Meputso ea Tlhaho le Meriana Molao oa Common Neural Plasticity Mekhoa e nang le DFFB e le Mokena-lipakeng oa Motlakase (2013)

Phuputso ena e hlahlobile litlamorao tsa moputso oa thobalano ho DeltaFosB le litlamorao tsa DeltaFosB mabapi le boits'oaro le moputso. Liphetoho tse tloaelehileng tsa limolek'hule tse tsejoang hore lia etsahala ka ho lemalla lithethefatsi li fumanoe li ts'oana le tse etsahalang ka thobalano. Ka mantsoe a mang, DeltaFosB e fetohile molemong oa thobalano, leha ho le joalo lithethefatsi li utsoa ona mokhoa ona. Sena se felisa ngangisano ea hore na ho lemalla lithethefatsi ho fapane joang le ho lemalla boitšoaro, le hore na ho lemalla boitšoaro ke litlamo feela (eng kapa eng e bolelang). Lisekete tse tšoanang, mekhoa e ts'oanang, liphetoho tse tšoanang tsa lisele, boits'oaro bo ts'oanang bo amanang le phapang e nyane.

J Neurosci. 2013 Feb 20;33(8):3434-3442.

THUTO E TLAHANG

Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM.

mohloli o moholo

Lefapha la Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 3K7, Canada, Lefapha la Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg Department of Neuroscience le Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, le Mafapha a Neurobiology le Anatomical Sciences le Physiology le Biophysics, Setsi sa Bongaka sa Univesithi ea Mississippi, Jackson, Mississippi 39216.

inahaneloang

Lithethefatsi tsa tlhekefetso li etsa hore li-neuroplasticity li fumane tsela ea moputso oa tlhaho, haholo-holo nucleus accumbens (NAc), kahoo li baka tsoelo-pele le polelo ea boitšoaro bo hlephileng. Bopaki ba morao tjena bo fana ka maikutlo a hore litlhohonolofatso tsa tlhaho li ka baka liphetoho tse joalo ho NAc, ho fana ka maikutlo a hore lithethefatsi li ka etsa hore lisebelisoa tsa polasetiki li kopane le meputso ea tlhaho, 'me li lumella ho bapala ka tsela e ikhethang pakeng tsa meputso ea tlhaho le lithethefatsi.

Phuputsong ena, re bonts'a hore phihlelo ea thobalano ka likhoto tsa banna ha e lateloa ke nako e khutšoanyane kapa e telele ea tahlehelo ea thobalano e etsa hore moputso oa amphetamine o ntlafatsoe, o bontšitsoeng ka mokhoa o amohelehang oa sebaka se nang le tekanyo e tlaase (0.5 mg / kg) amphetamine. Ho feta moo, ho qala, empa eseng nako e telele, ho ntlafatsa moputso oa amphetamine ho ne ho amana le ho eketseha ha nakoana ha lihlahla tsa dendritic ho NAc. Ka mor'a moo, karolo ea bohlokoa bakeng sa mokhachane oa ho ngolisa ΔFosB ka moputso oa amphetamine o matlafalitsoeng ka ho kopanela liphate le ho eketseha ho amanang le likhahla tsa dendritic ho NAc neurons ho ile ha thehoa ho sebelisoa motsoako oa liphatsa tsa lefutso tsa molekane ea nang le tšusumetso e mpe ho eena. Ho feta moo, ho ile ha bontšoa hore moputso oa litsebi tsa ho kopanela liphate o ntlafalitsoeng, ΔFosB le spinogenesis li itšetlehile ka ho kenyelletsa ho sebelisoa ha motsoako D1 ho amohela activation ho NAc. Ho thibela tšebetso ea litlhapi tsa D1 receptor, empa e seng mokamoli oa D2, ho NAc nakong ea boitšoaro ba ho kopanela liphate bo fokolisitsoe ke ΔFosB ho kenngoa ha tsona le ho thibela ho eketseha ha spinogenesis le ho matlafatsoa moputso oa amphetamine.

Tliphihlelo tsena li bontša hore lithethefatsi tsa tlhekefetso le mekhoa ea boipheliso ea tlhaho li nka mekhoa e tloaelehileng ea limolek'hule le lichelete tsa polasetiki tse laolang kotsing ea ho lemalla lithethefatsi, le hore ts'oaetso ena e eketseha e sebelisana le DFFB le merero ea eona e tlase.

Selelekela

Mekhoa ea boithabiso ea tlhaho le meriana ea lithethefatsi li fetoha ka tsela e tloaelehileng ea neural, mokhoa oa mesolimbic dopamine (DA), oo nucleus accumbens (NAc) e nang le karolo ea bohlokoa (Kelley, 2004). Lithethefatsi tsa tlhekefetso li etsa hore motho a se ke a hlola a e-ba le bothata ba ho sebelisa lithethefatsi ho lemalla lithethefatsi (Hyman et al., 2006; Kauer le Malenka, 2007; Kalivas, 2009; Chen le al., 2010; Koob le Volkow, 2010; Wolf, 2010a; Mameli le Luscher, 2011). E 'nile ea tšeptjoa hore lithethefatsi le meputso ea tlhaho ha li sebelise li-neurone tse tšoanang mokhoeng oa mesolimbic, kahoo lithethefatsi li etsa hore ho be bonolo hore li fetole le ho fetola potoloho ena (Cameron le Carelli, 2012). Leha ho le joalo, ho se ho hlakile hore meputso ea tlhaho le ea lithethefatsi e ama mokhoa oa mesolimbic ka mekhoa e ts'oanang le e fapaneng e lumellang puisano pakeng tsa moputso oa tlhaho, e leng moputso oa thobalano, le litlamorao tsa lithethefatsi tsa tlhekefetso (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Boitšoaro ba thobalano boa putsa haholo (Tenk et al., 2009),

Liphuputso tsena li fana ka maikutlo a hore liphihlelo tsa meputso ea tlhaho le tsa lithethefatsi li arolelana mekhoa e tloaelehileng ea polasetiki ea neural, e leng eona e nang le tšusumetso ea ho sebelisa lithethefatsi hampe

Sepheo sa thuto ea morao-rao e ne e le ho tseba mekhoa ea lisele tsa mokokotlo ea ho kopanela liphate tsa liporotiki, e leng se ileng sa etsa hore moputso oa lithethefatsi o ntlafatsoe. Ka ho khetheha, karolo ea ntho ea ho ngolisa ΔFosB e ne e phenyekolloa hobane e ameha liphellong tsa melemo ea bobeli le ea lithethefatsi (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Ho phaella moo, karolo ea dopamine receptors ea D1 (D1R) bakeng sa bokooa ba neural plasticity e bakoang ke thobalano e ile ea hlahlojoa kahobane NAC ΔFosB e kenngoa ka bongata le ho eketseha ha sekhahla ka mor'a hore psychostimulant tsamaiso e hlahisoa li-neurons tse nang le D1R (Lee le al., 2006; Kim et al., 2009) mme o itšetlehile ka ts'ebetso ea D1R (Zhang et al., 2002).

Mona, re ne re sebelisa molekane ea nang le matla a likokoana-hloko a nang le matla a likokoana-hloko bakeng sa DFFB, diOlistic labeling, le mekhoa ea phekolo ea meriana ho leka tekano ea hore liphello tsa tšoaetso ea ho kopanela liphate li lateloa ke moputso oa ho ipholosa ho ntlafatsoa ha Amph. Tlhaloso ea D1R e itšetlehileng ka DFBB ho NAc le keketseho e latelang ea NAc ea sekhahla sa mokokotlo. Ka kakaretso, liphuputso li fana ka bopaki ba hore meputso ea tlhaho le ea lithethefatsi e arolelana mekhoa e tloaelehileng ea polasetiki ea neural, le DFF e le moemeli oa bohlokoa.

Lisebelisoa le mekhoa

Liphoofolo.

Batho ba baholo (225-250 g ha ba fihlile) le basali (210-220 g) Maqeba a Dawley a qhalakantsoeng (Charles River Laboratories) a ne a kenngoa matlong a li-Plexiglas ka likhapha tse tšoanang tsa thobalano ho pholletsa le liteko, tlas'a mocheso le mocheso oa mongobo le 12 / 12 h potoloho e khanyang / lefifi le lijo le metsi a fumanehang ka bolokolohi. Basali ba batšehali bakeng sa likhallelo tsa ho kopanela liphate ba ne ba e-na le 'mele' me ba fuoa li-implants tse nyenyane tse nang le 5% estradiol benzoate (Sigma-Aldrich) le liente tsa 500 μg ea progesterone (ka 0.1 ml ea oli ea sesame; Sigma-Aldrich) 4 pele e lekoa. Mekhoa eohle e ile ea amoheloa ke Likomiti tsa Tlhokomelo ea liphoofolo le tsa Lik'hamphani tsa Univesithi ea Bophirimela ea Ontario le Univesithing ea Michigan 'me li lumellane le Canadian Council on Animal Care le melao-motheo ea Sechaba ea Bophelo ea lihlahisoa tse akarelletsang liphoofolo tse nang le likokoana-hloko lipatlisisong.

Boitšoaro ba thobalano.

Litšebeletso tsa ho kopanya li etsahetse nakong ea matšoao (pakeng tsa 2 le 6 h kamora nako ea lefifi) tlas'a khanya e khubelu e khanyang, litlamong tse hloekileng tsa tlhahlobo (60 × 45 × 50 cm). Litoeba tsa banna li ne li itšetlehile ka ho ejella nakong ea li-4 kapa 5 letsatsi le letsatsi. Lihlopha tse hlano li khethiloe hobane re kile ra bontša hore paradigm ena e etsa hore ho be le nako e telele ho tsamaisa boitšoaro ba thobalano (Pitchers et al., 2010b), ho tseba-tšoa-tšoa-tšoa-tšebetso ho moetsi oa moetsi oa Amph (Pitchers et al., 2010a), le moputso (Pitchers et al., 2010a). Ho khaotsa ho khethoa e le bofelo ba nako e 'ngoe le e' ngoe ea ho kopanya hobane re kile ra e bontša e le ea bohlokoa bakeng sa liphello tsa ho kopanela liphate ho tsebisang mohopolo oa Amph (Pitchers et al., 2010a), e sa kang ea etsahala ha liphoofolo li lumelloa hore li kopane le basali ntle le ho bontšoa ha metsi. Likarolo tsa boitšoaro ba thobalano (ke hore, latency ho ea pele holimo, ho kenya letsoho le ho phalla, le palo ea li-mounts le li-intromissions) li ngotsoe joalokaha ho hlalositsoe pele (Pitchers et al., 2010b). Bakeng sa liteko tsohle, lihlopha tse nang le phihlelo ea ho kopanela liphate li ne li lekana bakeng sa boitšoaro ba thobalano (kakaretso ea li-ejaculations le latency ho ejaculation nakong ea nako ka nako ea ho kopanya). Ka mor'a thuto ea bohlano ea ho kopanya liphate, banna ba ile ba lula ba e-na le balekane ba tšoanang le ba bong bo fapaneng 'me ba sa lumelloa ho kopanela nakong ea ho ipolaea ea 1, 7, kapa 28 d. Liphoofolo tse ileng tsa lula li e-na le thobalano li ile tsa sebetsoa 'me tsa lula likamoreng tse tšoanang le banna ba nang le thobalano. Ho phaella moo, litsamaiso tse nang le boikhohomoso li behiloe likampong tse hloekileng tsa teko bakeng sa hora nakong ea matsatsi a 5 a latellanang, ntle le ho fumana mosali ea amohelehang.

Tlhaloso ea FosB.

Liphoofolo li ne li sa rutehe haholo (pentobarbital ea sodium; 390 mg / kg; ip) le ho sebelisoa hampe ka 50 ml ea 0.9% saline, e lateloa ke 500 ml ea 4% paraformaldehyde (Sigma-Aldrich) ho 0.1 m phosphate buffer (PB) ea nako lintlha le liteko tsa DR tse hanyetsang. Bokooa bo ile ba tlosoa 'me ba kenngoa ka morao ho 1 h ka mocheso oa motsoako o lekanang le ho lokisa, ebe ba bolokoa 4 ° C ho 20% sucrose le 0.01% sodium azide ho 0.1 m PB. Bakeng sa liteko tsa DR tse loantšanang, boko bo ile ba tlosoa 'me ba aroloa halofo ka lehlakoreng la sagittal. Halofo e 'ngoe e ne e bolokoa PB mme e sebelisetsoa Diolistics,' me e 'ngoe ea etsoa bakeng sa ΔFosB. Likarolo tsa Coronal (35 μm) li ne li khaotsoe ka microtome e khanyang (Microm H400R), e bokelloa ka lihlopha tse 'nè tse tšoanang le sekhahla sa cryoprotectant (30% sucrose le 30% ethylene glycol ka 0.1 m PB)' me li bolokiloe ka -20 ° C. Likarolo tse sa phaphameng li hlatsuoa haholo ka 0.1 m PBS, pH 7.35, pakeng tsa ho tsubella, le mehato eohle e ne e le mocheso oa kamore. Likarolo li ne li pepesehetse 1% H2O2 (10 min) le tharollo ea motlakase (1 h; PBS e nang le 0.1% BSA, Fisher; le 0.4% Triton X-100, Sigma-Aldrich). Likarolo li ne li kenngoa ka bosiu bosiu ka anti-man-o-pan-FosB ea rabbit polyclonal (1: 5K; sc-48 Santa Cruz Biotechnology), e neng e tiisitsoe pele (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Sesole sa 'mele sa pan-FosB se holisitsoe khahlanong le sebaka se ka hare se arolelanoeng ke FosB le ΔFosB,' me se kile sa tsejoa e le ho bona lisele tsa ΔFosB ka nako e sebelisitsoeng phuputsong ena (> 1 d kamora ts'usumetso) (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Ka mor'a moo, likarolo li ne li kenngoa ka IgG (1 h; 1: 500 ka PBS;; Vector Laboratories), li-peroxidase tse nang le li-acotin-biotin (1 h; ABC elite; 1: 1000 ho PBS; Vector Laboratories) , le 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) le 0.02% nickel sulfate ka 0.1 m PB le hydrogen peroxide (0.015%). Likarolo li ne li kenngoa holim'a li-slide tsa Superfrost hammoho le li-slides (Fisher) tse koahetsoeng ka dibutyl phthalate xylene.

Lintlha tsa lisele tsa DFFB-IR li ne li baloa sekhethong sa NAc le mantlha ka har'a maemo a tloaelehileng a tlhahlobo (400 × 600 μm) joalokaha ho hlalositsoe pele (Pitchers et al., 2010b). Likarolo tse peli li ne li baloa ka li-NAC tse ling, liphoofolo tse arohaneng. Ka nako ea teko, liteko tsa lisele tsa DFB-IR li ne li hlahisoa e le ho fetoha ha sehlopha sa taolo ea boipheliso ka nako e loketseng 'me li bapisoa pakeng tsa lihlopha tse nang le phihlelo le tse se nang boiketlo bakeng sa karolo e' ngoe le e ngoe ea nako ka nako e sebelisoang ntle ho boipheliso t liteko tse nang le boemo ba bohlokoa p <0.05. Litekong tsa bahanyetsi ba ΔJunD-AAV le DR, ANOVA ea mahlakore a mabeli kapa e le 'ngoe, ka ho latellana, le mokhoa oa Holm-Sidak li sebelisitsoe. Ntle le moo, lisele tsa ΔFosB-IR li ne li baloa ka har'a dorsal striatum (sebaka sa tlhahlobo: 200 × 600 μm), hang-hang ho ea ho NAc le haufi le ventricle ea lateral, liphoofolong tsohle tsa teko ea mohanyetsi oa DR. ANOVA e le 'ngoe le t liteko li ne li sebelisoa ho bapisa pakeng tsa lihlopha.

Diolistics.

Bakeng sa ntlha ea nako le tekanyetso ea kokoana-hloko ea VDJunD, litoe li ile tsa sebelisoa hampe ka 50 ml saline (0.9%), e lateloa ke 500 ml ea 2% paraformaldehyde ho 0.1 m PB. Bokooa bo ne bo arotsoe (100 μm coronal) ho sebelisa vibratoma (Microm) le likarolo tse bolokiloeng 0.1 m PB le 0.01% sodium e tseba ho 4 ° C. Ho apara li-particle tsa tungsten (1.3 μm bophara, Bio-Rad) le lipophilic carbocyanine tee DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate; Invitrogen) e ile ea etsoa joalokaha ho hlalositsoe pele (Forlano le Woolley, 2010). Mefuta e mengata ea tungsten e entsoeng ka mahlaseli e ne e fetisetsoa meleng ea 160-180 psi e sebelisa Helios Gene Gun tsamaiso (Bio-Rad) ka sefahleho sa 3.0 μm pore size (BD Biosciences) 'me e lumelloa ho fapana ka li-membrane tsa neuronal ho 0.1 m PB bakeng sa 24 h ha e sirelelitsoe ka leseli ho 4 ° C. Ka mor'a moo, likhahla li ne li kenngoa ka 4% paraformaldehyde PB bakeng sa 3 h ka mocheso oa motsoako, o hlatsoitsoe PB, 'me e kenngoa ka likamoreng tse tiisitsoeng (Bio-Rad) le gelvatol e nang le 1,4-diazabicyclo (2,2) octane (anti-fading agent) 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

Li-neurone tse ngotsoeng ka mela e ne e le litšoantšo tse sebelisitsoeng Seiss LSM 510 m microscope ea confocal (Carl Zeiss) le helium / neon 543 nm laser. Bakeng sa phoofolo e 'ngoe le e' ngoe, 2-5 neurons karolong e 'ngoe le e' ngoe ea Nac, kapa ho khetla (e thehiloeng sebakeng seo ho amanang le matšoao, ho kenyelletsanoa le sebaka sa lateralle le tlhahiso ea anterior) liphuputsong tsa ΔJunD-AAV le DR, li sebelisetsoa ho fumana sebaka sa thahasello ka dendrite ea bobeli bakeng sa quantification ea mokokotlo. Bakeng sa neuron e 'ngoe le e' ngoe, 2-4 dendrites e ne e sekiselitsoe ho lekanya bolelele ba dendritic ea 40-100 μm. Likarolo tsa dendritic li ile tsa haptjoa li sebelisa 40 × sepheo sa ho qoelisoa metsing ho nako ea 0.25 μm haufi le z-axis, le setšoantšo sa 3D se ile sa tsosolosoa (Seiss) 'me ho ile ha e-ba le boikutlo ba ho fetoha (Autoquant X, Media Cybernetics) ho sebelisa mokhoa o feto-fetohileng (o foufetseng) le mokhoa oa theknoloji oa PSF joalokaha ho khothalletsoa ke software. Boima ba sekhahla bo ne bo hlahlojoa ka mokhoa oa Filament oa package ea software ea Imaris (version 7.0, Bitplane). Lipalo tsa li-spin tsa dendritic li ne li hlahisoa ka 10 μm, e lekanngoang bakeng sa neuron ka 'ngoe le ka phoofolo e' ngoe le e 'ngoe. Ho se tšoane ha li-statisti ho ile ha khethoa ho sebelisa li-ANOVAs tse peli nakong ea liteko tsa linako tsa nako pakeng tsa liphoofolo tsa bokooa le tse nang le phihlelo nako le nako ntlha (lintlha: boiphihlelo ba ho kopanela liphate le boipheliso ba NAc) le tekong ea HA (maqheka: phihlelo ea thobalano le vector virase) -e leng ANOVA ho teko ea bohanyetsi ba DR. Litšoantšiso tsa sehlopha li entsoe ka mokhoa oa Holm-Sidak ka boemo ba bohlokoa p <0.05.

Sebaka se khethiloeng sa sebaka.

Moqapi oa tlhahlobo oa CPP o ne o tšoana le o hlalositsoeng pele (Pitchers et al., 2010a), ho sebelisa lik'hamphani tse tharo tse nang le likarolo tse tharo (Med Associates), le moqapi o se nang boikemelo, o etsoang o le mong oa li-amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc e baloang ka lebaka la setsi sa mahala) ka kamoreng e kopantsoeng le saline ka kamoreng e sa sebetsaneng ka matsatsi a mang a mang, 'me a etsoa nakong ea halofo ea pele ea leseli. Liphoofolo tsa taolo li fumane saline likamoreng ka bobeli.

Lipalo tsa CPP li ne li baloa bakeng sa phoofolo e 'ngoe le e' ngoe e le nako e sebelisitsoeng (ka metsotsoana) ka kamoreng e kopantsoeng nakong ea tlhahlobo ea tlhahlobo e fokolang. Mokhoa o mong oa ANOVA le mokhoa oa Holm-Sidak o ne o sebelisetsoa ho bapisa lihlopha nakong ea liteko tsa nako. Ha e na thuso t tlhahlobo ka bohlokoa bo behiloeng p <0.05 e ne e sebelisetsoa ho bapisa Naive-Sal le Naive Amph ka nako e 'ngoe le e' ngoe nakong ea liteko tsa nako, le kalafong e 'ngoe le e' ngoe ea vaerase ea liteko tsa ΔJunD. Nakong ea teko, li-ANOVA tsa tsela e le 'ngoe le mokhoa oa Holm-Sidak li sebelisitsoe ho bapisa lihlopha tse nang le boiphihlelo ba thobalano (Exp-Sal, 7 d Exp Amph le 28 d Exp Amph), le tse sa sebetsoang t teko e ne e sebelisetsoa ho bapisa lihlopha tsa batho ba 2. Tsela e 'meli ea ANOVA le mokhoa oa Holm-Sidak o ne o sebelisetsoa ho bapisa lihlopha tsohle tsa teko ea bohanyetsi ba DR. Tse peli tse sa sebetsane t tlhahlobo e ne e sebelisetsoa ho bapisa lihlopha tsa Naive-Sal le tsa Naive Amph ka boemo bo bong le bo bong ba phekolo ea likokoana-hloko (GFP kapa ADJunD), kaha lintlha li ne li fapane haholo le lihlopha tsa HA tse lumellang tlhahlobo ea ANOVA. Likarolo tsohle tsa bohlokoa li behiloe p <0.05.

Liteko tsa velera ea vera.

Li-rats li ne li sa sebelisetsoe ke ketamine (87 mg / ml / kg; ip) le xylazine (13 mg / ml / kg ip), li kenngoa ka lisebelisoa tsa stereotaxic (Kopf Instruments), 'me li fumane microinjection tse peli tsa li-viral vec GFP (protheine e tala e tala), kapa molekane ea nang le mohopolo oa PASB (ea nang le matla a maholo ka ho fetisisa oa khothaletso ea ΔFosB) le GFP, ho NAc (likopano: AP + 1.5, ML ± 1.2 ho tloha bregma; DV -7.6 ho tloha lehata), ka molumo oa 1.5 μl / hemisphere ho feta 7 min sebelisa seringe ea Hamilton (Harvard Apparatus). Ha ho bonolo ho fokotsa ΔFosB-tlhaloso e kopanetsoeng ka ho hloriderizing ka tlhōlisano ka ΔFosB ka hona ho thibela ho tlama ΔFosB sebakeng sa AP-1 ka hare ho libaka tsa ts'ebetso ea liphatsa tsa lefutso (Winstanley et al., 2007; Pitchers et al., 2010b). Le hoja ma-junD a ikamahanya le ho ba le kamano e phahameng le DFFB, ho ka etsahala hore tse ling tsa liphello tse hlokometsoeng tsa ΔJunD li ka 'na tsa e-ba lipakeng tsa ho hanyetsa liprotheine tse ling tsa AP-1. Leha ho le joalo, ho bonahala eka ΔFosB ke protheine ea AP-1 e hlalositsoeng tlas'a maemo a lekiloeng (Pitchers et al., 2010b). Pakeng tsa libeke tsa 3 le li-4 hamorao, liphoofolo li ile tsa fumana tsebo ea ho kopanela liphate nakong ea 4 lihlahisoa tse latellanang kapa tsa lula e le lihlong ho theha lihlopha tsa 4: GFP ea liphate, ba nang le phihlelo ea ho kopanela liphate GFP, ba nang le bokooa ba thobalano, le ba nang le phihlelo ea ho kopanela liphate. Boiphihlelo ba ho kopanela liphate bo ne bo e-na le setlhopha se kopaneloang sa 4 letsatsi le leng le le leng. Liphoofolo li ile tsa lekoa bakeng sa CPP le diOlistics. Tlhahlobo ea libaka tse entsoeng ka ente e entsoe joalokaha ho hlalositsoe pele (Pitchers et al., 2010b). Nac likarolo (coronal; 100 μm) li ne li sebetsana le 'mele ka lebaka la GFP (1: 20,000; anti-GFP antibody; Invitrogen). Ho ata ha kokoana-hloko ho ne ho lekanyelitsoe haholo karolong ea shell ea NAC, 'me ho eketsehileng ho ata ho ea mantlha.

Bahanyetsi ba D1R / D2R.

Lipoe tsa banna li ne li sa sebelisetsoe ke enteperitoneal (0.1 ml / kg) ea ketamine (87 mg / ml) le xylazine (13 mg / ml), ebe e kenngoa lisebelisoa tsa stereotaxic (Kopf Instruments). Palo ea 21-gauge guide cannulas (Plastics One) e theoleloa ho NAc ho AP + 1.7, ML ± 1.2 ho tloha bregma; -6.4 DV ho tswa ho lehata mme e sirelelitsoe ka meno ea acrylic, e khomaretsoeng ke lisebelisoa tse tharo tse behiloeng lekaneng. Liphoofolo li ne li sebetsoa letsatsi le leng le le leng bakeng sa mekhoa ea ho itšireletsa nakong ea ho phomola ha beke ea 2. Metsotso e leshome le metso e mehlano pele ho ts'ebetso ea 4 letsatsi le leng le le leng pele ho ts'oaetso ka ho hlahisa basali ba amohelang, litoeba tse tona li fumane microinjection tse peli tsa mohanyetsi oa D1R R (+) SCH-23390 hydrochloride (Sigma-Aldrich), mohanyetsi oa D2 (D2R) S- ( -) eticlopride hydrochloride (Sigma-Aldrich) e ne e qhibiliha ka saline e nyopa (0.9%; e 'ngoe le e' ngoe e le 10 μg ho 1 μl ka ho hemisphere; e qhibilihisoa 0.9% saline), kapa saline (1.0 μl ka hemisphere), ka tekanyo ea phallo ea 1.0 μl / min ka nako ea 1 metsotsoana e lateloa ke 1 min le kankere e entsoeng ka ente e siiloeng sebakeng sa ts'ebetso ea lithethefatsi. Molumo oa ente ena o tla hlahisa mohoho le shell, kaha infusions ea 0.5 μl e thibetsoe ho khetla kapa likarolo tse ka sehloohong (Laviolette et al., 2008). Litekanyetso li ne li thehiloe lithuputsong tse fetileng tse bontšang hore tsena kapa tse tekanyo ea litekanyetso li amme boitšoaro ba lithethefatsi kapa meputso ea tlhahoLaviolette et al., 2008; Roberts le al., 2012). Banna ba laolang ba ile ba lula ba se na bokooa ba thobalano empa ba fumana salate ea intra-NAc pele ba kenngoa kahare ea teko ea lefeela, nakong ea mananeo a letsatsi le letsatsi a 4. Beke e 'ngoe ka mor'a thuto ea ho qetela ea ho kopanya kapa ea ho sebetsana, banna ba ile ba lekoa bakeng sa Amph CPP, le mokokotlo le tlhahlobo ea ΔFosB. Tšebeliso ea mananeo a mane, ho e-na le mananeo a mahlano ho latela liteko tse ling, o ile a khethoa ho felisa tšenyo e fetisisang ho NAc e bakoang ke ho pheta-pheta ka makhetlo a mangata 'me kahoo a lumella mokokotlo le tlhahlobo ea ΔFosB. Ha e le hantle, tšenyo e ne e se e totobetseng, 'me tlhahlobo ea mokokotlo le ΔFosB ho NAc ea liphoofolo tse kenngoeng ka saline li bontšitse lits'ebeletso tse tšoanang le lihlopha tse sa kenngoa liphuputsong tse fetileng. Mokhoa oa bobeli oa ANOVA le Holm-Sidak ka bohlokoa bo behiloeng p <0.05 e ne e sebelisetsoa ho fumana boits'oaro bo susumetsoang ke boiphihlelo ba thobalano.

Results

Tlhekefetso ea ΔFosB e nang le phihlelo e nka nako e telele

Ntlha ea pele, likamano tsa nakoana pakeng tsa likamano tsa botona le botšehali tse hlahisoang ke likamano tsa DFFB, likhahla tsa dintritic NAC, le Amph-CPP li ne li ikemiselitse, ka ho khetheha ka mor'a nako e khutšoanyane le e telele ea ho ithiba ho tsoa thobalanong (7 kapa 28 d). Pele ho moo, ho ile ha bontšoa hore phihlelo ea ho kopanela liphate ea mananeo a 5 letsatsi le leng le le leng a ile a etsa hore ho be le pokello ea ΔFosB ho pholletsa le tsamaiso ea mesoli, haholo-holo NAc (Wallace et al., 2008; Pitchers et al., 2010b). Liphuputsong tsena tse fetileng, likarolo tsa FosB li ne li lekantsoe ka hare ho 1 d ka morao ea boitšoaro bo bobe ba thobalano, 'me ha hoa tsebahala hore na ΔFosB e bokella ka nako e telele ka mor'a nako e telele ea ho ipolaea. Banna ba nang le botona kapa botšehali ba nang le thobalano ba ne ba sebelisa 1, 7, kapa 28 d hampe ka mor'a ho qeta nako ea ho kopanya letsatsi le leng le le leng la 5, nakong eo banna bao ba neng ba phela ka nako e le 'ngoe. Tlhompho ea botona kapa botšehali ka ho kopanela liphate e ne e etsoa hampe ka nako e le 'ngoe ka mor'a nako ea ho qetela ea mananeo a letsatsi le letsatsi a tsamaiso ea 5. Numere ea lisele tsa DFFB-IR ka shell ea NAC le mantlha e ne e phahametse haholo ho feta taolo ea boikhohomoso ea thobalano ka linako tsohle (Feie. 1A, shell; 1 d, p = 0.022; 7 d, p = 0.015; Feie. 1B: mantlha; 1 d, p = 0.024; 7 d, p <0.001; 28 d, p <0.001), ntle le ho khetla ea NAc kamora ho ithiba ha 28 d (p = 0.280). Ka hona, ho fokotsa taolo ea FFB ho tsoelapele nakong ea ho ipholoha ka mor'a ho ba le thobalano ka nako ea bonyane 28 d.

Setšoantšo sa 1.     

Boiphihlelo ba thobalano bo entse hore ho be le keketseho e potlakileng le e tsitsitseng ea lisele tsa ΔFosB-IR. Phetoho ea palo ea lisele tsa ΔFosB-IR ka shell ea NAc (A) le mokokotlo (B) liphoofolong tse nang le phihlelo (tse ntšo) tse amanang le thobalano ha li bapisoa le taolo ea ho kopanela liphate (tšoeu)n = Sehlopha sa sehlopha sa 4). Lintlha ke sehlopha se bolelang ± SEM. *p <0.05, phapang e kholo ha e bapisoa le taolo e se nang kelello. Moemeli oa litšoantšo tsa Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), le Exp Exp 28 d (F). khalaletso, ts'ebetso ea Anterior. Sebaka sa sekala, 100 μm.

Thobalano e bakoang ke ho kopanela liphate ka likhahla tsa dendritic ke nako e khutšoanyane

Pitchers et al. (2010a) ba neng ba tlalehile pele ba sebelisa mekhoa ea boipheliso ea Golgi hore phihlelo ea ho kopanela liphate e latetsoeng ke 7 d, empa e seng 1, ea ho itokolla ha moputso e ile ea etsa hore ho eketsehe sebata sa dendritic le lenane la likhahla tsa dendritic ho NAc shell le methapo ea mantlha (Pitchers et al., 2010a). Mona, spinogenesis ho banna ba nang le thobalano le ba nang le boiphihlelo ba ile ba hlahlojoa ka 7 d kapa 28 d ka mor'a hore nako ea ho qetela e kopane. Liphuputso tsa morao-rao tse sebelisoang ka mokhoa oa ho ngolisa li-diOlistics li tiisitse hore phihlelo ea thobalano e latetsoeng ke nako ea ho ikhutsisa thobalano ea 7 e ekelitse palo ea likhahla tsa dendritic (F(1,8) = 9.616, p = 0.015; Feie. 2A-C). Ha e le hantle, palo ea likhahla tsa dendritic e ne e eketsehile haholo ho NAc shell le mantlha (Feie. 2A: shell, p = 0.011; mokokotlo, p = 0.044). Leha ho le joalo, sena se eketseha sekhahla sa mokokotlo se ne se le nakoana 'me ha se sa hlokomeloa ka mor'a nako ea ho ipolaea ka nako e telele ea 28 d ho NAC e tlase ho naha (Feie. 2B).

Setšoantšo sa 2.    

Boiphihlelo ba ho kopanela liphate bo entse hore ho be le keketseho ea likhahla tsa dendritic ka NAc le ho amoheloa ha Amph moputso. A, B, Palo ea likhahla tsa dendritic ka shell ea NAc le mantlha oa 7 d (A) kapa 28 d (DB ea liphoofolo tse nang le bothata ba ho kopanela liphate le ba nang le phihlelo; n = 4 kapa 5). Lintlha ke sehlopha se bolelang ± SEM. #p <0.05, phapang e kholo ha e bapisoa le taolo e se nang kelello. C, Lihlopha tsa dendritic tse tsoang ho Naive 7 d le Exp 7 tsa lihlopha tse sebelisetsoang ho lekanyetsa sekhahla sa masapo. Sebaka sa sekala, 3 μm. D, Nako ea nako e sebelisitsoeng ka kamoreng ea bobeli (Amph kapa saline) nakong ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhahlobo ea boipheliso (lipalo) tsa bo-'mametsana kapa ba nang le boiphihlelo (ba batšo) ba lekiloeng ke 7 d kapa 28 d ka mor'a ho kopanya ho qetela kapa Tlhophiso: Naive-Sal (7 d ka mor'a ho sebetsana; n = 8), Mohlankana ea nang le Ntoa (7 d ka mor'a ho sebetsana; n = 9), Exp-sal (lihlopha tse kopantsoeng tsa liphoofolo li lekoa ke 7 kapa 28 d ka mor'a ho nyalana; n = 7), 7 d Exp Amph (7 d ka mor'a ho nyalana; n = 9), le 28 d Exp Amph (28 d ka mor'a ho kopanya; n = 11). Lihlopha tsa Sal li amohetse Sal li kopane le likamore ka bobeli. *p <0.05, phapang e kholo ha e bapisoa le taolo ea letsoai e nang le boiphihlelo.

Ho kopanela liphate ho susumelitsoeng ke ho kopanela liphate Amph moputso ke oa nako e telele

Re kile ra bontša hore phihlelo ea ho kopanela liphate e latetsoeng ke 7-10 ea ho ithiba e entse hore Amph e ntlafatsoe (Pitchers et al., 2010a). Ka ho khetheha, liphoofolo tse nang le phihlelo ea likamano tsa botona le botšehali li thehile sebaka se khethehileng sa sebaka seo (CPP) se nang le maemo a fokolang a Amph (0.5 kapa 1.0 mg / kg) e sa kang ea etsa hore CPP e be le taolo ea ho kopanela liphate. Thuto ea morao tjena e tiisitse mme e atolose liphetho tsena tsa pele ka ho bonts'a ho ntlafatsa Amph ho liphoofolo tse nang le phihlelo ka thobalano ka morao ho 7 d hammoho le nako ea ho ikhutsa thobalano ea 28 (Feie. 2D; F(2,24) = 4.971, p = 0.016). Ka ho khetheha, liphoofolo tse nang le phihlelo ea ho kopanela liphate tse nang le 7 kapa 28 ea nako ea boithaopo li sebelisitse nako e kholo ka ho fetisisa kamoreng ea li-Amph nakong ea tlhahlobo ea tlhahlobo ha e bapisoa le taolo e mpe ea ho kopanela liphate e fumanoeng ka saline ka kamoreng ka bobeli (Feie. 2D: Exp-Sal le 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Ho netefatsa liphuputso tse fetileng, liphoofolo tsa boikhohomoso tsa botona le botšehali ha lia ka tsa qeta nako e eketsehileng ka kamoreng ea Amph-paired nakong ea tlhahlobo ea tlhahlobo 'me ha ea ka ea fapana ho e-na le sehlopha sa ho laola saline sa botona le botšehali (Feie. 2D) (Pitchers et al., 2010a).

Mosebetsi oa FosB ke oa bohlokoa bakeng sa phihlelo ea ho kopanela liphate-e susumelitsoeng ho utloisisa bohloko ba Amph

Liphello ho fihlela hona joale li bontša hore phihlelo ea ho kopanela liphate e bakoa ke ho bokella nako e telele ea ΔFosB ho NAc neurons e amanang le ho ntlafatsa Amph moputso. Ho fumana hore na mosebetsi o moholo oa ΔFosB ke oa bohlokoa bakeng sa boipheliso ba Amph bo ntlafatsang, DNA, molekane ea khomarelang-ea nang le tšusumetso ea ΔFosB e thibelang ho ngolisoa ha DFFB (medios)Winstanley et al., 2007), o ne a tšoenyehile haholo ka liphatsa tsa lefutso tsa kokoana-hloko ea kokoana-hloko ea NAV (Feie. 3A,B). Liphello tsa litlhahlobo tsa Amph CPP li bontšitse hore ho hlokomoloha mosebetsi oa ΔFosB ka ho bontša THATO ho NAC e thibelitse liphello tsa boiphihlelo ba thobalano le moputso oa thobalano oa 7 oa ho itokolla ho Amph e ntlafetseng. Ho na le liphoofolo tse nang le thobalano liphatsa tsa liphoofolo tse sa tšoaneng ha lia ka tsa e-ba le CPP e kholo bakeng sa Amph 'me e ne e sa fapane le batho ba nang le thobalano le liphoofolo tsa liphoofolo tse jang (Feie. 3B). Ka lehlakoreng le leng, liphoofolo tsa taolo ea GFP tse nang le likamano tsa botona le botšehali li thehile CPP bakeng sa Amph joalokaha ho bontšitsoe ke palo e kholo ka ho fetisisa ea CPP ha e bapisoa le litaolo tsa GFP tsa thobalano (Feie. 3B, p = 0.018).

Setšoantšo sa 3.    

Ho hlokomelisa mesebetsi ea FFBB ho NAC e koetsoeng e matlafatsa moputso oa AMPH le ho eketsa palo ea likhahla tsa NAc liphoofolong tse nang le phihlelo. A, Litšoantšo tsa liphatlalatso tsa GFP lihlahisoa tse tharo tse amohelang likokoana-hloko tsa adeno-tse amanang le kokoana-hloko e nang le kokoana-hloko e tsamaisanang le nucleus accumbens, e bontšang libaka tse nyenyane (tse ka ho le letšehali), tse bohareng (tse bohareng) le tse kholo (ka ho le letona). ac, ts'ebetso ea pele; LV, li-ventricle tsa lateral. Sebaka sa sekala, 250 μm. B, Papiso ea setsi sa libaka tse tummeng haholo le mekhoa ea ho ata ha vaerase. Har'a liphoofolo tsohle, GFP e ne e fumanoa ka har'a khetla, empa e fetisetsoa mokokotlong e ne e fetoha. C, Nako ea nako e sebelisitsoeng kamoreng ea li-Amph nakong ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhahlobo ea tlhahlobo ea boipheliso (lipalo) tsa batho ba kopanelang liphate le ba nang le boiphihlelo (ba batšo) ba amohelitsoeng ka jelo ea velisi ea taolo ea GFP (Naive, n = 9; Exp, n = 10) kapa mochine o motle (Naive, n = 9; Exp, n = 9). D, Litšoantšo tsa litšoantšo tsa likarolo tsa dendritic tse tsoang ho GFP e nang le phihlelo ea ho kopanela liphate le ΔJunD e sebelisetsoang ho lekanyetsa boholo ba mokokotlo oa mokokotlo. Sebaka sa sekala, 3 μm. E, Palo ea likhahla tsa dendritic ho NAc ea ba nang le bothata ba ho kopanela liphate (ba basoeu) le liphoofolo tse nang le tsebo (tse ntšo) tse amohelitsoeng ka ente ea velisi ea taolo ea GFP kapa vector VCD. Lintlha ke sehlopha se bolelang ± SEM. *p <0.05, phapang e kholo ha e bapisoa le taolo e se nang kelello. #p <0.05, phapang e kholo ho tsoa ho taolo ea boiphihlelo ea GFP.

Liphello tsa ho hlokomoloha ho ba le maikutlo a feteletseng ha hoa bakoa ke ho ferekana ha boitšoaro bo bobe nakong ea ho fumana phihlelo ea thobalano. Tlhaloso ea Ntho e 'ngoe ho NAC e kile ea bontšoa ho thibela ho tsamaisa boitšoaro bo bobe ka mor'a thobalano (Pitchers et al., 2010b). Ka sebele, sena se tiisitsoe tekong ea morao tjena. Liphoofolo tsa taolo ea GFP li bonts'a maqhubu a mokhutšoanyane ho phahamisa, ho senya, le ho phalla, le ho fokotseha ha likhahla le ts'ebetso ea tlhaho nakong ea letsatsi la bone la ho latellana ha liteko, ho bapisoa le letsatsi la pele la ho nyalana (Lethathamo 1). Ka lehlakoreng le leng, liphoofolo tse sa jeng tse nang le jO ha lia ka tsa bonahatsa nako e khutšoanyane haholo ea ho phahamisa kapa ho theola kapa ho fokotsa linomoro tse ngata nakong ea letsatsi la bone la ho nyaloa ha li bapisoa le tsa pele. Ka lebaka leo, ho ba le tšusumetso e matla ho NAC ho kokobetse liphello tsa boiphihlelo ba thobalano. Leha ho le joalo, ho ne ho se na phapang e khōlō ho tse ling tsa lipalangoang pakeng tsa thibelo ea GFP le lihlopha tse kenngoeng ke mekhatlo ka nako leha e le efe ea liteko, ho bonts'oa hore liphello tsa likamano tsa ho kopanela liphate ka ho kopanela liphate-ho susumelletseha ho matlafatsa Amph CPP hase phello ea ho se tšoane phihlelo ea ho holisa ka ho lekaneng (Lethathamo 1).

Sheba tafole ena:     

Tafole 1.    

Litlhaloso tsa boitšoaro ba thobalano nakong ea ho fumana phihlelo ea thobalano ka lihlopha tse amohetseng NAc infusions tsa GFP kapa li-VDJ-expressing vectors vectorsa

DFFB e bohlokoa bakeng sa keketseho e bakoang ke thobalano ho li-NAC dendritic spines

Mosebetsi oa FosB o ne o boetse o hlokoa bakeng sa ho eketseha ha sekhahla sa mokokotlo oa NAC neurons ka mor'a thobalano le thobalano ea 7 ea thobalano ea boithaopo (Feie. 3C,D). Bakeng sa tlhahlobo ea mokokotlo ho NAC ea liphoofolo tse hlalositsoeng ka holimo bakeng sa CPP, tsela e 'meli ANOVA e bontšitse liphello tse kholo tsa phihlelo ea thobalano (F(1,34) = 31.768, p <0.001) le kalafo ea vector ea vaerase (F(1,34) = 14.969, p = 0.001), hammoho le ho sebelisana (F(1,34) = 10.651, p = 0.005). Ka ho khetheha, liphoofolo tsa taolo ea GFP tse nang le likamano tsa botona le botšehali li na le palo e kholo ea lihlahisoa tsa NAc ha li bapisoa le lichelete tsa GFP tsa thobalano (Feie. 3D: p <0.001), e tiisa seo re se fumaneng pejana (Pitchers et al., 2010a). Ka lehlakoreng le leng, liphoofolo tse nang le tsebo tsa thobalano li ne li sa fapane ka ho feletseng le lihlopha tsa mafu a likobo, 'me li ne li le tlaase ha li bapisoa le liphoofolo tse laolang ka ho kopanela liphate tsa GFP (Feie. 3D: p <0.001). Kahoo, polelo ea JUND ho NAc e thibetse litlamorao tsa boiphihlelo ba thobalano mme ea putsa ho ithiba ho NAc spinogenesis.

Mohanyetsi oa D1R o thibela ho fokotsa taolo ea ΔFosB ea ho kopanela liphate

Ho fumana hore na D1R kapa ts'ebetso ea D2R ho NAc nakong ea ho nyalana e hlokahalang bakeng sa ho kopanela liphate tsa ΔFosB le ho khothaletsoa Amph CPP, liphoofolo li amoheloa ke mafu a sebaka sa D1R kapa bahanyetsi ba D2R (kapa saline) ho NAc 15 min pele e mong le e mong oa 4 letsatsi le leng le le leng liketsahalo tse latellanang. Habohlokoa, ha ho na D1R kapa D2R ea hanyetsanang le bothata ba ho kenngoa ha NAC qalong kapa mokhoa oa boits'oaro ba ho kopanela liphate nakong efe kapa efe ea likamano tsa ho kopanela liphate (Feie. 4D-F). Ka ho tšoanang, Tlhōlisano ea D1R kapa D2R ha ea ka ea thibela liphello tsa boiphihlelo ba thobalano nakong ea ho nyalana, kaha lihlopha tsohle li bonts'a ho tsamaisa boitšoaro ba thobalano, e bonahatsitsoeng ka nako e khutšoanyane ejaculation latencies ka letsatsi 4 e bapisoa le letsatsi 1 (Feie. 4F) (F(1,40) = 37.113, p <0.001; Letsoai, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Setšoantšo sa 4.    

Li-antagonists tsa Dopamine tse kenang ka har'a NAC ha lia ka tsa ama boitšoaro ba thobalano. Coronal NAc likarolo (A, + 2.2; B, + 1.7; C, + 1.2 ho tloha bregma) e bontšang lisebelisuoa tsa intra-NAc bakeng sa liphoofolo tsohle. Li-cannula li ne li e-na le linaha tse peli empa li emela unilaterally bakeng sa boiketlo ba ho hlahisa liphoofolo tsohle (Naive-Sal, e tšoeu, n = 7; Exp-Saline; bohlooho bo lefifi, n = 9; Exp D1R Ant, e bohlooho bo bobebe, n = 9; Exp D2R Ant, e ntšo, n = 8). ac, ts'ebetso ea pele; LV, li-ventricle hamorao; CPu, caudate-putamen. Thaba ea latency (D), latency ea ts'oaetso (E), le latency ejaculation (F) bakeng sa lihlopha tsohle tse nang le bokooa (Saline, tšoeu; D1R Ant, ea bosoeu; D2R Ant, e ntšo). Litaba li emela ± SEM. *p <0.05, phapang e kholo lipakeng tsa letsatsi la 1 le letsatsi la 4 kalafo.

Ho hlahlojoa ha palo ea likarolo tsa ΔFosB-IR ka NAC 7 d ka mor'a ho phalla ha NAc ho qetela le lenaneo la ho kopanya kapa ho sebetsana le likarabo li senotse phapang e khōlō pakeng tsa lihlopha tse peli tsa NAc shell (F(3,29) = 18.070, p <0.001) le mantlha (F(3,29) = 10.017, p <0.001). Taba ea mantlha, boiphihlelo ba thobalano litlamong tse kenngoeng ke letsoai bo bakile phokotso e kholo ea ΔFosB ha e bapisoa le taolo ea bohloka ba thobalano (Feie. 5A, shell p <0.001; Feie. 5B: mantlha, p <0.001), e netefatsa liphetho kaholimo. Antagonism ea D1R, empa eseng D2R, e thibetse kapa ea thibela phokotso ena ea ΔFosB. Khetleng ea NAc, mohanyetsi oa D1R ea ts'oereng banna ba nang le boiphihlelo ba thobalano ha a bontše keketseho ea lisele tsa ΔFosB-IR ha li bapisoa le taolo ea botona le botšehali (Feie. 5A: p = 0.110), 'me polelo ea DFF e ne e le tlase haholo ha e bapisoa le banna ba nang le letsoai la balekane ba thobalano (Feie. 5A: p = 0.002). Mofuteng oa NAC, likhohlano tsa D1R li bile le phello e fokolang: DFFB e ile ea eketseha haholo ho banna ba tšoaroang ke bahanyetsi ba D1R ha bapisoa le taolo ea saline ea naine (Feie. 5B: p = 0.031), empa phetoho ena e ne e le tlase haholo ha e bapisoa le banna ba nang le letsoai la banna ba nang le thobalano (Feie. 5B: p = 0.012). Phekolo ea bahanyetsi ba D2R ha ea ka ea ama ΔFosB ho qhoqhoa ha banna ba nang le botona kapa botšehali ba neng ba fumane mohanyetsi oa D2R ba na le palo e kholo haholo ea lisele tsa ΔFosB-IR tse bapisoang le lisebelisoa tsa saline tsa naive (Feie. 5A: shell, p <0.001; Feie. 5B: mantlha, p <0.001) le banna ba tšoaroang ba lireng ba D1R (Feie. 5A: shell, p <0.001; Feie. 5B: mantlha, p = 0.013), 'me e ne e sa fapane le banna ba nang le thobalano ba nang le thobalano.

Setšoantšo sa 5.     

Ho thibela D1R ho NAc ho thibela keketseho ea palo ea DFBB-IR lisele tse NAC tsa liphoofolo tse nang le phihlelo ea ho kopanela liphate. Phetoho ea palo ea lisele tsa ΔFosB-IR ka shell ea NAc (A) le mokokotlo (B) ka liphoofolo tse nang le phihlelo (tse ntšo) tse amanang le thobalano ha li bapisoa le taolo ea bohloeki (bohloeki) (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Lintlha ke sehlopha se bolelang ± SEM. *p <0.05, phapang e kholo ha e bapisoa le taolo e se nang kelello. #p <0.05, phapang e kholo ha e bapisoa le letsoai le D2R Ant liphoofolo tse nang le boiphihlelo. Moemeli oa litšoantšo tsa Naive Sal (C), Exp Sal ​​(D), Exp D1R Ant (E), le Exp ExpXXUMA Ant (F). khalaletso, ts'ebetso ea Anterior. Sebaka sa sekala, 100 μm.

E le ho laola hore ho ka ba le tšoaetso ea D1R kapa bahanyetsi ba D2R ho ea lebaleng la storum, polelo ea DFFB e ile ea hlahlojoa sebakeng seo hang-hang ho ea ho NAc le haufi le ventricle ea lateral, kaha ho kenngoa ha ΔFosB ho dorsal striatum ke psychostimulants le opiates ho itšetlehile ka D1R mosebetsi (Zhang et al., 2002; Muller le Unterwald, 2005). Boiphihlelo ba ho kopanela liphate bo ekelitse palo ea lisele tsa ΔFosB-ir tse ling tsa banna ba tšoeroeng ke saline (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), e tiisa tlaleho ea rona ea pele (Pitchers et al., 2010b). Ho feta moo, ha ho na D1R kapa D2R ea hanyetsanang le bothata ba ho ba le bothata ba ho kopanela liphate ka NAC-e entseng ΔFosB ka dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir lisele; Exp-D2R: 83.9 ± 4.4 ir lisele; p <0.001 ha e bapisoa le taolo ea Naive-Sal). Liphuputso tsena li fana ka maikutlo a hore ho ata ha infusions tsa bahanyetsi ho ne ho lekantsoe ho NAc feela.

Mohanyetsi oa D1R ka NAc o thibela ho fumana mohau oa Amph

D1R e thibeletse ho NAc nakong ea ho kopanela liphate hape ho thibeloa ho kopanela liphate ka lebaka la ho kopanela liphate Amph ho ntlafatsoa, ​​ho hlahlojoa 7 d kamora 'mele oa ho qetela oa NAC le tlhahlobo ea mating (F(3,29) = 2.956, p = 0.049). Liphoofolo tse nang le likamano tsa botona le botšehali tse ileng tsa fumanoa saline ka NAc nakong ea likhallelo tsa ho kopanya li qetile nako e ngata haholoanyane kamoreng ea Amph-paired ha e bapisoa le banna ba batona le ba batšehali (Feie. 6A, p = 0.025), ho netefatsa liphetho tse ka holimo. Ka lehlakoreng le leng, liphoofolo tse nang le phihlelo ea ho kopanela liphate tse ileng tsa fumana mohanyetsi oa intra-NAc D1R nakong ea ho nyalana ha lia ka tsa theha CPP bakeng sa Amph. Ba ne ba sa fapane le taolo ea boikhohomoso ba ho kopanela liphate, 'me ba qeta nako e seng kae haholo kamoreng ea Amph-paired ha ba bapisoa le saline (Feie. 6A: p = 0.049) kapa mohanyetsi oa D2R (Feie. 6A: p = 0.038) e kentse banna ba nang le phihlelo ea ho kopanela liphate. Likhohlano tsa D2R tse fapaneng ha lia ka tsa ama Amph e ntlafetseng ha liphoofolo tse nang le phihlelo ea ho kopanela liphate le NAC D2R tse hanyetsanang le tšoaetso e entsoeng ka mahlaseli a mabeli li ile tsa theha bo-'mampo-ba-CPP ba bohlokoa ha ba bapisoa le lithiamo tsa saline (Feie. 6A: p = 0.040) le liphoofolo tse nang le phihlelo ea D1R (Feie. 6A: p = 0.038), 'me e ne e sa fapane le banna ba nang le thobalano ba nang le thobalano.

Setšoantšo sa 6.     

Ho thibela li-receptors tsa D1 ho NAC li felisa ho matlafatsa liphahla le ho eketsa likhahla tsa dintritic liphoofolong tse nang le phihlelo. A, Nako ea nako e sebelisitsoeng kamoreng ea li-Amph nakong ea tlhahlobo ea kamora 'tlhahlobo ho feta tekanyo ea pele (CPP, metsotsoana) bakeng sa batho ba kopanelang liphate (ba makhooa, n = 6) le liphoofolo tse nang le phihlelo (tse ntšo) tse amohetseng saline (n = 7), mohanyetsi oa D1R (n = 9), kapa mohanyetsi oa D2R (n = 8). Lintlha ke sehlopha se bolelang ± SEM. *p <0.05, phapang e kholo ha e bapisoa le taolo ea letsoai e senang tsebo. #p <0.05, phapang e kholo ho liphoofolo tse nang le boiphihlelo tsa D1R. B, Palo ea li-spin dintritic (ka 10 μm) bakeng sa batho ba kopanelang liphate (ba makhooa, n = 7) le liphoofolo tse nang le phihlelo (tse ntšo) tse amohetseng saline (n = 8), mohanyetsi oa D1R (n = 8), kapa mohanyetsi oa D2R (n = 8). Lintlha ke sehlopha se bolelang ± SEM. *p <0.05, phapang e kholo ha e bapisoa le taolo ea letsoai e senang tsebo. #p <0.05, phapang e kholo ho tsoa ho taolo ea letsoai e nang le boiphihlelo.

Ts'oaetso ea li-D1R e thibela liketso tsa thobalano-e bakisitse NAc spinogenesis

Ho hlahlojoa ha sekhahla sa mokokotlo ho NAC ea liphoofolo tsena ho bonts'a hore ts'ebetso ea D1R nakong ea ho nyalana e ne e hlokeha bakeng sa ho eketseha ha pelo ea Nac ka mor'a ho ba le likamano tsa thobalano le 7 ea thobalano ea ho kopanela liphate (Feie. 6B; F(3,26) = 41.558, p <0.001). Haholo-holo, taolo ea letsoai le nang le boiphihlelo ba ho kopanela liphate le liphoofolo tse hanyetsanang tsa D2R li ne li na le mefuta e mengata haholo ea mokokotlo ha e bapisoa le taolo ea letsoai le sa tsotelleng ea letsoai (Feie. 6B: p <0.001) e netefatsa liphetho tsa rona tsa pele (Pitchers et al., 2010a) le liphuputso tse nang le likokoana-hloko tsa kokoana-hloko ea GFP tse hlalositsoeng ka holimo. Ka lehlakoreng le leng, mohanyetsi oa D1R ea nang le likamano tsa botona le botšehali-o ne a kenya liphoofolo liphoso ha a fapane le saline ea boitšoaro bo hlephileng ba ho kopanela liphate-Feie. 6B). Ho ne ho e-na le phello e fokolang ea ho kenngoa ha mohanyetsi oa D2R ha D2R e kenya liphoofolo matšoao a bontšang matla a sefate sa mokokotlo ho feta ho laola litebelisoa tsa saline (Feie. 6B: p = 0.02), empa lipalo tse phahameng ka ho fetisisa tsa li-spines ha li bapisoa le litebelisoa tsa saline tsa ho kopanela liphate le banna ba nang le phihlelo ba tšoaroang ke D1R (p <0.001; Feie. 6B). Ka hona, D1R e thibelitse ho NAC nakong ea ho nyalana e koetsoe liphello tsa boiphihlelo ba thobalano le ho ipeha molato ho NAc spinogenesis.

Puisano

Thutong ea morao tjena, re bonts'elitse ho matlafatsoa ha tšebetso pakeng tsa moputso oa tlhaho le lithethefatsi, ha moputso oa tlhaho o lateloa ke nako ea ho ila. Haholo-holo, re bontšitse phihlelo eo ka boitšoaro ba thobalano, e latetsoeng ke 7 kapa 28 d ea ho ipholosa, e etsa hore moputso oa Amph o ntlafatsoe. Liphuputso tsena li na le ts'ebetso le karolo ea bohlokoa ea nako ea boithaopo ho tsoa lithethefatsi tsa tlhekefetso ka ho kopanyelletsa litakatso tsa lithethefatsi (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ho phaella moo, ΔFosB ea tlhaho e fumanoang moputso ho NAC ke ea bohlokoa bakeng sa ho fokotsa tšusumetso ea liphello tsa tlhaho ea tlhaho ho itokolla ho psychostimulant moputso, mohlomong ka tsela ea spinogenesis ho NAc nakong ea moputso oa ho itokolla. Re bonts'a hore ho bokella ΔFosB ho NAC kamora ho ba le phihlelo ea ho kopanela liphate ke nako e telele ebile e itšetlehile ka mosebetsi oa NAC D1R nakong ea ho nyalana. Ka lehlakoreng le leng, tsamaiso ena ea DCNUMXR e fokolisitsoeng ea DFFB ka NAC e ile ea bontšoa e le ea bohlokoa bakeng sa moputso o matlafalitsoeng bakeng sa Amph le ho eketseha ha metsoako ea mokokotlo ho NAc, le hoja liphello tsa boiphihlelo ba thobalano li itšetlehile ka nako ea ho itokolla ho moputso oa thobalano (Pitchers et al., 2010a). Qetellong, re ile ra bontša hore NAc spinogenesis e ka tlatsetsa ho nts'etsopele ea pele ea polelo e khutšoanyane ea Amph e khotsofatsang empa ha e bobebe bakeng sa ho tsoela pele ho bontša ts'ebetso ea lithethefatsi e ntlafetseng, kaha ho eketseha ha sekhahla sa mokokotlo ho NAc ho ne ho feta nako e khutšoanyane ka mor'a 7 d, empa eseng 28 d, nako ea boithaopo.

Ho 'nile ha tsejoa nako e telele hore dopamine e lokolloa NAC nakong ea boitšoaro ba meputso ea tlhaho, ho kopanyelletsa le boitšoaro ba thobalano. Ha ho kenyelletsoa mosali ea amohelang, extracellular dopamine e NAc e eketsehile mme e sala e phahame nakong ea ho nyalana (Fiorino et al., 1997). Phuputso ea morao-rao e bontšitse hore ho kenella ka li-antipoprotein dopamine ho NAC nakong ea ho nyalana ha hoa ka ha e-ba le phello ho qaleng kapa ts'ebetsong ea boitšoaro ba thobalano, e lumellanang le khopolo ea hore dopamine ha e amehe polelong ea moputso ka bobeli, empa ho e-na le hoo bakeng sa ho fana ka ts'ehetso ea ts'ehetso ea likamano tse amanang le thobalano (Berridge le Robinson, 1998). Ha e le hantle, ho bolela hore ho na le moputso oa ho kopanela liphate ho etsa hore lisele tsa dopamine li sebetse hantle, ho akarelletsa lisele tsa dopaminergic sebakeng sa ventral tekete le sepheo sa bona, NAC (Balfour et al., 2004). Boitšoaro bo bobe ba ho kopanela liphate bo susumelletsa DFFB ho NAC, e leng eona e kopanelang ho matlafatsa boitšoaro bo bobe ba ho kopanela liphate (phihlelo)Pitchers et al., 2010b). Liphetho tsa morao-rao li bontša hore phallo ea ΔFosB e susumelitsoeng ke ho kena-kenana le bothata, e hlile e itšetlehile ka ts'ebetso ea D1R ho NAc nakong ea ho kopanya. Tlhaloso ena e lumellana le lithuto tsa khale tse bontšang hore ts'ebetsong ea ts'ebetso ea psychostimulant e sa khaotse ho eketsa ΔFosB li-NAC tse nang le li-neuron tse nang le li-spin tse hlalosang D1R (Lee le al., 2006; Kim et al., 2009) le hore tsamaiso e joalo ea DFFB e itšetlehile ka ts'ebetso ea D1R (Zhang et al., 2002). Ho phaella moo, likarabo tsa lithethefatsi tse matlafatsang, tseo ka tloaelo li bonngoeng ke liphoofolo tse nang le phihlelo ea lithethefatsi, li ka hlahisoa ka ho ba sieo ha lithethefatsi pele ho nako ka ho feteletsa maikutlo ha DFBB ho D1R e hlalosang li-neurons ho statum (Kelz et al., 1999). THona, ho eketseha ha moputso oa tlhaho le lithethefatsi ΔFosB ho NAc ka mokhoa o itšetlehileng ka D1R ho matlafatsa boitšoaro ba moputso.

Ho feta moo, liphuputso tsa morao-rao li bontša hore ΔFosB ke mokena-lipakeng oa bohlokoa oa ho fokotsa tšebetso pakeng tsa phihlelo ea tlhahiso ea tlhaho le moputso oa psychostimulant. Joalokaha ho boletsoe, mosebetsi oa ΔFosB ho NAc o kile oa kenngoa mofuteng oa likarabo tsa lithethefatsi tse matlafatsang, joalo ka hore ΔFosB e feteletse maikutlo ho NAC e nolofalletsa motho hore a sebelise k'hok'heine ka mor'a tsamaiso ea pele kapa e pheta-phetoang (Kelz et al., 1999), ho eketsa kutloisiso ea cocaine le morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), 'me e etsa hore motho a itšepe ka tsela e fokolang ea cocaine (Colby et al., 2003). Thuto ea morao tjena e bontša hore thibelo ea D1R kapa mesebetsi ea DFFB nakong ea NAc nakong ea ho nyalana e felisitsoe ke phihlelo ea ho kopanela liphate-ho susumelletseha ho matlafatsa Amph moputso.

Phuputso ea morao tjena e bontšitse hore nako ea ho ithiba ho tsoa moputsong oa thobalano e hlokeha bakeng sa ho lemoha ha Amph moputso le NAc spinogenesis. Re nahana hore ΔFosB nakong ena ea ho ikhutsa e ama boemo ba neuronal ka ho fetola maikutlo a liphatsa tsa lefutso ho theosa le limela tsa lefutso ho qalisa spinogenesis le ho fetola matla a synaptic. Ka sebele, ho thibela ho kenngoa ha ΔFosB ho NAc nakong ea ho nyalana ho thibeloe ho eketseha ha mokokotlo oa mokokotlo ho NAC ho fumanoa ka mor'a moputso oa ho ithiba. Ho feta moo, ho kenyelloa ha mohanyetsi oa D1R ho NAc pele setsi ka seng se finyella ho thibela ho eketseha ha likamano tsa botona le botšehali ho DFF le ho eketsa bongata ba sekhahla.

ΔFosB ke ntho e ngotsoeng ka mokhoa oa phetolelo e ka sebetsang joaloka motlatsi oa khatiso ea mantsoe kapa ho hatella ho susumetsa polelo ea likarolo tse ngata tsa liphatsa tsa lefutso tse ka 'nang tsa ama tšusumetso ea matla le matla a synaptic ho NAc (Nestler, 2008). Ka ho toba, ΔFosB e etsa hore khanya-dependent kinase-5 e itšetlehile ka eona (Bibb et al., 2001; Kumar et al., 2005), nuclear nyenyane κ B (NF-κB) (Russo et al., 2009b), le karolo ea GluA2 ea receptor ea glutamate ea AMPA (Vialou et al., 2010) le re hatisa tlhaloso ea hang-hang ea liphatsa tsa lefutso tsa c-fos (Pitchers et al., 2010b) le histone methyltransferase G9 (Maze et al., 2010). Cxc-dependent kinase-5 e laola liprotheine tsa cytoskeletal le phahlo ea neurite (Taylor le al., 2007). Ho feta moo, ho etsa NF-κB ho eketsa palo ea likhahla tsa dendritic ho NAc, athe ho thibela NF-κB ho fokotseha likhahla tsa basal dendritic le ho thibela ho eketseha ha k'hok'heine ka likhahla (Russo et al., 2009b). Ka hona, moputso oa thobalano o eketsa ΔFosB ho NAc, e ka fetolisang lekaneng la NAc ka sepheo se sengata (ke hore, ho itšetlehile ka li-cyclic-dependent kinase-5, NF-κB) le hore phello e akaretsang ke moputso oa lithethefatsi o matlafatsang, joalokaha ho ne ho tšoaetsoa ke Russo et al. (2009a) bakeng sa liketso tsa cocaine e pheta-phetoang.

Ho shebella ho sa lebelloang thutong ea morao-rao ke hore palo e eketsehileng ea lesapo la mokokotlo ho NAc e ne e le ea nakoana, 'me ha e sa hlola e fumanoa ho 28 d kamora boiphihlelo ba thobalano. Kahoo, letsoalo le matla la lesapo la mokokotlo le ile la kopanngoa le ho qaleha ha moputso oa Amph o ntlafalitsoeng mme o ka kenya letsoho kholisong ea pele kapa polelo ea nakoana ea likarabo tsa Amph tse ntlafalitsoeng. Leha ho le joalo, letsoalo le matla la lesapo la mokokotlo le ne le sa hlokoe bakeng sa ho phehella ha moputso oa Amph ka mor'a ho qeta nako e telele. Re kile ra bonts'a hore boiphihlelo ba thobalano bo baka nako e kgutshwane (7, empa eseng 28, matsatsi kamora ho hoqeta ho ho qetela) keketseho ea NMDA receptor subunit NR-1 ho NAc, e khutlelang mehatong ea motheo kamora nako e telele ea ho khaotsa ho lefuoa (Pitchers et al., 2012). Mantsoe ana a eketsehileng a NMDA a amohelehang a ne a tšoaetsoa hore e be pontšo ea li-synapses tsa ho kopanela liphate tse nang le phihlelo (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), le ho hlahisa maikutlo a hore monyetla oa hore ho ba le phihlelo ea thobalano-e bakoang ke ho hōla ha mokokotlo ho itšetlehile ka mosebetsi o matlafatsang oa ho amohela lihlahisoa tsa NMDA (Hamilton et al., 2012).

Qetellong, phuputso ea morao-rao e totobatsa ho fokotsa sehlabelo sa lithethefatsi ka moputso oa tlhaho (ho kopanela liphate) le ho itšetleha ha eona ka nako ea ho itokolla. Ho feta moo, polasetiki ena ea boitšoaro e ne e sebelisana le ΔFosB ka ts'ebetso ea D1R ho NAc. Ka lebaka leo, boitsebiso bo bontša hore ho lahleheloa ke moputso oa tlhaho ka mor'a phihlelo ea moputso ho ka etsa hore batho ba ipehe kotsing ea nts'etsopele ea ho lemalla lithethefatsi le hore mokena-lipakeng a le mong oa kotsing ena ke ΔFosB le lipakane tsa eona tse ka tlaase.

Mongolo o botlaaseng ba leqephe

  • Re amohetse October 16, 2012.
  • Phetolelo e fumanoeng ka December 12, 2012.
  • E amohetse December 23, 2012.

  • Mosebetsi ona o ne o tšehetsoa ke Mekhatlo ea Lekala la Bophelo ba Mokhatlo oa Canada (LMC), National Institute of Mental Health (EJN), le Natural Sciences le Engineering Research Council of Canada (KKP le LMC). Re leboha Dr. Catherine Woolley (Univesithing e Leboea-bophirimela) bakeng sa thuso ka mokhoa oa diylistic oa ho roala.

  • Bangoli ha ba phatlalatse lithahasello tsa lichelete.

  • Lipuisano li lokela ho lebisoa ho Dr. Lique M. Coolen, Lefapha la Physiology le Biophysics, Setsi sa Bongaka sa Univesithi ea Mississippi, 2500 North State Street, Jackson, MS 39216. [imeile e sirelelitsoe]

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Lihlooho tse qotsitsoeng sehloohong sena

THUTO E TLETSENG - KAROLO EA PUISANO:

Thutong ea hajoale, re bonts'itse maikutlo lipakeng tsa moputso oa tlhaho le oa lithethefatsi, ha moputso oa tlhaho o lateloa ke nako ea ho ila. Ka ho khetheha, re bontšitse boiphihlelo boo ka boits'oaro ba thobalano, bo lateloang ke 7 kapa 28 d ea ho ila thobalano, bo bakang moputso oa Amph o ntlafalitsoeng.

Liphumano tsena li na le lintlha tse ts'oanang le karolo e qaqileng ea nako ea ho khaotsa ho sebelisa lithethefatsi tlhekefetsong ea takatso ea lithethefatsi (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ho feta moo, moputso oa tlholeho o tlisoang ke moputso oa tlhaho? FosB ho NAc e bohlokoa bakeng sa tšusumetso e khahlano le moputso oa tlhaho oa ho se thibele moputso oa psychostimulant, ka mokhoa o ka khonehang ka spinogenesis ho NAc nakong ea ts'oaetso ea moputso.

Re bontšitse hore? Ho bokellana ha FosB ho NAc kamora boiphihlelo ba thobalano bo nka nako e telele ebile bo its'epahalla ketsahalong ea NAc D1R nakong ea ho hola. Ka hona, ho emisoa hona hoa D1R? NA ho bontšitsoe ho bohlokoa bakeng sa moputso o ntlafalitsoeng oa Amph le ho ba le letsoalo le matla la lesapo la mokokotlo ho NAc, leha liphetho tsena tsa boiphihlelo ba thobalano li its'etleha nakong ea ho se thibele moputso oa thobalano (Pitchers et al., 2010a). Kamora moo, re bonts'itse hore NAc spinogenesis e kanna ea kenya letsoho kholisong ea pele ea polelo ea nakoana ea moputso oa Amph empa ha e bohlokoa bakeng sa polelo e tsoelang pele ea moputso oa lithethefatsi tse ntlafalitsoeng, joalo ka ha letsoalo le matla la mokokotlo ho NAc le ne le nka nako ebile le bonoa kamora 7 d, empa eseng 28 d, nako ea thibelo.

Ke khale ho tsejoa hore dopamine e lokolloa ho NAc nakong ea boitšoaro ba tlhaho ba moputso, ho kenyelletsa le boitšoaro ba thobalano. Kamor'a ho hlahisoa ha mosali ea amohelang, dopamine ea extracellular ho NAc e eketseha mme e lula e phahame nakong ea ho ruruha (Fiorino et al., 1997). Phuputso ea morao-rao e bontšitse hore ho kenella ka li-antipoprotein dopamine ho NAC nakong ea ho nyalana ha hoa ka ha e-ba le phello ho qaleng kapa ts'ebetsong ea boitšoaro ba thobalano, e lumellanang le khopolo ea hore dopamine ha e amehe polelong ea moputso ka bobeli, empa ho e-na le hoo bakeng sa ho fana ka ts'ehetso ea ts'ehetso ea likamano tse amanang le thobalano (Berridge le Robinson, 1998). Ho joalo, likhakanyo tse boletsoeng esale pele tsa moputso oa thobalano li baka ts'ebetso ea li-neuron ka har'a sisteme ea meputso ea mesolimbic dopamine, ho kenyelletsa lisele tsa dopaminergic tse sebakeng sa "ventral tegmental" le sepheo sa tsona, NAc (Balfour et al., 2004).

FosB ea NAc, eo ka nako e 'ngoe e arolelanang khothatso ea boits'oaro ea thobalano (Pitchers et al., 2010b). Liphetho tsa hona joale li bonts'a hore ts'usumetso ea ho emisa? Tlholeho ea FosB, ehlile e its'etleha ts'ebetsong ea D1R ho NAc nakong ea ho hola. Phumano ena e lumellana le lithuto tse fetileng tse bonts'ang hore taolo ea psychostimulant e phetoang e ntse e eketseha khafetsa? FosB ho NAc katie spiny neurons e hlahisang D1R (Lee et al., 2006; Kim et al., 2009) le hore joalo? Phapang ea FosB e itšetlehile ka ts'ebetso ea D1R (Zhang et al., 2002). Ntle le moo, likarabo tsa maikutlo tsa lithethefatsi, tse bonoang hangata ho phoofolo e nang le boiphihlelo ba lithethefatsi, li ka hlahisoa ntle le tšenyo ea lithethefatsi tsa pele ho feta ka ho hlalosoa ke matla? FosB ho D1R e hlahisang li-neurons ho striatum (Kelz et al., 1999). Kahoo, meputso ea tlhaho le ea lithethefatsi e ea eketseha? FosB ho NAc ka mochini o itšetlehileng ka D1R ho khothaletsa boitšoaro ba moputso.

Ho feta moo, liphetho tsa hona joale li bonts'a seo? FosB ke mokena-lipakeng oa maikutlo a sefapano lipakeng tsa boiphihlelo ba moputso oa tlhaho le moputso oa psychostimulant. Joalokaha ho hlokometsoe, ts'ebetso ea FosB ho NAc e ne e bile le tšusumetso likarolong tsa maikutlo a lithethefatsi, joalo ka ha FosB overexpression ho NAc e hlokomelisa ts'ebetso ea locomotor ho cocaine kamora ho tsamaisoa ka mokhoa o bohloko kapa ho pheta-phetoang (Kelz et al., 1999), ho phahamisa maikutlo ho cocaine le morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), mme e baka taolo ea litekanyetso tse tlase tsa cocaine (Colby et al., 2003). Boithuto ba hajoale bo bontša seo blockade ea D1R kapa? mosebetsi oa FosB ho NAc nakong ea ts'ebetso ea thobalano e felisitsoeng mabapi le thobalano ea Amph moputso. Thus, moputso oa tlhaho le oa lithethefatsi ha o kopane feela tseleng e ts'oanang ea neural, li kopana le baemeli ba tšoanang ba limolek'hule (Nestler et al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), mme ho ka etsahala hore ho na le neurons e tšoanang NAC (Frohmader et al., 2010b), ho susumetsa moferefere le "ho batloa" ha mefuta ena ka bobeli ea meputso (Berridge le Robinson, 1998).

Boithuto ba hajoale bo bonts'itse hore nako ea ho ila thoko ho moputso oa thobalano e ea hlokahala bakeng sa ho susumetsa moputso oa Amph le NAc spinogeneis. Re ferekanya seo? FosB nakong ena ea ho itlosa bolutu e ama ts'ebetso ea methapo ka ho fetola polelo ea methapo ea methapo ho theha spinogenesis le matla a ho fetolela. Ka 'nete, Ho thibela ho kenella ha FosB ho NAc nakong ea ho ruruha ho ile ha thibela bongata ba lesapo la mokokotlo ho NAc e fumanoeng kamora ho khaotsa moputso. Ho feta moo, iTlhatlhobo ea mohanyetsi oa D1R ho NAc pele karolo e 'ngoe le e' ngoe ea ho tlolelana ha mosali e emisa ho eketseha ha bohlola?. FosB ke ntho e hatisang e ka sebetsang joalo ka ho kenya letsoho ho kenya letsoho ho hlahisa maikutlo a mangata a mefuta ea sepheo a ka fetolang letsoalo la lesapo la mokokotlo le matla a synaptic ho NAc (Nestler, 2008). Ka ho khetheha, FosB e kenya tšebetsong cyclic-based kinase-5 (Bibb et al., 2001; Kumar et al., 2005), factor factor? B (NF-? B) (Russo et al., 2009b), le GluA2 subunit ea glutamate AMPA receptor (Vialou et al., 2010) le pheta phetisetso ea mofuta oa pele oa gene c-fos (Pitchers et al., 2010b) le histonetrylferase G9 (Maze et al., 2010). Cyclicdependent kinase-5 e laola liprotheine tsa cytoskeletal le ho phatloha ha neurite (Taylor et al., 2007). Ho feta moo, ho kenya letsoho NF-? B ho eketsa palo ea methapo ea methapo ho NAc, athe ts'oaetso ea NF-? B e fokotsehile methapo ea methapo ea basal le ho thibela keketseho e bakoang ke koae (csoine-ikiwa). Ke moputso oa thobalano o eketsehang? FosB ho NAc, e ka fetolang letsoalo la lesapo la mokokotlo la NAc ka merero e mengata (ke hore, kinase-5 e tsamaeang ka cyclic, NF-? B) ake hore sephetho ka kakaretso ke moputso oa lithethefatsi tse khothalletsoang, joalo ka ha e ne e le hypothesised ke Russo et al. (2009a) bakeng sa liketso tsa khafetsa koae

Ho shebella ho sa lebelloang thutong ea morao-rao ke hore palo e eketsehileng ea lesapo la mokokotlo ho NAc e ne e le ea nakoana, 'me ha e sa hlola e fumanoa ho 28 d kamora boiphihlelo ba thobalano. Kahoo, letsoalo le matla la lesapo la mokokotlo le ile la kopanngoa le ho qaleha ha moputso oa Amph o ntlafalitsoeng mme o ka kenya letsoho kholisong ea pele kapa polelo ea nakoana ea likarabo tsa Amph tse ntlafalitsoeng. Leha ho le joalo, iTekanyetso ea lesapo la mokokotlo e ntlafalitsoeng e ne e sa hlokehe bakeng sa ho phehella ha moputso oa Amph ka mor'a ho qeta nako e telele. Re kile ra bonts'a hore boiphihlelo ba thobalano bo baka nako e kgutshwane (7, empa eseng 28, matsatsi kamora ho hoqeta ho ho qetela) keketseho ea NMDA receptor subunit NR-1 ho NAc, e khutlelang mehatong ea motheo kamora nako e telele ea ho khaotsa ho lefuoa (Pitchers et al., 2012). Polelo ena e eketsehang ea li-receptor tsa NMDA e ne e nahanoa hore e supa matšoao a khutsitseng a batho ba nang le thobalano (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), hape a fana ka maikutlo a hore monyetla oa ho etsa thobalano o ts'oeroe. kholo ea lesapo la mokokotlo e itšetlehile ka tšebetso e ntlafalitsoeng ea NMDA receptor (Hamilton et al., 2012).

Qetellong, thuto ea hajoale e totobatsa ho teba ha moputso oa lithethefatsi ka moputso oa tlhaho (thobalano) le ho its'etleha hoa nako ea ho se fuoe meputso. Ntle le moo, boits'oaro bona ba boitšoaro bo ne bo kopantsoe ke FosB ka ts'ebetso ea D1R ho NAc. Ka hona, data e fana ka maikutlo a hore tahlehelo ea moputso oa tlhaho kamora boiphihlelo ba moputso e ka etsa hore batho ba hlaselehe habonolo kholisong ea lithethefatsi le hore mokena-lipakeng a le mong oa tlokotsi e atileng ke FosB le sepheo sa eona sa ho ngola se tlase.