Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Department of Behavioral Medicine and Psychiatry, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
Psychopharmacology (Berl). 2017 Oct;234(20):3143-3151. doi: 10.1007/s00213-017-4697-3. Epub 2017 Jul 27.
Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior.
The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models.
Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice.
Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram.
These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 inhibitors may be a novel class of drugs for treatment of alcoholism.
戒断症状是酒精依赖的核心特征。我们之前的研究结果表明，抑制磷酸二酯酶 4（PDE4）可减少酒精偏好性啮齿动物的乙醇觅药和饮酒。然而，目前尚不清楚 PDE4 是否参与乙醇戒断相关行为。
本研究旨在探讨 PDE4 在不同动物模型的乙醇戒断引起的焦虑和抑郁样行为发展中的作用。
我们使用三种乙醇戒断的啮齿动物模型，研究了罗利普兰（一种典型的选择性 PDE4 抑制剂）对（1）幼态白头（FH/Wjd）大鼠反复乙醇戒断引起的高架十字迷宫焦虑样行为，（2）C57BL/6J 小鼠急性乙醇戒断后在开阔场和明暗过渡试验中的焦虑样行为，以及（3）C57BL/6J 小鼠长期乙醇戒断引起的高架十字迷宫、强迫游泳和悬尾试验中的焦虑和抑郁样行为的影响。
罗利普兰（0.1 或 0.2mg/kg）预处理显著增加了反复乙醇戒断大鼠高架十字迷宫试验中进入和开放臂的时间。同样，在急性乙醇戒断的小鼠中，罗利普兰（0.25 或 0.5mg/kg）剂量依赖性地增加了开放场试验中中央区的穿越次数以及明暗过渡试验中亮侧的持续时间和转换次数，提示罗利普兰具有抗焦虑样作用。与此一致的是，慢性给予罗利普兰（0.1、0.3 或 1.0mg/kg）增加了高架十字迷宫试验中进入开放臂的次数；它还减少了长期乙醇戒断后小鼠强迫游泳和悬尾试验中不动时间的增加，提示罗利普兰具有抗抑郁样作用。
这些结果首次证明 PDE4 在调节与乙醇戒断相关的负性情绪反应的发展中发挥作用，包括焦虑和抑郁。PDE4 抑制剂可能是治疗酒精中毒的一类新药物。
