I-potentiation ekhishwe izidakamizwa emasinaphonti okuthakazelisayo ku-VTA

Isifundo sokuphayona ngu-Ungless nozakwethu ku 2001 kubonise ukuthi ukuchayeka okukodwa kwe-cocaine kubangele ukuthuthukisa amandla we-synaptic kuma-syapses e-excitatory kuma-neurons we-VTA DA uma kulinganiswa i-24 kamuva emuva kokuqothula ubuchopho (Ungless et al., 2001). Lokhu kwalinganiswa njengokunyuka kwesilinganiso se-AMPA-mediated currents postsynaptic currents (EPSCs) phezu kwe-NPSDA-e-EPSC elamulelwe (ebizwa ngokuthi i-AMPA / NMDA ratio). I-LTP esetshenziselwa ukushisa kagesi ikhonjiswe ukuba ivuliwe kwi-VTA synapses yama-excitatory kuma-cecedine-tracted ciceine kanti i-LTD yayithuthukisiwe. Lezi ziphakamiso kanye nezinye izinyathelo ze-electrophysiological kubonise ukuthi ushintsho lwe-plasticity lugcine lungahle lusetshenziswe izindlela ezifanayo ukuze kusetshenziswe i-LTP (i-Ungless et al., 2001). Kuye kwaboniswa ukuthi ukuphathwa kwezinye izidakamizwa zokuhlukumeza okubandakanya i-amphetamine, i-morphine, i-ethanol, i-nicotine, ne-benzodiazepines nakho kungabangela ukwanda kwamandla ase-synaptic ku-VTA, umphumela ongabonakali ngezidakamizwa ezingasebenzi ezingenakho ukuhlukumeza (Saal et al., 2003; UGao et al., 2010; I-Tan et al., 2010). Lokhu kuboniswa kubonisa ukuguqulwa kwezimpendulo zamaselula ngaphakathi kwe-VTA yizo zonke izidakamizwa ezihlukunyezwe futhi kunikeza indlela engenzeka ngayo ye-neural lapho i-neuroadaptations yokuqala eyayihloswe ngayo izidakamizwa ingabangela.

Umphumela wokulawulwa kwezidakamizwa ezingekho emthethweni ku-VTA synaptic plasticity kuvezwe ngesikhashana, okuhlala okungenani i-5 kodwa ngaphansi kwezinsuku ze-10 futhi kuboniswe ukuthi ihambisana ngokuqondile nokuthuthukiswa kokuqala kokugqugquzela ukuziphatha kepha hhayi ngezwi layo (Ungless et al., 2001; Saal et al., 2003; Borgland et al., 2004). Uma i-cocaine ilawulwa ngokweqile, umphumela uhlukile uma i-plasticing i-VTA iphikelela futhi ingatholakala ngisho nezinsuku ze-90 zihoxiswa (Chen et al., 2008).

I-potentiation ye-synapses ye-glutamatergic kuma-VTA DA amangqamuzana kungenzeka ahlotshaniswe nekhono lezidakamizwa zokuhlukunyezwa ukuze kuthuthukiswe i-DA engaphandle kwe-NAc (I-Di Chiara ne-Imperato, 1988) futhiNgingabonisa ukuqaliswa kokufundiswa kwe-"pathological" lapho kutholakala khona "ukugxila" kwezinhlangano zezidakamizwa. Ngempela, ukunyuka kwe-NMDA ekuxhaseni kwamathambo kwamandla kagesi ase-glutamatergic kubikiwe ku-VTA DA neurons ngesikhathi kutholakala inhlangano yokuzijabulisa (Stuber et al., 2008) futhi maduzane kwaqinisekiswa ukuthi i-cocaine yandisa ngokuphawulekayo isilinganiso se-AMPA / NMDA se-VTA neurons ezenza i-NAc ngokumelene ne-PFC (Lammel et al., 2011); kuqinisekiswe ukuthi ukudluliswa kwe-dopamine ngaphakathi kwe-NAc kubalulekile ekuthengeni inhlangano yePavlovia (Kelley, 2004). Ngakho-ke kungenzeka ukuthi lezo zithako ze-VTA DA neurons zingase zimelele i-neural coding efana ne-LTP, mhlawumbe inqubo yokufunda enobungozi, okungenzeka ibalulekile ekuphenduleni kokuziphatha okuqala kwe-cocaine futhi inamandla okubangela ukujwayela kwesikhashana eside okungaphansi kokulutha, nakuba engabonisi isimo somlutha ngokwawo. Njengoba kuhlongozwa ngabanye, kungenzeka ukuthi izidakamizwa eziluthayo zikhethela umvuzo wokuphefumula kobuchopho ukuze "ukhululeke" ukubaluleka kwesidakamizwa emzimbeni (UKauer noMalenka, 2007).

Imvelaphi yezinto ezibonakalayo ze-glutamatergic ku-VTA ezibandakanyeka epulasitiki ezenzelwe izidakamizwa zihlale zichazwe ngokugcwele. Ucwaningo olunye luveze ukuthi i-VTA i-synapses ye-glutamatergic ehloswe yi-VTA ngokwayo kanye ne-pedunculopontine nucleus (PPN) ibonisa amandla angcono avela ku-cocaine kodwa kuphela ama-synapses ayamukelayo okuvela kuma-PPN ama-afferents angaba ne-Δ⁹-tetrahydrocannabinol (i-THC) (Okuhle ne-Lupica, 2010). Ngakho-ke, kubonakala sengathi izimbangela ezithile ze-glutamatergic ezihilelekile ekukhusheni okubangelwa izidakamizwa zingashintsha ngokusho kwesidakamizwa esibucayi futhi kungase kube njalo ukuthi ukubonakala okuthile kujwayelekile kuwo wonke amapulasitiki okwenyusa izidakamizwa ku-VTA; lokhu okulandelayo kuyadingeka. TI-VTA ithola izilinganiso ezijulile ezivela ezindaweni eziningi zobuchopho kuhlanganise ne-PFC, i-amygdala ne-subthalamic nucleus (i-Geisler ne-Wise, 2008), eziningi zazo eziye zaboniswa ukuthi zithonya ukuqhuma okukhulu kwe-VTA DA neurons (I-Grillner ne-Mercuri, 2002). Ukuhlolwa kwesikhathi esizayo ukusebenzisa amasu optogenetic kungasiza ekunqumeni ukucatshangelwa okuthile okubhekiselele ekutheni izidakamizwa ezikhishwe izidakamizwa ku-VTA synapses zibheke ekuphenduleni izidakamizwa ezihlukumezayo zokuhlukumezeka, ngaleyo ndlela zikhanyise ngokuqondene nalokho okushiwo yi-neuroadaptation.

Izinqubo ezisekela ubuciko be-synaptic ye-drug-excoked synapse ku-VTA

Njengoba nge-LTP eyenziwe ngogesi phakathi kwe-DA ne-neurons, ukwandiswa kwamandla we-synaptic ku-VTA okubangelwa yi-cocaine ne-nicotine kuye kwaboniswa ukuthi kuxhomeke ekusebenziseni kwe-NMDA ukwamukela (Bonci noMalenka, 1999; Ungless et al., 2001; Mao et al., 2011). Ngokuphambene nalokho, ukugcinwa kwe-potentially-cocaine-potentiated potentiation kwakuboniswe kamuva ukuthi kudinga umsebenzi weprotein kinase Mζ (Ho et al., 2012), i-isoform ye-protein kinase C (PKC) esebenza ngokuzimela, kuyilapho i-LTP encike isikhathi esika-spike ku-VTA DA neurons yamagundane e-drug-naïve incike kuma-isoforms avamile we-PKC (uLu no-Malenka, 2008). Endabeni ye-nicotine i-VTA synaptic potentiation idinga ukuxhaswa kwama-neurons e-DA aphikisana yi-somatodendritic α4β2 i-acetylcholine receptors (i-NAChRs) (i-Mao et al., 2011). Ukukhululwa kwe-nicotine eyenziwe yi-presynaptic glutamate ukukhululwa kubangele nokufakelwa kwe-plastiki ye-synaptic, mhlawumbe ngokukhuphula ukusebenza kwe-NMDA receptors (Mao et al., 2011).

Ngokuyaziwa kabanzi mayelana nezinqubo ezitholakala nge-cocaine-plasticed-powered plasticicity kune-plastic element eyangelwa yizinye izidakamizwa zokuhlukunyezwa. Uhlelo lwe-Cocaine kuya kumathanga we-midbrain lubangela ukukhishwa kwe-NMDA yokudluliselwa kwamaminithi kungakapheli amaminithi futhi kuhlongozwa ukuthi ngokufaka ama-NMDAR a-NR2B aqukethe ama-synapses ngokusebenzisa uhlelo oludinga ukusebenza ku-D₅ i-receptors ne-protein entsha synthesis (i-Schilstrom et al., 2006; Argilli et al., 2008). I-Orexin A nayo iboniswe ukuthi iyadingeka kokubili ukufakwa okufakwe ngaphakathi kwe-cocaine ye-receptor ene-NR2B nokwandisa amanani we-AMPA / NMDA; ngokufanayo i-orexin₁ umphikisi we-receptor uSB334867 uye waboniswa ukuvimbela ukuthuthukiswa kokukhuthaza uketshezi lwe-cocaine (iBorgland et al., 2006). Ngaphandle kwezinguquko kwinkulumo ye-submit receptor subunit, amazinga akhulisiwe we-GluR1 aqukethe (i-GluR2-engenakho) ama-receptors we-AMPA ku-synapses aboniswe ngokushesha uma i-3 h ngemuva kwe-cocaine exposuree (Argilli et al., 2008). Lokhu okuhlanganyelwe kuhlangene nobunye ubufakazi bamuva buye kwaholela ekutheni ukufakwa kwe-synaptic ye-GluR2-lacking receptors ephezulu kufaka isandla ekuboniseni amandla okusebenzisana kwe-cocaine-potentiated in the VTA (Dong et al., 2004; UBellone noLuscher, 2006; Mameli et al., 2007; Brown et al., 2010; Mameli et al., 2011), ukuze izibuyekezo zibone (uKauer noMalenka, 2007; Wolf and Tseng, 2012). Lokhu kufakwa kwama-receptors ka-GluR2-ayitholakali AMPA kuncike ekuthunyeleni kwe-NMDA emithonjeni ye-VTA DA ngoba engekho emagundini ahlulekayo abamukelayo be-NMDA ema-neurons e-DA (Engblom et al., 2008; Mameli et al., 2009). II-nsertion ye-GluR2-ayinayo i-AMPA receptors ibalulekile ngoba inezakhiwo eziyingqayizivele; ziyi-calcium permeable, zinezikhulu eziningi zokuziphatha kwesiteshi kunama-receptors ane-GluR2, ngakho-ke zinamandla amakhulu okuguqula ukudluliswa kwe-synaptic (U-Isaac et al., 2007). Ngakho-ke, ukufakwa kwe-AMP receptors ye-GluR2-engenayo i-VTA kubonisa ukuthi kungenzeka ukuthi izidakamizwa zokuhlukunyezwa zingasungula kanjani ukushintshashintsha kwepulasitiki ezisezingeni lokuqala zokusetshenziswa kwezidakamizwa.

Ukufakwa kwe-GluR2-engenayo AMP receptors ibe yi-VTA synapses yama-excitatory manje iboniswe ukuthi iyatholakala ekuphenduleni ukuphathwa kwezidakamizwa kusuka emakilasini amaningi afana ne-nicotine ne-morphine kanye nokusebenza kwe-optogenetic kwe-DA VTA neurons (Brown et al., 2010). Twakhe uye waba nesiphakamiso sokuthi ukufakwa kwe-GluR2-engenayo i-AMPA receptors i-calcium-permmeable imelela indlela esebenza ngayo yonke indawo engase ibe ngaphansi kwamandla okuvimbela izidakamizwa ze-VTA synapses (Brown et al., 2010), nakuba idatha ye-amphetamine ayihambisani nalesi sizathu (Faleiro et al., 2004). Ngaphezu kwalokho, njengoba i-GluR2-engenakho i-AMPA receptors ivuselela kwangaphakathi futhi ngaleyo ndlela iqhuba amancane kakhulu ku-40 mV, ukufaka kwabo yedwa akukwazi ukuchaza ukunyuka kwezidakamizwa ezibalwe ngama-AMPA / NMDA. Ucwaningo lwamuva olwalinganisa izimpendulo ezihlangene ezihlanganisiwe ezikhishwe umthombo we-glutamate otholakale kakhulu (ukukhanya kwe-photon photolysis ye-caged glutamate) kubonise ukuthi ngaphezu kokuphazamisa ama-EPSC, i-cocaine exposure ibuye ihlehlise ama-EPSCs ahlangene ne-NMDA. al., 2011), ngaleyo ndlela unikeza indlela okungenzeka ngayo ukwakhiwa kwe-AMPA / NMDA kulesi simo (ngokunciphisa inani le-ratio). Lokhu kusadingeka kuphhenywe nezinye izidakamizwa zokuhlukunyezwa.

Ukushintshaniswa kwe-GluR2 okwenziwe izidakamizwa nge-GluR2-engenayo AMP receptors kungashintshwa ngokuqaliswa kwamamukeli weMGluR1 ku-VTA (Bellone noLuscher, 2006; Mameli et al., 2007). Ngakho, ukushintshaniswa kweMGluR1-mediated yama-receptors we-AMPA kunikeza indlela engachaza ukuthi kungani ukuvama kwezidakamizwa ezivuthwa izidakamizwa ze-VTA synapses kungokwemvelo, i-5 ehlala njalo kodwa hhayi izinsuku ezingu-10 (Ungless et al., 2001; Mameli et al., 2007). Ngempela, uma i-MGluR1 isebenza ku-VTA incishisiwe i-24 h ngaphambi kokuphathwa kwe-cocaine i-cocaine-eyenzelwe ukulungiswa kwangaphakathi iphikelela ngaphezu kwezinsuku ze-7 (Mameli et al., 2007, 2009). Ngakho-ke enye incazelo yokuthi kungani i-cocaine ekhishwa ukuqiniswa kwe-synaptic iqhubeka ne-VTA elandela ukuzilawula kwe-cocaine (ngokungafani nokulandela ukuphathwa okungezona okungekho emthethweni) kungenzeka ukuthi i-cocaine self-administration iholela ekucindezelweni kwe-MGluR1 ekuboniseni i-VTA.

I-plasticaplasticity evumeliswa yizidakamizwa e-synapses engavimbelekile ku-VTA

EAma-synapses angama-xcitatory ayilona uhlobo olulodwa lwe-synapse ku-VTA DA neurons ezithintekayo ukuphathwa okungekho okungapheli kwezidakamizwa zokuhlukunyezwa. I-synapses engavimbelekile ku-VTA nayo ineqhaza elibalulekile ekulawuleni izinga lokudubula kwama-neurons e-DA, ngakho-ke i-plasticity ku-GABAergic synapses inamandla okuba negalelo elikhulu ekudluliseni i-DA. Ngempela, i-cocaine, i-morphine ne-ethanol ingaphazamisa upulasitiki we-synaptic ekuvimbeleni i-VTA (Melis et al., 2002; Liu et al., 2005; Nugent et al., 2007). Ukuvezwa kwe-cocaine okuphindaphindiwe vivo Izinsuku ze-5-7 zenza ukunciphisa ama-amplitudes we-GABA-mediated currents currents, ngaleyo ndlela lula ukufakwa kwe-LTP kumaseli e-VTA ngokunciphisa amandla okuvimbela i-GABAergic (Liu et al., 2005). Ucwaningo olulandelayo lubonisa indlela yokuvimbela lokhu i-endocannabinoid-dependent LTD ku-Synapses ye-GABAergic kufaka phakathi ukusebenza kwe-ERK1 / 2 (Pan et al., 2008, 2011). GABA_A I-receptor synapses ku-VTA i-dopamine neurons ibuye ikhombise i-LTP encike kakhulu e-NMDA (ebizwa ngokuthi i-LTP_Gaba) ekuphenduleni ukukhuthazwa okuphezulu kwe-frequency (Nugent et al., 2007). Le LTP_Gaba ayisekho ku-VTA tincetu 2 kanye / noma emuva kwe-24 h vivo ukuphathwa kwe-morphine, i-nicotine, i-cocaine noma i-ethanol (i-Nugent et al., 2007; UGuan noYe, 2010; Niehaus et al., 2010). Endabeni ye-ethanol ukuvimbela i-LTP_Gaba iyanqanyulwa yi-μ-opioid receptor (Guan noYe, 2010) Kanye ne-potential synaptic kuma-syapses okuthakazelisayo, lokhu kulahlekelwa kwe-LTP_Gaba kufanele ukwandise ukudubula kwama-neurons e-VTA DA elandela ukutholakala kwezidakamizwa.

Ukudluliswa kwe-GABA kancane kancane kuboniswe ukuthi kuthinteka izidakamizwa zokuhlukunyezwa. Ngako-ke umthamo owodwa we-methamphetamine noma i-cocaine ukwanele kakhulu ukwehlisa amandla e-GABA_B i-receptors yokulawula i-VTA GABA neuron ukudubula uma kulinganiswa ex vivo I-24 h kamuva (Padgett et al., 2012). I-methamphetamine-yaholela ekulahlekelweni kwe-postsynaptic engakwazi ukuvimbela ukuhamba kancane (i-IPSC) evela ekunciphiseni kwe-GABA_B i-receptor-G amaprotheni-ehlanganiswa ngaphakathi kwe-potassium channel (GIRK) yamanzi, ngenxa yezinguquko ekuthengiseni amaprotheni, futhi ihambisana nokwehla okukhulu ekuzweleni kwe-GABA ye-presynaptic_B ama-receptors ku-GABA neurons we-VTA. Ngokungafani nemithonya eyenziwa yizidakamizwa ku-GABA_A i-synapses le ukucindezeleka kwe-GABA_BUkusayinwa kwe-R-GIRK kuqhubeka izinsuku ezimbalwa ngemuva komjovo (Padgett et al., 2012).

Ama-correlates wokuziphatha okubangelwa yizidakamizwa ku-VTA DA amaseli

Njengoba kukhulunywe ngaphambilini umphumela wokulawulwa kwezidakamizwa ezingekho emthethweni kwi-syntax plasticity ku-VTA DA neurons ichazwe ngokuhamba kwesikhathi, ihlala njalo okungenani i-5 kodwa ingaphansi kwezinsuku ze-10 futhi iboniswe kahle ngokuhambisana nokuthuthukiswa kokuqala kokugqugquzela ukuziphatha kepha hhayi ngezwi layo (Ungless et al., 2001; Saal et al., 2003; Borgland et al., 2004). Ekusekeleni ukucatshangelwa ukuthi ukuvuthwa kwezidakamizwa ezivuthwe izidakamizwa ze-VTA synapses kubonisa ukukhishwa kwe-sensibilisation yokuziphatha, ukuphathwa kwe-intra-VTA ye-glutamate antagonists kunciphisa, futhi ukulawulwa kwe-GluR1 up-up-virtual-mediated virtual kwandisa izakhiwo zokukhuthaza izidakamizwa (Carlezon et al., 1997; UCarlezon noNestler, 2002). Ubufakazi obunamandla bokubandakanyeka kwe-NR2A- B kanye no-B obandakanya ukungena kwempahla kunikezwa ngokubona ukuthi ukuvimbela imithi ye-pharmacy noma okuvimbela kokubili ukuthuthukiswa kokuqwashiswa nokunyuka kwe-cocaine okwenziwe ngama-AMPA / NMDA (Schumann et al., 2009). Kodwa-ke, amagundane anekhono lokususwa kwe-NR1 noma i-GluR1 (ekhethiwe kuma-neurons ama-DA) noma ukukhishwa kwe-GluR1 emhlabeni wonke ukubonisa ukuziphatha okungahambisani nokuziphatha kodwa okwamanje kubonisa ukungahambi kahle kwe-AMPA kwemifudu ye-receptor ngemuva kokwelashwa kwe-cocaine (Dong et al., 2004; Engblom et al., 2008). I-twist eyengeziwe yanikezwa ngumbono wokuthi i-CPP nokuziphatha okuhlelekile okungekho emkhakheni we-GluR1 wokungqongqoza (Dong et al., 2004) kanye nokuqedwa kweCCC coineine engekho emagundini okukhishwa kwe-GluR1 okuhloswe ku-neurons yama-DA (Engblom et al., 2008), kanti ku-NR1 ukukhishwa kabusha kwe-cocaine CPP nokubonakaliswa kokuzwela kokuziphatha kuyanciphisa (Engblom et al., 2008; Zweifel et al., 2008). Ngakho-ke, ngisho ne-caveat yenxephezelo yokuthuthukiswa engase ibe khona kumagundane ashukumisayo kanye / noma kungenzeka ukususwa okungaphelele, kungenzeka ukuthi lezo zinqubo ze-neural ezilawula ukukhishwa kwezidakamizwa ezikhishwa izidakamizwa ze-DA ne-sensational sensitization zihlukanisiwe. Kunalokho kungase kube ukuthi ukukhishwa kwe-VTA synapses kungase kube nomthelela ekunikezeni amandla okukhuthaza okubhekiswe kwezidakamizwa.

Ukulinganisa izinguquko ze-synaptic ezilandela ukuphathwa kwezidakamizwa okungezona okulinganiselwe kunomkhawulo ngokuqondene nokwazisa isimo sokukhubazeka kwesifo. Okunye okuhambisana nesimo somuntu yizifundo lapho ukuguqulwa kwe-plasticaplasticity kuyalinganiswa emva kokulawulwa kwezidakamizwa ezingezansi, isib. Kulokhu, ukuqiniswa kwe-synaptic kwama-VTA DA amangqamuzana abanjwe yi-self-administration of cocaine iphikelela ngokungafani, izinyanga ezihlala njalo ze-3 ziyeka ukuzibonakalisa ziphikisana nokuqedwa kokuqothulwa (Chen et al., 2008). Ngakho-ke, nakuba okokuqala kuhlongozwa ukuba kube umcimbi osesikhashana, kubonakala sengathi i-plastic-evoked plasticing in the VTA inamandla okuhlala isikhathi eside, kubonisa ukuthi indlela yokuphatha (okungahambisani nalokho okungezansi) iyinhloko ebalulekile yokuphila kwayo isikhathi eside . Lokhu kusekelwa ukubonwa ukuthi ukulawulwa kwamajoka kulesi sifundo akubonanga ukwanda okufanayo kwenani le-AMPA / NMDA; kuphakamisa ukuthi kuwukufunda kombuthano wokukhipha umphumela noma isenzo-isiphumo esishayela i-plasticity. Ngokuphambene nalokho, ukuzilawula kokudla noma ukudlala okuncane ngaphansi kwemingcele efanayo kufaka ukwanda kwama-AMPA / NMDA okubambisana okuqhubekayo kwe-7 kodwa hhayi izinsuku ezingu-21 ukuziyeka, okungafani isikhathi eside uma kuqhathaniswa nalokho okubangelwa i-cocaine (Chen et al., 2008). Ukuntuleka kokuphikelela kwe-plasticity eyenziwe ngokudla kubonisa ukuthi ukuguqulwa kwamandla ase-synaptic okubangelwa i-cocaine akuyona nje ukumelela kwe-neural yezinqubo zokufunda ezenzakalelayo noma zokukhokha ezihilelekile ku-paradigm yokusebenza ngokuzimela ngayinye se, kunalokho umthelela othize wezidakamizwa okungenzeka ubhekisele ekuqinisekiseni ukuphathwa kwezidakamizwa. Njengoba kukhulunywe ngaphambilini, ukukhomba ukubikezela umvuzo kuye kwafunyanwa okwenyuka ukwanda kwama-AMPA / NMDA ngezilinganiso ku-VTA, nakuba kungenjalo njengokuphikelela, ukusekela indima yalokhu kuguqulwa komsebenzi we-synaptic wokuthakazelisa ekufundeni umvuzo (Stuber et al., 2008).

Ngokuthakazelisayo, ukuphakama kwenani le-AMPA / NMDA kufana naphezu kwenani lemijovo (single vs. multiple), i-protocol yokuphatha (i-contingent vs. non-contingent), nobude bokufinyelela (ukufinyelela okulinganiselwe nokufinyelela okunwetshiwe) (Borgland et al., 2004; Chen et al., 2008; Mameli et al., 2009). Lokhu kubonisa ukuthi ukwanda kwezinga le-AMPA / NMDA elibhekwe kuma-VTA DA amangqamuzana kungase kube umcimbi wokuvumela, mhlawumbe ukusayina "ubuqili" ngokuphambene nokumelela ukuqaliswa kwe-neuropathology engaphansi okungenzeka ukuthi yanda ngokuvezwa okuqhubekayo.

I-plasticity ekhishwe yizidakamizwa kuma-syntapses e-excitatory ku-NAc

Ngokungafani ne-VTA umjovo owodwa we-cocaine awubangeli ukwanda kwamandla we-synaptic ku-NAc uma kulinganiswa i-24 kamuva (Thomas et al., 2001; Kourrich et al., 2007). Lokhu okubhekwayo kanye ne-bidirectional timescale elandela ukuphathwa okuphindaphindiwe nokuhoxiswa dkubonisa ukuthi ukukhishwa kwezidakamizwa ku-NAc kuhluke kakhulu kulokho okubonwe ku-VTA. Ngempela, uma kusetshenziswa i-cocaine ngokuphindaphindiwe (ukuze kukhuthazwe ukuziphatha), ukwehla kwezinga le-AMPA / NMDA kubonakala ku-NAc shell synapses uma kulinganiswa i-24 h ngemuva kokuphatha okugcinan (Kourrich et al., 2007). Lokhu ukucindezeleka kwe-synaptic kusuka cocaine ephindaphindiwe kubonakala kuhlotshaniswa nopulasitiki ku-VTA; lapho ukuphazanyiswa kokukhetha komsebenzi weGGRRNUMX ku-VTA kuphela umjovo owodwa we-cocaine kuyadingeka ukuthi kubangele ukucindezeleka okufanayo kwe-NAc synapses (Mameli et al., 2009). TAbalobi beli cwaningo bathi ukukhuthazwa okuthuthukisiwe kwe-VTA ukuhlola kungenza kube lula ukukhululwa kwe-DA kanye ne-glutamate ku-NAc ngokusebenzisa ukukhululwa kwe-DA okuthuthukisiwe.. Lokhu kungase kuguqule umkhawulo wokufakelwa kwepulastiki yendawo ku-NAc ngokuthinta ukuvakasha kwesifunda noma ngokuhlanganisa izinqubo ze-intracellular signaling (Mameli et al., 2009).

Ukubaluleka kokusebenza kokucindezeleka kwe-NAc synapses ngesikhathi sokuhoxiswa ngokucacile akucaci ngalesi sigaba. Enye incazelo kungenzeka ukuthi ukucindezeleka kwe-NAc medium spiny neurons (MSNs) kunciphisa impendulo yabo emthonjeni wemvelo ovuzayo, ngakho-ke kunomthelela e-anhedonia okuhlangenwe nakho ngesikhathi sokuhoxiswa okukhulu. Kungenzeka nokuthi ukunciphisa okuphawulwe ngaphakathi kwe-AMPA / NMDA kungaba umphumela wokufakwa komfutho we-NR2B-aqukethe ama-receptors we-NMDA (okwandisa inani le-ratio) njengoba kutholakala ukuthi ama-syapses amasha atholakala kugobolondo le-NAc lapho kuvezwa i-cocaine (Huang et al., 2009). Ama-synapses e-glutamatergic angenalutho, aveza ama-currents mediated receivers-currents-mediated currents ngokungabikho kwemifudlana ehambelana ne-AMPA, bacatshangwa ukuthi banomthamo okwandisiwe wokuqinisa ukudluliselwa kwe-synaptic (u-Isaac et al., 1995). Uma kwenziwa, lezi synapses ezingenalutho zingahle zenze ukuqashwa kwama-receptors we-AMPA ngaleyo ndlela zithuthukise ukudluliselwa kwe-synaptic. Lokhu kunikeza indlela engachaza ngayo ukunyuka kwezinga eliphezulu le-receptors ye-AMPA nesilinganiso esilandelayo se-AMPAR / NMDAR esibonwe ku-NAc ngenkathi kukhishwa isikhathi eside (UBoudreau noWolf, 2005; Boudreau et al., 2007; Kourrich et al., 2007; Conrad et al., 2008). Ama-receptors e-NR2B e-NAc nawo angahileleka ekwakheni izinhlangano zezidakamizwa-izimo njengokwenqotshwa kwe-siRNA yalesi sunithi kuvimbela i-CPP ye-morphine kumagundane kodwa hhayi ukukhuthaza ukuziphatha (Kao et al., 2011).

Ngokungafani ne-cocaine, ukuphathwa okuphindaphindiwe kwe-ethanol ukuchayeka kwemiphumela kubangelwa ukuvumelanisa kwe-syapses ngokuphendulela kwangaphambili kwe-LTD-ekunciphiseni inqubo yokuvuselela uma kulinganiswa i-24 h ngemuva kokuchayeka kokugcina (uJeses et al., 2011). Lezi zinzuzo ezixhomeke ku-NMDA zingakapheli isikhathi eside ngemuva kokuba i-48 h yokuhoxiswa okunye ilahlekile futhi ayikho i-LTP noma i-LTD engasetshenziswa (uJees et al., 2011). Abalobi bahumusha lezi zinguquko ezinamandla ku-NAc plasticity njengombonakaliso wokubaluleka kwalokhu kwenqubo e-neuroadaptations eyenziwe nge-ethanol. Ngaphezu kwalokho, ngokungafani ne-psychostimulants, i-ethanol ingasebenza kuma-receptors we-NMDA ngakho-ke inamandla okuba nomthelela ngqo ekuboniseni i-glutamatergic.

I-Synaptic potentialation ekhonjiswe ku-NAc ngemva kwesikhathi sokuhoxiswa

Ngokuphambene nokucindezeleka okwenziwa ngesikhathi sokuhoxiswa okunamandla, ukutholakala kwe-shell ye-shell ye-NAc kubonakala emva kwezinsuku ze-10-14 zokuxoshwa kokuqondiswa kwe-cocaine noma i-morphine yokuphatha (Kourrich et al., 2007; Wu et al., 2012). Ngaphezu kwalokho, emva kwezinsuku ze-7 ukuhoxiswa ngokulawulwa okukodwa kwe-cocaine, ukwanda kwe-amplitude ye-mEPSC kanye nokulahlekelwa kwe-LTP okubangelwa ukukhushulwa kwamazinga aphezulu (HFS) kutholakala kokubili okuyinhloko kanye negobolondo i-NAc neurons eveza i-dopamine D₁ receptor (Pascoli et al., 2012). Tukuguqulwa kwakhe ekwenzeni i-plastiki ye-syaptic kubhekiselwa njengokuthi i-metaplasticity. I-metaplasticity eyenziwa nge-Cocaine iphinde ibonwe ngemuva kokuhoxiswa kwe-cocaine self-administration. Ngakho-ke, amagundane aphethe i-cocaine elandelwayo elandelwa amaviki e-3 okuphela kokuqedwa noma ukuyeka ukuziveza abonisa uphawu vivo ukwehluleka kokwazi ukuthuthukisa i-LTP kwinhloko ye-NAc ngemuva kokugqugquzelwa kwe-PFC. Lokhu kubhekwa kuhambisane nokushiya kwesokunxele emgqeni wokufakelwa-okuphumayo okuphakamisa amandla okuba yi-fEPSP amplitude (Moussawi et al., 2009). I-Potentiation ye-NAc synapses iphinde ibhekwe ngendlela yokwanda kwe-AMPA-currents currents emva kwesikhathi eside sokuziqeda ngemuva kokuzibusa (Conrad et al., 2008). Ngokubambisana, le datha ibonisa ukuthi amandla e-synaptic ku-NAc aqala njengokusebenza kwesikhathi sokuhoxiswa, noma njengesikhathi sokusebenza kusukela ekulawulweni kokuqala kwe-cocaine. Ucwaningo lwamuva lusekela ukuchazwa kokugcina njengoba ukunyuka okufanayo kumvamisa we-MEPSCs kubonwe ku-D₁ ama-MSN e-receptor eveza ama-MSN naphezu kokungabikho noma ukutholakala kwesikhashana sokuhoxiswa okwesikhashana ngemuva kokuphathwa kwe-cocaine ephindaphindiwe (Dobi et al., 2011). Ngakho-ke, kubonakala sengathi izenzakalo eziholela ekushintsheni kokudluliselwa kwe-glutamatergic ku-NAc kuthatha isikhathi sokuthuthukisa.

Umnikelo wezingxenye ezithile ze-AMPA ezinamamukeli kulolu shintsho kuyahluka ngokuya kwesiteji sokuhoxiswa kanye nendlela yokuphatha; Izinsuku ze-10-21 ekuhoxisweni kokubili okungahambisani nokuzilawula kwe-GluR2-aqukethe AMP receptors kubonakala sengathi iyabangela ushintsho ekudlulisweni kwe-AMPA (UBoudreau noWolf, 2005; Boudreau et al., 2007; Kourrich et al., 2007; Ferrario et al., 2010) kanti ngaphezu kwezinsuku ezingu-21 i-AMPA receptors ye-GluR2 ayengeziwe kuma-synapses. Ukutholwa okulandelayo kubonakala sengathi kunjalo kuphela uma i-cocaine ilawulwa ngokwazo (Conrad et al., 2008; McCutcheon et al., 2011), nakuba ubona (Mameli et al., 2009). Njengoba kunikezwe ukuqhutshwa okwenyuka kwama-receptors we-GluR2-missing AMP receptors kungenzeka ukuthi ukufakwa kwabo kwenzeka ngokuphendula ukucindezeleka kwama-NAc synapses okubangelwa yi-cocaine self-administration, ngaleyo ndlela kubangele ukwandisa ukutholakala kwe-MSN emithonjeni yokuthakazelisa eyenza ukufuna i-cocaine esikhathini esizayo. Ngempela, ukuvimbela i-AMC receptors ye-GluR2-ye-NAc evimbela ukusho ukuthi i-cocaine ifunwa ngamakhophi (Conrad et al., 2008), nokufuna i-cocaine okubangelwa i-AMPA noma i-cocaine iphinde ivinjelwe ukujova kwe-anti -ense oligonucleotide ye-GluR1 mRNA ku-NAc (Ping et al., 2008).

Inselelo yezidakamizwa ngemuva kokuhoxiswa kuvuselela amandla we-synaptic ekucindezelekeni

Ukwanda kwamandla ase-synaptic kanye nokubonakaliswa kwamanzi ama-sub-ampha ase-AMPA abanjwe i-cocaine ku-NAc ngemuva kokuhoxiswa ekuphathweni okungapheli okwenziwa ngemuva kokulawulwa kweminye imithi ye-cocaine (inselelo kabusha) (Thomas et al., 2001; Boudreau et al., 2007; Kourrich et al., 2007; Ferrario et al., 2010). Ngakho-ke, ukucindezeleka kwe-synaptic kuphinda kubonwe kugobolondo le-NAc uma kulinganiswa i-24 h ngemuva kwalesi sijoca se-cocaine (Thomas et al., 2001), nakuba ubona (Pascoli et al., 2012). Ukuziphatha lokhu kubonakala kuqhathaniswa nenkulumo yokwehliswa, futhi esimweni sokuthi okungenani i-amphetamine, iboniswe njenge-clathrin-mediated futhi ixhomeke ekupheleni kwe-GluR2 ekuxhasweni kwe-AMPA receptors (Brebner et al., 2005). Ukunciphisa ukuboniswa kwama-receptors we-AMPA okulandela inselelo ye-cocaine kungakapheli isikhathi eside ngaphakathi kwezinsuku ze-7 ukubonakaliswa kwamanzi kubuyele kumazinga afana namagundane angenayo i-cocaine-pretreated (Ferrario et al., 2010). Ngenxa yalokho, kubonakala sengathi umlando we-cocaine ukuchayeka nokuhoxiswa kungashintsha kalula isiqondiso se-synaptic plasticity ku-NAc.

Isixhumanisi esiqondile samuva senziwe phakathi kwamandla we-cortico-accumbal synapses ku-D₁ amaseli-receptor-positive ngemuva kwezinsuku ze-7 ukuhoxiswa kanye nenkulumo yokwazisa. Njengoba kukhulunywe ngaphambilini, ngemuva kwezinsuku ze-7 ukuhoxiswa ekulawuleni okukodwa kwe-cocaine, lawa ma-synapses atholakale angabonakala kuwo wonke ama-core kanye negobolondo (njengoba kulinganiswa nokwanda kwe-MEPSC amplitude) ne-LTP eyenziwa yi-HFS incishisiwe. Okufanayo akutholakalanga nge-synapses ku-D₂ amaseli-receptor-positive (Pascoli et al., 2012). Lapho kuguqulwa i-optogenetically vivo nge-protocol eyaziwa ukuthi idonse i-LTD, i-synapses ye-cortico-accumbal ku-D₁-Amaseli alamukelekile aboniswa ama-MEPSCs anciphise futhi ukukhulunywa kwe-locomotor ukunciphisa kwavinjelwa. Okubaluleke kakhulu, ikhono le-HFS yokwenza i-LTP libuyiselwe kulezi zine-neurons (Pascoli et al., 2012), ngaleyo ndlela kubonisa ukuxhumana okuqondile phakathi kwalokhu okuguquguqukayo kwesimo se-syaptic kwi-cortico-accumbal synapses kanye nokuboniswa kwe-cocaine.

Izici zombhalo

Izici zokubhala ziyimaphrotheni ezibopha ezilandelwaneni ezithile ze-DNA ukuze zilawulwe ngokubhalwa komzimba ngokusebenzisana ne-RNA polymerase II eyinkimbinkimbi (Mitchell neTjian, 1989). Izici zombhalo zingadluliswa noma zinyunyiswe ngokuphendula okubangelwa kwemvelo, okuholela ekuguqulweni kwesimo sezakhi kanye nokugcina umsebenzi we-neuronal. Kunezici eziningi zokubhaliwe eziye zabonwa ngendima yabo engaba khona ekugqilazweni ngoba ukukhuluma nokusebenza kwazo kulawulwa emgwaqeni we-mesocorticolimbic lapho kuvezwa izidakamizwa zokuhlukunyezwa. I-FosB ingenye yezinto ezibhaliwe ezitholwe ngokukhethekile ngenxa yokuzinza okungavamile. I-FosB iyinhlangano ye-FosB eyisixuku esinezintambo, futhi ikwabelana nge-homology namanye amalungu omndeni we-Fos kuhlanganise c-Fos, FosB, Fra1, ne-Fra2 okuyinto yonke i-heterodimerise ne-Jun yomndeni amaprotheni (i-c-Jun, JunB, noma i-JunD) ifomu i-activator amaprotheni-1 (AP-1) izici zokubhala (uMorgan no-Curran, 1995). Lawa amanye amalunga omndeni kaFos ashukunyiswa ngokushesha kwi-striatum ngokuphendula ukuphathwa okunzima kwama-psychostimulants, kodwa ngenxa yokungazinzile le nkulumo yesikhashana futhi ibuyele kumazinga ayisisekelo phakathi namahora (iGreybiel et al., 1990; Young et al., 1991; Ithemba ne-al., 1992). Ngakolunye uhlangothi, i-ΔFosB iqoqa ku-striatum elandela ukulawulwa kwezidakamizwa ezingapheli, futhi inkulumo yayo iphikelela amasonto ambalwa emva kokutholakala kwezidakamizwa zokugcina (Hope et al., 1994; Nye et al., 1995; Nye noNestler, 1996; Pich et al., 1997; U-Muller no-Unterwald, 2005; McDaid et al., 2006). Idatha evela ekuhlolweni kokuziphatha isekela indima ye-ΔFosB kwezinye zezinto ezihlala njalo ezinikezwe izidakamizwa zokuhlukunyezwa. Ukubhekwa ngokweqile kwe-ΔFosB ku-striatum kuholela ekuphenduleni ukwandisa izimpendulo kuzo zombili i-cocaine enamandla futhi engapheli, futhi kwandisa izindawo zokuqinisa i-cocaine ne-morphine (i-Kelz et al., 1999; I-Colby et al., 2003; UZachariou et al., 2006), kanti ukuvimbela i-ΔFosB kuveza imiphumela ehlukile yokuziphatha (Peakman et al., 2003). Ngenxa yikhono layo lokukhulisa isikhuthazo sezakhiwo zokugqugquzela izidakamizwa zokuhlukunyezwa, lesi sici sokubhaliselwa siphakanyisiwe ukuba simele "ukushintshwa kwamangqamuzana" okusiza ukuguqulwa ekugqiliseni (Nestler, 2008).

I-cAMP impendulo yamaprotheni ehlanganisa izimpendulo (i-CREB) yinye isici se-transcription esiye sigxile emkhakheni omkhulu wocwaningo ngenxa yendima ehlongozwayo ye-plasticity eyenziwe yizidakamizwa (McPherson noLawrence, 2007). I-CREB iboniswa ngokujwayelekile ebuchosheni, futhi ingasetshenziswa yizinqwaba zezindlela zokubonisa izimpawu ze-intracellular eziqeda iphosphorylation yayo ku-serine 133 (Mayr no-Montminy, 2001). I-PBREB ye-Phosphorylated (i-pCREB) ivuselela ukuqashwa kwe-CREB-binding protein (CBP) eyenza ukubhalwa kwezakhi zofuzo ezihlukahlukene (Arias et al., 1994). i-pCREB iqhutshwa ngokushesha kwi-striatum lapho ivuleka kuma-psychostimulants (Konradi et al., 1994; Kano et al., 1995; UWalters noBlendy, 2001; Choe et al., 2002) futhi lokhu kuhloswe ukuthi kubhekise indlela yokwakha ekhaya ephikisana nezimpendulo zokuziphatha ezidakamizwa zokuhlukunyezwa (McClung noNestler, 2003; Dong et al., 2006). Ngokuvumelana nalokhu, ukucindezeleka okukhulu kwe-CREB kugobolondo le-NAc kunciphisa izindawo ezivuzayo ze-cocaine endaweni ye-preference preference (CPP), kuyilapho okuphambene kubonakala ekuvinjweni kwe-CREB kule ndawo (i-Carlezon et al., 1998; I-Pliakas et al., 2001). Ngokufanayo, ukuguqula izakhi zofuzo noma ukuvinjelwa kwe-CREB ku-storum striorum kunika ukwandisa izakhiwo ezisebenzayo zokusebenza kwe-psychostimulants, kwenezela ukwesekwa okuqhubekayo kule nqubo (Fasano et al., 2009; Madsen et al., 2012).

Nakuba idatha evela ku-CPP yokuhlola isekela umqondo we-CREB osebenza njenge-modulator engalungile yomvuzo wezidakamizwa, okungenani ngokuqondene ne-cocaine, lokhu kungase kube ukugqithisa okukhulu. Izifundo eziningana zisebenzisa amasu ahlukahlukene ukushintsha umsebenzi we-CREB kugobolondo le-NA ziveze ukuthi ukuvinjelwa kwe-CREB kunciphisa i-cocaine ukuqiniswa kwipharadigm yokuzibusa (Choi et al., 2006; Green et al., 2010; Larson et al., 2011), kuyilapho ukwenziwa kwe-cocaine kuqiniswa yi-CREB ngokweqile kule ndawo (uLarson et al., 2011). Lokhu kutholakala okungaqondakali kungenzeka ngenxa yokungafani okuyisisekelo phakathi kwezinqubo zezinsimbi kanye ne-Pavlovian conditioning kanye nokuzithandela vs. ukuphathwa kwezidakamizwa ezingenasidingo. I-CPP ihilela izinqubo zokufunda ezihlangene, futhi kucatshangwa ukuthi yizici eziqondile ze-hedonic zezidakamizwa kunokuba kuqiniswe izidakamizwa ngayinye se (Bardo noBevins, 2000). Ukuzivocavoca kwezidakamizwa ngokuzikhethela kungathonywa izici eziningana ezingokomzwelo, kanye nekhono lomsebenzi we-CREB ku-NAc ukunciphisa izimpendulo ezenzakalweni ze-anxiogenic (i-Barrot et al., 2002) nokuvimbela ukucindezeleka (Pliakas et al., 2001) lingathonya amandla okuzibulala. Ngokuthakazelisayo, ukususwa kwe-CREB evela ku-PFC kubangela ukuthi kunciphise ukugqugquzela ukulawula i-cocaine (McPherson et al., 2010), ebonisa ukuthi umphumela wokuguqulwa kwe-CREB ekuphatheni kubuyehlukahluka ezindaweni ezihlukahlukene zobuchopho. Lokhu mhlawumbe akumangazi ukuthi le-CREB transcriptome ihluke ngokuphawulekayo ngokwendlela yeseli (Cha-Molstad et al., 2004) ngakho-ke-ke kuyoba kubalulekile ukukhomba izinguquko ezenzakalweni zezakhi zofuzo ezenzeka ngaphansi kwe-CREB efaka isandla kulezi zingu-phenotypes. Ukuphoqa izinto ngokuqhubekayo yilokhu okushiwo ukuthi i-CREB kugobolondo le-NAc ibalulekile ku-CPP ye-nicotine (Brunzell et al., 2009), ephakamisa ukuthi izindlela ezihlinzekwa umvuzo we-nicotine ezihlukile zihlukahluka kulelo cocaine ne-morphine, okubili kokuthuthukiswa yi-CREB ekuvimbeleni kwegobolondo le-NAc (i-Carlezon et al., 1998; I-Pliakas et al., 2001; UBarrot et al., 2002).

Izindlela ze-Epigenetic

I-Epigenetics inezincazelo eziningi, kodwa nge-neuroscience ngokuvamile ichazwa njengezinguquko ekukhulumeni kwezakhi zofuzo ezenzeka nge-modulation ye-chromatin engahambisani nezinguquko ekulandelaneni kwe-DNA ngokulandelana (iMcQuown ne-Wood, 2010). I-Chromatin ichaza isimo se-DNA uma ihlanganiswa ngaphakathi kweseli. I-unit yokuphindaphinda eyisisekelo ye-chromatin yi-nucleosome, equkethe ama-147 ayisisekelo se-DNA ehlanganiswe i-octamer eyakhiwe ngamabili we-histones amane omlando (H2A, H2B, H3, ne-H4) (Luger et al., 1997). Imisipha yokugcina i-amino yalezi zinhlobonhlobo ze-histones ingaba nezinombolo eziningi zokuguqulwa ngemuva kokuhumusha okuhlanganisa i-acetylation, i-methylation, i-phosphorylation, i-ubiquitination, ne-sumoylation (i-Berger, 2007). Ukwengezwa nokukhishwa kwala maqembu asebenzayo kusuka emiceleni ye-histone kwenziwa yinani elikhulu le-enzyme i-histone eguquguqukayo, kuhlanganise nama-acetyltransferases, ama-acaclalases, ama-methyltransferases, ama-demethylases, nama-kinase (Kouzarides, 2007). Lezi zindlela zokuguqula i-histone zifakazela ukuqashwa kwezici zokubhala kanye namanye amaprotheni abandakanyeka emithethweni yokubhalisa, futhi aguqule ukuguqulwa kwe-chromatin ukwenza i-DNA ibe yinto engatholakali kalula kwimishini yokubhala (Strahl no-Allis, 2000; Kouzarides, 2007; I-Taverna et al., 2007). Ngakho-ke izindlela ze-epigenetic zimelela izindlela ezibalulekile lapho ukuvimbela imvelo kungakwazi ukulawula ukukhuluma kwezakhi zofuzo futhi ekugcineni ukuziphatha.

Muva nje, ukuchithwa kwe-chromatin kuye kwaqalwa njengendlela ebalulekile ekusetshenzisweni kwezinguquko ezibangelwa izidakamizwa ku-plasticity nokuziphatha (Renthal noNestler, 2008; Bredy et al., 2010; McQuown and Wood, 2010; Maze noNestler, 2011; URobison noNestler, 2011). Ubufakazi bokuqala balokhu buvela ekuhlolweni kuka-Kumar nabasebenza nabo abasebenzisa izivivinyo ze-chromatin immunoprecipitation (ChIP) ukuze bakhombise ukuthi i-cocaine idala ukuguqulwa kwe-histone kumgqugquzeli othile wezakhi zofuzo (Kumar et al., 2005). Ngokuqondile, ukuphathwa okunamandla kwe-cocaine kuholele ku-H4 hyperacetylation of the cFos umgqugquzeli, kanti ukuphathwa okungapheli kuholele ekutheni i-H3 hyperacetylation ye- BDNF futhi Cdk5 abagqugquzeli. I-histone acetylation ifaka ukudluliswa kwe-enzymatic kweqembu le-acetyl kumsila we-N-terminal oyisisekelo we-histone, owenza kungasebenzi ukuxhumana kwe-electrostatic phakathi kwe-histone ne-DNA ekhokhiswe kabi, kuyenze ifinyeleleke kakhudlwana kuzinto zokubhala (i-Loidl, 1994). Lokhu kuhambisana nekhono le-cocaine ukwandisa ukubonakaliswa kwezici zokubhaliselwa komndeni weFos (Greybiel et al., 1990; Young et al., 1991), kuyilapho i-BDNF neCdk5 ingeniswa kuphela ekuvezweni okungapheli (Bibb et al., 2001; Grimm et al., 2003).

I-histone hyperacetylated state ingabuye ifinyelelwe ngokuhlola ngokulawulwa kwe-histone deacetylase (HDAC) inhibitors, futhi le mithi isetshenziselwe ukuhlola imiphumela yokwanda komhlaba ku-histone acetylation ekuphenduleni kokuziphatha kwezidakamizwa zokuhlukunyezwa. Ukuphathwa kwe-HDAC inhibitors ngendlela ehlelekile kukhulisa ukwanda kwe-hyperacetylation ekubhekaneni ne-cocaine ngaphakathi kwe-striatum (Kumar et al., 2005), futhi lokhu kungabangela ukukhishwa komkhiqizo we-cocaine nomvuzo we-cocaine (Kumar et al., 2005; I-Sun et al., 2008; USanchis-Segura et al., 2009). Ukuvinjelwa kwe-HDAC kungakwandisa ukukhuthaza ukuqhutshwa kwe-locomotor ku-ethanol ne-morphine, nokusiza i-morphine CPP (i-Sanchis-Segura et al., 2009), Noma kunjalo, ama-inhibitors e-HDAC nawo atholakale ekuvimbeleni ukuthuthukiswa kokwehliswa komuntu owodwa wokudalwa kwe-morphine (Jing et al., 2011), futhi kuncishiswe isisusa sokuziphathisa i-cocaine (Romieu et al., 2008). Lokhu okutholwa okungafaniyo kungabonisa ukungafani emiphakathini yokuphatha, futhi kubalulekile kubonisa ukuthi i-HDAC inhibitors ayikhethi ngokukhethayo izimpendulo zokuziphatha kwezidakamizwa kuzo zonke izimo.

Ngenxa yomphumela wabo wokuvumela ukuguqula izakhi, ama-inhibitors e-HDAC angase enze nokusiza izinhlobo ezithile zokufunda (Bredy et al., 2007; I-Lattal et al., 2007). Kusanda kuboniswa ukuthi ukuphathwa kwe-HDAC inhibitor ngokulandela ukuvezwa kabusha kwendawo ephakathi kwe-cocaine kungasiza ekuqothulweni kwe-CPP eyenziwe nge-cocaine, futhi kungenzeka ukuthi kuhlobene nokukhula kwe-histone H3 ku-NAc (Malvaez et al., 2010). Ukumnika i-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) ngokuqondile ku-NAc ngesikhathi isigaba sesimo se-CPP sikhula umvuzo we-cocaine (Renthal et al., 2007), okubonisa ukuthi ukuvinjelwa kwe-HDAC kulesi sifundazwe kungenza kube lula ukufunda nokufunda kokuphela kokuthola umvuzo, kuye ngokuthi umuthi ulawulwa kanjani. Ukuhlolwa okuqhubekayo kwembise indima ye-HDAC5, futhi i-HDAC engapheli ivezwe kakhulu ku-NAc ekudaluleni umklamo we-cocaine. Ukuphathwa kwe-Cocaine kwandisa umsebenzi we-HDAC5 ngokulawula i-dephosphorylation yayo kanye nokungenisa kwe-nyukliya okulandelayo, futhi i-dephosphorylation ye-HDAC5 ku-NAc iyonakalisa ukuthuthukiswa kwe-cocaine CPP (Taniguchi et al., 2012). Ngokufanayo, ukuchazwa ngokweqile kwe-HDAC5 ku-NAc ngenkathi isimo sesimo se-CPP sinciphisa umvuzo we-cocaine, futhi lokhu kuguqulwa lapho kuboniswa ifomu le-HDAC5 ku-NAc (Renthal et al., 2007). Kungenzeka ukuthi i-HDAC5 yenza le miphumela ngokuvimbela ukuguqulwa kofuzo olwenziwe izidakamizwa ngokuvamile okwandisa izakhiwo ezivuzayo ze-cocaine.

Ukuhlaziywa kwe-genome-wide kwe-chromatin ukuguqulwa okwenzeka ku-NAc ngenxa ye-cocaine ukuvezwa kwembula kuye kwaveza eziningi ze-chromatin ukuguqulwa ezindaweni ezikhuthazayo zezakhi zofuzo ezincane kokubili i-CREB ne-ΔFosB (Renthal et al., 2009). Lokhu kuhlaziywa kwaveza futhi-ukulawulwa kwe-sirtuine emibili, i-SIRT1 ne-SIRT2, eyi-proteins ene-HDAC yomsebenzi futhi ingahle ikhiqize amanye amaprotheni weselula (Denu, 2005). Ukwehla kwe-SIRT1 no-SIRT2 kuhlotshaniswa nokwanda kwe-acetylation ye-H3 nokwandiswa kokubopha kwe-ΔFosB kubagqugquzeli babo bezakhi zofuzo, okuphakamisa ukuthi ziyizinhloso zokungena ngaphansi kwe-ΔFosB (Renthal et al., 2009). I-up-regulation of SIRT1 ne-SIRT2 kucatshangwa ukuthi ihambisana nokuziphatha; ama-sirtuin anciphisa ukukhushulwa kwama-NAc MSNs kwesibeletho, futhi ukuvimbela kwemithi yama-nuritini kunciphisa umvuzo we-cocaine, kanti ukuvuselela kwawo kwandisa izimpendulo eziwusizo nge-cocaine (Renthal et al., 2009).

Ngaphandle kwendima yokusebenza yama-HDAC, ukuhlolwa kofuzo kuye kwaveza indima ye-histone acetyltransferases (i-HATs) ekuxhumaniseni ezinye zezimpendulo zokuziphatha ezidakamizwa zokuhlukunyezwa. Ngokusobala indlela ebaluleke kunazo zonke i-CBP ekwazi ngayo ukuthuthukisa ukubhalwa kwezakhi nge-HAT umsebenzi wayo (Bannister and Kouzarides, 1996), kanye nokuthola okwakamuva kunomthelela umsebenzi we-HAT we-CBP kwezinye izinguquko ze-epigenetic ezibangelwa ukutholakala kwezidakamizwa. Ngokuphendula i-cocaine enamandla, i-CBP iyabhalwa ku- I-FosB umgqugquzeli lapho i-acetylates i-histone i-H4 futhi ikhulisa ukubonakaliswa kwe-FosB (i-Levine et al., 2005). Emagundeni ayitholakali nge-CBP, i-CBP encane iyabhalwa kumgqugquzeli okuholela ekunciphiseni kwe-histone acetylation nokukhuluma kwe-FosB. Lokhu kuhambisana nokuqoqwa okuncane kwe-ΔFosB ku-striatum, futhi akumangalisi ukuthi le mbukiso ibonakele ukukhushulwa ekuphenduleni inselelo ye-cocaine (Levine et al., 2005). Muva nje, usebenzisa uhlelo lokubuyisela kabusha i-Cre-lox Malvaez kanye nozakwabo baphenye indima yomsebenzi we-CBP otholakala ngqo ku-NAc uma kuqhathaniswa ne-cocaine eyenziwe nge-cocaine nokuziphatha (Malvaez et al., 2011). Kwabikwa ukuthi ukususwa okuhlosiwe kwe-CBP ku-NAc kubangele ukunciphisa i-histone acetylation nokukhuluma kwe-c-Fos, nokusebenza okusebenzayo okungahambi kahle ekuphenduleni kokubili i-cocaine enamandla futhi engapheli (Malvaez et al., 2011). Umvuzo we-cocaine owenziwe futhi wawuvinjelwe kulezi zinhlanzi, unikeza ubufakazi bokuqala bokuthi umsebenzi we-CBP ku-NAc ubalulekile ekwakheni izinkumbulo ezihlobene nezidakamizwa (Malvaez et al., 2011).

Muva nje, izivivinyo ezivela kwelebhu yaseKandel ziveze ukuthi izindlela ze-epigenetic zingase zenze amandla e-nicotine acatshangelwe ukuthi abe "ngumuthi wokungena". Amagundane aphethwe ngokungapheli nge-nicotine ngaphambi kokuvezwa kwe-cocaine akhombise ukukhuthazwa kwe-locomotor sensitization kanye nomvuzo we-cocaine kuqhathaniswa namagundane angama-nicotine naive (Levine et al., 2011). Ukwengeza, ukuguqulwa kwe-nicotine kwaholela ekucindezelekeni kwe-cocaine okwenziwe ngcono kwe-LTP emasimini e-excitatory e-NAc, umphumela ongazange ubonwe nge-nicotine yedwa. Ukuhlaziywa kokuguqulwa kwe-histone okubangelwa ukuthungulwa kwe-nicotine yosuku lwe-7 kuye kwanda kakhulu i-H3 ne-H4 acetylation I-FosB umgqugquzeli ku-striatum, umthelela ongazange ubizwe njengokuphendula ukuphathwa kwe-cocaine yezinsuku eziyi-7. Umsebenzi we-HDAC wehlisiwe ku-striatum yamagundane aphathwe i-nicotine, kepha awashintshiwe kumagundane aphathwe nge-cocaine. Ngokumangazayo, ukumnika i-HDAC inhibitor ngqo ku-NAc ikwazile ukulingisa imiphumela ye-nicotine pretreatment emiphumeleni yemiphumela ye-cocaine. Azikho kulezi zinguquko ezibonwe ngenkathi amagundane elashwa nge-cocaine ngaphambi kwe-nicotine, eqinisekisa ukucaciswa kwesikhashana kwale miphumela. Lesi setha esihle sokuhlolwa sinikeze incazelo ye-epigenetic yokuthi kungani ukubhema ugwayi cishe njalo kwandulela ukusetshenziswa kwe-cocaine kubantu (uKandel, 1975; Kandel et al., 1992).

Ngaphandle kwe-histone acetylation, i-histone methylation isanda kubonakala njengento eguquguqukayo yokuguquguquka kwe-chromatin eyenziwa yizidakamizwa zokuhlukunyezwa (i-Laplant et al., 2010; Maze et al., 2010, 2011). I-methylation ye-historone ihlanganisa ukwengeza nge-enzymatic kweyodwa, emibili, noma emithathu ama-methyl ama-lysine noma i-arginine izinsalela ku-N-terminal yemicu yomlando we-histone, futhi ihlotshaniswa nokuvuselelwa kwe-transcriptional noma ukucindezelwa, kuye ngokuthi isimo sokuguqulwa (iRis and Allis , 2001). Izifundo zokuqala zokuhlola i-histone methylation eyenziwa yi-cocaine zaholela ekudaleni i-histone methyltransferases, i-G9a kanye ne-G9a-like protein (GLP), eyayigcinwa phansi-elawulwa ku-NAc 24 h elandela kokubili ukungcola ne-cocaine self - ukuphathwa (Renthal et al., 2009; Maze et al., 2010). Lo mgomo-phansi wawuhlanganiswe nokuncipha okufanayo kumlando we-histone H3 lysine 9 (H3K9) kanye ne-27 (H3K27) methylation. Ngokulandelayo, ukuphakama okukhulu kwe-G9a ku-NAc kuboniswe ukunciphisa ukuboniswa kwe-cocaine eyenziwe ngamakhemikhali akhethiwe, ukunciphisa umvuzo we-cocaine njengoba kulinganiswa yi-CPP, futhi kuvimbela ukunyuka kwesibindi se-dendritic umgogodla ovame ukubhekwa ngokuphendula kwe-cocaine ephindaphindiwe (Maze et al., 2010). Okuphambene kwenzeke lapho ukukhuluma kwe-G9a ku-NAc kungavinjelwa, okwenza kube nokwanda kwe-dendritic spine mass kanye nomvuzo we-cocaine othuthukisiwe. Kunobunye ubufakazi bokuthi lezi zinguquko ezenziwe nge-cocaine ekukhulumeni kwe-G9a nokuncipha okulandelayo ku-H3K9 ne-H3K27 zilawulwa ngu -ΔFosB (Maze et al., 2010). Ngokubambisana, lezi zivivinyo ziveze indima ebalulekile i-histone methylation yi-G9a kwezinye izimo zokuziphatha ezide isikhathi eside kanye nemiphumela yezinto eziphilayo zokudonswa ngokuphindaphindiwe kwe-cocaine.

Muva nje, i-trimethylation ye-histone H3 i-lysine 9 (H3K9me3) eyayicatshangwa ukuthi iyimpawu ye-heterochromatic eqinile, iboniswe ukuthi ilawulwa ngokunamandla ku-NAc nge-exposure ye-cocaine enamandla futhi engapheli (Maze et al., 2011). I-cocaine ephindaphindiwe yaholela ekunciphiseni okuqhubekayo ekucindezelweni kwe-H3K9me3 okuye yahlotshaniswa ikakhulukazi ezindaweni ezingezona zokufaka ikhodi (Maze et al., 2011). Lokhu okutholwa kokuqala kusikisela ukuthi ukuchayeka ngokuphindaphindiwe kwe-cocaine kungabangela ukungaqiniseki kwezakhi ezithile ze-retrotransposable kuma-nec neurons, futhi kungaba nesithakazelo esikhulu ukuqonda imiphumela yokuziphatha yalezi zindlela zokuguqula i-epigenetic.

Njengoba kunikezwe ukukhubazeka okuqhubekayo, ucwaningi lwakamuva luye lwahlola indima ye-DNA methylation, okuyi-adaptation epigenetic ezinzile ngokuqhathaniswa nokuguqulwa kwe-histone. I-methylation ye-DNA ihilela ukwengeza amaqembu e-methyl kuma-cysteine ​​asekelwe ku-DNA, futhi ngokuvamile ihlotshaniswa nokucindezelwa kwe-transcriptional (Stolzenberg et al., 2011). Ukuhlaziywa kobuchopho bamagundane abathola ama-cocaine engavunyelwe ngaphezu kwezinsuku ze-7, noma ukuthi i-cocaine yokuziphathisa ngaphezu kwezinsuku ze-13 yembula phansi-isimiso se-DNA methyltransferase DNMT3a ku-NAc 24 h ngemuva kokudalwa kwe-cocaine (Laplant et al., 2010). Ngakolunye uhlangothi, ngokulandela ukutholakala kwe-cocaine okungapheli (kokubili okungahambisani nokuphathwa kwamasonto e-3 noma ngaphezulu) kanye nesikhathi sokuhoxiswa kwelanga le-28, dnmt3a I-mRNA itholakala ukuthi ikhuliswa kakhulu ku-NAc (Laplant et al., 2010). Ukuvinjelwa kwe-DNAM / DNMT3a ikakhulukazi e-NAc kamuva yaboniswa ukukhulisa kokubili ukucutshungulwa kweCPP kanye nokukhuthaza ukukhiqiza i-cocaine, kanti okuphambene kwakubhekwa ukulandela ukucindezeleka okukhulu kwe-DNMT3a kule ndawo. Ngaphezu kwalokho, ukuvinjelwa kwe-DNMT3a ku-NAc nakho kwavimbela ukunyuka kwe-cocaine okwenziwe nge-dendritic spine mass (Laplant et al., 2010). Ukuhambisana kokuziphatha kwezinguquko ze-cocaine ku-NAc spine wiensity akukaqondwa kahle. Izinyathelo ezivimbela ukungena kwezidakamizwa ezibangelwa izidakamizwa ziye zaboniswa ukunciphisa izindawo ezivuzayo ze-cocaine (Russo et al., 2009; Maze et al., 2010); Kodwa-ke, ezinye izifundo zithole ukuthi ukuvinjelwa kwe-spinogenesis kungabangela umvuzo we-cocaine (Pulipparacharuvil et al., 2008; Laplant et al., 2010). Njengoba i-cocaine ibonakala ibangela ukulawulwa okunamandla kakhulu kwezinhlanzi ezihlukahlukene ze-dendritic ngaphezu kwe-exposure and withdrawal (Shen et al., 2009), kuye kwaphakanyiswa ukuthi lokhu kungezwani kungase kuxhomeke kuhlobo lwezinhlanzi ze-dendritic eziguqulwayo (i-Laplant et al., 2010).

Kusukela ekuhlolweni okuchazwe lapha, kucacile ukuthi ukulawulwa kwezidakamizwa ezithinta izidakamizwa zamandla amangqamuzana e-cells kubonisa indlela eyisihluthulelo esithonya izimpendulo zokuziphatha ezifundweni ezihlobene nezidakamizwa kanye nomvuzo. Isinyathelo esibalulekile esilandelayo kungaba ukukhomba ukuthi iyiphi yalezi zinguquko ze-epigenetic ezihambisana kakhulu nesifo somuntu wesimo sokulutha. Ngenxa yokuthi ukuvezwa kwezidakamizwa akuwanele ukukhiqiza "ukulutha" kokubili kubantu nasezilwaneni, ukufakwa kwamamodeli okubheke ngokucacile okuphawulekayo kokuziphatha kabi, njengokusebenzisa izidakamizwa nokucindezela kuzoba nenani elikhulu.