Dopamine D2 receptors le phetoho ea striatopallidal ho lemalla le botenya (2013)

Curr Opin Neurobiol. 2013 May 28. pii: S0959-4388 (13) 00101-3. Doi: 10.1016 / j.conb.2013.04.012.

Kenny PJ, Voren G, Johnson PM.

mohloli o moholo

Laboraro la Boitšoaro ba Boitšoaro ba Mahlale le Bolepi ba Limolek'hule, Lefapha la Phekolo ea Limolek'hule, Setsi sa Lipatlisiso sa DRM, Jupiter, FL 33458, USA; Lefapha la Neuroscience, Setsi sa Patlisiso ea DRM, Jupiter, FL 33458, USA; Kellogg Sekolo sa Saense le Theknoloji, Setsi sa Lipatlisiso sa Dheps, FL, USA. Aterese ea elektroniki: [imeile e sirelelitsoe].

inahaneloang

Bokhoba ba lithethefatsi le botenya bo arolelana karolo ea mantlha eo ba nang le bothata ba ho sithabela ba hlalosang takatso ea ho fokotsa ts'ebeliso ea lithethefatsi kapa lijo empa ba ntse ba phehella le ha ho na le litlamorao tse mpe.. Bopaki bo hlahang bo fana ka maikutlo a hore tšusumetso e hlalosang litšitiso tsena e ka hlaha, ho isa tekanyong e itseng, ho tsoa lits'ebetsong tse tloaelehileng tse tlasa methapo ea kutlo. Haholo-holo, mathata ana ka bobeli a amana le ho fokotseha ha striatal dopamine D2 receptor (D2R)y, mohlomong ho bonts'a ho fokotseha ha kholo ea 'mele le sebopeho sa sefahleho. Ho striatum, li-D2R li hlahisoa ke hoo e ka bang halofo ea methapo e ka sehloohong ea li-spiny projection neurons (MSNs), methapo ea kutlo ea striatopallidal ea tsela e bitsoang 'e sa tobang'. Li-D2R li boetse li hlahisoa ka mokhoa o ts'oanang le li-terminals tsa dopamine le li-interneuron tsa cholinergic. Ts'oaetso ena ea polelo ea D2R e sitisitse liteko, haholo-holo ho sebelisa mekhoa ea setso ea litlhare, ho utloisisa tlatsetso ea bona ho keneng ha lithethefatsi kapa lijo tse tlamang.

Ho hlaha ha mahlale a mofuta oa liphatsa tsa lefutso ho lebisa palo e kholo ea li-neuron, hammoho le lisebelisoa tsa optogenetic le chemicogenetic ho etsa mesebetsi ea bona, ho fane ka mokhoa oa ho qopitsa litlatsetso tsa striatopallidal le cholinergic ho qobelloang. Mona, re lekola bopaki ba morao-rao bo tšehetsang karolo ea bohlokoa bakeng sa ho saena hoa D2R ho supa ts'ebelisong e matla ea lithethefatsi le ho ja lijo. Re ela hloko ka ho khetheha li-neuron tsa "striatopallidal" le karolo ea bona ea ho arabela ka mokhoa o phehellang bakeng sa lijo le lithethefatsi. Kamora nako, re bonts'a menyetla ea ho etsa lipatlisiso tsa botenya nakong e tlang re sebelisa mekhoa e tsebahalang ea ho lemalla e le morusu, hape re phahamisa lisebelisoa tse ncha ho qhekella mesebetsi ea batho ba itseng ba methapo ea kutlo hore ba utloisise tlatsetso ea bona bokhobeng le boteng.

Ho felloa ke taolo ea tšebeliso ea lijo ho batho ba batenya haholo ba loanang ebile ba sa khone ho laola boima ba 'mele hoa tšoana le linthong tse ngata tse amanang le lithethefatsi tse lemalloang.1,2]. Ho ipapisitse le lintho tsena tse tšoanang, ho 'nile ha nahanoa hore mekhoa e rarahaneng kapa ea maiketsetso e ka kenya letsoho litloaelo tsena tse hatellang [1,3-6]. Ho khahlisang, liphuputso tsa batho tsa ho nahana ka batho li thehile hore ho fumaneha ha dopamine D2 (D2R) hangata ho tlase maemong a amanang le botona le botšehali ho batho ba sekhahla [7 ••, 8 ••, 9]. Liphoso tse tšoanang ho fumaneheng ha D2R le tsona li fumanoa ho ba nang le bothata ba tlhekefetso ea lithethefatsi [10-12]. Batho ka bomong ba nang le TaqIA A1 allele, e fellang ka ~ 30-40% fokotsa ho striatal D2Rs ha e bapisoa le ba sa jereng allele [13-15], li emeloa ke batho ba batenya le ba ts'ebeliso ea lithethefatsi [7 ••, 8 ••, 9, 16-18]. Kahoo, liphetoho tse bang teng D2R li ka ba le tšusumetso ea ho ja kapa ts'ebeliso e mpe ea lithethefatsi bothateng le bokhobeng ka ho latellana.

Dopamine D2 li-receptors tsa ho lemalla le botenya

Haufinyane tjena, re fuputse hore na boitšoaro bo hatellehang joalo ka ha bo lekantsoe ke tšebeliso e tloaelehileng ea lijo tse hananang le kotlo ea khatello (kapa litemoso tse boletsoeng esale pele) li hlaha ka likhoto tse nang le phihlello ea ho ja lijo tse matlafatsang tse bakang hyperphagia le ho nona haholo. Re ile ra fana ka likhoto tse nang le monyetla oa ho fumana "lijo tsa kofi" tse se nang meeli letsatsi le leng le le leng tse fumanehang ka bongata lihlahisoa tse matlafatsang tse jang matla tse fumanehang khoebong libakeng tse ngata tsa thekiso ea thekiso ea lijo le tse rekisoang ke batho, tse kang cheesecake le bacon, tse etsang hore motho a be le mafura a mangata. joalo ka likhoto tsa bona tse lekanang le batho [19,20]. Ha litoeba tsena li ntse li eketseha ka boima ba tsona, li bonts'itse mokhoa oa ho ja o hananang le litlamorao tsa lits'ebetso tse boletsoeng esale pele ho qala hoa footshock [21 ••]. Ho ja ka mokhoa o ts'oanang le ho qobelloang joalo ka ho likhoto ho arabela bakeng sa ts'oaetso ea koae ka mor'a nako e telele ea ho fumana lithethefatsi [22,23 ••].

In ntle le ho rata ha bona haholo le ho ja ka thata joalo ka likhoto tsa lijo tsa kofi le tsona li fokotsehile polelo ea D2Rs ka striatum [21 ••]. Ka hona re ile ra lekola hore na ho kokota ha li-D2Rs ho ka potlakisa ho hlaha ha tšebeliso e ts'oanang le e matla ea li-rats tsa lijo tsa kapejana. Ha ho nahanoa hore lentivirus e feta lipapatsong tse tlase haholo tsa sephethephethe, mokhoa ona o ile oa tiisa hore li-postynaptic D2R tsa li-neurons ka har'a striatum, eseng tse ipapisitseng le liphetho tsa dopamine, re anngoe ke sena se thetsang [21 ••]. Ho tsitsipana ha Striatal D2R ka sebele ho ile ha potlakisa ho hlaha ha ts'ebeliso e joalo-joalo ea ts'ebeliso ea lijo tse matlafatsang tse nang le letsoai. Leha ho le joalo, ho kokota ha D2R ha hoa ka ha etsa hore motho a arabele ka mokhoa o tloaelehileng, a fana ka maikutlo a hore liphoofolo li tlameha ho kopana le ho ts'oaroa ha D2R esita le ho pepesehela lijo tse matlafatsang pele ho qobelloang ho hlaha [21 ••]. Ka mokhoa o makatsang, litlamorao tsa ho sitisa ho ts'oaroa ha driatal D2R ho supa ka mekhoa e qobelloang ea tšebeliso ea lithethefatsi ha li e-so hlahlojoe.

Phetisetso ea Striatopallidal le moputso oa lithethefatsi

Kakaretso ea li-neurons tsa projeke tsa MSN li pakeng tsa 90-95% ea li-neurons tse ho striatum. Li-MSN ka kakaretso li arotsoe ka likarolo tse peli tse sa utloiseng letho, li bitsoang li-neuron tsa tsela e tobileng le e sa tobang, leha e le hore tšobotsi ena e kanna ea ba bobebe ba tšebelisano ea li-MSNs tsa striatal; mohlala, bona Ref. [24-26]. To tsamaisa tsela li-MSNs, tse tsejoang hape ka hore ke li-striatonigral neurons, o hlahisa dopamine D1 receptors (D1Rs) le projeke ka kotloloho ho tsoa ho striatum ho ea substantia nigra pars reticulata (SNr) le karolo e ka hare ea globus pallidus (GPi). Litsela tse sa tsamaelaneng tsa li-MSNs, tse tsejoang hape ka hore ke li-striatopallidal neurons, li hlahisa li-D2R le projeke ka kotloloho ho tloha ho striatum ho ea SNr / GPi ka karolo e kantle ea globus pallidus (GPe) le subthalamic nucleus (STN).

Ts'ebetso ea li-neuron tsa striatonigral hangata e thusa boitšoaro ba locomotor, athe li-neurons tsa striatopallidal li na le tšusumetso e khahlanong le eona. Ntle le li-neuron tsa striatopallidal, li-interneurons tsa cholinergic ho striatum le tsona li hlahisa D2R [27, 28 ••, 29]. Le heterogeneity ea polelo ea D2R ka har'a striatum e na le liteko tse thata ho utloisisa mekhoa eo li-D2R li ka kenyang letsoho ho ntlafatsa ts'ebeliso e matla ea lithethefatsi le lijo. Leha ho le joalo, nts'etsopele ea litoeba tse hlalosang Cre recombinase kahare ho palo e hlalositsoeng ea li-neuron, hammoho le ho hlaha ha mekhoa ea ts'ebetso ea ts'ebetso ea Cre ho laola ts'ebetso ea li-neuron tse hlalosang Cre, joalo ka optogenetics [30 •] le li-Receptors tsa Moqapi li sebetsa ka mokhoa o ikhethang ke Lithethefatsi tsa Moqapi (DREADDs) [31,32 •], e se e qala ho hlalosa tlatsetso ea lipalo tse ikhethang tsa lisele tsa striatal ho lithethefatsi le lijo. Joalokaha ho akarelelitsoe ka tlase, mekhoa ena ea nova e senola liphallelo tsa mantlha tsa li-neuron tse hlahisang D2 ho striatum ho hanyetsa thepa e matlafatsang le e khotsofatsang ea lithethefatsi tse lemalloang, hape e hanana le ho hlaha ha mekhoa e sa fetoheng, e qobelloang e kang ea lijo kapa tšebeliso ea lithethefatsi.

Striatopallidal neurons empa eseng li-interinuron tsa cholinergic li hlahisa adenosine 2A receptors (A2AR). Motheong oa 'nete ena, Durieux le basebetsi-mmoho ba sebelisitse litoeba tsa A2AR-Cre ho tsamaisa polelo ea diphtheria toxin receptor ho (DTR) ka li-neurons tsa striatopallidal, ba ntan'o kenya likokoana-hloko tsa liphoofolo ka chefo ea diphtheria ho kenya ts'oaetso e ikhethang haholo ea li-neuron tsena [33 ••]. Mokhoa ona o qhekellang o ile oa baka hyperlocomotion e matla le keketseho e kholo ea maikutlo ho litlamorao tse thabisang tsa amphetamine [33 ••]. Lobo le basebetsi mmoho le yena ba tlaleha hore ho hlakolwa ho hlakotsoe ha Tropomyosin-kinase B (TrkB), receptor bakeng sa boko-based neurotropic factor (BDNF), ka striatonigral ho fokotsitse thepa e khahlisang ea koae, athe TrkB ho tlaleha ha moputso oa D2 o hlahisang moputso oa cocaine [34 ••]. Ho feta moo, ho kokota ha TrkB ho D2-e hlalosang li-MSN ho ekelitse thabo ea bona, ka ts'usumetso ea optogenetic ea li-neurons tsena ka mokhoa o ts'oanang li fokotsa moputso oa koae [34 ••]. Haufinyane tjena, Neumeier le basebetsi-mmoho ba sebelisitse li-DREADD ho bontša hore thibelo ea li-neuron tsa "striatonigral neurons" e thibetse ho hlaha ha likarabo tsa maikutlo tsa locomotor ho amphetamine, athe thibelo ea methapo ea kutlo ea li-striatopallidal [sensorization]35 •]. Liphumano tsena li fana ka maikutlo a hore ho tšoaea striatopallidal ho hanyetsa mekhoa e amanang le moputso mme ho ka sireletsa khahlanong le ts'ebetso ea neuroplasticity e amanang le bokhoba.

Phetisetso ea Striatopallidal le ts'ebeliso e mpe ea lithethefatsi

Liphumano tsa morao-rao li thatafalitse ho tšoaetsoa ha "striatopallidal" ho arabela "ho fetoha habonolo" - bokhoni ba ho khaotsa ho araba ha ho tswela pele ka boitsoaro ho ka baka litlamorao tse mpe - pherekano eo ho eona e ka bakang ho hlaha ha khatello. Kravitz le basebetsi-mmoho ba fumane hore ts'usumetso ea optogenetic ea li-neuron tsa striatopallidal li felletse ka likarabo tse kang kotlo ho liphoofolo, tse bonts'itsoeng ho qoba ts'usumetso ea mahlo [36 •]. A sebelisa polelo e khethehileng ea sele ea toana ea tetanus toxin ho thibela ho lokolloa ha methapo ea methapo, Nakanishi le basebetsi mmoho le bona ba fumane hore tšitiso ea ts'ebetso ea "striatopallidal signal" e felisitse bokhoni ba liphoofolo ba ho ithuta boitšoaro ba thibelo ea tšireletso (ho qoba tikoloho eo ho eona ho ileng ha tsamaisoa likhoele tsa motlakase).37 ••]. Ba sebelisa mokhoa ona o thehiloeng ho taolo ea tautano ea tautonus, Nakanishi le basebetsi mmoho le bona ba fumane hore tšitiso ea phetisetso ea striatopallidal e bakile boits'oaro bo bobebe joalo ka litoeba moo ba sitiloeng ho fetola boits'oaro ba bona ka lebaka la likoluoa ​​tsa mosebetsi tse lemositsoeng [38]. Liphumano tsena li tsamaisana le karolo ea li-neurons tsa striatopallidal ho laola maemo a boitšoaro, karolo ea bohlokoa e fang phetoho lipakeng tsa maano a fapaneng a boits'oaro ho eketsa menyetla ea meputso [38]. Kahoo, polasetiki e hlahisoang ke lithethefatsi ho li-neuron tsa striatopallidal tse hlahisang ts'ebetso ea bona e fokotsehileng li ka fana ka litekanyetso tsa boitšoaro bo sa fetoleng maikutlo, tse qobelloang. Tumellanong le monyetla ona, Alvarez le basebetsi-mmoho ba sa tsoa supa hore matlafatso ea synaptic ho D2 e hlahisang li-MSNs ka li-nucleus accumbens li etsahala ka litoeba tse nang le nalane ea ho ipusa ea koae [ea koae]39 ••]. Matlafatso ena ea synaptic e ne e tsamaisana hantle le ho hlaha ha ts'ebeliso e ts'oanang ea koae ea cocaine [39 ••]. Ho feta moo, DREADD-Mediated inhibition, kapa e susumetsang ea mahlo, ea li-neurons tsa striatopallidal e ile ea eketseha kapa ea fokotseha, ka ho latellana, e qobelloang-joalo ka ho arabela cocaine litoeba [39 ••].

Phetisetso ea striatopallidal le lijo tse qobelloang

Tlipatlisiso tsa hese tse kaholimo li fana ka bopaki bo tobileng ba ts'ehetso ea karolo ea bohlokoa bakeng sa D2- ho hlahisa li-MSN ho arabela ka mokhoa o qobelloang oa koae. Sena se hlahisa potso ea bohlokoa ea hore na li-neuron tsa striatopallidal le tsona li kenelletse tšebelisong e matla ea lijo tse matlafatsoang ke botena. Ho makatsang ke hore monyetla ona ha o e-so ho hlahlojoe mme sena se bontša lekhalo le leholo la tsebo. Leha ho le joalo, ho na le likeletso tse khahlisang hore ehlile e kanna eaba ho joalo. Joalokaha ho boletsoe ka holimo, li-A2AR li bontšoa ka ho hlaka ke li-neuron tsa striatopallidal [40]. Kahoo, li-pharmacological agents tse fetolang tšebetso ea A2AR li lebelletsoe ho susumetsa phetisetso ea li-agonists tsa striatopallidal, tse eketsang phetiso ea striatopallidal, tse fokotsang tšebeliso ea tsona tse fumanehang habonolo le tse tloaelehileng maemong a litoeba [41], le ho fokotsa khatello ea manonyeletso bakeng sa meputso ea lijo [42]. Ka lehlakoreng le leng, li-receptor tsa pharmacological tsa li-receptor tsa A2A li ile tsa eketsa ts'ebeliso ea lijo tse matlafatsang ha li tsamaisoa li le ling, le lijo tse matlafatsoang tsa lijo tse susumetsoang ke tsamaiso ea "intra-drabens" ea "receptor agonist" ea µ-opioid reconor [DAMGO] [43]. Tliphumano tsa hese li hopotsa litlamorao tsa tšusumetso e sa tobang ea moputso oa lithethefatsi tse hlalositsoeng kaholimo, mme ba fana ka tlhahiso ea hore li-D2 tse sa bontsheng tsela e sa tsamaelaneng ea li-MSN li ka tsamaisa tšebeliso ea lijo ka tsela e tšoanang le eo li laolang meputso ea lithethefatsi.

Liphetho le mekhoa ea nako e tlang

Liphumano tse kaholimo li tšehetsa moralo oa nako e telele moo tšebeliso ea lithethefatsi e tsoelang pele kapa boima ba 'mele bo tsamaisang likarabo tse feto-fetohang tsa methapo ea kutlo, e hlahisang litekanyetso tse sa fetoheng tsa tšebeliso ea lintho tse ntseng li thatafala butle-butle ka tlhaho. Kahoo, sebaka se ka sehloohong sa ts'ebetso ea nakong e tlang lipatlisisong tsa botena li kanna tsa hlalosa karolo e nepahetseng bakeng sa li-neuron tsa striatopallidal ho laola ho hlaha ha khatello e matla. Hape ho tla ba bohlokoa ho tseba hore na mofuta ona oa ho ja o sa fetoleheng o ka theha motheo oa leano le sebetsang la ho fihlela boima ba nako e telele. Sebaka se seng sa lipatlisiso se ka bang sa khahleha haholo litabeng tsa bokhoba le botenya li tla ba hantle ho hlalosa karolo ea li-receptor tsa D2 tse fumanehang litsing tsa cholinergic. Optical inhibition ea cholinergic interneurons in striatum e felisa litholoana tse monate tsa cocaine [44]. Li-receptor tsa D2 ho li-interneuron tsa cholinergic li laola mokhoa oa ho phatloha ho phatloha ha lisele tsena ho arabela molemong oa tšusumetso ka ho sebelisana le li-receptor tsa nicotinic acetylcholine (nachRs) tse fumanehang moetlong oa dopamine [28]. Ho khahlisang, ho hanyetsa li-nAChR ho thibela ho ata ha koae ka likhoto tse nang le phihlello e telele ea lithethefatsi [45]. Ka hona, ho tla ba bohlokoa ho tseba hore na li-receptor tsa D2 li tšoaeang ho li-interneurons tsa striatal cholinergic le tsona li kenya letsoho ts'ebelisong e mpe ea tšebeliso ea lithethefatsi le boits'oaro.

Lintlha-khōlō Tsa

  • Ho nona haholo le ho lemalla ho etsa hore ho fokotsehe ho fumaneha ha D2 receptor ho striatum.
  • Li-receptors tsa D2 li laola lijo tse qobelloang.
  • Li-DREADD le li-optogenetics li senotse karolo ea bohlokoa bakeng sa li-neuron tsa striatopallidal ts'ebelisong e matla ea lithethefatsi.

Liteboho

Mosebetsi ona o tšehelitsoe ke chelete e tsoang ho National Institute on Drug Abuse (DA020686 ho PJK). Ena ke nomoro e ngotsoeng ea 23035 e tsoang ho The DRMps Research Institute.

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Likarabo le ho bala ho khothalletsoang

Lingoloang tsa lithahasello tse khethehileng, tse phatlalalitsoeng nakong ea tlhahlobo, li hlakisitsoe e le:

• ea lithahasello tse khethehileng

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