Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders
Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders
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DOI：
10.1038/s41386-018-0015-y
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发表时间：
2018-08-01
影响因子：
7.6
通讯作者：
Heilig, M.
中科院分区：
文献类型：
--
作者：
Domi, E.;Barbier, E.;Heilig, M.
先前的研究表明卡帕阿片类信号传导在控制饮酒中发挥作用，特别是当酒精引起的长期神经适应导致饮酒量增加时。在这里，我们在酒精相关行为的大鼠模型中检查了小分子选择性 kappa 拮抗剂 CERC-501，目的是评估其作为酒精使用障碍候选疗法的潜力。我们首先测试了 CERC-501 对急性酒精戒断引起的焦虑样行为的影响。然后对 CERC-501 进行了基础酒精自我给药以及由 20% 酒精间歇性摄入诱导的逐步酒精自我给药测试。最后，我们确定了 CERC-501 对由压力和酒精相关线索触发的酗酒复发的影响。进行对照实验以确认 CERC-501 对酒精相关行为影响的特异性。 CERC-501 逆转了戒酒引起的焦虑样行为。它不会影响基础酒精的自我给药，但会剂量依赖性地抑制长期间歇性饮酒后逐渐增加的自我给药。 CERC-501 可以阻止由压力引起的酗酒复发，但当酒精相关线索触发类似复发的行为时则不起作用。 CERC-501 的作用是在没有镇静副作用的情况下观察到的，并且不是由于对酒精代谢的影响。因此，在一系列广泛的临床前酒精模型中，CERC-501 具有抗应激化合物的活性特征。结合其已证实的临床前和临床安全性，这些数据支持 CERC-501 针对酒精使用障碍的临床开发，特别是对于负强化、压力驱动的寻求和使用酒精的患者。
Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.