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首页> 外文期刊>Addiction biology >The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice
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The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice

机译：抗高血压药物脱洛尔衰减长期但不是短期的小鼠诸如小鼠的乙醇消耗

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Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge-ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12weeks) binge-ethanol intake, compared with short-term (4weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency of BLA principal neurons from long-term ethanol-consuming mice but not naive mice. Additionally, this effect was blocked by the 5-HT1A/1B receptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies.
机译：酒精依赖性是一种衰弱的疾病，具有目前的疗法，呈现有限的疗效和/或遵守性。因此，改善药房治疗策略的危急需要管理酒精使用障碍（AUDS）。以前的研究表明，酒精依赖性的发展涉及重复的诸如乙醇的乙醇摄入和禁欲的循环。因此，我们使用小鼠中泪水消耗（饮用黑暗）的模型来测试已知的化合物改性含有含有酒精成瘾的神经递质的活性的作用。由此，我们已经确定了FDA批准的抗高血压药物饰面，作为管理澳元的潜在候选人。我们表明，在短期（12周）的乙醇摄入量，与短期（4周）摄入相比，长期（12周）的乳咯醇降低乙醇消费的疗效增强。此外，施林对自然奖励蔗糖的运动活性或消费没有影响。因为施林作为双β-肾上腺素能拮抗剂和5-HT1A / 1B部分激动剂，所以我们研究了对基底外侧Amygdala（BLA）的自发突触活性的影响，由血清素和含去甲肾上腺素的纤维密度地密集地神经化的脑区域。 Pindolol从长期乙醇消耗小鼠中增加BLA主神经元的自发兴奋性后突触电流频率，但不是幼稚小鼠。另外，这种效果被5-HT1A / 1B受体拮抗剂甲硫酸阻断，表明BLA中的血清onOronergic活性改变可能有助于在长期暴露后降低辛溶胶的效果降低乙醇摄入量。虽然需要进一步的机制调查，但本研究证明了施林作为可以快速追踪到人类临床研究的澳元的新治疗选择。

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