Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459. Issue 3 (April 2015)

• Record Type: Journal Article
• Authors: Goonawardena, Anushka V.; Plano, Andrea; Robinson, Lianne; Ross, Ruth; Greig, Iain; Pertwee, Roger G.; Hampson, Robert E.; Platt, Bettina; Riedel, Gernot
• Is Part Of: Behavioural pharmacology. Volume 26:Issue 3(2015)
• Publication Date: 2015-04
• Subjects: Psychopharmacology -- Periodicals; Nervous System -- drug effects -- Periodicals; Behavior -- drug effects -- Periodicals; 615.78
• DOI: 10.1097/FBP.0000000000000108
• Languages: English
• ISSNs: 0955-8810

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p>The brain endocannabinoid system is a potential target for the treatment of psychiatric and metabolic conditions. Here, a novel CB<sub>1</sub> receptor antagonist (ABD459) was synthesized and assayed for pharmacological efficacy <italic>in vitro</italic> and for modulation of food consumption, vigilance staging and cortical electroencephalography in the mouse. ABD459 completely displaced the CB<sub>1</sub> agonist CP99540 at a <italic>K</italic><sub>i</sub> of 8.6 nmol/l, and did not affect basal, but antagonized CP55940-induced GTPγS binding with a <italic>K</italic><sub><italic>B</italic></sub> 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 CB<sub>1</sub> 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.</p> </sec> </abstract>