AnaisdaAcademiaBrasileiradeCi - PDF document

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AnaisdaAcademiaBrasileiradeCiências(2009)81(3):521-538(AnnalsoftheBrazilianAcademyofSciences)ISSN0001-3765www.scielo.br/aabcParadoxicalSleepDeprivation:neurochemical,hormonalandbehavioralalterations.Evidencefrom30yearsofresearchSERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLODisciplinadeMedicinaeBiologiadoSono,DepartamentodePsicobiologia,UniversidadeFederaldeSãoPauloEscolaPaulistadeMedicina(UNIFESP/EPM),RuaNapoleãodeBarros,925,VilaClementino,04024-002SãoPaulo,SP,BrasilManuscriptreceivedonJuly25,2008;acceptedforpublicationonApril3,2009;presentedbyLUIZR.TRAVASSOSABSTRACTSleepcomprisesapproximatelyone-thirdofaperson’slifetime,butitsimpactonhealthandmedicalconditionsre-mainspartiallyunrecognized.Theprevalenceofsleepdisordersisincreasinginmodernsocieties,withsignicantrepercussionsonpeople’swell-being.Thisarticlereviewspastandcurrentliteratureontheparadoxicalsleepde-privationmethodaswellasdataonitsconsequencestoanimals,rangingfrombehavioralchangestoalterationsinthegeneexpression.Morespecically,wehighlightrelevantexperimentalstudiesandourgroup’scontributionoverthelastthreedecades.Keywords:sleep,sleepdeprivation,rebound,dopamine,erection,corticosterone,memory.INTRODUCTIONSleepoccupiesapproximatelyone-thirdofaperson’slife,butitsimpactonhealthandmedicalconditionsre-mainspartiallyunrecognized.Theprevalenceofsleepdisordersisincreasinginmodernsocieties,wherecon-stantexposuretoarticiallightandinteractiveactivities,suchastelevisionandtheinternet,combinewithsocialandeconomicpressurestoshortenthetimespentasleep.Mostsleepdisorders,suchassleepapnea,periodiclegmovementsdisturbance,restlesslegssyndrome,jetlag,andinsomnia,leadtosleepdeprivation.Sleepde-privationperserepresentsacommontypeofstressthatcanhaveharmfulphysiologicalconsequences,possiblyleadingtodeathinexperimentalanimals(Rechtschaf-fenetal.1983).Chronicinsomnialeadstopersistenttirednessandfrustrationduetolackofenergy.Respi-ratorypathologicalconditionsandothermedicalcondi- Incommemorationofthe75thanniversaryofEscolaPaulistadeMedicina/UniversidadeFederaldeSãoPaulo.Correspondenceto:Dr.SergioTukE-mail:stuk@psicobio.epm.brtionsthataffectsleephavepotentiallyseriouscomplica-tionsthatmayreducelifeexpectancy.Disturbancesinthesleep-wakerhythmandsleepdeprivationareincreasinglyfrequentduetoeventsthatareprogressivelymorecommoninmodernlifeinmoredevelopedcountries(Spiegeletal.1999).Manysub-jectscanbechronicallysleep-deprivedasaresultoftheircurrentlifestyle(Miróetal.2002).Sleepdepriva-tioncanleadtotrafcaccidentsduetofatigueandalter-ationsinthebiologicalrhythm.Indeed,16%ofBrazil-ianinterstatebusdriversreportedsleepinesswhiledriv-ing,withanaverageofeightnaps/trip(DeMelloetal.2000),and38%ofthosedrivershavebeendiagnosedwithobstructivesleepapnea(Santosetal.2004).Re-cently,anewlegislationwasapprovedthatwillrequirenewmedicalandpsychologicalexaminationsforallBraziliandrivers.Theseexaminationswillbeinitiallycarriedoutbyaphysicianwhospecializesintrafcme-dicine.Asaresult,itcanbeexpectedareductioninthenumberofaccidentsanddeathsresultingfromsleepyAnAcadBrasCienc(2009)81(3) 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522SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLOdriving(DeMelloetal.2009).AnepidemiologicalstudyperformedbytheDepartmentofPsychobiologyofUnifespinthecityofSãoPaulohasshownthat,in1995,27.6%(1.7million)ofinhabitantsofSãoPaulocomplainedofdifcultyinstayingasleep.Furthermore,habitualsnoringwasthemostcommoncomplaintandwasreportedbyabout20%oftheinterviewees(Piresetal.2007).In2007,obstructivesleepapneasyndromewasfoundin32.8%ofthepopulationofSãoPaulo,Brazil(S.Tuketal.,unpublisheddata).Sleephasacyclicalorepisodicphasethatalter-nateswithwakefulness.Animportantcharacteristicofsleepthatdifferentiatesitfrommostofotherstatesofalteredconsciousnessisthatitispromptlyreversible.Electrophysiologicalstudiesinthe1950sdemon-stratedthattherearetwomainstatesofsleep:non-rapideyemovement(NREM)andrapideyemovement(REM).ThelighterstagesofNREMsleep(phase1and2)appearrstandoftenalternatewithbriefepisodesofwakeful-nessbeforethedeeperNREMsleepstagessetin.NREMsleep,particularlyitsdeeperstages(phase3and4),pre-dominateearlyinthenight,whileREMsleepoccursatapproximately90-minuteintervals.Thereareusuallyfourtosixsleepcycleseachnight,and,asthenightpro-gresses,theREMepisodesbecomelonger,andNREMepisodesbecomebothshorterandlighter.NREMsleepisrecognizedbyitslowfrequencyandhighamplitude,inadditiontothepresenceofsleepspindlesandhypotoniaasregisteredonanelectroencephalogram(EEG).ResearchsuggeststhatREMsleepenablestheestablishmentofbehaviorpatternsandemotionalre-sponses.DuringREMsleep,theinformationobtainedduringwakefulnessappearstobereprocessedandin-tegratedintoexistingneuraltemplates,sothatfutureresponsescanbemodiedormaturedtoreectboththeexperienceoftheindividualandtheinherentpoten-tial(Jouvet1998).TheelectrophysiologicalfeaturesofREMsleepincluderecordingofawiderangeofde-synchronizedEEGfrequencies,lossofEMGactivityandrapideyemovement.TheEEGreectstheintensecerebralcorticalactivitythatdistinguishesREMfromNREMsleep,butthesimilarityofREMtotheEEGofwakefulnesshasledittobecalled“paradoxical”sleep(PS).Thistermhasbeenadoptedforthedescriptionofanimalsinthisreview.Acommonirregularsleep-wakescheduleisasfol-lows:restrictingsleepduringaworkingweek,leadingtoanaccrualofsleepdebt,andrepayingthedebtbysleepinglongeronweekends.Duringthesenights,thereishighsleepefciency,shortsleeplatency,andin-creaseddurationofstages3and4NREMsleep.Wakinglaterinthemorning,however,causesaphasedelaythenextday,whichisoftenfollowedbyanearlywake-uptimeatthestartoftheworkingweek.Thedurationofsleepistherebyconsiderablyshortened,andsleepdepri-vationbeginsagain(Shneerson2000).ThehomeostaticsleepdriveappearstocontrolNREMratherthanREMsleep.Sleepisnormallyen-teredthroughNREMratherthanREMsleepinadults,andanincreaseinthehomeostaticdrivewillincreasethedurationanddepthofNREMsleepattheexpenseofREMsleep.NREMsleepprovidestimeforrestorativeprocesseswithinthecentralnervoussystem(CNS)andotherpartsofthebody.Overall,NREMsleepappearstobeaphaseinwhichenergyisconservedandinwhichboththeCNSandothersystemsareabletoeitherrecoverfromtheactivityofthepreviousepisodeofwakefulnessortoprepareforthenextepisode.Currently,mostsleepdeprivationoccursintheREMphase,whichoccursdur-ingthelasthalfofthetotalsleepsession.Itisinthisphasethatmostrestorativeprocessestakeplace.ThereareseveraldifferentapproachesthatmaybetakentounderstandthefunctionalpropertiesofPS.AcommonprocedureinvolvesdeprivationofPSinvar-iousorganismsandsubsequentobservationofbehav-ioralandphysiologicalchanges.Thus,moststudiesofsleepdeprivationfocusonPSdeprivation(PSD).ThepresentpaperreviewsvariousstudiesthathaveutilizedthePSDstrategy.PSDMETHODSThePSDtechniqueentailsanarousalofexperimentalanimalsbyexternalstimulationattheonsetofeachPSperiod.Mostoftheinstrumentalmethodsutilizedtoin-ducePSDinanimalsaremodicationsofasinglemethoddevelopedbyJouvetetal.(1964)forcats,knownastheowerpottechnique.Shortlyafterward,thismethodwasadaptedtoratsbyCohenandDement(1965).Themethodconsistsofplacingaratonanarrowplatform(6.5cmindiameter)surroundedbywater.Onceha-AnAcadBrasCienc(2009)81(3) 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SLEEPDEPRIVATIONINANIMALS523bituatedtothissituation,theanimalscanobtainslowwavesleep(SWS),whereasPSisrestricted.ThelossofmuscletoneassociatedwiththeonsetofPSresultsintheanimalstouchingthewaterandawakening.In-formationregardingtheefciencyofthetechniquein-dicatesthatthedegreeofPSDmayvaryconsiderably.Thediameteroftheplatformrelativetothesizeoftheanimalseemstobemainlyresponsibleforthisvariabil-ity(SteinerandEllman1972,Mendelsonetal.1974,Hicksetal.1977).Thismethodhasbeencriticizedbecauseitsubmitstheanimaltoadditionaladversestim-ulithatcouldinduceseveraloftheeffectsobservedafterPSD.Toattenuatetheeffectsoftheseinterveningvari-ables,themultipleplatformmethodwasdeveloped.Inthisparadigm,oneratisplacedinsidealargewatertankcontainingsevenplatforms,whicheliminatestheres-trictionofmovementandallowstheanimaltoambulate(VanHulzenandCoenen1981).Thismethodwasfur-thermodiedinanattempttoeliminatethesocialiso-lationexperiencedbytheanimalinboththeowerpotandthemultipleplatformtechniques(NunesandTuk1994a).Inthisparadigm,10animalson18nar-roworwideplatforms(asacontrolforthedeprivationenvironment)areused,thusavoidingbothsocialisola-tionandmovementrestriction.Thistechniqueispro-cedurallysimpleandallowsforalargenumberofan-imalstobesleepdeprivedsimultaneously.In2000,SucheckiandTukproposedthemodiedmultipleplat-formmethod(MMPM)usingsociallystablegroups(10animalsfromonecage)insteadofanimalscomingfromseveralcages.Theresultsofthisworksuggestthatthestress-relatedvariablesoftheMMPMcanbeattenuatedinstablegroups.Regardingthecontrolgroup,mostattentionhasbeenfocusedupontheselectionofcontrolsubjects.Whenananimalisplacedonasmallplatforminthewatertank,manyeventshappeninadditiontoPSD.Forexample,theanimalisexposedtoagooddealofstress.Controlgroupsusuallyconsistofeithercage-controlan-imalsorratsplacedonawideplatform(14cmindi-ameter)underthesameenvironmentalconditions.Thislargeplatformenablestheanimaltocurlupandexpe-riencebothSWSandPSwithoutcontactingthewater.Itiscommonlyusedasacontrolfortheconfoundingfactorsinherenttothistechnique.Althoughthiscontrolmaybeappropriatetoaddressmostoftheconfoundingfactors,itremainscontroversial(Landis1996,Machadoetal.2004).Indeed,whenexposedtotheMMPM,theanimalsplacedonthewideplatformsexhibitadrenalhypertrophysimilartothatproducedbyplacementonnarrowplatforms(NunesandTuk1994a).Inaddi-tion,awideplatforminducessomedegreeofPSD,asreectedbyaugmentedreboundduringtherecov-eryperiod(Machadoetal.2004).IntherotationdiskmethodproposedbyRechtschaffenetal.(1983),non-specicconcomitantsofthistechniquearecontrolledbya“yoked”controlanimal,whichisconcurrentlyarousedwiththeexperimentalanimal(VanHulzenandCoenen1979).Inthediskmethod,whenevertheex-perimentalratbeginstosleeporentersaspecicsleepstage,thediskautomaticallyrotates,whichawakenstheexperimentalratandforcesbothratstowalkintheop-positedirectiontothedisk’srotationtoavoidthewa-ter(Rechtschaffenetal.1983).Anotherproposedcon-trolgroupforthedeprivationenvironmentconsistedofanimalslyingonagridplacedinsidethewatertank(SucheckiandTuk2000).Inthissituation,theanimalscouldliedownwithoutfallingintothewater,althoughtheirtailsmighthavedoneso.Thedatasuggestthatthisisagoodcontrol;however,sleepreboundwasobserved.Theanimalisexposedtoasimilarenvironmentwithout,intheory,beingsubmittedtoPSD.Itisimportanttonotethatonlysocialstableanimalswereplacedonthegrid,asdescribedinthesamepaper.Recently,weproposedaparadigmforchronicsleeprestrictioninratsinwhichtheanimalsaresubmittedtoascheduleof18hofsleepdeprivationwitha6hsleepwindowfor21days(Machadoetal.2005).Asaresultofthisrestriction,therewasacompletesuppressionofPSandlossofSWS,whichwerepartiallycompensatedduringthe6hsleepwindow.Ofnote,amajorsleepcon-solidationwasobservedduringthe6hsleepopportunity,reectedbyanintensereductionofawakenings.REBOUNDSLEEPTheimportanceofPStoanorganismcanbepartlyde-ducedfromrecoverysleepafterdeprivation.PSDin-variablyleadstoastrikingcompensationphenomenon,knownasthePSrebound.AccordingtoVanLuijtelaarAnAcadBrasCienc(2009)81(3) 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524SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLOandCoenen(1984),reboundsleepisdeterminedbothbyrecoveryprocessesandcircadiantiming.Thein-creases(abovebaseline)insleepdurationduringthere-coveryfromsleepdeprivationareusuallyonlyafractionofthesleeptimethatwaslost.Becauseitiswidelyassumedthatsleepishomeostaticallyregulated,manybelievethatlostsleepiscompensatedby“intensesleep”thatsatisestheunfullledsleepneedinarela-tivelyshortperiod(Rechtschaffenetal.1999).Inad-ditiontoanincreasedsleepduration,thelatencytotherstPSepisodeisshortened,andthetimespentinPSislengthened(Dement1960,Mendelsonetal.1974,Mordenetal.1967).Sleepreboundisalsoobservedinratssubmittedtodifferentstressmodalities(Tuketal.1995,Palmaetal.2000,Papaleetal.2005).Forinstance,immobilizationledtoareboundofSWSandPS,whereascoldstressproducedanexclusivereboundofSWSandfootshockpromotedsustainedalertnessduringtheanimal’srestingperiod.Together,theseob-servationsindicatethatdifferentstimulialterthesleeppatternindistinctmanners(Palmaetal.2000).EFFECTSOFPSDONBRAINNEUROTRANSMITTERSThenatureofPSDtechniqueshasledtomuchdiscus-sionaboutitsconsequences(Vogel1975,Ellmanetal.1978).Mostoftheconsequencesarebelievedtobecontrolledbycentralneurotransmittersystems.Tothatend,manyneurotransmitters,suchascatecholamines,acetylcholine,serotonin,andGABA,havebeenassoci-ated,eitheraloneorintrans-synapticrelationships,withseveralbehavioralalterations.Theseassociationssug-gestthatthebehavioralalterationsobservedafterPSDresultfromdeprivation-inducedalterationsinbrainneurotransmitterfunction.EvaluationofexperimentsthatemployedthewatertankPSDtechniqueindicatedthatthisprocedurealterssomebehaviorsthatcanbeinducedbydrugsthatactonneurotransmittersystems.TheneurochemicalbasisoftheconstellationofbehavioralchangesthatfollowPSDisnotcompletelyclear,butmanyobservationssuggestamajorroleforcentraldopamine(DA).In1978,TukandcolleaguesreportedthatPSDresultedinaugmentedapomorphine-inducedaggressionandseveralstereotypicalbehaviors,includingbiting,rearingandhypothermiainrats.Thesebehaviorsoc-curredwithgreatermagnitudeandwithsmallerdosesofapomorphineinthePSDratswhencomparedwithcontrolanimals,andhavebeenusedtostudytherespon-sivenessofDAreceptorstoagonistagents.TheauthorssuggestedthatthendingsledtothebeliefthatPSDinducedsupersensitivityofbrainDAreceptors.Shortlythereafter,furtherexperimentssupportedthehypothesisthattheexacerbatedaggressivenesselicitedbyapomor-phineinPSDratswasduetoastateofsupersensitiv-ityofpost-synapticdopaminergicreceptorsinthebrain(Tuk1981a).Thisstudyshowedthat,inadditiontoapomorphine,PSDintensiedtheeffectsoftwootherdopaminergicagonists(bromocriptineandpiribedil).Thesecondndingofthisstudywasthatco-adminis-trationofPSDandaninjectionofhaloperidol24hbe-foreapomorphineadministrationinducedmoreaggres-sivebehaviorwhencomparedtothatofratsthatwereonlysubjectedtoPSD,indicatingthatapomorphinewassignicantlymoreactiveinratssubmittedtothedou-bletreatment.Finally,administrationofhaloperidol2hbeforeapomorphineadministrationblockedtheaggres-sivebehaviorinratssubmittedeithertoPSDaloneortoPSDandaninjectionofhaloperidol24hpreviously.Thisresultfurthersupportsthehypothesisthatthepost-synapticdopaminergicreceptorsareinastateofsuper-sensitivity.Alternatively,thesedatamayindicatethatpre-synapticdopaminergicactivitywasaugmentedbytheabove-describedtreatmentregimen.Ghoshetal.(1976)reportedthatstriatalDAlevelswereincreasedafterPSD,raisingthehypothesisthatthehyperresponsive-nesstoapomorphineafterPSDcouldmerelyreectanexcessofagonisticsubstancesatthepost-synapticre-ceptors.Tuk(1981b)reportedthatsucharesponsewasnotduetoamodicationinDAturnoverorlevels,sinceitwasdemonstratedthatanimalstreatedwithL-DOPAandinjectedwithapomorphinefailedtoshowaggressivebehavior.However,PSDratspre-treatedwith-methyl-para-tyrosinecontinuedtoshowanintenseresponsetoDAagonists,suggestingthatpresynapticmechanismsarenotofprimeimportanceforthisaugmentedPSD-inducedresponse(Tuk1981b).Inalaterstudy,itwasshownthattheincreaseinapomorphine-inducedstereo-typyandaggressioninPSDratswasreversedbyDAagonistpretreatment(Tronconeetal.1988).AnAcadBrasCienc(2009)81(3) 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SLEEPDEPRIVATIONINANIMALS525InteractionbetweentheDAandnorepinephrine(NOR)systems,whichwasachievedthroughmodula-tionoftheDAdrugregimen,inducedaggressivebe-haviorinPSDratsthatwerepretreatedwithadrenergicdrugs.ThisresultindicatesthatNORhadaslightin-hibitoryactionontheaggressivenesselicitedbydopa-minomimeticagentsinPSDrats(TronconeandTuk1991).ThereducedlevelofaggressioncouldbeduetoasmallincreaseinDAreleaseassociatedwithalackofsecondarynoradrenergicinhibitionratherthantoalackofNORactivity.Thissituationwouldevidencearoleforbeta-adrenoceptorsinthemodulationofthisbehav-ior.Thispropositionissupportedbytheobservationthatareducednumberof-adrenoceptorsarepresentinthecortexofratssubmittedtoPSD(Mogilnickaetal.1986).ThistissuehasbeenshowntobesubsensitivetoNOR,whichisreectedbyevaluationofinvitrocyclic-AMPsynthesis(Tronconeetal.1986).Autoradiographicanal-ysisshowsageneralizedbutregionallyheterogeneousreductioninthenumberofreceptorssubtypesinthebrain,aswellascleartrendsofdown-andup-regulationof1and2sites,respectively(Hipólideetal.1998).InanothersetofexperimentsthatevaluatedPSDandDA,yawningbehaviorwasusedtoassessthesensi-tivityofDAandacetylcholinereceptorsinratssubmit-tedtoPSD(Tuketal.1987).TheresultsdemonstratedthatPSDsignicantlydecreasedtheyawningresponseinducedbypresynapticdosesofapomorphineandsmalldosesofphysostigmineandpilocarpine,suggestingthatPSDinducessubsensitivityofpresynapticDAreceptorsand/orpostsynapticacetylcholinereceptors.Alargebodyofevidenceindicatesthatdrug-in-ducedyawninginratsisabehavioralconsequenceofdopaminergicautoreceptorstimulation,whichresultsindecreasedDAsynthesisandrelease,impaireddopamin-ergictransmission,andconsequentremovalofthein-hibitionofcholinergicneuronsexertedbyDAneurons(YamadaandFurukawa1981).Thus,yawningbehav-iorseemstoinvolvebothdopaminergicinhibitionandcholinergicactivation.Byevaluatinganimalsafterare-coveryperiodof24h,Neumannetal.(1990)observedthat,whileapomorphine-inducedyawningwasstillsig-nicantlyreduced,pilocarpine-inducedyawninghadre-turnedtonormal,suggestingthatPSDaltersthesesys-temsdifferently.Itseemsthatinterferenceonthedopa-minergicsystemoccursmorestronglyandatanearliertimethanoncholinergicsystem.Withrespecttotheevidencementionedabove,thesendingsledtothehypothesisthatPSDinducesanupregulationofdopaminergicreceptors(Tuketal.1978,1987).However,becauseapomorphineisamixedD1/D2agonist,itwasnotpossibletodeterminefromthoseexperimentswhichsubtypeofdopaminergicre-ceptorisunregulatedafterPSD.Nunesetal.(1994b)usedautoradiographicanalysistoaddressthisquestion.TheyfoundthatPSDincreasedD2butnotD1recep-torbindinginthebrain,suggestingthattheunregulatedD2receptorsareresponsibleforthepreviouslyreportedchangesinapomorphine-inducedbehaviorsafterPSD.AnincreaseinDAreleaseinthePSDgroupexertsgreaterdopaminergic-mediatedeffectsduetoupregula-tionofDAreceptorsinthestriatumofPSDratscom-paredtocontrolgroup(Farooquietal.1996).Thisnd-ingfurthersupportstheearlystudiesonbehavioraleffectsofdopaminergicstimulantsinPSDanimals(Tu-ketal.1978,Clarketal.1987,Asakuraetal.1992).However,thedecreaseinyawningbehaviorinducedbycholinergicagonists(Tuketal.1987)ledtoaninves-tigationofcholinergicreceptorsinanimalssubmittedtoPSD.Again,anautoradiographicstudyshowedthatPSDresultedinageneralizeddownregulationofM2-typemuscarinicreceptorsinthebrainofarat,corrob-oratingthenotionthatpontineM2-typereceptorsmayparticipate,butdonotnecessarilyplayanintegralrole,inthedevelopmentofPSDeffects(Nunesetal.1994c).SomeevidencesuggeststhatPSDenhancessero-tonergictransmission.Bearingthisinmind,directex-aminationof5-HTreceptorbindingafterPSDwasre-strictedtoearlystudiesthatusedanon-selectiveligand[3H]5-HTinalimitednumberofbrainareas.Thesestudiesshowedthatbindingto5-HT1awasnotsigni-cantlyalteredbyPSDinanyofthebrainareasexam-ined.However,therewasanoveralltrendtowardde-creasedbindinginthetargetparadoxicallysleepdeprivedgroup.Thesamephenomenonoccurredwithserotonintransporter(SERT)bindingafterPSD.Thefrequencyofligandbindingto5HT2siteswasgenerallydecreasedaf-terPSDin81brainareas,andthisreductionwasmorepronouncedinthesleeprecoveryperiod(Hipólideetal.2005).AnAcadBrasCienc(2009)81(3) 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526SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLOOrexinsareanewlydiscoveredclassofneuro-peptidesthatregulatefeedingandvigilance.Initiallyrecognizedfortheirimportanceinappetitecontrol,orexins(alsocalledhypocretins)arealsoinvolvedinregulatingsleep,arousal,andcardiovascularfunction.Lossoforexinappearstobetheprimarycauseofnar-colepsy(KilduffandPeyron2000,SutcliffeanddeLecea2002).Expressionoforexinsisrestrictedtoadiscreteregionofthehypothalamus,buttheterminalprojectionsoforexin-producingcellsarewidelydistrib-utedthroughoutthebrain.Intherat,orexininducesadose-dependentincreaseinwakefulnesswhenitisinjectedintracerebroventricularly(Piperetal.2000).Thedensestprojectionoforexinergiccellsintheratisinthelocuscoeruleus(Horvathetal.1999),thenora-drenergicoutputthatfavorscorticalarousalofwakingandopposesPS-associatedarousal(Hobsonetal.2000,Aston-Jonesetal.2001).Pedrazzolietal.(2004)measuredhypocretinlev-elsat6and96hafterPSDandfollowing24hofre-bound.PSDwasfoundtoincreasecerebralspinaluidorexin-1collectedatzeitgebertime(ZT)8,butnotatZT0.DecreasedcerebralspinaluidorexinlevelswerealsoobservedatZT8after24hofPSrebound.TheseresultssuggestthatPSDactivatesandthatreboundin-hibitstheorexinsystem.TheauthorssuggestedthatincreasedorexintoneduringPSDmightbeimportantforsomeoftheeffectsofPSD,suchasantidepressanteffects,hyperphagia,andincreasedsympatheticactiv-ity.AnotherexperimentperformedbyD’Almeidaetal.(2005)showedthatthelevelofprepro-orexin(theprecursorofbothformsoforexin)mRNAincreasedby30%at96hoursafterinthePSDgroupandby88%after24hoursinthereboundgrouprelativetocontrols.SleepdeprivationproducedaheterogeneouseffectonbrainmRNAlevelsofbothorexinreceptors(OXR).TheOX1RmRNAlevelsincreasedinmorethan30dif-ferentregions,particularlyintheamygdalaandhypo-thalamusinthereboundgroupcomparedtocontrolandsleepdeprivedgroups.ChangesinOX2RmRNAlev-elswerealsoseenonlyinthesleepreboundgroup,butthelevelsweredecreasedratherthanincreased,andtheywerepredominantlyconnedtothecerebralcortex.Theseobservationssuggestthatcontinuedsleepdepriva-tionprogressivelyincreasesprepro-orexinmRNAlevelsandaltersorexinreceptorexpression.Theseeffectsarenotimmediatelyreversedbysleeprecovery,indicatingalastingactivationoftheorexinergicsystem.Collectively,theoverallchangesinbrainneurotransmittersafterPSDmayindicatethatthemechanismsinvolveintheprocessofsleeprecovery.PSDANDGENEEXPRESSIONSleepdeprivationofshortdurationorprolongedforseveraldaysalterstheexpressionofdistinctcategoriesofgenesinthebrain,includingimmediate-earlygenes,suchastranscriptionfactors;genesthatencodeproteinsinvolvedinmetabolicprocesses,neuronalplasticity,andthestressresponse;andgenesthatencodeneuro-transmitters,hormonereceptorsandtransporters,andenzymes(Cirellietal.2004,Cirelli2006,Teraoetal.2008,Maretetal.2007).Inaddition,ithasbeenshownthatthepatternofchangesisconsistentacrossspecies(Cirelli2002)andindistinctbrainregions(Cirellietal.2004,Teraoetal.2008).Throughtheuseofmicroarraystoevaluatetheexpressionof−30;000transcripts,werecentlyiden-tiedatotalof78uniquetranscriptsthatwerediffer-entiallyexpressedinanimalssubmittedtoPSDrela-tivetocontrols(Guindalinietal.2009).Thesediffer-entiallyexpressedtranscriptsincludegenesfrommanyfunctionalclasses,includingmetabolicprocesses,thecircadiansleep-wakecycle,theresponsetoastimulus,regulationofcellproliferation,andsignalingpathways.After24hofsleeprebound,expressionof61:5%ofthesleepdeprivation-regulatedtranscriptswasdetectedasbeingdifferentiallyexpressedintherecoveryperiod,resemblingthegeneexpressionpatternofthecontrols,relativetothePSDgroup.However,asoccurswithanumberofbehavioralandphysiologicalparameters,theexpressionlevelsoftheremaining38.5%oftran-scriptswereamongthelevelsobservedforcontrolandsleep-deprivedanimals,suggestingthatalongerrecov-eryperiodisnecessarytocompletelyreversetheef-fectsofprolongedPSD.Noteworthy,DNAdamageisanimportantstepineventsleadingtogenomicinstabil-ity.Werecentlyconductedanexperimentdemonstrat-ingthatDNAdamagewaspreferentiallyinducedinthebrainandbloodcellsofparadoxicallysleepdeprivedrats,whereasnodetectablechangeswereobservedinAnAcadBrasCienc(2009)81(3) 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SLEEPDEPRIVATIONINANIMALS527theliverorheartcells(Andersenetal.2009).Thisstudyrepresentsarelevantcontributiontotheunderstandingofthepotentialhealthrisksassociatedwithsleepdepri-vation.Collectively,theseresultssuggestthatPSDelic-itsapatternofgeneexpressionthatissimilartothoseobservedforotherparadigmsofsleepdeprivation,andthatPSDhascharacteristicsthatmightberelatedtotheregulationofPS.Inaddition,24hofsleeprecoverywasnotsufcientforcompletereversaloftheeffectscausedbyprolongedperiodsofPSDofanumberofbehavioralandphysiologicalparameters(Andersenetal.2005a,Antunesetal.2006).Interestingly,Maretandcolleaguesdemonstratedthatsleepdeprivationinducedalargernumberoftran-scriptionalchangesintheliverthaninthebrain,sug-gestingthatsleepdeprivationmighthaveastrongeffectonperipheraltissuesand/orthatthebrainmightbepro-tectedfrommajorchangesintranscription(Maretetal.2007).Thisstudycorroboratesourresults,whichindi-catethatthereislessvariationinthegeneexpressioninthebraincomparedtoothertissues,suchasbloodandcavernosum,followingPSD(Leeetal.2009).PSDANDBEHAVIORALALTERATIONSYAWNINGApartfromtheconstellationofbehavioralandneuro-pharmacologicalconsequencesofPSD,yawningispar-ticularlyinterestingbecauseitcanbeelicitedbysev-eralcholinergicagonists(Urbá-Holmgrenetal.1977,Woodetal.1979),suchaslowdosesofdopaminergicagonists(MogilnickaandKlimek1977)andpolypep-tidessuchas-MSHandACTH(Ferrarietal.1963,YamadaandFurukawa1981,Loboetal.1990).Thisndingsuggeststhatmultipleneurotransmittersystemsmodulatethisbehavior.PSDfor96hresultsinnearlycompletesuppressionofyawninginducedbydopamin-ergicandcholinergicagonists(Tuketal.1987).Sincetheactivityofbothoftheseneurotransmittersystemsisalsoalteredbystress(DeKloet1991),animalswerechronicallyexposedtodifferentstressmodalities.Theevaluationofyawninginducedbydopaminergicandcholinergicdrugsshowedthatimmobilizationcausedsuppressionofthisbehavior,whereasforcedswimmingandfootshockincreasedthenumberofyawns.Thesendingssuggestthatyawningisdifferentiallyalteredbyconstantandintermittentstressors(Tuketal.1995).Asthesestressfulmanipulationsaltereddrug-in-ducedyawning,Hipólideetal.(1999)investigatedtheeffectsofsingleandrepeatedtreatmentswithasyn-theticglucocorticoid,dexamethasone(DEXA)onapo-morphine-andpilocarpine-inducedyawninginrats.NeithersinglenorrepeatedtreatmentwithDEXAal-teredapomorphine-inducedyawning.Asingleinjec-tionofDEXA,however,causedanincreasednumberofyawnsinducedbypilocarpine.RepeatedtreatmentwithDEXAledtoadecreasednumberofyawnsin-ducedbypilocarpine.Theauthorsconcludedthatdopa-minergicandcholinergicsystemsaredistinctlyalteredbyDEXAintermsofyawningbehavior.Furthermore,yawningbehaviorwasevaluatedtoexaminewhetherconcomitanttreatmentwithPSDandDAagonistscouldreversePSDeffects(Loboetal.1995),asobservedwithstereotypyandaggressiveness(Tronconeetal.1988).Morerecently,theeffectsofacuteandchronic18-and19-tetrahydrocannabinol(18and19-THC)wereexaminedonyawninginducedbypilocarpineorapo-morphine.Thedatasuggestthatcannabinoidagonistsinhibitedyawninginducedbycholinergicanddopamin-ergicagonists.Inaddition,theincreasedfrequencyofspontaneousyawningfollowingcessationofchronicad-ministrationofacannabinoidagonistmaybeofimpor-tanceasawithdrawalsignforthesedrugs(Nakamura-Palaciosetal.2002).CannabisalsoinducesaggressivebehaviorinPSDrats.Thiseffectisprobablyrelatedtobraincatecholamines,asDAmayplayanagonistroleandNORaninhibitoryrole(Carlinietal.1977).COGNITIONSleephasrolesinlearningandmemoryprocessesatseverallevels(StickgoldandWalker2007).Twomainlinesofevidencesupportthishypothesisinrodents.Firstly,PSfollowingtheacquisitionoflearningtasksleadstoincreasesinthenumberanddurationofepis-odesandPSdensity(SmithandWong1991).Secondly,manystudiesreportanimpairedacquisitionwhenPSDisperformedbeforeorafterthetrainingperiodforsev-erallearningtasks(Smith1985,Silvaetal.2004a,b).PSDperformedbeforethetrainingperiodresultedinacquisitiondecitsthatwerenottask-specic.ThisisAnAcadBrasCienc(2009)81(3) 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528SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLObecausetheprocedureaffectedinhibitoryavoidanceandanappetite-motivatedtask(Stern1971).Incontrast,us-ingappetitivemotivation,noeffectonaccuracyofT-mazediscriminationwasfoundwithPSD(HicksandPaulus1973).Thenatureofthetaskmightbeonefac-torthataccountsforthesediscrepancies.TodeterminewhetherPSDadministeredpriortotrainingwouldhavedifferentialeffectsontwoaversivelymotivatedtasks(classicalconditioningoffearandinhibitoryavoidance),Buenoetal.(1994)submittedratstoPSD,andtheratsweretrainedonadoubleaversivelymotivatedtask.ThedatashowthatPSDadministered24or72hbeforethetrainingsessionhadnoeffectoneithertask.However,whentheperiodofdeprivationwasextendedto96hbeforethetrainingsession,acquisitionofinhibitoryavoidancewasimpaired,butnoeffectonclassicallyconditionedfearwasobserved.Thus,theauthorscon-cludedthatPSDhaddifferentialeffectsonthetwotasks,bothaversivelymotivatedandtrainedatthesametimeandunderthesameconditions.Moreover,thestudyontheeffectsofpharmacologicalinterferencewiththecholinergicsystemonPSD-inducedmemoryimpairmentshowthatactivationofthissystemduringtheperiodofdeprivationcanpreventmemorydecitsinducedbyPSD(Buenoetal.2000).Laterdatafromourgroupsuggestthatproactivelearning/memorydecitsinducedbyPSDcouldbeattributedtoalteredM1bindingeitherimmediatelyafterPSD(whenavoid-ancetrainingoccurs)oraftersleeprecovery(whenacquisition/retentionaretested)(Moreiraetal.2003).In2000,SilvaandFrussa-Filhoproposedtheuseoftheplus-mazediscriminativeavoidancetask(PM-DAT),whichisabehavioralparadigmthathasthead-vantageofindependentlyevaluatelearning,memory,andanxietyaswellasmotoractivity.PM-DATcom-plieswithethicalprotocolssincethereisnofootshock,whichisimposedbyclassicalavoidancetests.Consid-eringtheeffectsofPSDinmicesubmittedtothePM-DAT(Silvaetal.2004b),pre-trainingPSD-inducedanx-iogenicandhypolocomotoreffectswereobservedinthetrainingsession,buttheydidnotmodifytheacquisi-tionofthetask.Recently,Alvarengaetal.(2008)investigatetheeffectsofPSDfor96honthelearning/memorypro-cessesinratssubmittedtothePM-DAT,whichsimulta-neouslyevaluateslearning,memory,anxietyandmotorfunction.OurresultsdemonstratethatPSDinducedim-pairmentintheacquisition,consolidationandretrievalofadiscriminativeavoidancetask.Inthethreeexperi-mentalconditions,a24hsleeprecoveryperiodwasef-fectiveinabolishingthePSDcognitiveeffects,butwasineffectiveinmodifyingthemperse.Inaddition,PSDproducedsignicantalterationsinanxiety-likebehav-iorandlocomotoractivity,whichmayberelatedtotheimpairmentinretrieval(butnotinacquisitionorcon-solidation).ThisstudystrengthenedthecriticalroleofPS(butnotsleeprebound)inallthephasesoflearn-ingandmemoryformation.Inaddition,itsuggeststhatPSDeffectsonacquisitionandconsolidationdonotseemtoberelatedtootherbehavioralalterationsin-ducedbythisprocedure.LOCOMOTORANDANXIETY-LIKEBEHAVIORRegardingtheeffectofPSDonlocomotoractivity(TukandSilveira-Filho1983,Frussa-Filhoetal.2004,Andersenetal.2005b,Perryetal.2007),somestudieshavefocusedonlocomotoractivityandsleeppatterns.Consequently,speculationsabouttheeffectoftheexer-ciseonsleepduetosleepdeprivationhavebeenraised(Martinsetal.2001).Fromourdata,itcanbeassumedthatPSDinducedsignicantbutheterogeneouseffectsinanimals.Forin-stance,PSDincreasedgrooming,butithadnoeffectonstereotypedbehaviors,locomotion,ortheelevatedplusmazetest.Importantly,itsignicantlydecreasedrear-ingbehavior,whichisassociatedwithpotentiationofstereotypyandexploratoryactivity(Andersenetal.2005b).Inaddition,anotherstudyshowedthatsingleplatformPSDratshadreducedlocomotoractivityandaugmentedanxiety-likebehavior(Sucheckietal.2002).Recently,Martinsandcolleagues(2008)pointedoutthatPSDincreasedgnawingbehaviorundirectedtofeeding,supportingtheviewthatspontaneousoralstereotypy,ratherthanhunger,isthemajorcauseofincreasesinfoodremovedfromfeedersinratsdeprivedofsleepforupto96hours.Inmice,sleepdeprivationfor72h,achievedbythemultipleplatformmethod,inducesincreasedanxietyasevaluatedbythePM-DATandintheconventionalplus-maze(decreasedtimespentintheopenarms)(SilvaetAnAcadBrasCienc(2009)81(3) “main”—2009/7/27—14:50—page529—#9 SLEEPDEPRIVATIONINANIMALS529al.2004a,b),aswellasintheopen-eldtest(decreasedincentrallocomotionfrequency).Thisanxiogeniceffectwasnotobservedafter24hofsleepdeprivation.SEXUALBEHAVIORAsmentioned,PSDresultsinseveralbehavioralalter-ationsinratsthatarelikewiseinducedbydopaminergicagonists(Tuketal.1978,1987,AndersenandTuk2005);however,thereissomecontroversyabouttheef-fectofPSDonsexualbehavior.DAplaysakeyroleinthemodulationofthisbehavior(BitranandHull1987).Mordenandco-workers(1968)reportedincreasedsex-ualperformanceinPSDmalerats.Inanotherstudy,however,fourdaysofPSDdidnotsignicantlyaltermalesexualperformance(Hicksetal.1991).Inthiscontext,wehaveconsistentlydemonstratedthefacilitatoryeffectsofPSDongenitalreexes(penileerection,orPE,andejaculation,orEJ)inrats(Ander-senetal.2000).ThedatarevealedthatonlyPSDratsexhibitedPEandEJbehaviors,whichwereabsentincontrolanimals.Indeed,combinedadministrationofPSDandcocaineelicitedgenitalreexesmuchmoremarkedlythandidadministrationofPSDorcocainealone(AndersenandTuk2002).AlthoughanumberoffactorsareinvolvedinacomplexphenomenonsuchasPE,theauthorssuggestthatthepreviouslydocumentedDAreceptorsupersensitivityinducedbyPSDmaybeanimportantcontributortothepotentiationofgenitalre-exesbycocaineaftersleepdeprivation.Importantly,otherdopaminergicdrugs,suchascocaine(Andersenetal.2004a,b),methamphetamine(Andersenetal.2003a)andapomorphine(Andersenetal.2003b),alsoincreasedtheeffectsofPSDongenitalreexesinbothyoung(Andersenetal.2003c)andoldmalerats(Andersenetal.2002,2004a).TheperiodofexposuretoPSDseemstointer-ferewiththeresponsesofgenitalreexes.After24hofPSDfollowedbycocaineadministration,adultan-imalsstartedtodisplayPEandEJ,whichpeakedat96hofPSD.Morethan96hofPSDdecreasedgenitalreexes,asobservedat120and144hours(Andersenetal.2003d).Interestingly,hormonelevelsseemtoplayacriti-calroleintheseerectileevents(forreview,seeAnder-senandTuk2006,2008).Indeed,PSDdecreasestheleveloftestosterone,whereasprogesteronelevelswereincreasedinbothyoungandoldgroups,suggestingthat,althoughsexualfunctioncommonlydecreaseswithage,testosteronealonecannotbeconsideredthemainhor-moneinvolvedinsexualactivity(Andersenetal.2002,2003c,2004a,b).ESTROUSCYCLEThusfar,littleattentionhasbeengiventowhethersleepisdifferentiallyregulatedbetweengendersandthemag-nitudeoftheconsequencesofsleeploss.Studieshavedocumentedthat,whilehealthywomenappeartohavebettersleepqualitythanmen,theyreportmoresleepproblems,includinginadequatesleeptimeandinsom-nia(Bixleretal.2002,ZhangandWing2006).More-over,nightmareswerereportedtobetwiceasfrequentinwomen(Ohayonetal.1997).Thereasonsforsuchdiscrepanciesareattributedtohormonaluctuationsoverthemenstrualandestrouscycles,afactorthathasbeenassociatedwithsleepvariationsinbothhumansandrats(Hachuletal.2006,Antunesetal.2006,2007).Inparticular,alterationsinreproductivehormonereleasecoincidentalwithsleephavebeensuggestedasamanifestationofentrainedlinksbetweenCNSregula-tionandendocrinefunction.Notably,ourresultsdemon-stratethatfemaleratssubmittedtoPSDinthediestrousphase(PSD-diestrous)hadtheirestrouscyclesdisruptedduringtherecoveryperiod.Thiswasevidencedbyaconstantdiestrusduringtherstweekofrecovery.Asforhormonealterations,progesteroneconcentrationswerestatisticallyhigherinPSD-diestruscomparedtotherespectivephasecontrolandtoPSD-proestrousandPSD-estrousrats,whileCTRL-metestrousratshadhigherlevelsthanCTRL-proestrousandestrousgroups.Inaddition,thePSD-diestrousphaseexhibitedhigherconcentrationsofcorticosteroneandlowerestrogenlevelsthantherespectivecontrolrats.Thesedatain-dicatethatPSDmaymodulateovarianhormonereleasedthroughalterationsinhormonal-neurochemicalsystems.OXIDATIVESTRESSSleephasbeendescribedtoprovideanantioxidativefunction(Reimund1994),whichleadstothehypothe-sisthatsleepdeprivationisassociatedwithanaccumu-lationoffreeradicals.ItisknownthatPSDinducesAnAcadBrasCienc(2009)81(3) 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530SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLOanumberofalterationsinsystemicandbrainenergymetabolism(Bergmannetal.1989,Eversonetal.1994),aswellasmotorweakness,lesionsinorgans,andevendeath(Rechtschaffenetal.1983).Itispossiblethattheseeffectsoccurasaresultofreactiveoxygenspecies(ROS)accumulation.AnumberofstudieshavereportedthatROSareinvolvedinthepathogenesisofseveraldiseasesandpsychologicalstress(HalliwellandGut-teridge1989).D’Almeidaandcoworkershavestudiedtheoxida-tivestressstatusfollowingPSD.First,theydescribedareductionintotalglutathione(GSH)levelsinthewholebrain;however,anumberofantioxidantswerefoundtobeunchangedinthebrainafterPSD(D’Almeidaetal.1997).Furthermore,reducedGSHlevelsweredemon-stratedinthehypothalamusandthalamus(D’Almeidaetal.1998),suggestingthatthesespecicbrainregionscouldbemoresusceptibletooxidativestressduringPSD(D’Almeidaetal.2000).Toinvestigatethehypothesesthat(i)sleepinvolvesaprocessofdetoxicationatthecellularlevel(Inouéetal.1995)and(ii)thatsleepmayserveasanantioxidantfunctionbyremovingfreeradi-calsorROSproducedduringwaking(Reimund1994),and,consideringthatGSHlevelswerecounteractedbymelatoninadministration(Floreanietal.1997),theau-thorstestedtheeffectsofexogenousmelatoninadmin-istrationonthePSD-induceddecreaseinGSH.TwicedailyadministrationofmelatoninduringthePSDpe-riod,andequivalentdosingincontrols,resultedinsim-ilarlyloweredhypothalamicGSHlevels,indicatingthattheantioxidantpropertiesofmelatoninwerenotabletopreservehypothalamicGSHlevelsafterPSD,andthatexogenousmelatoninmayleadtodecreasesinhypo-thalamicGSHlevelsandfurtherthedecreaseinducedbyPSDinthisbrainregion(D’Almeidaetal.2000).ReducedGSHlevels,akeyindicatorofoxidativestress,havebeenshowntoprecipitateapoptoticcelldeathinthebrainunderdifferentconditions(Tanetal.1998).Basedupontheabove-describedndingsofD’Almeidaandcolleagues,astudywasperformedthatshowedthatbindingofthe“peripheral-type”benzodi-azepineligand[3H]PK11195toreactiveastrocytes,areliableandsensitiveindexofnecroticchanges,wasnotalteredin14examinedbrainregions,andmRNAlev-elsoftheapoptosis-relatedgenesbcl-2andbaxinanyof24brainareasstudied(Hipólideetal.2002)werelikewiseunchanged.Thesendingssuggestthattheoxidativestressthatdevelopsinthebrainsofratssub-mittedtoPSDdoesnotresultincellloss.ConsideringthestressfulnatureofthePSDmethod,whichisassociatedwiththedisruptionofvariousphysiologicalprocesses,D’Almeida’sgroupdescribedthatplasmahomocysteine(anintermediateaminoacidinmethionine-cysteinemetabolism)wasreducedinPSDratsascomparedwiththecagegroup,anddidnotreverttonormallevelsafter24or48hofrecovery.Decreasedglutathioneandincreasedthio-barbituricacidreactivesubstancelevelswereobservedinPSDrats(Oliveiraetal.2002).Theauthorssug-gestedthattheobserveddecreasesinhomocysteinelevelsmayrepresentaself-correctingresponsetode-pletedglutathioneinPSDrats,whichwouldcontrib-utetotheattenuationofthedeleteriouseffectsofPSD.Homocysteinelevelsweredecreasedinolderratsascomparedtoyoungones;PSDdidnotfurtherre-ducetheloweredlevelsinagedanimals.Additionally,PSDhadnoeffectontotalcholesterolorfolatelev-els,whileitincreasedHDL,LDL,andvitaminB12,anddecreasedtriglycerideandVLDLlevels(Andersenetal.2004c).Indeed,theincreaseinLDLlevels,whichwasmuchmorepronouncedthantheincreaseinHDL,wouldconstituteanunfavorablefactorsincetheLDL/HDLratiorepresentsabetterassessmentofcardiovas-culardiseaseriskthanHDLcholesterollevelsalone(Lemieuxetal.2001).TheseresultsindicatethatPSDhassignicantbutheterogeneousphysiologicaleffectsinagedrats,anditmayintensifycertainage-relatedeffectsthatcontributetocardiovasculardiseaserisk(Andersenetal.2004c).Oneofthemostcommonsleepdisorders,obstruc-tivesleepapnea,ischaracterizedbyanairowinterrup-tiondespitepersistentrespiratoryefforts,thuscausingchronicsleepdeprivationduetothefrequentawakeningattheterminationofapneicepisodes.Assleepdepriva-tionmayaggravatehypertensivefeatures,andsincecar-diorespiratorychangesareobservedafterPSD,Palmaetal.(2002)studiedtheparticipationofendothelin-1inthegenesisofhypertensionandheartdiseasebydeter-miningplasmaendothelin-1/2levelsinPSDrats.ThedataevidencedthatPSDalteredendothelin-1/2concen-AnAcadBrasCienc(2009)81(3) 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SLEEPDEPRIVATIONINANIMALS531trations,suggestingthattheincreaseintheendothelinlevelsmaybeinvolvedinthegenesisofarterialhyperten-sionandcardiorespiratorychanges,whichareobservedaftersleepdeprivation(Palmaetal.2002).Ithasbeenproposedthatbothhypoxiaandsleepfragmentationareimplicatedinthecardiovascularriskassociatedwithobstructivesleepapnea.StudieshavedemonstratedthathypoxiareducesdeltaandREMsleepandprolongsstages1and2ofNREMsleep(Bers-senbruggeetal.1984).However,itisnotpossibletodeterminewhethertheeffectsofobstructivesleepap-neainhumansarecausedbyhypoxiaperseorwhethertheyareduetothefrequencyofarousalsinducedbybreathingalterationsduringsleeporboth(Berssenbrug-geetal.1983).Toaddressthisissue,wehavebeenconductingstudiesusingintermittenthypoxiainrats.AsdescribedbyPerryetal.(2007),subchronicexposuretointermittenthypoxia(10%O2)didnotaffectthebio-chemicalbloodparametersrelatedtocardiovascularrisk,butsubchronicPSDreducedtriglyceride.TheseparametersremainedreducedwhenPSDwascombinedwithintermittenthypoxia.Furtherinvestigationintotheassociationbetweenhypoxiaandsleepdeprivation,whichisknownassequelaeofobstructivesleepapnea,maybeusefulinunderstandingtheinuenceofbothfactorsonthecardiovascularsystem.STRESSInadditiontosleepdeprivation,achievedbyeitherthesingleplatformmethodorvariations,thetechniquesin-ducehighlevelsofstressandhavebeenasubjectofdebate.Ifsleepisessentialforhealthandlife,thensleepdeprivationisabiologicalstressor.Indeed,somesignsofsleepdeprivationareweightloss,reducedthymusweight(CoenenandVanLuijtelaar1985),increasedadrenalweight(CoenenandVanLuijtelaar1985,SucheckiandTuk2000),augmentedcorticosterone(SucheckiandTuk2000,Andersenetal.2003c,2004b,d,2005a,Hipólideetal.2006),andACTHlevels(Andersenetal.2005a).Sleepdeprivationproducesamarkednega-tiveenergybalance,indicatingthathypercatabolismisacentraleffectofsleepdeprivationinrats(Everson1997)inadditiontotermorregulationalteration(SeabraandTuk1993,Hoshino1996).Moreover,c-fosexpressionisincreasedinthepreopticareaofcatssubmittedtotheowerpottechnique(Ledouxetal.1996).IncreasedbindingofCRFreceptorsinseveralbrainareasandre-ducedhypothalamicCRFcontentisobservedinsleepdeprivedrats(FaddaandFratta1997).Asthesleep-wakecycleisdistinctlyaffectedbystress(Papaleetal.2005),furtherresearchiswarrantedtoelucidatebothhowsleepisinterruptedbystressandthelong-termeffectsinictedbysleepdeprivation,aninherentstresscondition,ontheorganism’scopingskills.DEPRESSIONSinceitsrstexperimentaldemonstration(PugandTölle1971),theantidepressanteffectofsleepdepri-vationforonenighthasbeenwidelyinvestigated.Af-termanyyears,theprocedureofsleepdeprivationhasprovenitsefcacyforalleviatingdepressioninapprox-imately60%ofthecasesafterasinglesession,andinalmost90%afterthreesessionsperformedatone-weekintervals(forreviewseeWuandBunney1990,Wirz-JusticeandVanderHoofdakker1999).However,thiseffectisnormallyonlytransient,and,inmostcases,relapseoccursaftertherstepisodeofrecoverysleep(Southmaydetal.1990).Despitethenumerousstudiesoftotalsleepdeprivation,andbasedonthetheorythatPSpressureisincreasedindepressedpatients(Vogeletal.1980),someattemptsweremadetoevaluatetheef-fectsofselectivePSD.ApartfromtherapeuticPSD,therelationshipbe-tweenPSDeffectsandnoradrenergic,serotonergicandothereffectsofantidepressantdrugshasbeeninvesti-gated.In1983,TukandSilveira-FilhodemonstratedthatPSDratsweremoresensitivetoimipramineanduoxetineandalsotonomifensive,whichshowedabi-phasiceffect.Ashasbeensuggested,PSDmayunderlietheclinicaleffectsofantidepressantsinthecontextofdepression(Vogel1975).Thus,potentiationofthether-apeuticeffectsofantidepressantsbyPSDsuggeststhatthedepressantsinclinical,aswellasinlocomotorac-tivity(asusedinthisreport)inrodents,shareacom-monmechanism(TukandSilveira-Filho1983).Thedevelopmentofanhedonia,characterizedbylossofin-terestfollowingrewardingstimuli,wasrecentlystud-iedbyPezzatoetal.(unpublisheddata)inPSDratssincetheoccurrenceofadepressivelike-statemaybeanimportantfactortoconsiderinsleep-deprivedstud-AnAcadBrasCienc(2009)81(3) 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532SERGIOTUFIK,MONICAL.ANDERSEN,LIAR.A.BITTENCOURTandMARCOT.DEMELLOies.TheresultsindicatethatPSDpromotesaprogressivedecreaseindailysucroseintake,whereastheincreaseinsucroseintakeobservedduringthereboundperiodcouldbeattributedtoachangeinthestrategyofcoping.Themajorityofinvestigatorshaveconcludedthattheimmediateeffectofasinglesessionofsleepde-privationinhumansisnotinuencedbytheadminis-trationofantidepressantdrugs(forreviewseeGiedkeandSchwärzler2002,Adrien2002).Thecommonneu-robiologicalmechanismsaffectedbypharmacologicalantidepressantsandsleepdeprivationsuggestthatsleeplossinsomeinsomniacordepressedpatientsmightbeanendogenouscompensatoryprocessthatisthera-peuticratherthanpathological.Thisproposalshouldopenupnewstrategiesforthetreatmentofdepression(Adrien2002).CONCLUSIONOverthepastfewdecades,aremarkableexplosionofresearchhasallowedustoconstructamuchmorecom-pletepictureoftheneurotransmitter,genetic,cellular,neurophysiologicalandbehavioralchangesthatareaf-fectedbysleepdeprivation.Sleepdeprivationseemstodisruptvitalbiologicalprocessesnecessaryforcognitivefunctionandphysi-calhealth,yetthewaysinwhichthebodyiscompro-misedarenotfullyunderstood.Thereisapressureinmodernsocietytocarryoutanincreasingvarietyandnumberofactivitiesduringwakefulness.Theexpecta-tionthattheseactivitiesshouldbeachievedtendstopushsleepintobackground.Thistrendstowardsleepdepri-vationandirregularsleep-wakepatternswithresultantimpairedconcentrationandmemoryreducesthequalityoflifeandtheabilitytoenjoyandcompleteactivities.Thebalancemayneedtoswingbacktowardawarenessthatadequateandregularsleepisrequiredtopromoteastateofwell-beingduringwakefulness.Onceawareofthisrelationship,itbecomestheresponsibilityofeachindividualtoselecthis/herowncombinationofsleepandwakefulnessbyprioritizingtheopportunitiesthatpresentthemselveseveryday.ACKNOWLEDGMENTSThisworkwassupportedbygrantsfromtheAssocia-çãoFundodeIncentivoàPsicofarmacologia(AFIP),ConselhoNacionaldeDesenvolvimentoCientícoeTec-nológico(CNPq)andFundaçãodeAmparoàPesquisadoEstadodeSãoPaulo(FAPESP)CentrosdePesquisaInovaçãoeDifusão(CEPID)(#98/14303-3toST).AllauthorsarerecipientsoffellowshipsfromCNPq.RESUMOOsonoocupacercadeumterçodenossasvidas,entretantoseuimpactonasaúdeesuainuêncianascondiçõespatoló-gicasaindanãofoicompletamenteelucidado.Aprevalênciadosdistúrbiosdesonoécadavezmaior,sobretudonasregiõesmaisindustrializadas,repercutindodiretamentenobem-estardapopulação.Esteartigotemcomoobjetivosintetizareatua-lizaraliteraturaarespeitodométododeprivaçãodesonoparadoxaleseupanoramadeconseqüênciasdesdecompor-tamentaisatégenéticasemanimais.Ainda,destacamosacon-tribuiçãoerelevânciadosestudosexperimentaisrealizadospornossogruponasultimastrêsdécadas.Palavras-chave:sono,privaçãodesono,rebote,dopamina,ereção,corticosterona,memória.REFERENCESADRIENJ.2002.Neurobiologicalbasesfortherelationbe-tweensleepanddepression.SleepMedRev6:341–351.ALVARENGATA,PATTICL,ANDERSENML,SILVARH,CALZAVARAMB,LOPEZGB,FRUSSA-FILHORANDTUFIKS.2008.Paradoxicalsleepdeprivationimpairsacquisition,consolidation,andretrievalofadiscrimina-tiveavoidancetaskinrats.NeurobiolLearnMem90:624–632.ANDERSENMLANDTUFIKS.2002.Distincteffectsofparadoxicalsleepdeprivationandcocaineadministrationonsexualbehaviorinmalerats.AddictBiol7:251–253.ANDERSENMLANDTUFIKS.2005.Theeffectsofdopamin-ergicagonistsongenitalreexesinparadoxicalsleepde-privedmalerats.PhysiolBehav84:205–210.ANDERSENMLANDTUFIKS.2006.Doesmalesexualbe-haviorrequireprogesterone?BrainResRev51:136–143.ANDERSENMLANDTUFIKS.2008.Theeffectsoftestos-teroneonsleepandsleep-disorderedbreathinginmen:itsbidirectionalinteractionwitherectilefunction.SleepMedRev12:365–379.ANDERSENML,PALMABD,RUEDAADANDTUFIKS.2000.Theeffectsofacutecocaineadministrationinpara-doxicalsleep-deprivedrats.AddictBiol5:417–420.AnAcadBrasCienc(2009)81(3) 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