BiochemicalPha macology157(2018)97–107
Re iew
Theendocannabinoidsys eminmen aldiso de s:E idence omhumanb ains udies
InésIba a‐Lecuea,b,1,FuencislaPila ‐Cuélla b,c,d,1,Ca olinaMugu uzaa,b,E aFlo ensa‐Zanuyb,c,d,
Ál a oDíazb,c,d,Ley eU igüena,b,e,ElenaCas ob,c,d,AngelPazosb,c,d,LuisF.Calladoa,b,e,
aDepa men o Pha macology,Uni e si yo heBasqueCoun yUPV/EHU,Leioa,Spain
bCen odeIn es igaciónBiomédicaenReddeSaludMen alCIBERSAM,Spain
cIns i u odeBiomedicinayBio ecnologíadeCan ab ia(IBBTEC);Uni e sidaddeCan ab ia‐
CSIC,San ande ,Spain
dDepa amen odeFisiologíayFa macología,Facul addeMedicina,Uni e sidaddeCan ab ia,
San ande ,Spain
eBioc ucesHeal hResea chIns i u e,Bizkaia,Spain
Co espondingau ho a :Depa men o Pha macology,MedicalSchool,Uni e si yo he
BasqueCoun y(UPV/EHU),Ba ioSa ienas/n,48940Leioa,Bizkaia,Spain.
E‐mailadd ess:L[email p o ec ed](L.F.Callado).
1Theseau ho scon ibu edequally o hiswo k.
h ps://doi.o g/10.1016/j.bcp.2018.07.009Recei ed29May2018;Accep ed12July2018
Keywo ds:Humanb ain,Dep ession,Anxie y,Schizoph enia,Endocannabinoids,Cannabinoid
ecep o s
ABSTRACT
Men aldiso de sha eahighp e alencecompa edwi hmanyo he heal hcondi ionsanda e
heleadingcauseo disabili ywo ldwide.Se e als udiespe o medin helas yea ssuppo
hein ol emen o heen‐docannabinoidsys emin hee iopa hogenesiso diffe en men al
diso de s.Thep esen e iewwillsumma ize hela es in o ma ionon he oleo he
endocannabinoidsys eminpsychia icdiso de s,speci icallydep ession,anxie y,and
schizoph enia.Wewill ocuson he indings omhumanb ains udies ega dingal e a ionsin
endocannabinoidle els,cannabinoid ecep o sandendocannabinoidme abolizingenzymesin
pa ien ssuffe ingmen aldiso de s.
S udiesca iedou inhumansha econsis en lydemons a ed ha heendocannabinoidsys em
is unda‐men al o emo ionalhomeos asisandcogni i e unc ion.Thus,de egula iono he
diffe en elemen s ha a epa o heendocannabinoidsys emmaycon ibu e o he
pa hophysiologyo se e almen aldiso de s.Howe e , he esul s epo eda econ o e sial.
In hissense,diffe en al e a ionsingeneand/o p o einex‐p essiono CB1 ecep o sha e
beenshowndependingon he echnicalapp oachusedo heb ain egions udied.Despi e he
cu en disc epancies ega dingcannabinoid ecep o schangesindep essionandschizo‐
ph enia,p esen indingspoin o heendocannabinoidsys emasapi o alneu omodula o y
pa hway ele an in hepa hophysiologyo men aldiso de s.
This is a pos p in o an a icle published by Else ie . The inal e sion o Inés Iba a-Lecue, Fuencisla Pila -Cuélla , Ca olina
Mugu uza, E a Flo ensa-Zanuy, Ál a o Díaz, Ley e U igüen, Elena Cas o, Angel Pazos, Luis F. Callado, The endocannabinoid
sys em in men al diso de s: E idence om human b ain s udies, Biochemical Pha macology 157 : 97-107 (2018) is a ailable a
h ps://doi.o g/10.1016/j.bcp.2018.07.009 © 2018 This manusc ip e sion is made a ailable unde he CC-BY-NC-ND 4.0 license
h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/
1.
In oduc ion
Men aldiso de sa e esponsible o hela ges p opo iono heglobalbu deno disease
wo ldwide.I hasbeensugges ed ha by2030dep essionwillbe heleadingcauseo disease
bu denglobally.In hisway,mood‐ ela eddiso de scon ibu emos o henon‐ a albu deno
men alillness ollowedbyanxie y‐ ela eddiso de s,subs anceabuseandschizoph enia[1].
Theyp esen amajo medical,socie alandeconomicbu den ha hasala geimpac on
indi iduals, amiliesandcommuni ies.
Ac ualknowledgeabou hee iologyandpa hophysiologyo men aldiso de sismainlya esul
o anin e ac ionbe ween hede elopmen o new echnologyand hedi ec s udyo heb ain
issueo pa ien s.Thus, hedesc ip iono mo phologicaldiffe ences, unc ionalde ici sand
molecula al e a ionsiswidelyaccep ed odayasexis ingin heb aino psychia icpa ien sdue
o head anceo in i oneu oimaging echniques,gene icandgenomicde elopmen ,and he
useo pos ‐mo emb ain issueasakeysubs a eo hedisease[2].Ne e heless,despi e he
hugeeconomicandscien i iceffo de elopedin helas decades, hepa hophysiologyo
men aldiso de s emainselusi e.In hiscon ex ,manys udiesha e ocusedin hepossible
in ol emen o al e a ionso heendocannabinoidsys em(ECS)in hepa hophy‐ siologyo
men aldiso de ssuchasdep essiono schizoph enia.TheECSpa icipa es,inpa ,in he
con olo emo ionalbeha io andmood h ougha unc ionalcouplingwi hmonoamine gic
sys emsin heb ain[3].These unc ionalin e ac ionsha esugges edapo en ial ole o ECS
signalingin heneu obiologyo a iouspsychia icdiso de s[4–7].TheECSiscomposedo wo
inhibi o yG‐p o eincoupled e‐cep o s(GPCRs),cannabinoid ecep o 1and2(CB1andCB2,
espec‐ i ely),and womajo endogenousligands,N‐a achidonoyle hanola‐ mine
(anandamide/AEA)and2‐a achidonoylglyce ol(2‐AG).TheECSalsoincludes womain
me abolicenzymes, he a yacidamidehy‐d olase(FAAH)and hemonoacylglyce ollipase
(MAGL)whichhy‐d olyzeAEAand2‐AG, espec i ely;and womainsyn he izingen‐zymes,N‐
acylphospha idyle hanolamine‐phospholipaseD(NAPE‐PLD)and hediacylglyce ollipase
(DAGL)whichsyn hesizeAEAand2‐AG, espec i ely.Theco ec in e playbe weenall hese
ECSelemen splaysanimpo an oleincen alne oussys em(CNS)de elopmen ,sy‐nap ic
plas ici y,and hehomeos a icmain enanceo cogni i e,beha‐ io al,emo ional,
de elopmen al,andphysiologicalp ocesses[8,9].In heb ain,CB1 ecep o sa ep esen in
GABAe gicandglu ama e gicneu ons,exe ingap esynap icinhibi o y unc ionwhen heya e
ac‐ i a edby he eleasedendocannabinoids[10,11].Theya e hemos abundan G‐p o ein
coupled ecep o sanda ewidelyexp essedall h oughou heb ain,beingloca edinco ical,
subco ical,ce ebella andb ains ems uc u es[8].TheCB2 ecep o sa elessnume ousand
we eini ially hough obeloca edmainlyin heimmunesys em;howe e ,cu en ly heyseem
obewidelydis ibu edin heCNS, akingpa inimmune‐media ed esponsesandsuppo ing
aneu o‐p o ec i e oleagains in lamma ion[12].The womainendogenousligands,AEAand
2‐AG,a eeicosanoidneu omodula o ylipidsde i ed ommemb anephospholipids,
syn hesizedwhenandwhe e heya e equi ed,andac ingp esynap icallyonbo h ypeo
cannabinoid e‐cep o s[8].
In hep esen e iew,wewillsumma izeda aob ained omhumans udiesp o idinge idence
abou he oleo hediffe en ECScompo‐nen s(endocannabinoids,me abolizing/syn he izing
enzymesandcannabinoid ecep o s)in hepa hophysiologyand ea men o se e al
psychia icdiso de s,wi ha ocuson esul s ompos mo emandli inghumanb ains udies.
Wewill e iew indings ompa ien ssu ‐ e ingamood‐ ela eddiso de (dep ession,anxie y,
pos auma ics essdiso de (PTSD))o schizoph eniacompa ed oheal hysubjec s.
2.
Theendocannabinoidsys emand heemo ionalhomeos asis
TheECSin luences heac i i yo mul ipleb aina easin ol edin he egula iono he
hypo halamic‐pi ui a y‐ad enalsys em(HPA),mood,anxie yando he ela edbeha io s(i.e.
ex inc iono ea lea ning, ewa d…).Indeed, heECSenables heefficien in e ac ionwi hin
andbe weenb ain egions ha modula ecogni i eandbeha‐ io al unc ioning.
Aconside ablenumbe o s udiessugges he ela ionshipbe weenchangesinoneo mo e
componen so heECSandsomeo hesymp oms ha a ep esen indep essionandanxie y‐
ela eddiso de s.TheECSmodula es ea andanxie y‐ ela edbeha io sinbo hhumansand
oden s[13–15].Augmen edECSsignalingisusually ollowedby educedcondi ioned ea and
anxie y,whe eas heopposi eeffec isobse edwheni isinhibi ed[16–19].Thisisno
su p isingsince heECSisp esen inkeys uc u eswi hin heb ainsuchasp e on alco ex
(PFC),amygdala,andhippocampus[20–25].
The ea ealsoanimals udiesshowing heco ela ionbe weenCB1 ecep o ‐de iciencyand
dep essi e/como bidsymp oms(anhedonia,anxie y,andheigh eneds ess‐ esponse)[26–28].
Inlinewi h his e‐la ionship,ch onics ess,asapa hogenic ac o o dep essi e‐beha‐ io ,
hasbeenassocia edwi hadys unc ionalendocannabinoidsig‐nalingin heb ain[29].Thus,
s a egies ha a edi ec ed o heaugmen a iono heendocannabinoidsignalinga e epo ed
omi i‐ga emanyo head e seeffec so ch onics ess,suchasanhedoniaandanxie y[30–
32].The eade sa edi ec ed ocomp ehensi e e‐ iewson his opic ha isbeyond hescope
o his e iew[33–38].
3.
Theendocannabinoidsys emanddep ession
Dep essionisoneo hemos p e alen majo neu opsychia icdiseases,affec ing20%o he
popula ion,beingalmos wiceascommonin emales hanmales[39].The ea e womain
challenges o igh agains dep ession.Fi s ,wes illpoo lyunde s andi sneu o‐biologicaland
pa hologicalbases.Second, he eneeds obemo ee ‐ ec i ean idep essan d ugso e coming
he he apeu iclagbe weend ugadminis a ionand heonse o clinicalimp o emen , helack
o esponseinsomepa ien sandsa e y/ ole abili yissues[40,41].
Theimplica iono heECSindep essioncomes omobse a ional indings ega ding hemood‐
ela edeffec so cannabisinhumans, houghcon adic o y esul sa e epo ed.Ononehand,
hehea yuseo cannabisisassocia ed oahighe incidenceo dep essi ediso de s[42].A
ecen me a‐analysisshowedaposi i eco ela ionbe weencannabisuseanddep ession,being
mo ee iden amonghea ycan‐nabisuse s[43].Mo eo e , heabuseo cannabishasbeen
linked oahighe isko suicideinpa ien swi hmooddiso de s[44].On heo he hand,o he
au ho sindica e ha heuseo ma ijuana,o i smainpsychoac i ecomponen Δ9‐
e ahid ocannabinol(THC), educes hedep essi ebeha io [45–48].Inaddi ion,o he au ho s
desc ibe ha headminis a iono THC opa ien swi hmode a e ose e ede‐p essionshows
alacko effec onmood[49],o on hesuicidalidea ion[50],bu aninc easedanxie y[49].
Cu iously, hepha macologicalblockadeo CB1 ecep o susingan agonis so in e seagonis s
wasini iallysugges edasapo en ialno el a ge o an idep essan ea men ,acco ding o
diffe en e i‐dencesinp eclinicals udies[51].Howe e , u he s udies e ealed ha d ugsas
heCB1 ecep o an agonis imonaban (SR141716A) ha wasma ke ed o ea obesi y,
induceddep essedmood[52,53].Inanimals udies, hepha macologicalac i a iono blockade
o CB1 e‐ cep o salsogi e ise ocon adic o y esul s,sincebo happ oacheslead oan
an idep essan ‐likeeffec [5,51,54–58].
Al hough heses udiesd awcon lic ing indings, heypoin o hein ol emen o heb ainECS
in hemodula iono moodand,espe‐ cially, hecon ibu iono CB1 ecep o s omajo
dep essionha e e‐cei edpa icula a en ion[59].Theac i a iono cannabinoid e‐cep o s
p oduces he eleaseo s essho monesasACTHandco isolin heHPAaxis[60],whichhas
beenobse ed ollowingacu ema ijuanaadminis a ion[61].Howe e , hisp esen s ole ance
a e ch onicadminis a ion[62],as heTHC‐inducedco isol eleaseisblun edin equen
ma ijuanause s[63].
Neu oimagings udiesinnon‐cannabisuse sshow ha headmin‐is a iono THCp oducesa
educedac i a iono someb aina easin esponse oanega i econ en [64,65].Con e sely,
he eisanin‐c easedac i a ionin esponse oaposi i econ en ,media edby heac i a ion
o a eassuchasp e on alandoccipi alco ices,amygdala,hippocampusando bi o on al
gy us[65],whichisassocia ed oa educ ionin henega i ea en ionalbias,and he
po en ia iono po‐si i ea en ionalbias[65].This ypeo s udiesha ealsoshown ha he
ac i a iono cannabinoid ecep o sleads omo phologicalchanges,suchas he educ ionin
whi ema e (WM)obse edinma ijuanause s ha nega i elyco ela eswi h hese e i yo
hedep essi ediso de [66,67].Thisdec easeinWM olumehasbeenassocia edwi h he
p esenceo cannabinoid ecep o sinoligodend ocy es, hemyelin‐ o mingcells[68].
3.1.
Cannabinoid ecep o sindep ession
Humans udiesha eco obo a ed heexis enceo anal e edECSac i i yassocia ed omajo
dep ession[34,69].TheCB1 ecep o densi y[70]andmRNA[71]isinc easedin hedo sola e al
p e on alco exo pa ien swi hmajo dep ession,inpa allel oCB1 ecep o unc ionali y
(e alua edby[35S]GTPγSbindings udies)[70](Ma oe al.,in hisissue).Howe e ,nochanges
inCB1immuno eac i i yin hedo sola e alp e on alco ex[72],o a educ ionin
CB1immuno eac i i yinglialcellsin hean e io cingula eco ex[73]ha ebeen epo ed
(Table1).Rega dingCB2 ecep o ,nochangesha ebeende ec edini smRNAle elsin
p e on alco exo dep essedpa‐ ien s[71](Table1).
The oleo heECSin heeffec o an idep essan d ugshasalsobeene idencedins udies
epo inganinc easedCB1 ecep o exp es‐sion[74],andalacko changesinCB1‐media ed
ac i a iono Gi/op o einsinp e on alco ex(Ma oe al.,in hisissue)in hean i‐dep essan ‐
ea edg oup.O he a eassuchas hehippocampusonlyelici edinc easedCB1 ecep o
densi ya e ch onicmonoamineoxi‐ daseinhibi o s(MAOI) ea men [74].Oncon as ,
s udiesinhumanb ainsamplesha eshowna educ ioninCB1 ecep o im‐muno eac i i yin
hean e io cingula eco exo pa ien s ea edwi hse o oninselec i e eup akeinhibi o s
(SSRIs)[73].
Thep esenceo diffe en singlenucleo idepolymo phismsin hecannabinoid ecep o 1(CNR1)
geneappea s omodula eei he hedep essi epheno ype,and/o he esponse o
an idep essan ea men .Theca ie so CNR1gene a ian sin luences he ulne abili y o
suffe men aldiso de s,includingmajo dep ession[75].The equencyo heGalleleo he
CNR1genepolymo phism s806371ishighe inpa ien swi hmajo dep essionshowing
como bidpsycho icsymp oms,while hehaplo ypeC‐G‐T( s806368, s1049353, s806371)is
associa edwi haninc eased isk o melancholicandpsycho icsymp omso majo dep ession
[76].Thisisconsis en wi h hemelancholicde‐ p essi e‐likesymp omsobse edinanimal
modelswi hpha macolo‐gicalo gene icblockadeo heECS[4].O he s udies epo alowe
incidenceo dep essioninPa kinsons’diseasepa ien sca ying wolongalleleso heCNR1
genepolymo phism(AAT)n[77].TheCalleleca ie so heCNR1genepolymo phism
s2023239p esen alowe incidenceo majo dep essionwi hinag oupo me hadone‐
esponde pa ien s[78].
Inpa ien swi h heCNR1genepolymo phism s1049353,ca ie so oneo mo ecopieso he
mino allele(AA/AG)exhibi abuffe ingeffec oanhedoniaanddep essiona e ea lychildhood
auma[79].Mo eo e , heGalleleo he s1049353polymo phismisassocia ed o he
esis ance o hean idep essan ea men in emalesdiagnosedwi hmajo dep ession ha
p esen como bidanxie y[80].Pa ien swi h heGalleleo heCNR1 s1049353alsop esen a
subco icalhypo‐ esponsi enessin hebila e alamygdala,pu amen,andpallidumac i i yand
le la e alizedcauda eand halamusac i i y, ospeci iccues,whichmigh belinked oa
de icien effec on hep ocessingo emo ionalandsocialbeha io [80].Oncon as ,o he
au ho s epo abe e esponse o ea men o malep esen ing heGGgeno ype[76].In
pa ien s ea edwi hci alop am,TThomozygousca ie s o he s806368and s806371
polymo phisms,showahighe incidenceo no emission,compa ed o heGca ie s[76].
Mo eo e , he esponsein he s806368Gca ie swasdiffe en dependingon hegende ,p e‐
sen ingabe e an idep essan ou comeinmen haninwomen[76].
Al hough heCB2 ecep o sub ypeislessabundan hanCB1 e‐cep o sub ypein heb ain,
somes udiesalsodesc ibeanassocia ionwi hmen aldiso de s.In hissense, heRRgeno ype
o heQ63Rpolymo phismin heCNR2genep esen sahighe associa ionwi hdep essionin
heJapanesepopula ion[81].ThisQ63Rpolymo phismp esen salsoahighincidenceinpa ien s
wi hea ingdiso de s(ano ‐ exiane osaandbulimiane osa)[82]andschizoph enia[83].
S udiesincellsexp essing hismu a ed o mo heCNR2geneshowed ha he unc ional
ele anceo hispolymo phismisdue ochangesinCB2ligandaffini y,cons i u i eac i i yand
a educed2‐AG‐inducedade‐ nylylcyclaseinhibi ion[84].Rega ding heCNR2gene
polymo phism s2501431, heAAca ie sp esen ahighe se e i yo hedisease,compa ed o
heGca ie s[85].
Theac i i yo cannabinoid ecep o sisassocia ed o hec oss‐ egula ion ha heCB1
ecep o sexe o e heNMDA ecep o smedia edby hei in e ac ion ia hehis idine iad
nucleo idebindingp o ein1(HINT‐1),inwhicha educ ionin henumbe o CB1 e‐cep o s
maybeassocia ed o heNMDAhype unc ionobse edindep ession[86].In hissense,
molecula s udiesha eshownanin‐c easein heHINT‐1p o einand heNR1subuni o he
NMDA e‐cep o sin hep e on alco exo dep essedpa ien s,inpa allel o esul sob ained
inCB1 ecep o knockou mice[86].
Table1
S udiesabou al e a ionso hediffe en componen so heECSin heb aino pa ien swi h
dep essiono anxie y‐ ela eddiso de s.
↑Inc ease;↓dec ease;≈nosigni ican change.ACC:an e io cingula eco ex;BA:B odmann’sa ea;CB1,CNR1:
cannabinoid ecep o 1;CB2:cannabinoid ecep o 2;Co‐IP:co‐immunop ecipi a ion;C :con ol;DLPC:do sola e al
p e on alco ex;FAAH: a yacidamidehyd olase; MRI: unc ionalmagne ic esonanceimage;GM:g eyma e ;
HINT‐1:his idine iadnucleo idebindingp o ein1;IHC:immunohis ochemis y;MDD:majo dep essiondiso de ;
PET:posi onemission omog aphy;PFC:p e on alco ex;PMBT:pos ‐mo emb ain issue;PTSD:pos auma ic
s essdiso de ;SSRI:se o oninselec i e eup akeinhibi o ;TC: aumacon ols;WB:wes e nblo .
3.2.
Endocannabinoidme abolizingenzymesindep ession
Oneo hemos equen polymo phismo FAAHinhumansisa unc ionalnon‐synonymous
single‐nucleo idepolymo phism(C385A; s324420)associa edwi ha educedcellula
exp essiono hisenzyme.TheC385Apolymo phismo heFAAHgene,p esen sag ea e asso‐
cia ioninAalleleca ie swi hpa hologiessuchasdep essionandbi‐ pola diso de [87].
Mo eo e , hep esenceo hispolymo phismcons i u esasuscep ibili y ac o ode elop
dep essi eandanxiouspheno ypesinadul indi iduals ha ha ebeenexposed ochildhood
auma[88].ThehighAEAle elsbecause he educedFAAHac i i yin heAalleleca ie s,
induce hedesensi iza iono CB1 ecep o s.This educ ioninCB1 ecep o sp omo esa
glu ama e gichype ac i i y ha , oge he wi hhighco isolle elsdue ochildhood aumain
c i icneu ode elopmen alpe iods, esul sinanxiousand/o dep essi edis‐o de s[88].TheCC
ca ie so he s324420polymo phismin heFAAHgenep esen a educ ionin heWM
in eg i yo ibe s ha con‐nec wi h hean e io cingula eco exand heo bi alco ex,and
g ea e incidenceo sel ‐ epo eddep essi esymp oms[67].
3.3.
Endocannabinoidsle elsindep ession
These umcon en o endocannabinoidsisalsoal e edinmajo dep ession.Someau ho s
epo lowe le elso heci cula ingen‐ docannabinoidsAEAand2‐AGinpa ien swi h
dep ession[89,90].Mo eo e , he2‐AGle elsa elowe inpa ien swi halonge du a iono
hedep essi eepisode,whilepa ien swi hmino dep essionp esen highe le elso AEA[89].
Incon as ,o he au ho s epo nochangesinAEAand2‐AGle elsindep essedwomen[91].
Thele elso heendocannabinoidsAEAand2‐AGwe eno mod‐i iedin esponse oSSRIssuch
as luoxe ine,while hech onicad‐minis a iono MAOIsinduceda educ ionina eassuchas
ECS elemen Finding (% change) B ain egion Coho (n: disease-C )
Me hod/sample
Re e ences
CB1 (mRNA)
↑ (60%)
DLPC (BA46) MDD:C 26:46 Gene exp ession mic oa ay/PMBT
[71]
CB1 (p o ein)
≈
DLPC (BA46) MDD:C 14:14
IHC/PMBT
[72]
↑ (38%)
DLPC (BA9) MDD wi h suicide:C 10:10
WB/PMBT
[70]
↓ (22.1%)
Glial
+
cells in ACC GM MDD:C 15:15
IHC/PMBT
[73]
≈
Neu ons
+
cells in ACC
MDD:C 15:15
IHC/PMBT
[73]
CB1 (densi y)
↓ (
∼
8.5–9.5%)
↑ (31%)
Neu ons
+
cells in ACC
DLPC (BA9)
MDD+SSRI:MDD no-SSRI
MDD wi h suicide:C 10:10
IHC/PMBT
[
3
H]CP-55,940 binding/PMBT
[73]
[70]
CB1 ( unc ionali y)
↑ (45%)
DLPC (BA9) MDD wi h suicide:C 10:10
[
3
H]CP-55,940 and [
35
S]GTPγS
[70]
binding/PMBT
CB1 (a ailabili y)
↑ (19.5%)
B ain-wide
PTSD:C 25:23
In i o b ain PET scan [
11
C]OMAR
[100]
↑ (14.5%)
B ain-wide
PTSD:TC 25:12
In i o b ain PET scan [
11
C]OMAR
[100]
↑
Amygdala
PTSD:TC:C 12:4:4 In i o b ain PET scan [
11
C]OMAR
[101]
CNR1 gene s1049353
(A)
↑ ac i i y associa ed o emo ional
Bila e al amygdala, pu amen MDD(AG) MDD(GG) 13:20 Gene ic associa ion s udy wi h
[80]
p ocessing
and pallidum
MRI/pe iphe al cells
CB1-HINT1 (p o ein)
≈
PFC (BA9) MDD:C 24:24
Co-IP/PMBT
[86]
CB1-NR1 C1 (p o ein)
≈
PFC (BA9) MDD:C 24:24
Co-IP/PMBT
[86]
CB2 (mRNA)
≈
DLPC (BA46) MDD:C 26:46 Gene exp ession mic oa ay/PMBT
[71]
p e on alco ex,hippocampusandhypo halamus[74].Theseda aa econsis en wi has udy
ha associa es hebene icialeffec o exe ciseindep es‐sionwi haninc easein heplasma
le elso AEA,BDNFandco isol[92].
4.
Theendocannabinoidsys emandanxie y‐ ela eddiso de s
Fewneu ochemical,molecula gene icsandneu oimagings udiessugges apo en iallink
be weendys egula iono heendocannabinoidsignalingandanxie y‐ ela edbeha io inbo h
heal hyandpa ien swi hmen aldiso de sinwhichanxie yisaco esymp om(PTSD,social
phobia,ago aphobia,e c…).
4.1.
Cannabinoid ecep o sinanxie y
Twosinglenucleo idepolymo phism(SNP) a ian s(C‐AandC‐G)o hehaplo ype o medby
hepolymo phisms s806368and s1049353a heCNR1geneshowedasigni ican associa ion
wi hPTSD[93].Mo eo e ,ahighe isk osuffe anxie yisobse edwhenhomozygous‘SS’o
hepolymo phismo se o onin anspo e (5‐HTTLPR)in heSLC6A4p omo e iscombined
wi h hehomozygous’GG’ s2180619o CNR1gene[94].Thishighligh s hes ongin e ‐ac ion
be ween hese o one gicsys emand heECSonanxie ydis‐o de sasex ensi elydesc ibedin
manyp eclinicalandclinicals udies,usingpha macologicalandgene icapp oaches[37,95,96].
Mo eo e ,Hei lande al.[97]published he i s e idence,inheal hymedica ion‐ eehuman
subjec s,o heimplica iono ECSin he ea ex inc ionphenomenon,a ele an mechanism
unde lying hepa hophysiologyo humananxie ydiso de s.Theseau ho sdesc ibe heeffec
o heCNR1genepolymo phism s2180619in he esponse o ea condi ioningandex inc ion.
They ound ha bo hhomozygo e(G/
G) andhe e ozygo e(A/G)G‐alleleca ie so hispolymo phismshowedaclea ex inc iono
ea ,whe eas his esponsewasabsen inhomozygo es(A/A).
Recen indingssugges ha du ingchildhoodandadolescence, heECSisc i ical omedia ea
co ec balancebe weenexci a o yandinhibi o yneu o ansmission,especiallywi hin he
p e on alco ex[98].Thismakes heendocannabinoidsignalingqui esensi i e o
de elopmen al luc ua ionsdue oen i onmen alcauses,whichmayinc ease he isko anxie y
ando he s ess‐ ela eddiso de s.In e ‐ es ingly,a ecen s udyshows heimpac o he
a ia ionin heCNR1,CNR2,andFAAHgenesinasampleo child enwi hap ima yanxie y
diso de diagnosis[99].Theseau ho snicely epo edanassocia ionbe ween woSNPs
( s12133557and s6454676)in heCNR1geneand hechangeinsymp omse e i yinbo h he
en i esampleandasubse o pa ien swi h ea baseddiagnoses[99].Mo eo e ,a a o able
andapoo e esponsedu ing heac i e ea men pe iodwe eassocia edwi hmino alleleo
s12133557and s6454676, espec i ely.Re‐ga ding heCNR2gene,unlike op e ious indings
indep ession[81], he s2501431geno ypewasno associa edwi hanxie ysymp omso
ea men esponse[99].
In i oneu oimagings udiesalsosuppo heexis enceo anab‐no malCB1 ecep o ‐media ed
signalingespeciallyinPTSD.Usingposi onemission omog aphy(PET)wi h[11C]OMAR,aCB1‐
selec i e ace ,Neumeis e andcolleagues[100] epo edahighe CB1 ecep o a ailabili yin
un ea edindi idualswi hPTSD, ela i e ocon olsubjec s(wi ho wi hou li e imehis o ies
o auma),whichwasmos p onouncedinwomen.Thisup‐ egula iono CB1 ecep o swas
p esen inanxie y‐ ela edb aina eas,especially heamygdala‐hippocampal‐ co ico‐s ia al
neu alci cui .Inala e epo , hesameg oup[101]assessed hea en ionalbias o h ea ,
whichisconside edoneo hemainendopheno ypiccha ac e is icso auma‐ ela edmen al
dis‐o de s.Inlinewi h hei p e ious indings, hey epo edaposi i eco ela ionbe weenan
inc easedCB1 ecep o a ailabili y([11C]OMARbinding)in heamygdalaandinc easedinbo h
a en ionalbias o h ea and hese e i yo h ea .In e es ingly, hisg ea e CB1 e‐cep o
a ailabili yin heamygdalawasassocia edwi hlowe plasmale elso AEA.
4.2.
Endocannabinoidme abolizingenzymesinanxie y
Pha macologicals a egies ha educe heac i i yo ei he FAAHo MAGLha ebeen epo ed
o educeanxie y‐likebeha io sin o‐ den sandhumans[37];howe e ,dualFAAH/MAGL
inhibi o sdidno educes ess‐ ela edaffec i edys unc ion ega dlesso ea men iming
[102].The ea ese e als udieslinking heac i i yo FAAH,especiallyin heamygdala,wi h
s ess‐ eac i i yand isk osuffe an‐xie y‐diso de s.
Inheal hy olun ee s, he ea esomes udiesexamining heimpac o heFAAHgene
polymo phismC385A( s324420)on h ea ‐and e‐wa d‐ ela edhumanb ain unc ion.Using
imaginggene ics,ade‐c eased h ea ‐ ela edamygdala eac i i ybu inc eased ewa d‐ ela ed
en als ia al eac i i ywasde ec edinca ie so heAalleleo heFAAHenzymegene[103].
Inala e s udy,aquicke habi ua iono amygdala eac i i y o h ea andlowe sco eson he
pe sonali y ai o s ess‐ eac i i ywas ound obeassocia edwi hca ie so alow‐exp essing
FAAH a ian (385Aallele; s324420)[104].Mo e ecen ly,anenhanced ea ex inc ionwas
demons a edinbo hmouseandhumanA‐alleleca ie so hisFAAHgeneC385A
polymo phism,highligh ingagain heassocia iono heinc eased on o‐amygdalaconnec i i y
wi henhanceds ess‐ eac i i y[105].Thisgene ical‐ e a ionappea s oha e unc ional
consequencessinceama kedly e‐ ducedFAAHp o einexp essionwasde ec edinmany
co ico‐limbica easusing he i s a ailablePET adio ace ([11C]CURB)inhumanb ain[106].
Rega ding he oleo FAAHonPTSD,Pa dinie al.[107] epo edanassocia iono he s2295633
SNPo FAAHgenewi hPTSDdiagnosisinmaleVie namWa e e answi hou lesionsin he en‐
omedialp e on alco ex.E enmo e, heCallelewasp esen insubjec s ha hadamo e
nega i e epo edexpe ienceo auma.
4.3.
Endocannabinoidle elsinanxie y
P eclinical indingssugges ha hepha macologicalmanipula iono endogenousei he AEAo
2‐AGle elsunde s ess ulcondi ionscould ep esen agoods a egy o ea men o anxie y‐
ela eddis‐ o de s[108].Thus,i isplausible ohypo hesize heexis enceo al e ed
endocannabinoidle elsin heb aino pa ien sdiagnosedo psychia icdiseasesinwhich
anxie yisei he co eo acomo bidsymp om.
Dec easedplasmaAEAle elsa e oundinPTSDpa ien s ela i e oheal hycon olsubjec s
wi hou aumahis o y[109], houghele a‐ ionsa ealso epo edinch onicPTSD[110].The
AEAde iciencyseems obespeci ico PTSDpa ien ssinceheal hysubjec swi hli e‐ ime
his o ieso auma,bu wi hou PTSD,exhibi no malAEAplasmale els[100].Asmen ioned
abo e,aposi i eco ela ionbe weenlowe plasmale elso AEAandinc easedCB1 ecep o
a ailabili yin heamygdalahasbeen epo ed;inaddi ion,AEAle elswe enega i ely
associa edwi ha en ionalbias o h ea [101].In iguingly, hisin‐ e se ela ionshipbe ween
AEAle elsandanxie yappea s obedis‐ease‐speci icsinceacu es essinc eases heci cula ing
le elso AEAando he endocannabinoids,inpa allelwi hco isol[111].Rega ding he2‐AG,
educed[112]andinc eased[110]le elsamongindi idualsmee ingdiagnos icc i e ia o PTSD
we edesc ibed.Heal hyhumans ha we esubjec ed op olongeds ess(520‐dayisola ion
pe iodandsimula inga ligh oMa s)showed educedbloodle elso 2‐AG,bu no AEA[113].
All hese indingssugges hein e ac ionbe ween heECSandHPAaxisac i i yin esponse o
s ess,especiallya hele elo heamygdala[19].Inlinewi h his ela ionship,a ecen imaging
gene icss udy[114] e ealedamolecula in e ac ionbe weengene icpolymo phisms
associa edwi hdiffe en ialAEAle els(FAAH s324420)andco ico‐ ophin eleasingho mone
(co ico opin‐ eleasingho mone ecep o 1,CRHR1 s110402)signaling.andamygdala unc ion.
Howe e ,ina e y ecen s udy, hele elso ci cula ingendocannabinoidswe emeasu edin
subjec swi handwi hou his o yo psychia icdiso de and he ela ionshipswi hca ego ically
DSM‐5de ineddiso de so s a edimensionalmeasu eso dep essiono anxie ywe es udied.
Su p isingly,nei he AEAno 2‐AGle elsdiffe edasa unc iono anysynd omal/pe sonali y
diso de andnei he co ela edsigni ican lywi hs a edep essiono s a eanxie ysco es[115].
The e o e,wemus becau ioussincepe iphe alendocannabinoidle elsmaybeno well
co ela edwi hb ainconcen a ions.
5.
Theendocannabinoidsys emandschizoph enia
Schizoph eniaisoneo hemainpsychia icsynd omes oge he wi hMajo Dep ession.I isa
ch onicandde as a ingdiso de affec ing1%o hepopula ionwo ldwide.Indi iduals
diagnosedwi hschizo‐ph eniaha eimpai edsocialandoccupa ional unc ioning.Thus, he
combinedeconomicandsocialcos so schizoph eniaplacei as hewo ld’s15 hcauseo
disease‐ ela eddisabili y[116].Theclinical ea u eso schizoph eniaa eclus e edinposi i e
symp oms(i.e.hal‐lucina ionsanddelusions);nega i esymp oms(i.e.socialwi hd awaland
blun edaffec )andcogni i ede ici s(i.e.impai edwo kingmemo yandcogni i e lexibili y).
Cu en an ipsycho icd ugs,whicha e hemain ea men o schizoph enia,a eno effec i e
inallpa‐ ien sand hei bene i sa e es ic ed o heamelio a iono heposi i esymp oms,
ha ingnoneo limi edimpac innega i esymp omsandcogni i eimpai men .
Despi e heeffo so hescien i iccommuni yin helas decades oelucida e hee iological
basiso schizoph enia, hee iopa hogenesiso hedisease emainsunknown.Sincemanyyea s,
hep edominan ocuso s udiesconce ning hebiologicalsubs a eso schizoph eniahasbeen
p ima ilycen e edonuniqueneu o ansmi e sincludingdopa‐mine,se o onin,glu ama eand
γ‐aminobu y icacid(GABA).None heless, helimi edefficacyo cu en an ipsycho icd ugs o
ea someo hesymp omso schizoph eniahasleadup esea che s oin‐ es iga eo he
po en ialneu o ansmi e sys ems ha maybeal e edin hisdisease.
In hissense, heECShasbecomeaho ‐ opicinschizoph enia e‐sea chin helas yea s.Se e al
s udiess a ing om he40sup onowadaysag ee ha heECS ep esen samajo
neu omodula o ysys empa icipa ingin oneso physiologicalp ocesses[117,118].The eby,
de egula iono heECShasbeenspecula ed obeap oximalpa hologyinsome o mso
schizoph enia.In hissense, wo‘canna‐ binoidhypo heses’o schizoph eniaha ebeen
p oposed[119].Theendogenoushypo hesis e e s o he ac ha de egula iono heECSmay
con ibu e o hepa hophysiologyo schizoph enia,whe eas heexogenous heo y e e s o he
I isalsono ewo hy ha CSFendocannabinoidle elsha ebeenshown obeaffec ed
dependingon hehis o yo cannabisuse.Thus,ma kedlyal e edAEAconcen a ions(>10‐ old
highe )we e epo edinCSFo asubg oupo schizoph enicpa ien swhohadlow equency
cannabisusecompa ed ocon ols(wi hhighandlow equencyuse),aswellascompa ed o
schizoph enichigh‐ equencyuse s[161].Howe e , hisimpac o cannabisusewasno
obse edino he s udies[160,162].
Compiling hein o ma iona ailable om heses udiesise iden ha he ela ionshipbe ween
le elso endocannabinoidsmeasu edin heCSF,pe iphe albloodandconcen a ionso
endocannabinoidsinb ain issueisno clea ye .Thus, heunde s andingo unc ionalim‐
plica ionso al e edle elso endocannabinoidsineach ypeo sampleo schizoph enicpa ien s
emains obeelucida ed.
6.
Conclusions
Se e ale idencessugges he ela ionshipbe weenchangesinoneo mo ecomponen so he
ECSandsomeo hesymp oms ha a ep esen indep ession,anxie y‐ ela eddiso de sand
schizoph enia.Indeed, ecen humanpos mo emandin i oneu oimagings udiesa e
p o idingmo eknowledgeabou heimplica iono heECSin hesemen aldiso de s.Mos o
he indingsindep essionandanxie ya e ela ed o heexp essionand/o unc ionali yo CB1
ecep o sandFAAHinb aina easbelonging o heamygdala‐hippocampal‐co ico‐ s ia al
neu alci cui ,especially he on alco exindep essionand heamygdalainanxie ydiso de s.
Rega dingschizoph enia, he indingsinpos mo emandli inghumanb ainshighligh a
de egula iono CB1 ecep o inspeci icb aina eas ha a ehighlyaffec edin hisdisease.The
indingsonpe iphe alendocannabinoidle elsa eingoodcon‐sonancewi h heseadap i e
changes.Howe e ,wemus becau ioussincepe iphe alendocannabinoidle elsmayno be
wellco ela edwi hb ainconcen a ions.
Thepha macologicalmanipula iono heECSisen isagedasana ac i eal e na i e ea men
o hesemen aldiso de s.Fo ins ance,d ugsas hephy ocannabinoidcompoundCBDha e
been epo ed obeeffec i e o ea schizoph enia.
Thead ancein his ield, oge he wi h he ansla ionalp eclinical esea chisopeningan
a ac i e esea chscena io o hede elopmen o p omisingnewpha macologicals a egies
basedond ugs a ge ing heECS o ea men aldiso de s.
Acknowledgemen s
Thiss udywassuppo edby heSpanishMinis yo EconomyandCompe i i eness(SAF2015‐
67457‐R,MINECO/FEDER), hePlanEs a aldeI+D+i2013‐2016, heIns i u odeSaludCa losIII‐
Subdi ecciónGene aldeE aluaciónyFomen odelaIn es igación,SpanishMinis yo Economy,
FEDER(PI13/01529)and heBasqueGo e nmen (IT616/13).II‐Lisa ecipien o aP edoc o al
Fellowship om heBasqueGo e nmen .EF‐Zisa ecipien o aP edoc o alFellowship om
heUni e si yo Can ab ia.CMisa ecipien o aPos doc o alMa ieSkłodowska‐Cu ie
Indi idualFellowship(H2020‐MSCA‐IF‐2016,ID747487).
Con lic o in e es s
The eisnocon lic o in e es odecla e.
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