title: Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour.
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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, Missouri 63104, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, Missouri 63104, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Griffett
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kazantzis
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Amador
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Bahaa M
authors.initials: BM
authors.lastname: El-Gendy
authors.affiliation: Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Salvador
authors.initials: S
authors.lastname: Huitron-Resendiz
authors.affiliation: Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, Missouri 63104, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects* / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012201:Reward; D015398:Signal Transduction; D012895:Sleep, REM / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C498262:Nr1d1 protein, mouse; C499650:Nr1d2 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; D011759:Pyrrolidines; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C572451:SR9009; C572450:SR9011; D013876:Thiophenes; D056926:CLOCK Proteins