title: LY2033298, a positive allosteric modulator at muscarinic M₄ receptors, enhances inhibition by oxotremorine of light-induced phase shifts in hamster circadian activity rhythms.
abstract: BACKGROUND
  Entrainment of circadian rhythms to the light-dark cycle is essential for restorative sleep, and abnormal sleep timing is implicated in central nervous system (CNS) disorders like depression, schizophrenia, and Alzheimer's disease. Many transmitters, including acetylcholine, that exerts its actions via muscarinic receptors modulate the suprachiasmatic nucleus, the master pacemaker.
  
  
  OBJECTIVE
  Since positive allosteric modulators of muscarinic M(4) receptors are candidates for treatment of mood and cognitive deficits of CNS disorders, it is important to evaluate their circadian actions.
  
  
  METHODS
  The effects of intraperitoneally applied muscarinic agents on circadian wheel-running rhythms were measured employing hamsters, a model organism for studying activity rhythms.
  
  
  RESULTS
  Systemic administration of the muscarinic receptor agonist oxotremorine (0.01-0.04 mg/kg) inhibited light-induced phase delays and advances of hamster circadian wheel-running rhythms. The M₄ positive allosteric modulator, LY2033298 (10-40 mg/kg), had no effect on light-induced phase shifts when administered alone, yet significantly enhanced (at 20 mg/kg) the inhibitory influence of oxotremorine on light-induced phase delays. In addition, the muscarinic receptor antagonist, scopolamine, which was without effect on light-induced phase shifts when administered alone (0.001-0.1 mg/kg), antagonized (at 0.1 mg/kg) the inhibitory effect of oxotremorine and LY2033298 on light-induced phase delays.
  
  
  CONCLUSIONS
  These results are the first to demonstrate that systemically applied muscarinic receptor agonists modulate circadian activity rhythms, and they also reveal a specific role for M₄ receptors. It will be of importance to evaluate circadian actions of psychotropic drugs acting via M₄ receptors, since they may display beneficial properties under pathological conditions.
authors.affiliation: Department of Biology, Valdosta State University, Valdosta, GA, 31602, USA. rlgannon@valdosta.edu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gannon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D008027:Light; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D010095:Oxotremorine / Q000008:administration & dosage / Q000494:pharmacology*; D043588:Receptor, Muscarinic M4 / Q000819:agonists* / Q000037:antagonists & inhibitors; D012601:Scopolamine / Q000008:administration & dosage / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C531529:3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamide; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D009539:Nicotinic Acids; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D010095:Oxotremorine; D012601:Scopolamine