substituting a long-acting dopamine uptake inhibitor

8/9/2019 Substituting a Long-Acting Dopamine Uptake Inhibitor

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Substituting a long-acting

dopamine uptake inhibitorfor cocaine preventsrelapse to cocaine seeking

PSYC463SITI NOR FATIMAH MAT JUSOP

NURDIYANA ABD HALIM


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OUTLINES

Introduction

Materials and MethodsResults

Discussion


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RELAPSE• Relapse to d !" !se as #a$o p o%le# &'

t(e t eat#e't o) d !" add&*t&o'• Ca!ses

– Re+e,pos! e to t(e d !" &tsel) – Co'd&t&o'ed d !"+ elated *!es a'd st esso s

• Use t(e #odel o) e&'state#e't to

e-al!ate %e(a-&o al a'd p(a #a*olo"&*al&'te -e't&o's to p e-e't elapse


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EFFORTS TO DE.ELOP LON5+ACTIN5REPLACEMENT MEDICATION

• A*t as a s!%st&t!te1 0(&le esett&'"d&s !pted dopa#&'e'e! ot a's#&ss&o'

• Repla*e#e't app oa*( (as %ee'ple#e'ted

– To t eat op&ate add&*ts – To #a'a"e '&*ot&'e add&*t&o'

• S!%st&t!t&o' t eat#e't #a2%e a'e e*t&-e st ate"2 &' *o*a&'eadd&*t&o'


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• Fo e,a#ple7 – s2't(et&* op&o&d1 %!p e'o p(&'e1 )a*&l&tated

e,t&'*t&o' o) *o*a&'e sel)+ad#&'&st at&o' a'datte'!ated *o*a&'e+&'d!*ed e&'state#e't &'

ats – o al ad#&'&st at&o' o) de,a#p(eta#&'e a'd

#et(a#p(eta#&'e (a-e s(o0' pos&t&-eo!t*o#es &' *o*a&'e add&*ts

• Re#a&' to %e s(o0' t(at a dopa#&'e+l&8es!%st&t!te 0&t( lo0 a%!se pote't&ala o ds lo'" te # p ote*t&o' ) o# elapseto *o*a&'e see8&'" as p ed&*ted %2 t(eo 2


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CURRENT STUDY• Used a (&"(+a9'&t21 lo'"+a*t&'" dopa#&'e

!pta8e &'(&%&to DUI 1 t(e N+s!%st&t!ted%e':ot op&'e a'alo" AHN+;


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• Tested t(e a%&l&t2 o) AHN+;


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MATERIALS AND METHODS OF THE STUDY


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SUBJECTS• =@ Male Lo'" E-a's ats @=+3=


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DRU5S

• All d !"s a-a&la%le &' t(e sel)+ad#&'&st a&o'*(a#%e 0e e d&ssol-ed &'


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SUR5ERY• Rats 0e e a'est(et&:ed 0&t( A-e t&'1

a'd *at(ete s 0e e pla'ted &'to t(e&"(t $!"!la -e&'1 e,&t&'" do sall2

%et0ee' t(e s*ap!lae• Rats 0e e t eated posts! "&*all2 0&t(

da&l2 &'$e*t&o's o) a't&%&ot&* )o @ da2s• Cat(ete s 0e e !s(ed 0&t(

(epa &'&:ed sal&'e %e)o e a'd a)teea*( sel)ad#&'&st at&o' sess&o'


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SELF ADMINISTRATION PROCEDURE

• Rats 0e e t a&'ed to le-el p ess )o *o*a&'e&')!s&o' a*t&-e a'd &'a*t&-e le-e s

• F&,ed+ at&o FR; s*(ed!led o)e&')o *e#e't &s !sed =<e&')o *e#e't sess&o' d! &'" ; (o!

sess&o'•

U'de 0e't da&l2 ;+(o! sess&o' !'t&lsta%&l&t2 * &te &o' ea*(ed• P &'" &'$e*t&o' 0e e 'ot "&-e' d! &'"

t a&'&'"


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• Fo! s!%st&t!t&o' " o!ps –

CO+SAL *o*a&'esal&'e 1 CO+AMPH *o*a&'e+AMPH


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• Rats 0e e e,posed to ;G s!%st&t!t&o'sess&o's %e)o e t(e *o*a&'e+p ed

e&'state#e't tests 0e e *o'd!*ted?• T(e %e(a-&o #et * &te &o' )o e,t&'*t&o'

0(e' t(e last 3 da2s o) s!%st&t!t&o'd& e ed o' a-e a"e ) o# t(e last 3 da2so) *o*a&'e t a&'&'"

• S!%st&t!t&o' sess&o's *o't&'!ed !'t&l all" o!ps #et t(&s * &te &o'1 e,*ept t(e" o!p e*e&-&'" AMPH s!%st&t!t&o'10(&*( s(o0ed 'o e-&de'*e o) e,t&'*t&o'


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REINSTATEMENT TEST• Co*a&'e ;< #" 8" o sal&'e 0as

ad#&'&ste ed &' t(e (o#e *a"e ;< #&'!tesp &o to pla*&'" t(e a'al &' t(e ope a't

*(a#%e s -&a &'$e*t&o' &'t ape &to'eal1 &?p?• t(e l&"(t st!l!s a'd t(e &')!s&o' p!#ps

0e e d&s*o''e*ted a'd p esses o' t(ea*t&-e o &'a*t&-e le-e (ad 'op o" a##ed *o'se !e'*es

• D !"+see8&'" %e(a-&o 0as assessedd! &'" ; (o! ?


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BRAIN SAMPLEPREPARATION

• T(e % a&'s 0e e ap&dl2 e#o-ed a'd pla*ed o'a % a&' #at &,1 a'd ;+## *o o'al sl&*es 0e e*olle*ted o' &*e+*old %! e

•

B&late al sa#ples ) o# t(e #PFC 0e e d&sse*tedo!t !s&'" a % a&' p!'*(e 1 ) o:e' &' l& !&d'&t o"e' a'd sto ed at +G< C?

• Ho#o"e'&:ed %2 "e'tle so'&*at&o' &' &*e *oldl2s&s %! e

• F&'all21 sa#ples 0e e %o&led )o 4 #&'!tes1d&-&ded &'to 0o 8&'" al& !ots a'd sto ed at+ < C !'t&l !se


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IMMUNOBLOTTIN5 ASSAYS ANDUANTIFICATION OF TAR5ET PROTEINS

• /este ' %lott&'" &s !sed to!a't&Ked t(e ta "et p ote&'s

)ollo0&'" sta'da d p o*ed! es• a't&%od&es !sed &' t(&s st!d2

&'*l!ded – a't&+*+Fos1 a't&+BDNF1 a't&+FADD1 a'd

a't&+p+Se ; ; FADD


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•

I##!'o ea*t&-&t2 o) ta "et p ote&'s0as dete*ted 0&t( t(e e'(a'*ed*(e#&l!#&'&s*e'*e ECL /este 'Blot Dete*t&o' s2ste# a'd -&s!al&:ed%2 e,pos! e to H2pe Kl# ECLa!to ad&o" a#s

• E,pe e'ts 0e e pe )o #ed %2!s&'" p ote&' a#o!'ts 8'o0' to %e0&t(&' t(e l&'ea a'"e o)#!'ola%el&'" )o ea*( ta "et

p ote&'


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RESULTS OF THE

E PERIMENT


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DUI SUBSTITUTION LEADS TO E TINCTION OF LE.ER ACTI.E PRESSESIN RATS /ITH A STABLE HISTORY OF COCAINE SELF+ADMINISTRATION


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• A)te ;G e,t&'*t&o'

sess&o's1 s!%st&t!t&'"sal&'e )o *o*a&'e st&ll"e'e ated so#e a*t&-ele-e espo'ses?

• AHN+;


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DUI SUBSTITUTION BLOC S COCAINE+INDUCED REINSTATEMENT OF DRU5+

SEE IN5 BEHA.IOUR• Co*a&'e &'$e*t&o's p od!*ed

o%!st e&'state#e't o) d !"+see8&'" %e(a-&o! &' t(e" o!p t(at e*e&-ed sal&'es!%st&t!t&o' CO+SAL+CO 10(e eas sal&'e &'$e*t&o's CO+SAL+SAL " o!p &'d!*ed o'l2 asl&"(t &'* ease &' espo'd&'"?

• CO+AHN


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PATTERNS OF PROTEIN E PRESSION IN THE #PFC PARALLEL CHAN5ES INREINSTATEMENT BEHA.IOUR AFTER

COCAINE PRIMIN5• DRU5 NAI.E RATS7 a*!te ad#&'&st at&o' o)*o*a&'e SAL+SAL+CO s&"'&K*a'tl2 &'* easedt(e #!'o ea*t&-&t&es o) *+Fos 6 1

p e*! so =G a'd #at! e ;;= BDNF1a'd total FADD p ote&' 6 &' t(e #PFC?

• RATS PRE+E POSED TO COCAINE7#!'o*o'te'ts o) t(ese p ote&'s d&d 'otd& e ) o# t(ose o) d !" 'a&-e ats a)te t(ee,t&'*t&o' o) *o*a&'e sel)+ad#&'&st at&o'? CO+SAL+SAL


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*+Fos• Co*a&'e p &'" p od!*ed

o%!st ele-at&o's &' *+Fose,p ess&o'? CO+SAL+CO

• AHN+;


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BDNF• I' ats 0&t( e,pe &e'*e &'*o*a&'e sel)+ad#&'&st at&o'1*o*a&'e *(alle'"e %e)o et(e e&'state#e't test&'d!*ed s&"'&K*a'tele-at&o's &' p e*! soBDNF1 a'd &' #at! e BDNF?

• DUI s!%st&t!t&o' dose+

depe'de'tl2 a'ds&"'&K*a'tl2 de* eased t(eo-e +e,p ess&o' o) #at! ea'd #at! e BDNFsel&*&ted %2 *o*a&'e

*(alle'"e?


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FADD•

FADD le-el &s ele-ateda)te *o*a&'e 0as "&-e'd! &'" e&'state#e't?

• Co*a&'e p et eat#e't )a&led to&'* ease t(e le-els o)FADD &' t(e #PFC &'

ats t(at -ol!'ta &l2 sel)+

ad#&'&ste ed t(e DUIs!%st&t!te o pass&-el2e*e&-ed &t d! &'" 2o8ed

p o*ed! e?


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5ENERAL O.ER.IE/• Repla*e#e't t eat#e't &' t(e d !" ta8&'"

*o'te,t 0&t( a DUI 0&t( lo0 a%!se l&a%&l&t2*a' lead to e,t&'*t&o' a'd p o-&de

es&sta'*e to elapse?• It &s asso*&ated 0&t( t(e %l!'ted

espo's&-e'ess to *o*a&'e *(alle'"e &'d !"+e,pe &e'*ed s!%$e*ts?

• De* eased *o*a&'e+&'d!*ed e,p ess&o' o)*+Fos1 BDNF a'd FADD p ote&'s &' t(e #PFCd! &'" t(e e&'state#e't p o*ed! e?


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THE DOPAMINE HYPOTHESIS• C(a'"es &' dopa#&'e t a's#&ss&o' t(at o**!

d! &'" a'd a)te d !" e,pos! e a e %el&e-ed to*o't &%!te to d !" e&')o *e#e't1 0&t(d a0ala'd elapse?

• It (as %ee' (2pot(es&:ed t(at a"e'ts 0&t( (&"(a9'&t2 )o t(e dopa#&'e t a'spo te DAT*o!ld %e !sed to s!pp ess 0&t(d a0al a'd d !"* a-&'"1 t(e e%2 #&t&"at&'" elapse %e(a-&o! ?

• St ate"2 &'-ol-es t(e !se o) a *o#pet&'"a"o'&st 0&t( slo0e e*epto o'set a'd o seta'd lo'"e (al)+l&)e t(a' *o*a&'e


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AHN+;


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AHN+;


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DUI SUBSTITUTION•

Res!lts o) t(e 2o8ed " o!p -ol!'ta 2 &'ta8eo) t(e s!%st&t!te a'd e,t&'*t&o' le-ep ess&'" 0as 'ot e !& ed )o t(e

epla*e#e't t eat#e't to p od!*e e'd! &'"

es&sta'*e to *o*a&'e+p ed e&'state#e't?• S!%st&t!t&o' t eat#e't p od!*ed e,t&'*t&o'

o) *o'd&t&o'ed &'te o*ept&-e *!es asso*&ated0&t( *o*a&'e 0&t(d a0al?

• Co*a&'e p &'" e&'state#e't o) *o*a&'esee8&'" de* eases 0&t( epeated *o*a&'ep &'"?


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NEURAL MECHANISM

P oposed *& *!&t 2 &'-ol-ed &' *o*a&'e+p &'" &'d!*ede&'state#e't S*(#&dt et al?1


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NEURAL MECHANISM• Bot( p el%&* a'd a'te &o *&'"!late *o t&*es a e

*e't al ele#e'ts o) t(e *& *!&ts #ed&at&'" * a-&'" a'dd !"+see8&'" %e(a-&o! ?

• Tet ototo,&'+&'d!*ed &'a*t&-at&o' o) t(e P LC %lo*8s

*o*a&'e+p ed e&'state#e't o) d !" see8&'" &' sel)ad#&'&st at&o' assa2s Cap &les et al ?


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NEURAL MECHANISM• T(e &'d!*t&o' o) *+Fos1 BDNF a'd

FADD p ote&'s &' t(e #PFC #a2 %easso*&ated 'ot o'l2 0&t( *o*a&'e+p ed e&'state#e't %!t also 0&t("e'e al se's&t&-&t2 to *o*a&'e?


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NEURAL MECHANISM• A*t&-at&o' o) *+Fos a'd ea l2 espo'se "e'es &'

t(e #PFC o**! s )ollo0&'" *!e+ a'd *o*a&'e+&'d!*ed e&'state#e't o) d !" see8&'"

C&**o*&oppoet al ?


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NEURAL MECHANISM• Data s!""est t(at DUI s!%st&t!t&o' a)te *o*a&'e

ta8&'" ed!*es *o*a&'e+&'d!*ed BDNF e,p ess&o'&' t(e #PFC o) ats 0&t( d&'&s(ed d !"

ea*t&-&t2 a'd s!s*ept&%&l&t2 to d !"+&'d!*edelapse?

•

T(e &'d!*t&o' o) FADD %2 *o*a&'e *(alle'"e 0as&'(&%&ted &' ats t(at e*e&-ed DUI s!%st&t!t&o't eat#e't?

• Ele-ated le-els o) %asal FADD (a-e %ee' )o!'d &'ats t(at d&spla2 e'(a'*ed *o*a&'e se's&t&:at&o'

a'd (a-e " eate p ope's&t2 to sel)+ad#&'&ste*o*a&'e 5a *&a+F!ste et al ?


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STREN5TH AND LIMITATION• T(e #ole*!la data p ese'ted s(o!ld %e &'te p eted

0&t( *a!t&o' d!e to t(e a%se'*e o) add&t&o'al " o!pso) ats t(at *o!ld (a-e %ee' t eated 0&t( sal&'e a)tes!%st&t!t&o'

•

T(e 'e! o*(e#&*al e-&de'*e p ese'ted &s o'l2*o elat&o'al?

• T(e spe*&K* #e*(a'&s#s e"a d&'" *(a'"es &'dopa#&'e t a's#&ss&o'1 espo's&%le )o s!%st&t!t&o't(e ap2 e e*t&-e'ess &' t(&s #odel o) elapse e#a&'to %e dete #&'ed?

• Data a e *l&'&*all2 ele-a't


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FUTURE RESEARCH•

Dete #&'e 0(et(e t(e t(e ape!t&*e e*ts o) t(e s!%st&t!t&o' t eat#e't a e*o'te,t spe*&K*?

• F! t(e &'-est&"at&o' &s 'eedede"a d&'" t(e elat&-e *o't &%!t&o' o)

DAT &'(&%&t&o' a'd M; e*epto %lo*8adeto t(e t(e ape!t&*+l&8e e e*ts o) AHN+

;


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CONCLUSION• DUI s!%st&t!t&o' 'ot o'l2 leads to

e,t&'*t&o' o) sel) ad#&'&st at&o'%e(a-&o! %!t also p e-e'ts

e&'state#e't o) d !" see8&'"&'d!*ed %2 *o*a&'e e+e,pos! e?


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REFERENCES• Cla a .el : !e:+S '*(e: et al?

substituting a long-acting dopamine uptake inhibitor

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