title: Modulation of food consumption and sleep-wake cycle in mice by the neutral CB1 antagonist ABD459.
abstract: The brain endocannabinoid system is a potential target for the treatment of psychiatric and metabolic conditions. Here, a novel CB1 receptor antagonist (ABD459) was synthesized and assayed for pharmacological efficacy in vitro and for modulation of food consumption, vigilance staging and cortical electroencephalography in the mouse. ABD459 completely displaced the CB1 agonist CP99540 at a Ki of 8.6 nmol/l, and did not affect basal, but antagonized CP55940-induced GTPγS binding with a KB of 7.7 nmol/l. Acute ABD459 (3-20 mg/kg) reliably inhibited food consumption in nonfasted mice, without affecting motor activity. Active food seeking was reduced for 5-6 h postdrug, with no rebound after washout. Epidural recording of electroencephalogram confirmed that ABD459 (3 mg/kg) robustly reduced rapid eye movement (REM) sleep, with no alterations of wakefulness or non-REM sleep. Effects were strongest during 3 h postdrug, followed by a progressive washout period. The CB1 antagonist AM251 (3 mg/kg) and agonist WIN-55,212-2 (WIN-2: 3 mg/kg) also reduced REM, but variously affected other vigilance stages. WIN-2 caused a global suppression of normalized spectral power. AM251 and ABD459 lowered delta power and increased power in the theta band in the hippocampus, but not the prefrontal cortex. The neutral antagonist ABD459 thus showed a specific role of endocannabinoid release in attention and arousal, possibly through modulation of cholinergic activity.
authors.affiliation: aDepartment of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA bSchool of Medical Sciences, University of Aberdeen, Aberdeen, UK cDepartment of Pharmacology & Toxicology, University of Toronto, Canada.
authors.forename: Anushka V
authors.initials: AV
authors.lastname: Goonawardena
authors.forename: Andrea
authors.initials: A
authors.lastname: Plano
authors.forename: Lianne
authors.initials: L
authors.lastname: Robinson
authors.forename: Ruth
authors.initials: R
authors.lastname: Ross
authors.forename: Iain
authors.initials: I
authors.lastname: Greig
authors.forename: Roger G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hampson
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology; D004569:Electroencephalography; D005247:Feeding Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: C000603333:5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-yl) 4-methoxyphenyl methanone; D048588:Benzoxazines; D063387:Cannabinoid Receptor Antagonists; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol