Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism

J Neurosci. 2017 Aug 9;37(32):7656-7668. doi: 10.1523/JNEUROSCI.0885-17.2017. Epub 2017 Jul 3.


Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2 Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness.SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in humans. Whereas some of these alterations recover quickly upon cessation of stress, others persist. Administration of a kappa-opioid receptor (KOR) antagonist reduced stress effects or hastened recovery, consistent with the previously reported antistress effects of this class of agents. Use of endpoints, such as sleep and circadian rhythm, that are homologous across species will facilitate the implementation of translational studies that better predict clinical outcomes in humans, improve the success of clinical trials, and facilitate the development of more effective therapeutics.

Keywords: EEG; gene expression; kappa-opioid receptor; mice; sleep; stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Random Allocation
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / physiology*
  • Sleep / drug effects
  • Sleep / physiology*
  • Social Behavior
  • Stress, Psychological / drug therapy
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology
  • Tetrahydroisoquinolines / pharmacology*
  • Tetrahydroisoquinolines / therapeutic use


  • 7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide
  • Piperidines
  • Receptors, Opioid, kappa
  • Tetrahydroisoquinolines