Ts'usumetso e hlahisoang ke lithethefatsi lithutong tse thabisang ho VTA

Boithuto ba bopula-maliboho bo entsoeng ke Ungless le basebetsi mmoho le 2001 e bontšitse hore ho pepesehela k'hok'heine e le 'ngoe ho bakile ntlafatso ea matla a synaptic ho li-synapses tsa thabo ho li-neurons tsa VTA DA ha e lekantsoe 24 h hamorao litekong tsa boko (Ungless et al., 2001). Sena se lekantsoe e le keketseho ea karo-karolelano ea maqhubu a maqhubu a matla a fetisisang a AMPA-Mediated interring posynaptic currents (EPSCs) mabapi le li-EPSC tsa NMDA-Mediated (e bitsoang karolelano ea AMPA / NMDA). LTP e ileng ea emisoa ka motlakase e ile ea bontšoa e kengoa ke liphoso tsa VTA tse thabisang ho litoeba tse tšoaroang ke koae, athe LTD e ile ea ntlafatsoa. Tlhahlobo ena hammoho le mehato e meng e mengata ea motlakase e bonts'itseng hore phetoho ea polasetiki e hlokometse mekhoa e ts'oanang e kopaneng ea PDP (Ungless et al., 2001). Ho tloha joale ho bontšitsoe hore tsamaiso ea lithethefatsi tse ling tsa tlhekefetso ho kenyelletsa amphetamine, morphine, ethanol, nicotine, le benzodiazepines le tsona li ka baka keketseho ea matla a synaptic ho VTA, phello e sa bonoeng le lithethefatsi tsa psychoactive tse se nang ts'ebeliso e mpe ea matla (Saal et al., 2003; Gao et al., 2010; Tan et al., 2010). Tlhahlobo ena e bonts'a ho kopana ha likarabo tsa seleng kahare ho VTA ke lithethefatsi tsohle tse hlekefelitsoeng mme e fana ka mochine o ka khonehang oa neuraladaptations e ka tlisoang ke tšibollo ea mantlha.

Kameho ea ts'ebetso ea lithethefatsi tse se nang khang ho VTA synaptic plasticity e hlahisoa hanyane, e tšoarella bonyane 5 empa e le tlase ho matsatsi a 10 mme e bontšitsoe hore e lumellana hantle le nts'etsopele ea pele ea maikutlo a boits'oaro empa eseng ka polelo ea eona (Ungless et al., 2001; Saal et al., 2003; Borgland et al., 2004). Haeba k'hok'heine e laoloa sephetho se fapana le ho ba polasetiki ho VTA e phehella mme e ka bonoa le matsatsing a 90 hore e tloheloe. (Chen et al., 2008).

Monyetla oa "glutamatergic synapses" ea lisele tsa VTA DA ka mokhoa o hlakileng o hokahane le bokhoni ba lithethefatsi tsa tlhekefetso ho matlafatsa DA ea kantle ho Nac (Di Chiara le Imperato, 1988) ae kanna ea emela ho qalisoa ha thuto ea moputso oa "thuto ea bophelo" eo ho eona "ho hatakeloa" ha mekhatlo ea litokelo tsa lithethefatsi ho bang teng. Ka 'nete, keketseho e itšetlehileng ka li-receptor-NMDA ea matla a glutamatergic synaptic e tlalehiloe ho li-neurons tsa VTA DA nakong ea ho fumanoa ha mokhatlo oa moputso oa moputso oa cue (Stuber et al., 2008) mme haufinyane tjena ho netefalitsoe hore koae e khetha ka mokhoa o ikhethileng palo ea AMPA / NMDA ea li-neurons tsa VTA tseo projeke e eang ho NAc ho fapana le PFC (Lammel et al., 2011); ho thehiloe hantle hore phetisetso ea dopamine kahare ho NAc e bohlokoa bakeng sa ho fumana mokhatlo oa Pavlovian (Kelley, 2004). Kahoo ho ka etsahala hore monyetla oa "li-neurons tsa VTA DA" o ka emisa kh'outu e tšoanang le ea PDP, mohlomong mokhoa oa ho ithuta o amanang, o ka bang bohlokoa bakeng sa likarabo tsa boitšoaro bo khothalletsoang ke koae 'me o na le bokhoni ba ho tsosa litheko tsa nako e telele tse tlatsetsang bokhobeng ba tsona, leha e le hore ha e emele naha e lemalloang. Joalokaha ho hlalositsoe ke ba bang, ho ka etsahala hore lithethefatsi tse lemalloang li bokelle "bokhabane" ba boleng ba lithethefatsi ho setho sa setho (Kauer le Malenka, 2007).

Tšimoloho ea likhakanyo tse loketseng tsa glutamatergic ho VTA e amehang polasing e susumetsoang ke lithethefatsi e ntse e hlakisoa ka botlalo. Phuputso e 'ngoe e senotse hore VTA glutamatergic synapses e lebisitsoeng ke likhakanyo tse tsoang ho VTA ka boeona le senotlolo sa pedunculopontine (PPN) li bonts'a ts'ebetso e ntlafalitsoeng ho tsoa ho koae empa leha ho le joalo li-synapses tse amohelang litlatsetso ho tsoa ho barekisi ba PPN li hlahisoa ke Δ⁹-tetrahydrocannabinol (THC) (E ntle le ea Lupica, 2010). Kahoo, ho bonahala eka lithahasello tse ikhethileng tse amanang le tšusumetso ea lithethefatsi li ka fapana ho latela setheo seo ho buuoang ka sona hape ho ka etsahala hore ebe monahano o itseng o tloaelehile ho polasetiki eohle e tlisoang ke lithethefatsi ho VTA; tsa morao li sa ntse li tla ikemisetsa. The VTA e amohela likhakanyo tse pharalletseng ho tsoa libakeng tse ngata tsa boko ho kenyeletsa le PFC, amygdala le subthalamic nucleus (Geisler le Wise, 2008), tseo bongata ba tsona bo bontšitsoeng ho susumetsa ho thunya ho hoholo ha li-neuron tsa VTA DA (Mofumahali le Mercuri, 2002). Liteko tsa nako e tlang tse sebelisang mahlale a optogenetic li ka thusa ho tseba hore na ho na le menahano e joang e anngoeng ke ts'ebetso ea lithethefatsi ho VTA synapses e hlokometsoeng ho arabela lithethefatsi tse fapaneng tsa tlhekefetso, ka hona e fana ka leseli mabapi le mofuta o hlakileng oa neuroadaptation ena.

Mekhoa e tlatselletsang ea polasetiki ea evaptic e kentsoeng ke lithethefatsi nakong ea thabo e nyane ho VTA

Joalo ka ts'ebetso ea motlakase e kentsoeng ke motlakase ho li-neuron tsa li-midbrain DA ho eketseha ha matla a synaptic ho VTA e hlahisitsoeng ka bobeli ke koae le nikotine ho bontšitsoe e le e itshetlehile hodima ts'ebetso ea li-receptor tsa NMDA (Bonci le Malenka, 1999; Ungless et al., 2001; Mao et al., 2011). Ho fapana le moo, tlhokomelo ea phepelo e bakoang ke koae e sa tsoa bontšoa ho hloka tšebetso ea protheine kinase Mζ (Ho et al., 2012), protheine ea tlhaho ea protheine kinase C (PKC) e ikemelang ka nako e le 'ngoe, athe EPP e its'epahalletseng nako ea litoeba tsa VTA DA ea litoeba tsa lithethefatsi-naïve e its'etleha ho li-isoforms tsa PKC tse tloaelehileng (Luu le Malenka, 2008). Maemong a nicotine the VTA synaptic potentiation e hloka hore ho nkoe ha li-neurons tsa DA tse pakelitsoeng ke somatodendritic α4β2 nicotinic acetylcholine receptors (nAChRs) (Mao et al., 2011). Keketseho e susumetsoang ke Nicotine ea ho lokolloa ha glynamate ea presynaptic le eona e kenya letsoho ho kenyellelitsoeng polasetiki ena ea synaptic, mohlomong ka ts'ebetso e eketsehileng ea li-receptors tsa NMDA (Mao et al., 2011).

Haholo-holo ho tsebahala ka mekhoa e tlisoang ke polokelo ea koae e tsoakiloeng ke koae ho feta polasetiki e bakoang ke lithethefatsi tse ling tsa tlhekefetso. Ts'ebeliso ea cocoaine ho lisepa tsa midbrain e baka phepelo ea phetisetso ea li-receptor tsa NMDA kamora metsotso e seng mekae mme e rehelloa hore e kenngoe NR2B-NMDAR e nang le li-synapses ka mochine o hlokang ho kengoa tšebetsong ha D.₅ li-receptors le syntheine e ncha ea protheine (Schilstrom et al., 2006; Argilli et al., 2008). Orexin A e boetse e bontšitsoe hore e hlokahala bakeng sa ho kenngoa ka mokhoa o potlakileng oa koae oa cocaine oa li-receptor tse nang le NR2B le li-receptor tse eketsehileng tsa AMPA / NMDA; ho latela orexin₁ SB334867 ea receptor e bontšitsoe ho thibela nts'etsopele ea sensitization ho cocaine (Borgland et al., 2006). Ntle le liphetoho tsa polelo ea subunit ea NMDA, maemo a ntseng a eketseha a GluR1-e nang le (GluR2-ea haelloang) li-receptor tsa AMPA ho li-synapses li hlokometsoe hang ha 3 h ka mor'a ho phatloha ha koae.e (Argilli et al., 2008). Tlhokomeliso ena e kopantsoeng le bopaki bo bong ba morao-rao e lebisitse ho tšibollo ea maikutlo ea hore ho kenyelletsoa ha li-receptors tse sa sebetseng tse phahameng tsa GluR2 ho kenya letsoho ho hlahiseng phello e kopantsoeng ea cocaine e kenyellelitsoeng ho cocaine e hlahisitsoeng ho VTA (Dong et al., 2004; Bellone le Luscher, 2006; Mameli et al., 2007;; Brown et al., 2010; Mameli et al., 2011), bakeng sa litlhahlobo bona (Kauer le Malenka, 2007; Wolf le Tseng, 2012). Ho kenyelletsoa hona hoa li-receptor tsa GPAR2 tse haelloang ke AMPA ho latela phetisetso ea li-receptor tsa NMDA ho li-neuron tsa VTA kaha e le sieo ka litoeba tse haellang li-receptor tsa NMDA tse sebetsang ho li-neurons tsa DA (Engblom et al., 2008; Mameli et al., 2009). Kensertion ea li-receptor tsa GluR2 tse haellang tsa AMPA li bohlokoa hobane li na le thepa e ikhethang; li na le calcium e lekaneng, 'me li na le boits'oaro bo boholo bo fetang bo le bong ho feta li-receptor tse nang le GluR2, ka hona li na le matla a maholo a ho fetola phetiso ea synaptic (Isaka et al., 2007). Kahoo, ho kenngoa ha li-receptor tsa GPAR2 tse se nang VPA ho emela mokhoa o ka etsahalang oo lithethefatsi tsa tlhekefetso li ka tiisang liphetoho tsa polasetiki tse tlasa methati ea pele ea ts'ebeliso ea lithethefatsi..

Ho kenngoa ha li-receptor tsa GPAR2 tse se nang VPA ho li-synapses tse thabisang tsa VTA hona joale ho bontšitsoe hore ho etsahala ka lebaka la tsamaiso ea lithethefatsi tse tsoang lihlopheng tse ngata tse kang nicotine le morphine hammoho le ts'ebetsong ea optogenetic ea ts'ebetso ea li-neurons tsa DA VTA (Brown et al., 2010). Tea hae e lebisitse ho tlhahiso ea hore ho kenyelletsa li-receptor tse haelloang ke calcium GluR2-e se nang mohloli oa AMPA ho emela mochini o ka sebelisang lithethefatsi tsa VTA tse se nang lithethefatsi.Brown et al., 2010), leha ho le joalo, lintlha tsa amphetamine ha li hlile ha li tsamaisane le khopolo-taba ena (Faleiro et al., 2004). Ho feta moo, ha li-receptors tsa AMPA tse se nang GluR2 tse ntseng li haella li ntse li bokellana kahare, 'me ka hona li etsa lintho tse nyane haholo ho + 40 mV, ho kenyelletsoa ha eona feela ho ke ke ha hlalosa keketseho e bakoang ke lithethefatsi tekanyong ea AMPA / NMDA. Phuputso ea morao-rao e ileng ea lekanya likarabo tsa unapticic tse kopaneng tse hlahisitsoeng ke mohloli oa tikoloho ea glutamate ea fumanehang haholo (setšoantšo sa lifoto tse peli tsa "glutamate") se bonts'itse, ntle le ho ama li-EPSC tsa AMPA, ho pepesoa ha koae ho boetse ho fokotsehile ka li-EPSC tse sa kopaneng tsa NMDA (Mameli et al., 2011), ka hona ho fana ka mochine o ka khonehang oo litekanyetso tsa AMPA / NMDA li ka eketsoang boemong bona (ka ho theola mokokotlo oa keketseho). Sena se sa ntse se lokela ho hlahlojoa le lithethefatsi tse ling tsa tlhekefetso.

Phapanyetsano e entsoeng ke lithethefatsi ea GluR2-e nang le li-receptor tse se nang AMlux2 e haellang e ka khutlisoa ka ts'ebetso ea li-receptor tsa mGluR1 ho VTA (Bellone le Luscher, 2006; Mameli et al., 2007). Kahoo, mGluR1-Mediated exchange of AMPA receptors e fana ka mochine o ka hlalosang hore na hobaneng ts'ebetso e hlahisoang ke lithethefatsi ea li-synapses tsa VTA e le ea nakoana ka tlhaho, e sa feleng matsatsi a 5 empa eseng matsatsi a 10 (Ungless et al., 2001; Mameli et al., 2007). Ehlile, haeba ts'ebetso ea mGluR1 ho VTA e fokotsoa 24 h pele ho tsamaiso ea koae joale ho ts'oaroa ha cocaine e kenelletseng kahare ho phehella ho feta matsatsi a 7 (Mameli et al., 2007, 2009). Kahoo, tlhaloso e le 'ngoe ea hore na ke hobaneng ha matlafatso ea cocaine-evoke synaptic e phehella ho VTA kamora ho itaola ha koae (ho fapana le tsamaiso e seng ea khang) e kanna ea ba hore taolo ea koae e tlisa khatello ea maikutlo ea mGluR1 ho supa ho VTA.

Drug-evoked synaptic plasticity at inhibitory synapses ho VTA

Excitatory synapses ha se mofuta o le mong feela oa synapse ho li-neurons tsa VTA DA tse anngoeng ke taolo e se nang khang ea lithethefatsi tsa tlhekefetso. Inhibitory synapses ho VTA le eona e na le karolo ea bohlokoa ho laoleng sekhahla sa ho thunya ha li-neuron tsa DA, ka hona polasetiki ho GABAergic synapses e na le matla a ho susumetsa phetiso ea DA ka tsela e makatsang. Ehlile, koae, morphine le ethanol kaofela li ka susumetsa polasetiki ea inhibitory ea synaptic ho VTA (Melis et al., 2002; Liu et al., 2005; Nugent et al., 2007). Ho pepesetsoa koae khafetsa Ka vivo bakeng sa matsatsi a 5-7 a baka phokotso ea maqhubu a maqhubu a GABA-Mediated synaptic, ka hona ho nolofalletsa ho kenella kahare ho LTP liseleng tsa VTA ka ho fokotsa matla a thibelo ea GABAergic (Liu et al., 2005). Boithuto bo latelang bo senola mochine oa thibelo ena ho ba mochini o itšetlehileng ka endocannabinoid LTD ho GABAergic synapses ho kenyelletsa ts'ebetso ea ERK1 / 2 (Pan et al., 2008, 2011). GABA_A receptor synapses ho VTA dopamine neurons le tsona li bonts'a matla a ts'ehetsoang ke NMDA e ts'ehehileng (e bitsoang LTP)_GABA) ha a arabela khahlolong e phahameng ea maqhubu a matla (Nugent et al., 2007). LTP ena_GABA ha a eo ka hara li-VTA tsa 2 le / kapa 24 h kamora Ka vivo Tsamaiso ea morphine, nikotini, cocaine kapa ethanol (Nugent et al., 2007; Guan le Ye, 2010; Niehaus et al., 2010). Tabeng ea ethanol thibelo ea LTP_GABA e kenella pakeng tsa μ-opioid receptor (Guan le Ye, 2010) Hammoho le ts'ebeliso ea synaptic ho li-synapses tsa thabo, tahlehelo ena ea PDP_GABA e lokela ho eketsa ho thunya ha li-neuron tsa VTA DA kamora ho pepesetsoa ha lithethefatsi.

Ho fetisoa ha Slow GABA le hona ha morao tjena ho bonts'itsoe ho ama lithethefatsi tsa tlhekefetso. Kahoo tekanyetso e le 'ngoe ea methamphetamine kapa cocaine e lekane ho fokolisa bokhoni ba GABA_B li-receptors ho laola li-neuron tsa VTA GABA ho thunya ha li lekantsoe Ex vivo 24 h hamorao (Padgett et al., 2012). Tahlehelo ea methamphetamine e bakang tahlehelo ea lithibelo tse liehang ho liehisa tsa inhibitory postsynaptic (IPSC) e hlaha ka lebaka la phokotso ea GABA_B li-protein tsa "receptor-G protein" tse kopantsoeng le methapo ea potasiamo ea potasiamo (GIRK), ka lebaka la liphetoho lipapatsong tsa liprotheine, 'me li tsamaisana le ho fokotseha ho hoholo hoa kutloelo-pele ea "presynaptic GABA"_B li-receptors ho GABA li-neurons tsa VTA. Ho fapana le litšusumetso tse tlisoang ke lithethefatsi ho GABA_A e lumellana le khatello ena ea maikutlo ea GABA_BR-GIRK signaling e phehella matsatsi kamora ho ente (Padgett et al., 2012).

Litekanyetso tsa boitšoaro mabapi le tšusumetso e bakoang ke lithethefatsi liseleng tsa VTA DA

Joalokaha ho boletsoe pejana phello ea taolo ea lithethefatsi tse se nang khang ka polasetiki ea synaptic ho li-neurons tsa VTA DA e hlalosoa butle-butle, e tšoarella bonyane 5 empa e le ka tlase ho matsatsi a 10 mme e bontšitsoe hore e lumellana hantle le nts'etsopele ea pele ea maikutlo a boits'oaro empa eseng ka polelo ea eona. (Ungless et al., 2001; Saal et al., 2003; Borgland et al., 2004). Ho ts'ehetsa maikutlo a hore tšusumetso ea motsoako oa VTA e emisitsoeng ke lithethefatsi e emela ho kenella ha maikutlo a boitšoaro, taolo ea intra-VTA ea bahanyetsi ba glutamate e fokotsa, 'me melaoana ea up-regation ea GluR1 e ntlafatsang ka bongata e ntlafatsa thepa ea litheko tsa locomotor (Carlezon et al., 1997; Carlezon le Nestler, 2002). Bopaki bo matla ba ho nka karolo ha NR2A- le B e nang le NMDA receptor ho fanoa ke tlhokomeliso ea hore inhibition ea pharmacological ea e ka ba e thibela bobeli nts'etsopele ea maikutlo le keketseho e amanang le cocaine e bakoang ke litekanyetso tsa AMPA / NMDA (Schumann et al., 2009). Leha ho le joalo, litoeba tse nang le morero o tlositsoeng oa NR1 kapa GluR1 (e khethiloeng ho midbrain DA neurons) kapa ho tlosoa ha GluR1 lefatšeng ka bophara e bonts'a kutloisiso e ntle ea boits'oaro mme leha ho le joalo e bonts'a maqhubu a amohelang a AMPA a receptor ka mor'a kalafo ea koae (Dong et al., 2004; Engblom et al., 2008). Twist e ekelitsoeng e fanoa ke tlhokomeliso ea hore CPP le maemo a mekhoa ea locomotor ha a eo ho litoeba tsa GluR1 Knoutout (Dong et al., 2004) le ho timela ha cocaine CPP ha e eo ho litoeba ka ho tlosoa ha GluR1 e lebisitsoeng ho li-neuron tsa methapo ea DA (Engblom et al., 2008), athe ho NR1 ho koeteloa hoa litoeba tsa cocaine CPP le polelo ea boits'oaro bo botle bo ntlafalitsoe (Engblom et al., 2008; Zweifel et al., 2008). Ka hona, leha e le ka lebaka la puseletso e ka bang teng ea nts'etsopele ho litoeba tsa phetoho le / kapa ho ka hlakolwa ho sa phethahalang, ho ka etsahala hore lits'ebetso tsa neural tse tsamaisang tšusumetso ea ts'oaetso ea lithethefatsi tsa methapo ea DA le maikutlo a boitšoaro li sa aroloe. Sebakeng seo ho kanna ha etsahala hore ebe litheolelo tsa VTA synapses li ka tlatsetsa ho hlahiseng tšusumetso ea ts'usumetso ho litheko tse amanang le lithethefatsi.

Ho lekanya liphetoho tse tlisoang ke taolo ea lithethefatsi tse se nang khang ho lekantsoe mabapi le ho tsebisa ka lefu leo ​​motho a lemalloang ka lona. Tse amanang haholo le boemo ba motho ke lithuto moo liphetoho lipakeng tsa polasetiki ea synaptic li lekantsoeng ho latela ts'ebetso e amanang le lithethefatsi mohlala, ts'ebetso ea boits'ebetso. Ntlheng ena, matlafatso ea synaptic ea lisele tsa VTA tse khothatsoang ke boits'oaro ba koae e ntse e phehella, e sa feleng likhoeling tsa 3 ebile e bontšoa e hanela koetliso ea ho timela (Chen et al., 2008). Kahoo, leha ho ne ho reriloe pele hore ke ketsahalo ea nakoana, ho bonahala eka polasetiki e hlahisitsoeng ke lithethefatsi ho VTA e na le bokhoni ba ho phela halelele, e bonts'a hore mokhoa oa tsamaiso (contingent le o se nang khang) ke qeto e hlakileng ea ho phela halelele ho feta . Sena se ts'ehetsoa ke ho bona hore taolo ea jekoe thutong ena ha e bontše keketseho e ts'oanang ea karo-karolelano ea AMPA / NMDA; Ho fana ka maikutlo ke thuto ea mokhatlo oa "cue-moputso" kapa "sephetho sa sephetho" se khothalletsang polasetiki. Ho fapana le moo, ho itlhomme lijo kapa ho ikakhela ka tlas'a li-paramente tse tšoanang ho hlahisa keketseho ea tekanyo ea AMPA / NMDA e ntseng e phehella 7 empa eseng matsatsi a 21 hore e se ke ea hlola e eba teng, e ka ba nakoana ha e bapisoa le e hlahisitsoeng ke cocaine (Chen et al., 2008). Ho haella ha phepelo ea polasetiki e hlahisoang ke lijo ho bonts'a hore phetoho ea matla a kopantsoeng ke cocaine ha se sesupo sa neural feela sa ts'ebetso ea ho ithuta e fanoang ke "cueine" ea ho ithuta e kentseng tšebetso ea paradigm e sebetsang. ka bobeli, e na le ts'usumetso e ikhethileng ea lithethefatsi e ka emisang ho matlafatsoa hoa likamano tsa litokelo tsa lithethefatsi. Joalokaha ho boletsoe pejana, likhakanyo tsa moputso oa likhakanyo tsa boithabiso le tsona li fumanoe li baka keketseho ea tekanyo ea AMPA / NMDA ho VTA, leha e sa phehelle, e ts'ehetsa karolo ea ho fetoloa hoa ts'ebetso ea synaptic e thabisang ho ithuteng moputso (Stuber et al., 2008).

Ho khahlisang, boholo ba keketseho ea karo-karolelano ea AMPA / NMDA bo ts'oana ho sa tsotelehe palo ea liente (single vs. multiple), protocol ea tsamaiso (contingent vs. e se nang khang), le bolelele ba phihlello (phihlello e lekanyelitsoeng e nang le phihlello e atolositsoeng) (Borgland et al., 2004; Chen et al., 2008; Mameli et al., 2009). Sena se bonts'a hore keketseho ea tekanyo ea AMPA / NMDA e hlokometsoeng liseleng tsa VTA DA e kanna ea ba ketsahalo e lumellehang, mohlomong ho supa "salience" ho fapana le ho emela ho qalisoa ha neuropathology e ka tlase e neng e ka eketseha ka mokhoa o hlakileng.

Polasetiki e hlahisitsoeng ke lithethefatsi maemong a hlasimollang a NAc

Ho fapana le VTA ente e le 'ngoe ea koae ha e bake keketseho ea matla a synaptic ho NAc ha e lekantsoe 24 h hamorao (Thomas et al., 2001; Kourrich et al., 2007). Tlhahlobo ena le nako ea boipiletso tse latelang ka taolo e pheta-phetoang le ho ntša chelete demonstrates hore polasetiki e susumetsoang ke lithethefatsi ho NAc e fapane hole le e boneng ho VTA. Ka 'nete, ha ho kenngoa liente ka makhetlo a mangata tsa koae (e le ho etsa hore maikutlo a boitšoaro a fokotsehe), ho fokotseha ha tekanyo ea AMPA / NMDA ho bonoa ho li-synapses tsa NAc shell ha li lekantsoe 24 h kamora taolo ea ho qetelan (Kourrich et al., 2007). Ho sithabela hona ha synaptic ho tsoa cocaine e phetoang hangata ho bonahala ho hokahane le polasetiki ho VTA; holim 'a khethollo e khethiloeng ea ts'ebetso ea mGluR1 ho VTA feela ente e le' ngoe ea cocaine e hlokahalang ho baka khatello e tšoanang ea NAc synapses (Mameli et al., 2009). Teena bangoli ba thuto ena ba tiisa hore boithabiso bo ntlafalitsoeng ba merero ea VTA bo ka tsamaisa tokollo e kopanetsoeng ea DA le glutamate ho NAc ka tokollo e ntlafalitsoeng ea DA. Sena se ka fetola mokhoa oa ho kenyelletsa polasetiki ea lehae ho NAc ka ho ama thabo ea potoloho kapa ka ho hokahanya lits'ebetso tse tšoaeang tse akaretsang (Mameli et al., 2009).

Bohlokoa ba tšebetso ba khatello ea maikutlo ea li-synces tsa NAc nakong ea ho khaotsa ho matla ha bo hlake mohatheng ona. Tlhaloso e le 'ngoe e kanna ea ba hore khatello ea maikutlo ea NAc medium spiny neurons (MSNs) e fokotsa karabelo ea bona mohopolong oa moputso oa tlhaho, ka hona ba kenya letsoho ho anhedonia e neng e le teng nakong ea ho tlohela ka matla. Hape ho ka etsahala hore ebe ho fokotseha ha tekanyo ea AMPA / NMDA ho bakoa ke ho kenyelletsoa ha li-membrane tse nang le li-NR2B tse nang le li-NMDA recensor (ka hona ho eketsa mokhahlelo oa karo-karolelano) ha li-synapses tse ncha tse khutsitseng li fumaneha ho hlaha ka mokokotlo oa NAc ka lebaka la ho peperana le koae. (Huang et al., 2009). Li-synapses tse khutsitseng tsa glutamatergic, tse hlahisang maqhubu a sebetsang a NMDA receptor-mediated ha ho na melapo ea li-receptor-mediated ea AMPA, ho nahanoa hore li na le bokhoni bo eketsehileng ba ho matlafatsoa ke phetiso ea synaptic (Isaac et al., 1995). Hang ha e hlahisitsoe, li-synapses tsena tse khutsitseng li ka nolofalletsa ho haptjoa ha li-receptor tsa AMPA ka ho etsa joalo ho ntlafatsa phetiso ea synaptic e thabisang. Sena se fana ka mochine o ka khonehang oa ho hlalosa ho eketseha ha li-receptor tsa AMPA le karo-karolelano ea AMPAR / NMDAR e hlokometsoeng ho NAc nakong ea ho ikhula ho sa feleng (Boudreau le Wolf, 2005; Boudreau et al., 2007; Kourrich et al., 2007; Conrad et al., 2008). Li-receptors tsa NR2B tse nang le NMDA ho NAc le tsona li ka ba karolo ea ho theha mekhatlo e amanang le lithethefatsi joalo ka haSRNA ho kokobela setsing sena se thibela morphine CPP ka litoeba empa eseng boits'oaro ba boits'oaro (Kao et al., 2011).

Ho fapana le k'hok'heine, mofuta o pheta-phetoang oa ethanol o hlahang khafetsa o baka tšusumetso ea li-synapses ha a arabela protocol ea pele ea ts'usumetso ea LTD ha a lekanya 24 h kamora ho pepesetsoa ha ho qetela (Jeanes et al., 2011). Ts'ebetso ena e itšetlehileng ka NMDA e lieha ho latela ha 48 h ea ho e tlosa e felisitse 'me ha ho na mothehi oa LTP kapa LTD. (Jeanes et al., 2011). Bangoli ba toloka liphetoho tse matla joalo ka polokelong ea NAc e le sesupo sa bohlokoa ba ts'ebetso ena ho li-neuroadaptations tsa ethanol. Ntle le moo, ho fapana le psychostimulants, ethanol e ka sebetsa ho li-receptor tsa NMDA ka hona e na le bokhoni ba ho susumetsa ka ho toba lets'oao la glutamatergic.

Tekanyo ea Synaptic e hlokometsoeng ho NAc kamora nako ea ho tlohela

Ho fapana le khatello ea maikutlo e ileng ea bonoa nakong ea ho khaoha ka matla, ts'ebetso ea li-synapses tsa nahano ea NAc e bonoa kamora matsatsi a 10-14 a ho tlohela ho tsoa ho pheta-phetoa ea koae kapa a morphine (Kourrich et al., 2007;; Wu et al., 2012). Ho feta moo, kamora matsatsi a 7 a tlohe pusong e le 'ngoe ea cocaine, keketseho ea maqhubu a li-mEPSC hammoho le tahlehelo ea LTP e susumetsoang ke ts'usumetso e phahameng ea maqhubu (HFS) e fumaneha methapong ea methapo ea mantlha ea mokokotlo le ea Noc e hlalosang dopamine D₁ receptor (Pascoli et al., 2012). Tphetoho ea hae matleng a ho susumetsa polasetiki ea synaptic ho thoe ke metaplasticity. Metaplasticity e hlahisang koae e boetse e bonoa ka mor'a ho khaotsa ho itaola. Ka hona, likhoto tse nang le koae e ikemetseng e lateloang ke libeke tsa 3 tsa ho fela kapa ho ila li bontša letšoao Ka vivo khaello ea bokhoni ba ho nts'etsapele LTP mantlha a NAc kamora ho hlohlelletsoa ha PFC. Peho ena e ne e tsamaisana le phetoho ea letsoho le letšehali mokokotlong oa tlhahiso ea tlhahiso e bonts'ang matla a ho fetoha ha maemo a fEPSP (Moussawi et al., 2009). Potentiation ea NAc synapses e boetse e bonoa ka mokhoa oa ho eketseha ha maqhubu a kopanetsoeng a AMPA ka mor'a nako e telele ea ho itima lijo ka mor'a ho itaola (Conrad et al., 2008). Ka kopanelo, lintlha tsena li fana ka maikutlo a hore matla a kopantsoeng ho NAc a nts'etsapele joalo ka ts'ebetso ea nako ea ho tlosoa, kapa joalo ka ts'ebetso ea nako ho tloha ts'ebetsong ea pele ea cocaine. Phuputso ea morao-rao e tšehetsa toloko ea morao-rao ha keketseho e ts'oanang khafetsa ea li-MEPSC e hlokometsoe ho D₁ li-receptor-expression tse hlalosang li-MSN ka litoeba le hoja li le sieo kapa hona ho ba teng ha nako ea ho tlohela e le ho latela taolo e pheta-pheto ea koae (Dobi et al., 2011). Ka hona, ho bonahala liketsahalo tse lebisang ho phetoho ea phetiso ea glutamatergic ho NAc e nka nako ho nts'etsapele.

Tlatsetso ea li-receptor tse ikhethang tsa AMPA e ipeha ka phetoho ena e fapana ho latela sethala sa ho tlohela le mokhoa oa tsamaiso; Matsatsi a 10-21 a ho tlohela ho tsoa tsamaisong ea GluR2 e nang le li-receptors tsa AMPA ho bonahala a ikarabella bakeng sa liphetoho phetisong ea AMPA (Boudreau le Wolf, 2005; Boudreau et al., 2007; Kourrich et al., 2007; Ferrario et al., 2010) athe matsatsi a fetang 21 a GluR2-e se nang li-AMPA receptors a eketsoa ka li-synapses. Ho fumaneha hoa morao ho bonahala ho le joalo feela ha koae e sebelisoa ka boeona (Conrad et al., 2008; McCutcheon et al., 2011), leha ho le joalo bona (Mameli et al., 2009). Ka lebaka la ts'ebetso e ntseng e eketseha ea li-receptor tsa AMPA tse se nang GluR2 e kanna ea ba hore ho kenella ha bona ho etsahala ka lebaka la khatello ea maikutlo ea NAc synapses e bakoang ke ho itaola ha k'hok'heine, ka hona e baka ho eketseha ha karabelo ea MSN ho liphetho tse thabisang tse bakang ho batla koae nakong e tlang. Kannete, ho thibela li-receptor tse se nang matla tsa AMPA tsa GluR2 ho NAc ho thibela polelo ea batho ba batlang koae ea cocaine e kentsoeng (Conrad et al., 2008), 'me ho batla k'hok'heine e susumetsoang ke AMPA kapa cocaine e boetse e thibetsoe ka liente tsa antisense oligonucleotides tsa GluR1 mRNA ho NAc (Ping et al., 2008).

Phephetso ea lithethefatsi kamora ho khaotsa e khutlisa matla a kopantsoeng le khatello ea maikutlo

Keketseho ea matla a synaptic le ponaletso ea kameho ea AMPA receptor e hlohlellelitsoeng ke cocaine ho NAc kamora ho khaotsa ho tsoa taolong e se nang khang e khutlisetsoa morao ho taolo ea liente tse ling hape tsa koae (koae-phephetso) (Thomas et al., 2001; Boudreau et al., 2007; Kourrich et al., 2007; Ferrario et al., 2010). Ka hona, khatello ea maikutlo ea synaptic e boetse e bonoa khetla ea NAc ha e lekantsoe 24 h ka mor'a ente ena ea cocaine (Thomas et al., 2001), leha ho le joalo bona (Pascoli et al., 2012). Ka boitsoaro sena se bonahala se lumellana le polelo ea maikutlo, 'me maemong a amphetamine bonyane, ho bontšitsoe hore ke ba-strathrin-mediated le ba itšetlehileng ka li-endocytosis tse itšetlehileng ka GluR2-postocytosis ea li-postynaptic AMPA receptors (Brebner et al., 2005). Ho fokotseha ha polelo ea holimo ea li-receptor tsa AMPA tse latelang phephetso ea koae ho lieha ha nako ea matsatsi a 7 e bua ka maemo a ka bapisoang le likhoto tse sa tsejoeng tsa cocaine tse entsoeng ke (Cerrario et al., 2010). Ha ho le joalo, ho bonahala eka nalane ea ho pepesetsoa koae le ho itlhahisa ho ka fetola habonolo tataiso ea polokeho ea synaptic ho NAc.

Khokahano e tobileng e sa tsoa etsoa pakeng tsa bokhoni ba li-cortico-accumbal synapses ho D₁ lisele tse amohelang tse latelang li-7 tsa ho tlosoa ha matsatsi a XNUMX le polelo ea maikutlo. Joalokaha ho se ho boletsoe pejana, kamora ho qeta matsatsi a 7 ho tsoa ho tsamaiso e le 'ngoe ea cocaine, li-synaps tsena li fumanoa li le matla kahare le khetla (joalo ka ha ho lekantsoe ke keketseho ea matla a MEPSC) mme LTP e hlahisitsoeng ke HFS e fokotsehile. Ho ne ho sa fumanehe li-synapses ho D₂ lisele tse amohelang botle (Pascoli et al., 2012). Ha e fetoha optogenetically Ka vivo ka protocol e tsejoang ho hohela USB, cortico-accumbal synapses ho D₁Lisele tse ntle tsa -receptor tse bonts'itsoeng li fokotsa li-MEPSC mme polelo ea sensomization ea locomotor e ile ea thibeloa. Habohlokoa le ho feta, bokhoni ba HFS ba ho qobella LTP bo ile ba khutlisetsoa ho li-neuron tsena (Pascoli et al., 2012), ka hona ho bonts'a khokahano e tobileng lipakeng tsa phetoho ena e ikhethileng ea li-synaptic ho li-capsico-accumbal synapses le polelo ea maikutlo ho cocaine.

Lintho tse ngotsoeng

Mabaka a ho ngoloa ke liprotheine tse tlatsanang le tatellano e ikhethang ea DNA ho tsamaisa phetisetso ea liphatsa tsa lefutso ka ho sebelisana le RNA polymerase II tata (Mitchell le Tjian, 1989). Lintho tse hatisitsoeng li ka hoheleha kapa tsa hatisoa ka lebaka la ts'usumetso ea tikoloho, tsa baka phetoho lipuong tsa gene mme qetellong ea tšebetso ea methapo. Lintlha tse 'maloa tsa mongolo li fumanoe bakeng sa karolo ea bona e ka bang tlatsetsong ea bokhoba hobane polelo le ts'ebetso ea bona e laoloa tseleng ea mesocorticolimbic ha ba pepesehetse lithethefatsi tsa tlhekefetso. ΔFosB ke e 'ngoe ea liphatlalatso tse joalo tse fumaneng tlhokomelo e khethehileng ka lebaka la botsitso ba eona bo sa tloaelehang. ΔFosB ke mofuta oa mefuta-futa oa mofuta oa FosB, 'me e arolelana thuto ea lapeng le litho tse ling tsa lelapa la Fos ho kenyelletsa c-Fos, FosB, Fra1, le Fra2 eo li-heterodimerise tsohle li nang le liprotheine tsa lelapa tsa Jun (c-Jun, JunB, kapa JunD) lintlha tse sebetsang tsa protheine-1 (AP-1) (Morgan le Curran, 1995). Litho tsena tse ling tsa lelapa la Fos li kenella ka potlako ho striatum ho sebetsana le ts'ebetso e matla ea li-psychostimulants, leha ho le joalo ka lebaka la ho tsitsipana ha eona polelo ena e tsamaea butle mme e khutlela maemong a basal ka mor'a lihora tse 'maloa (Graybiel et al., 1990; Mocha et al., 1991; Tšepo et al., 1992). Ka lehlakoreng le leng, ΔFosB e ipokella setulong se latelang taolo ea lithethefatsi tse sa foleng, 'me polelo ea eona e phehella libeke tse' maloa ka mor'a ts'ebeliso ea lithethefatsi tsa ho qetela (Hope et al., 1994; Nyeoe le al., 1995; Nyeoe le Nestler, 1996; Pich et al., 1997; Muller le Unterwald, 2005; McDaid et al., 2006). Lintlha tse tsoang litekong tsa boits'oaro li ts'ehetsa karolo ea ΔFosB liphellong tse ling tse sa feleng tse tlisoang ke lithethefatsi tsa tlhekefetso. Ho hlahisoa haholo ha ΔFosB ho striatum ho hlahisa likarabo tse eketsehileng tsa locomotor ho cocaine e bohloko le e sa foleng, mme e eketsa thepa ea matlafatso ea cocaine ka bobeli le morphine (Kelz et al., 1999; Colby et al., 2003; Zachariou et al., 2006), athe inhibition ea ΔFosB e hlahisa litlamorao tse fapaneng tsa boitšoaro (Peakman et al., 2003). Ka lebaka la bokhoni ba eona ba ho eketsa matla a susumetsang a lithethefatsi tsa tlhekefetso, ntho ena e ngolisitsoeng e hlahisitsoe ho emela "phetoho ea limolek'hule" e thusang ts'ebetso ea phetoho ho bokhoba ba tahi (Nestler, 2008).

protheine e kopanyang karohano ea cAMP (CREB) ke ntlha e 'ngoe e' nileng ea lebisa ho lipatlisiso tse ngata ka lebaka la karolo eo e e fuoeng mabapi le polasetiki e kentsoeng lithethefatsi (McPherson le Lawrence, 2007). CREB e hlahisoa ka mokhoa o hlakileng ka bokong, hape e ka ts'ebetsoa ke mekhoa e mengata ea maqhubu a ho bonts'a litsebo e fihlang sehlohlolong sa phosphorylation ho serine 133 (Mayr le Montminy, 2001). Phosphorylated CREB (pCREB) e phahamisa ho bokella protheine e tlamang CREB (CBP) e thusang ho fetisoa ha mefuta e fapaneng ea molapo o phoroselang (Arias et al., 1994). pCREB e kenella ka potlako ho striatum holim'a ho pepesetsoa li-psychostimulants (Konradi et al., 1994; Kano et al., 1995; Walters le Blendy, 2001; Choe et al., 2002) 'me sena se thehiloe ho bontša mokhoa oa homeostatic o hananang le karabelo ea boitšoaro ho lithethefatsi tsa tlhekefetso (McClung le Nestler, 2003; Dong et al., 2006). Tumellanong le sena, ho feta ha CREB khetla ea NAc ho fokotsa thepa e khahlisang ea koae ka mokhoa o khethiloeng (CPP) paradigm, athe lehlakoreng le leng le bonoa ka thibelo ea CREB sebakeng sena (Carlezon et al., 1998; Pliakas et al., 2001). Ka mokhoa o ts'oanang ho ts'oaroa hoa liphatsa tsa lefutso kapa thibelo ea CREB ka har'a dorsal striatum confers sensitivity to the locomotor activating thepa ea psychostimulants, e eketsa ts'ehetso ho hypothesis ena (Fasano et al., 2009; Madsen et al., 2012).

Le ha data e tsoang litekong tsa CPP e ts'ehetsa mohopolo oa CREB ho sebetsa e le modulasetara ea moputso o fosahetseng oa lithethefatsi, bonyane mabapi le cocaine, sena e kanna ea ba ho fetisa maikutlo. Liphuputso tse ngata tse sebelisang mekhoa e fapaneng ho fetola tšebetso ea CREB khetla ea NAc li senotse hore thibelo ea CREB e fokotsa matlafatso ea k'hok'heine ea k'hok'heine papaling ea taolo ea boikhethelo (Choi et al., 2006; Green et al., 2010; Larson et al., 2011), athe matlafatso a koae a ntlafatsoa ke CREB overexpression seterekeng sena (Larson et al., 2011). Liphetho tsena tse fapaneng li kanna tsa bakoa ke phapang ea mantlha lipakeng tsa lipallo tsa boemo ba sebopeho le lipallo tsa Pavlovian hammoho le boithatelo vs. tsamaiso ea lithethefatsi e sa ikemiseng. CPP e kenyelletsa mekhoa ea ho ithuta e amanang, 'me ho nahanoa hore ke tekanyetso e sa tobang ea thepa ea hedonic ho e-na le matlafatso ea lithethefatsi. ka bobeli (Bardo le Bevins, 2000). Ts'ebetso ea boithatelo ba boithaopo e ka susumetsoa ke lintlha tse 'maloa tsa maikutlo, le bokhoni ba ts'ebetso ea CREB ho NAc ho fokotsa likarabo ho susumetso ea kelello (Barrot et al., 2002) le boitšoaro bo nyenyefatsang (Pliakas et al., 2001) e ka ba le tšusumetso e matla ea ho sebelisa lithethefatsi. Ho khahlisang ke hore ho tlosoa ha CREB ho tsoa ho PFC ho fella ka ho fokotseha hoa tšusumetso ea ho iketsetsa cocaine (McPherson et al., 2010), ho bonts'a hore phello ea ho thetsisa CREB holim'a boitšoaro le eona e fapana bakeng sa likarolo tse fapaneng tsa boko. Mohlomong sena ha se makatse ha ho thoe transcriptome ea CREB e fapana haholo ho latela mofuta oa sele (Cha-Molstad et al., 2004) ka hona ho tla ba bohlokoa ho khetholla liphetoho liphatlalatsong tsa gene tse hlahang tlase-molomong oa CREB tse tlatsetsang ho phenotypes tsena. Ho thatafatsang lintho le ho feta ke ho bona hore CREB khetla ea NAc e bohlokoa ho CPP ea nicotine (Brunzell et al., 2009), ho fana ka maikutlo a hore mekhoa e tlisoang ke moputso oa nicotine e nang le maemo a fapaneng e fapana le ea koae ea koae le morphine, tseo ka bobeli li ntlafalitsoeng ke ts'ebetso ea CREB khetla ea NAc (Carlezon et al., 1998; Pliakas et al., 2001;; Barrot et al., 2002).

Mekhoa ea epigenetic

Epigenetics e na le litlhaloso tse ngata, empa ho neuroscience hangata e hlalosoa e le liphetoho liphatlalatsong tsa gene tse etsahalang ka ho feto-fetoha ha chromatin e sa tlisoang ke liphetoho ka tatellano ea motheo ea DNA (McQuown le Wood, 2010). Chromatin e hlalosa boemo ba DNA ha bo kentsoe kahare ho sele. Karolo ea mantlha e pheta-phetang ea chromatin ke nucleosome, e nang le lipara tsa motheo tsa 147 tsa DNA tse lohiloeng ka li-octamer tse entsoe ka lipara tsa li-histones tse 'ne tsa mantlha (H2A, H2B, H3, le H4) (Luger et al., 1997). Mohatla oa "amino terminal" oa li-histones tsena tsa mantlha o ka fetoloa ka mekhoa e mengata ea phetolo ea morao-rao ea phetolelo ho kenyelletsa acetylation, methylation, phosphorylation, ubiquitination le sumoylation (Berger, 2007). Ho eketsoa le ho tlosoa hoa lihlopha tsena tse sebetsang ho tsoa mehatong ea histone ho etsoa ke palo e kholo ea li-enzyme tse ntlafatsang tsa histone, ho kenyelletsa li-acetyltransferase, deacetylases, methyltransferases, demethylases, le kinases (Kouzarides, 2007). Liphetoho tsena tsa histone li sebeletsa ho bonts'a ho bokelloa ha lintlha tsa liprotheine le liprotheine tse ling tse kenyellelitsoeng ho molaoana oa ho ngola, le ho fetoha ha chromatin ho etsa hore DNA e fumanehe kapa e fumanehe hanyane mochineng o hatisang (Strahl le Allis, 2000; Kouzarides, 2007; Taverna et al., 2007). Mekhoa ea Epigenetic ka hona e emetse mokhoa oa bohlokoa oo ka oona tšusumetso ea tikoloho e ka laolang polelo ea liphatsa tsa lefutso le boitšoaro bo qetellang.

Haufinyane, ntlafatso ea chromatin e amoheloe e le mokhoa oa bohlokoa o fetotseng litheko tse susumetsoang ke lithethefatsi ho polasetiki le boits'oaro (Renthal le Nestler, 2008; Ebredy et al., 2010; McQuown le Wood, 2010; Maze le Nestler, 2011; Robison le Nestler, 2011). Bopaki ba pele ba sena bo tsoa litekong tsa Kumar le basebetsi mmoho le bona ba sebelisitseng chromatin immunoprecipitation (ChIP) ba bonts'a ho bonts'a hore phetoho ea cocaine induces histone ho baetsi ba khethehileng ba gene ho striatum (Kumar et al., 2005). Ka ho khetheha, taolo e matla ea cocaine e hlahisitse H4 hyperacetylation ea cFos papatso, athe tsamaiso e sa fetoheng e hlahisitse H3 hyperacetylation ea BDNF 'me Cdk5 babapatsi. Histone acetylation e kenyelletsa phetiso ea enzymatic ea sehlopha sa acetyl ho ea mohatleng oa N-terminal oa histone, o fokolisang tšebelisano ea motlakase pakeng tsa histone le DNA e lefisitsoeng hampe, e etsang hore e fihlellehe habonolo ho lisebelisoa tsa sengoloa (Loidl, 1994). Sena se tsamaisana le bokhoni ba koaeine ho eketsa polelo ea lintlha tsa tšibollo ea lelapa la Fos ka mokhoa o hlakileng (Graybiel et al., 1990; Mocha et al., 1991), athe BDNF le Cdk5 li qobelletsoa feela ho pepesoa nako e telele (Bibb et al., 2001; Grimm et al., 2003).

Histone hyperacetylated state e ka boela ea fumaneha ka liteko ke li-inhibitors tsa histone deacetylase (HDAC), 'me lithethefatsi tsena li sebelisitsoe ho hlahloba litlamorao tsa keketseho ea lefats'e ho histone acetylation holim'a likarabo tsa boitšoaro ho lithethefatsi tsa tlhekefetso. Tsamaiso ea tsamaiso ea HDAC inhibitors synergistically e eketsa hyperacetylation e bonoang ha e arabela cocaine ka har'a striatum (Kumar et al., 2005), mme sena se fana ka moputso oa tšebeliso ea koae ka koae le moputso oa koae (Kumar et al., 2005; Letsatsi et al., 2008; Sanchis-Segura et al., 2009). HDAC inhibition e ka eketsa sensitization ea locomotor ho ethanol le morphine, le ho tsamaisa morphine CPP (Sanchis-Segura et al., 2009), Leha ho le joalo, li-inhibitors tsa HDAC le tsona li fumanoe ho thibela nts'etsopele ea maikutlo le ho bonts'a morphine e le 'ngoe (Jing et al., 2011), le ho fokotsa ts'usumetso ea ho ikoetlisa koae (Romieu et al., 2008). Liphumano tsena tse fapaneng li ka bonts'a phapang liprothong tsa tsamaiso, 'me ka bohlokoa li bonts'a hore li-inhibitors tsa HDAC ha li khetholle karabelo ea boitšoaro ntle le tšebeliso litabeng maemong ohle.

Ka lebaka la phello ea bona e lumellang ho fetisoa ha liphatsa tsa lefutso, li-inhibitors tsa HDAC li kanna tsa nka bohato ho tsamaisa mefuta e meng ea ho ithuta (Bredy et al., 2007; Lattal et al., 2007). Haufinyane ho bonahetse hore taolo ea inhibitor ea HDAC kamora ho pepesetsoa tikoloho e neng e entsoe ka koae ka nako e telele e ka thusa ho felisoa ha CPP e kentsoeng koae, mme mohlomong sena se amana le ho eketseha ha histone H3 acetylation ho NAc (Malvaez et al., 2010). Ts'oaetso ea HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) ka kotloloho ho NAc nakong ea boemo ba boemo ba CPP e eketsa moputso oa cocaine e nang le maemo (Renthal et al., 2007), ho bonts'a hore thibelo ea HDAC tikolohong ena e ka tsamaisa ho ithuta ho amanang le moputso le thuto ea ho felisoa, ho latela moelelo oa lithethefatsi. Liteko tse ling li senoletse karolo ea HDAC5, le HDAC ea morao-rao e bontšitsoe haholo ho NAc phetolelong ea moputso oa koae. Tsamaiso ea cocoaine e eketsa ts'ebetso ea HDAC5 ka ho laola dephosphorylation ea eona le ho kenella ha nyutlelie ka morao ho moo, le dephosphorylation ea HDAC5 ho NAc e sitisa nts'etsopele ea CPP ea koae (Taniguchi et al., 2012). Ka mokhoa o ts'oanang, tšibollo e fetelletseng ea HDAC5 ho NAc nakong ea boemo ba boemo ba CPP e fumana moputso oa koae, mme ts'usumetso ena e khutlisoa ha ho hlahisoa mofuta oa phetoho oa HDAC5 ho NAc (Renthal et al., 2007). Ho ka etsahala hore HDAC5 e fana ka litlamorao tsena ka ho thibela sengoloa sa gene se kentsoeng lithethefatsi seo ka tloaelo se eketsang thepa ea moputso ea koae.

Tlhahlobo e pharalletseng ea liphetoho tsa chromatin tse etsahalang ho NAc ka lebaka la ho pepesetsoa ha koae li senoletse liphetoho tse ngata tsa chromatin libakeng tse ntlafatsang tsa mefuta ea liphatsa tsa lefutso tsa CREB le ΔFosB (Renthal et al., 2009). Tlhahlobo ena e boetse e senoletse ntlafatso ea li-Sirtuin tse peli, SIRT1 le SIRT2, e leng liprotheine tse nang le ts'ebetso ea HDAC hape li ka etsa liprotheine tse ling tsa cellular (Denu, 2005). Induction ea SIRT1 le SIRT2 e amahanngoa le ho eketseha hoa acetylation ea H3 le ho eketseha ha binding ea ΔFosB ho bahlahisi ba bona ba gene, ho fana ka maikutlo a hore ba fihlelletse liphofu tsa ΔFosB (Renthal et al., 2009). Molao-up oa SIRT1 le SIRT2 ho nahanoa hore o na le boitšoaro bo amanang; li-Sirtuins li fokotsa thabo ea NAc MSNs a vitro, le inhibition ea pharmacological ea sirtuins e fokotsa moputso oa koae, athe ts'ebetso ea bona e eketsa likarabelo tse khotsofatsang ho koaeine (Renthal et al., 2009).

Ntle le karolo e sebetsang ea li-HDAC, lithuto tsa liphatsa tsa lefutso li boetse li senotse karolo ea histone acetyltransferases (HATs) ho arabelang tse ling tsa likarabo tsa boitšoaro ho lithethefatsi tsa tlhekefetso. Ka mokhoa o arohanang mochine oa bohlokoahali oo CBP e khonang ho ntlafatsa phetisetso ea liphatsa tsa lefutso ka ts'ebetso ea eona ea HAT e kenelletseng (Bannister le Kouzarides, 1996), mme liphumano tsa morao-rao li beha ts'ebetso ea HAT ea CBP ho tse ling tsa liphetoho tsa epigenetic tse hlahisoang ke ho pepesetsoa hoa lithethefatsi. Ha a arabela cocaine e hlobaetsang, CBP e ngolisoa ho FosB papatso moo e acetylates histone H4 mme e eketsa polelo ea FosB (Levine et al., 2005). Ka litoeba tse fumanehang bakeng sa CBP, CBP e nyane e hiroa ho ea papatso e bakang ho fokotseha ha histone acetylation le polelo ea FosB. Sena se tsamaisana le ho bokellana ho fokolang ha ΔFosB ka har'a striatum, mme ha ho makatse hore lipontšo tsena tsa litoeba li fokotse maikutlo a ho arabela phepheng ea phephetso ea koae (Levine et al., 2005). Haufinyane tjena, ho sebelisoa sistimi ea ho kopanya lintho tsa cre-lox Malvaez le basebetsi mmoho le bona ba fuputse karolo ea tšebetso ea CBP e fumanehang ka kotloloho ho NAc holim'a mongolo le boitšoaro ba motsoako oa koae (Malvaez et al., 2011). Ho ile ha tlalehoa hore ho tlosoa hoa sepheo sa CBP ho NAc ho fokotsehile ha histone acetylation le polelo ea c-Fos, le ts'ebetso e senyehileng ea ts'ebetso ha e arabela cocaine e mpe le e sa foleng (Malvaez et al., 2011). Moputso oa cocaine o nang le maemo o bile o thibetsoe ho litoeba tsena, ho fana ka bopaki ba pele ba hore ts'ebetso ea CBP ho NAc e bohlokoa bakeng sa ho theha mehopolo e amanang le lithethefatsi (Malvaez et al., 2011).

Haufinyane, liteko tse tsoang labong ea Kandel li senotse hore mekhoa ea epigenetic e ka ts'ehetsa bokhoni ba nicotine ba ho sebetsa joalo ka "setlhare se kenang". Litoeba tse qhekelloang ka nako e telele ka nicotine pele ho pepeseha k'hok'heine li bonts'a matlafatso a locomotor sensitization le moputso oa cocaine ha o bapisoa le litoeba tsa nicotine naive (Levine et al., 2011). Ntle le moo, ho hlohlona ha nikotine ho bakile khatello ea maikutlo e matlafatsang ea koae ea koae ka ts'ebeliso ea "cocaine" maemong a monate a NAc, phello e neng e sa bonoe ke nicotine feela. Tlhahlobo ea liphetoho tsa histone tse hlahisitsoeng ke ho pepesetsoa ha nicotine ea letsatsi la 7 e senotse ho eketseha ha H3 le H4 acetylation ho FosB morekisi ho striatum, phello e neng e sa phatlalatsoe ho latela taolo ea matsatsi a 7 ea k'hok'heine. Mosebetsi oa HDAC o ile oa fokotsoa ka har'a litoeba tse tšoaroang ke nicotine, empa ha oa fetoha ka litoeba tse tšoaroang ka cocaine. Ho tsotehang ke hore ho tšeloa ha inhibitor ea HDAC ka kotloloho ho NAc ho ile ha khona ho etsisa litlamorao tsa ts'ebeliso ea meriana ea "nicotine" litlamorao tse ka bang teng ka har'a cocaine. Ha ho le e 'ngoe ea liphetoho tsena e ileng ea bonoa ha litoeba li ne li phekoloa ka cocaine pele ho nicotine, e tiisa bonnete ba litlamorao tsena. Mefuta ena e metle ea liteko e fane ka tlhaloso ea epigenetic ea hore na hobaneng ho tsuba sakerete hangata ho etella tšebeliso ea koae bathong (Kandel, 1975; Kandel et al., 1992).

Ntle le histone acetylation, histone methylation le eona e sa tsoa amohela e le phetoho e amanang le boitšoaro ba chromatin e khothalletsoang ke lithethefatsi tsa tlhekefetso (Laplant et al., 2010; Maze et al., 2010, 2011). Histone methylation e kenyelletsa tlatsetso ea enzymatic ea sehlopha se le seng, tse peli, kapa tse tharo ho masala a lysine kapa arginine ho N-terminal ea mohatla oa histone, mme e amana le ts'ebetso kapa phetisetso, ho latela mofuta oa phetiso (Rice le Allis) , 2001). Boithuto ba pele ba ho hlahloba histone methylation e hlahisitsoeng ke cocaine bo lebisitse ho tsebiso ea li-protone tse ling tse peli tsa histone, G9a le G9a-like protein (GLP), tse neng li ntse li tsoela pele ho laoloa ka tlase ho NAc 24 h ho latela ho pepeseha ha koae ea cocaine e se nang phehisano le boiqapelo ka bo eona. -adminication (Renthal et al., 2009; Maze et al., 2010). Ts'ebetso ena ea tlase e ne e hokahane le ho fokotseha ho tšoanang ha histone H3 lysine 9 (H3K9) le 27 (H3K27) methylation. Kamora moo, G9a overexpression ho NAc e bonts'itsoe ho fokotsa polelo e khothalletsoang ke koae ka mefuta e khethiloeng, ho fokotsa moputso oa koae joalo ka ha ho lekantsoe ke CPP, le ho thibela keketseho ea letsoele la dendritic spine ka tloaelo e bonoang ka karabelo ea koae e phetoa hape (Maze et al., 2010). Ho fapaneng ho etsahetse ha polelo ea G9a ho NAc e thibetsoe, e lebisang ho eketseha ha dendritic spineens le phaello e ntlafalitsoeng ea koae. Ho na le bopaki ba hore liphetoho tsena tse susumetsoang ke koae ka tšebeliso ea koae ho polelo ea G9a le ho fokotseha ho latelang ha H3K9 le H3K27 li laoloa ke ΔFosB (Maze et al., 2010). Ka kopanelo, liteko tsena li bonts'a karolo ea bohlokoa ea histone methylation ke G9a ho tse ling tsa litlamorao tsa boits'oaro bo botle le biochemical tsa ho pepesetsoa khafetsa khafetsa.

Haufinyane, trimethylation ea histone H3 lysine 9 (H3K9me3) eo pele ho neng ho nahanoa hore ke letšoao le tsitsitseng la heterochromatic, e bonts'itsoe hore e laoloa ka mokhoa o matla ho NAc ka ho pepeseha ha cococaine e mpe le e sa foleng (Maze et al., 2011). Cocaine e phetoang khafetsa e bakile ho fokotseha ho phehellang ha H3K9me3 binding e ileng ea ruisoa haholo libakeng tse sa kopaneng tsa coding (Maze et al., 2011). Liphumano tsena tsa mantlha li bonts'a hore ho pepesetsoa hoa koae khafetsa ho ka lebisa ho sa hlakisoeng ha lintho tse ling tse ka khutlisetsoang li-neuron tsa NAc, mme e tla ba ho khahlisang haholo ho netefatsa litlamorao tsa boits'oaro ba liphetoho tsena tsa nopigenetic.

Ha ho fanoa ka mofuta o tšoarellang oa ho lemalla, lipatlisiso tsa morao tjena li boetse li lekola karolo ea methapo ea DNA, e leng mokhoa o tsitsitseng oa epigenetic o bapisoang le tokiso ea histone. DNA methylation e kenyelletsa ho eketsoa ha lihlopha tsa methyl maemong a cysteine ​​ho DNA, 'me hangata e amana le khatello ea khatello (Stolzenberg et al., 2011). Tlhahlobo ea likhoto tsa likhoto tse amohetseng ente ea cocaine ka nako ea matsatsi a 7, kapa cocaine e itlhommeng pele ho matsatsi a 13 e senoletse melaoana ea DNA methyltransferase DNMT3a ho NAc 24 h kamora ho pepesetsoa ha koae (Laplant et al., 2010). Ka lehlakoreng le leng, ho latela ho pepesetsoa ha koae e sa foleng (ho sa laoleheng le ho ipusa bakeng sa libeke tsa 3 kapa ho feta) le nako ea ho ikhula ea 28, dnmt3a mRNA e fumanoe e ntlafatsoa haholo ho NAc (Laplant et al., 2010). Thibelo ea DNA methylation / DNMT3a ka ho khetheha ho NAc e ile ea bontšoa kamorao ho nts'etsopisa maikutlo a CPP le sensomotor ho cocaine, athe lehlakoreng le leng le ile la bonoa kamora ho tebela ho feteletseng ha DNMT3a sebakeng sena. Ho feta moo, thibelo ea DNMT3a ho NAc e boetse e thibetse keketseho e bakoang ke koaeine ho dendritic spine density (Laplant et al., 2010). Kameho ea boitšoaro ea liphetoho tse bakoang ke koae ka mokokotlo oa NAc spine e ntse e sa utloisisehe hantle. Manolo a thibelang ho kenngoa ha lesapo la mokokotlo ka tšebeliso ea lithethefatsi a bontšitsoe ho fokotsa thepa e ruisang ea koae (Russo et al., 2009; Maze et al., 2010); leha ho le joalo, lithuto tse ling li fumane hore thibelo ea moputso oa spinogenesis potentiates cocaine (Pulipparacharuvil et al., 2008; Laplant et al., 2010). Ha k'hok'heine e bonahala e baka molao o thata haholo oa mefuta e meng e fapaneng ea dendritic nakong ea ho pepeseha le ho ikhula (Shen et al., 2009), ho boletsoe hore liphapang tsena li ka ipapisa le mofuta oa methapo ea methapo e fetotsoeng (Laplant et al., 2010).

Ho tsoa litekong tse hlalositsoeng mona, ho hlakile hore molao-taelo oa tšebeliso ea lithethefatsi ea bokhoni ba ho ngola ba lisele o emela mochini o ka sehloohong o susumetsang karabelo ea boitšoaro ho lithethefatsi le ho ithuta ho amanang le moputso. Mohato o latelang oa bohlokoa e tla ba ho supa hore na ke liphetoho life tsa "epigenetic" tse amanang hantle le boemo ba bokuli ba batho. Ka lebaka la ho pepesehela lithethefatsi ha ho na ho lekana ho hlahisa "bokhoba" ho batho le liphoofolo, ho kenyelletsoa ha mehlala e lekanyang haholo litloaelo tsa bokhoba, joalo ka tšebeliso e mpe ea lithethefatsi le ho khutlela morao e tla ba tsa bohlokoa haholo.