Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour

Nat Commun. 2014 Dec 23;5:5759. doi: 10.1038/ncomms6759.

Abstract

Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBβ-null mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety.

Publication types

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

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Anxiety / drug therapy*
  • Anxiety / genetics
  • Anxiety / metabolism
  • Anxiety / physiopathology
  • Behavior, Animal / drug effects*
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Clocks / drug effects*
  • Circadian Clocks / genetics
  • Circadian Rhythm / genetics
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Pyrrolidines / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Repressor Proteins / agonists*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reward
  • Signal Transduction
  • Sleep, REM / drug effects*
  • Thiophenes / pharmacology*

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cryptochromes
  • Nr1d1 protein, mouse
  • Nr1d2 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Period Circadian Proteins
  • Pyrrolidines
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • SR9009
  • SR9011
  • Thiophenes
  • CLOCK Proteins