Phosphodiesterases:novel targets for treatment of alcoholism

作     者：LIU Xin WEN Rui-ting GONG Mei-fang XU Ying Nicolas GRAHAME XU Jiang-ping LIANG Jian-hui Marco CONTI 张汉霆 

作者机构：Institute of PharmacologyTaishan Medical University Departments of Behavioral Medicine & Psychiatry and Physiology & PharmacologyBlanchette Rockefeller Neurosciences InstituteWest Virginia University Health Sciences Center Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking University Department of PharmacologySchool of Pharmaceutical SciencesSouthern Medical University Department of Pharmaceutical SciencesState University of New York at Buffalo Department of PsychologyIndiana University-Purdue University Indianapolis Center for Reproductive SciencesDepartment of ObstetricsGynecology and Reproductive SciencesUniversity of California 泰山医学院药理学研究所 泰山医学院药学院 美国西弗吉尼亚大学医学院 中国旅美科技协会西弗吉尼亚分会 美国西弗吉尼亚华人协会 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2017年第31卷第5期

页      面：454-455页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

主　　题：phosphodiesterase alcohol drinking alcoholism anxiety depression rodents 

摘      要：OBJECTIVE Alcoholism is one of the most damaging psychiatric disorders and causes serious social and health problems in the world. However,there are no ideal treatments for this disease in ***(PDEs) are a superfamily of enzymes consisting of 11 PDE families that hydrolyze cyclicAMP(cA MP) and/or cyclicGMP(cGMP). Among them,PDE4 is critical in the control of intracellular cAMP levels and has been shown to play an important role in the regulation of ethanol ***,the functional role of PDE4 in mediating alcoholism remains unclear. METHODS Ethanol drinking and preference were examined using the two-bottle choice and/or drinking-in-dark(DID) test in high alcohol preferring(HAP) animals,including C57,HAP,and PDE4-subtype knockout mice,and Fawn-Hooded(FH/Wjd) rats,treated with or without the PDE4 inhibitor rolipram or roflumilast. Ethanol withdrawal-induced anxiety-and depressive-like behaviors were examined using the elevated plusmaze,holeboard,forced-swim,and tail-suspension tests in C57 mice or FH rats in the presence of PDE4 inhibition. Levels of cAMP,CREB were determined in brain regions. RESULTS Treatment with rolipram or roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in C57 and HAP mice as well as FH rats. Mice deficient in PDE4 B,but not PDE4 D,displayed similar effects to general PDE4 inhibition. In addition,rolipram reversed ethanol withdrawal-induced anxietyand depressive-like behaviors 1 d and 14 d,respectively,following withdrawal from ethanol drinking in the two-bottle choice in C57 mice or FH rats. Locomotor activity was not changed in either mice or rats treated with the PDE4 inhibitors. Levels of cAMP,p CREB in the brain were increased by *** The results provide solid evidence for the important role of PDE4 in ethanol consumptionand ethanol withdrawal-induced symptoms. Inhibitors of PDE4,in particular the PDE4 B isoform,can be a novel class of treatment for alcohol