Pha maceu icals 2011, 4, 976-991; doi:10.3390/ph4070976
pha maceu icals
ISSN 1424-8247
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Re iew
Psychos imulan D ugs and Neu oplas ici y
Emilio Fe nandez-Espejo * and Nie es Rod iguez-Espinosa
Depa amen o de Fisiología Médica, Facul ad de Medicina, Uni e sidad de Se illa, A . Sanchez
Pizjuan 4, 41009 Se illa, Spain
* Au ho o whom co espondence should be add essed; E-Mail: [email p o ec ed];
Tel.: +34-95-455-6584; Fax: +34-95-455-1769.
Recei ed: 19 Ap il 2011; in e ised o m: 15 June 2011 / Accep ed: 23 June 2011 /
Published: 30 June 2011
Abs ac : D ugs o abuse induce plas ic changes in he b ain ha seem o unde lie
addic i e phenomena. These plas ic changes can be s uc u al (mo phological) o synap ic
(biochemical), and mos o hem ake place in he mesolimbic and mesos ia al ci cui s.
Se e al addic ion- ela ed changes in b ain ci cui s (hypo on ali y, sensi iza ion, ole ance)
as well as he ou come o ea men ha e been isualized in addic s o psychos imulan s
using neu oimaging echniques. Repea ed exposu e o psychos imulan s induces
mo phological changes such as inc ease in he numbe o dend i ic spines, changes in he
mo phology o dend i ic spines, and al e ed cellula coupling h ough new gap junc ions.
Repea ed exposu e o psychos imulan s also induces a ious synap ic adap a ions, many o
hem ela ed o sensi iza ion and neu oplas ic p ocesses, ha include up- o
down- egula ion o D1, D2 and D3 dopamine ecep o s, changes in subuni s o G p o eins,
inc eased adenylyl cyclase ac i i y, cyclic AMP and p o ein kinase A in he nucleus
accumbens, inc eased y osine hyd oxylase enzyme ac i i y, inc eased calmodulin and
ac i a ed CaMKII in he en al egmen al a ea, and inc eased del aFosB, c-Fos and AP-1
binding p o eins. Mos o hese changes a e ansien , sugges ing ha mo e las ing plas ic
b ain adap a ions should ake place. In his con ex , p o ein syn hesis inhibi o s block he
de elopmen o sensi iza ion o cocaine, indica ing ha ea angemen o neu al ne wo ks
mus de elop o he long-las ing plas ici y equi ed o addic ion o occu .
Sel -adminis a ion s udies indica e he impo ance o glu ama e neu o ansmission in
neu oplas ic changes unde lying ansi ion om use o abuse. Finally, plas ic changes in
he addic ed b ain a e enhanced and agg a a ed by neu oin lamma ion and neu o ophic
disbalance a e epea ed psychos imulan s.
OPEN ACCESS
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Keywo ds: cocaine; amphe amine; neu oplas ici y
1. In oduc ion
The e m neu onal plas ici y, in wide sense, e e s o he neu obiological basis ha allows adap i e
changes in beha io , mo i a ion and emo ions, and i is also on he basis o maladap i e changes
ela ed o addic i e phenomena [1]. Two ypes o neu oplas ici y can be dis inguished: s uc u al
plas ici y and synap ic plas ici y. S uc u al plas ici y e e s o changes in neu onal mo phology
(including axons, dend i es and dend i ic spines), he genesis and supp ession o synapses, and he
genesis o new neu ons (neu ogenesis) and neu i es (neu i ogenesis). Synap ic plas ici y e e s o
biochemical and neu ochemical modi ica ions ela ed o changes in synap ic ac i i y, which leads o
endu ing changes in synap ic e icacy, and in beha io acco dingly. O he addic ion- ela ed p ocesses
a e associa ed wi h neu oplas ici y, o ins ance d ug sensi iza ion, sel -adminis a ion, d ug-seeking
and hypo on ali y. These phenomena ha e been analyzed in dep h, mos ly in ela ion o epea ed
psychos imulan s, du ing he las yea s.
Addic i e d ugs o abuse ha e he po en ial o induce addic ion h ough endu ing changes in
neu onal plas ici y, al e ing neu o ansmission sys ems, he s eng h and du a ion o synap ic con ac s,
neu onal mo phology, e c. In o he e ms, addic ion is a disease whose neu opa hology is based on
abe an s uc u al and synap ic plas ici y. By changing b ain ci cui s, addic i e d ugs impai he
de elopmen o beha io al s a egies owa ds biological s imuli in a o o p og essi ely g ea e
o ien a ion o beha io s owa ds d ug seeking and d ug- aking s a egies. Endu ing d ug-induced
neu oplas ici y es ablishes a maladap i e o ien a ion o he en i onmen ha mani es s as: i) impai ed
abili y o egula e he d i e o ob ain and use d ugs, and ii) educed d i e o ob ain na u al ewa ds.
Psychos imulan d ugs such as amphe amine and cocaine a e p o o ypic d ugs inducing neu oplas ici y
changes, and hey ha e been ex ensi ely s udies du ing he las yea s.
2. Sensi iza ion, a Model o Neu al Plas ici y
The epea ed adminis a ion o d ugs o abuse such as cocaine and amphe amine p oduces a
p og essi e inc ease in locomo o ac i i y o e ime, e e ed as mo o sensi iza ion. Mo o
sensi iza ion is conside ed as a model o neu al plas ici y [2-4], and neu oadap a ions media ing
sensi iza ion could unde lie some o he beha io al changes associa ed wi h ch onic d ug abuse [5].
Ch onic psychos imulan exposu e p oduces biochemical adap a ions in speci ic b ain egions hough o
media e ac i a ing p ope ies o hese d ugs [3,6]. The mesolimbic sys em is he mos impo an sys em
in ol ed in hese adap a ions, which comp ises dopamine gic neu ons in he en al egmen al a ea
(VTA) and hei p ojec ions o he limbic o eb ain such as he nucleus accumbens [3,7]. O he s uc u es
such as p e on al co ex, amygdala and hippocampus a e also in ol ed. Recen ly Pe ez e al. [8]
epo ed ha sensi iza ion o cocaine gene a es a high e iciency o hippocampal synap ic plas ici y
ha may unde lie he abe an engagemen o lea ning p ocesses occu ed du ing d ug addic ion.
A a biochemical le el, y osine hyd oxylase (TH) and N-me hyl-
D-
aspa a e ecep o 1
(NMDAR1) exp ession in he VTA a e ound o be inc eased a e epea ed psychos imulan and o he
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978
d ugs o abuse [9-12], and hese changes a e known o be ela ed o mo o sensi iza ion. Thus TH
up- egula ion leads o augmen ed dopamine neu o ansmission in he VTA and nucleus accumbens [9,10],
a c i ical ea u e o he de elopmen o sensi iza ion. Repea ed d ug exposu e is known o inc ease
ex acellula dopamine le els in he nucleus accumbens [13,14], and acu e o ch onic cocaine di ec ly
induces augmen a ion o dopamine elease in he nucleus accumbens. Repea ed cocaine exposu e also
leads o down- egula ion o D2 ecep o s in he en al egmen al a ea, oge he wi h sensi iza ion o
D1 ecep o s loca ed o he glu ama e gic e minals o he VTA, all oge he inducing an augmen ed
dopamine gic ac i i y in his a ea as well [3,15-18]. NMDA ecep o s become mo e pe meable o
calcium a e ch onic cocaine’s adminis a ion, ano he c i ical ea u e in he mo o sensi iza ion
p ocess [19]. D1 ecep o s o he nucleus accumbens become up egula ed du ing sensi iza ion, and
in usion o a D1R agonis in o his nucleus a e known o enhance cocaine-induced beha iou al
sensi iza ion [20]. NMDARs a e loca ed on non-DA neu ons wi hin he VTA and hey play a majo
ole in cocaine-induced sensi iza ion addic i e beha io [21].
The endocannabinoid sys em is also in ol ed in sensi iza ion p ocesses o psychos imulan s. The
b ain con ains an endogenous cannabinoid sys em ha pa icipa es in se e al p ocesses such as
nocicep ion, emo ion, mo o con ol, and ewa d [22]. The endocannabinoid sys em and CB
1
ecep o s
(CB
1
Rs) a e in ol ed no only in he ein o cemen p ope ies o ∆
9
- e ahyd ocannabinol [23], bu
also o se e al d ugs o abuse such as cocaine [24]. The o e all pic u e is ha cannabinoid CB
1
R
appea o be in ol ed in he pe sis ence o cocaine addic ion [25], a ec ing he exp ession, no
induc ion, o sensi iza ion. Thus, sys emic injec ions o imonaban , ligand o CB
1
ecep o s wi h
imonaban does no a ec he de elopmen o cocaine’s sensi iza ion in a s [26], bu he exp ession
o cocaine’s sensi iza ion has been epo ed o be educed by p e ea men wi h imonaban [27,28].
Silencing accumbal CB
1
R wi h siRNAs (using len i i al-media ed silencing o CB
1
R) leads o s ong
inc ease in mo o ac i a ing e ec s o cocaine, and mo o sensi iza ion is no a ec ed
(unpublished esul s).
Ou s udies indica e ha , a he le el o he en al egmen al a ea,
D-
se ine, an endogenous ligand
o he glu ama e gic NMDA ecep o , is in ol ed in sensi iza ion e ec s o psychos imulan s [29].
As ocy es and neu ons exp ess
D
-amino acid oxidase (DAO, syn hesizing enzyme o
D
-se ine) and elease
D-
se ine [30-32].
D-
se ine modula es NMDA ecep o ac i i y in he cen al ne ous sys em [33-35], and i
ac s h ough binding o NMDA ecep o s a he glycine si e, he eby acili a ing hei ac i a ion [25].
In his con ex , sensi iza ion- ela ed changes in he VTA ha e been compa ed o long- e m po en ia ion
(LTP) in he hippocampus. Besides i is known ha a single injec ion o cocaine can induce LTP o
AMPA ecep o -media ed cu en in dopamine gic neu ons in he VTA [36]. S imula ion o NMDA
ecep o s is needed o he de elopmen o cocaine’s sensi iza ion [37-39]. The NMDA ecep o
consis s o se e al dis inc binding si es iden i ied by he ligand: glu ama e o NMDA, PCP o
MK-801, glycine, as well as Mg
2+
-binding si e.
D-
Se ine and glycine a e co-agonis s wi h glu ama e
o he NMDA ecep o ionopho e [40], and co-agonism in he VTA is needed o he ini ia ion o
locomo o sensi iza ion o cocaine.
Sensi iza ion is also media ed by calcium and calmodulin-kinase II (CaMKII) signaling in he
en al egmen al a ea. Thus, enhanced le els o calcium in he VTA media e locomo o ac i a ing
e ec s o cocaine [16,18]. Glu ama e gic AMPA and NMDA ecep o s along wi h
L
- ype calcium
channels a e in ol ed in hese ac i a ing e ec s, because hey become mo e pe meable o calcium
Pha maceu icals 2011, 4
979
a e cocaine’s adminis a ion [18]. Calcium binds calmodulin (calcium/CaM complex) and hen
calcium-dependen kinases such as CaMKII bind calcium/CaM become phospho yla ed and ac i a ed
by calmodulin kinase-kinase (CaMKK). I is well known ha cocaine injec ions enhance o al CaMKII
p o ein in he VTA [39]. Supp essing CaMKII ac i i y in he en al egmen al a ea enhances he acu e
esponse o 15 mg/kg cocaine, and a enua es he ini ia ion o cocaine-induced beha io al sensi iza ion
in a s [39]. CaMKII is a ansduce o calcium signaling, his kinase being exp essed in many b ain
egions [41,42], including he VTA [39]. Calcium signaling pa hways play a pi o al ole in synap ic
plas ici y and memo y o ma ion [43,44], as well as CaMKII [45]. CaMKII unc ions as a po en
s imula o o calcium-dependen gene exp ession, and i ac i a es se e al ansc ip ion ac o s such as
CREB, which is phospho yla ed on he egula o y Se 133 esidue [46,47]. CREB ac i a ion in he
VTA is di ec ly in ol ed in sensi iza ion as explained, and egula es y osine hyd oxylase (TH)
ansc ip ion [48].
3. S uc u al Plas ici y a e Psychos imulan Consump ion
Repea ed exposu e o psychos imulan s induces mo phological changes in he mesolimbic a ge a eas
such as inc ease in he numbe o dend i ic spines, changes in he mo phology o dend i ic spines, and
al e ed cellula coupling h ough new gap junc ions [49-51]. Se e al expe imen al da a sugges ha
ea angemen o neu al ne wo ks mus de elop o he long-las ing plas ici y equi ed o sensi iza ion
o occu . P o ein syn hesis inhibi o s block he de elopmen o sensi iza ion o cocaine [52], and pups
younge han h ee weeks old, which a e oo imma u e o de elop neu al ne wo ks, do no become
sensi ized o psychos imulan s [53]. Hence sensi iza ion is also linked o mo phological changes in
ewa ding ci cui s.
A c mRNA and A c p o ein, ma ke s o neu i ic ou g ow h, ha e been epo ed o be up egula ed in
he do sal s ia um a e ch onic cocaine in a s [54], and down egula ion o mielin- ela ed genes akes
place in he nucleus accumbens o human cocaine abuse s [55]. Enhancemen o del aFosB and AP-1
p o eins has been pos ula ed o subse e hese mo phological changes [3]. In ac , he ansc ip ion ac o
del a osB accumula es in dopamine- e minal ields in he co ex and s ia um [3,56], and i is a s ong
candida e o media ing endu ing changes in hese egions. In ac , inc ease in dend i ic spine densi y has
been epo ed in accumbens spiny neu ons du ing ex ended abs inence om psychos imulan s [57], and
his inc ease is media ed by del aFosB s imula ion o Cdk5 [51].
Ano he change in p o ein syn hesis ha is pa icula ly impo an in es ablishing d ug-induced
neu oplas ici y is a ise in b ain-de i ed neu o ophic ac o (BDNF). The endu ing changes in BDNF
accumula e wi h inc easing pe iod o abs inence [27,58,59], and BDNF p omo es o ms o synap ic
plas ici y such as dend i ic spine o ma ion [60]. This p o ein is ano he s able neu oplas ici y
candida e ha may con ibu e o pe sis ence o addic ion and d ug-seeking beha io .
I is o g ea in e es ha simila neu oplas ic changes ake place in di e en ein o cemen - ela ed
beha io s. Thus epea ed sexual beha io induces a sensi ized locomo o esponse o amphe amine in
a s, and he numbe o dend i es and spines in he nucleus accumbens is inc eased wi h sexual
expe ience. Sexual expe ience induces unc ional and mo phological al e a ions in he mesolimbic
sys em simila o epea ed exposu e o psychos imulan s, hence some al e a ions in he mesolimbic
sys em a e common o na u al and d ug ewa d and migh play a ole in gene al ein o cemen [61].
Pha maceu icals 2011, 4
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4. Sel -Adminis a ion and Neu oplas ici y
The e is an impo an li e a u e on he neu oplas ic changes a exci a o y synapses in he b ain
ewa d ci cui s associa ed wi h psychos imulan sel -adminis a ion in oden , an expe imen al model
which is much mo e likely o help unde s anding he neu al basis o d ug addic ion. In ac , se e al
s udies ha e demons a ed ha olun a y d ug in ake h ough a sel -adminis a ion pa adigm induce
di e en changes o hose obse ed a e non-con ingen d ug-exposu e [62-65]. Sel -adminis a ion
s udies indica e ha cocaine induces an enhancemen o glu ama e gic unc ion in VTA dopamine
neu ons. This e ec o cocaine is no by i sel because i is necessa y a s ong pai ing be ween he d ug
and a cue, poin ing o he g ea impo ance o condi ioned esponses o synap ic plas ici y a e d ugs
o abuse [65]. Glu ama e ecep o s such as mGlu5 ecep o s a e in ol ed in cocaine-induced plas ici y
in VTA dopamine gic cells, bu mGlu5 ecep o may no be essen ial o psychos imulan beha iou al
sensi iza ion and consolida ion o addic ion [66].
In his con ex , he nucleus accumbens and i s NMDA ecep o s, ano he ype o glu ama e
ecep o s, a e mo e in ol ed in pe sis en addic ion, h ough he modula ion o long e m dep ession
(LTD), a o m o synap ic plas ici y. Kasane z e al. [67] ha e sugges ed ha a ailu e o an indi idual
o coun e ac he impai men in NMDAR-LTD a e ch onic cocaine con ibu es o he ansi ion o
addic ion. Sel -adminis a ion s udies also indica e ha AMPA ecep o s in he nucleus accumbens a e
in ol ed in cocaine-seeking a e addic ion consolida ion. Thus he numbe o AMPA ecep o s in he
nucleus accumbens is inc eased a e p olonged abs inence om cocaine sel -adminis a ion. New
AMPA ecep o s lacking glu ama e ecep o 2 (GluR2) a e added, and hese ecep o s media e he
incuba ion o d ug c a ing [68]. All hese s udies s eng hen he concep han ansi ion om use o
abuse akes place in limbic s uc u es such as he nucleus accumbens and ha glu ama e
neu o ansmission is associa ed o plas ic changes media ing his ansi ion and c a ing esponses
du ing wi hd awal.
5. Neu oimaging and Psychos imulan s
Addic ion- ela ed changes in co ical ci cui s has been isualized in addic s o psychos imulan s
using neu oimaging echniques. These s udies indica e ha he e is a educ ion in p e on al co ex
(PFC) me abolism and blood low in addic ed o cocaine [69]. This “hypo on ali y” is a s ong
indica o o educed abili y o egula e d ug-seeking o o inhibi mo i a ional d i es ela ed o d ug
addic ion, because a ec ed egions a e an e io cingula e and en al o bi al co ex, which a e s ongly
linked o mo i a ed beha io , swi ching and a en ion esponses [70,71]. D2 dopamine ecep o
unc ionali y seems o be linked o his hypo on ali y, as sugges ed by Volkow e al [72]. These
au ho s obse ed ha he e is an associa ion be ween le el o dopamine D2 ecep o s, and me abolism
in he o bi o on al co ex in me hamphe amine and cocaine abuse s. They p opose ha D2
ecep o -media ed dys egula ion o he o bi o on al co ex could unde lie a common mechanism o
loss o con ol and compulsi e d ug in ake in d ug-addic ed subjec s. Fu he mo e, i addic ed subjec s
a e exposed o cues p e iously associa ed o he d ug, he e is a ma ked ac i a ion in he p e on al
co ex [69,73]. The ac i i y in he PFC has been posi i ely co ela ed wi h he in ensi y o cue-induced
desi e o he d ug, an index o c a ing.

Pha maceu icals 2011, 4
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Psychos imulan s induce dopamine elease in en al and do sal s ia al nuclei. Thus Willei e al. [74]
ha e obse ed ha
D
-amphe amine induces displacemen o he D2/3 agonis adioligand
[
11
C]-(+)-4-p opyl-9-hyd oxynaph hoxazine [(+)-PHNO], a neu oimaging way o measu e dopamine
elease in he li ing human b ain. Sensi iza ion o amphe amine has also been modeled using
neu oimaging by Boileau e al [75]. Thus hey epo ha an ini ial dose o amphe amine causes
dopamine elease in he en al s ia um, as e alua ed by he educ ion in [
11
C] aclop ide binding.
Consis en wi h a sensi iza ion-like phenomenon, 14 and 365 days a e he hi d dose o amphe amine
he e is a g ea e psychomo o esponse and inc eased dopamine elease (a g ea e educ ion in
[
11
C] aclop ide binding), ela i e o he ini ial dose, in he en al s ia um, p og essi ely ex ending o
he do sal cauda e and pu amen. This phenomenon pe sis s o a leas one yea .
Neu oimaging echniques ha e also e ealed ha he e is a educ ion in dopamine ecep o
ac i a ion in esponse o low doses o psychos imulan s [76,77]. Me hylphenida e-induced dopamine
elease in o he s ia um is impai ed in cocaine addic s, and addic s show educed le els o D2
ecep o s in he s ia um [78]. Subjec s wi h low D2 densi y epo pleasu able e ec s om
me hylphenida e, whe eas subjec s wi h highe D2 densi y do no like he e ec s o his
psychos imulan d ug [79]. The binding o cocaine and o he psychos imulan s o DAT can be assessed
in humans by measu ing he dose-dependen displacemen o [
11
C]cocaine by a non- adiac i e
compe i o . The ex en o eupho ia expe ienced ollowing adminis a ion o cocaine co ela ed
posi i ely wi h he occupancy o [
11
C]cocaine-binding si es in he s ia um, and all subjec s wi h
g ea e han 60% occupancy o DAT expe ienced eupho ia [80].
Neu oimaging s udies con i m ha cocaine and me hamphe amine abuse induce down- egula ion o D2
ecep o s, and his down egula ion wea s o a e p olonged abs inence. Thus in ch onic cocaine use s,
[
11
C] aclop ide is educed by 15% in he s ia um [81], and simple a io o [
11
C]NMSP up ake in he
s ia um is also educed, bu e u ns o no mal a e p olonged abs inence [82]. Rega ding
me hamphe amine abuse s, i has been de ec ed a 10-15% educ ion in s ia al [
11
C] aclop ide binding [72].
Finally, ea men esponse in cocaine abuse s is ela ed o dopamine signaling as ecen ly
demons a ed by Ma inez e al. [83], who ha e epo ed ha low dopamine ansmission is associa ed
wi h ea men ailu e. Thus hey quan i ied, p io o ea men , [
11
C] aclop ide binding be o e and
a e he adminis a ion o me hylphenida e, and he ou come measu es we e lowe in he olun ee s
who did no espond o ea men han in hose who expe ienced a posi i e ea men esponse. The
au ho s p opose ha he combina ion o beha io al ea men wi h me hods ha inc ease s ia al
dopamine signaling migh se e as a he apeu ic s a egy o cocaine dependence [83].
6. Psychos imulan s and Neu oin lamma ion
Neu oin lamma ion o he cen al ne ous sys em seems o pa icipa e in neu oplas ici y changes
and sensi izing e ec s o d ugs such as psychos imulan s [84-86]. I wo h ecalling ha in lamma ion
is pa o a complex biological esponse o ha m ul s imuli, such as pa hogens o i i an s. D ugs o
abuse could be included among i i an s, and neu oin lamma ion would be a p o ec i e a emp by he
o ganism o emo e he inju ious s imuli. In his con ex , i is well known ha psychos imulan s
enhance ac i a ion o in lamma o y cells such as as ocy es and glial cells in neoco ex [87]. Ac i a ed
as ocy es and glia elease nume ous p o-in lamma o y ac o s such as ni ic oxide, ATP, TGF-α,
Pha maceu icals 2011, 4
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in e leukin-1β, in e leukin 2 and in e leukin 6 [88-90], and se e al in lamma o y cy okines such as
in e e on-gamma and in e leukin 10 a e enhanced by ch onic cocaine [91]. Cocaine is also known o
enhance he ansc ip ion ac o nuclea ac o -kappaB (NF-κB), and i educes le els o TNF-α [92].
In his con ex , NF-κB is an impo an in lamma o y ac o ha con ols many genes in ol ed in
in lamma ion, and NF-κB is ound o be ch onically ac i e in many in lamma o y diseases.
Apa om p oin lamma o y ac o s eleased by as ocy es and glia, i is o in e es ha pe oxisome
p oli e a o -ac i a ed ecep o s (PPARs) a e in ol ed in neu oin lamma ion and d ug dependence,
because PPAR-γ has a signi ican ole in he exp ession o mo o sensi iza ion o me amphe amine in
mice [86]. Pe oxisome p oli e a o -ac i a ed ecep o is a ligand-ac i a ed ansc ip ion ac o
belonging o a nuclea ho mone ecep o supe amily. Th ee PPAR iso ypes (α, β, γ) ha e been
cha ac e ised and can be ansloca ed o he nuclea ac ion o cells as he e odime s wi h he e inoid
X ecep o (RXR). The ligand-ac i a ed he e odime s can bind o PPAR esponse elemen (PPRE) o
egula e he ansc ip ion o a ge genes. In lamma ion is known o be egula ed by PPAR-γ and
PPAR-α, whose ac i a ion nega i ely egula es he ansc ip ion o in lamma o y esponse genes by
an agonizing he AP-1 and NF-κB signalling pa hways [93-95]. In ac , PPARs play p ominen oles in
se e al physiological p ocesses including he in lamma o y esponse apa om hei ole in he
con ol o lipid and lipop o ein me abolism, and glucose homeos asis [96-98]. Recen ly we ha e
obse ed ha PPAR-α plays a homeos a ic ole a enua ing mo o sensi izing e ec s o epea ed
mo phine ea men , bu no cocaine, likely h ough a educ ion o in lamma ion-associa ed changes [99].
I seems ha , among PPARs, PPAR-γ bu no PPAR-α, is mo e in ol ed in sensi izing e ec s o
psychos imulan s. Howe e i is wo hno ing ha PPAR-α has been linked o he ein o cing e ec s o
some d ugs such as nico ine, because PPAR-α agonis s sup ess nico ine-induced ac i a ion o
mesolimbic dopamine neu ons h ough PPAR-α [100].
7. Psychos imulan s and Al e ed Neu o ophism
The eme gence o neu o ophic disbalance, mainly wi hin he mesolimbic egions and o he egions
such as amygdala and hippocampus, seems o be impo an in he de elopmen o addic i e p ocesses
and neu oplas ic changes a e psychos imulan s and o he d ugs o abuse. Neu o ophic ac o s ha e
been implica ed in many o ms o plas ici y in he adul ne ous sys em, hence changes in dopamine
sys ems a e epea ed d ugs sugges ha neu o ophic ac o s such as GDNF, BDNF o FGFs a e
in ol ed in d ug’s addic i e p ocesses [3,9,101-106].
Among hese ophic ac o s, ib oblas g ow h ac o s (FGFs) and hei ecep o s pa icipa e in
many p ocesses such as egula ion o synap ic plas ici y, lea ning and memo y [107], and FGF-2
( ib oblas g ow h ac o -2) has been in ol ed in he sensi izing e ec s o psychos imulan s [105,106].
Fib oblas g ow h ac o -1 o FGF-1, ano he membe o he FGFs amily, is also in ol ed in he
egula ion o synap ic plas ici y [107], and i is implica ed in sensi iza ion o d ugs o abuse [108].
Fumagalli e al. [109] ha e demons a ed ha s ess in e ac s wi h cocaine o al e he pa e n o FGF-2
exp ession in a egionally selec i e ashion. These esul s iden i y a po en ial molecula a ge h ough
which s ess al e s cellula sensi i i y o cocaine and migh p o e use ul in unde s anding he
mechanisms unde lying b ain ulne abili y o s ess.
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A he le el o en al egmen al a ea, de ici o GDNF and up egula ion o neu o ophins such as
NT-3 a e linked o sensi iza ion phenomena a e psychos imulan s. This dual change ep esen s qui e
well he eme gence o a neu o ophic disbalance du ing addic ion, because bo h GDNF dow egula ion
and NT-3 up egula ion acili a es dopamine ac i i y wi hin he VTA. GDNF is eleased by dopamine
neu ons o VTA ac ing e og adely on GABAe gic e minals enhancing GABA elease a e
enhancemen o he calcium binding p o ein equenin inside e minals [110]. Down egula ion o
GDNF leads o a highe ac i i y o dopamine neu ons ha as a consequence a e subjec ed o less
inhibi ion om GABAe gic in e neu ons.
As al eady men ioned, ano he change in p o ein syn hesis ha is pa icula ly impo an in
es ablishing d ug-induced neu oplas ici y is a ise in b ain-de i ed neu o ophic ac o (BDNF).
Changes in le els o BDNF p o ein and mRNA ha e been obse ed in he b ain ollowing
adminis a ion o d ugs o abuse such as psychos imulan s, and hese changes ha e been obse ed in
he nucleus accumbens, p e on al co ex, en al egmen al a ea, and amygdala [111-114]. BDNF
signaling can induce di e en e ec s depending on he b ain egion examined. Fo ins ance, inc eased
BDNF in he NAc enhances cocaine-induced beha io s [113], whe eas in he p e on al co ex BDNF
sup esses hem [115]. Besides BDNF in used in o he hippocampus is an idep essan , bu in he
nucleus accumbens exe s p odep essan e ec s. In he medial p e on al co ex, up egula ed BDNF
acili a es LTP and con ibu es o neu obeha io al adap a ions o psychos imulan s [116].
Co ico- egmen al BDNF is also in ol ed in long- e m amphe amine sensi iza ion [117].
Calcium in lux and CaMKII ha e been also implica ed in he p oduc ion and esponsi eness o
BDNF [118,119]. BDNF pa icipa es on he de elopmen o sensi iza ion o cocaine o amphe amine
because di ec in usion o BDNF in o he VTA blocks he abili y o cocaine o p oduce some biochemical
and mo phological e ec s in his egion, such as he induc ion o y osine-hyd oxylase [9,101], and
epea ed amphe amine ea men inc eases BDNF wi hin he VTA, an e ec ha is enhanced in
sensi ized animals [117]. BDNF also pa icipa es du ing abs inence, and ecen ly i has been obse ed
ha ele a ed BDNF exp ession a e cocaine wi hd awal sensi izes he exci a o y synapses in he
medial p e on al co ex, and his ac may con ibu e o cue-induced d ug c a ing and d ug-seeking
beha io [116]. In he medial p e on al co ex, up egula ed BDNF acili a es LTP and con ibu es o
neu obeha io al adap a ions o psychos imulan s.
8. Conclusions
Psychos imulan s induce plas ic changes in he b ain ha seem o unde lie addic i e phenomena.
These plas ic changes ake place in he mesolimbic and mesos ia al ci cui s. Se e al addic ion- ela ed
changes in b ain ci cui s (hypo on ali y, sensi iza ion, mo phological al e a ions) as well as he
ou come o ea men ha e been isualized in addic s o psychos imulan s using neu oimaging
echniques. Repea ed exposu e o psychos imulan s induces mo phological changes such as inc ease in
he numbe o dend i ic spines o changes in he mo phology o dend i ic spines. Besides epea ed
exposu e o psychos imulan s also induces a ious synap ic adap a ions, many o hem ela ed o
sensi iza ion and neu oplas ic p ocesses, ha include up- o down- egula ion o D1, D2 and D3
dopamine ecep o s, changes in subuni s o G p o eins, inc eased adenylyl cyclase ac i i y, cyclic
AMP and p o ein kinase A in he nucleus accumbens, inc eased y osine hyd oxylase enzyme ac i i y,
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inc eased calmodulin and ac i a ed CaMKII in he en al egmen al a ea, and inc eased del aFosB,
c-Fos and AP-1 binding p o eins. Mos o hese changes a e ansien , sugges ing ha mo e las ing
plas ic b ain adap a ions should ake place. Sel -adminis a ion s udies indica e he impo ance o
glu ama e neu o ansmission in neu oplas ic changes unde lying ansi ion om use o abuse. Finally,
plas ic changes in he addic ed b ain a e enhanced and agg a a ed by neu oin lamma ion and
neu o ophic disbalance a e ch onic psychos imulan adminis a ion.
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