Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference.
Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference.
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DOI：
10.1111/acer.13616
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Harris RA
中科院分区：
文献类型：
--
作者：
Blednov YA;Da Costa AJ;Tarbox T;Ponomareva O;Messing RO;Harris RA
磷酸二酯酶4(PDE4)抑制剂在几种啮齿动物模型中可以产生广泛的抗炎作用，并减少乙醇的消耗。这些药物是几种疾病的潜在治疗方法，包括中枢神经系统疾病，但它们的呕吐活性限制了临床使用。阿普米司特是一种选择性的PDE4抑制剂，胃肠道副作用较少，FDA批准用于治疗银屑病。采用连续和间歇性24小时两瓶选择饮酒模型，测定了阿普司特对雄性和雌性C57BL/6J小鼠酒精消耗量的急性和慢性影响。我们还研究了阿司司特对蔗糖或糖精的偏好、自发活动和血液乙醇清除的影响。最后，在注射后1或2小时测定血浆、肝脏和脑中的阿司匹林水平。在连续和间歇饮水试验中，阿司米司特(15-50 mg/kg，P.O.)剂量依赖性地降低了雄性和雌性小鼠的酒精摄入量和偏好。较高剂量的安非司特(30-50 mg/kg)也减少了这些小鼠的总液体摄入量。长期服用安非司特(20 mg/kg)可以稳定地减少两种饮酒试验中的酒精消耗量，而对总的液体摄入量没有影响。用车辆给药(生理盐水)替代药物治疗2~4d后，饮酒效应可逆。每天注射六次阿波司特并没有改变雄性或雌性小鼠对糖精或蔗糖的偏好。阿普利司特(20 mg/kg)可短暂降低小鼠的自发活动，但不改变血液中乙醇的清除。阿波司特在肝脏中的含量最高，其次是血浆和脑。阿普利司特能稳定地减少自愿的乙醇消耗，并迅速分配到血浆和组织(包括大脑)，这表明它可能是一种改进的PDE4抑制剂，用于药物开发和改变治疗酒精滥用的努力。
Phosphodiesterase type 4 (PDE4) inhibitors produce widespread anti-inflammatory effects and reduce ethanol consumption in several rodent models. These drugs are potential treatments for several diseases, including central nervous system disorders, but clinical use is limited by their emetic activity. Apremilast is a selective PDE4 inhibitor with fewer gastrointestinal side effects that is FDA approved for the treatment of psoriasis. We measured the acute and chronic effects of apremilast on ethanol consumption in male and female C57BL/6J mice using the continuous and intermittent 24-h two-bottle choice drinking models. We also studied the effects of apremilast on preference for sucrose or saccharin, spontaneous locomotor activity, and blood ethanol clearance. Finally, apremilast levels in plasma, liver, and brain were measured one or two hours after injection. In the continuous and intermittent drinking tests, apremilast (15-50 mg/kg, p.o.) dose dependently reduced ethanol intake and preference in male and female mice. Higher doses of apremilast (30-50 mg/kg) also reduced total fluid intake in these mice. Chronic administration of apremilast (20 mg/kg) produced a stable reduction of ethanol consumption in both drinking tests with no effect on total fluid intake. The drinking effects were reversible after drug treatment was replaced with vehicle administration (saline) for 2-4 days. Six daily apremilast injections did not alter preference for saccharin or sucrose in male or female mice. Apremilast (20 mg/kg) transiently decreased spontaneous locomotor activity and did not alter blood ethanol clearance. The highest levels of apremilast were found in liver followed by plasma and brain. Apremilast produces stable reductions in voluntary ethanol consumption and is rapidly distributed to plasma and tissues (including the brain), suggesting that it may be an improved PDE4 inhibitor for medication development and repurposing efforts to treat alcohol abuse.
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影响因子：
6.2
作者：
Ghosh, Mousumi;Garcia-Castillo, Daniela;Aguirre, Vladimir;Golshani, Roozbeh;Atkins, Coleen M.;Bramlett, Helen M.;Dietrich, W. Dalton;Pearse, Damien D.
通讯作者：
Pearse, Damien D.
影响因子：
7.6
作者：
Metz, Verena E.;Jones, Jermaine D.;Comer, Sandra D.
通讯作者：
Comer, Sandra D.
影响因子：
4.7
作者：
Avila DV;Myers SA;Zhang J;Kharebava G;McClain CJ;Kim HY;Whittemore SR;Gobejishvili L;Barve S
通讯作者：
Barve S
影响因子：
3.2
作者：
Blednov, Yuri A.;Da Costa, Adriana J.;Messing, Robert O.
通讯作者：
Messing, Robert O.
影响因子：
2.3
作者：
Forgèt, MA;Sisson, JH;Wyatt, TA
通讯作者：
Wyatt, TA