Time minDMIGBR n3 PUFA deficient Figure3EffectofblockageofnoradrenalineDMI20mgkgipanddopamineuptakesGBR1290920mgkgiponthereleaseofdopamineinthefrontalcortexof2monthsoldratsfedadie ID: 947283
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Thesedatasuggestedthattheprocessofpresynapticdopaminestoragecouldbealteredinde cientanimals.Tosupportthishypoth-esis,welookedatthevesicularstage,usingdual-probemicrodialysistomonitorthereleaseofdopaminefromthevesicularpoolbytyraminestimulationinthefrontalcortexandinthenucleusaccumbens,bothstructuresbeinginvolvedinrewardandlearningprocess.Theresultsshowedthattheresponsetotyraminewassigni cantlyreducedinde cientrats,by70%inthefrontalcortex( gure4A)andby90%inthenucleusaccumbens( gure4B)[32-34].However,thiseffectwasabolishedbyaresepinepretreatment,whichdepletesthedopaminevesicularstore,show-ingareduceddopaminereserveinthepresyn-apticvesicles.Theseresultshavebeencon- rmedbythestudyofthedensityofdopaminevesicles,usingimmunolabelingwithadopam-ineantibodyandinsituhybridizationofvesicu-lartransporters[31,33,34].Allthisledtotheconclusionthatthedopaminevesiclecompartmentwasreducedby30%inthefrontalcortexofde cientrats,resultinginareducedcorticalinhibitionontheventralparts,particularlyonthenucleusaccumbens.More-over,themRNAexpressionofD2receptorswas30%lowerinthefrontalcortexand20%
higherinthenucleusaccumbensofde cientrats[31,33].Moreover,Kupersteinetal.[11]hasstudiedindetailtheconsequencesofDHAdeprivationinratsduringtheearlydevelopmentontheexpressionofabatteryofgenesincodingneu-rotransmitterreceptors.Inparticular,theyshowedaremarkableelevationofthedopam-ineD1andD2receptorsgenes,indiscreteregionsofthemesolimbicandmesocorticalpathways,notablythenucleusaccumbens,theprefrontalcortexandthehippocampus,oryetintheventraltegmentalarea.Theauthorsattributedthisover-expressiontoacompensa-torymechanismresultingfromthepossibleimpairmentofthedopaminesynthesis,storageorprocessing,inordertoenablethetargetedsynapsestoactevenwithlowlevelsofDHA.Tosumup,allthesedatasuggestthataninadequateintakeofDHAresultsinadysfunc-tionofthedopaminemesocorticolimbicloop,leadingtoanhypodopaminergiainthecorticalareas,responsibleforinattention,andtoanhyperdopaminergiainthenucleusaccumbens,responsibleforhyperactivityandforanineffi-cientrewardprocess.Thereductionofdopam-inereservescanthenberelatedtotheinappro-priatebehaviouralresponsepreviouslyobservedinde cientanimals,sincetheymaynown
otbesufficienttoachieveahighreleaseduringstimulatedcognitiveprocesses.Alterationofdopamine-relatedInterestingly,alowerdopaminergicactivityinthefrontalcortexassociatedtoahigheroneinthenucleusaccumbens,asweobservedinthede cientrats,isconsideredtobeabiologicalsubstrateofsensation-seekingthatcouldinducelocomotorhyperactivity[35,36].Toexplorethisrelationship,wemeasuredthe Time (min)DMIGBR n-3 PUFA deficient Figure3.Effectofblockageofnoradrenaline-(DMI,20mg/kgi.p.)anddopamine-uptakes(GBR12909,20mg/kg,i.p.)onthereleaseofdopamineinthefrontalcortexof2-months-oldratsfedadietde cientinalpha-linolenicacidoracontroldiet(%basallevel;mean±SD;n=8).*Signi cantlydifferentfrombasallevel(p0.05,ANOVA) Tyramine 50001000020000 Controls n-3 PUFA deficient Tyramine Figure4.Dopaminereleaseundertyraminestimulation(200M,insituperfusion)inthefrontalcortex(A)andinthenucleusaccumbens(B)of2-months-oldratsfedadietde cientinalpha-linolenicacidoracontroldiet(%basallevel;mean±SD;n=8).**Signi cantlydifferentbetweendietarygroups(p0.01,ANOVA)[32,33]. 0100200300400DHA (% TFA) Figure5.CorrelationsbetweenDHAc
ontentsofphosphatidylethanolamine(PE)expressedas%oftotalfattyacids(%TFA)infrontalcortexandactivitiesinresponsetonoveltymeasuredinacagefor1hour.ValuesofBravais-Pearsonscorrelationtestareindicated[37]. 166 Wehaveshownthatmodi cationsofDHAlevelsinthephospholipidmembranesofthethreecelltypesledtochangesinglucosetransport[43]butalsoingapjunctioncoupling[44].ThehypothesiscanbemadethattheproportionsofDHAinmembranesmayhaveanimpactonthemorphologicalplasticityandonthediffer-entastrocytefunctionsinvolvedintheregula-tionofsynaptictransmission,andmorepar-ticularlyinthereleaseofneurotransmitterinthesynapticcleft.Thesedatawillhelptounderstandtherelationshipbetweenthen-3PUFAmetabolismandsomeneu-ropsychiatricdisorders,suchasdepressionorschizophrenia,inwhichalteredneurotransmissionsystemsarewellknowntoday.Thus,aPUFAimbal-ancecouldcontributetothepredispositiontocentralnervoussystempathologiesbyactingontheregulationoftheneurotransmissionfunction.Thishighlightstheimportanceofoptimalnutri-tionaln-3PUFAsupplytopreventoratleastbufferimpairmentsofbrainfunctioning.1.CLANDININMT.Braindevelopmen
tandassessingthesupplyofpolyunsaturatedfatty1999;34:131-7.2.GREENP,GLOZMANS,KAMENSKYB,YAVINE.Developmentalchangesinratbrainmem-branelipidsandfattyacids:thepreferentialprenatalaccumulationofdocosahexaenoicJLipidRes1999;40:960-6. KCl 100 mMB 020406080100120140160180200Time (min)020406080100120140160180200 14Ach basal efflux(pmoles/20 µL dialysate) 01234Ach basal efflux(pmoles/20 µL dialysate)AKCl 100 mM Figure8.Achreleaseinthefrontalcortex(A)andthehippocampus(B)of2-months-oldcontrol(opencircles)andalpha-linolenicacid-de cientrats(blacktriangles)(%basallevel;mean±SEM;n=6to9).*Signi cantlydifferentbetweendietarygroups(p0.01,ANOVA).:basalAchreleaseincontrol(whitebars)andalpha-linolenicacid-de cientrats(blackbars).ValuesareexpressedastheaverageLofdialysate)ofthethree20-minutedialysatecollectionsimmediatelypreceding100mMKClperfusion.*Signi cantlydifferentbetweendietarygroups(Studentst-test;P0.05)[27]. B ControlDHA 0EPL100EPL200EPL300ControlDHA 0EPL100EPL200EPL300 baabb Figure9.Basal(A)andmaximalrelease(KCl100mM,perfusion)(B)ofAchfromthehippocampusofcontrol(n=9),n-3PUFAde ci
ent(DHA0,n=7),andeggphospho-lipidssupplemented(EPL,mgDHA/100gdiet)(n=5to8)2-months-oldrats(mean±SD).Meanswithoutacommonletterdiffer(P0.05,ANOVA)[42]. 168 36.DELLUF,PIAZZAPV,MAYOW,LEMOALM,SIMONH.Novelty-seekinginrats--biobehavioralcharacteristicsandpossiblerela-tionshipwiththesensation-seekingtraitin1996;34:136-45.37.VANCASSELS,BLONDEAUC,LALLEMANDS,etal.Hyperactivityintheratisassociatedwithspontaneouslowlevelofn-3polyunsaturatedfattyacidsinthefrontalcortex.BehavBrainRes2007;180:119-26.38.KODASE,GALINEAUL,BODARDS,etal.toninergicneurotransmissionisaffectedbyn-3polyunsaturatedfattyacidsintherat.JNeuro-2004;89:695-702.39.FADDAF,COCCOS,STANCAMPIANONR.Hippocampalacetylcholinereleasecorrelateswithspatiallearningperformanceinfreelymovingrats.2000;11:2265-9.40.MCGAUGHYJ,DALLEYJW,MORRISONCH,EVERITTBJ,ROBBINSTW.Selectivebehavioralandneurochemicaleffectsofcholinergiclesionsproducedbyintrabasalisinfusionsof192IgG-saporinonattentionalperformanceina ve-choiceserialreactiontimetask.JNeurosci2002;22:1905-13.41.RAGOZZINOME,UNICKKE,GOLDPE.Hip-pocampalacetylcholinereleaseduringmemorytesti
nginrats:augmentationbyglu-ProcNatlAcadSciUSA1996;93:4693-8.42.AÏDS,VANCASSELS,LINARDA,LAVIALLEM,GUESNETP.Dietarydocosahexaenoicacid(22:6n-3)asphospholipidsortriglyceridesbothenhancetheKCl-evokedreleaseofacetyl-cholineintherathippocampus.JNutr135:1008-13.43.PIFFERIF,ROUXF,LANGELIERB,etal.polyunsaturatedfattyacidde ciencyreducestheexpressionofbothisoformsofthebrainglucosetransporterGLUT1inrats.JNutr135:2241-6.44.CHAMPEIL-POTOKARG,CHAUMONTETC,GUESNETP,LAVIALLEM,DENISI.Docosa-hexaenoicacid(22:6n-3)enrichmentofmem-branephospholipidsincreasesgapjunctioncouplingcapacityinculturedastrocytes.EurJ2006;24:3084-90. 170 DHAinvolvementinneurotransmissionprocessSylvieVANCASSELSabahAÏDIsabelleDENISPhilippeGUESNETMoniqueLAVIALLEUnitédeNutritionetRégulationLipidiquesdesFonctionsCérébrales,NuRéLiCe,INRA,domainedeVilvert,78352Jouy-en-Josascedex,Theveryhighenrichmentofthenervoussysteminthepolyunsaturatedfattyacids,arachidonic(AA,20:4n-6)anddocosahexaenoicacids(DHA,22:6n-3),isdependantofthedietaryavailabilityoftheirrespectiveprecursors,linoleic(18:2n-6)and-linolenicacids(18:3n-3).Inadequa