V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice.
V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice.
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DOI：
10.1111/acer.13544
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发表时间：
2018-01
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影响因子：
--
通讯作者：
Kreek MJ
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文献类型：
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作者：
Zhou Y;Rubinstein M;Low MJ;Kreek MJ
最近的一项临床试验发现，药物阻断V1 b受体可减少酒精依赖患者的酒精复发。SSR 149415是一种选择性V1 b受体拮抗剂，具有开发酒精依赖治疗的潜力。在这项研究中，我们研究了SSR 149415单独使用或与μ阿片受体[MOP-r]拮抗剂纳洛酮（NTN）联合使用是否会改变小鼠的过度饮酒。C57 BL/6 J（B6）小鼠的两种性别均经受慢性间歇性获取（IA）饮用范例（两瓶选择，每隔一天24小时获取）3周。饮用蔗糖和糖精作为酒精特异性药物作用的对照。神经元前阿黑皮素（POMC）增强子（nPE）敲除小鼠与下丘脑特异性损失的POMC（包括β-内啡肽，MOP-r的主要内源性配体）被用作遗传控制的NTN的影响。急性给药SSR 149415（1-30 mg/kg）以剂量依赖性方式降低IA后雄性和雌性B6小鼠的酒精摄入量和偏好。为了研究NTN和SSR 149415之间的潜在协同效应，我们测试了SSR 149415和NTN的六种不同组合剂量，发现SSR 149415（3 mg/kg）和NTN（1 mg/kg）的组合在低于B6小鼠的个体有效剂量的剂量下显著降低了酒精摄入量。我们证实了SSR 149415对nPE−/−雄性小鼠减少酒精摄入量的作用，这与SSR 149415和NTN减少饮酒的独立机制一致。V1 b拮抗剂SSR 149415与NTN在个体阈下剂量下的组合显示出治疗酒精中毒的潜力，可能具有较少的不良反应。
A recent clinical trial found that pharmacological blockade of V1b receptors reduces alcohol relapse in alcohol-dependent patients. SSR149415 is a selective V1b receptor antagonist that has potential for development as an alcohol dependency treatment. In this study, we investigated whether SSR149415 alone or in combination with the mu-opioid receptor [MOP-r] antagonist naltrexone (NTN) would alter excessive alcohol drinking in mice. Both sexes of C57BL/6J (B6) mice were subjected to a chronic intermittent access (IA) drinking paradigm (two-bottle choice, 24-h access every other day) for 3 weeks. Sucrose and saccharin drinking were used as controls for alcohol-specific drug effects. Neuronal proopiomelanocortin (POMC) enhancer (nPE) knockout mice with hypothalamic-specific loss of POMC (including beta-endorphin, the main endogenous ligand of MOP-r) were used as a genetic control for the effects of NTN. Acute administration of SSR149415 (1–30 mg/kg) reduced alcohol intake and preference in a dose-dependent manner in both male and female B6 mice after IA. To investigate potential synergistic effects between NTN and SSR149415, we tested six different combination doses of SSR149415 and NTN, and found that a combination of SSR149415 (3 mg/kg) and NTN (1 mg/kg) reduced alcohol intake profoundly at doses lower than the individual effective doses in both sexes of B6 mice. We confirmed the effect of SSR149415 on reducing alcohol intake in nPE−/− male mice, consistent with independent mechanisms by which SSR149415 and NTN decrease alcohol drinking. The combination of V1b antagonist SSR149415 with NTN at individual subthreshold doses shows potential in alcoholism treatment, possibly with less adverse effects.