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Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system

Donahue, Rachel J.a,*; Landino, Samantha M.a,*; Golden, Sam A.b; Carroll, F. Ivyc; Russo, Scott J.b; Carlezon Jr, William A.a

doi: 10.1097/FBP.0000000000000155
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Accumulating evidence indicates that kappa-opioid receptors (KORs) and their endogenous ligand, dynorphin (DYN), can play important roles in regulating the effects of stress. Here, we examined the role of KOR systems in the molecular and behavioral effects of acute (1-day) and chronic (10-day) social defeat stress (SDS) in mice. We found that acute SDS increased DYN mRNA levels within the nucleus accumbens, a key element of brain dopamine (DA) systems. In contrast, chronic SDS produced long-lasting decreases in DYN mRNA levels. We then examined whether disruption of KOR function would affect development of SDS-induced depressive-like behaviors, as measured in the intracranial self-stimulation and social interaction tests. Ablation of KORs from DA transporter-expressing neurons delayed the development of SDS-induced anhedonia in the intracranial self-stimulation test, suggesting increased stress resilience. However, administration of the long-lasting KOR antagonist JDTic (30 mg/kg, intraperitoneally) before the SDS regimen did not affect anhedonia, suggesting that disruption of KOR function outside DA systems can oppose stress resilience. Social avoidance behavior measured after the 10-day SDS regimen was not altered by ablation of KORs in DA transporter-expressing neurons or by JDTic administration before testing. Our findings indicate that KORs expressed in DA systems regulate the effects of acute, but not chronic, social stress.

aBehavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts

bFishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

cResearch Triangle Institute, Research Triangle Park, North Carolina, USA

* Rachel J. Donahue and Samantha M. Landino contributed equally to the writing of this article.

Correspondence to William A. Carlezon Jr, PhD, Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA E-mail: bcarlezon@mclean.harvard.edu

Received March 23, 2015

Accepted May 27, 2015

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