AlcoholsEffectsonthe

AdolescentBrain

WhatCanBeLearnedFromAnimalModels

SusanneHillerSturmhfel,Ph.D.,andH.ScottSwartzwelder,Ph.D.
Because of legal and ethical constraints on alcohol research in human adolescents, many studies of alcohols effects on the developing brain have been conducted in animal models, primarilyratsandmice.Theadolescentbrainmaybeuniquelysensitivetoalcoholseffects because major changes in brain structure and function occur during this developmental period. For example, adolescent animals are more sensitive than adults to the effects on memory and learning that result from alcohols actions on the hippocampus. Conversely, adolescent animals appear to be less sensitive than adults to alcoholrelated motor impairment, alcoholinduced sedation, and the development of seizures during withdrawal. Alcohol exposure during adolescence can have longlasting effects and may interfere with normalbrainfunctioningduringadulthood. KEY WORDS: adolescent;bingedrinking;animalstudy; animalmodel;physiologicalAODE(alcoholandotherdrugeffects);biologicaldevelopment;brain; brain function; cognition; learning; memory; motor coordination; AODR (alcohol and other drug related)seizure;hippocampus;neurotransmitterreceptors

dolescenceandyoungadult hoodaredevelopmentalstages oftransitionduringwhich humans,aswellasmembersofmany otherspecies,mature physicallyand behaviorallyintotheiradultstate. Adolescentsandyoungadultsneedto acquire thephysicalandbehavioralskills thatwillallowthemtoliveindependently oftheirparents,sustainthemselves,and reproduce.Thisperiodismarkedby morefrequentandsophisticatedsocial interactionswithpeers,explorationof new situationsandbehaviors,andan increasedwillingnesstotakerisks.In humans,thisofteninvolvestheinitia tionofalcoholandotherdruguse. Atthesametime,thebrainundergoes considerablestructuralandfunctional changes,atleastinpartinresponseto
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theindividualsmanynewexperiences. Connectionsamongnervecells(neu rons)inthebraincanchangebasedon whichneuronsorgroupsofneurons are regularlystimulated,acharacteristic knownasplasticity. Thisnaturalprocess servestoeliminateunnecessary or unusednervecellconnections,1 allow ingthesurvivalofonlythoseneurons
thatmakemeaningfulcontactswith otherneurons.Thiswinnowingofneu
ronsisinfluencedby,amongotherfac tors,theadolescentsinteractionswith andexperiencesintheoutsideworld. Adolescenceissuchacriticalphase inbraindevelopmentthattheactions ofalcoholandotherdrugsonthebrain canbeassumedtohaveaparticularly profoundimpactduringthisdevelop mentalperiod.Indeed,researchhas

shownthatcomparedwiththeadult brain,theadolescentbrainisparticularly sensitivetosomeeffectsofalcohol,yet moreresistanttoothereffects.Muchof

1

Humaninfantsarebornwithfarmoreneuronsthanare foundintheadultbrain.Basedonachildsinteractions withtheenvironment,theneuronsandconnectionsthat

aremostmeaningfulcanbeselected.

SUSANNE HILLERSTURMHFEL, PH.D.,

is seniorscienceeditorforAlcoholResearch & Health. H.SCOTT SWARTZWELDER, PH.D.,isa professorintheDepartmentofPsychiatry andBehavioralSciencesatDuke UniversityMedicalCenterandasenior researchcareerscientistattheDurham VeteransAffairsMedicalCenter,both positionsinDurham,NorthCarolina.
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thisresearch,especiallyinvestigationsof specificeffectsofacutealcoholadmin istration,hasbeenconductedinanimals becausestudiesinvolvingadministration ofalcoholtohumanadolescentsare subjecttoverystringentregulations,and certainstudiesofalcoholseffectson theadolescentbraincanbeconducted onlyusinganimalmodels.Thisarticle reviewssomeofthedifferencesinalco holseffectsontheadolescentandadult brainthatwereidentifiedusingthese animalmodels.Theaccompanyingarticle byTapertandcolleagues(pp.205212) summarizesinformationthathasbeen obtainedinstudiesofhumanadoles centsandyoungadults.

MajorChangesinBrain StructureandFunction DuringAdolescence

Adolescenceinhumansisbroadlydefined astheseconddecadeoflife,although someresearchersconsideragesupto25 yearsaslateadolescence.Thecorre spondingperiodinlaboratory animals thatare frequentlyusedasstudysubjects isjustaslooselydefined.Inratsittypi callyspanspostnataldays3050(i.e., PD30PD50).Inbothhumansand ani malmodels,adolescenceisaperiod whenthebrainundergoesextensive remodeling.New connectionsamong neuronsarebeingformed;atthesame time,asubstantialnumberofexisting connectionsarelost(seeSpear2000). Itishypothesizedthatthisplasticityallows theindividualsbraintobesculptedbased onhisorherpersonalexperiencesand interactionswiththeoutsideworld (Chugani1998). One brainregionwhere particularly extensiveremodelingoccursisthefrontal regionoftheouterlayerofthebrain theprefrontalcortexwhichisthought tobeinvolvedinworkingmemory,vol untarymotorbehavior,impulsecontrol, rulelearning,spatiallearning,planning, anddecisionmaking(seeSpear2000; WhiteandSwartzwelder2005).These changesareespeciallyextensivein humans.Althoughthenumberofneu ronsandneuronalconnectionsinthe prefrontalcortexappeartodeclineduring
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adolescence,therelativeimportanceof thefrontallobesincreases. Developmentalchangesinthebehav ioral relevanceofcertainbrainareasare accompaniedbyincreasesordecreases intheactivitiesofchemicalscalledneuro transmitters,whichhelptransmitnerve signalsfromoneneurontoanother. Thissignalingtakesplacewhenneuro transmittersreleasedbyoneneuronbind toproteinmoleculescalledreceptors onthesurfaceofthereceivingneuron. Theinteractionbetweentheneurotrans mitter anditsreceptorinitiateschemical andelectricalchangesinthesignal receivingneuronthatinfluencethe generationofanew nerve signalinthat cell.Inthisway,nervecellsandcircuits communicateanddrivebehavior. Excitatoryneurotransmitterspromote thegenerationofnewnervesignals, whereasinhibitoryneurotransmitters makeitmore difficulttogeneratea nerve signalinasignalreceivingneuron. Numerousneurotransmittersandtheir receptorshave beenidentifiedthatact onspecificcellsorgroupsofcellsand havespecificeffectsonthosecells. Twoimportantneurotransmitter systemsthatundergosubstantialchanges duringadolescenceandare affectedby alcoholconsumptionaredopamine andgammaaminobutyricacid(GABA). Dopaminecanhavebothexcitatory andinhibitory effects,dependingon thecellsitactson.Dopaminereleasing anddopaminereceivingcellsare found innumerousbrainareas.Oneprominent region,whichliesdeepwithinthe brain,iscalledthestriatum.Itconsists ofseveralcomponentsthatareinvolved inbehaviorssuchaslearningtoauto maticallyexecutecomplexmovements triggeredbyavoluntarycommand (e.g.,drivingacar).Anotherdopamine usingareaisthenucleusaccumbens, whichplaysaroleinlearningandper formingcertainbehaviorsinresponse toincentivestimuli(i.e.,motivation) (DiChiara1997).Activityinthenucleus accumbensinpart accountsforthe factthatpeopleperceivetheeffectsof drinkingalcoholortakingotherdrugs aspleasurable(DiChiara1997). Duringadolescence,thedopamine systeminthestriatumappearsto undergosubstantialchanges.Forexam

ple,studiesinratshavefoundthat dopaminereceptorlevelsinthestria tumincreaseduringearly adolescence butthendecreaseduring late adolescence andyoungadulthood(Teicheretal. 1995).Atthesametime,dopamine receptorlevelsinthenucleusaccum bensincreasedramatically. GABAistheprimaryinhibitory neurotransmitterinthebrainthatis, itrepressestheactivityofotherbrain cells.Alcoholgenerallyenhancesthe effectsofGABAonitsreceptors.This enhancedGABAactivationmayplaya roleinmediatingthesedativeeffectsof alcoholandothersedatingagents(Mihic andHarris1997).Inaddition,alcohols effectsonGABAanditsreceptorsare thoughttocontributetothedevelop mentoftolerancetoanddependence onalcohol(MihicandHarris1997). Likedopamine,theGABAsystem changessubstantiallyduringadoles cence.Studiesinratshavefoundthat thenumberofGABAreceptors,and thustheactivityoftheGABAsystem, increasesmarkedlyinseveralbrain structuresduringearlyadolescence (Moyetal.1998). Inadditiontothesetwoneurotrans mittersystems,asystemusingtheneu rotransmitterglutamatealsoappears to undergochangesduringadolescence. Glutamateinteractswithseveralrecep tors,includingonecalledtheNMDA receptor.Evidencefromanimalstudies indicatesthattheNMDAreceptor complexchangesduringpostnatal development,andthesechangesmay continueintoadolescence(McDonald etal.1990). Althoughitisbeyondthescopeof thisarticletoreviewthechangesoccur ringinvariousbrainstructuresand neurotransmittersystemsinmore detail,thisbriefdescriptiondemon stratesthatadolescenceisaperiodof profoundalterationsinbrainfunction. Therefore,itisreasonabletoexpect thatalcoholseffectsonthebrainand behaviormaydifferforadolescentsand adults.Thefollowingsectionswill reviewsomeofthedifferencesinsensi tivitytoalcoholthathavebeenidenti fiedusinganimalmodels.
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AlcoholandtheAdolescentBrain:AnimalModels

AdolescentsAreMore SensitiveThanAdults toAlcoholsMemory ImpairingEffects

AlcoholsEffectsonMemory Amongitsmanyeffectsonthebrain andbrainfunctionsuchasimpairing balance,motorcoordination,and decisionmakingalcoholinterfereswith thedrinkersabilitytoformmemories (i.e.,itisanamnesticagent).However, alcoholdoesnotimpairalltypesofmem ory equally.Alcoholdisruptsapersons abilitytoformnew, lastingmemories toafargreaterextentthanitinterferes withtheabilitytorecallpreviously establishedmemoriesortoholdnew informationinmemoryforjustafew seconds(seeWhiteandSwartzwelder 2004).Onestudyconductedwithyoung adultsages21to29foundthatintoxi

catedstudyparticipantscouldrecall itemsonwordlistsimmediatelyafter thelistswerepresented,buttheyhad greaterdifficultyrecallingtheinforma tion20minuteslater(Achesonetal. 1998).Interestingly,thiseffectwasmuch morepowerfulintheyoungersubjects inthisagegroupthatis,peopleintheir earlytwenties.Inaddition,alcohol particularlyaffectstheabilitytoform explicitmemoriesthatis,memories offacts(e.g.,namesandphonenum bers)orevents(e.g.,whatthedrinker didthepreviousnight).Becausediffer entbrainareasplayaroleintheforma tionofdifferenttypesofmemories, thispatternofalcoholrelatedmemory impairmentallowsresearcherstomake assumptionsaboutthebrainregions thataremostaffectedbyalcohol.Thus, thepatternofmemoryimpairment observedafterintoxicationissimilarto thatfoundinpatientswithdamageto a brainareacalledthehippocampus.

AlcoholandtheHippocampus
Thehippocampusislocateddeep underthebrainssurface(seefigure1) butisextensivelyconnectedwiththe outerlayerofthebrain(i.e.,theneo cortex).Itconsistsofonlyafewlayers ofcellsarrangedinacharacteristic shapewithseveralbendsandfolds. Theprimarycellsinthehippocampus arecalledpyramidalcellsbecauseof theirshape.Thehippocampuscanbe dividedintoseveralareas,andstudies inhumanshavefoundthatinsome patientswithaninabilitytoform newexplicitmemories,braindamage waslimitedtoasingleregionofhip pocampalneuronscalledtheCA1 region(ZolaMorganetal.1986). In rodents,theactivityofCA1cells correlatesstrikinglywithbehavior: EachCA1neurontendstoemit signalsprimarilywhentheanimalis inaspecificareaofitsenvironment. Forexample,cellAmaybeactive predominantlywhentheanimalis inthenortheastcornerofitscage, whereascellBmaybecomeactive whentheanimalentersthesouthwest cornerofthecage.Asaresult,these cellscanplayavery strongandspecific roleinspatiallearning(e.g.,theability tolearnthepaththroughamaze orthe locationofacertainitem,suchasa foodreward). Researchershaveusedthischarac teristicoftheCA1cellstoassessthe effectsofalcoholexposureandother interventionsonhippocampalcell activityinintact,livingrodents.Inone study, electrodeswere implantedinthe hippocampusofratsthatthenwere abletomovefreelyaroundtheircages. Aftertheanimalswereadministered alcohol,theactivitiesoftheirCA1cells were measured.Thisstudyfoundthat theactivityoftheCA1cellswasreduced whenalcohollevelsreachedatleast0.5 gramsperkilogram(g/kg)ofbodyweight andceasedalmostcompletelyathigher alcoholdoses(WhiteandBest2000). Thisfindingisconsistentwiththe hypothesisthatalcoholcaninterferewith theformationofnewexplicitmemories bydisruptinghippocampalfunction.
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Hippocampus

Hippocampus

Hippocampus

Hippocampus

Figure1 Locationofthehippocampus,anareaofthebrainthatappearstobe particularlyvulnerabletoalcohol'seffects.Itsitsbelowthesurfaceofthe neocortexintheratbrain(left)andthehumanbrain.

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AlcoholsEffectsonLongTerm Potentiation
Inadditiontointerferingwiththeactivity ofCA1cells,alcoholcanimpairother hippocampalfunctions.Oneofthese, a processcalledlongtermpotentiation (LTP),isanexperimentallyinduced adaptationofthenervecellconnec tionsinresponsetorepeatedactivation orstimulationoftheseconnections.2 Toillustrate,imaginetwoneuronsin thehippocampusaCA1neuron and a neuronfromaregioncalled CA3 thatconnectinthehippocampus,with theCA3neuronsendingsignalstothe CA1neuron.Totransmitthesignals, theCA3neuronreleasesaneurotrans mitter,whichtheninteractswithrecep torsonthesurfaceoftheCA1neuron,3 resultingintheformationofanew nervesignalintheCA1neuron(see figure2).Theintensityofthissignal dependsonvariousfactors,including thenumberofreceptorsontheCA1 neuron.WhentheCA3neuronfirst isexposedtoastimulus,itwillemita signalthatleadstoacertainlevelof responseintheCA1neuron.Thisis calledthebaselineresponse.TheCA3 neuronthencanbestimulatedexperi mentallyinaspecificpattern,aprocess thatresembleswhathappensduring actuallearningevents.Iftheoriginal stimulussubsequentlyisreapplied totheCA3neuron,itwillevokea responseintheCA1neuronthatis substantiallygreaterthantheresponse thatoccurredaftertheinitialstimula tion(i.e.,theresponseispotentiated). In otherwords,astheresultofthe patternedstimulation,theCA1cell becomesmore responsivetosignals emittedbytheCA3cell.Thispotenti atedresponseoftenpersistsforalong periodoftime,hencethenamelong term potentiation.Thereisaccumu latingevidencethatsomethinglike
2 Althoughtherehavebeensomedemonstrationsof LTPlikephenomenainthebrainduringcertaintypesof learning,thetermLTPitselfreferstoanexperimentally inducedchangeinbrainfunction. 3 Innormalbrainfunction,nervesignalsduringmemory formationarepassedfromotherareasofthecortextoa regionknownasdentategyrus,thentoCA3cells,CA1 cells,andfinallybacktothecortex.

LTPoccursnaturallyduringlearning andmemoryformation. Alcoholhasbeenshowntointerfere withLTPduringexperimentsusing hippocampalbrainslicesfromrats.In theseexperiments,alcoholconcentra tionscorrespondingtothoseachieved inhumansafterconsumingonlyone

ortwodrinksinterferedwiththeestab lishmentofLTP(Blitzeretal.1990). Thebrainsliceswerekeptinaspecial fluid,andtwoelectrodeswereintro ducedintothetissue,onethatallowed stimulationoftheCA3cellsandone thatrecordedtheresponsesoftheCA1 cells.Ifsufficientalcoholwaspresentin

CA3cell

CA1cell

CA3cell

CA1cell

Glumatereceptors

BeforeLTPInduction Response of CA1 cell to a given stimulation of the CA3 cell

AfterLTPInduction

Postconditioning measurements

LTP Baseline measurements

Time(minutes)
Applyconditioningstimulationtoproduce strongNMDAreceptoractivation

Figure2 Schematicrepresentationofthelongtermpotentiation(LTP)process. WhenahippocampalCA3cellisinitiallystimulated,itreleasesthe neurotransmitterglutamate,whichbindstoNMDAreceptorsonaCA1 cellandinducesaresponseofacertainsize(baselineresponse).One mechanismunderlyingtheinductionofLTPmaybethatwhentheCA3 cellisrepeatedlystimulatedintheproperpattern,thenumberofgluta matereceptorsontheCA1cellincreasesandthereceptorsbecome activated.IftheoriginalstimulusisthenreappliedtotheCA3cell,the resultingglutamatereleasewillinduceamuchgreaterresponseinthe CA1cell.Thisiscalledlongtermpotentiation.

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thesurroundingfluidduringtherepeated patternedstimulationoftheCA3cells, LTPwasnotdetectedintheCA1cells thatis,theirresponseremainedatthe baselinelevel.However,addingalcohol tothefluidafterthepatternedstimulation hadnoeffectonLTP,whichisconsis tentwiththeobservationthatalcohol consumptiondoesnotimpairrecall ofpreviouslyestablishedmemories. Althoughexperimentslikethismake ittemptingtoequateLTPwithactual learning,itisimportanttoremember thatLTPreallyisamanifestationof neuralplasticitythatsharessomecom monmechanismswithlearning.Even thoughactuallearningiscertainlymore complexthansimpleLTPinduced inthelab,theLTPprocessrepresents anexcellentopportunitytostudythe brainmechanismsunderlyingmemory andtheeffectsofdrugssuchasalcohol onthesemechanisms. Oneneurotransmittersysteminvolved intheestablishmentofLTPistheexci tatory neurotransmitterglutamateand itsNMDAreceptor.Whenthisrecep torisactivatedbyglutamate,itallows calciumtoenterthecells.Repeated calciuminflux,inturn,setsoffachain reactionleadingtolonglastingchanges inthestructureand/orfunctionofthe cellsthatcauseLTP.Alcoholhasbeen showntointerferewithactivationof theNMDAreceptor, therebyreducing calciuminfluxand,thus,thesubsequent changesincellfunctionthatresultin LTP.Researchersthinkthatthisisthe mainmechanismthroughwhichalco holpreventsestablishmentofLTP, althoughotherneurotransmittersystems alsomayplayarole(seeWhiteand Swartzwelder2004).

DifferentialEffectsofAcuteAlcohol onMemoryinAdolescentsandAdults Someevidencesuggeststhatalcohols effectsonmemoryandlearningare muchmoresevereinadolescentsthan inadults.Althoughdifficulttoassessin humans,agedifferencesinalcohols effectsonmemory canbestudiedin rodents.Oneapproachusesatestcalled theMorriswatermazetask.Inthistype ofexperiment,animalsareplacedina largecirculartankfilledwithopaque
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water.Theanimalsmustthenlocatea platform,submergedaboutaninch beneaththesurface,wheretheycanrest. Theabilitytorememberthelocation oftheplatformacrossrepeatedtrials requiresactivityofthehippocampus; thus,changesinhippocampalfunction canbedetectedbymeasuringtheani malsabilitytolearnthelocationofthe platform. Toassessagedependenteffectsof alcohol,Markwieseandcolleagues(1998) comparedtheperformanceofalcohol exposedadolescentandadultratsin theMorriswatermazetask.Eachanimal underwent5daysoftrainingtolearn thelocationoftheplatform.Before each trainingsession,onegroupofanimals receivednoalcohol,andtwoother groupsreceivedoneoftwodifferent alcoholdoses.Theinvestigatorsthen comparedhowlongittookthealcohol exposedandcontrolanimalstoremember thelocationoftheplatform.Among theadultanimals,onlythoseexposed tothehighestalcoholconcentration showedlearningimpairmentscompared withthecontrolgroup.Incontrast, adolescentanimalsalsoshowedimpair mentsaftertheyhadreceivedthelower alcoholdose(Markwieseetal.1998). Thisexperimentdemonstratesthat adolescentratsaremorevulnerableto alcoholseffectsonmemoryandlearn ingthanare adultrats.It isnotknown ifthesameagerelateddifferenceexists inhumans,ascorrespondingexperiments inhumanadolescentscannotbedone forobviousreasons.However,asmen tionedpreviously,onestudycomparing peopleintheirearlytwentieswithpeo pleintheirlatetwentiesfoundthatthe youngeragegroupseemedmorevul nerabletoalcoholinducedmemory impairment(Achesonetal.1998). Researchersalsohaveinvestigated themechanismsunderlyingagerelated differencesinsensitivitytoalcohols effectsonmemory.Theseanalyseshave demonstratedthatalcoholinduced inhibitionofLTPandofNMDA receptormediatedactivityweregreater inbrainslicesfromadolescentratsthan inbrainslicesfromadultrats.Forexam ple, instudiesusinghippocampalslices takenfromadolescentandadultrats, repeatedstimulationintheabsenceof

alcoholinducedLTPinsamplestaken frombothagegroups(Swartzwelderet al.1995a; Pyapalietal.1999).Infact, intheabsenceofalcohol,theLTPwas morepronouncedinadolescentthanin adultbraintissue.Whenalcoholwas added,however,LTPinductionwas reducedsubstantiallyoralmostcom pletelyblockedintheadolescenttissue, whereasittookmuchhigheralcohol concentrationstoinhibittheLTPprocess intissuefromadults. Similarexperimentscomparedthe activityoftheglutamate/NMDAsystem inresponsetostimulationinthepres enceorabsenceofalcoholinhippocam palbrainslicesfromadolescentand adultrats.Ittooksignificantlyhigher concentrationsofalcoholtoreduce NMDAreceptoractivityintheadult brainslices,comparedwiththosetaken fromadolescentanimals(Swartzwelder etal.1995b).4 Allofthesestudiesconfirmthe heightenedsusceptibilityoftheadoles centrodentbraintoalcoholinduced inhibitionofhippocampalfunction andmemoryformation.

AdolescentsAreLess SensitiveThanAdults toOtherAlcoholEffects

Astheprecedingsectionhasshown, adolescentanimalsare uniquelysensitive tosomeofalcoholseffectsonmemory. However,adolescentsseemlesssensitive thanadultstoothereffectsofdrinking, suchasimpairmentofmotorcoordina tion,sedation,andsusceptibilityto seizuresduringwithdrawal.

MotorCoordination
Oneofthemostobviouseffectsof alcoholconsumptioninhumansaswell aslaboratory animalsistheimpairment ofmotoractivityandcoordination. Alcoholinterfereswithapersonsability toperformtasksthatrequirebalance andmotorcoordination,suchasstand ingstill,walkinginastraightline,or
4

Greatersensitivityoftheglutamate/NMDAsystemin adolescentsisnotlimitedtothehippocampusbutalsois foundinotherregionsofthecortex.

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drivinganautomobile.Inanimals,alco hols effectsonmotorcoordinationcan bedemonstratedusingthetiltingplane test,inwhichananimalisplacedona horizontalplatformthatisgradually tilted,sothattheanimalmustadjust itspositiontomaintainitsbalance. Motorcoordinationisoneofthe primaryfunctionsofthecerebellum,an areaatthebaseofthebrain.Because thecerebellumcontinuestodevelop duringadolescence,itisreasonableto assumethatalcoholmightaffectmotor coordinationinadolescentsdifferently thaninadults.Toinvestigatethispossi bility,Whiteandcolleagues(2002a) analyzedthemotorcoordinationof adolescentandadultratsusingthetilting planetestbefore,andatvarioustime pointsafter,administeringalcoholat threedifferentdoses(1.0,2.0,and3.0 g/kgbodyweight).Theseresearchers foundthatthelowestalcoholdosedid notaffecttheanimals performancein eitheragegroup.Atalmostalltimepoints aftertheadministrationofthetwo higherdoses,however,theadultanimals weremoreimpairedthantheadolescent animals.Thesefindingsclearlydemon stratethat,incontrasttoalcoholseffects onmemory, adolescentratsappearto belesssensitivetoalcoholseffectson motorcoordinationthanadultrats.It isnotclearpreciselywhytheadolescent animalswere lesssensitivetoalcohol inducedmotorimpairment.Itisclear, however,thatthecerebellum,which playsacriticalroleinmotorcoordina tion,stillisdevelopingquiterapidly duringadolescence.Ifthecerebellum is lesssensitivetoalcoholduringthis period, thiscouldaccountforthedevel opmentaldifferenceinsensitivityto alcohol.Currently,itisnotknownif thisdifferenceinsensitivityalsoapplies tohumanadolescents.

theanimalsgetbackonallfourfeetif theyfallover.Whentreatedwithseda tiveagents,animalstemporarilylose thisrightingreflex,andtheduration ofthislossisameasureofthesedative potencyofanagent. Tobettercharacterizealcoholseffects onthedevelopingorganism,researchers alsohaveevaluatedalcoholssedative effectsinratsofdifferentages.Little andcolleagues(1996)injectedanimals fromthreeagegroupsjuvenileanimals (PD20),adolescentanimals(PD30), andadultanimals(PD60)withthree differentalcoholdoses,andfoundthe following: Whentreatedwiththelowestalco holdose(3g/kgbodyweight),none oftheadolescentanimalslosttheir rightingreflex,whereasonehalfof thejuvenileratsandtwothirdsof theadultratsdid. Adolescentanimalslosttherighting reflexforasignificantlyshorter periodoftimethanadultanimals. Whentheyregainedthereflex,ado lescentanimalsalsohadsignificantly higherbloodalcoholconcentrations thantheadultanimalshadwhen theyregainedtherightingreflex. Thejuvenileanimalsalsolostthe rightingreflexforasignificantly shortertimethantheadultanimals, althoughnotasshort astheadoles centanimals. Theseobservationsdemonstrate that,aswithalcoholsmotorimpairing effects,adolescentanimalsare substan tiallylesssensitivetoalcoholssedative effects.Mechanismsthatmaycontribute tothislowersensitivityarediscussedin thefollowingsection.

Sedation Anothercommoneffectofalcoholcon sumption thatcanbeobservedbothin humansandinanimalsissedation.With increasingalcoholconsumption,drinkers tendtobecomesleepyandeventually mayevenpassout.Inlaboratoryanimals, sedationcanbeassessedbyobserving therightingreflexthatnormallyhelps
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MechanismsThatMayContribute toReducedMotorImpairingand SedativeEffectsinAdolescents Researchershavenotyetidentifiedthe mechanismsthataccountforthefact thatadolescentsarelesssusceptibleto alcoholrelatedmotorimpairmentand sedationthanolderindividuals.Itis likely, however,thattheneurotransmit

terGABAanditsreceptorsplayarole inbothoftheseeffects.Asmentioned earlier,GABAisaninhibitoryneuro transmitter,andtheactivityofGABA anditsreceptorsisenhancedbyalco hol.Asaresult,theGABAsystemhas beenimplicatedinbothalcoholsseda tiveanditsmotorimpairingeffects. Studiesusingratshavefoundthatthe levelsofGABAreceptorsinvarious brainstructures,includingthecerebel lum,increasemarkedlythroughout adolescenceandreachtheirfinallevels duringearlyadulthood(Moyetal.1998). Thus,itappearspossiblethatadolescent ratsarelesssensitivetoalcoholinduced motorimpairmentandsedationbecause, comparedwitholderanimals,they havefewerGABAreceptorsonwhich alcoholcanact.Anotherpossibilityis thatthefunctionofGABAreceptorsis alteredacrossadolescentdevelopment inawaythatresultsinincreasedsensi tivitytoalcoholastheanimalgetsolder. Thecombinationofreducedsensi tivitytoalcohols motorimpairingand sedativeeffectsontheonehandand increasedsensitivitytoalcoholsmemory impairingeffectsontheotherhand couldbeparticularlyharmfultoadoles cents.Formostpeople,themaximum amountofalcoholtheycanconsumeis determinedbyalcoholsmotorimpairing andsedative effectsthatis,iftheydo notstopdrinkingvoluntarily, drinkers atsomepointbecomesoincapacitated thattheycannotcontinuetodrinkeven iftheywantto. If,likeadolescentani mals,humanadolescentsalsoare less sensitivetothesealcoholeffects,itappears plausiblethattheymightcontinueto drinklongerthanadults,achieving higherbloodalcoholconcentrationsin theprocess.Asaresult,theadolescents couldbecomeevenmorevulnerableto theeffectsofalcoholonmemoryand otherfunctionstowhichtheyaremore susceptiblethanadultsevenatlower bloodalcohollevels.

SusceptibilitytoSeizuresDuring Withdrawal Likeallneurotransmitters,GABAhas numerousfunctionsandeffectsinreg ulatingbrainactivity.Forexample,in additiontoplayingaroleinmotor

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AlcoholandtheAdolescentBrain:AnimalModels

impairmentandsedation,GABAalso isinvolvedinthedevelopmentofseizures duringalcoholwithdrawal.Longterm drinkingcausesthebodytoadjustto thecontinuedpresenceofalcoholso thatiteventuallyfunctionsnormally onlyinthepresenceofthedrug.At thatpoint,cessationofdrinkingcan leadtoanarrayofadversesymptoms, collectivelycalledwithdrawal,which includesymptomsmediatedbyGABA. Becausealcoholstimulatestheactivity ofGABAreceptors,longtermdrink ingcausesthebraintoproducefewer ofthesereceptors.Ifalcoholthenis withheld,GABAactivitysuddenlydrops offbecausefewerGABAreceptorsare availableandalcoholnolongeracti vatestheonesthatremain.Thisinsuf ficientGABAactivityhasbeenlinked tothedevelopmentofseizuresduring withdrawal.Ifadolescentsarelesssensi tive thanadultstoalcoholseffectson GABAanditsreceptors,adolescents alsoshouldbelesspronetoseizures duringwithdrawalfromalcohol. Thishypothesishasbeeninvestigated inrats.Fortheseexperiments,Acheson andcolleagues(1999)administered alcoholtoadolescentandadultratsfor 5 days,theninjectedtheanimalswitha chemicalthatinducesseizuresandrated theseverityanddurationoftheseizures. Thestudyfoundthatalthoughadoles centandadultanimalsexperienced seizuresofvariousseveritiesatasimilar rate,themore severe seizureslasted significantlylongerintheadultanimals thanintheadolescentanimals.Thus, thisstudysupportsthehypothesisthat adolescentanimalsarelesssensitive thanadultstoalcohols effectsonthe GABAsystem.

AlcoholExposureDuring AdolescenceAffectsBrain FunctionDuringAdulthood

Wheninvestigatingalcoholseffectson theadolescentbrain,itisimportantnot onlytofocusontheimmediateeffects (e.g.,memory impairment,motor impairment,orsedation)butalsoto exploretheconsequencesofalcoholuse ontheadolescentsfuturedevelopment. Becausethebrainundergoessuchexten
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sivechangesandremodelingduring adolescence,itisreasonabletoassume thatdisruptionoftheseprocessesby alcoholcouldleadtolongtermalterations thatinfluenceadultbehaviorand responsestoalcohol. Theprecedingsectionshavedescribed howacutealcoholexposureaffectsthe bodydifferentlyduringadolescence thanduringadulthood,withadolescents beingmoresensitivetosomeeffectsof alcoholandlesssensitivetoothers.In addition,adolescentsmayresponddif ferentlytorepeatedheavyalcoholexpo sure, adrinkingpatternalsoknownas chronicintermittentexposureorbinge drinking,whichisparticularlycommon amongadolescents.Bingedrinkingis characterizedbyrepeatedepisodesof heavydrinkingfollowedbywithdrawal. Severallinesofevidencesuggestthat theserepeatedwithdrawalepisodes contributetomanyoftheeffectsof chronicalcoholexposure onthebrain (seeWhiteandSwartzwelder2004). In onestudyofthelongtermcon sequencesofbingedrinkingduring adolescence,Whiteandcolleagues (2002b) studiedanimalsthatwere repeatedlyexposedtohighlevelsof alcoholduringadolescence.Thealcohol exposedandcontrolanimalswereeval uatedasadultswithrespecttoalcohols effectsonmotoractivity, usingthe tiltedplanetest.Asmentionedearlier, adultratsnormallyaremoresensitive thanadolescentstoalcoholinduced motorimpairment(i.e.,therats sensi tivitytomotorimpairmentincreases betweenadolescenceandadulthood). Thisstudyfound,however,thatrats repeatedlyexposedtoalcoholduring adolescencedidnotshowthisincrease insensitivitytoalcoholseffects(White etal.2002b);theseanimalsperformed aswellonthetiltedplanetestinadult hoodastheyhadinadolescence.In a controlexperiment,adultratswere exposedtothesameregimenofalcohol administrationasweretheadolescent animals.Whentheseadultratswere subsequentlytested,theirsensitivity toalcoholinducedmotorimpairment wasunchangeddespitetherepeated alcoholexposure.Thus,itisnotthe alcoholtreatmentpersethatleadsto reducedsensitivitytomotorimpair

ment;instead,itappearsthatalcohol exposureduringadolescenceinterferes withthedevelopmentalprocessesthat leadtoadultsensitivitytoalcohols effectsonmotorcoordination. Inasimilarexperiment,Whiteand colleagues(2000)evaluatedhowchronic intermittentalcoholexposureduring adolescenceaffectsratsspatialmemory inadulthood.Asdiscussedearlier,acute alcoholadministrationimpairslearning andmemorymoreinadolescentanimals thanitdoesinadults.Forthisexperi ment,adolescentandadultanimals wererepeatedlyexposedtohighdoses ofalcohol.Whenalltheanimalshad reachedadulthood,theinvestigators comparedtheirabilitytolearnwhere toretrievefoodinamazewiththat ofanimalswhichhadneverreceived alcohol.Theyfoundthatanimalsinall testgroups(i.e.,withorwithoutalco holadministrationduringadolescence oradulthood)learnedtoperformthe memorytaskequallywell.However, whentheanimalsreceivedalow dose ofalcoholjustbeforebeingtestedon thememorytask,thosethathadbeen exposedtoalcoholasadolescentsper formedworsethananimalsintheother threegroups(Whiteetal.2000).These resultsindicatethatrepeatedalcohol exposureduringadolescenceenhances theindividualssensitivitytoalcohols memoryimpairingeffectsduring adulthood.Similarresultswere obtainedinastudyofcollegestudents, whichfoundthatstudentswithahis tory ofbingedrinkingperformedworse onmemorytasksafterconsumingalco holthandidstudentswithoutsucha history (WeissenbornandDuka2003). Researchersalsohavedemonstrated thelongtermconsequencesofadoles centalcoholexposureonadultbrain functionbymeasuringtheelectricalbrain activityofadultratsthathadorhad notbeenrepeatedlyexposedtoalcohol duringadolescence.Usingelectrodes implantedinvariousregionsofthe animals brains,researchersexamined boththeelectroencephalogram(EEG), whichisameasure ofongoingbrain activity,andeventrelatedpotentials (ERPs),whicharespikesinbrainactiv ityinducedbyasuddenstimulus(e.g., a lightorsound).Oneofthestudies
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found that animals which had been exposed to alcohol during adolescence showed changes in the EEG pattern as well as in ERPs measured in various brain regions, particularly the hippocampus (Slawecki et al. 2001). These investiga tors noted that although similar effects have been reported following long-term alcohol exposure during adulthood, alcohol exposure during adolescence appears to result in more stable effects, especially on the hippocampus, after shorter periods of exposure than would be observed in adult animals. Similar experiments have examined the effects of an acute alcohol dose on the EEG of adult rats that had or had not been exposed to alcohol repeatedly during adolescence. A study by Slawecki (2000) found that although the acute alcohol dose significantly altered several EEG variables in the hippocampus and other brain regions of the control ani mals, these variables were not altered in the animals that had been exposed to alcohol during adolescence. In addition, the alcohol-exposed animals showed fewer behaviors indicative of intoxication in response to the acute alcohol dose than did the control animals. These findings suggest that alcohol exposure during adolescence leads to persistent and brain regionspecific changes in electrical brain activity in response to an acute alcohol dose during adulthood. In particular, the observation that some EEG responses to alcohol were reduced in the alcohol-exposed animals indicates that adolescent alcohol exposure can produce long-lasting changes in respon siveness to at least some alcohol effects.

Conclusions
Various avenues of research have demon strated that at least in laboratory animals, adolescence is a unique stage of brain development which is particularly sensi tive to the disrupting effects of alcohol. For example, in rodents, adolescent alcohol exposure increases the brains sensitivity to some alcohol effects (e.g., memory impairment) and decreases sensitivity to other effects (e.g., motor impairment and sedation). Furthermore, in rodents, alcohol exposure during
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adolescence not only has an immediate impact on brain function, it also may lead to consequences for various brain functions that last even into adulthood. To what extent these findings are appli cable to humans is a matter of debate, particularly because of the differences between humans and rodents in terms of the plasticity and time course of brain development. Nevertheless these findings suggest that similar processes might occur in humansa conclusion that is especially pertinent and worrisome because adolescence in humans often is the period when alcohol consumption begins and when particularly dangerous drinking patterns, such as binge drink ing, are common. This combination of frequent high alcohol consumption and increased vulnerability of the brain to alcohols harmful effects may result in cognitive deficits and other problems that persist far beyond adolescence. One brain area that seems to be par ticularly affected by adolescent alcohol consumption is the hippocampus, which plays a role in numerous cogni tive functions, including learning and memory. In fact, preliminary studies in humans have found that alcohol abuse during adolescence may be associated with a reduction in the size of the hip pocampus (De Bellis et al. 2000), which in turn could be a sign of impaired hippocampal function. Theoretically, alcohol could lead to cell death in the hippocampus through several mecha nisms (e.g., by excessive activation of the glutamate/NMDA receptor system). Several studies, however, have failed to detect obvious nerve cell loss after repeated exposure to various patterns of alcohol administration during ado lescence or early adulthood (see White and Swartzwelder 2004). Other studies, in contrast, have found that high-dose binge exposure to alcohol led to brain damage in adolescents but not in adults (Crews et al. 2000). These differences in findings may be accounted for by differences in the rodent strain used; in the pattern, dose, and route of alcohol administration; and in the brain regions studied. In addition, the long-term behavioral changes that follow chronic intermittent alcohol exposure during adolescence may involve subtle changes

in neuronal connections which are not easily measurable. Thus, additional research is necessary to elucidate the exact effects of alcohol on the adoles cent hippocampus and other brain structures and to better understand the long-term implications of adoles cent alcohol exposure.

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