Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol "Relapse" Drinking.
Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol "Relapse" Drinking.
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DOI：
10.13188/2327-204x.1000032
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
Kreek, M J
中科院分区：
文献类型：
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作者：
Zhou, Y;Zhou, D C;Kreek, M J
酒精复发是酒精依赖药物开发的治疗目标。Aticaprant是一种选择性短效阿片受体（KOR）拮抗剂，最近正在开发新的临床应用（抑郁症或快感缺失）。最近的研究还发现，阿替卡普兰通过KOR介导的机制减少啮齿动物的酒精摄入量并防止应激触发的酒精寻求。在这里，我们进一步研究了阿替卡普兰单独或与纳洛酮（μ-阿片受体[莫尔]拮抗剂）组合是否改变了酒精复发样饮酒，使用小鼠酒精剥夺效应（ADE）范例来模拟人类酗酒者的复发发作。使用长效和选择性KOR拮抗剂nor-BNI作为KOR拮抗作用对ADE的影响的参比化合物。在3周的无节制饮酒（两瓶选择，24小时访问，每隔一天）后，雄性和雌性小鼠显示过量的酒精摄入量，然后在1周的禁欲后出现明显的ADE。在雄性和雌性动物中，单独使用阿替卡普兰以剂量依赖性方式（1-3 mg/kg）降低酒精ADE。与有效剂量（3 mg/kg）相比，较低剂量（0.3 mg/kg）的阿替卡泮与低剂量纳洛酮（1 mg/kg）联合使用可降低两种性别动物的ADE，并且在多次给药方案（禁欲期间每日注射5次）后，该联合用药有效，未出现耐受性，表明该联合用药具有协同效应。相比之下，单独使用nor-BNI或与纳洛酮合用对两种性别的ADE均无影响。我们目前的研究表明，临床开发的短效KOR拮抗剂aticaprant与低剂量纳洛酮的组合在酒精“复发”治疗中具有治疗潜力。
Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1–3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol “relapse” treatment.