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.

中文翻译：

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κ阿片受体拮抗剂CERC-501作为酒精使用障碍候选药物的临床前评估。

先前的工作表明，κ-阿片样物质信号传导在控制饮酒中的作用，尤其是由于酒精引起的长期神经适应而使饮酒量增加时。在这里，我们检查了酒精相关行为的大鼠模型中的小分子选择性κ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对急性酒精戒断所致焦虑样行为的影响。然后对由20％酒精间歇性进入引起的基础以及逐步加重的酒精自我管理进行了CERC-501的测试。最后，我们确定了CERC-501对压力和酒精相关暗示触发的酒精寻找复发的影响。进行对照实验以证实CERC-501作用于酒精相关行为的特异性。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步升级的自我给药。CERC-501阻止了由压力诱导的酒精寻觅的复发，但是当与酒精相关的线索触发了类似复发的行为时却没有。在没有镇静副作用的情况下观察到了CERC-501的作用，并且不是由于对酒精代谢的影响。因此，在广泛的临床前酒精模型电池中，CERC-501具有抗应激化合物的活性特征。结合其已证明的临床前和临床安全性，