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首页> 外文期刊>Behavioural pharmacology >Modulation of food consumption and sleep-wake cycle in mice by the neutral CB1 antagonist ABD459
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Modulation of food consumption and sleep-wake cycle in mice by the neutral CB1 antagonist ABD459

机译：中性CB1拮抗剂ABD459对小鼠食物消耗和睡眠觉醒周期的调节

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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 K-i of 8.6 nmol/l, and did not affect basal, but antagonized CP55940-induced GTP gamma S binding with a K-B 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. Behavioural Pharmacology 26:289-303 Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.
机译：脑内大麻素系统是治疗精神病和代谢病的潜在靶标。在这里，合成了一种新型的CB1受体拮抗剂（ABD459），并在体外测定了其药理功效，并调节了小鼠的食物消耗，警戒分期和皮质脑电图。 ABD459以8.6 nmol / l的K-i完全取代了CB1激动剂CP99540，并且不影响基础，但以7.7 nmol / l的K-B拮抗了CP55940诱导的GTPγS的结合。急性ABD459（3-20 mg / kg）可以可靠地抑制非禁食小鼠的食物消耗，而不会影响运动活动。服药后5-6 h，主动寻找食物减少，冲洗后无反弹。硬膜外脑电图记录证实，ABD459（3 mg / kg）强烈减少了快速眼动（REM）睡眠，而觉醒或非REM睡眠均未改变。药物后3小时内效果最强，随后是逐步清除期。 CB1拮抗剂AM251（3 mg / kg）和激动剂WIN-55,212-2（WIN-2：3 mg / kg）也降低了REM，但是对其他警戒阶段有不同的影响。 WIN-2导致对归一化频谱功率的全局抑制。 AM251和ABD459降低了海马区theta带的delta功率并增加了其功率，但不降低前额叶皮层。因此，中性拮抗剂ABD459可能通过调节胆碱能活性而显示出大麻素释放在注意力和唤醒中的特定作用。行为药理学26：289-303版权所有（C）2015 Wolters Kluwer Health，Inc.保留所有权利。

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