School of Pharmacy, Pharmacology Unit, University of Camerino, 62032, Camerino, Italy.
Center for Social and Affective Neuroscience, BKV, Linköping University, 581 83, Linköping, Sweden.
Psychopharmacology (Berl). 2020 Oct;237(10):2983-2992. doi: 10.1007/s00213-020-05586-w. Epub 2020 Jul 16.
Peroxisome Proliferator Activator receptors (PPARs) are intracellular receptors that function as transcription factors, which regulate specific metabolic and inflammatory processes. PPARs are broadly distributed in the body and are also expressed in the central nervous system, especially in areas involved in addiction-related behavioral responses. Recent studies support a role of PPARs in alcoholism and pioglitazone: a PPARγ agonist used for treatment of type 2 diabetes showed efficacy in reducing alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats.
In the current work, we tested the pharmacological effects of pioglitazone on binge-like alcohol consumption using an intermittent two-bottle choice paradigm in Wistar rats and on the "drinking in the dark" (DID) model in mice with selective deletion of PPARγ in neurons.
Our data show that repeated administration of pioglitazone (10, 30 mg/kg) reduces high voluntary alcohol consumption in Wistar rats. Pre-treatment with the selective PPARγ antagonist GW9662 (5 mg/kg) completely prevented the effect of pioglitazone, demonstrating that its action is specifically mediated by activation of PPARγ. In line with this result, repeated administration of pioglitazone (30 mg/kg) attenuated binge alcohol consumption in PPARγ mice. Whereas in PPARγ mice, which exhibit reduced alcohol consumption, pioglitazone had no effect. Of note, PPARγ mice exhibited lower patterns of alcohol drinking without showing difference in sucrose (control) intake. Interestingly, PPARγ mice displayed a higher sensitivity to the sedative and ataxic effect of alcohol compared with their wild-type counterpart.
Collectively, these data suggest that PPARγ agonists, and specifically pioglitazone, could be potential therapeutics for the treatment of binge alcohol drinking.
过氧化物酶体增殖物激活受体（PPARs）是细胞内受体，作为转录因子发挥作用，调节特定的代谢和炎症过程。PPARs 在体内广泛分布，也在中枢神经系统中表达，特别是在与成瘾相关的行为反应有关的区域。最近的研究支持 PPARs 在酒精中毒中的作用和吡格列酮：一种用于治疗 2 型糖尿病的 PPARγ 激动剂在减少大鼠饮酒、应激诱发的复发和酒精戒断综合征方面显示出疗效。
在目前的工作中，我们使用 Wistar 大鼠的间歇性双瓶选择范式和神经元中选择性缺失 PPARγ 的小鼠的“暗饮”（DID）模型测试了吡格列酮对 binge-like 酒精消费的药理学作用。
我们的数据表明，重复给予吡格列酮（10、30mg/kg）可减少 Wistar 大鼠的高自愿饮酒量。选择性 PPARγ 拮抗剂 GW9662（5mg/kg）预处理完全阻止了吡格列酮的作用，表明其作用是通过激活 PPARγ 特异性介导的。与这一结果一致，重复给予吡格列酮（30mg/kg）可减轻 PPARγ 小鼠的 binge 酒精消费。然而，在酒精摄入量减少的 PPARγ 小鼠中，吡格列酮没有作用。值得注意的是，PPARγ 小鼠表现出较低的酒精饮用模式，而在蔗糖（对照）摄入方面没有差异。有趣的是，与野生型相比，PPARγ 小鼠对酒精的镇静和共济失调作用更敏感。
总之，这些数据表明，PPARγ 激动剂，特别是吡格列酮，可能是治疗 binge 酒精消费的潜在治疗方法。
