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Brain adenylate cyclase activity in the amphetamine sensitized rat
Prog. Neuro-PsychophormocoI 6 Biol Psychmt. Printed m Great Bntam. All rights reserved.
1985. Vol. 9. pp
721-724 CopyrIght
0
0278-5846185 $0.00 + 50 1985 Pergamon Press Ltd
BRAIN ADENYLATE CYCLASE ACTIVITY IN THE AMPHETAMINE SENSITIZED RAT MDKTIMER M&MEL&l, Deprtmnts
W&&ker
sm
cliId~*~
of Psychiatry,Lniversityof University*, Cntario,Canada,
RAM
MISHRA2,
mronto~ and
(Finalform,August 1985) Abstract Chiu,SimmandMishra,Ram:Bra.in adenylatecyclaseactivityinthe mlak,mkim?r., an@etamhe sensitizedrat.Pmg.Neurc-Psychp harmacol.& Biol. Psychiat.1985,2 (5/6): 721-724.
2. 3.
Agreateracti~ti~ofadenylatecyclasewas foundindopahne richareasofthese ratsbrains thsn innomalcontrolswhentheenzymewas testedwithscdi~fluorideand quanylimidcdiphosphate. These results parallelsimilarfindingsin the brainsof schizophmnics0bMned at postmrtfmand supporttheuseofanphetamine sensiti7ation in rats as armdel for schizophrenia.
Keywxds:
adenylatecyclase, d-m@&mine,
schizophrenia.
Introduction kpeated~strationof aqhetamines inmanproduces a syndruwofparsnoiddelusions ~l~withauditoryandvisualhallucinatians ina settingof clear consciousness (Angrist,1983; Segal and Schuckit,1983).Cncetheqndraneisestablish&loherdosesof aqhetahnes andevenstressful life circumstances canleadtiitsreawae (Utena, 1966; Segal and Schuckit,1983).The clinicalsynplmsandthe tendmcytorelapsegreatly resemblethepatterns foti inthe fmctionalqndrcmofparanoidschizophr~a. For thisreascol,considerableefforthasbeenexpendedinattemptstoclarifythenatureof this anphetaminesensitization.Ithasbeen suggestedthattheaugmmtation inkhaviour producedinanifialsbytherepeated~strationofd-Earphetaminemayserveasa~~ for this process (Segaland Schuckit,1983).In rats, for exaqle, the repeatedadministration of d-amphetamine prcducesearlier,mre intense,stereotypedactivity and apmgressMany days after the finaldoseofd-aqhetamine, reivelygreaterlocamtorreqmse. administrationofadosewhich initiallyhadonly armdesteffect, ncwpmduces a far greaterrespcmse. ESpwrimentalstudiescnthemechanismofthissensitizationhave focussedmthechanges in the rxnnker ofdopaminerecognitionsites,shcethisisamajor locus of d-aqhetamineaction. It has beenproposedthat repeated ahinistrationof d~~~p~~anincreaseinthen~ofpost_synapticdopaminereceptDrsora decreaseinthenu&erofdopamheautm-recepWrs. Eithermechanismcouldauqmznttk effectsof the dopmine releasedby d-aqhetamine. Homve~~,theexpezimentalfindingshave not consiskmtly supportedeitherhypothesis( Segal and Schuckit,1983). F&zcently,Msm,KleinmantiHanbau~ (1983)reportedthat a greateractivationof&mylate cyclasecould bs elicitedin hamgenates of the cmdate nucleusobW fran the brainsofschi~~csubjectsatpost-mortemthanincorresponding~~obtained franthebrainsof~~~~lsubjects~thisenymewastestedwiththespecificD1 agonist,SKF 38393,or with sodim fluorideor guanylimidodiphosphate. Greateractivati~ofadenylatecyclaseby~~fluoride~sdlsonoted inthenucleusaccm&nsOf schizophrenic~~butnotinthecerebellarmrtexorhippacanpus. Inkeepingwith sarlierstudies,nopreferentialzLctiMti~ofadenylatecyclasein~~~tes ~franschizophrenicswaso~~~dopaminewasusedastheagcsist(Carenzi et al, 1975). It~arglzedthatthis~sbecausedapamineactedthroughbothDlandD* recognitionsites and thesemediatedappositeeffects~theenzyrre,D1acti~~ itand D2 inhibitingit. AgreateradiMtionof~latecyclaseinthehrainsofschizophrenics,could,howsver,be denrmstratdwith a specificDlaqnistorwithactiva~rs sunmrizedtkirfindingsbysuggesting whichbypassedthereceptor. The investigators thatthecouplingofD1 recognitionsiteswith adenylatecyclasewas mre efficient-in the brainsof schizcphrenics. 721
M. Mamelaket al.
722
Iftheauqmzntationinbshaviourproducedbyrepeatedadbbtrationofd-artpheQmine in the rat is a nude1 for the ~tofparanoidschizophreniainman,thensimilax nxhanisu~shouldbeoperatinginboth. Wetherefore exami.nedthechangesindopamhe, scdiumfluorideandguanylimidcdipbsphate stimulatedaderylatecyclaseactivityin the brainsofratsduringthecourseofd-aqhetaminesensitization. We found similarchanges totbseinn!an. Sodi~fluorideand~limidodiphosphate~a~~latecyclase *a significantincrease inactivity,whilebpamineactivatedadenylatecyclaseciid not. Methods
~~~ofsixSpragueDawleyratsweretreatedintraperitolaeally~ceadayfor10 consecutivedayswitheitherd-aqhetaminesulphate, lOmg/kg, dissolvedinlmlof saline, ortithlmlsalinesolution. rrxxxrotoractivitywas assessedonday 5 z&day 11 for 45 minuteswithan~~~yregisteredphotocellactivitymeter. Theanimalswere sacrificed48 hours after the lastintrap&hxealdose. Huqienatesw~eprepxedfrom thestriatdlandfiesol~~hrainr~i~s~adenylatecyclasea~~ty~determined withdifferentccncentrationsof~,~~fluorideandguanyli using themethods previouslydescribedbytishraetal (1974). Results Alltheresults~inthetablesrepresentthemeanofG_~~fthestandard deviation. Tablel,detrmstratesthe significantincrease inl~toractivitywhich occurr&withrepeatedd-anphetamineS&ration. Tables 2 and 3 demrmst.ra*the effectsofrepeatedd-anp~tamirxachninistrationonsodi~fluoride,guanylimidodiphosphate arddopambe stirmlateaadenylatecyclaseactivityin~~tesof theratstriataland meso lhrbicregionsrespectively.InhothregionsbasdLadenylatecyclaseacti~tywasthe sameinthesalineandd-aqhebmineix!atedglxPJps. In&d-anphetaminetreatedgroups, bjever, scdi~fluorideandguanylhidodiphosphateproducedasignificantly greater actimvationoftheen!qmathaninthesalinetreatedcJroup. This effectof d-anqhetamine istrationwasnotobserv& whendopiDninewasusedastheenzynkzactivator. Table1 Effectsofchxmic anphetamineadministrationonlocarptor activity. ThEvaluesiMicatethe1 ocatlotoractivityincountsperforty five rrh-lutes Treaimsnt Group
DaY 5
Day 11
saline
l29+
35
240 +
26
A@Aznine
196 +
16
838*+ 40
DiSCUSSiC9l
melinkbetween ’ recepMrandadenylatecyclaseisregulatedby anintrjnsicmembraneproteiJlLS~G/Frotein. Thecouplingofthisprotein toadenylatecyclase,andhence, theactivityofadenylatecyclaseis enhancedby specific DlagonistsorbyagentssuchasNaFandguanylimi&x% 'p~sphatehichactdirectlycnit. Cm et al, 1983). Inthebrainsofschix@xenics,theexperim3ntal findingssuggest thatin~richareas,theG/Fproteinis~~closelycoupledtoadenylatecyclase thanitisinbrainsobtainedfrannannalrmbjects.This,then,couldserveasthebasis for the increasein dcphner gicactivitywhichhaslxenprqxxedas themsbbolicbasis for s&i* (-, 1981). CxlrprelilniMry datasuggestthatsimilarnebbolic eventsmediatethea~~~inbehaviaurproducedby~repeatedacBninistrationof d~tamineintherat~furthersupportsthe~~ti~that~sensitizaticnIMy8erveasan&elforparanoidschizqhrenh
D-amphetamine
effects
on brain
adenylate
cyclase
723
Table 2 Effectofchmnic anphetaminea&ninistrationon ratstriataladenylatecyclaseactivity DrugTreatment Group
# Basal
## Fluoride n Dqmine ** C+pNHp Sensitive Sensitive Stimulatfd
Saline
52.6 + 5.8
230.4+ 18.1
127.9+ 5.5 211.9 i 16.0
h&&anhe
56.7 + 2.6
370.4*f15.8
106.8+ 1.8 343.9*+15.8
enzymactivityis expressedbyFarples/qprotein/min. ### mzu.malstimulation&zainedby lO~@ofNaF. A maxim1 st.im.lation obtainedby 100 n+lof dopemine. ** maximalstimJ_ationcbtainedbylOnMofGppNHp (guanyUmidod-iPWte) * indicatesthatthevalueis significantly greaterthan the axrespondingvalue of the salinetreatedgroups.(p7 O.Ol,N=6) Table 3 Effectsofchronica@&amimadministrationonrat msolimbicadenylatecyclaseactivity !t!Jreatlnent Group
Drug
Saline
#Basal 48.22 3.7
hq&etamine 57.3f 4.2
## Fluoride4Dopmine ** GPPMIP Sensitive Stimulated Sensitive 280.8 + 18.4
134.0+ 18.2 363.8214.8
419.0*+3.7
122.8+ l.l.7 521.7*+17.8
enzymaticactivityis~ressedinproles/mgprotein/min. #f maximalstimlationobtamedby10rrMofNaF. A mximalstbmlationobtainedby1OOnMofdopamhe. ** mximlstirrpilationabtainedby1O~~p (guanylimih diphosphate,. * indicatesthatthevdlueissignificantlygreaterthanthe corresponding value of the salinetreatedgroup.(p> 0.01,~=61
References ANGRIST,B. (1983)
F%ychxes induced by central nervoussystemstimlantsandrelated drugs.In: Stimlants: Newcchemical,Behavioraland ClinicalPerspectives, I.creese (ed), ppl30. Rwen Press,New York. CAREhlZI,A.;GiEn,J.,tidotti,A, Scbartz,M.Trabucchi,M.,Wyatt,R. (1975) Dqqmine sensitiveadenylcyclaseinhuman caudatinucleus. Astudyincontrolsubjectsand schizqphrenicpatients.Zxch. Gen. Psychiatry32: 1056-1059. MEEID, M.,IUeirmm,J.,Hanbam,I. (1983). CoupUng of Dl recognitionsiteswithadenylate cyclaseinnuclei aamhns and caudatusof schizophrenics.Science,221: l304 - 1307. MISHFA,R.,Gardher,E.,Katmm,R.,Marhan ,M.(1974).mhancmmtofd~stimiLated ~y~acti~tyinratcaudateafterlesionsin substantianigra:evidence supersensitivity. Prcc.Natl.Acad,Sci.71: 3883-3887. SEW&P. (19811 Brain dopmhe recepimrs. P~logical Peviem 32: 229 - 313.
M. Mamelak
724
SEAT,, In:
et
al.
D., Sohuokit, M (19831.
Atximalxik3aelsofstilnulantinduced~. StiIInllants: NeurochemicalBehavioraandclinical Perspscti~,
I. creese (ed),pp 131 - 167, RavenPress,New York. mENA,H. (1966) Behaviouralabbwations in msthmphetarnizintoxicx&ed animalsandchmicalcoxrelatesinthebrain.In: PrcgresshBrain &search, T. Tbkizansand J. Schode, teds),pi 192 - 207, Elsevi~Publishhg0xpany,Ant3tmzdam. Irquiriesaridreprintrequests shculdbe addressedto: Dr.M.Mamzlak, Ehmn~Msdicalcentre, 2075 BayviewAvenue, !Ibmti, Cmtario. Canada. M4N3M5
1985. Vol. 9. pp
721-724 CopyrIght
0
0278-5846185 $0.00 + 50 1985 Pergamon Press Ltd
BRAIN ADENYLATE CYCLASE ACTIVITY IN THE AMPHETAMINE SENSITIZED RAT MDKTIMER M&MEL&l, Deprtmnts
W&&ker
sm
cliId~*~
of Psychiatry,Lniversityof University*, Cntario,Canada,
RAM
MISHRA2,
mronto~ and
(Finalform,August 1985) Abstract Chiu,SimmandMishra,Ram:Bra.in adenylatecyclaseactivityinthe mlak,mkim?r., an@etamhe sensitizedrat.Pmg.Neurc-Psychp harmacol.& Biol. Psychiat.1985,2 (5/6): 721-724.
2. 3.
Agreateracti~ti~ofadenylatecyclasewas foundindopahne richareasofthese ratsbrains thsn innomalcontrolswhentheenzymewas testedwithscdi~fluorideand quanylimidcdiphosphate. These results parallelsimilarfindingsin the brainsof schizophmnics0bMned at postmrtfmand supporttheuseofanphetamine sensiti7ation in rats as armdel for schizophrenia.
Keywxds:
adenylatecyclase, d-m@&mine,
schizophrenia.
Introduction kpeated~strationof aqhetamines inmanproduces a syndruwofparsnoiddelusions ~l~withauditoryandvisualhallucinatians ina settingof clear consciousness (Angrist,1983; Segal and Schuckit,1983).Cncetheqndraneisestablish&loherdosesof aqhetahnes andevenstressful life circumstances canleadtiitsreawae (Utena, 1966; Segal and Schuckit,1983).The clinicalsynplmsandthe tendmcytorelapsegreatly resemblethepatterns foti inthe fmctionalqndrcmofparanoidschizophr~a. For thisreascol,considerableefforthasbeenexpendedinattemptstoclarifythenatureof this anphetaminesensitization.Ithasbeen suggestedthattheaugmmtation inkhaviour producedinanifialsbytherepeated~strationofd-Earphetaminemayserveasa~~ for this process (Segaland Schuckit,1983).In rats, for exaqle, the repeatedadministration of d-amphetamine prcducesearlier,mre intense,stereotypedactivity and apmgressMany days after the finaldoseofd-aqhetamine, reivelygreaterlocamtorreqmse. administrationofadosewhich initiallyhadonly armdesteffect, ncwpmduces a far greaterrespcmse. ESpwrimentalstudiescnthemechanismofthissensitizationhave focussedmthechanges in the rxnnker ofdopaminerecognitionsites,shcethisisamajor locus of d-aqhetamineaction. It has beenproposedthat repeated ahinistrationof d~~~p~~anincreaseinthen~ofpost_synapticdopaminereceptDrsora decreaseinthenu&erofdopamheautm-recepWrs. Eithermechanismcouldauqmznttk effectsof the dopmine releasedby d-aqhetamine. Homve~~,theexpezimentalfindingshave not consiskmtly supportedeitherhypothesis( Segal and Schuckit,1983). F&zcently,Msm,KleinmantiHanbau~ (1983)reportedthat a greateractivationof&mylate cyclasecould bs elicitedin hamgenates of the cmdate nucleusobW fran the brainsofschi~~csubjectsatpost-mortemthanincorresponding~~obtained franthebrainsof~~~~lsubjects~thisenymewastestedwiththespecificD1 agonist,SKF 38393,or with sodim fluorideor guanylimidodiphosphate. Greateractivati~ofadenylatecyclaseby~~fluoride~sdlsonoted inthenucleusaccm&nsOf schizophrenic~~butnotinthecerebellarmrtexorhippacanpus. Inkeepingwith sarlierstudies,nopreferentialzLctiMti~ofadenylatecyclasein~~~tes ~franschizophrenicswaso~~~dopaminewasusedastheagcsist(Carenzi et al, 1975). It~arglzedthatthis~sbecausedapamineactedthroughbothDlandD* recognitionsites and thesemediatedappositeeffects~theenzyrre,D1acti~~ itand D2 inhibitingit. AgreateradiMtionof~latecyclaseinthehrainsofschizophrenics,could,howsver,be denrmstratdwith a specificDlaqnistorwithactiva~rs sunmrizedtkirfindingsbysuggesting whichbypassedthereceptor. The investigators thatthecouplingofD1 recognitionsiteswith adenylatecyclasewas mre efficient-in the brainsof schizcphrenics. 721
M. Mamelaket al.
722
Iftheauqmzntationinbshaviourproducedbyrepeatedadbbtrationofd-artpheQmine in the rat is a nude1 for the ~tofparanoidschizophreniainman,thensimilax nxhanisu~shouldbeoperatinginboth. Wetherefore exami.nedthechangesindopamhe, scdiumfluorideandguanylimidcdipbsphate stimulatedaderylatecyclaseactivityin the brainsofratsduringthecourseofd-aqhetaminesensitization. We found similarchanges totbseinn!an. Sodi~fluorideand~limidodiphosphate~a~~latecyclase *a significantincrease inactivity,whilebpamineactivatedadenylatecyclaseciid not. Methods
~~~ofsixSpragueDawleyratsweretreatedintraperitolaeally~ceadayfor10 consecutivedayswitheitherd-aqhetaminesulphate, lOmg/kg, dissolvedinlmlof saline, ortithlmlsalinesolution. rrxxxrotoractivitywas assessedonday 5 z&day 11 for 45 minuteswithan~~~yregisteredphotocellactivitymeter. Theanimalswere sacrificed48 hours after the lastintrap&hxealdose. Huqienatesw~eprepxedfrom thestriatdlandfiesol~~hrainr~i~s~adenylatecyclasea~~ty~determined withdifferentccncentrationsof~,~~fluorideandguanyli using themethods previouslydescribedbytishraetal (1974). Results Alltheresults~inthetablesrepresentthemeanofG_~~fthestandard deviation. Tablel,detrmstratesthe significantincrease inl~toractivitywhich occurr&withrepeatedd-anphetamineS&ration. Tables 2 and 3 demrmst.ra*the effectsofrepeatedd-anp~tamirxachninistrationonsodi~fluoride,guanylimidodiphosphate arddopambe stirmlateaadenylatecyclaseactivityin~~tesof theratstriataland meso lhrbicregionsrespectively.InhothregionsbasdLadenylatecyclaseacti~tywasthe sameinthesalineandd-aqhebmineix!atedglxPJps. In&d-anphetaminetreatedgroups, bjever, scdi~fluorideandguanylhidodiphosphateproducedasignificantly greater actimvationoftheen!qmathaninthesalinetreatedcJroup. This effectof d-anqhetamine istrationwasnotobserv& whendopiDninewasusedastheenzynkzactivator. Table1 Effectsofchxmic anphetamineadministrationonlocarptor activity. ThEvaluesiMicatethe1 ocatlotoractivityincountsperforty five rrh-lutes Treaimsnt Group
DaY 5
Day 11
saline
l29+
35
240 +
26
A@Aznine
196 +
16
838*+ 40
DiSCUSSiC9l
melinkbetween ’ recepMrandadenylatecyclaseisregulatedby anintrjnsicmembraneproteiJlLS~G/Frotein. Thecouplingofthisprotein toadenylatecyclase,andhence, theactivityofadenylatecyclaseis enhancedby specific DlagonistsorbyagentssuchasNaFandguanylimi&x% 'p~sphatehichactdirectlycnit. Cm et al, 1983). Inthebrainsofschix@xenics,theexperim3ntal findingssuggest thatin~richareas,theG/Fproteinis~~closelycoupledtoadenylatecyclase thanitisinbrainsobtainedfrannannalrmbjects.This,then,couldserveasthebasis for the increasein dcphner gicactivitywhichhaslxenprqxxedas themsbbolicbasis for s&i* (-, 1981). CxlrprelilniMry datasuggestthatsimilarnebbolic eventsmediatethea~~~inbehaviaurproducedby~repeatedacBninistrationof d~tamineintherat~furthersupportsthe~~ti~that~sensitizaticnIMy8erveasan&elforparanoidschizqhrenh
D-amphetamine
effects
on brain
adenylate
cyclase
723
Table 2 Effectofchmnic anphetaminea&ninistrationon ratstriataladenylatecyclaseactivity DrugTreatment Group
# Basal
## Fluoride n Dqmine ** C+pNHp Sensitive Sensitive Stimulatfd
Saline
52.6 + 5.8
230.4+ 18.1
127.9+ 5.5 211.9 i 16.0
h&&anhe
56.7 + 2.6
370.4*f15.8
106.8+ 1.8 343.9*+15.8
enzymactivityis expressedbyFarples/qprotein/min. ### mzu.malstimulation&zainedby lO~@ofNaF. A maxim1 st.im.lation obtainedby 100 n+lof dopemine. ** maximalstimJ_ationcbtainedbylOnMofGppNHp (guanyUmidod-iPWte) * indicatesthatthevalueis significantly greaterthan the axrespondingvalue of the salinetreatedgroups.(p7 O.Ol,N=6) Table 3 Effectsofchronica@&amimadministrationonrat msolimbicadenylatecyclaseactivity !t!Jreatlnent Group
Drug
Saline
#Basal 48.22 3.7
hq&etamine 57.3f 4.2
## Fluoride4Dopmine ** GPPMIP Sensitive Stimulated Sensitive 280.8 + 18.4
134.0+ 18.2 363.8214.8
419.0*+3.7
122.8+ l.l.7 521.7*+17.8
enzymaticactivityis~ressedinproles/mgprotein/min. #f maximalstimlationobtamedby10rrMofNaF. A mximalstbmlationobtainedby1OOnMofdopamhe. ** mximlstirrpilationabtainedby1O~~p (guanylimih diphosphate,. * indicatesthatthevdlueissignificantlygreaterthanthe corresponding value of the salinetreatedgroup.(p> 0.01,~=61
References ANGRIST,B. (1983)
F%ychxes induced by central nervoussystemstimlantsandrelated drugs.In: Stimlants: Newcchemical,Behavioraland ClinicalPerspectives, I.creese (ed), ppl30. Rwen Press,New York. CAREhlZI,A.;GiEn,J.,tidotti,A, Scbartz,M.Trabucchi,M.,Wyatt,R. (1975) Dqqmine sensitiveadenylcyclaseinhuman caudatinucleus. Astudyincontrolsubjectsand schizqphrenicpatients.Zxch. Gen. Psychiatry32: 1056-1059. MEEID, M.,IUeirmm,J.,Hanbam,I. (1983). CoupUng of Dl recognitionsiteswithadenylate cyclaseinnuclei aamhns and caudatusof schizophrenics.Science,221: l304 - 1307. MISHFA,R.,Gardher,E.,Katmm,R.,Marhan ,M.(1974).mhancmmtofd~stimiLated ~y~acti~tyinratcaudateafterlesionsin substantianigra:evidence supersensitivity. Prcc.Natl.Acad,Sci.71: 3883-3887. SEW&P. (19811 Brain dopmhe recepimrs. P~logical Peviem 32: 229 - 313.
M. Mamelak
724
SEAT,, In:
et
al.
D., Sohuokit, M (19831.
Atximalxik3aelsofstilnulantinduced~. StiIInllants: NeurochemicalBehavioraandclinical Perspscti~,
I. creese (ed),pp 131 - 167, RavenPress,New York. mENA,H. (1966) Behaviouralabbwations in msthmphetarnizintoxicx&ed animalsandchmicalcoxrelatesinthebrain.In: PrcgresshBrain &search, T. Tbkizansand J. Schode, teds),pi 192 - 207, Elsevi~Publishhg0xpany,Ant3tmzdam. Irquiriesaridreprintrequests shculdbe addressedto: Dr.M.Mamzlak, Ehmn~Msdicalcentre, 2075 BayviewAvenue, !Ibmti, Cmtario. Canada. M4N3M5