Genetic Deficiency in Neprilysin or Its Pharmacological Inhibition Initiate Excessive Stress-Induced Alcohol Consumption in Mice 英文参考文献.docVIP

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Genetic Deficiency in Neprilysin or Its Pharmacological Inhibition Initiate Excessive Stress-Induced Alcohol Consumption in Mice 英文参考文献.doc

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Genetic Deficiency in Neprilysin or Its Pharmacological Inhibition Initiate Excessive Stress-Induced Alcohol Consumption in Mice 英文参考文献

GeneticDeficiencyinNeprilysinorItsPharmacological InhibitionInitiateExcessiveStress-InducedAlcohol ConsumptioninMice Bjo¨rnMaul1.,MatthiasBecker1.,FlorianGembardt2,3,AxelBecker4,Heinz-PeterSchultheiss5 ,Wolf- EberhardSiems1,ThomasWalther6,7* 1Department forBiochemicalNeurobiology,Leibnizinstitutfu¨rMolekularePharmakologie,Berlin,Germany, 2Department ofCardiacPathobiology,ExcellenceCluster Cardio-Pulmonary System, Giessen, Germany, 3Department for Nephrology – MK3, University Hospital Dresden, Dresden, Germany, 4Institute of Pharmacology and Toxicology, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany, 5Department Cardiology, Charite′ – Campus Benjamin Franklin, Berlin, Germany, 6Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim – University Heidelberg, Mannheim, Germany, 7Centre for Fetal Medicine,DepartmentofPediatricSurgeryDepartmentofObstetrics,DivisionofWomenandChildHealth,UniversityofLeipzig,Leipzig,Germany Abstract Both acquired and inherited genetic factors contribute to excessive alcohol consumption and the corresponding development of addiction. Here we show that the genetic deficiency in neprilysin [NEP] did not change the kinetics of alcoholdegradationbutledtoanincreaseinalcoholintakeinmiceina2-bottle-free-choiceparadigmafteronesinglestress stimulus(intruder).Arepetitionofsuchstressledtoanirreversibleelevatedalcoholconsumption.Thisphenomenoncould bealsoobservedinwild-typemicereceivinganorallyactiveNEPinhibitor.Wethereforeelucidatedthestressbehaviorin NEP-deficientmice.InanElevatedPlusMaze,NEPknockoutscrossedmoreoftentheareabetweenthearms,implicating asignificantstrongerstressresponse.Furthermore,suchanimalsshowedadecreasedlocomotoractivityunderintenselight inalocomotoractivitytest,identifyingsuchmicetobemoreresponsiveinaversivesituationsthantheirwild-typecontrols. Since the reduction in NEP activity itself does not lead to significant signs of an altered alcohol preference in mice but requires