Karolo ea krase accumcums glutamatergic plastiki ho lemalla lithethefatsi (2013)

inahaneloang

Bokhoba ba tahi le lithethefatsi

Kutloisiso ea karolo ea karolo ea glutamate ts'ebetsong ea ho khutlisetsa lithethefatsi e bohlokoa ho utloisise hore na hobaneng lithethefatsi tse lebisitsoeng tsamaisong ea glutamatergic li ntse li sebelisoa. Ho amoheloa hore ts'ebetso ea dopaminergic system maemong a li-nucleus accumbens (NAc) e sebelisana le ts'ebeliso e qobelloang ea lithethefatsi; athe, ts'ebetso ea tsamaiso ea glutamatergic e le boemong ba NAc haholo e laola ho khutla hape ka mor'a ho felisoa ha lithethefatsi.1,2 Ho se ho tsebahala hore liphetoho tse amanang le "glutamate" tse amanang le polasetiki ka har'a potoloho ho tloha preortal cortex (PFC) ho ea ho NAc li bohlokoa bakeng sa ho khutla ha lithethefatsi;2 lisele tsa glial li fetole liphetoho tsena tsa polasetiki tse bonojoana.2 Hape litsebi tsa linaleli ke lisele tsa glial tse susumetsang haholo matla a bokhoba ba tahi ka ho etsa lintho tse ling tse ka thusang ho kenya ts'ebetsong ea "cysteine-glutamate exchanger" (xCT) le transutterate ea glutamate 1 (GLT-1).3-5 Leha ho le joalo, tlhahlobo e eketsehileng ea karolo ea lisele tse ling tsa glial, joalo ka microglia le oligodendrocyte, lits'ebetsong tsa bokhoba ba lithethefatsi li ntse li hlokahala.

Ka lehlakoreng le leng, ho boetse ho amoheloa hore ho itaola ka lekhoakhoa le ho ikhula ho eketsang maikutlo a holimolimo a glutamate receptor subunit 1 (GluA1) ea alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors hape e khothaletsa sebopeho sa subunit GluA2 e haelloang ke Ca²⁺Li-receptor tsa AMPA tse pepesitsoeng (li-CP-AMPAR) ho NAc; ho thibela li-CP-AMPAR ho fokotsa polelo ea ho lakatsa.6-8 Leha ho le joalo, ho bohlokoa ho tsoela pele ho lekola sebopeho sa subunit ea AMPA receptors le liphetoho tse fapaneng mehatong e fapaneng (lithethefatsi-naïve, tšebeliso ea lithethefatsi, ho tlosoa hoa lithethefatsi, le ho khutla hape) bakeng sa ho fumana kutloisiso e ntle ea liphetoho tsa polasetiki tsa glutamatergic ho NAc.

Ntle le moo, ho pakoa hore ho itaola ha k'hok'heine ho eketsa maemo a bokong a neurotrophic factor (BDNF) ho NAc, mme ho phahama hona ha BDNF ho lebisa keketseho ea nakoana ea polelo ea sebopeho sa GluA1 ho NAc.9 Ho feta moo, BDNF e ka fetola dendritic le spine morphology, e ipapisitse le lithuto tsa setso ho hippocampus.10,11 Leha ho le joalo, hore na bobuelli ba BDNF liphetoho tsa morphological bo etsahala boemong ba NAc ha bo so ka bo buloa.

Mosebetsi oa morao-rao o bapisitse kabo ea li-subunits tsa AMPA tsa receptor ka li-membrane tsa synaptic le extrasynaptic tsa NAc.12 Hoa tsebahala hore ho khaotsa koae ka nako e telele ho eketsa maemo a phosphorylated S845 GluA1 ho li-NAc extrasynapses.13 Hape ho amoheloa hore extrasynaptic metabotropic glutamate receptor 2 (GRM2) le metabotropic glutamate receptor 3 (GRM3) ho NAc e ka susumetsa ho khutla ha lithethefatsi.14 Leha ho le joalo, lipatlisiso tse ling li ntse li hlokahala ho tseba tšebelisano lipakeng tsa extrasynaptic AMPA receptors (phosphorylated S845 GluA1), GRM2 le GRM3 ho NAc nakong ea ho khaotsa koae.

Ho amoheloa hore dopamine agonism ho NAc e etsa hore o khutlisetsoe ka boeona, ka boithatelo ha glutamate.15 Ntlha ea tšebelisano lipakeng tsa lits'ebetso tsa glutamatergic le dopaminergic ho NAc ke Ca²⁺/ proteinodase e itšetlehileng ka proteinodase kinase 2 (CaMKII).15 Patlisiso ea nako e tlang e ka lekola kalafo e kopaneng bakeng sa ho khutla hape hoa lithethefatsi tse lebisang glutamate le dopamine dynamics ho NAc. CaMKII e kanna ea ba sepheo sa sepheo sa lipatlisiso tse ling.

NAc ke sebaka sa bokong sa "vertebrate" se sebakeng sa boteng ba basal. NAc e boetse e fumaneha litsing tse ling tse tšoanang le litoeba.16 NAc ke eona sepheo se ka sehloohong sa lithethefatsi tse lemalloang (mohlala, nicotine, cocaine le amphetamines). E arotsoe libakeng tse peli tsa bohlokoa tse sebetsang: khetla ea NAc (NAcs) le mantlha ea NAc (NAcc).16 Li-NAc li na le khokahano e pharaletseng ho sistem ea limbic le hypothalamus.16 Ntle le bokhoba ba tahi, NAc e bapala karolo e loketseng moputsong, tšabong, ts'ebetsong ea placebo, ho susumetsa, ho ithuta le ho ba mabifi.17,18

Patlisiso ea Rodent ka micodialysis e fana ka maikutlo a hore kamora ho entetsoa ha lithethefatsi tse lemalloang joalo ka heroin, cocaine, nikotine, kapa joala ho litoeba, ho na le keketseho ea maemo a dopamine sebakeng sa extracellular sa NAc.1 Keketseho ena ea dopamine e hokahane le litlamorao tse matlafatsang tse ileng tsa khothaletsa boitšoaro ba ho ts'oara lithethefatsi hamorao.1 Ka lehlakoreng le leng, lithuto tse inahaneloang tse sebetsang ho batho li bontšitse hore mekhoa ea tikoloho e amanang le lithethefatsi tse lemalloang e lokolla dopamine ho NAc.1 Litsi tsa litlhahlobo tsa hajoale li potoloha kamano pakeng tsa tsamaiso ea glutamatergic e maemong a NAc le ho khutla hape hoa lithethefatsi; leha ho le joalo, ho bohlokoa ho khetholla hore matla a dopamine ho NAc boholo bo kenella phetohong ea kelello e amanang le ts'ebeliso e mpe ea lithethefatsi. Ntle le moo, matla a glutamate a ho NAc a buella mekhoa e mengata ea ho batla lithethefatsi kamora ho timela.

Ho ea ka Tlhatlhobo le Buka ea Bophatlalatsi ea Mathata a Kelello, 4th Edition, Tlhahlobo ea Mongolo (DSM-IV-TR), a mang a matšoao a amanang le tšebeliso ea lithethefatsi ke ho senyeha kelellong kapa mokhoeng oa matšoafo, matšoenyeho, ho nahana ka lintho tse itseng, ho qhekella le ho tsietsana.19 Ka lehlakoreng le leng, tšobotsi ea bohlokoa ea ho its'etleha ha ntho ke sehlopha sa matšoao a mmele, a boits'oaro, le a kelello, a bonts'a hore motho eo o tsoela pele ho sebelisa ntho eo, leha a na le mathata a amanang le ntho. Ho feta moo, ts'epahalo ea thepa e khetholloa ke mokhoa oa ho itaola hangata. Sena se ka susumetsa ho mamella, ho tlohela, le ho qobella ho sebelisa lithethefatsi.19 Ho latela DSM-IV-TR, ho itšetleha ka lintho ho tsebahala ka mekhoa e supileng e ka sehloohong.19 Criterion 1 ke mamello; e hlalosoa e le tlhoko ea ho nyolla palo ea thepa ho fumana litlamorao tse hlokoang ke ntho eo.19 Ho mamella ho fapana ka lintho.

Criterion 2a ke ho tlosa. E na le phetoho ea boits'ebetso bo sa sebetseng ka li-concencitants tsa kelello kapa tsa mmele, tse qalang kamora ho theoha ha maemo a 'mele a ntho e sebelisitsoeng khafetsa ke taba.19 Ka lebaka la matšoao a khaotsoang a ho tlohela, taba e ka 'na ea sebelisa ntho eo ho e fokotsa kapa ea fokotsa mats'oao a (testosterone 2b).19 Matšoao a bang teng ha a fapana ho ea ka lintho.

Criterion 3 ke mohlala oa tšebeliso ea lintho tse tlamang. Taba e ka nka sehlahisoa ka bongata bo boholo kapa ka nako e telele ho feta kamoo e neng e reriloe qalong.19 Criterion 4 e amana le ho hloleha ha sehlooho ho fokotsa kapa ho khaotsa ts'ebeliso ea lithethefatsi.19 Ntle le moo, taba e ka qeta nako e ngata e fumana ntho, e e qeta, kapa e fokotsa litšenyehelo tsa ntho ena.19 Criterion 6 e ka hlalosoa e le ho se tsotelle ha sehlooho bakeng sa mesebetsi e amanang le bophelo ba setjhaba, e tloaelehileng le e amanang le mosebetsi, hobane ntho e fetohile setsi sa bophelo ba sehlooho.19 Kamora nako, khokahano ea 7 ke hore motho o tsoelapele ts'ebeliso ea ntho eo, leha a tobane le litlamorao tse mpe (tsa kelello kapa tsa mmele).19

Ho latela Kalivas le O'Brien,20 tšebeliso ea lithethefatsi e ka hlalosoa e le phetoho taolong ea tšebeliso ea likarabo ho matlafatso ea lithethefatsi.20 Ho potoloha ha boko ho amanang haholo le ts'ebeliso ea lithethefatsi tse tsoetseng pele ho etsoa haholo-holo ka morero oa ho tloha ho PFC ho ea ho NAc, empa le merero e tlatselletsang ho tloha Amygdala le hippocampus ho ea NAc.20 Ka ho khetheha, liphuputso li bonts'itse hore amygdala e amana le ho khutlisetsoa hoa cueine ka lebaka la ho batla koae. Bangoli ba boetse ba bontšitse hore tšusumetso ea motlakase ea hippocampus e khutlisetsa boits'oaro bo batlang cocaine.21,22

Glutamate ke "neurotransmitter" e ka sehloohong le e ngata ka ho fetesisa bokong. E bohlokoa bakeng sa ts'ebetso ea lits'ebetso tsa polasetiki tsa synaptic tse lumellang setho hore se arabe le ho phela tikolohong.23,24 Lits'ebetso tsena tsa polasetiki ea synaptic li hlahlobisitsoe haholo ke Kalivas et al.24 Plastiki e kopantsoeng le li-receptor tsa glutamatergic e bapala karolo ea ts'oaetso ea lithethefatsi le mafu a mang a kang dyskinesia ea levodopa, bohloko ba neuropathic, schizophrenia le 'dementia'.23 Glostamate homeostasis bokong le deregulation tsa eona, ka ho fapana, li amana le tloaelo e tloaelehileng le e sa tloaelehang ea boits'oaro tikolohong.24 Ntle le glutamate le dopamine, li-neurotransmitter tse ling - joalo ka norepinephrine le serotonin - li ka fetolela boiphetetso ba boits'oaro ba ho batla koae.25,26

Boemong bo boholo ba sele, litlamorao tsa bokhoba ba litlamorao ke litlamorao tsa tšebelisano ea neuronal le glial, haholo maemong a NAc.5 Mekhoa ea ho ja ea lithethefatsi e sa foleng e lebisa ho sitisoeng ha ho lokolloa ha glutamate ho tloha ho PFC ho ea NAc, e ileng ea ama homeostasis ea morao-rao ho NAc, e lebisang keketseho ea boits'oaro ba bokhoba, haholoholo ho khutlela morao.5,27 Ka ho khetheha, pherekano ena ea glostamate homeostasis e na le ho fokotseha ha lintlha tsa glutamate tsa extrasynaptic tseo hamorao li lebisang ho fokotseha ha molumo oa lentsoe la presynaptic ho GRM2 le GRM3.28 Hobane presynaptic GRM2 le GRM3 li na le litlamorao tse tlisoang ke ho tlosoa ha glutamate presynaptic, ho fokotseha ha molumo ho feta GRM2 le GRM3 ka lebaka la maemo a fokolang a glutamate perisynaptic a lokolla phello ea inhibitory ea GRM2 le GRM3. Ka lebaka leo, e lumella keketseho ea tokollo ea glutamate ha merero ea PFC-NAc e ts'ebetsoa nakong ea boits'oaro ba ho batla lithethefatsi.14

Ka lebaka la tšebeliso ea lithethefatsi tse pheta-phetoang, liphetoho lipakeng tsa glutamate mokhatlong oa "presynaptic" li eketsa ts'ebetso ea li-receptor tsa postynaptic terminal AMPA; ka kotloloho, e bonts'itsoe ho eketseha ha polelo ea lefats'e ea GluA1 ea AMPA receptor kamora ho itaola le ho ts'oara, mme ka lebaka leo, ts'ebeliso ea ts'ebeliso ea post-synaptic ho NAc.6,7 Ntle le moo, thuto e 'ngoe e amanang15 fumana hore ho khutlisetsoa ha koae ho fokotsehile ha thekiso ea GluA1-e nang le AMPA receptors 'e sitisoa ke ts'oaetso ea vaerase e amanang le adeno 10-GluA1-C99. Hobane ho khutlisoa ha koae ho hokahanngoa le keketseho ea ponahalo ea sele ea sefahleho sa li-receptor tsa GluA1 tse nang le AMPA li-NAcs, joale phello e khahlanong le vaerase e amanang le adeno 10-GluA1-C99 mabapi le ho khutlisetsoa ha koae e ka hlalosoa ke ho senyeha. leetong la li-receptor tsa AMPA tse nang le GluA1.15

Ho khutlisetsoa cocoaine ho amana le mofuta oa "dopamine" 1 receptor (D₁) -keketseho e atamelaneng ea li-NAcs, CaMKII phosphorylated ho Thr286, le keketseho ea phosphorylated ea GluA1 ho Ser831 (sebaka se tsebahalang sa phosphorylation ea CaMKII), ho kenyelletsa le keketseho ponts'ong ea sele e nang le li-receptor tsa GluA1 tse nang le AMPA khetla.

Phuputso e 'ngoe e ts'oanang e fumane hore infusion ea glutamate receptor agonist, AMPA, ho NAc e kentse ts'ebetso ea koae; ka boiphetetso, ente ea AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione e koetsoe hape.29

Polasetiki e hlahisoang ke lithethefatsi ea AMPA e ithutile haholo ho NAc.30,31 Palo e kholo ea li-receptor ea AMPA e sebetsang ho NAc e na le li-subunits glutamate receptors 1 le 2 (GluA1A2); palo ea baahi ba li-recunit receptors 2 le 3 (GluA2A3) le tsona li teng.32 Ka lehlakoreng le leng, baahi ba subunits glutamate receptors 4 (GluA4) ba haelloa haholo.32 Ho nahanoa hore boholo ba lipapatso tsa li-receptors tsa AMPA ho NAc li kopantsoe ke lipalo tsa GluA1A2, empa GluA2A3 le GluA1A3 le eona e bapala karolo ea bohlokoa phetisetsong ea li-receptor, mme esita le boits'ireletso ba koae bo khona ho fetola GluAX.6,33 Bangoli ba bang ba bontšitse tlhokahalo ea ho hlakisa sebopeho sa li-receptor tsa AMPA ho NAc le libakeng tse ling tsa boko tse amanang le tšebeliso ea kelello bokong bo tloaelehileng ho khona ho utloisisa ts'ebetso e latelang e sa sebetseng libakeng tsena.32

Ho likhoto tsa batho ba baholo, ho bontšitsoe hore kamora ho khaotsa ho itaola ka nako e telele, ho ba le sebopeho sa li-CP-AMPAR tse haellang tsa li-CP-AMPAR ho NAc; ho thibeloa ha li-CP-AMPAR tsena ho fokotsa polelo ea ho tsosa takatso ea takatso ea cue ea litheko.6,8 Keketseho ena ea li-CP-AMPAR tse bonoang ho NAcc le li-NAcs ho latela mohlala oa tšohanyetso oa tsamaiso ea koae; haeba koae e sebelisoa ho ratoa ka kalafo e sa laoleheng, ha ho na keketseho ea li-CP-AMPAR.8 Ho bonahala eka sebopeho sa li-receptor tsa CP-AMPA se ka fetoloa ka mekhoa e 'meli ea phumaneho ea lithethefatsi le ho tlosoa hoa moriana.

Mohala o mong oa lithuto o bontšitse keketseho ho li-receptors tsa NAc AMPA tse hlahisitsoeng ke BDNF.9 Ka ho khetheha, infusion ea BDNF ho NAcc - empa eseng ho li-NAcs tsa likhoto - e eketseha ka potlako (metsotso ea 30) polelo ea sefahleho sa GluA1 ka mokhoa oa protheine synthesis le extracellular receptor kinase mechanism.9 Leha ho le joalo, ts'ebetso ena e ea lieha, 'me ha ho liphetoho tse ling tse bonoang hamorao.9 Sena se fana ka maikutlo a khokahano lipakeng tsa tšebeliso ea koae, ho phahamisoa ka bongata ba BDNF, phetisetso e ntlafalitsoeng ea AMPA ho NAc, le mokhoa o ka sebelisang BDNF oa ho sebelisa tšebeliso ea koae ho likhoto.

Ntle le moo, ts'ebeliso e sa foleng ea ts'usumetso e lebisa ho liphetoho mokhoeng oa dendritic le letsoalo la mokokotlo, hape e phahamisa boemo ba BDNF libakeng tsa boko tse amanang le moputso.34,35 Tlhahlobo ea lithuto tse fapaneng e sebelisang mehlala ea ho tlosa BDNF le receptor ea eona, tyrosine kinase B (TrkB), e ts'ehelitse bohlokoa ba bona phetohong ea letsoalo la lesapo la mokokotlo le tlhokomelo ea lesapo la mokokotlo nakong ea methati ea kholo le ea batho ba baholo.10 Ntle le moo, lithuto tsa setso sa hippocampal li ts'ehetsa karolo ea BDNF ho matlafatsong ea protheine ea methapo ea methapo.11 Sena se fana ka maikutlo a hore tsela ea BDNF e ka kenya letsoho phetolelong ea letsoalo la lesapo la mokokotlo le lekala la dendritic le amanang le tšebeliso ea sefutho. Leha ho le joalo, patlisiso e tsoelang pele ho lekola karohano e tobileng ea tsela ea BDNF mabapi le liphetoho tsa morphological ho NAc kamora ts'ebeliso ea lithethefatsi e lokela ho lateloa. Tsamaiso ea BDNF libakeng tsa boko tse amanang le bokhoba ba taolo (sebaka sa karolelano ea methapo kapa NAc) e eketsa khafetsa ea boits'oaro bo amanang le ho lemalla ho ts'oaroa ke sethoathoa, ho batla koae, ho itlhokofatsa ka koae, le ho oela hape; ka boits'oaro, ho fokotseha ha BDNF ho hokahane le boits'oaro bo fapaneng.36-39

Boithuto bo bong bo khahlisang12 e hlakisitse ho ajoa ha li-subcom tsa AMPA receptor ka li-membrane tsa synaptic le extrasynaptic tse ling maemong a NAc. Ka ho khetheha, GluA1 phosphorylated setsing sa protheine kinase A (PKA) (S) 845 e bontšoa haholo ka li-membrane tsa extrasynaptic. Ho feta moo, ho ea ka lithuto tsa in vitro, ho kenella ka matla hoa li-receptor tsa GluA1 tse nang le AMPA li-synapses ho latela ts'ebetso ea mekhahlelo e 'meli. Karolo ea pele e kenyelletsa ho kenngoa ha li-receptor tsa GluA1 tse nang le AMPA sebakeng sa extrasynaptic, tse matlafalitsoeng haholo ke phosphorylation ea GluA1 ho Serine 845 ke PKA. Karolo ea bobeli e sebakeng sa kameho e latelang ea GluA1-e nang le li-receptors tsa AMPA sebakeng sa membrane ea synaptic, 'me e kenella ka li-receptors tsa N-methyl-D-aspar-tate (NMDA).31,40 Mokhoa ona oa ho kenyelletsa ho tloha ho li-extrasynapses ho li-synapses o kenella ka PKA le NMDA, hape o shebiloe hantle libakeng tse ling tsa boko, joalo ka ha bangoli ba bang ba boletse.31,41-44 Mohlala, e fumanoe hippocampus hore botsitso ba li-CP-AMPAR ho extrasynapses bo hokahantsoe ke PKA phosphorylation ho Ser845 GluA1; ebe ho na le monyetla oa hore keketseho ea li-CP-AMPAR ho NAc kamora ho khaotsa nako e telele ho iphetetseng hoa koae ho kopantsoe ke mochini o tšoanang oa PKA phosphorylation.6,45-47 Ha e le hantle, patlisiso e tlaleha keketseho ea maemo a phosphorylated S845 GluA1 litekong tsa NAc extrasynapses kamora ho khaotsa koae ka nako e telele, ho ts'ehetsa mohopolo ona.13

Liprotheine tse tataisang tsa Transmembrane AMPA li-protein receptor (TARPs) ke sehlopha se seng sa liprotheine tse laolang tumellano ea glutamate, thepa ea seteishene, le thekiso ea khoebo ea AMPA-receptor.48 Boemong ba NAc, karolo ea TARPs e hlakisitsoe ke mosebetsi oa Ferrario et al;12 ka kotloloho, mosebetsi ona o bonts'a hore TARP γ-2 e ruisitsoe ka har'a li-membrane tsa synaptic, athe TARPs γ-4 e ne e fumaneha haholo ka har'a li-membran tsa extrasynaptic.12 Sena se fana ka maikutlo a hore ion e kholo e phalla ka har'a li-receptor tsa AMPA tse eketsehileng.12 Ho phalla ho hoholo ha ion ho fetela ho li-extrasynaptic AMPA receptors (TARPs γ-4) ha ho bapisoa le li-receptors tsa AMPA tsa synaptic (TARPs γ-2) ho hlalositsoe hobane TARPs γ-4 e na le ntlafatso e matla ea phetiso ea AMPA receptor ha e bapisoa le TARPs γ-2 .48

Phuputso e 'ngoe e fumane phapang pontšong ea holimo ea li-receptor tsa AMPA pakeng tsa ente e le' ngoe le tse ngata tsa koae ka likhoto. Ente e le 'ngoe ea koae e eketsa polelo ea AMPA ea li-receptor ka lihora tsa 24, empa eseng ka lihora tsa 2.49 Ka lehlakoreng le leng, li-receptor tsa AMPA tse ka holim'a lefatše li ile tsa eketseha ka mor'a ho khaotsa ho ts'oara maikutlo a koae, empa hamorao tsa fokotseha ho li-rats tsa sensitised tsa 24 ka mor'a phephetso.49 Ntle le moo, patlisiso eo e fumane hore D2 receptors agonism e ikhethileng ka mokhoa oa quinpirole intraperitoneal (ip) e fokotsitseng polelo ea holimo ea li-receptor tsa AMPA ho NAc; leha ho le joalo, D₁ agonism e khethang li-receptors ka SKF-81297 e ikhethileng le e tsamaeang le D₁+D₂ agonism ka ho sebelisa subcutaneous apomorphine ha e a ka ea susumetsa mofere-fere oa GluA1 le GluA2 ho tloha holimo ho ea matamong a makatsang a NAc.49

Tlhahlobo e kholo mabapi le li-receptor tsa AMPA le NAc e bontšitse hore liphetoho tse fetisetsong ea li-receptor tsa AMPA ho NAc kamora taolo ea koae li its'etleha hodima mabaka a fapaneng, joalo ka tšenyo ea nako, nako ea ho khaotsa, ho ba teng ha thupelo ea ho felisoa, kapa esita le ho ba teng ha lithane tse entsoe ka koae.31 Ho hlakile hore liphetoho tse tlisoang phetisong ea li-receptors tsa AMPA ho NAc li ipapisitse le maemo a tšohanyetso a ho pepesoa ha koae ka bobeli le ponts'o ea ho khaotsa. Ho feta moo, tlhahlobo ena e phethile tlhokahalo ea ho se nke hore cocaine le methamphetamines li na le litlamorao tse tšoanang le polasetiki ea AMPA receptor maemong a NAc.31

Li-receptors tsa GluA2 AMPA ka bohareng kapa khetla ea NAc le tsona li boelana le ho khutlisetsoa ka boitsoaro ba koae.50 Ka ho khetheha, thuto e tummeng ke Famous et al50 e tlaleha hore antagonism ea AMPA / kainate receptor ka 6-cyano-7-nitroquinoxaline-2,3-dione ho NAcc kapa lethal dose la NAcs ka ho fokotseha ho khutlisetsoa ka matla ho koae ea koae. Hape, boithuto bo tšoanang bo fumane hore tšitiso ea ho ts'oaroa ha GluA2 ke peptide Pep2-EVKI ho NAcc kapa NAcs e fumane cocaine-e kenyelletse ho khutlisetsoa morao hoa boits'oaro bo batlang lithethefatsi.50

Ho feta moo, thuto51 e tlaleha hore metabotropic glutamate receptor 5 (GRM5) maemong a postynaptic terminal e nka karolo ho matlafatseng le ho ts'oaroeng hoa koae.51 Ka ho khetheha, infusion ea GRM5 antagonist, 2-methyl-6- (phenylethynyl) pyridine (MPEP) (1 μg / 0.5 μL), ho li-NAcs e fokotsa ts'ebetso ea ho ts'oara lithethefatsi tsa koae.51 Phuputso ena e boetse e tlaleha hore MPEP le 3 - ((2-methyl-1,3-thiazol-4-yl) ethynyl) pyridine (MTEP) e fanoa ka mokhoa o hlophisitsoeng, ka mokhoa o itšetlehileng ka mokhoa o itšetlehileng oa ho ts'oara koae, e hlahisoang ke ente ea cocaine.51

Ho amoheloa hore ntle le glutamate, keketseho ea litekanyetso tsa dopamine ho NAc e amana le ho batla koae, e ipapisitseng le mohlala oa phoofolo. Li-neurotransmitters ka bobeli - glutamate le dopamine - li ka tsosa ho ikhula hape.15 Ho feta moo, thuto e ntle e ngotsoeng ke Anderson et al15 ho hlakisitsoe hore tšebelisano lipakeng tsa li-neurotransmitter ka bobeli ho NAc li ne li kopantsoe ke CaMKII. Ka ho khetheha, thuto eo e bontšitse hore ho khutlisetsoa ha koae ho ne ho amana le keketseho ea D₁Bofokoli bo kang dopamine receptor ho NAc, 'me ka morao ho moo, keketseho ea NAcs ea phosphorylated ea CaMKII ho Thr286, le mofuta oa L²⁺ ts'ebetso ea seteishene; ka tatellano, CaMKII le mofuta oa L-Ca²⁺ seteishene se eketsang polelo ea seleng ea mahlaseli a GluA1 AMPA receptors ka khetla ke GluA1 phosphorylation ho Ser831 (sebaka sa sepheo sa CaMKII phosphorylation).15

Boithuto bo bong bo bontšitse hore mohanyetsi oa NMDA ka ho kenella ha mohanyetsi oa tlholisano, AP5, ebang ke NAcc kapa NAcs o ile a khona ho kenya ts'ebetso e khutlisetsang morao ea ts'ebeliso ea koae ea koae; leha ho le joalo, antagonism ea AP5 e na le litlamorao tse matla khetla ha e bapisoa le mantlha.52 Boithuto bo eketsehileng29 o fumane sephetho se ts'oanang - hore ho hanyetsa ha NMDA receptor ka lethathamong la NAc le ts'ehetso ea koae ka botlalo; leha ho le joalo, thuto e 'ngoe53 e tlaleha hore microinfusion ea mohanyetsi oa li-receptor oa NMDA, CPP, ho NAc ha e ame boitšoaro ba motho ea batlang lithethefatsi tsa koae.29,53

Joalokaha ho ka bonoa, karolo ea AMPA, GRM, le li-NMDA receptors tsa NAc ho khutlisetseng koae li rarahane. Bangoli ba bang ba bile ba tlaleha litlamorao tse hanyetsanang tsa li-receptor tsa AMPA le NMDA ka ho khutlisetsoa hoa koae.53

Khethong, ka lebaka la boitsoaro bo pheta-pheto ba ho ts'oara koae le ho itaola, ho ba le liphetoho tse latelang ho homeostasis ea maemo a glutamate ho extrasynapses ea NAc, 'me ka lebaka leo ho na le tokollo e feteletseng le phetoho e kholo ea glutamate nakong ea puseletso.5 Lisele tsa Glial le tsona li bapala karolo ea bohlokoa molemong oa ho khutlisetsa lintho tse boletsoeng, 'me karolo ea tsona ho bokhabane ba glutamate e tla tšohloa ka ho eketsehileng karolong e latelang.

Karolo ea Glial boteng ba glutamatergic

Karolo ea lisele tsa glial bokhobeng ba bokhoba e amohetse lingoli tse fapaneng.14,54,55 Li-Astrocyte ke lisele tsa glial tse laolang boholo ba ho hapa lisele le ho lokolloa ha glutamate, tse susumetsang boits'oaro ba bokhoba. Leha ho le joalo, ha ho tsejoe letho ka karolo ea micoglia le oligodendrocyte tlhekefetsong ea lithethefatsi. Litsebi tsa linaleli li angoa haholo ke ho pepesetsoa ha ethanol le lithethefatsi tse ling tsa tlhekefetso.

Boithuto bo bonts'itse hore xCT le tumellano e phahameng ea GLT-1 e bapala karolo ea bohlokoa ho hlokeng maemo a glutamate ho NAc.28,56,57 XCT e bontšoa haholo-holo ka liseleng tsa glial.4,5 GLT-1 e ikarabellang bakeng sa bongata ba ho bokelloa ha glutamate bokong, e hlahisoa haholo liseleng tsa glial.3

Boemong ba NAc, liphetoho tse bonoang ka mor'a ho itaola ka lithethefatsi le ho timela li hlalosoa ke ho se sebetse hantle kapa polelo e senyehileng ea glial xCT.24,28,56 XCT e ruta 1: Ho lokolloa ha stoichiometric ea 1 ka phapanyetsano ea ho ts'oaroa ha cysteine.58 Patlisiso e fana ka maikutlo a hore maemo a liprotheine tsa xCT a fokotsehile kamora libeke tsa 2 ho isa ho libeke tsa 3 tsa cocaine kapa tsamaiso ea nicotine.56 Maemong a tloaelehileng, xCT e ts'ehetsa maemo a feto-fetohang a perisynaptic; glutamate e bonoa ke GRM2 le GRM3, e nang le phello e thibelang ho lokolloa ha glutamate presynaptic.14 Leha ho le joalo, nakong ea ho ts'oaroa ha lithethefatsi, maemo a xCT a tlase, 'me maemo a glutamate perisynaptic a fokotseha.14 Ho fokotseha hona ha maemo a glutamate ho etsa hore molumo oa glutamatergic o fokotsehe ho feta GRM2 le GRM3, 'me ka morao ho moo o hlakola phello ea inhibitory ea GRM2 le GRM3; ka lebaka leo, e lumella keketseho ea tokollo ea glutamate presynaptic nakong ea boits'oaro ba ho batla lithethefatsi.14

NAC ke amino acid cysteine ​​prodrug e khothalletsang tšusumetso ea glutathione. Litšebelisong, tsamaiso e hlophisitsoeng ea NAC e thibetse ho ts'oaroa ha koae- le cocoa ka ho khutlisa maemo a bokhoba.59,60 (S) -4-carboxyphenylglycine, inhibitor ea xCT, e thibela litlamorao tsa NAC ho khutlisetsong ea lithethefatsi kamora ho kenngoa ka bongata ho NAc, ho paka hore litlamorao tsa NAC ho khutlisetsong ea lithethefatsi li tsamaisoa ke xCT.61 Litlamorao tsa NAC ho phetiso ea glutamatergic synaptic le eona e ka ba e sa hlakoheng, ka mokhoa oa ho lokolla glutamate ka systemic xCT ho khothaletsa li-GRM tsa extrasynaptic.5 Li-inhibitors tsa GRM2 le GRM3 li thibela bokhoni ba NAC ho thibela ho ts'oaroa ha koae, bo fana ka maikutlo a hore litlamorao tsa NAC mabapi le ho khutlisoa li bakoa ke litlamorao ho li-receptors tsa sehlopha sa II tsa preynaptic.62 Litlamorao tsa NAC mabapi le ho khutlisetsoa ho li-presynaptic GRM2 le GRM3, ho fapana le ho li-postynaptic terminal receptors kapa glial receptors.5

Glial GLT-1 e boetse e thusa ho boloka taolo maemong a glutamate sebakeng sa extracellular, e behang tsitsipano ea neuronal le kinetics ea activation ea receptor.5,63 GLT-1 e susumetsa maemo a glutamate, 'me e fetolela tokollo ea glutamatergic extrasynaptic ho tsoa ho xCT. Hape, GLT-1 e tlosa glutamate sebakeng sa perisynaptic; ka tsela ena, e laola habeli taolo ea preextrasynaptic le postextrasynaptic GRMs. Li-GRM tsa Preextrasynaptic li fetolela tokollo ea presynaptic ea glutamate, le li-postextrasynaptic GRMs li fetolela polasetiki ea synaptic.5 Bohlokoa ba GLT-1 ts'ebelisong ea lithethefatsi bo bontšitsoe ke lithuto tse tlalehang ho theoha ha GLT-1 ho NAcc kamora ho itaola ka nicotine kapa cocaine.57,58,64 Ho feta moo, kalafo ea ceftriaxone e ile ea khutlisetsa maemo a GLT-1 ho NAcc ea likhoto tse neng li koetliselitsoe ho itaola k'hok'heine, 'me ea sitisa cueine le ts'usumetso ea koae ea cocaine.58

Ho ka bonoa hore glia e bapala karolo ea bohlokoa maemong a phahameng a glaptamate ea synaptic ho NAc nakong ea ho khutlisoa ha lithethefatsi. Litšusumetso tsa Glial ho khutlisetsong li kenyelletsa ho nolofalletsa tokollo e kholo ea glutamate ho tsoa ho terminal ea synaptic, hobane ho na le ho fokotseha ha maemo a xCT le GLT-1 ho glia. Tšusumetso e 'ngoe ea glia ho khutlisetsong e bakoa ke ho fokotseha hoa khanya ea glutamate libakeng tsa extynacicular tsa postynaptic ka lebaka la ho fokotseha ha maemo a GLT-1 ho glia.

Menehelo ea liphetoho tse amanang le apoptosis le neurogeneis lits'ebetsong tsa ts'ebeliso ea lithethefatsi

Boithuto ba batho le ba liphoofolo bo supa hore tlhekefetso ea koae e baka liphetoho lits'ebetsong le polelo ea gene e amanang le apoptosis, lefu la sele, le ts'ebetso ea mitochondrial.65,66 Cocaine e boetse e kenya apoptosis bokong, e ipapisitse le lisele tsa setso le ho nts'etsapele lithuto tsa boko; leha ho le joalo, ha ho na bopaki bo fumanoeng ba hore koae e etsa liphetoho tse amanang le apoptosis bokong ba motho e moholo.67 Ka ho khetheha, phuputso ea morao tjena67 e bonts'itse ho hloka ts'ebetso ea litsela tsa extrinsic le intrinsic apoptotic ka har'a cortex ea motho le lithethefatsi tsa koae. Bophelong ba batho ba hlekefetsang koae ka koae, ho fokotsoa ha FS7-amanang le cell cell antigen (Fas) receptor, adapta ea lefu la Fas-amanang le lefu (FADD), le mitochondrial cytochrome c li fumanoe. Liphetoho tsena ke lipontšo tsa nonapoptotic (liphetoho tsa neuroplastic). Leha ho le joalo, keketseho ea ho senyeha ha polymerase 1 ea nyutlelie - bopaki bo ka bang teng ba lefu le amanang le apoptosis67 - e fumanoe. Ho ile ha fumanoa lintho tse tšoanang ka har'a kokoana-hloko ea likhoto tseo e neng e le lithethefatsi tsa koae; Haholo-holo, ho ile ha bonoa ho se be le liphetoho mokhoeng oa Fas-FADD receptor, mitochondrial cytochrome c, caspase-3 / fragments, apoptosis-inducing factor, le mofuta oa polymerase 1 oa polymerase. Leha ho le joalo, ho litoeba tse pepesitsoeng ke cocaine e sa foleng le ho itima lijo, ho eketseha ha mofuta oa tropamine le cyclic adenosine monophosphate (cAMP) e fumanehang phosphoprotein (t-DARPP) e fumanoe cortex ea "cerebral".67

Phuputso e 'ngoe ea litekanyetso e fana ka maikutlo a hore neurogeneis ha e hlokahale bakeng sa tlhahiso ea sebaka se khothalletsoang ke koae.68 Phuputso eo e bonts'itse hore kamora ho hlongoa ha X X ea bongoana, e fokotsang matlafalo ea sele ka har'a li-ventricles tsa morao le meno ea meno, ho se tšoane ho teng pakeng tsa polelo ea cocaine e kentsoeng sebakeng se ikhethileng e sa fumanehe.68

Kamano pakeng tsa liphetoho tsa polasetiki ho li-spiny neurons tse mahareng (MSN), morphology morphology, le li-receptor tsa glutamatergic

Morphology ea dendritic spines ha e le hantle e itšetlehile ka tšebelisano lipakeng tsa lintlha tse khothalletsang kapa tse emisang ho potoloha hoa monino oa lefats'e oa monomeric. Ho bonts'itsoe hore cocaine le morphine li khona ho tlisa liphetoho morphology ea dendritic spines kamora ho ikhula ts'ebetsong ea cocaine (kapa morphine) e sa foleng ka ho susumetsa.67,69 Phatlalatso ea koae e sa foleng, e lateloang ke ho khaotsa le ho ts'oaroa ka morao ho ts'ebetso ea koae, e etsa ts'ebetso ea phetoho ea mekhahlelo e 'meli, e kenyang keketseho ea pele ea bophara ba lesapo la mokokotlo (45 metsotso kamora ho entoa), e lateloe ke karolo ea bobeli ea mokokotlo oa hlooho ea mokokotlo ka boholo (120 metsotso). Karolong ea pele, ho na le keketseho ea lekala la F-Actin le maemo a holimo a li-receptor tsa AMPA mokokotlong; ka lehlakoreng le leng, mokhatlong oa bobeli, ho na le disassembly e nyarosang ea lifilimi tsa F-actin le phokotso ea polelo ea li-receptor tsa AMPA maemong a methapo.15,33,70 Ntle le moo, ho bohlokoa ho kenyelletsa hore - kamora lihora tsa 24 tsa tsamaiso ea koae (e sa tsitsang noncontingent paradigm) - polelo ea sebopeho sa GluA1 subunit e fokotsehile, e leng se fapaneng le keketseho ea pele ea li-receptor tsa AMPA tsa pele.15,33

Boemong ba limolek'hule tse ling, actin e mamella ts'ebetso ea potoloho eo ho eona sebapali sa filimi se kenngoang mothong o mong le o mong ka lehlakoreng le leng la filimi, 'me se atolosoa ka ho kenyelletsa "li-monomers" qetellong e' ngoe ea filimi.71 Boithuto bo bontšitse mochine oo ho otsoang kofuto ea cocaine le morphine.69 Haholo-holo, ka mor'a ho khaotsa koae, ho na le phokotso ho Liminaase, e leng kinase e sebelisang cofilin, protheine e tsamaisang karolo ea "actin" e laolang ho phatloha ha filaments ea actin.69,72 Ebe kamora taolo ea koae e sa foleng, cofilin e tsoa taolong ea inhibitory ea LIM kinase, 'me e khona ho khothaletsa litšila tsa "actin filaments" ho li-monomers ka bomong. Hona joale, hore li-moniners li sebetse hantle le ho theha makala a actin, ho hlokahala phosphorylation ea liprotheine tsa mofuta oa Vas le vasodilator tse susumetsang phosphoprotein (VASP) ka cocaine.73 Liprotheine tsa Ena le VASP ke sehlopha sa liprotheine tse laoloang ke li-actin tse kentsoeng ts'ebetsong lits'ebetso tse thehiloeng ho li-actin tse kang ho falla ha fibroblast le tataiso ea axon. Ka ho khetheha, liprotheine tsa Ena le VASP li hokahana le lipheo tse thibetsoeng tsa li-filaments tsa actin le lits'ebetso tsa antagonize filament-ciling.73 Hoa hlokahala ho supa hore koae e boetse e na le litlamorao tse fapaneng (thibelo ea lekala) e kopantsoeng le phokotso ea protheine e amanang le Actin 3 (ARP 3), le ka keketseho ea phosphorylation ea proteni ea cortical Actin-binding ( cortactin) - bobeli ba tsona bo sitisang matla a cofilin ho kenya makala.74 Joale, hobane cocaine e na le litlamorao tse hanyetsanang ho makala, ho nahanoa hore litlamorao tsa ts'usumetso ho makala tse hlahisitsoeng ke phosphorylation ea Ena le VASP li feta litlamorao tsa makala tse hlahisoang ke thibelo ea ARP 3 le phosphorylation ea cortactin.73

Ho kopanya mekhoa e fapaneng

Bangoli ba fapaneng7,75-77 ba lekile ho kenyelletsa likhopolo tsa mantlha ka glutamatergic neuroadaptations maemong a NAc a susumetsoang ke tsamaiso ea koae. Tsena li kenyelletsa liphetoho maemong a recaptor ea testaptic AMPA, liphetoho maemong a fetohang a nonsynaptic a extracellular nortynic, le liphetoho ho MSN intrinsic membrane thabo.7,75-77 Ho feta moo, ho fanoe ka maikutlo a hore lithuto tse ling li ka hlahloba liphetoho ho litlatsetso tsa Prescaptic ho NAc.75

Molaetsa oa bohlokoa oa ho nkela hae ke hore ts'ebetso e phahameng ea koae e ka lebisa ho thehoeng ha li-CP-AMPAR, hammoho le ho kenngoa ha eona ka har'a synapse, mme keketseho ena ea li-CP-AMPAR e kanna ea mamella esita le haeba maemo a glutamate a tloaelehile. Boemo bona bo ka ntlafatsa karabelo ea morao-rao ea postynaptic ho tahi e latelang ea koae, ntle le tokollo ea "presynaptic glutamate".75 Ebe karabelo ea setsi sa postynaptic ho NAc MSNs ke kopanyo ea tokollo ea presynaptic e nkiloeng ho litekanyetso tsa glutamate tsa extrasynaptic (hypothesis ea Kalivas) le keketseho ea maemo ho li-receptor tsa AMPA (CP-AMPAR; lipatlisiso tsa sehlopha sa Wolf).6,14 Ntle le sena, lebaka la boraro le etsang hore karabo ea MSN e fokotsehe ke ho fokotseha ha lera kahare ka lebaka la ho khaotsa koae; ho fokotseha hona ho hlaha ka lebaka la ho fokotseha hoa Na⁺ le Ca²⁺ boikoetliso le ho tloha keketseho ea K⁺ boitshwaro.76,78-80 Taba ea bohlokoa ke hore ho fokotseha hona hoa thabo ea tlhaho ho kenelletse tšebetsong ea membrane ea homeostatic e tsamaeang le li-liphetoho ho liprotheine tsa kinase le phosphatase.79,81 Polasetiki ea homeostatic synapse e tsamaisoa ke sebopeho sa mofuta oa homeostatic mme e na le liphetoho tse tlatselletsang maikutlong a makatsang, kamora ho mamella liphetoho phetisong ea li-receptor tsa NMDA; ka kotloloho, e kenyelletsa mofuta oa SK-Ca²⁺-e qapiloe K⁺ dikanale. Ha lipehelo tse thabisang ho MSN li phahame, polasetiki ea homeostatic e tsamaeang le methapo ea mokokotlo e etsa hore ho be le ts'ebetso ea SK chate e kopantsoeng ka mor'a bokhoni ba hyperpolarization.

Kamano lipakeng tsa ho fokotseha hoa litekanyetso tsa tlhaho tsa cocaine le "cocaine" e tšehelitsoe ke phuputso ea likhoto tse feteletseng ho K⁺ mocha subunit Kir2.1, e neng e bontša karabelo e eketsehang ea phephetso phephetsong ea koae (sensitization).82 Kir2.1 ke mokhoa o ka hare oa ho hlophisa K⁺ seteishene sa subunit se ts'episang pherekano ea mefuta e fapaneng ea lisele tsa neuronal ha e lekantsoe ka botlalo.82 Ho feta moo, thuto e 'ngoe77 ho bapisa lits'oants'o tsa litekanyo ka maemo a phahameng a bapisoang le maemo a tlase a MSN-intrinsic excitability, ho bonts'itse hore likhoto tse nang le ts'oaetso e tlase li bonts'itse ts'ebetso ea ntlafatso ea cocaine le karabelo ea locomotor ha e bapisoa le sehlopha se phahameng. Ka lehlakoreng le leng, ho pepeseha ha lithethefatsi tse sa foleng ho boetse ho amana le keketseho ea tsela ea cAMP le ho saena PKA ho NAc.83,84 Li-neuroadaptations tsena ho NAc li ama thepa ea motlakase ea MSN; ka kotloloho, tsena tsohle li eketseha tseleng ea cAMP, 'me ho tšoaea PKA ho fokotsa thabo ea MSN ka litlamorao tse tobileng tsa PKA liteisheneng tsa ion.82 Leha ho le joalo, cAMP le PKA hape e kenya protheine ea karabo ea cAMP (CREB) NAc, mme e thefula ka morao tekanyo ea phokotseho ea thabo ena.82

Sena se fana ka maikutlo a hore ho fokotseha ha thabo ea MSN ho lebisitse keketseho ea ho tsoma koae le ho ts'oaroa ha maikutlo, e ka bonahalang e le ho hanyetsa. Tlhaloso e kopaneng ea sena ke hore ho fokotseha ha menahano ea maqhubu a MSN ho matlafatsa tekanyo ea molumo-le-lerata bakeng sa tšusumetso e amanang le koae.85 Ebe ho fokotseha hona ha maikutlo a MSN a ho hlasimoloha ho tlisoang ke tšebeliso ea koae ho ka hlakisa karabelo e tlase ea boitšoaro ho ts'usumetso e tloaelehileng ea moputso, (khothatso e sa amaneng le cocaine) mme ts'usumetso ena e kenya mohopolo o nyane oa nyakallo.85 Hape, ho fokotseha hona ha marang-rang a kenang kahare a MSN ho ka boela ha hlalosa karabelo e ntlafalitsoeng ea boitšoaro ho cocaine le khothalletso e amanang le eona (e amanang le ho kenella ho matla).85 Tlhaloso e 'ngoe e ka bang teng ke bangoli ba bang ke hore ho fokotseha hoa thabo nakong ea ha ho khaotsa koae ho etsa hore ho be le ntlafatso e hanyetsanang le maemong a amanang le "captine" a amanang le cocaine.82

Boemo ba hona joale ba lithethefatsi bo thehiloeng holim'a glutamate polasetiki litekong tsa batho

Bangoli ba bang ba bontšitse haufinyane bohlokoa ba phekolo e thehiloeng ho glutamate, hara ba bang, bakeng sa ho phekola bokhoba ba lithethefatsi.86,87 Plasticity ea glutamate e fumanoe mefuteng ea preclinical ea ho khutlela morao le litekong tsa bongaka tsa mofofisi; Kalivas le Volkow2 ba hlahisitse mekhoa ea ho phekola bokhoba ba koae e kopantseng terminal ea "presynaptic", post-synaptic terminal le mekhoa ea glial. Mohlala, joalo ka ha ho hlalositsoe pejana, xCT e fetoloa kamora ts'ebeliso e mpe ea lithethefatsi, mme teko ea ho hlahloba protheine ena bakeng sa kalafo ea lithethefatsi e fumane litholoana tse atlehileng qalong. NAC ke amino acid cysteine ​​prodrug e eketsang maemo a xCT le GLT-1 mme e khothaletsa ho kenella ha glutathione.5,61 NAC e hlahlojoe bakeng sa ho fokotsa ho khutlisetsa lithethefatsi lithutong tsa bongaka ba kalafo le tsa kalafo. Ka mokhoa o ikhethileng oa boiphetetso bocha, ts'ebetso ea ts'ebetso ea NAC e thibetse ho ts'oaroa hoa koae- le heroin ka ho khutlisetsa maemo a glutamate.59,60 Ntle le moo, tsamaiso e sa foleng ea NAC e latelang ho itaola ha heroin e ka thibela ho khutlisetsoa kamora libeke tsa 6 tsa ho tlohela kalafo.59,60

Leha ho le joalo, liteko tsa tleliniki le NAC li bonts'itse litholoana tse fapaneng. Setheo sa Naha sa Naha sa Bophelo sa Sechaba sa US mabapi le Tlhekefetso ea lithethefatsi inthaneteng (www.drugabuse.gov/news-events/nida-notes/2013/01/n-acetylcysteine-postsynaptic-effect-limits-efficacy) e re NAC e sebetsa hantle ka tsela e itekanetseng ho thibela ts'ebetso ea lithethefatsi. Ka lehlakoreng le leng, lithuto tse ling li rata phello ea modulating ea NAC mabapi le ho khutlela mokhoeng oa lithethefatsi. Ka ho khetheha, patlisiso e tlaleha hore NAC e fokotsa takatso ea lithethefatsi kamora ho entetsoa koae.88 Phuputso e entsoeng ka mahlo a mabeli e tiisa hore NAC (1,200 mg kapa 2,400 mg) e feta placebo bakeng sa phokotso ea ho khutla ha koae ha lithuto li ne li sa tlohe beke pele ho kalafo.89 Ho feta moo, lithuto tsa monahano oa batho li tiisa hore NAC e khona ho fetola maemo a bokhopo bo tsoang bokong ba batho ba lemaletseng koae.90,91 Sena se bula monyetla oa hore NAC e ka fokotsa ho khutlisetsa koae ka ho fetola maemo a glutamate. Ka ho khetheha, thuto ea Madache90 e tlaleha hore NAC e tloaetse maemo a glutamate ho bakuli ba ts'ehetsang koae. Patlisiso e ngoe hape e ka ba molemo ho matlafatsa ts'ebeliso ea NAC bakeng sa ho phekola ho khutla ha lithethefatsi.90 Patlisiso e 'ngoe e nahanang (matla a bonohe a cosonance) e tsebisa hore batho ba lemaletseng koae ba na le phokotso ea litheko tsa "cortex" tsa kamorao ho tsamaiso e ikhethileng ea NAC.91

Modafinil, e leng alpha-adrenergic / glutamate agonist, ke mofuta o mong o khothaletsang oa ts'ebeliso ea koae, e thehiloeng phetolelong ea glutamate; e bontšitse katleho e itseng litekong tsa bongaka.92,93 Leha ho le joalo, ts'ebetso ea eona ea subjacent ha e itšetlehe ka botlalo ho glutamate mme, ho fapana le moo, e ka hlalosoa ke synergism ea li-neurotransmitters tse fapaneng (dopamine, glutamate, gamma aminobutyric acid [GABA], noradrenalin, le hypocretin / orexin system; ts'ebetso ea ts'ebetso ea eona e hloka ho hlakisoa.93 Modafinil e na le mochine oa ts'ebetso o ts'oanang le NAC; e phahamisa maemo a bokantle ba glutamate, e etsa hore ho be le keketseho ea molumo oa glutamatergic ho GRM2 ea Presynaptic le GRM3.94 Joalokaha ho se ho hlalositsoe, GRM2 le GRM3 li na le litlamorao tse tlatselletsang ho lokollotsoeng ha glynamic glutamate, ho lumella ho fokotseha ha tokollo ea glutamate ha merero ea PFC-NAc e ts'ebetsoa nakong ea boits'oaro ba ho batla lithethefatsi.14 Katleho ea ho khutlisetsoa ha koae ea modafinil e tšehelitsoe ke lithuto tse fapaneng.94-96

Topiramate ke setheo se seng se setle sa ho thibela ts'oaetso, ho ipapisitse le litlamorao tsa eona tsa GABA le glutamate neurotransmissions.97 Haholo-holo, ho boemo ba NAc, ho bontšitsoe hore topiramate e thibela li-receptor tsa AMPA / kainate mme e thibela ho khutlisetsoa ha koae ho likhoto.29 Sena se hlalositsoe hobane ho kenngoa ha cocaine kapa glutamate receptor agonist, AMPA, ho khutlisetsoa ho NAc ho kenya; ebe, mohanyetsi oa li-receptor tsa AMPA ke topiramate ho NAc o thibela ho khutlisoa.29 Boithuto ba kliniki bo boetse bo tšehelitse phokotso ea ts'ebeliso ea koae ka mor'a ho phekoloa ka topiramate.98

Acamprosate ke sethethefatsi se lumelletsoeng ke US Food and Drug Administration bakeng sa ho phekola ts'ebeliso ea lino tse tahang. Ho nahanoa hore mochine oa acamprosate oa ts'ebetso o itšetleha ka ho fokotseha ha molumo oa glutamatergic ka ho hanyetsa li-receptors tsa NMDA kapa GRM5.99 Leha ho le joalo, phello ea acamprosate ho li-receptor tsa glutamate e kanna ea itšetleha ka ho phomola mosebetsi oa NMDA receptor; ka hona, acamprosate e kanna ea nkuoa hamolemohali e le agonist e sa sebetseng ea NMDA.99 Kameho ea li-acamprosate ho khutlisetseng joala ho motho ha e lumellane; bangoli ba bang ba tlaleha ho fokotseha, 'me ba bang ba tlaleha litla-morao tse bonolo ho thibela joala hape.100-102

Ka lehlakoreng le leng, phuputso e entsoeng ho bakuli ba ts'ehetsang koae ba banna le basali e tlalehiloe hore acamprosate e ne e se betere ho fapana le sebaka sa ho fokotsa takatso ea koae le ho fokotsa matšoao a ho khaotsa koae.99 Setšoantšo se hlalosang liphofu tsa mantlha tsa litlhare tsa kalafo boemong ba NAc bakeng sa ho fokotsa ho khutla ha lithethefatsi ho hlalositsoe ho Setšoantšo sa 1.

 

Setšoantšo sa 1

Lipheo tsa mantlha tsa meriana ea kalafo e maemong a NAc bakeng sa ho fokotsa lithethefatsi hape.

Ntho e khutlelang morao le ts'ebeliso ea lithethefatsi e kenyelletsa litsamaiso tse fapaneng tsa li-neurotransmitter ntle le dopamine le glutamate. Nakong e tlang, ho ka ba molemo ho hlahloba maano a mangata a thehiloeng ho synergism. Ho lebisa litsamaiso tse fapaneng tsa li-neurotransmitters (mohlala, glutamate + GABA; hypocretin + GABA) e nang le litekanyetso tse tlase e ka fokotsa kotsi ea litlamorao tse sa rateheng. Ka nako e ts'oanang, ho nahana ka sistimi e fapaneng ea neurotransmitter ho ka lumella ho ts'oaroa, mohlomong, ka mekhoa e fapaneng e fokotsang ts'ebeliso ea lithethefatsi le ho khutla hape. NAC e fumane sephetho se sa lumellaneng litekong tsa bongaka tsa batho, leha e ts'episitse litlamorao tsa tlhahlobo ea pele (www.drugabuse.gov/news-events/nida-notes/2013/01/n-acetylcysteine-postsynaptic-effect-limits-efficacy).59,60,88,89

Hape, ho bohlokoa ho ela hloko hore bokhoba ba batho e ka ba basebelisi ba polydrug (batho ba sebelisang lithethefatsi tse peli kapa ho feta tse fapaneng). Potso ea ho qetela e ka ba hore na phapang pakeng tsa liphetho tsa liteko tsa preclinical le tsa motho tse lekolang lithethefatsi tsa kalafo (tse lebisitsoeng ho glutamatergic kapa lits'ebetso tse ling) li ka hlalosoa, hobane mehlala ea morao-rao e lebisa tlhokomelo ho moriana o le mong oa tlhekefetso, empa mathata a lithethefatsi tsa batho a bolela mekhoa ea polydrug. Mohlomong ho ka ba molemo ho ntlafatsa litlhare tse fapaneng tsa kalafo ha u ntse u nahana ka mehlala ea preydinical polydrug.

Karolo ea glutamate mathateng a mang a neuropsychiatric

Liphetoho tsa tsamaiso ea glutamatergic li hokahane le lits'ebetso tse ikhethileng tsa maloetse a mang a neuropsychiatric ntle le mathata a bokhoba ba lithethefatsi. A mang a maloetse ana a kenyelletsa mathata a ho feto-fetoha ha maikutlo, ho ferekana kelellong, khatello ea maikutlo, lefu la Alzheimer, ho senyeha ha pono ea kelello, likarolo tsa neuropsychiatric tsa Fusile X syndrome (FXS), lefu la Parkinson, ho se bone hantle le khatello ea methapo.103-117

Ka ho khetheha, ho schizophrenia, ho kenella ha tsamaiso ea glutamatergic ho tšehelitsoe ke liphumano tse hlalosang ponahalo ea matšoao a kang a schizophrenia kamora ho qhekella ha li-receptor tsa NMDA ka phencyclidine le lithethefatsi tsa ketamine; ho feta moo, bopaki bo eketsehileng ba khokahano pakeng tsa sistimi ea glutamatergic le schizophrenia bo tsoa litlalehong tse hlalosang liphetoho liphatlalatsong tsa gene le metabolic pathways tse amanang le li-receptor tsa NMDA ho schizophrenics.103,118,119

Mefuta e meng ea litoeba tse feto-fetohang e khothalelitse kamano lipakeng tsa NMDA receptor le schizophrenia. Mohlala e ka ba phetoho ea panya le phokotso ea 90% ea receptor ea NMDA, le panya e 'ngoe e nang le phetoho e nang le lintlha phetohong ea glycine ea NMDA receptor.120,121

Matšoao a lupus neuropsychiatric a hokahantsoe le liphetoho tsamaisong ea glutamatergic. Hoo e ka bang halofo ea bakuli ba nang le lupus ba bonts'a matšoao a neuropsychiatric; Har'a liphetoho tse ling, bakuli ba lupus ba bonts'a li-autoantibodies tsa pathogenic tse ikemiselitseng ho kenya NR2A le NR2B ea li-receptors tsa NMDA. Ha e le hantle, ho pota 50% ea bakuli ba nang le neurolupus ba na le li-antibodies tsena mohloling oa bona oa cerebrospinal.104

FXS ke lefu le ferekanyang le bakoang ke tšitiso ea ts'ebetsong ea protheine ea kelello ea retelehile ea X (FMRP). Phokotso ho FMRP e ama metabotropic glutamate receptor (sehlopha 1) e sebetsang, eo e ka bang karolo ea methapo ea kutlo ea likarolo tsa neuropsychiatric tsa FXS.106 Ntle le moo, bopaki bo bongata ba khokahano pakeng tsa glutamate le FXS bo tsoa lithutong tse mabapi le mefuta ea litoeba tsa phetoho ea FXS, le lithuto tsa bongaka tsa bakuli ba FXS tse tlalehang ntlafatso ea maemo kamora kalafo le li-modulators tsa allrateic tsa receptors tsa metabotropic.106

Ka lehlakoreng le leng, liphetoho tsa lefu la Parkinson ha li hlalosoe feela ke liphetoho tsa tsamaiso ea dopaminergic, empa le liphetoho tsa tsamaiso ea glutamatergic. Lithuto tsa Positron emission tomography ho 6-hydroxy-dopamine (6-OHDA) li-rats tse halikiloeng li bontšitse keketseho ea ho ts'oaroa ha tracer e amanang le GRM5 ligand ([11C] -MPEP) ka har'a methapo ea methapo ea methapo.122 Sena se ts'ehetsa tlatsetso ea kamano ea boiphetetso lipakeng tsa dopamine le glutamate ho basal ganglia le cortex ea "cortex" ea lefu la mafu.123 Bopaki bo bong ke hore bohanyetsi ba GRM5 (MPEP) bo fokotsa bofokoli ba koloi ba likhoto tsa 6-OHDA.124 Ho feta moo, litoeba tse feto-fetohang tse haelloang ke li-receptor tsa GRM5 (li-Kniple) ha lia ka tsa ba le bothata ba ho hloka taolo le liphetoho tsa methapo ea kutlo e ileng ea latela likotlo tsa 6-OHDA.125

Lefu la sethoathoa le boetse le amahanngoa le liphetoho tsa tsamaiso ea glutamatergic, haholo-holo li-receptor tsa kaine.114-116 Moetso oa rodent oa lefu la sethoathoa o neng o kenyelletsa ho fokotseha hoa mofuta oa li-receptor tsa GluR6 o ithutile; mofuta ona oa litoeba o bonts'itse monyetla oa ho ts'oaroa ka likhoka ka likhoka.114 Ntle le moo, phuputso e 'ngoe ea litoeba e tlalehile hore mohanyetsi oa li-receptor tsa GluK1 li sitisa likhapo tse hlahisoang ke pilocarpine, e ts'ehetsang khokahano pakeng tsa li-kaine receptors le sethoathoa.116 Leha ho le joalo, bohlokoa ba li-receptor tsa kaine ho sethoathoa sa batho ha li hlake hantle.105

Boloetse bo qhekellang bo sa sebetseng bo boetse bo hokahane le liphetoho tse ling tsamaisong ea glutamatergic, haholo-holo le mofuta oa kainate oa li-receptors.111,112 Ka ho khetheha, glutamate receptor, ionotropic kainate 2 (GRIK2), e hokahane le bokuli bo qobelloang bo khothalletsang lithutong bo sebelisang polymorphisms e le 'ngoe.111

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References