Blockade of alcohol excessive and "relapse" drinking in male mice by pharmacological cryptochrome (CRY) activation.
Blockade of alcohol excessive and "relapse" drinking in male mice by pharmacological cryptochrome (CRY) activation.
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DOI：
10.1007/s00213-020-05757-9
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发表时间：
2021-04
影响因子：
3.4
通讯作者：
Kreek MJ
中科院分区：
文献类型：
--
作者：
Zhou Y;Kreek MJ
代谢功能障碍、情绪障碍、焦虑症和物质滥用障碍与昼夜节律和昼夜节律钟基因机制的破坏有关。虽然在啮齿动物模型中已经描述了酒精对时钟基因的几个核心成分的影响，但尚未研究酒精饮酒行为对时钟基因功能的药理学激活或抑制。我们研究了隐花色素（p53 1/2）激活剂KL 001是否改变了过量和复发样饮酒模型小鼠的酒精摄入量。小鼠，进行3周的慢性间歇性饮酒（两瓶选择，24小时访问，每隔一天）（IAD）开发过量的酒精摄入量和高偏好。我们使用酒精剥夺效应（ADE）模型评估了KL 001在1天急性戒断或1周慢性戒断后的药理作用。1-4 mg/kg的KL 001单次预处理以剂量相关的方式减少了急性戒断后的酒精摄入量和偏好。KL 001减少过量饮酒的作用似乎是酒精特异性的，因为该化合物不会改变小鼠的蔗糖（热量补充剂）或糖精（无热量补充剂）消耗。有效剂量的KL 001（4 mg/kg）的单次和多次给药方案均可预防慢性戒断后的ADE，多次给药方案后未出现耐受性。用KL 001（一种β 1/2激活剂）预处理可减少小鼠过度饮酒和“复发性”饮酒。我们使用CRY激活剂的体内结果表明酒精治疗干预可能是一个新的靶点。
Metabolic dysfunction, mood disorders, anxiety disorders, and substance abuse disorders are associated with disruptions in circadian rhythm and circadian clock gene machinery. While the effects of alcohol on several core components of the clock genes have been described in rodent models, pharmacological activation or inhibition of clock gene functions has not been studied on alcohol drinking behaviors. We investigated whether cryptochrome (CRY1/2) activator KL001 altered alcohol intake in mice in excessive and relapse-like alcohol drinking models. Mice, subjected to 3 weeks of chronic intermittent alcohol drinking (two-bottle choice, 24-h access every other day) (IAD) developed excessive alcohol intake and high preference. We evaluated the pharmacological effects of KL001 after either 1-day acute withdrawal from IAD or 1-week chronic withdrawal using the alcohol deprivation effect (ADE) model. Single pretreatment with KL001 at 1–4 mg/kg reduced alcohol intake and preference after acute withdrawal in a dose-related manner. The effect of KL001 on reducing excessive alcohol consumption seems alcohol-specific, as the compound does not alter sucrose (caloric reinforcer) or saccharin (non-caloric reinforcer) consumption in mice. Both single- and multiple- dosing regimens with an effective dose of KL001 (4 mg/kg) prevented the ADE after chronic withdrawal, with no tolerance development after the multi-dosing regimen. Pre-treatment with KL001 (a CRY1/2 activator) reduces excessive and “relapse” alcohol drinking in mice. Our in vivo results with a CRY activator suggest a possible novel target for alcohol treatment intervention.
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影响因子：
5.2
作者：
Griebel G;Ravinet-Trillou C;Beeské S;Avenet P;Pichat P
通讯作者：
Pichat P
DOI：
10.1038/nrg2430
发表时间：
2008-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.95.11.6097
发表时间：
1998-05-26
影响因子：
11.1
作者：
Miyamoto, Y;Sancar, A
通讯作者：
Sancar, A
影响因子：
3
作者：
De Bundel D;Gangarossa G;Biever A;Bonnefont X;Valjent E
通讯作者：
Valjent E
影响因子：
64.8
作者：
Lamia, Katja A.;Papp, Stephanie J.;Yu, Ruth T.;Barish, Grant D.;Uhlenhaut, N. Henriette;Jonker, Johan W.;Downes, Michael;Evans, Ronald M.
通讯作者：
Evans, Ronald M.