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EvolvingBehaviorintheClinicalandExperimentalAmphetamine
1088
A
mJPsychiatry130:10.October1973
(Model)Psychosis
BYEVERETTH.ELLINWOOD,JR.,M.D..ABRAHAMSIJDILOVSKY,M.D.,ANDLINDAM.NELSON
Aparallelisdrawnbetweenseveralbehavioralcon-siellationsobservedintheevolutionofthehumanam-phetaminepsychosisandthemotor-postural-attitudinalmanifestationsinducedinanimalsbychronicampheta-mineintoxication.Onthebasisoftheresultsreported.atriple-layeredmodelofpsvchosisissuggestedandtherolesplayedbyparticipatingneurotransmittersandmechanismsarefurtherelaborated.
INACLINICALSETTING,
theamphetaminepsychosisde-velopsoveraperiodoftimeastheusergraduallyin-creaseshisintakeofamphetaminetoamountsrangingfrom150to2000mg.perday.Althoughtheparanoidpsychoticstateevolvesgraduallyasaresultofthischronicabuse,thepatientisseldomseenbyaphysicianuntiltheprocessisfaradvanced.Bythistimehepresentsafairlydistinctsyndrome,withdelusionsofpersecution,ideasofreference,visualandauditoryhallucinations,changesinbodyimage,hyperactivity,agitation,and
panic.
Inpreviousstudieswehaveaskedwhethertherearebehaviorsthatprecedethelaststageandmay,infact,berelatedtothedevelopmentoftheparanoid
schizo-
phrenic-likepicture.Morespecifically,wehavebeenin-terestedintheanlagenofthebehaviorsthatevolveovertimesinceseveraloftheantecedentbehaviorswehaveobservedinhumanchronicamphetamineabuserspresentfairlydistinctconstellationsorclusters(I,2).Oneoftheseconstellationsinvolvesanintensefeelingofcuriosity,oftenmanifestedbyrepetitious,stereotypedexamining,searching,andsortingbehaviors.Thisrepeti-tiousactivityhasbeenvariouslycalled“punding”(3),“hung-upactivity”(4),“obsessive-compulsivetenden-cies”(1,5),and“knick-knacking”(byinhabitantsoftheHaight-Ashburyscene).Itscharacteristicfeatureisen-gagementintasksthatprimarilyinvolvesmallbitsorminutiaeandamarkedenhancementofperceptualacuity
Readatthe125thannualmeetingoftheAmericanPsychiatricAssocia-tion,Dallas,Tex.,May1-5,1972.TheauthorsarewiththeBehavioralNeuropharmacologySection,De-partmentofPsychiatry.DukeUniversityMedicalCenter,Durham,NC.27710,whereDr.EllinwoodisDirectorandProfessorofPsychia-try.Dr.SudilovskyisResearchAssociate,andMs.NelsonisSeniorResearchTechnician.ThisworkwassupportedbyPublicHealthServicegrantsMH-07073andMH-l8904fromtheNationalInstituteofMentalHealthandby
funds
fromtheVeteransAdministration.
directedtowardtheseminuteobjects.Attimesthereareperceptuo-motorcompulsions,manifestedasrepetitiousstringingofbeadsorasactsofarranging,sorting,andlininguppebbles,rocks,orothersmallobjects(2).Mostoftheso-called“speedart”isrepletewithcomplicatedsynthesesofamultitudeofminutedetails,oftendepictinguniversalthemesormandalas.Speedusersarefrequentlyobservedtakingapartsuchobjectsastelevisionsets,watches,radios,andphonographs.Subsequently,thepartsmaybeanalyzed,arranged,sorted,filed,andcatalogedand,rarely,putbacktogether(2).Manypatientsreportasenseofsatisfactionassociatedwiththiscompulsive-likeconduct.Perhapsthebest-knownexampleofsearchingandex-aminingbehavioristhatofSherlockHolmes,whoseco-cainehabitwasdescribedbyDr.Watson:
Finallyhethrustthesharppointhome,presseddownthetinypiston,andsankbackintothevelvet-linedarm-chairwithalongsighofsatisfaction.Threetimesaday
formany
monthsIhadwitnessedthisperformance....
“Itiscocaine,”he[Holmes]said,“aseven-per-centsolu-
tion....
Isupposethatitsinfluenceisphysicallyabadone.Ifind
it,however,sotranscendentlystimulatingandclarifying
tothemindthatitssecondaryactionisamatterofsmallmo-
ment.
...
“Mymind,”hesaid,“rebelsatstagnation.Givemeprob-
lems,givemework,givemethemostabstrusecryptogram,
orthemostintricateanalysis,andIaminmyownproperat-
mosphere.Icandispensethenwithartificialstimulants.ButIabhorthedullroutineofexistence.Icraveformentalex-altation.Thatiswhy
Ihavechosenmyownparticularpro-
fession,orrathercreatedit,forIamtheonlyoneinthe
world.
...
“TothetrainedeyethereisasmuchdifferencebetweentheblackashofaTrichinopolyandthewhitefluffofabird’s-eyeasthereisbetweenacabbageandapotato.”“You
haveanextraordinarygeniusforminutiae,”I
[Watson]remarked(6,pp.610-612).Holmes’sdescriptionofhis“groovingon”puzzlesandcryptogramsandhispenchantformagnificentsynthesisofdetailstosolveagivencasearequiteanalogoustotheamphetamineaddict’sintensecuriosityandpre-occupationwithminutiae.Evenatalowpointinthedrug-usecycle,thesepersonswillseekoutstimulatingmechanicalorintellectualpuzzles.Thiscompulsionforanalysisiswidelyrecognizedinthe“speedscene.”Amphetamineaddictsfrequentlystatethattheearlyscanning,prying,probingbehaviorssubsequentlyevolveintoapleasurablesenseof“suspiciousness”intheorigi-
ELLINWOOD,SUDILOVSKY,ANDNELSON
AmJPsychiatry130:10.October1973
1089
nalmeaningoftheword-thatis,lookingbeneaththesurfaceforthetruthormeaning(literally,“tolookfrombelow”).Theydescribelookingformeaningfuldetailsorrelationshipsbetweendetails.Anotherprogressivesymptomnotedbythesepatientsisincreasedthinkingabout“meaningsandessences.”In-sightsarefrequentlyreceivedassignificantmajorrevela-tions,or“eurekaexperiences.”Forexample,onepatientstated,“Iputthingstogetherfromthepastandpresent.NowIthinkIknowwhatisgoingtohappentothisworld.”Thesesuddenemotionalinsightsandthecom-pulsiontoanalyzeavarietyofdetailstofindmeaningandexplanationwerecommontobothphilosophicalanddelusionalconcerns(2).Laterinthecourseofamphetamineaddiction,thedi-rectionoftheinquisitivebehaviorisreversedandtheaddictfeelsthatotherpeopleareprobing-watchingandspyingonhim.Atthistimethepreviouslypleasantsus-piciousnesstakesamoreparanoidform,leadingeven-tuallytofearorevenagitation,hyperreactivity,andpanic.Theaddictmaythenbegintomisinterpretslim-uliandoftentohaveillusionsandhallucinations.Thusitmightbesaidthattheinitialperiodsofpleasurablecur-iosityandsuspiciousnesssetthestagefortheeventualparanoidreaction.
EXPERIMENTALSTUDIESINANIMALS
Intheexperimentallaboratory,chronicallyintoxicatedanimalsmanifestevolvingclustersofbehaviorcorn-parabletothosejustdescribedinamphetaminead-dicts(7).Inourexperimentswehaveusedtheopera-tionalapproachthatthelaboratoryobservationshaveheuristicvalueinelucidatingthenatureoftheampheta-minepsychoticstateitself:wearesummarizinginthispapertheanimalbehaviorsthatareanalogoustothoseseeninhumanamphetamineabusers.Thedetailsoftheseexperiments,performedonrats,cats,andrhesusmon-keys,havebeenreportedelsewhere(7II).
Stereotypies
Stereotypedmovementsarethehallmarkofbothacuteandchronicamphetamineintoxication.Theymayconsistofasingleactivityperformedcontinuouslyorasequenceofafewactivitiesthatdominatebehavior(8,12,13).Usuallythesestereotypiesappearnondistractibleand“driven”(performedinarapid,repetitiousmanner).Theymostoftenevolvefrommotorcomponentsofinves-tigativebehavior.Inbothouracuteandchronicin-toxicationstudiesacrossspecies,theonecommonde-nominatorofamphetamine-inducedstereotypedmovementswasthattheywerecomposedofpatternsofsearchingandexamining(10).Themotorcomponents,atleast,ofthesepatternsarepresentinthestereotypiesofallspeciesstudied.Inmacrosmaticanimals,suchastherat,theprimarystereotypedmodeisthatofsniffing,althoughbitingandlickingarealsonoted.Asonemovesupthephylogenetic
scaletocats,thesniffingmovementsremain,butheadmovementsassociatedwithlookingarealsoprominent.
Inprimatesanewdimension,eye-handexaminationpat-terns,isadded.Thesehandmovementsarequitespecificandconsistprimarilyofforefingerprobing,pincer-likegrasping,picking,palm-clasping,andhand-examining.Theunderlyingpostural-motorcomponentsaresimilarinallofthesemotoractivities.Anindividualmotorcom-ponentofthesearching-examiningpatternscanbein-tegratedintoseveralstereotypiesandmaybedirectedci-thertowardexternalobjectsortowardtheanimal’s
own
body(asinpatternsofgrooming).Overtime,thestereotypedpatternsbecomemorerepe-
titious
andmoreconstricted.Figure1illustratesthegradualconstrictionofacat’sheadandneckmovementsthatorienttheheadforvisualregard.Overaperiodoftwoweeks,theorientingbackgroundmovementsoftentendtodropout,leavingasmall,pecking-likemovementoftheheadinanextremelyconstrictedpattern,asifthecatweresniffingatasmallcrumbortinymorseloffood.
AttitudesandPostures
Oneofthemostcharacteristicseriesofchangesob-servedincatsduringtheperiodofchronicintoxicationoccurredintheanimal’sattitude.’Themostfrequentcharacteristicofearlyamphetamineintoxicationwasanabnormalinvestigativeattitudeoperationallydefinedasactivelyreachingouttoorapproachingrestricteddc-mentsoftheenvironment,withanexcessivelycompulsiveappearance.Theevolutionofthestereotypedmotorbe-haviorwasintimatelyrelatedtotheabnormalinvestiga-tiveattitude(figure2)andattimesthisattitudewouldpersistinagivenanimalevenafterthemotorstereotypyhadceased.Anotherdistinctiveattitude,whichappearedprimarilyinthelaterdaysoftheintoxicationcycle,wasthereactiveattitudecharacterizedbysudden,disproportionatestartlereactionswithajumpy,agitatedquality.Thisab-normalreactivenesswasheraldedbyanincreaseinthespeedandsuddennessofmovementsand
was
laterac-companiedbyageneralincreaseinactivityandagitation.Attimestheanimals’movementsweresuggestiveofaka-thisiaanddyskinesia.Intheendstagesofthechronicin-toxicationcycle,eventhoughtheanimalmightheinafrozenposture,suddenorientingmovementstowardarealor“hallucinated”stimuluswereoftenobserved.
Manyanimalsappearedtobeincreasinglyawareofmi-
norstimuliintheirenvironmentandacutelyapprehen-siveaboutit.Thisintensehypersensitivity
to
theenvironment
wasa
dramaticreversalofthecompletedisregardfortransientenvironmentalstimulithatcharacterizedtheabnormal
investigativeattitude.Althoughintheendstagemuchof
thereactivenessappearedtobeorientedtoward“inter-nal”cues,therewasnoquestionthatminorexternalstimulioftenoverwhelminglyimpingedontheanimalinawaythattriggeredafearful,overreactiveorientingre-sponse.Aslight,remotesoundinthelaboratory,forcx-
‘Inourstudies“attitude”isoperationallydefinedas
bodypostureandactivityinrelationtotheenvironment.Thisincludestheanimal’sre-gardandreactionnotonlytohissurroundingsbutalsotohisownbody.
10MIN20MIN30MIN90MIN.
*Eachtracingrepresents30
seconds
ofactivityattheindicatedtimeafterthe
injection
ofamphetamineondayI.P10203090
FIGURE2
RelationshipBetweenAttitudesandStereotvpvDuringtheCourseofAmphetaminelnioxicaiion*
100Abnormalreactiveattitude
50
if)
-J
>
UJ
z
-J
0
U-
0
Li
0
z
Li
0
Li
a-
10050
0
10050
P10203090P10203090P
Abnormalinvestigativeattitude
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Stereotypyofhead-neckregion
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r
r
*hbarrepresentsthe
occurrence
ofthebehavior
inathree-minuteobserva-tion
period
ontheindicateddayduringthepreinjectionperiod(P)oratten,
20,30.or90minutesafterinjection.
AMPHETAMINEPSYCHOSIS
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AmJ
Psychiatry130:10.October1973
FIGURE1
ProgressoftheTipofa(‘at’sNose.TracedfromaSlow-MotionVideotape*
ample,mightcauseaviolentturningoftheheadorjump-ingbyacatthatignoredgrossmovementswithinitsimmediatefieldofvision.Oraglimpseofitsownimageontheshinywallofthecagewouldcauseacattojumpbackinapparentpanic.Notinfrequentlyacatwouldjumpbackandturnvigorouslytoonesideinresponsetoanonexistent(apparentlyhallucinatory)stimulus.Intheearlydaysofintoxication,thepersistentrestnc-tivenessanddirectednessoftheanimals’behaviorwerereflectedintheir“postural-attitudinal”setaswellasintheirstereotypedmovements.Asintoxicationprogressed,however,therewasincreasingdissociationbetweentheanimals’underlyingposturalbaseandthesuperimposedmovementsandattitude.Towardtheendofthein-toxicationperiod,agivenanimalmightchangehisactiv-itywhilemaintainingthesameposture-withtheresultthatthebehavior-posturerelationshipappeareddysjunc-tiveandbizarre.Thelaststageofintoxicationwasoftencharacterizedbyakathisia-likerepositioningandsteppingmovementsthathadthesameagitatedstarting-and-stoppingqualityfrequentlynotedinpsychiatricpatientswithmorechronicextrapyramidalmanifestationsinducedbyneuro-lepticdrugs.Towardthelastdayofthetwo-weekstudyperiod
many
animalsshowedtransientoradventitiousmovementsthatappearedtohavelittleornorelationshiptothemainvectorofbehaviorandthatattimesappearedincongruenttotheoverallbehavioralconfiguration.Thecompositepicturewasoneofhyperkinesia,inwhichthegradualbreakdownoforganizedbehavioraccompaniedanabnormallyarousedandoftenfearfulstate.
DISCUSSION
SimilaritiesBetweenExperimentalandClinicalAmphetamineIntoxication
Wehaveattemptedtorelatetheprogressivestagesof
chronicamphetamineintoxication
inanimalstotheevolvingstagesofbehavioralpsychopathologyobservedinhumanamphetamineabusers.
Becauseoftheircogni-
tive-perceptualnature,thesymptomsmosteminentlyre-latedtotheevolvingparanoidpsychosisaredifficulttocorrelatedirectlywithbehavioralmanifestationsinloweranimals.Remarkablesimilaritiesdoexist,however,andingeneralitappearsthattheevolutionofbehaviorinani-malmodelsisinmanywaysanalogoustothatnotedinhumanpatients.TableIpresentsourtriple-layered
p
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