NeuroscienceLetters579(2014)130–133
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Neuroscience
Letters
j ou rn a l h om epa g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u l e t
Acute
total
sleep
deprivation
potentiates
cocaine-induced
hyperlocomotion
in
mice
L.F.
Berro
a,
R.
Santos
b,
A.W.
Hollais
b,
R.
Wuo-Silva
b,
D.F.
Fukushiro
b,
E.
Mári-Kawamoto
b,
J.M.
Costa
b,
T.F.
Trombin
b,
C.L.
Patti
b,
S.B.
Grapiglia
b,
S.
Tufik
a,
M.L.
Andersen
a,∗,
R.
Frussa-Filho
a,b,1aDepartamentodePsicobiologia,UniversidadeFederaldeSãoPaulo(UNIFESP),RuaNapoleãodeBarros,925,04021-002SãoPaulo,SP,Brazil
bDepartamentodeFarmacologia,UniversidadeFederaldeSãoPaulo,R.Botucatu,862,Ed.LealPrado,1◦andar,04023-062SãoPaulo,SP,Brazil
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•Totalsleepdeprivationpotentiatedcocaine-inducedhyperlocomotioninmice. •Totalsleepdeprivationpotentiatedtheimpulsivityofmiceundercocaineeffect. •Datasuggestthecontributionofthesleepconditiontococaineprimaryeffects.
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Articlehistory:
Received23April2014
Receivedinrevisedform20June2014 Accepted16July2014
Availableonline24July2014
Keywords: Cocaine Sleepdeprivation Hyperlocomotion Openfield Impulsivity
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Sleepdeprivationiscommonplaceinmodernsociety.Nowadays,peopletendtoself-imposelesssleep inordertoachieveprofessionalorsocialgoals.Inthesocialcontext,late-nightpartiesarefrequently associatedwithhigheravailabilityofrecreationaldrugswithabusepotential.Physiologically,allofthese drugsinduceanincreaseindopaminereleaseinthemesolimbicdopaminergicsystem,whichleads tohyperlocomotioninrodents.Sleepdeprivationalsoseemstoplayanimportantroleintheevents relatedtotheneurotransmissionofthedopaminergicsystembypotentiatingitsbehavioraleffects.Inthis scenario,theaimofthepresentstudywastoinvestigatetheeffectsoftotalsleepdeprivation(6h)onthe acutecocaine-inducedlocomotorstimulationinmalemice.Animalsweresleepdeprivedormaintained intheirhomecagesandsubsequentlytreatedwithanacutei.p.injectionof15mg/kgcocaineorsaline andobservedintheopenfield.Totalsleepdeprivationfor6hpotentiatedthehyperlocomotioninduced byacutecocaineadministration.Inaddition,thecocainesleepdeprivedgroupshowedadecreasedratio central/totallocomotioncomparedtothecocainecontrolgroup,whichmightberelatedtoanincrease intheimpulsivenessofmice.Ourdataindicatethatacuteperiodsofsleeplossshouldbeconsideredrisk factorsforcocaineabuse.
©2014ElsevierIrelandLtd.Allrightsreserved.
1. Introduction
Sleepdeprivationisbecomingafeatureofthehuman’scurrent lifestyle.Nowadays,itisnotunusualtoskiponenight’ssleepdue tojoborparties[1].Thehomeostaticchangescausedbythesleep
∗ Corresponding author at: Departamento de Psicobiologia, UNIFESP, Rua NapoleãodeBarros,925,04024-002SãoPaulo,SP,Brazil.
Tel.:+551121490155/160;fax:+551155725092.
E-mailaddresses:berro.lf@gmail.com(L.F.Berro),ml.andersen12@gmail.com,
mandersen@unifesp.br(M.L.Andersen).
1 ThispaperisinmemoryofDr.RobertoFrussa-Filho,whodedicatedhisentire
lifetoScience,becauseamanisalivewhilehisnameisstillspoken.
patternsofa 24/7life-scheduleleadtoseveraldeleterious con-sequences,includinginnumerous psychiatricdisorders.Of note, late-nightpartiesareusuallyassociatedwiththeuseofrecreational drugsofabuse,whichcontinuestoexpandwithoutlimitations[2]. Regardlessoftheirspecificmechanisms,alldrugswithabuse potentialinduceanincreaseindopaminereleaseinthemesolimbic dopaminergicsystem,particularlyinthenucleusaccumbens[3], whichmodulatesboththeirrewardingandpsychomotorarousal effects [4,5].In fact,locomotor stimulationinrodents hasbeen extensivelyrelatedtoincreaseddopaminergicneurotransmission in the mesoaccumbens system [6,7], and acute administration ofmostcommondrugsofabusestimulatelocomotoractivityin rodents[8–11].
http://dx.doi.org/10.1016/j.neulet.2014.07.028
L.F.Berroetal./NeuroscienceLetters579(2014)130–133 131
Sleepdeprivationalsoseemstoplayanimportantroleinthe eventsrelatedtotheneurotransmissionofthedopaminergic sys-tem.Increaseddensityofboth D1 [12,13]and D2 dopaminergic receptors[14]inthemesoaccumbensdopaminesystemhasbeen reportedfollowingsleepdeprivationperiods.Inaddition,animal studiesdescribeincreaseddopaminereleaseandincreasedfiring ofdopaminergicneuronsassociatedwithfunctionalhyperactivity ofthedopaminergicsystemaftersleepdeprivation[15,16].
Thus,bothsleeplossandpsychostimulantsadministrationseem toberelatedtoincreasedresponsivenessofthemesoaccumbens dopaminergicsystem.Bearingthisinmind,andbecausesleeploss isaconditionfrequentlyassociatedwithdrugavailabilityduring nighttimeparties,theaimofthepresentstudywastoinvestigate theeffectsofacutetotalsleepdeprivation(6h)ontheacute loco-motorstimulationproducedbycocaine.
2. Materialsandmethods
2.1. Subjects
Three-month-oldSwissmalemice(45–50g,outbred,raisedat
CEDEME,UNIFESP)wereusedintheexperiments.Animalswere
housed7percageundercontrolledtemperature(22–23◦C)and
lighting(12hlight,12hdark; lightsonat6:45a.m.)conditions withfreeaccesstofoodandwaterthroughouttheentirestudy. Theprotocolusedinthepresentstudywasinaccordancewiththe NationalInstitutesofHealthGuideforCareandUseofLaboratory AnimalsandwiththeBrazilianLawforProceduresforAnimal Sci-entificUse(#11794/2008),andwasapprovedbytheInstitutional EthicalCommitteeofUNIFESP(#1608/11).
2.2. Drug
Cocaine(Sigma®
)wasdissolvedin0.9%salinesolution,which wasusedascontrolsolution.Bothcocaineandcontrolsolutions weregivenintraperitoneallyatavolumeof10ml/kgbodyweight. Cocainewasadministeredatthedoseof15mg/kg.
2.3. Sleepdeprivation(SD)
Miceweresubjectedtototal SDthroughthegentlehandling method,whichconsistsofkeepingtheanimalsawakeintheirhome cagebygentlemanipulationswheneverbehavioralsignsofsleep wereobserved,aspreviously validatedinourlaboratory[9,17]. Miceweresleep-deprivedfor6h(startingat8a.m.)immediately beforebehavioralevaluations.Ithasbeenpreviouslydemonstrated thatthisprotocolofSDleadstoalmosttotalsuppressionofboth paradoxical(REM)andslowwavesleep(97.8%)inmice[18].
Besidesthegentlehandlingmethod,whichdeprivesmicefrom totalsleep(bothparadoxical/REMandslow-wavesleeps),the para-doxical(REM)sleepdeprivation(PSD)bythemultipleplatform methodis anotherwidelyusedmodeltoevaluatetheeffectsof sleeplossinmice.Thismethodselectivelysuppressesparadoxical (REM)sleepbecausemiceareplacedintoaplatformsurrounded bywaterandwhentheyexperiencemuscleatonia,whichis char-acteristicofparadoxical(REM)sleep,animalscontactthewater andwakeup[9].However,situationsoftotalSDaremore com-monthanaspecificPSDinhumans.Inthisscenario,wechoseto conductatotalSDprotocolinordertoachieveamorecircumspect translationalapplicability.
2.4. Assessmentoflocomotoractivity
Animalswereindividuallyplacedinthecenteroftheopen-field arenafordirectquantificationoflocomotoractivityduring10min aspreviouslydescribedbyChinenetal.[19].Duringthe10-min
0 100 200 300 400 500
Sal-CTRL Sal-SD Coc-CTRL Coc-SD
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Challenge
Habituation
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Fig.1.Totallocomotionofmiceintheopenfieldduringthethirdhabituationday orinthechallengesession,whenmiceweresleepdeprived(SD)ormaintained intheirhomecages(CTRL)andsubsequentlytreatedwithanacutecocaine(Coc, 15mg/kg)orsaline(Sal)i.p.injection.Totalsleepdeprivationfor6hpotentiated thehyperlocomotioninducedbyacutecocaineadministration.Dataarereportedas mean±SEM(n=12pergroup).䊉
p<0.05comparedtoitsrespectivesalinecontrol group(withinday);*p<0.05comparedtotheCoc-CTRLgroup.One-wayANOVA (habituation)ortwo-wayANOVAfollowedbyTukey’stest(challenge).
session,thetotallocomotion(totalnumberofentriesintoanyfloor unitwiththefourpaws)andthecentrallocomotion(numberof entriesintoanyfloorunitnotcontiguoustotheapparatuswalls) weremeasuredusinghandoperatedcountersbyanobserverwho wasblindtotreatmentallocation.
2.5. Experimentalprocedure
Forty-eightmiceweregivena10-minhabituationperiodinthe open-fieldon3consecutivedaysandbasallocomotoractivitywas measuredonday3.Fourgroupsofanimalswereformed(n=12 pergroup),whichwerestatisticallyequivalentwithrespecttothe basallevelsoflocomotoractivity.Twenty-fourhoursafterthethird dayofhabituation,micewerekeptintheirhomecages(Sal-CTRL andCoc-CTRLgroups)orweresleepdeprivedfor6h(Sal-SDand Coc-SDgroups).Aftertheendofthe6hperiod,animalsreceivedan i.p.injectionofsaline(Sal)or15mg/kgcocaine(Coc)5minpriorto beingplacedintheopen-fieldapparatusfor10minforthe quan-tificationoftheirlocomotionfrequency.
2.6. Statisticalanalysis
Fortheanalysisofthehabituationdata,1-wayANOVAwas per-formed.TheSD/cocainechallengedatawereevaluatedby2-way ANOVAwithtreatment(cocainevssaline)andsleepcondition(SD vsCTRL)asbetweensubjectfactors.Tukey’stestwasusedaspost hoctest.Apvaluelessthan0.05wasconsideredtobeastatistically significantdifference.
3. Results
Data fromthehabituation andchallengesessionsareshown inFig.1.Inthehabituationsession,1-wayANOVAdidnotshow significantdifferencesbetweengroups[F(3,44)=0.85,p>0.05].On thechallenge day,2-way ANOVAshowed a significant interac-tioneffectbetweensleepcondition(SDvscontrol)andtreatment (cocainevssaline)factors[F(1,46)=4.81,p<0.05],thereby revea-lingthepotentiationoftheacutecocainestimulanteffectinanimals undertotalSD.Infact,Tukey’sposthoctestshowedthatanacute cocaineinjectionincreasedthelocomotionfrequencyofmice (Coc-CTRL>Sal-CTRL),whichwaspotentiatedbyapreviousSDperiod (Coc-SD>Coc-CTRL).
132 L.F.Berroetal./NeuroscienceLetters579(2014)130–133
0 10 20 30
Sal-CTRL
Sal-SD
Coc-CTRL
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Fig.2.Ratiocentral/totallocomotioninmicesubmittedtosleepdeprivation(SD) ormaintainedintheirhomecages(CTRL)andsubsequentlytreatedwithanacute cocaine(Coc,15mg/kg)orsaline(Sal)i.p.injection.Cocaineinducedadecreasein centrallocomotionfrequencyofmice,whichwasrevertedbytotalsleepdeprivation for6h.Dataarereportedasmean±SEM(n=12pergroup).䊉
p<0.05comparedto theSal-CTRLgroup;*p<0.05comparedtotheCoc-CTRLgroup.Two-wayANOVA followedbyTukey’stest.
for thedataof thechallenge session, asshown in Fig.2. Two-wayANOVAshowedasignificantinteractioneffectbetweensleep condition(SDvscontrol)andtreatment(cocainevssaline)factors [F(1,46)=3.21,p<0.05].Tukey’sposthoctestrevealedahigherratio central/totallocomotionfrequency inmicetreatedwithcocaine andkeptintheirhomecages(Coc-CTRL),aswellasa decrease ofthisratiointhegrouppreviouslydeprivedofsleepinresponse tococaine(Coc-SD)comparedtothecocainecontrolgroup (Coc-CTRL).
4. Discussion
Inthepresentstudy,ourmajorfindingswerethatacutetotalSD (6h)potentiatedthehyperlocomotoreffectsofcocaineinmice,and thiseffectwasaccompaniedbyadecreaseinthecocaine-induced higherratiocentral/totallocomotion.
Asfarasweknow,thisisthefirststudyreportingtheeffects ofacute total SD oncocaine-induced locomotor stimulation. In this respect, it has been widely demonstrated that SD shares similarneurobiologicaleffectswithpsychostimulants.Drugssuch
ascocaine andamphetaminedramaticallyelevates
mesoaccum-bensdopaminefunction[3],andthesameeffectsoccurafterSD
[12–14,22–25].Thus, thehyperresponsivenessofsleepdeprived mice to cocaine could reflect an exacerbated function of the mesolimbicdopaminergicsystemduetothecombinationofthese twofactors.
Thispotentiatingeffectwasaccompaniedbydecreased ratio central/totallocomotioninthecocainesleepdeprivedgroup com-paredtothecocainecontrolgroup.Relativetothetotallocomotion frequencyduringthewholechallengesession,micetreatedwith cocaineshowedadecreasedcentrallocomotionfrequency com-paredtothose treatedwithsaline(Coc-CTRL>Sal-CTRL,Fig.2). Notwithstanding, animals that were sleep deprived before the acutecocainechallengeshowedareducedratiocentral/total loco-motioncomparedtothecocainecontrolgroup(Coc-SD<Coc-CTRL,
Fig.2).Thisisaninterestingfinding,becausechangesinrodents’ spatialdistributionareusuallyexplainedasaresultonemotionality
[26].Rodentsspontaneouslyprefertheperipheryoftheopenfield toactivityinthecentralpartsoftheapparatus,andanincreaseof theratiocentral/totallocomotionusuallyindicatesanxiolysis[27]. Inaddition,activityinthecentralpartsoftheopenfieldisalso usedasamarkerofimpulsivitybecausehighimpulsiveratsshow amarkedlyenhancedpreferencefortheopen-fieldcentralsquares
[28–31].Thus,ourdatasuggestthattotalSDmayhavereducedthe anxietyeffectsofcocaineorenhancedmice’simpulsivitydespiteof cocaine-inducedanxiety.Becausepreviousstudieshavereported thatbothacutecocaineadministrationandSDpersearecapable
ofinducinganxiogeniceffectsinrodents[32–35],thedecreased ratiocentral/totallocomotioninthecocainesleepdeprivedgroup mightberelatedtoanincreaseinimpulsivenessratherthantoan anxiolyticeffect.
High impulsive ratsshow greaterescalationof cocaine
self-administration [36] and an increased propensity to develop
compulsivecocaine-seekingandrelapsecomparedwithlow impul-siverats[37,38].Thus,impulsivityisabehavioralconstructthat is highly associated with drug addiction [39], being a vulner-ability marker for substance-usedisorders [20]. Preclinical and clinicalstudiesdemonstratethathighimpulsivityanditsrelated psychopathologicaldisordersinvolveadysregulationofthebrain dopaminergicsystems[40–42].Hence,theincreased
responsive-ness ofthe dopaminergicsystem inducedby both SD [43] and
cocaine[44]couldalsoberesponsiblefortheimpulsive-like behav-ioralprofileobservedinSDmiceundercocaineeffects.
Drug addiction has been conceptualized as a disorder that progresses from impulsivity to compulsivity [45]. Additionally, nowadaysitisnotunusualtoskiponenight’ssleepduetoaparty, forexample,wherethereisagreateravailabilityofabusivedrugs. Thus,althoughtheabovementionedassumptionsarespeculative, thefactthatSDpotentiatestheacutecocainestimulanteffectand theimpulsivityofmiceundercocaineinfluenceindicatethatacute periodsofsleeplossshouldbeconsideredriskfactorsforcocaine abuse.
5. Conclusions
Our data demonstrated that 6h total SD potentiated acute
cocaine-induced locomotor-stimulant effect and induced an
impulsive-like behavior in cocaine-treated mice. Although one mustalwaysbewaryofextrapolatingclinicalrelevancefrom ani-mal data, from a translational point of viewour data indicate that acute periods of sleep lossshould be consideredrisk fac-torsforcocaineabuse.Whenpresentimmediatelybeforecocaine’s firstuse,SDwouldelicitanimpulsivebehavior,therebyreversing cocaine-inducedanxiety,andpotentiatetheacutecocaine stim-ulanteffect.Thus,lackofsleep,aconditionfrequentlyobserved duringeventsinwhichdrugsofabusearesociallyavailable,might beastrongcontributortothecontinuationofcocaineuseafterits primaryexperience.
Conflictsofinterest
Theauthorsdeclaretherearenoconflictsofinterest.
Acknowledgements
ThisresearchwassupportedbyfellowshipfromtheFundac¸ãode AmparoaPesquisadoEstadodeSãoPaulo(FAPESP#2011/16580-0 toL.F.B.)Fundac¸ãoCoordenac¸ãodeAperfeic¸oamentodePessoalde NívelSuperior(CAPES),FundodeAuxílioaosDocenteseAlunos (FADA/UNIFESP) and Associac¸ão Fundode Incentivoà Pesquisa (AFIP).R.F-F,S.T.andM.L.A.receivedCNPqfellowships.Theauthors wouldliketothankWaldermarksLeite,TeotilaR.R.Amaral, Cleo-mar S. Ferreira and Antonio Rodrigues dos Santos for capable technicalassistance.
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