ducemid歌曲

DopaminemodulatestherewardexperienceselicitedbymusicLauraFerreria,b,c,1,2,ErnestMas-Herrerod,e,1,RobertJ.
Zatorred,e,PabloRipollésf,AlbaGomez-Andresa,b,HelenaAlicarta,GuillemOlivéa,b,JosepMarco-Pallarésa,b,g,RosaM.
Antonijoanh,i,MartaVallei,j,3,JordiRibak,3,andAntoniRodriguez-Fornellsa,b,l,2,3aCognitionandBrainPlasticityUnit,BellvitgeBiomedicalResearchInstitute,L'HospitaletdeLlobregat,08907Barcelona,Spain;bDepartmentofCognition,DevelopmentandEducationPsychology,UniversityofBarcelona,08035Barcelona,Spain;cLaboratoired'EtudedesMécanismesCognitifs,UniversitéLumièreLyon2,69676Lyon,France;dMontrealNeurologicalInstitute,McGillUniversity,Montreal,QCH3A2B4,Canada;eInternationalLaboratoryforBrain,MusicandSoundResearch,Montreal,QCH2V4P3,Canada;fDepartmentofPsychology,NewYorkUniversity,NewYork,NY10003;gInstituteofNeuroscience,UniversityofBarcelona,08035Barcelona,Spain;hCentred'InvestigaciódeMedicaments,ServeideFarmacologiaClínica,HospitaldelaSantaCreuiSantPau,08041Barcelona,Spain;iDepartamentdeFarmacologiaiTerapèutica,UniversitatAutònomadeBarcelona,08193Barcelona,Spain;jPharmacokinetic/PharmacodynamicModelingandSimulation,SantPauInstitutofBiomedicalResearch,08041Barcelona,Spain;kDepartmentofNeuropsychologyandPsychopharmacology,MaastrichtUniversity,6229Maastricht,TheNetherlands;andlInstitucióCatalanadeRecercaiEstudisAvanats,08010Barcelona,SpainEditedbySolomonH.
Snyder,TheJohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,andapprovedDecember14,2018(receivedforreviewJuly12,2018)Understandinghowthebraintranslatesastructuredsequenceofsounds,suchasmusic,intoapleasantandrewardingexperienceisafascinatingquestionwhichmaybecrucialtobetterunderstandtheprocessingofabstractrewardsinhumans.
Previousneuroimagingfindingspointtoachallengingroleofthedopaminergicsysteminmusic-evokedpleasure.
However,thereisalackofdirectevidenceshowingthatdopaminefunctioniscausallyrelatedtothepleasureweexperiencefrommusic.
Weaddressedthisproblemthroughadoubleblindwithin-subjectpharmacologicaldesigninwhichwedirectlymanipulateddopaminergicsynapticavailabilitywhilehealthyparticipants(n=27)wereengagedinmusiclistening.
Weorallyadministratedtoeachparticipantadopamineprecursor(levo-dopa),adopamineantagonist(risperidone),andaplacebo(lactose)inthreedifferentsessions.
Wedemonstratethatlevodopaandris-peridoneledtooppositeeffectsinmeasuresofmusicalpleasureandmotivation:whilethedopamineprecursorlevodopa,comparedwithplacebo,increasedthehedonicexperienceandmusic-relatedmotivationalresponses,risperidoneledtoareductionofboth.
Thisstudyshowsacausalroleofdopamineinmusicalpleasureandindicatesthatdopaminergictransmissionmightplaydifferentoradditiverolesthantheonespostulatedinaffectiveprocessingsofar,particularlyinabstractcognitiveactivities.
music|dopamine|reward|pleasure|motivationAfascinatingaspectofhumansistheircapacitytoexperiencefeelingsofpleasurefromhighlycomplexpatternsofaudi-toryorvisualstimulationsuchasmusicandartwork(1–4).
In-triguingly,asitisthecaseformusic,theseactivitiesdonotprovidesurvivalvalues,asprimarypleasures(suchasfoodorsex)do,thusraisingquestionsabouttheultimategoalofthereward-relatedsignalstheycaninduceinmosthumansandtheneuralcircuitsunderlyingsuchparticularpleasure.
Previousresearchhasconsistentlyshownthatmusic-evokedpleasureisaccompaniedbyphysiologicalchangesintheauton-omousnervoussystem,aswellasmodulationofthemesolimbicrewardpathway,whicharesimilartothosefoundinresponsetoprimary(suchassexorfood)andsecondaryrewards(e.
g.
,money)(refs.
5–17;seealso,refs.
18and19).
Notably,aPETstudy(11)foundthat,similartotheprocessingofbiologicallyrelevantrewards,preferredmusicinducesdopaminereleaseinstriatalregions,particularlyinthenucleusaccumbens(NAcc)andthecaudate.
Thesefindingshaveledtoamodelwherebythere-cruitmentofdopaminergiccircuitsbymusic—throughcommuni-cationwithsensoryandcognitiveareasinvolvedintheprocessingofmusicalinformation—wouldresultintochangesinemotionalintensityandarousal,leadingtopleasurableandrewardingfeelings(20–23).
Thisviewchallengespreviousevidencefromprimaryrewardsconductedinrodents,wheredopaminergicmanipulationsshowaclearroleofdopamineinmotivationandlearning,butacontroversialfunctioninregulatinghedonicresponsesinprimaryrewardssuchasfood.
Indeed,thepleasurablecomponentofrewardhasbeenassociatedwithhedonichotspotsintheNAccregulatedbyopioids,ratherthandopaminergictransmission(23).
However,exceptforthestudyofSalimpooretal.
(11),mostre-searchonmusicalpleasurehasreliedonindirectmeasuresofneu-ronalactivation,withnospecificityforneurotransmittersystemsthatmaybeinvolved,andthustheirinterpretationabouttheactualneurochemistrysupportingmusicalpleasurehastobetakenwithcaution.
Inaddition,thereisnodirectevidenceshowingthatdo-paminefunctioniscausallyrelatedtomusic-evokedpleasure.
In-deed,mostofthestudiesconductedrelyoncorrelationalmethods,suchasneuroimaging,oronchemicallynonspecificbrainstimula-tionmethods(24).
Indeed,sofarnostudieshaveshownthatdirectmanipulationofsynapticdopaminergicavailabilitycanmodulatemusicallyinducedpleasure.
Thus,itremainselusivewhetherdopa-minereleaseandtheengagementofdopaminergiccircuitsSignificanceIneverydaylifehumansregularlyseekparticipationinhighlycomplexandpleasurableexperiencessuchasmusiclistening,singing,orplaying,thatdonotseemtohaveanyspecificsurvivaladvantage.
Thequestionaddressedhereistowhatextentdopaminergictransmissionplaysadirectroleintherewardexperience(bothmotivationalandhedonic)inducedbymusic.
Wereportthatpharmacologicalmanipulationofdopa-minemodulatesmusicalresponsesinbothpositiveandnega-tivedirections,thusshowingthatdopaminecausallymediatesmusicalrewardexperience.
Authorcontributions:L.
F.
,E.
M.
-H.
,R.
J.
Z.
,M.
V.
,J.
R.
,andA.
R.
-F.
designedresearch;R.
M.
A.
providedlogisticalsupport;L.
F.
,E.
M.
-H.
,A.
G.
-A.
,H.
A.
,G.
O.
,andM.
V.
performedre-search;L.
F.
,E.
M.
-H.
,andG.
O.
analyzeddata;andL.
F.
,E.
M.
-H.
,R.
J.
Z.
,P.
R.
,J.
M.
-P.
,M.
V.
,J.
R.
,andA.
R.
-F.
wrotethepaper.
Theauthorsdeclarenoconflictofinterest.
ThisarticleisaPNASDirectSubmission.
PublishedunderthePNASlicense.
SeeCommentaryonpage3364.
1L.
F.
andE.
M.
-H.
contributedequallytothiswork.
2Towhomcorrespondencemaybeaddressed.
Email:laura.
ferreri@univ-lyon2.
frorantoni.
rodriguez@icrea.
cat.
3M.
V.
,J.
R.
,andA.
R.
-F.
contributedequallytothiswork.
Thisarticlecontainssupportinginformationonlineatwww.
pnas.
org/lookup/suppl/doi:10.
1073/pnas.
1811878116/-/DCSupplemental.
PublishedonlineJanuary22,2019.
www.
pnas.
org/cgi/doi/10.
1073/pnas.
1811878116PNAS|February26,2019|vol.
116|no.
9|3793–3798NEUROSCIENCEPSYCHOLOGICALANDCOGNITIVESCIENCESSEECOMMENTARYDownloadedbyguestonDecember4,2020observedinpriorstudiesisactuallycausing/facilitatingthepleasureweexperiencefrommusicor,incontrast,itisaconse-quenceofthatpleasure,engagingdopamine-relatedlearningandmotivationalsystemsasithasbeenshowninanimalstudiesusingprimaryrewards.
Furthermore,certainauthorshavedistinguishedbetweenvariouskindsofpleasures,rangingfrommoresensory-based,mastery-competencerelated,tomoreaesthetic(refs.
25–27;seeref.
28forarecentdiscussion).
Althoughdopaminemightnotbedirectlyinvolvedinmoresensorypleasurableexperiences,itcouldhoweverintertwinedifferentiallyorinamorecomplexwayintheprocessingofdiversetypesofpleasures,ascouldbethecaseinaestheticexperiences(29).
Directlymanipulatingdopa-minergictransmissionwouldthencriticallyshedlightontheneurobiologyandneurochemistryunderpinningrewardresponsestomusic.
Morebroadly,thisapproachwouldalsodisentanglethecausalroleofthedopaminergicsystem,characterizedbyimpor-tantdifferencesacrossspecies(30,31),inthepleasurablere-sponsesassociatedwithabstractrewardsinhumans.
Weaddressedthisquestionthroughadoubleblindwithin-subjectpharmacologicaldesigninwhichwedirectlymanipulateddopaminergicsynapticavailabilitywhilehealthyparticipantslis-tenedtoself-selectedandexperimenter-selectedmusicalexcerpts(24).
Therefore,weorallyadministratedtoeachparticipantado-pamineprecursor(levodopa),adopamineantagonist(risperidone),andaplacebo(lactose)inthreedifferentsessions(separatedbyatleast1wk).
Thedopamineprecursorlevodopadoesnotin-discriminatelyandmassivelyenhancetonicdopaminelevelsasotherdopamine-enhancingdrugsdo—likemethylphenidateord-amphetamine.
Incontrast,levodopaisrapidlytakenupbydopaminergicneurons,tobetransformedintodopamineandstoredinvesicles,enhancingsynapticdopaminelevelsinassociationwithstimulus-elicitedresponses.
RisperidoneisadopaminergicantagonistthatinterfereswithdopaminergicneurotransmissionbybindingtoaseriesofdopaminereceptorsknownasD2-likereceptors(32).
Wemeasuredpleasureresponsesthrough(i)aphysiologicalmeasureofarousal,electrodermalactivity(EDA),whichisagoodobjectiveindicatorofthehedonicimpactofmusic(19,33);and(ii)subjectiveratingsoftheexperiencedpleasure(real-timeratingsandgeneralpleasureratingsprovidedaftereachsong).
Motivationalresponsesweremeasuredbyaskingparticipantshowmuchoftheirownmoneytheywerewillingtospendforeachsong,usingapreviouslyvalidatedauctionparadigm(12,24).
Tocontrolforotherpossibledopaminergic-dependentmodulations,participantswererequestedtoprovide,foreachexcerpt,subjectiveratingsofemotionalvalence,arousal,andfa-miliarity.
Crucially,tocontrolfortheactualimplicationofrewardprocesses,wealsoemployedanonmusiccondition,themonetaryincentivedelay(MID)paradigm,awell-establishedandexten-sivelyusedprotocolabletoactivatethedopaminergicsystem,whichwasthefocusofstudyhere(19,34,35).
Wepredictedthatifdopamine,beyonditsroleinlearningandmotivation,playsacausalroleinmusic-evokedpleasure,levodopaandrisperidoneadministrationshouldleadtooppositeeffectsinmeasuresofbothmusicalpleasureandmotivation:whilethedopamineprecursorlevodopashouldincreasethehedonicexperienceandthemusic-relatedmotivationalresponses,risperidoneshouldleadtoareductionofboth.
Incontrast,ifdopamineonlyplaysaroleinmotivationaspreviouslydescribedinprimaryrewards,thepharmacologicalinterventionshouldleavepleasurereactionsintactandjustmodulatemusic-relatedmotivationalresponses.
ResultsListeningtopleasurablemusicisoftenaccompaniedbymea-surablebodilyreactionssuchasgoosebumpsorshiversdownthespine,commonlycalled"chills"or"frissons.
"Chillsaregenerallyusedasindicatorsofmusicalpleasure,althoughnoteverybodyexperienceschillsinresponsetomusic.
Inthecurrentexperi-ment,16(outof27)participantsreportedchillsduringtheplacebosessionwitheithertheirownfavoritemusicorourmusicselection.
Weexaminedthetimethesespecificparticipantsreportedchillsacrosssessionstoassesstheeffectsofthephar-macologicalinterventionsonchillresponses.
Tonormalizethesevaluesacrossparticipants(24),wecomputedchangeswithre-specttotheplacebointheamountoftimetheseparticipantsreportedchillsduringmusiclistening(i.
e.
,self-selectedandexperimenter-selectedexcerpts),followingbothlevodopaandrisperidoneadministration(butseeSIAppendix,Figs.
S1–S3forcompleterepresentationofthethreepharmacologicalsessionsandSIAppendix,Fig.
S4fordistributionofindividualresponsestodrugs).
AWilcoxonsigned-ranktestindicatedthatchillre-spondersspentmoretimereportingchillsfollowinglevodopathanrisperidone(Z=2.
341,P0.
173,Wilcoxonsigned-ranktests,seealsoSIAppendix,Fig.
S5).
Pharmacologicalinterventions(i.
e.
,drugs)bidirectionallyaffected(i.
e.
,higherpleasureunderpre-cursor,lowerunderantagonist)bothtypesofexcerptsinthesameway.
Importantly,thiseffectwasnotduetoageneralre-ductionofratingsunderrisperidone,asnosignificantdifferencesintotaltimereportingreal-timeratingswerefoundwhencom-paringthetwodrugs(Z=0.
952,P=0.
341,Wilcoxonsigned-ranktest).
Thesedrugeffectsdidnotdifferbetweenmenandwomen(allP>0.
706,Kruskal–WallisHtests).
WethenevaluatedchangesacrosssessionsinEDAassociatedwithreal-timeratingsofpleasureprovidedbytheparticipants.
PreviousstudieshaveshownthatlisteningtopleasurablemusicisgenerallyaccompaniedbyincreasesofEDAwhicharemodu-latedbytheintensityoftheexperiencedpleasure.
Thus,EDAassociatedwithhighpleasurablemusicalexcerptshasbeengenerallyusedasanobjectivemeasureofmusicalpleasure.
Therefore,wecomputedphysiologicalvaluesassociatedwithhigh-pleasuremusiclisteningperiodsbysubtractingchangesinEDAfollowinglow(real-timeratings1and2)tohighpleas-antnessratings(i.
e.
,refs.
3and4).
Placebo-correctedEDAval-uesassociatedwithhigh-pleasurestatesduringmusiclisteningshowedanincreaseunderlevodopa,significantlydifferentfromthedecreaseobservedunderrisperidone[effectofdrug(levodopa/risperidone),t(25)=2.
261,P=0.
033,pairedttest](Figs.
1Band2A).
NoEDAmodulationswereobservedduringabaselinerestperiod(beforethemusiclisteningtask).
Importantly,theseresultsindicatethatpharmacologicalinterventionsdidnotin-ducechangesinEDAitselfnorgenerallyinEDAresponsetomusic,butrather,affectedthesignalassociatedwithhighhe-donicresponsestomusic.
Inaddition,wealsoanalyzedtheav-erageEDAwhilelisteningtomusic(thusaveragingthe45sofmusiclisteningforallsongslistenedto)oneachsession.
WedidnotfinddifferencesinEDAamplitudefortheentiredurationofthesongsfollowinglevodopaorrisperidone[t(25)=0.
873;P=0.
391,pairedttest].
ThisresultindicatesthatthedopaminergicmanipulationdidnotleadtotonicchangesinEDAwhilelisteningtomusic,butratherspecificallymodulatedtheamplitudeofphasicEDAinresponsetohighlypleasantsectionsofmusic.
Forthecontrolmonetaryrewardtask(MID),andsimilarlytomusiclis-tening,adrug-dependentmodulationeffectwasobservedforhighincentivecondition.
EDAactivityassociatedwithhighmonetarygainsresultedinincreasedanddecreasedconditionsunder3794|www.
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org/cgi/doi/10.
1073/pnas.
1811878116Ferrerietal.
DownloadedbyguestonDecember4,2020levodopaandrisperidone,respectively[t(26)=2.
868,P=0.
008,pairedttest](Fig.
2B),whilenosignificantdifferenceswereob-servedduringtheneutral(i.
e.
,norewarding)condition[t(26)=0.
926,P=0.
363),pairedttest].
Next,wetestedwhetherdopaminergicmanipulationinflu-encedparticipants'aestheticjudgmentsprovidedaftereachsong(from1=nopleasantnessto5=intensepleasantness).
Fol-lowingthesamerationaleaswiththepreviousanalyses,wecomputedpercentofchangefollowingrisperidoneorlevodopaadministrationwithrespecttoplacebo.
Theanalysisrevealedamarginaldifferencebetweendrugs:individualstendtoreporthigherlikingratesfollowinglevodopathanrisperidone(Z=1.
947,P=0.
052,Wilcoxonsigned-ranktest).
Nosignificantchangeswereobservedbetweendrugsforothersubjectiverat-ingsprovidedaftereachsong,i.
e.
,familiarity,arousal,andemotionalvalence(allP>0.
105Wilcoxonsigned-ranktests).
Finally,andimportantlyforourhypothesis,thepharmaco-logicalinterventiondidmodulateparticipants'willingnesstopayfortheexperimenter-selectedmusic:individualssignificantlybidmoremoneyunderlevodopathanunderrisperidone(Z=2.
435,P=0.
015,Wilcoxonsigned-ranktest).
Aswasthecaseforpleasureresponses,motivationalrewardresponses(monetarybids)increasedunderdopaminergicstimulationanddecreasedunderdopaminergicinhibitionrelativetobaseline(Fig.
1C).
Inlinewithresultsinreal-timeratings,thegeneraldrugeffectonmotivationalresponsesdidnotdifferbetweenmenandwomen[χ2(1)=0.
462,P=0.
497,Kruskal–WallisHtest].
DiscussionOverall,ourresultsstraightforwardlyrevealedthatpharmacologi-calinterventionsbidirectionallymodulatedtherewardresponseselicitedbymusic.
Inparticular,wefoundthatrisperidoneimpairedparticipants'abilitytoexperiencemusicalpleasure,whereaslevo-dopaenhancedit.
Accordingly,emotionalarousalcorrespondingtohigh-pleasurereal-timeratings,asindexedbychangesinEDA,washigherunderthedopamineprecursorandlowerunderthedopa-mineantagonistcomparedwithplacebo.
ThesefindingsparallelthoseobservedinthecontrolMIDtask,whereEDAincreasedunderlevodopaanddecreasedunderrisperidoneinresponsetohigh-rewarding,butnottoneutralnonrewardingmonetarycues.
Finally,participantswerewillingtospendmoremoneyunderlevodopathanunderrisperidone,indicatingthattheyweremoremotivatedtolistentothemusicagainwhenpromotingthedopa-minergictransmissionthanwhenblockingit.
PreviousstudieshaveconsistentlyshowntheimplicationofthemesolimbicrewardsystemforbothhedonicandmotivationalresponsesusingPET(5,6,11,35),fMRI(7–17),andtranscranialmagneticstimulation(TMS)(24).
However,exceptforref.
11,noneofthesestudieswerespecifictodopaminetransmission,andallwerecorrelationalexceptforref.
24,whichhoweverattemptedtoindirectlymodulatedopaminebymeansofTMS.
Here,weprovidecausalevidencefortheimplicationofthedopaminergicsysteminmusicalrewardbydirectlyalteringdo-paminergicfunction.
Severalfindingssupportthatourpharma-cologicalmodulationsspecificallyaffectedrewardresponses,ratherthanamoregeneralmodulationofparticipants'arousalorwell-being.
First,resultsfromthecontrolMIDtask,previouslyrelatedtospecificbrainactivityanddopaminereleaseintheNAcc(34,36),confirmapharmacological-dependentmodula-tionoftherewardsystem.
Iftheinterventionwasaffectingdopamine-dependentrewardresponses,changesshouldbepre-sentinadopamine-dependenttasksuchastheMID.
Adminis-trationofdopamineprecursorwasindeedassociatedwithanincreaseinEDAforhighcomparedwithlowmagnitudeofmonetaryreward-predictingcues,andthisresponsedecreasedunderrisperidone.
Inaddition,neutraltrials,inwhichpartici-pantsdidnotloseorwinmoney,wereusedasanegativecontroltoascertainwhetherpharmacologicalmodulationwasconfinedtoreward-relatedprocesses,andthusruleoutunspecificdrugeffectsonbaselinedopaminergictone.
Crucially,nodifferencesacrossconditions(i.
e.
,drugs)werefoundfortheneutralcondi-tion,indicatinganinteractionbetweenrewardprocessingspe-cificallyanddopaminergicmodulation.
Second,EDAvaluesweresimilarlymodulatedinresponsetohigh-comparedwithlow-rewardingmusicalexcerpts,butnodifferencesacrossses-sionswerefoundinthebaselinecondition.
Finally,atthebe-haviorallevel,onlythereward-relatedsubjectiveratingsweremodulatedbypharmacologicalinterventions,whilenosignificantchangesinemotionalvalence,arousal,andfamiliarityratingswerefoundacrosssessions.
Thisisinlinewithrecentfindingsonwordlearning[sameinterventions,sameindividuals(37);par-ticipantscompletedthewordlearningtaskafterourmusicpara-digm]showingthatthebehavioralratingsassociatedwithrewardduringlearning,butnottheonesrelatedtoaneutralconditionortoarousal,wereaffectedbythepharmacologicalinterventionsinthesamemannerastheonesreportedhere.
Altogether,thesepointsofferconvergingevidencethatourfindingspointedlyreflectadrug-dependentmodulationofrewardexperienceandexcludeanunspecificandconfoundinggeneraldrugeffectaf-fectingparticipants'healthormoodstate.
Inthisvein,BerridgeandKringelbach(23)describethreeinterconnectedbutneurobiologicallydifferentpsychologicalcomponentsofreward:"liking,"namelythehedonicimpact,plea-surablecomponent;"wanting,"namelythemotivationforre-ward;and"learning,"namelytheassociations,representations,Fig.
1.
Changeswithrespecttoplaceboconditionunderlevodopaandrisperidone(means±SEM)formusic-relatedrewardresponses.
(A)Amountoftimereportingchills,highpleasure(HP),lowpleasure(LP),andnoplea-sure(NP)real-timeratings(i.
e.
,whilelisteningtoeachsong,includingself-andexperimenter-selectedsongs;e.
g.
,risperidoneandlevodopa,respectively,decreasedandincreasedby43%and65%thetimereportingchillswithrespecttotheplacebocondition).
Chillsvaluesincludechillsrespondersonly;HP,LP,andNPvaluesincludetheentiresample.
(B)EDAchangesassociatedwithhigh-pleasurereal-timeratings.
(C)Motivationalratings,i.
e.
,willingnesstospendmoneyforeachexcerpt.
*P<0.
05.
Fig.
2.
EDAchanges(means,solidlines±SEM,lightercolors)overtimewithrespecttoplaceboconditionunderlevodopa(green)andrisperidone(red)duringmusiclisteningassociatedwithhigh-rewardingexcerpts(i.
e.
,highminuslowreal-timelikingrates)(A)showsverysimilarresponsestoEDAchangesassociatedwithhigh-rewardingcues(i.
e.
,highmonetarygainminuslowmonetarygain)intheMIDcontroltask(B).
Ferrerietal.
PNAS|February26,2019|vol.
116|no.
9|3795NEUROSCIENCEPSYCHOLOGICALANDCOGNITIVESCIENCESSEECOMMENTARYDownloadedbyguestonDecember4,2020andpredictionsaboutfuturerewardsbasedonpastexperiences.
Ifontheonehandtheroleofdopamineinwantingandlearningcomponentsiswidelyaccepted,ontheotherhand,itsfunctioninregulatinghedonicresponsesappearscontroversial.
Forexample,nearcompletedestructionofnigrostriatalandmesolimbicdopa-minergicneuronsledtonochangesinpleasurealthoughitwasabletocompletelyabolishrats'interestinfood(38).
Nevertheless,thestudiesinvestigatingrewardprocessingusuallydealwithpri-maryrewards,suchasfood,andanimalmodels(e.
g.
,refs.
39–41).
Here,incontrast,studyingresponsestoabstractrewardsinhumansubjects,weshowthatmanipulationofdopaminergictransmis-sionaffectsboththepleasure(i.
e.
,amountoftimereportingchillsandemotionalarousalmeasuredbyEDA)andthemotivationalcomponentsofmusicalreward(moneywillingtospend).
Thesefindingssuggestthatdopaminergicsignalingisasinequanonconditionnotonlyformotivationalresponses,ashasbeenshownwithprimaryandsecondaryrewards,butalsoforhedonicreac-tionstomusic.
Thisresultsupportsrecentfindingsshowingthatdopaminealsomediatestheperceivedpleasantnessattainedbyothertypesofabstractrewards(37)andchallengespreviousfindingsinanimalmodelsonprimaryrewards,suchasfood(42,43).
Musicalpleasure,incontrasttowhatoccurswithprimaryre-wards,maydependonmodulationsofemotionalarousalandintensity(6)triggeredbyexpectationsandsurprisesdrivenbythepresenceofstructuralandtemporalregularitiesinmusicalpat-terns(12,44,45),associativeconditioning(29,46),orepisodicmemory(47)amongothers(48–50).
Importantly,mostoftheseelementsrelyoncognitivecomputationsdrivenbydopaminergictransmission:fromdopamine'sroleinlearningtoitsroleinmemoryorattention(seeref.
31).
Inthisregard,levodopahasbeenshowntoenhancecognitivefunctionespeciallyinmemoryandlearning(51–53),butalsoinotherdomains,suchassemanticactivationandpriming(54–56),andevenfeedback-basedgrammarlearning(57).
Onthecontrary,theblockadeofD2receptorsmayleadtocognitiveimpairments(58),especiallyinexecutivefunctionsandmemory(59,60).
Importantly,drugintakeonlyinfluencedreward-relatedratingssuchasreal-timeratingsofpleasure,physiologicalresponsetopleasure,andparticipants'willingnesstobuyourmusicselection,butitdidnotdistortotherfunctionsimportantformusicperception.
Drugintakedidnotaltertheirabilitytorecognizefamiliarmelodies—indicatingthatthedrugsdidnotinterferewiththerecallandrecognitionofpreviousmusicexperiences—anditdidnotmodulateperceivedemotionalvalenceorgeneralarousal,whichmayberelatedtoconcreteacousticattributessuchaspitch,mode,tempo,orloudness(49,50).
Thus,onepotentialinterpretationofourresults,togetherwithpreviousevidenceinataskinvolvingimplicitrewardthroughsuccessfullearning(37),isthatdopamine-dependentcognitiveprocessessuchaslearningandmemory—modulatedupanddownbylevodopaandrisperidone,respectively—maysub-stantiallyinfluencethepleasuregeneratedbyabstractactivities.
Thisviewdoesnotnecessarilyimplythatdopaminergictransmissiongeneratesthehedonicexperienceperse.
Itcouldbegeneratedbyotherneurotransmittercircuitriesthatinteractwiththedopaminesystem.
Previousanimalstudieswithprimaryrewardshaveshowntheexistenceofso-called"hedonichotspots"inthebrainthatareresponsibleforthegenerationofpleasure(61).
Thesehedonichotspots,foundalongtherewardcircuitryintheNAcc,insula,orbitofrontalcortex,andventralpallidum,aremodulatedbyopioidtransmission(62).
Bothopioidanddopa-minesystemsarecolocalizedandtheyinteractincomplexways.
Whileopioidmodulationofdopamineneuronshasbeenexten-sivelystudiedduetoitsrelevanceinaddiction(63–66),afewstudieshaveexploreddopaminemodulationofendogenousopi-oidpeptidereleases(67–69).
Interestingly,dopamine-stimulatingdrugs,actingviaD2dopaminereceptors,cancausethereleaseofendogenousopioidpeptideswithintheNAcc(69).
Thus,whiledopaminergicfunctionmaybeimportantandanindispensablestepformusicalpleasure,theultimatesystemresponsiblemightbetheopioidcircuit,asoccursinprimaryrewards.
However,theexactmechanismsandconsequencesofthisinteractionarestillunknownanditisuncleartowhatextentdopaminergicmodulationofopioidreleasemayaffecthedonichotspotsinparticular[representingaround10%oftheNAccneurons(62)].
Inthisregard,Malliketal.
(70),haverecentlyshownthatpharmacologicalreductionofopioidtransmissionvianaltrexoneledtoageneralreductionofpleasur-ableresponsestobothpleasantandnonpleasantmusic.
However,thefactthatthemanipulationalsoaffectedpleasureresponsesinnonpleasantmusic—inwhichnoopioidreleasewouldhavebeenconsequentlyexpected—doesnotallowtherulingoutofunspecificdrugeffects.
FurtherpharmacologicalinterventionsandPETstudiestargetingopioidanddopaminetransmissionarewarrantedtobetterunderstandthecomplexinterplaybetweenthesetwoneurotransmittersystemsinmusicalpleasure.
Conversely,analternativeexplanationofourresultsisthatthefeelingsofpleasureevokedbyabstractrewards,andmusicinparticular,maydifferfromthoseevokedbyprimaryrewardsandthusdrivenbydifferentpsychologicalandneurobiologicalsub-strates(refs.
25–27,butseeref.
28).
Indeed,theexistenceofdiversetypesofpleasurableexperiencesinhumansremainscurrentlyanopendebate(25–27).
Aspreviouslymentioned,music-evokedpleasureisdriven,amongotherthings,byitsintrinsicabilitytoinducefeelingssuchasanticipationandeuphoria.
Remarkably,previousstudieshaveshownthatdopamine-stimulatingdrugssuchascocaineoramphetamineelicitsimilarpositiveaffectivestatesinhumans(71).
DirectelectricalbrainstimulationoftheNAcchasbeenshowntoelicitsmilesandeuphoria(72).
Similarly,microin-jectionsofpsychostimulantsintotheNAccelicit50-kHzultrasonicvocalizationsinrats,proposedtoreflectapositiveappetitiveaf-fectivestate(73).
Althoughthesebehaviorshavebeenrelatedtothemotivationalaspectsofreward,onemaywonderifthesefeel-ingsmaybeinterpretedaspleasurable.
Inthisregard,dopaminereleasesdrivenbymusicmightincreasetheattractivenessofthesurroundingenvironmentandthemotivationtopursueanddesiresimilarexperiencesleadingtopositivefeelingsthatareattributedto"pleasurable"(12,21).
Thus,subjectiveexperienceofmusicalpleasure,similartoemotions(74),mayarisefrommotivationalsignalsandcognitiveappraisalratherthanthroughtheengagementofthehedonichotspotspreviouslyidentifiedwithprimaryrewards.
Inconclusion,thepresentfindingsshowacausalroleofdo-pamineinmusicalpleasureandshedlightontheroleofthehumandopaminergicsysteminabstractrewards.
Morebroadly,theseresultsindicatethatdopaminergictransmissionmightplaydifferentoradditiverolesthantheonespostulatedinaffectiveprocessingsofar,particularlyinabstractcognitiveactivities.
MaterialandMethodsParticipants.
ThestudywascarriedoutinaccordancewiththeDeclarationofHelsinkiandtheInternationalConferenceonHarmonization'sGoodClinicalPracticeGuidelines.
Allvolunteersgavetheirwritteninformedconsentforparticipationbeforeanyprocedure.
Twenty-ninevolunteers(seeref.
37andSIAppendixforprescreeningandselectioncriteria)wererandomizedandcompletedthestudy(19females,meanage=22.
83±4.
39)inexchangeformonetarycompensationaccordingtoSpanishlegislation.
Theoriginalsamplesizewaschosentobe30participants,but1participantdroppedoutearlyinthestudyandonly29finishedit.
SelectedparticipantswerealsotestedwiththeextendedversionoftheBarcelonamusicrewardquestionnaire(BMRQ)(ref.
19,seealsoref.
75).
Noparticipantspresentedsignsofamusia.
Twoparticipantsscoredwithintherangesconsideredtoindicatemusicalanhedo-nia(BMRQ=61and64)andgeneralanhedonia(physicalanhedoniascale=19and24),andwerethereforeexcludedfromtheanalysisherereported(totaln=27,18females,meanage=23±4.
48,meanBMRQ=77.
07±9.
89).
Procedure.
Thisdouble-blind,crossover,treatmentsequence-randomizedstudy(SIAppendix,TableS3)wasperformedattheNeuropsychopharmacologyUnitandCenterforDrugResearchoftheSantaCreuiSantPauHospitalof3796|www.
pnas.
org/cgi/doi/10.
1073/pnas.
1811878116Ferrerietal.
DownloadedbyguestonDecember4,2020Barcelona.
Experimentaltestingtookplaceoverthreesessions.
ThestudywasapprovedbytheethicscommitteeoftheHospitaldelaSantaCreuiSantPauandtheSpanishMedicinesandMedicalDevicesAgency(EudraCT2016–000801-35).
Foreachsession,participantsarrivedatthehospitalunderfastingconditionsandweregivenalightbreakfast.
Subsequently,theyreceivedinadouble-blindmaskedfashionacapsulecontainingthetreatment(seeSIAp-pendixformoredetailedinformationaboutdrugdoses):adopaminergicprecursorwithaninhibitorofperipheraldopaminemetabolism(levodopa,100mg+carbidopa,25mg),adopaminereceptorantagonist(risperidone,2mg),oraplacebo(lactose).
Onehourafterdrugadministration,theexper-imentalsessionstarted.
After3minofbaseline(silence,relaxed,openeyes),themusicrewardtasktookplace.
Thesessionthencontinuedwithothertasks(musicalmemoryandlanguagelearning,notreportedinthisarticle)andendedwiththecontroltask,theMID.
Thetotaldurationofthemusicrewardtaskwasabout15min.
ThetotaldurationoftheMIDtaskwasabout20min.
Thetotaldurationoftheexperimentalsessionwasabout2.
5h.
Next,partic-ipantsspenttheirtimeinarestingroomandwereallowedtoleavethehospitalafter6hfromthetreatmentadministration.
Atleast1wkpassedbetweenonesessionandthenext.
MusicTask.
Participantswererequestedtolistentothe10popsongsandtotheirfivefavoritemusicalexcerptsfollowingasimilarproceduretothatinref.
24.
Theorderofpresentationofmusicalexcerptswithineachgroupofsongswasrandomizedacrossparticipants.
Beforestartingwitheachsession,atrialpopsong("Sinsaberporqué"byVanessaMartín;neitherthesongnortheperformerwaspartofthemusicselectedfortheexperiment)wasplayedtomakesurethateachparticipantunderstoodthetaskandthesubjectiveratingstoprovide.
Participantswereseatedinacomfortablechairinfrontofascreen.
Eachexcerpt(seeSIAppendixfordetailsaboutmusicalstimuli)waspresentedviaheadphoneswhileamusicalnote(whitesymbolonblackbackground)appearedonthescreen.
Duringeachexcerpt,participantswereaskedtoindicateinrealtimethedegreeofpleasuretheywereexperiencingwhilelisteningtothemusic.
Participantswereinstructedtopressoneoffouravailablebuttonsonakeyboard(1=nopleasure,2=lowpleasure,3=highpleasure,4=chills)dependingonthepleasuretheywereexperiencing.
Theywereinstructedtochangetheratingbypressinganotherbuttonassoonastheyfeltthattheirexperiencedpleasurewaschanging.
Thesameprocedurehasbeenextensivelyusedinpreviousstudiesonmusicalrewardprocessing(11,17,19,24,33).
Similarly,aftereachexcerpt,participantsprovidedad-ditionalratingsonthatsongbyansweringquestionsappearingonthescreen.
Inparticular,theywereaskedtoratethegeneralpleasantness(from1=nogeneralpleasantnessto5=intensegeneralpleasantness),arousal(from1=veryrelaxingto5=veryarousing),andemotionalvalence(from1=verysadto5=veryhappy)theyfeltinresponsetoeachexcerpt.
Forpopmusic,participantswereadditionallyaskedtoratethefamiliarityofeachsong(from1=completelyunfamiliarto5=IhavethesonginmyPC,mp3,Spotifyplaylist,etc).
Rewardratings(i.
e.
,real-timeandpleasantnessratings)maybeconsideredmeasuresof"liking"processes.
Tohavea"wanting"motivationalrating,weintroducedanauctionparadigminwhichpartici-pantscouldpurchasethepopmusicwiththeirownmoney,asanindicationthattheywantedtohearitagain(adaptedfromrefs.
12and24).
Foreachexperimenter-selectedsong,participantscouldindicatewhethertheywerewillingtopayV0,V0.
29,V0.
99,orV1.
29(seerefs.
12and24andSIAp-pendixformoredetailedinformationabouttheauctionparadigm).
MIDTask.
TheMIDtaskconsistedof35trials.
Atthebeginningofatrial,participantssawoneoffivecueshapes(2s),signalingwhetherparticipantswereplayingtowinpotentialrewards(14trials;denotedbycircles)ortoavoidlosingpotentiallosses(14trials;denotedbysquares).
Themagnitudeofthepossibleoutcomeswasindicatedusinghorizontallinesinthecue,andcouldbelarge(1V,threehorizontallines,seventrialsforeachvalence)orsmall(0.
1V,onehorizontalline,seventrialsforeachvalence).
Sixsecondsaftercueoffset,participantshadtorespond,asfastaspossible,withabuttonpresstoawhitetargetsquarethatappearedforavariablelengthoftime(target,160–260ms).
Inwintrials,ifparticipantsrespondedontimetheyobtainedthecorrespondingamountofmoney.
Incontrast,inlosstrials,ifparticipantsrespondedontimetheyavoidedlosingthecorrespondingamountofmoney.
Sixsecondsafterparticipants'response,avisualfeedbackonthescreennotifiedwhethertheyhadwonorlostmoneyduringthattrial.
Eightsecondslater,anothercuewaspresented.
Additionally,aneutralcondition(seventrials;denotedbyatriangle)inwhichparticipantswerenotplayingformoneywasalsoincluded.
Taskdifficulty,basedonreactiontimescollectedduringthepracticesession,wassetsuchthateachparticipantcouldsucceedon66%ofhis/hertargetresponses.
Trialtypeswererandomlyorderedwithineachsession.
AnalysisofBehavioralRatingsandEDA.
Thepercentageofchangeunderrisperidoneandlevodopawithrespecttoplacebowascomputedforeachmeasure.
Placebo-correctedvaluesofsubjectiveratings(i.
e.
,realtimeandratingsprovidedaftereachsong)betweenpharmacologicalsessions,andgenderdifferencesingeneraldrugeffects(SIAppendix,Figs.
S4andS5)werecomparedusingnonparametrictests(i.
e.
,Wilcoxonsigned-rankandKruskal–WallisHtests,asfullydescribedinSIAppendix).
EDAwasrecordedfollowingtheproceduresdescribedinref.
17andanalyzedbycomputingtheproportionofamplitudechangescorrespondingtohigh-andlow-pleasureresponses,forbothmusicandMIDtasks.
Placebo-correctednormalizedvalueswerecom-paredbetweenpharmacologicalsessionsusingpaired-samplettests(allde-tailedinformationreportedinSIAppendix).
ACKNOWLEDGMENTS.
WethankthestaffoftheCentred'InvestigaciódelMedicamentdel'InstitutdeRecercadel'HospitaldelaSantaCreuiSantPau(HSCSP)fortheirhelp.
ThepresentprojecthasbeenfundedbytheSpanishGovernment(MINECOGrantPSI2011-29219toA.
R.
-F.
andAP2010-4179toP.
R.
).
L.
F.
waspartiallysupportedbyaMorelli-Rotarypostdoctoralfellow-ship.
M.
V.
waspartiallysupportedbyFondodeInvestigaciónenSaludthroughGrantCP04/00121fromtheSpanishHealthMinistryincollabora-tionwithl'InstitutdeRecercadeHSCSP;sheisamemberofCentrodeInvestigaciónBiomédicaenRedSaludMental(fundedbytheSpanishHealthMinistry,InstitutodeSaludCarlosIII).
H.
A.
wassupportedbyagrantfromtheSpanishGovernment(BES-2013-067440).
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3798|www.
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