Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance
Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance
复制标题
DOI：
10.1111/acer.13615
复制
发表时间：
2018-05-01
影响因子：
3.2
通讯作者：
Messing, Robert O.
中科院分区：
文献类型：
--
作者：
Blednov, Yuri A.;Da Costa, Adriana J.;Messing, Robert O.
背景在我们的配套论文中，我们报道了磷酸二酯酶4型抑制剂阿普斯特减少了雄性和雌性C57 BL/6 J小鼠在不同饮酒模型中的乙醇（EtOH）摄入量和偏好。方法在雄性和雌性C57 BL/6 J小鼠中研究了阿普斯特（20 mg/kg）对以下行为的影响：对新情境的运动反应、乙醇和氯化锂（LiCl）诱导的对糖精的条件性味觉厌恶（CTA）反应、阿普斯特（20 mg/kg）诱导的对糖精的条件性味觉厌恶（CTA）反应、阿普斯特（20 mg/kg）诱导的对糖精的条件性味觉厌恶反应、阿普斯特（20 mg/kg）诱导的对糖精的条件性味觉厌恶反应、阿普斯特（20 mg/kg）诱导的对糖精的条件性味觉厌恶反应、阿普斯特（20 mg/kg）诱导的对糖精的条件性味觉厌恶反应。对EtOH的条件性位置偏爱（CPP）和条件性位置回避（CPA）; EtOH给药后处理诱导的惊厥的严重程度;高架十字迷宫中EtOH诱导的抗焦虑样行为; EtOH诱导的翻正反射丧失（LORR）的持续时间;从EtOH诱导的运动损伤的rotarod恢复;和急性功能耐受性（AFT）EtOH的共济失调effects.ResultsApremilast没有改变收购EtOH诱导的CPP，严重程度急性退出EtOH，或EtOH的抗焦虑样作用。阿普斯特没有改变EtOH或LiCl诱导的CTA的消退，但可能干扰CTA向EtOH的获取。阿普斯特增加了CPA对EtOH的获得，减少了对新情况的运动反应，延长了LORR的持续时间和EtOH诱导的急性运动不协调的恢复。从共济失调效应的恢复时间较长可能是由于减少发展AFT EtOH.ConclusionsOur结果表明，阿普斯特通过减少AFT增加EtOH中毒的持续时间。阿普斯特还减少了一般奖励的某些方面，并增加了EtOH的厌恶性质，这也可能有助于其减少EtOH饮用的能力。
BackgroundIn our companion paper, we reported that the phosphodiesterase type 4 inhibitor apremilast reduced ethanol (EtOH) intake and preference in different drinking models in male and female C57BL/6J mice. In this study, we measured the effects of apremilast on other behaviors that are correlated with EtOH consumption.MethodsThe effects of apremilast (20mg/kg) on the following behaviors were studied in male and female C57BL/6J mice: locomotor response to a novel situation; EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA) to saccharin; conditioned place preference (CPP) and conditioned place avoidance (CPA) to EtOH; severity of handling-induced convulsions after EtOH administration; EtOH-induced anxiolytic-like behavior in the elevated plus maze; duration of EtOH-induced loss of righting reflex (LORR); recovery from EtOH-induced motor impairment on the rotarod; and acute functional tolerance (AFT) to EtOH's ataxic effects.ResultsApremilast did not change the acquisition of EtOH-induced CPP, severity of acute withdrawal from EtOH, or EtOH's anxiolytic-like effect. Apremilast did not alter the extinction of EtOH- or LiCl-induced CTA, but may interfere with acquisition of CTA to EtOH. Apremilast increased the acquisition of CPA to EtOH, reduced locomotor responses to a novel situation, and prolonged the duration of LORR and the recovery from acute motor incoordination induced by EtOH. The longer recovery from the ataxic effect may be attributed to reduced development of AFT to EtOH.ConclusionsOur results suggest that apremilast increases the duration of EtOH intoxication by reducing AFT. Apremilast also reduces some aspects of general reward and increases EtOH's aversive properties, which might also contribute to its ability to reduce EtOH drinking.