Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida.
Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida.
Alcohol Clin Exp Res. 2019 Oct;43(10):2167-2178. doi: 10.1111/acer.14165. Epub 2019 Aug 21.
The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse.
Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the "drinking in the dark" (DID) model in C57BL/6J mice.
We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake.
The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking.
孤啡肽/N 端前啡肽（NOP）受体及其内源性配体 N/OFQ 被认为参与了药物和酒精使用障碍（AUD）的调节。特别是，有证据表明，NOP 受体的激活可以阻断酒精的强化和激励作用，这一作用在一系列行为测量中都有体现，包括酒精摄入量、条件性位置偏好和复发易感性。
在这里，我们展示了 NOP 受体的药理学激活和抑制对 binge-like 酒精消费的影响，通过 C57BL/6J 小鼠的“暗饮”（DID）模型进行测量。
我们发现，两种强效且选择性的 NOP 激动剂 AT-202（0、0.3、1、3mg/kg）和 AT-312（0、0.3、1mg/kg）在不影响运动活动的剂量下不影响 binge 酒精摄入。当给予先前暴露于含酒精液体饮食的慢性酒精处理的小鼠时，AT-202 也未能改变 DID 行为。相反，高亲和力 NOP 受体拮抗剂 SB-612111（0、3、10、30mg/kg）或选择性拮抗剂 LY2817412（0、3、10、30mg/kg）的治疗均降低了 binge 饮酒。SB-612111 在所有检查剂量下均有效，而 LY2817412 在 30mg/kg 时有效。一致地，NOP 受体敲除小鼠比野生型小鼠消耗的酒精更少。SB-612111 在不影响运动活动的剂量下降低 DID 和增加蔗糖消耗。然而，SB-612111 的高剂量（30mg/kg）降低了酒精摄入量，但未能抑制在 2 瓶选择 DID 模型中的偏好，该模型可评估适度的酒精摄入量。
本研究结果表明，NOP 受体抑制而不是激活可能是治疗以 binge 饮酒为特征的 AUD 的一种有价值的方法。
