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 clinic.Phosphodiesterases(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 consumption.However,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 rolipram.CONCLUSION 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 alcoholism.
LIU XinWEN Rui-tingGONG Mei-fangXU YingNicolas GRAHAMEXU Jiang-pingLIANG Jian-huiMarco CONTI张汉霆
