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 (3mg/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.

Endocannabinoid Signaling Regulates Sleep Stability

“…The early facilitation of NREM sleep seen in the present study following activation of CB1 is largely in agreement with earlier findings [ 6 – 11 , 13 – 15 , 29 , 32 ], but the secondary (wake promoting/sleep fragmenting) effect of CP47 and JZL to reduce NREM sleep at a time of day when mice normally engage in most of their daily sleep is a novel finding. It should be mentioned that JZL had lower magnitude effects (change from vehicle) on NREM when it was administered before the LP, and did not produce substantial fragmentation of sleep during the subsequent DP.…”

“…It should be noted that we did not normalize our power spectral data as in other reports [ 17 , 28 , 29 , 32 ], and our presentation of raw power spectral results may explain some discrepancies between our findings and those of others. It is not clear why other researchers have not observed the large augmentation of delta and theta power following administration of CB1 antagonists reported here.…”

“…It is not clear why other researchers have not observed the large augmentation of delta and theta power following administration of CB1 antagonists reported here. In fact, several reports have observed reduced delta and theta power following administration of CB1 antagonists [ 19 , 28 ] while others have concluded that these drugs have little or no effect on the EEG power spectrum [ 29 , 32 ]. We can only speculate that the variability in methods used to normalize power spectral bandwidths has contributed to these inconsistencies.…”

“…Previous reports of CB1 antagonist effects in animal studies of sleep indicated either subtle augmentation of wake at the expense of NREM [ 15 , 19 , 28 , 29 ] or no effect [ 13 , 31 , 32 ]. The subtle differences observed with respect to CB1 antagonist effects on sleep time across these studies are likely due to different doses and times of administration.…”

Dose-dependent cannabis use, depressive symptoms, andFAAHgenotype predict sleep quality in emerging adults: a pilot study

“…THC exerts its effects on the brain and body by binding to CB1 and CB2 receptors in the endocannabinoid system, which modulates the sleep-wake cycle (4). CB1 receptor antagonists increase wakefulness and reduce rapid eye movement (REM) time in animal studies (5–8). In addition, CB1 knockout mice experience increased wakefulness (9).…”