antidepressant; defeat; intracranial self-stimulation (ICSS); ketamine; social interaction; stress