daCostaThesis.docx
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daCostaThesis.docx
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daCostaThesis
Formationoftestosterone’s5α-reduced,versusaromatized,productscanhavebeneficialcognitiveandanti-anxietyeffectswithoutnegativeeffectsonprostateorsexualbehaviorofmalerats.
Anhonorsthesispresentedtothe
DepartmentofBiologicalSciences,
UniversityatAlbany,StateUniversity
OfNewYorkinpartialfulfillment
oftheHonorsProgramRequirements.
DanieldaCosta
2010
DepartmentofBiologicalSciences
UniversityatAlbany
ThisHonorsThesishasbeenreadandapproved
bytheundersignedandisherebyrecommendedforacceptance.
ThesisCommittee:
ResearchAdvisor:
(Name)_______________________________________________________
(Signature)_______________________________________________________
(Date)_______________________________________________________
Member:
(Name)_______________________________________________________
(Signature)_______________________________________________________
(Date)_______________________________________________________
Member:
(Name)_______________________________________________________
(Signature)_______________________________________________________
(Date)_______________________________________________________
ACTION:
AcceptedNotAccepted
___________________________________________________________________________
RobertOsunaDate
DepartmentalHonorsProgramDirector
Abstract
Testosterone(T)canaltersexual,social,anxiety-like,and/orcognitivebehaviorofmalerodentsandexerttrophiceffectsontheprostate.However,whethertheseeffectsareduetoactionsofT,orits5α-reducedand/oraromatizedmetabolites,isofinterest.WetestedthehypothesisthatT’seffectstoenhanceprostateproliferation,sexual,social,cognitiveand/oranti-anxiety-likebehaviorrequireformationof5α-reducedand/oraromatizedmetabolites.Gonadectomized(GDX)orgonadally-intactratswereadministeredT-containing,orempty,silasticcapsulesinconjunctionwitha5α-reductaseinhibitor(finasteride;Experiment1)oranaromataseinhibitor(formestane;Experiment2).Theperformanceofratsinsexual,cognitive(objectrecognition,objectplacement,watermaze),anxiety-like(openfield,elevatedplusmaze,light–darktransition,mirrormaze,socialinteraction)taskswereexamined.ProstatemassandconcentrationsofTanditsmetaboliteswereassessed.RatsthatwereGDX,comparedtointactrats,hadlowerandrogenlevels,smallerprostates,longerlatenciestoinitiatesexualcontacts,hadpoorercognitiveperformanceintheobjectplacementandwatermazetasks,anddemonstratedmoreanxiety-likebehaviorinthelight/darktransitiontaskandthemirrormaze.FinasterideproducedeffectssimilartoGDXtodecreaseprostateweightandinhibitsexualbehaviorandspatialcognition,butnotaffectivebehaviors.Formestanedidnotalterprostatemassorsexualbehavior,butdidenhancecognitiveperformanceintheobjectrecognitiontaskandtendedtoincreasecentralentriesintheopenfield,anindicationofanti-anxietybehavior.Thus,shuntingT’smetabolismfromaromatizationtofavor5α-reductionhadbeneficialcognitiveandanti-anxietyeffectswithoutnegativeeffectsonprostateorsexualbehavior.
Acknowledgements
ThesestudiesweresupportedbyKaroBio,andinpartbyTheNationalInstituteofMentalHealth(MH0676980;RMH067698B).Dr.CherylFrye,JasonParis,Dr.AliciaWalf,andFryeLaboratoryassistedinthedatacollectionanalysis,whichareincludedinthiswork.
TableofContents:
Introduction:
6-9
MaterialsandMethods:
9-15
Results:
15-20
Discussion:
20-25
LiteratureCited:
26-38
Figures:
39-51
Introduction
Agingmencanexperiencedeclineingonadal,sexual,cognitive,andaffectivefunction.Formen,androgenlevelsbegintoriseafterpubertyandremainhighuntilmidlife(Hiort,2002),whenadecade-by-decadedeclineinendogenousandrogenlevelsoccurs(Morleyetal,.1997).Onaverage,thisdecline,involvesa0.4%reductionintotaltestosteroneanda1.2%reductioninbiologically-freetestosteroneperyear,causingmeantotalplasmatestosteronelevelsdecreasebyabout35%between25and75yearsofage(Schatzletal.,2003;Vermeulen,2000).Somebehavioralsequelaeassociatedwithagingincludepoorerperformanceinspatialtasks,greateranxietyanddepression,anddecreasedsexualmotivation(DavidsonKwanandGreenleaf,1982;Basaria&Dobs,2001;2002;Morleyetal.,2001;JanowskyOviattandOrwoll,1994;Seidman,2002).Inadditiontoandrogen-sensitivechangesinbehavior,therearephysicalchanges,suchasincreasedriskforbenignprostatehyperplasia(BPH)andprostatecancer(Untergasser,Rumpold,Hermann,Dirnhofer,JilgandBerger,1999).Thesephysicalchangesworsenwithaging,asfrequencyofmoderateandworseurinarysymptomsrelatedtoBPHrisefrom13%inthefifthto28%intheeighthdecadeoflife(Kaplan,2005).Affective,cognitive,andphysicaldeclineassociatedwithagingisofparticularimportancegiventhatdemographicssuggestthatolderagegroupsareincreasingasapercentageofthepopulation(Nieschlagetal.,2006).Manymenseektestosterone(T)replacementtherapy(TRT)tocombattheseeffects(Marks&Kaplan2009;Kaufman&Seftel,2004).TRTshavesuccessfullybeenusedtoimprovespatialcognition,libidoanddepression(Tenover,1998;Janowsky,Oviatt,andOrwoll,1994;Pope,Cohane,Kanayama,Siegel,andHudson,2003).However,TRTsarealsoassociatedwithnegativeconsequencesincludingincreasedriskforprostatecancer(Raynaud,2006).Greaterunderstandingisneededoftherelativetrophiceffectsofandrogensonperipheralandcentraltissues.
Inrodentmodels,declineinendogenousTcanproducenegativeeffectsonsexual,cognitive,andanxiety-like,behavior.Oldermalerodentsdemonstratesimilarbehavioraldeclinetothatofagingmen:
agedrodentsdisplaydecreasedsexualmotivationandcognitiveperformanceinspatialtasks(Chambers,Thornton,Roselli,1991;SpruijtMeyerson,andHodlund,1989;Barnes,1988).Extirpationofthetestes,aprimarysourceofandrogens,canreduceplasmalevelsofandrogens(Krey&McGinnis,1990).Separatestudieshaveshownthatgonadectomy(GDX)ofrodentsproducesbehavioraleffectssimilartothoseseenwithaging,includingdecreasedsexualproceptivity,cognition,increasedanxietyanddepressivebehavior(Adler,Vescovo,Robinson,andKritzer,1999;Hull&Dominguez,2007;Aubele,Kaufman,MontalmantandKritzer,2008;BernardiGenedani,Tagliavini,andBertolini,1989).Akintohormonereplacementtherapy,administeringTtoratsreinstatessexual,cognitive,andaffective,performancecommensuratetothatofgonadally-intactrats(Delhez,Hansenne,andLegros,2003;Kritzer,Brewer,Montalman,Davenport,andRobinson,2007),butcoincidenteffectsofprostateproliferationareofinterest.Thus,utilizingaGDXmodelisusefulfordeterminingtheeffectsofdecreasingandrogenlevelswithaging.
SomeofT’spsychologicalandphysiologicaleffectsmaybemediated,inpart,throughactionsofits5α-reducedand/oraromatizedmetabolites.Testosteroneismetabolizedby5α-reductaseenzymestoform5α-dihydrotestosterone(DHT;Handa,Pak,Kudwa,Lund,andHinds,2008).Inaddition,Tismetabolizedbyaromatasetoformestradiol(E2:
Alejandre-Gomez,Garcia-Segura,Gonzalez-Burgos.,2007;Ellem&Risbridger,2009;LephartLundandHorvath,2001;Séralini&Moslemi,2001).Interestingly,amongrats,levelsofTandits5α-reducedmetabolitesdeclinewithaging(Fryeetal.,2010).However,withagingamongmen,E2levelsremainunchangedorincrease,resultinginadecreaseintheratioofTtoE2(Ellem&Risbridger;Vermeulen,2000).Thus,theratioofTtoits5α-reducedand/oraromatizedmetabolitesinrelationtoeffectsonprostateandbehaviorisofinterest.
Thetestesareasignificantsourceofandrogens,butT,its5α-reduced,andaromatizedmetabolites,arealsoproducedinthebrain.TrophiceffectsofTinthebrainmaybeinpartdependant,andindependentof,gonadalcondition.Forexample,GDXreducesthenumberofaromatase-positiveneuronsinthehypothalamus,butnotlimbicareas(Jakab,Horvath,Leranth,Harada,andNaftolin,1993).Withinlimbicregions,suchasthehippocampus,androgen-mediatedspinesynapsedensitycanbeinpartindependentofsystemicandrogenicpotency(MacLusky,Hajszan,Prange-Kiel,andLeranth,2006).Interestingly,androgen-inducedremodelingofspinesynapsesinthehippocampusandprefrontalcortexoccurindependently,anddependently,respectivelyofactionsatandrogenreceptors(ARs;Hajszan,Milner,andLeranth,2007).Thus,androgenscanexertdiverseeffectsandmechanismsforitstrophicactionsinthebrain.
WeinvestigatedtherelationshipbetweenTanditsmetabolitesonreproductive,cognitive,andaffectivebehavioraswellastheirproliferativeeffectsintheprostateintwoexperiments.Ratsweregonadally-intact,orGDXandimplantedwithsilasticcapsulesthatwereemptyorcontainedT.InExperiment1,ratsalsohadsilasticcapsulescontaininga5α-reductaseinhibitor,finasterideorcontrolimplants.InExperiment2,ratsreceivedsilasticcapsulescontaininganaromataseinhibitor,formestane,orcontrolimplants.Allratsweretestedforreproductive,cognitive,andaffectivebehavior,ina7week-longbattery.Attheendofthebattery,prostatewascollectedandwetweightwasobtainedasanindicationofmass.Plasmaandbrainswerecollectedformeasurementofperipheralandcentralandrogenconcentrations.WeanticipatedthatGDXandfinasteridewoulddecrease,whileTandformestanewouldincrease,sexualmotivation,performanceincognitivetasks,anti-anxiety-likebehavior,andprostateweightsinco
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