Umthetho weMvelo kunye neMiphumo yoLwabiwo kwiindlela eziqhelekileyo ze-Neural Plasticity kunye ne-DFF njengoMlamli oPhambili (2013)

Olu pho nonongo luhlolisise imiphumo yomvuzo wesondo kwi-DeltaFosB kunye nemiphumo ye-DeltaFosB ngokuziphatha ngokwesondo kunye nomvuzo. Utshintsho oluqhelekileyo lweemolekyuli ezaziwayo ukuba zenzeka ngeziyobisi zafunyanwa zifana nokwenzeka ngesondo. Ngamanye amagama, i-DeltaFosB yavela kwisistim sezesondo, kodwa iziyobisi zaphanga le ndlela inye. Oku kuyayiphelisa ingxoxo malunga nendlela iziyobisi ezichaseneyo zahluke ngayo kwezokuziphatha, kunye nendlela yokuziphatha okunyanzelekileyo ukuba kube kukunyanzelwa (nokuba kuthetha ntoni). Iisekethe ezifanayo, iindlela ezifanayo, utshintsho olufanayo lweselfowuni, isimilo esifanayo sokuziphatha-nokwahluka okuncinci.

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

ISIFUNDO ESIFUNDILEYO

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

imvelaphi

ISebe le-Anatomy kunye neBiology Biology, iSchulich School of Medicine kunye noDentistry, kwiDyunivesithi yaseNtshona Ontario, London, Ontario N6A 3K7, Canada, Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg Department of Neuroscience and Friedman IZiko leBrain, iSikolo seNtaba iSinayi sezoNyango, eNew York, eNew York 10029, kunye namaSebe eNeurobiology kunye neAnatomical Sciences kunye nePhysics kunye neBiophysics, kwiDyunivesithi yaseMississippi Medical Centre, eJackson, eMississippi 39216.

Abstract

Izidakamizwa zokusetyenziswa gadalala zenza i-neuroplasticity kwindlela yokuvuza yemvelo, ngokukodwa i-nucleus accumbens (NAc), oko kubangela ukuphuhliswa nokubonakalisa ukuziphatha komlutha. Ubungqina bwakutshanje bubonisa ukuba umvuzo wendalo ungabangela utshintsho olufanayo kwi-NAc, ebonisa ukuba iziyobisi zingasebenzisa iinkqubo zeplastiki ezabelwana kunye nemivuzo yemvelo, kwaye ukuvumela ukusebenzisana okukhethekileyo phakathi kwembuyekezo yemvelo kunye neziyobisi.

Kule sifundo, sibonisa ukuba amava eentlobano zesini xa kulandelwa ixesha elifutshane okanye elide lokulahleka kwesini somvuzo kubangela umvuzo wokuphucula i-amphetamine, kuboniswe ngendawo ekhethiweyo yendawo yokuhlala (i-0.5 mg / kg) i-amphetamine. Ngaphezu koko, ukuqala, kodwa kungekhona ixesha elide, ukufumana umvuzo wokuphucula i-amphetamine kwakuhambelana nokunyuka kwexesha elide kwiintlobo ze-dendritic kwi-NAc. Ngokulandelayo, indima ebalulekileyo kwinto yokubhalwa kwephepha ΔFosB kwi-sex-incured reward amphetamine umvuzo kunye nokwanda okwenziwe kwiintlobo ze-dendritic kwi-NAc neurons yasungulwa usebenzisa i-viral vector ukudlulisela i-virtual con-negative negative partner. Ukongezelela koko, kuboniswe ukuba amava ezesondo-ayenze umvuzo wokunyusa izidakamizwa, i-DFFB kunye ne-spinogenesis kuxhomekeke ekusebenziseni i-dopamine yokufumana i-D1 ukufunyanwa kwe-NAc. Ukukhutshwa kwe-Pharmacological ye-D1 receptor, kodwa kungekhona i-receptor ye-D2, kwi-NAc ngexesha lokuziphatha kakubi ngokwesondo elithintekayo ΔFosB ukukhutshwa kunye nokuthintela ukunyuka kwe-spinogenesis kunye nomvuzo wokufumana i-amphetamine.

Tzonke, ezi ziphumo zibonisa ukuba iziyobisi zokusetyenziswa kakubi kunye nokuziphatha komvuzo wendalo zisebenza kwiindlela eziqhelekileyo zamathambo kunye namaselula eeplastiki ezilawula ukukhuselwa kwingozi yokusetyenziswa kweziyobisi, kwaye ukuba olu khuselo lukhutshwe yi-DFB kunye neethagethi zayo eziphantsi.

intshayelelo

Ukuziphatha kwemivuzo yemvelo kunye nomvuzo wezidakamizwa ziguqulela kwindlela eqhelekileyo ye-neural, indlela ye-mesolimbic dopamine (DA), apho i-nucleus accumbens (NAc) indima indima ebalulekileyo (Kelley, 2004). Izidakamizwa zokusetyenziswa gadalala zenza i-neuroplasticity kwinkqubo ye-mesolimbic, edlala indima yokubeka inxaxheba ekutshintsheni kwezidakamizwa ukuya kumlutha weziyobisi (Hyman et al., 2006; IKauer kunye neMalenka, i-2007; Kalivas, 2009; Chen et al., 2010; Koob noVolkow, i-2010; Wolf, 2010a; Mameli noLuscher, i-2011). Kuye kucatshulwa ukuba iziyobisi kunye nemivuzo yemvelo ayisebenzisi i-neurons efanayo kwindlela ye-mesolimbic, kwaye ngoko ke ukuba iziyobisi zisebenze ngokukhethekileyo kwaye ziguqula le circuit (ICameron ne-Carelli, i-2012). Nangona kunjalo, kuye kwacaca ngokucacileyo ukuba imivuzo yemvelo kunye neziyobisi ichaphazela inkqubo ye-mesolimbic kwindlela zombini kunye neendlela ezahlukeneyo ezivumela ukusebenzisana phakathi komvuzo wemvelo, umvuzo wesini, kunye nemiphumo yeziyobisi zokusetyenziswa gadalala (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Ukuziphatha ngokwesondo kuvuyisa kakhulu (Tenk et al., 2009),

Ezi ziphumo zibonisa ukuba amava omvuzo wezinto zendalo kunye neziyobisi zibandakanya iinkqubo eziqhelekileyo zeplastiki ye-neural, echaphazela ukusetyenziswa kakubi kweziyobisi.

Injongo yesifundo esilikhoyo kwakukukunqumla iindlela zamaselula ezixubungula ama-plasticity eyenziwa ngamava esini, okubangela ukuba umvuzo onokuphucula umvuzo. Ngokukodwa, indima yento yokubhalwa kwephepha ΔFosB iphenywe kuba ibandakanyekile kwimiphumo yemvelo kunye neziyobisi (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Ukongeza, indima ye-dopamine i-D1 receptors (i-D1R) ye-plastic neural plasticity eyenziwa ngamava ezesondo, yahlolwa ngenxa yokuba i-NAc ΔFosB induction kunye nokunyuka kwesantya emva kokulawulwa kwengqondo ye-psychostimulant kuboniswe kwi-neurons ene-D1R (ULee et al., 2006; UKim et al., 2009) kwaye kuxhomekeka kwi-D1R kusebenze (Zhang et al., 2002).

Apha, sasebenzisa ibinzana le-virtual-binding partner of ΔFosB, i-diOlistic yokubhaliweyo, kunye neendlela zokusebenzisa i-pharmacy ukuvavanya ingcamango yokuba imiphumo ebangela ukuba i-sex experience ilandelelwe ukuziyeka ukungabikho komvuzo kwi-Amph umvuzo. Ukufakelwa kwe-D1R kuxhomekeke kwi-DFNB kwi-NAc kunye nokwanda kwe-NAc kwintsipho. Ngokubonke, iziphumo zibone ubungqina bokuba imbuyekezo yemvelo kunye neziyobisi ikwabelana ngeendlela eziqhelekileyo zeplastiki ye-neural, kunye ne-DFF njengomlamli obalulekileyo.

Impahla nenkqubo

Izilwanyana.

Umntu omdala (225-250 g ekufikeni) kunye ne-female (210-220 g) Ukuphambanisa amagqabi e-Dawley (iCharles River Laboratories) babehlala kwii-Plexiglas ezigumbini kwiindidi ezifanayo zesini ngexesha lovavanyo, phantsi kobushushu kunye nolawulo lwe-humidity kunye ne-12 / 12 h umjikelezo omnyama / omnyama ngokutya kunye namanzi atholakalayo ngokukhululekileyo. Amaqabane abesifazana kwiiseshini zokuxhatshaza ayenze i-ovariectomized and received implants subcutaneous implants ene-5% estradiol benzoate (Sigma-Aldrich) kunye neenjini ze-500 μg ye-progesterone (kwi-0.1 ml yeoli yeesame; Sigma-Aldrich) 4 h ngaphambi kokuvavanya. Zonke iinkqubo zivunywe yiNkxaso yezilwanyana kunye neeKomiti zeNtsebenzo zeYunivesithi yaseNtshona Koloni kunye neYunivesithi yaseMichigan kwaye zihambelana neCanada Council malunga neZinyango zoLondolozo lwezilwanyana kunye neziKhokelo zeSizwe zezeMpilo ezibandakanya izilwanyana ezitshatyalaliswayo kuphando.

Ukuziphatha ngokwesondo.

Iseshoni zokuxubana kwenzeka ngexesha lokuqala elimnyama (phakathi kwe-2 kunye ne-6 h emva kokuqala kwexesha elimnyama) ekukhanyeni okubomvu okukhanyayo, kwiibhokisi zokuvavanya ezicoca (60 × 45 × 50 cm). Amakhwenkwe angamadoda athatyathwa ukunyuka kwixesha le-4 okanye i-5 iiseshoni zokuqhawula imihla ngemihla. Iiseshoni ezintlanu zakhethwa kuba sele sibonisile ukuba le paradigm ibangela ukuqhutywa kwexesha elide lokuziphatha ngokwesondo (Pitchers et al., 2010b), ulwaphulo-mnqamlezo kwi-Amph locomotor umsebenzi (Pitchers et al., 2010a), kunye nomvuzo (Pitchers et al., 2010a). Ukukhethwa kwe-Ejaculation kukhethwe njengophelo lokuseshoni nganye yokubambisana ngenxa yokuba ngaphambili sasibonisa ukuba kubalulekile kwimiphumo yesifo sobulili kwi-Amph locomotor sensitization (Pitchers et al., 2010a), okungazange kwenzeke xa izilwanyana zavunyelwa ukuba zithandane nabasetyhini ngaphandle kokubonakaliswa kwe-ejaculation. Iimpawu zendlela yokuziphatha ngokwesondo (oko kukuthi, ukuhamba kwexesha lokuqala ukuya kwintaba yokuqala, ukuxhoma kunye nokunyuka, kunye nenani lezintaba kunye ne-intromissions) kubhalwe njengoko kuchazwe ngaphambili (Pitchers et al., 2010b). Kuzo zonke izilingo, amaqela ahlangene ngesondo ahambelana nokuziphatha ngokwesini (inani elipheleleyo le-ejaculations kunye ne-latency ukuya ku-ejaculation ngexesha leseshoni nganye yokulinganisa). Emva kweseshoni yesihlanu yokuxhaswa, amadoda ayesehlala kunye nabalingani bobulili obufanayo kwaye abavunyelwe ukuba bathathane ngexesha lokuzilahla kwezesondo ze-1, 7, okanye i-28 d. Izilwanyana ezazihlala zingabonanga ngesondo zaphathwa kwaye zahlala kumagumbi afanayo njengamadoda azalwa ngokwesini. Ukongezelela, ukulawulwa kobukhohlakali kwafakwa kwiibhokisi zokuvavanya ezichanekileyo ngeyure ngexesha leentsuku ze-5 ezilandelanayo, ngaphandle kokufikelela kumfazi owamkelekileyo.

Imbonakalo yeFFB.

Izilwanyana zazixhamle kakhulu (i-sodium pentobarbital; i-390 mg / kg; ip) kwaye yatshatyalaliswa ngokungahambisani ne-50 ml ye-0.9% saline, ilandelwa yi-500 ml ye-4% ipalformaldehyde (Sigma-Aldrich) kwi-0.1 m phosphate buffer (PB) ngexesha ngongoma kunye novavanyo lweD DR. Ubuchopho babuyisusiwe kwaye bufihliweyo kwi-1 h kwisebni lokubumbisa kwindawo efanayo, kwaye igcinwe kwi-4 ° C kwi-20% i-sucrose kunye ne-0.01% ye-sodium azide kwi-0.1 m PB. Kwiingqungquthela ze-DR zenzalo, ubuchopho basuswa kwaye buncipha ngesigxina se-sagittal. Isiqingatha esinye sagcinwa kwi-PB kwaye sisetyenziselwa i-DiOlistics, enye isetyenziselwa i-ΔFosB. Iziqendu ze-Coronal (35 μm) zacutshungulwa nge-microtome ebandayo (Microm H400R), ziqokelelwe kwiinkomfa ezine ezifanayo kwi-solution ye-cryoprotectant (30% sucrose kunye ne-30% ethylene glycol kwi-0.1 m PB) kwaye igcinwe kwi-20 ° C. Iziqendu ezingenazikolo ezihlambulukileyo zihlanjwe ngokubanzi nge-0.1 m PBS, i-pH 7.35, phakathi kwamashishini, kwaye onke amanyathelo asemashishini ashushu. Amacandelo atyhila kwi-1% H2O2 (10 min) kunye nesisombululo sokuxubusha (i-1 h; i-PBS ene-0.1% BSA, i-Fisher; kunye ne-0.4% iTriton X-100, iSigma-Aldrich). Amacandelo awayebanjwe ngobusuku bobushushu kwi-pan-FosB yomnquba we-polyclonal antibody (1: 5K; sc-48 iSanta Cruz Biotechnology), eqinisekisiwe ngaphambili (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). I-pan-FosB antibody yaphakanyiswa ngokuchasene nengingqi yangaphakathi ekwabelwana ngayo yi-FosB kunye ne-osBFosB, kwaye ibikade ibonakalisiwe ngaphambili ukuba ibonakalise ngokungqalileyo iiseli ze-osBFosB ngamaxesha asetyenziswe kolu phononongo (> 1 d emva kwesikhuthazi) (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Emva koko, amacandelo ayengenwe kwi-biGin-guj-anti-rabbit IgG (1 h; 1: 500 kwi-PBS +; iVector Laboratories), i-avidin-biotin-horseradish peroxidase (i-1 h; i-ABC elite; i-1: i-1000 kwi-PBS; iiVector Laboratories) , kunye ne-0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) kunye ne-0.02% ye-nickel sulfate kwi-0.1 m PB ene-hydrogen peroxide (0.015%). Amacandelo aphakanyiswa kwiSlafrost kunye neesilayidi zeglasi (Fisher) kwaye zihlanganiswe ne-dibutyl phthalate xylene.

Inombolo yee-FosB-IR iiseli zazibalwa kwigobolondo le-NAc kunye nomyinge kwiindawo eziqhelekileyo zokuhlalutya (400 × 600 μm) njengoko kuchaziwe ngaphambili (Pitchers et al., 2010b). Amacandelo amabini ayebalwa kwi-NAc, ngaphantsi kwezilwanyana. Ngexesha lovavanyo, amaqela e-ΔFosB-IR iiseli zibonakaliswe njengenguqu yenkqubela yeqela lokulawula i-naive ngexesha elifanelekileyo kunye nokuthelekiswa phakathi kwamaqela anamava kunye namava e-subregion nganye kwixesha ngalinye elo xesha usebenzisa t iimvavanyo ngezinga lokubaluleka p <0.05. Kwi-ΔJunD-AAV kunye ne-DR yokuchasana nokuvavanywa, iindlela ezimbini okanye indlela enye ye-ANOVA, ngokwahlukeneyo, kunye nendlela yeHolm-Sidak. Ukongeza, iiseli ze-osBFosB-IR zabalwa kwi-dorsal striatum (indawo yohlalutyo: 200 × 600 μm), kwangoko yaya kwi-NAc nakufutshane ne-ventricle esecaleni, kuzo zonke izilwanyana kuvavanyo lwe-DR. Indlela enye ye-ANOVA kunye t iimvavanyo zisetyenziselwa ukuqhathanisa phakathi kwamaqela.

DiOlistics.

Ixesha lexesha kunye ne-ΔJunD vector vest test, iiliti zatshatyiswa ngokungenakucala kunye ne-50 ml saline (0.9%), ilandelwa ngu-500 ml we-2% ipolformaldehyde kwi-0.1 m PB. Ubuchopho babecwecwe (100 μm coronal) usebenzisa i-vibratome (Microm) kunye namacandelo agcinwe kwi-0.1 m PB kunye ne-0.01% ye-sodium azide kwi-4 ° C. Iingubo ze-tungsten (i-1.3 μm ububanzi, i-Bio-Rad) kunye ne-lipophilic carbocyanine idayi i-DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate; i-Invitrogen) yenziwa njengoko kuchaziwe ngaphambili (Forlano no Woolley, 2010). Iintlobo ze-tungsten ezenziwe nge-DiI zihanjiswe kwiisiski kwi-160-180 psi usebenzisa i-Helios Gene Gun system (i-Bio-Rad) ngokucoca kunye ne-3.0 μm ubukhulu bepore (BD Biosciences) kwaye ivumelekile ukuba idlulele kwiimbrane ze-neuronal kwi-0.1 m PB I-24 h ngelixa ikhuselwe ngokukhanya kwi-4 ° C. Emva koko, iiplani zazingeniswa kwi-4% ye-paraformaldehyde kwi-PB ye-3 h kwiqondo lokushisa lokushisa, ihlanjwe kwi-PB, kwaye iphakanyiswe kumagumbi aqhotyoshelweyo (Bio-Rad) kunye ne-gelvatol ene-anti-fading agent i-1,4-diazabicyclo (2,2) octane ( 50 mg / ml, Sigma-Aldrich) (ULennette, 1978).

Ii-neurons ezibhalwe nge-DiI ziyi-imagery esebenzisa Zeiss I-microscope ye-LSM 510 mUCarl Zeiss) kunye ne-helium / neon 543 nm laser. Ngesilwanyana ngasinye, i-2-5 neurons nganye kwi-NAc, okanye kwi-shell (esekelwe kwindawo ehambelana nemimandla-mhlaba, kuquka i-ventricle yangaphambili kunye nokukhishwa kwangaphambili) kwi-ΔJunD-AAV kunye ne-DR. inomdla kwinqanaba le-dendrite yesihlandlo yesibini. Kwi-neuron nganye, i-2-4 dendrites yahlaziywa ukulinganisa ubude be-dendritic ubude be-40-100 μm. Amacandelo e-Dendritic athathwe ngokusetyenziswa kwe-40 × Injongo yokucwiliswa kwamanzi kwixesha le-0.25 μm kunye z-axis, kunye nomfanekiso we3D wakhiwe kabusha (Zeiss) kwaye yenziwa i-deconvolution (i-X ngokuzenzekelayo, i-Media Cybernetics) isebenzisekayo (imfama) kunye ne-PSF yeendlela ezicetyiswa yi-software. Uxinzelelo lwesantya lwangqinisiswa usebenzisa i modyuli yeFilament ye-software ye-Imaris (i-7.0, i-Bitplane). Inani leentlobo ze-dendritic zaboniswa nge-10 μm, ezilinganiselwe kwi-neuron nganye kwaye emva kwesilwanyana ngasinye. Ulwahlulo lwama-statisti lwaluqulunqwe ukusebenzisa ii-ANOVA ezimbini kwixesha lovavanyo lwamaxesha phakathi kwezilwanyana zesini kunye nobuchule kwixesha ngalinye (izinto: amava ezesondo kunye ne-NAc ngaphantsi) kunye novavanyo lwe-AJJ (izinto: amava ezesondo kunye ne-vector vector), kunye -Okunjalo i-ANOVA kwimvavanyo ye-DR. Ukuqhathaniswa kweqela kwenziwa ngeendlela zeHolm-Sidak ngenqanaba lokubaluleka p <0.05.

Indawo ekhethwe ngayo.

Ukuqulunqwa kweprogram yeCPP kwakufana nangoko njengoko kuchazwe ngaphambili (Pitchers et al., 2010a), usebenzisa i-apparatus ye-three-quarry appliances (i-Med Associates), kunye noyilo olungabonakaliyo, kunye nesilingo esisodwa sokubambisana kwe-d-Amph sulphate (Amph; Sigma-Aldrich; i-0.5 mg / ml / kg esabalwa ngesiseko se-free) kwigumbi elibiniweyo kunye ne-saline kwikamelo elingenakunyulwa ngexesha lezinye iintsuku, kwaye kwenziwa ngexesha lesibini sokuqala kwesigaba sokukhanya. Izilwanyana zolawulo zifumene i-saline kumagumbi amabini.

Iziphumo ze-CPP zibalwe kwisilwanyana ngasinye njengethuba elichithwe (ngemizuzwana) kwigumbi elibiniweyo ngexesha lokuvavanywa kweposi emva kokunciphisa. Indlela enye ye-ANOVA kunye neHolm-Sidak indlela yayisetyenziselwa ukuqhathanisa amaqela ngexesha lokuhlola kwexesha. Ngaphandle t vavanyo ngokubaluleka okubekiwe p <0.05 yayisetyenziselwa ukuthelekisa iNaive-Sal kunye neNaive Amph ngaphakathi kwexesha ngalinye kwinqanaba lokuvavanywa, kunye nonyango ngalunye lwe-vector yonyango kwi-ΔJunD yokulinga. Ngexesha lokulinga, ii-ANOVA zendlela enye kunye nendlela yeHolm-Sidak yayisetyenziselwa ukuthelekisa amaqela anamava ezesondo (i-Exp-Sal, i-7 d i-Exp Amph kunye ne-28 ye-Exp Amph), kunye ne-unpaired t vavanyo lusetyenziswa ukuthelekisa amaqela angama-2. Iindlela ezimbini ze-ANOVA kunye neHolm-Sidak kwindlela esetyenzisiweyo ukuthelekisa onke amaqela kwi-DR antiagonist experiment. Ababini abangasebenzi t Uvavanyo lwalusetyenziswa ukuthelekisa amaqela aseNaive-Sal kunye neNowve Amph kunye nemeko yonyango ye-vel (GFP okanye i-JUND), njengoko idatha yayingatshintshi kumaqela angama-AA ukuze avumele uhlalutyo lwe-ANOVA. Zonke iinqanaba lokubaluleka zafakwa p <0.05.

Uvavanyo lwevolon vector.

Ii-rats zamadoda zazisetyenziselwa i-ketamine (i-87 mg / ml / kg; ip) kunye ne-xylazine (i-13 mg / ml / kg ip), ibekwa kwi-device ye-stereotaxic (i-Kopf Instruments), kwaye yafumana i-microinjections emibini ye-adeno-echaphazelekayo ne-viral vectors encoding I-GFP kuphela (iprotheni ye-green fluorescent), okanye i-AJunD (iqabane elibophelelayo-elingabikhoyo kwi-FosB) kunye ne-GFP, kwi-NAc (idilesi: AP + 1.5, ML ± 1.2 kwi-bregma; i-DV -7.6 kwi-kkull), kumqulu we-1.5 μl / i-hemisphere phezu kwe-7 min usebenzisa i-syringe yaseHamilton (i-Harvard Apparatus). I-DD iyanciphisa i-FosB-i-transcription transcription ngokuncintisana nge-competitively heterodiderizing ne-DFF kwaye ngoko kukuthintela i-ΔFosB kummandla we-AP-1 kwimimandla yokukhuthaza i-gene (Winstanley et al., 2007; Pitchers et al., 2010b). Nangona i-AJunD ibophelela ngokubambisana kakhulu ne-DFF, kunokwenzeka ukuba ezinye zeempembelelo eziqwalaselwe ze-ΔJunD zinokuthi zidibaniswe ngokuxhathisa ezinye iiproteti ze-AP-1. Nangona kunjalo, kubonakala ukuba ΔFosB iyona protein ephambili ye-AP-1 echazwe phantsi kweemeko ezivivinywe (Pitchers et al., 2010b). Phakathi kwe3 kunye nee-4 iiveki kamva, izilwanyana zafumana amava ezesondo ngexesha le-4 iiseseshini zokuxhatshazwa okanye zihlala zingenangqondo ukudala amaqela e-4: i-GFP yezocansi, i-GFP, i-GFP, kunye no-sexual experience ΔJunD. Amava ezesondo ahlanganiswe ne-4 iseshoni yokudibanisa imihla ngemihla. Izilwanyana zavanywa iCPP kunye ne-diOlistics. Ukuqinisekiswa kweendawo zokungenwa kwenzelwa njengoko kuchazwe ngaphambili (Pitchers et al., 2010b). Izigaba ze-NAc (i-coronal; i-100 μm) zachithwa ngama-GFP (1: 20,000; antibody GFP antibody; i-Invitrogen). Ukusasazeka kwintsholongwane kwakuxhomekeke kwingxenye yegobolondo ye-NAc, kunye nokwanda kweyona ndawo.

Abaxhasi be-D1R / D2R.

Amagundane angamadoda ayenziwe nge-intraperitoneal injection (0.1 ml / kg) ye-ketamine (i-87 mg / ml) kunye ne-xylazine (13 mg / ml), kwaye ibekwe kwi-device ye-stereotaxic (Kopf Instruments). I-21-gauge guide-cannulas (i-Plastics One) iyancitshiswa kwi-NAc kwi-AP + 1.7, i-ML ± 1.2 kwi-bregma; -6.4 DV kwi-skull kwaye igcinwe nge-acrylic yamazinyo, ilandelwe kwiintlanzi ezintathu ezibekwe kwikrele. Izilwanyana zaziphathwa imihla ngemihla ukuze ziqhube iinkqubo zokungeniswa ngexesha lokuphulukana kweveki ye-2. Imizuzu elineshumi elinesibhozo ngaphambi kokuqala kweeseshoni ze-4 zemihla ngemihla ngokuzisa i-female receptive, iirati zamadoda zafumana i-microinjections ye-D1R i-R (+) i-SCH-23390 hydrochloride (Sigma-Aldrich), i-D2 receptor (D2R) -) i-eticlopride hydrochloride (Sigma-Aldrich) yachithwa kwi-saline oyinyumba (i-0.9%; nganye kwi-10 μg kwi-1 μl nge-hemisphere; ichithwe kwi-0.9% saline), okanye i-saline (i-1.0 μl nge-hemisphere), kwizinga lokuhamba kwe-1.0 μl / imizuzu kwixesha elifutshane le-1 elilandelwa yiminithi ye-1 kunye ne-cannula yokujola eshiya endaweni yokusabalaliswa kweziyobisi. Umthamo walo mjoyilo uza kuguqula zombini umnqweno kunye negobolondo, njengoko i-0.5 μl i-infusions iyanqanda kwi-shell okanye i-subdivisions engundoqo (Laviolette et al., 2008). Iingqinisiso zisekelwe kwiingxelo zangaphambili ezibonisa ukuba ezi zi-dose okanye ezisezantsi zithintela izidakamizwa okanye ukuziphatha komvuzo wendalo (Laviolette et al., 2008; URoberts et al., 2012). Ukulawulwa kwamadoda kwahlala kungenasondo kodwa kwafumana i-intra-NAc saline ngaphambi kokufakwa kwi-cage yokunyanga engenalutho, ngexesha le-4 yeseshoni yokuphatha imihla ngemihla. Kwiveki enye emva kokuqhawula kokugqibela okanye iseshoni yokuphatha, amadoda ahlolwe i-Amph CPP, kunye nomgudu kunye nohlalutyo lwe-DFB. Ukusetyenziswa kweeseshoni ezine, ngaphezu kweeseshoni ezintlanu njengakwezinye izilingo, kukhethwa ukuphelisa umonakalo omkhulu kwi-NAc ebangelwa ukunyanzeliswa okuphindaphindiweyo kwaye ngoko ke vumela uhlalutyo kunye ne-DFFB. Ewe, umonakalo wawungabonakali, kwaye uhlalutyo lomgudu kunye ne-DFFB kwi-NAc yezilwanyana ezifakwe kwi-saline babonisa iinkcukacha ezifanayo njengamaqela angabandakanywanga kwizilingo zangaphambili. Iindlela ze-ANOVA kunye neHolm-Sidak ngendlela ebalulekileyo ebalulekileyo p <0.05 yayisetyenziselwa ukumisela amava ezesondo-ancedisa ekuziphatheni ngokwesini.

iziphumo

Ubundlobongela obunokufunyanwa-i-DFF isisigxina

Okokuqala, ukulungelelaniswa kwexeshana phakathi kwezesondo ezithintekayo ekutshintsheni kwimeko ye-FosB, iintlobo zeentlobo ze-dendritic kwi-NAc, kunye ne-Amph-CPP zazinqunywa, ngokukhawuleza emva kwexesha elifutshane kunye elide lokuziyeka kwisini somvuzo (7 okanye 28 d). Ngaphambili, kuboniswe ukuba amava e-sexu yeeseshoni ze-5 zokubambana kwansuku zonke kubangele ukuqokelela i-ΔFosB kuwo wonke umonakalo we-mesolimbic, ngokukodwa kwi-NAc (Wallace et al., 2008; Pitchers et al., 2010b). Kule zifundo ezidlulileyo, ama-DFFB ayalinganiswa ngaphakathi kwe-1 emva kokuziphatha ngokwesondo, kwaye kwakungaziwa ukuba ngaba i-FosB iqokelele emva kwexesha elide lokuzibamba. Amadoda afanelekileyo ngokwesondo axhatshazwa i-1, i-7, okanye i-28 d emva kokugqibela kweeseshoni zokuqhawula imihla ngemihla ye-5. Ukulawulwa kweentlobano zesini noxhatshazwayo kwangexesha elifanayo emva kokugqibela kweeseshoni zokuphatha i-5 zemihla ngemihla. Inombolo yee-FosB-IR iiseli ze-NAc kunye nomgaqo-siseko ziphezulu kakhulu kunokulawulwa kobuhlanga ngokwesini ngexesha lonke.Ikhiwane. 1A, igobolondo; 1 d, p = 0.022; 7 d, p = 0.015; Ikhiwane. 1B: engundoqo; 1 d, p = 0.024; 7 d, p <0.001; I-28 d, p <0.001), ngaphandle kweqokobhe le-NAc emva kwe-28 d yokuziyeka (p = 0.280). Ngaloo ndlela, i-DFFB iqhubekeka ngexesha lokuzilahla emva kwamava esondo ngokwesithuba se-28 d.

Umzobo 1.     

Umzobo 1.     

Amava ezesondo abangela ukunyuka okukhawulezayo kunye nokuqhubekayo kwinani lamaFFB-IR. Faka utshintsho lweenombolo ze-ΔFosB-IR kwiiseli ze-NAc (A) kunye nenqobo (B) kwizilwanyana ezimnyama (ezimnyama) ngokuthelekiswa nokulawulwa kwezesondo (ezimhlophe) zolawulo (ezimhlophe)n = I-4 iqela ngalinye). Idatha liqela lithetha i-± SEM. *p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo olungenalwazi. Ummeli wemifanekiso ye-Naive 1 d (C), IX Expl d (D), IX Expl d (E), kunye ne-Exp 28 d (F). ac, Ukukhishwa kwangaphambili. Ibha ye-Scale, 100 μm.

Ukunyuka kwenzelwa ngesondo ekhuthazwe ngamava e-dendritic yintsuku

Pitchers et al. (2010a) echazwe kwangaphambili basebenzisa iGolgi ubuchule bokungeniswa kwemvelo ukuba amava olwabelana ngesondo alandelwa ngu-7 d, kodwa kungekhona i-1, yomvuzo wokubanjwa obangelwe kubangele ukwandisa i-dendritic branching kunye nenani leentlobo ze-dendritic kwi-shell ye-NAc kunye ne-neurons engundoqo (Pitchers et al., 2010a). Apha, i-spinogenesis kwindoda yokuzibandakanya ngokwesondo kunye namadoda angamava ahlolwe i-7 okanye i-28 d emva kweseshoni yokugqibela yokubambisana. Iziphumo ezikhoyo ngoku usebenzisa indlela yokubhala i-diOlistics ziqinisekisile ukuba amava ezesondo alandelwa yixesha le-7 lokuzilahla ngesondo liye landisa inani leentlobo ze-dendritic (F(1,8) = 9.616, p = 0.015; Ikhiwane. 2A-C). Ngokukodwa, inani leentlobo ze-dendritic zanda kakhulu kwigobolondo le-NAc kunye nenqobo (Ikhiwane. 2A: igobolondo, p = 0.011; engundoqo, p = 0.044). Nangona kunjalo, oku kwandiswa kwentsholongwane yesantya kwakudlulileyo kwaye akusafunyanwa emva kwexesha elide lokulahla ngesondo le-28 d kwi-NAc ngaphantsi (Ikhiwane. 2B).

Umzobo 2.     

Umzobo 2.    

Amava ezesondo abangela ukwanda kwenani leentlobo ze-dendritic kwi-NAc kunye no-Amph umvuzo. A, B, Inani leentlobo ze-dendritic kwi-shell ye-NAc kunye nomxholo we-7 d (A) okanye i-28 d (i-DB yezilwanyana ezimnyama) kunye nezilwanyana [ezimnyama]. n = 4 okanye i-5). Idatha liqela lithetha i-± SEM. #p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo olungenalwazi. C, Amacandelo e-dendritic avela kwi-Naive 7 kunye ne-Exp 7 yamaqela asetyenziselwa ukulinganisa ukunyanzelana kwesantya. Ibha ye-Scale, 3 μm. D, Isixa sexesha esichithwe kwigumbi elibiniweyo (i-Amph okanye i-saline) ngexesha lokuvavanywa kokuvavanywa kwinqanaba eliphambili (i-CPP score) yezilwanyana ezingabonwayo ngokwesini (okanye ezimhlophe) okanye izilwanyana (ezimnyama) ezivivinywayo okanye i-7 okanye i-28 emva kokuqhawula kokugqibela okanye Iseshoni yokuphatha: I-Naive-Sal (7 d emva kokuphatha; n = 8), i-Naive Amph (7 d emva kokuphatha; n = I-9), i-Exp-Sal (amaqela adibeneyo yezilwanyana ahlolwe i-7 okanye i-28 emva kokuqhathaniswa; n = 7), 7 d Exp Amph (7 d emva kokulingana; n = 9), kunye ne28 d Exp Amph (28 d emva kokuqhathaniswa; n = 11). Amaqela e-Sal afumana uSol edibeneyo kunye namagumbi amabini. *p <0.05, umahluko obalulekileyo xa kuthelekiswa nolawulo olunamava ngetyuwa.

Ubundlobongela obunokubangela ukuba u-Amph umvuzo luzuze ixesha elide

Sasiveze kwangaphambili ukuba amava olwabelana ngesondo ngokulandela i-7-10 yokuziyeka ayiphumelele ekuphuculeni i-Amph (Pitchers et al., 2010a). Ngokukodwa, izilwanyana ezithandana ngesondo zakha indawo ekhethekileyo yokukhetha indawo (CPP) yee-doses ezisezantsi ze-Amph (0.5 okanye i-1.0 mg / kg) ezingazange zenze iCPP ekulawuleni ubulili. Uphononongo lwangoku luqinisekisile kwaye lwandise iziphumo ezidlulileyo ngokubonisa ukuhlaziywa kwe-Amph ekuphuculweni kwezilwanyana ezizibandakanya ngokwesondo emva kwe-7 d kwakunye nexesha le-28 yokuzilahla ngesondo (Ikhiwane. 2D; F(2,24) = 4.971, p = 0.016). Ngokukodwa, izilwanyana ezithandana ngesondo kunye ne-7 okanye i-28 yexesha lokuziyeka lichithe ixesha elikhulu kakhulu kwiCandelo le-Amph-paired ngexesha lokuvavanywa kovavanyo emva kokuqhathaniswa nokulawulwa kakubi ngokwesini kunye ne-saline kumagumbi amabini (Ikhiwane. 2DI-Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Ukuqinisekisa iziphumo ezidlulileyo, izilwanyana ezingabonanga ngesondo azizange zichithise ixesha elithile kwiCandelo le-Amph-paired ngexesha lokuvavanywa kwithuba emva kokuvavanywa kwaye alufani nolu khetho kwiqela lolawulo lwe-saline enobulili (Ikhiwane. 2D) (Pitchers et al., 2010a).

Umsebenzi we-FosB ubaluleke kakhulu kwi-sex-experience-induced Incentized Amph

Iziphumo ngoku zibonisa ukuba amava ezesondo abangela ukuqokelela kwexesha elide le-ΔFosB kwi-NAc neurons ezihambelanayo kunye ne-Amph eyongeziweyo. Ukuchonga ukuba ukwandiswa kwe-ΔFosB yomsebenzi kubaluleke kakhulu kumvuzo ophuculweyo lwe-Amph, ΔJunD, umlingani obophayo ongathandabuzekiyo we-ΔFosB okhupha i-DFF-e-transcription transcription (Winstanley et al., 2007), yayixhaswe ngokugqithiseleyo nge-virtual vector-mediated gene transfer in NAC (Ikhiwane. 3A,B). Iziphumo zeemvavanyo ze-Amph CPP zibonise ukuba ukucinywa komsebenzi we-FosB ngokubonakalisa i-AJunD kwi-NAc yayithintele imiphumo yamava ezesondo kunye ne-7 yesini yokuhlaziya ukuziyeka ekuhlaziyeni kwe-Amph. Izilwanyana ezizibandakanya ngokwesondo Izidalwa ze-ADN azizange zenze i-CPP ebalulekileyo kwi-Amph kwaye zahluke kwiintlobano zesini.Ikhiwane. 3B). Ngokwahlukileyo, izilwanyana zokulawula i-GFP zobulili zakha i-CPP ye-Amph njengoko kuboniswe ngumlinganiselo wePPP kakhulu kakhulu xa kuthelekiswa nokulawulwa kwe-GFP ngokwesini.Ikhiwane. 3B, p = 0.018).

Umzobo 3.    

Ukulumkisa i-DFF imisebenzi e-NAc ivaliwe ukukhuthaza umvuzo we-AMPH kunye nokwandiswa kwinani le-NAc kwizilwanyana ezithandana ngesondo. A, Imifanekiso engummeli ye-GFP ibonakaliso kwizilwanyana ezintathu ezitholwa ngumjovo we-adeno-ehambisana ne-viral-ΔJunD ejoliswe kwi-nucleus accumbens, ebonisa amancinci (asekhohlo), ama-intermediate (middle), kunye namakhulu amakhulu. ac, Ukukhishwa kwangaphambili; I-LV, i-ventricle. Ibha ye-Scale, 250 μm. B, Umfanekiso weskimu weendawo ezivelele kunye neepateni zokusasazeka kwegciwane. Kuzo zonke izilwanyana, i-GFP yafunyanwa kwinqabileyo, kodwa isasazeka kwiyona nto yayiyintlukwano. C, Isixa sexesha esichithwe kwiCandelo le-Amph-paired ngexesha lokuvavanywa kwe-post-test ngaphaya kwe-CPP (amanqaku asemhlophe) kunye nezilwanyana (ezimnyama) ezithe zafumana umjovo we-vector control GFP (i-Naive, n = 9; Exp, n = 10) okanye i-VINJunD vector (i-Naive, n = 9; Exp, n = 9). D, Imifanekiso yee-dendritic kwi-GFP kunye ne-AJunD esetyenziselwa ukulinganisa ukuxinwa kwesantya. Ibha ye-Scale, 3 μm. E, Inani leentlobo ze-dendritic kwi-NAc yezintlu zesondo (ezimhlophe) kunye nezilwanyana (ezimnyama) ezithe zafumana ijoyi ye-GFP vector control okanye i-VANJunD. Idatha liqela lithetha i-± SEM. *p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo olungenalwazi. #p <0.05, umahluko obonakalayo ovela kulawulo lwe-GFP olunamava.

Imiphumo yokulumkisa i-ADJunD yokunyanzeliswa akuzange ibe ngumphumo wokuphazamiseka kokuziphatha ngokwesondo ngexesha lokufumana amava ezesondo. Inkcazo ye-AJJD kwi-NAc iye yaboniswa kwangaphambili ukukhusela ukuziphatha ngokuziphatha ngokwesini emva kwamava esondo (Pitchers et al., 2010b). Enyanisweni, oku kuqinisekisiwe kwilingo langoku. Izilwanyana zokulawula i-GFP zibonise i-latency latency ukunyuka, ukungena kunye nokunyuka, kunye nokunyuka okuncinci kunye nokunciphisa ngosuku lwesine olulandelelanayo lweemvavanyo zokulinganisa, xa kuthelekiswa nomhla wokuqala wokubambana (1 Table). Ngokwahlukileyo, izilwanyana ezingenayo i-JJD ayibonakalanga ngokukhawuleza ukulandelelana okanye ukukhupha okanye inani elincinci leentaba ngexesha lomhla wesine lokuqhathaniswa nokuqhathaniswa neyokuqala. Ngaloo ndlela, i-AJunD ingenelelo kwi-NAc iyancipha imiphumo yamava ezesondo. Nangona kunjalo, kwakungekho nantlukwano ebalulekileyo kuyo nayiphi na imilinganiselo yokulinganisa phakathi kokulawulwa kwe-GFP kunye namaqela angaphantsi kwama-JUN ngexesha leyiphi na imvavanyo yokulinganisa, ebonisa ukuba iimpembelelo ze-AJJD kwi-sex-experience-stimulated sensitization ye-Amph CPP ayikho imbangela yokungafani amava okukhula ngokuzimela (1 Table).

Jonga le tafile:     

Ithebula 1.    

Iiparameters zesenzo sokuziphatha ngokwesondo ngexesha lokufumana amava ezesondo ngamaqela athola i-NAc infusions ye-GFP- okanye i-AJunD-ebonisa i-vectors vectorsa

I-FosB ibaluleke kakhulu kwi-sex-induced augmentation in NAc dendritic spines

Umsebenzi we-FosB wawufuneka kwakhona ukwenyuka kwe-spinal density ye-NAc neurons emva kwamava ocansini kunye ne-7 yesini yokuhlaziya isondo (Ikhiwane. 3C,D). Uhlalutyo lwesantya kwi-NAc yezilwanyana ezichazwe ngasentla kwi-CPP, i-ANOVA ezimbini ibonisa imiphumo ebalulekileyo yezobulili zesibini (F(1,34) = 31.768, p <0.001) kunye nonyango lwevector vector (F(1,34) = 14.969, p = 0.001), kunye nokusebenzisana (F(1,34) = 10.651, p = 0.005). Ngokukodwa, izilwanyana zokulawula i-GFP zesondo zineenani elikhulu lee-NAc eziqhathaniswa nokulawulwa kwe-GFP ngokwesini.Ikhiwane. 3D: p <0.001), eqinisekisa ukufumana kwethu kwangaphambili (Pitchers et al., 2010a). Ngokwahlukileyo, izilwanyana ezizibandakanya ngokwesondo izidalwa zeAJunD azizange zihluke ngokuthe ngqo kumacandelo angama-I-JunD ngokobulili, kwaye zazingaphantsi kakhulu xa zifaniswa nezilwanyana zokulawula ze-GFP zesondo (Ikhiwane. 3D: p <0.001). Ke, ukubonakaliswa kwe-JUND kwi-NAc kuthintele iziphumo zamava ezesondo kunye nokuvuza ukungabinakho kwi-NAc spinogenesis.

Umxhasi we-D1R uvimbela amava olwabelana ngesondo-ayenze i-DFNB

Ukwenza ukuba i-D1R okanye i-D2R isebenze kwi-NAc ngexesha lokuxhatshazwa kuyadingeka kwi-sex-induced ΔFosB ukulungiswa komgangatho kunye ne-Amph CPP, izilwanyana zamukelwe i-D1R okanye i-D2R inxamnye (okanye i-saline) kwi-NAc 15 min ngaphambi kwe-4 nganye. iiseshoni zokulandelelana zemihla ngemihla. Kubaluleke kakhulu, akukho D1R okanye i-D2R inxamnye ne-INC echaphazelekayo ukuqaliswa okanye ukubonakalisa ukuziphatha ngokwesondo ngeliphi na iseshoni zokulinganisa (Ikhiwane. 4D-F). Ngokufanayo, I-D1R okanye i-D2R yokuchasana ayinakuthintela imiphumo ebalulekileyo yokufumana amava ngokwesini, njengoko onke amaqela abonisa ukulungiswa kokuziphatha ngokwesondo, kubonakaliswe nge-shortjjulation latten latencies ngosuku lwe-4 xa kuthelekiswa nomhla 1 (Ikhiwane. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Umzobo 4.    

I-Dopamine receptor antagonists abangeniswe kwi-NAc ayinakuchaphazela ukuziphatha ngokwesondo. IiCononal NAc (A, + 2.2; B, + 1.7; C, + 1.2 ukusuka kwi-bregma) ebonisa ii-intra-NAc zenzelwa iziza kuzo zonke izilwanyana. Ama-Cannulas ayengamazwe angama-2 kodwa amelwa ngokubambisana ngokukhululeka ukunikezelwa kwazo zonke izilwanyana (i-Naive-Sal, emhlophe, n = 7; I-Exp-Saline; mnyama, n = 9; I-Exp D1R Intsimbi, imfutho emhlophe, n = 9; I-Exp D2R Intsimbi, emnyama, n = 8). ac, Ukukhishwa kwangaphambili; I-LV, i-ventricle; CPu, i-caudate-putamen. I-latency yentaba (D), latency intromission (E), kunye ne-ejaculation latency (F) kuzo zonke iindibano zamava ocansini (Saline, ezimhlophe; i-D1R Ant, igrey; i-D2R Int, emnyama). Idatha imele ukuthini ± SEM. *p <0.05, umahluko obonakalayo phakathi komhla woku-1 kunye nosuku lwe-4 kunyango.

Uhlalutyo lwenani le-ΔFosB-IR iiseli kwi-NAc 7 d emva kokunyuswa kwe-NAc yokugqibela kunye nokudibanisa okanye iseshoni yokuphatha ibonisa ukungafani okukhulu phakathi kwamacandelo kwi-shell ye-NAc (F(3,29) = 18.070, p <0.001) kunye nentloko (F(3,29) = 10.017, p <0.001). Okokuqala, amava ezesondo kulawulo lwe-saline-infused abangele ukonyusa okubalulekileyo kwe-ΔFosB xa kuthelekiswa nolawulo lwesini naive (Ikhiwane. 5A, igobolondo p <0.001; Ikhiwane. 5B: ingundoqo, p <0.001), eqinisekisa iziphumo ezingentla. Ukuchasana kwe-D1R, kodwa hayi i-D2R, kuthintelwe okanye kuthintelwe oku kulungiswa kwe-osBFosB. Kwigobolondo le-NAc, umchasi we-D1R waphatha abesilisa abanamava ngokwesini akabonisanga ukwanda kweeseli ze-osBFosB-IR xa kuthelekiswa nolawulo lwezesondo (Ikhiwane. 5A: p = 0.110), kunye ne-DFB ibonakaliswe kakhulu kakhulu xa kuthelekiswa nabesilisa abanobulili (Ikhiwane. 5A: p = 0.002). Kwinqanaba le-NAc, ukuxhatshazwa kwe-D1R kunempembelelo encinci: ΔFosB yayinyuke kakhulu kwii-D1R ezixhatshazwayo zamadoda xa kuthelekiswa nokulawulwa kwe-saline ye-saline (Ikhiwane. 5B: p = 0.031), kodwa lo mgangatho wawuphantsi kakhulu xa uthelekiswa nabesilisa abathintekayo ngokwesondo (Ikhiwane. 5B: p = 0.012). I-D2R unyango olungathinteliyo aluzange luchukumise i-APF ekuqulunqweni njengabantu abathandana ngokwesondo abafumana i-D2R inxamnye nombolo enkulu kakhulu yee-FosB-IR iiseli ezifaniswa nokulawulwa kwe-saline ye-saline (Ikhiwane. 5A: igobolondo, p <0.001; Ikhiwane. 5B: ingundoqo, p <0.001) kunye ne-D1R ephathwa ngokuchasene nabesilisa (Ikhiwane. 5A: igobolondo, p <0.001; Ikhiwane. 5B: ingundoqo, p = I-0.013), kwaye ayizange ihluke kwindoda yesilisa enobulili.

Umzobo 5.     

Umzobo 5.     

Ukukhusela i-D1R kwi-NAc igxininisa ukwanda kwenani le-ΔFosB-IR iiseli kwi-NAc yezilwanyana ezithandana ngesondo. Faka utshintsho lweenombolo ze-ΔFosB-IR kwiiseli ze-NAc (A) kunye nenqobo (B) kwizilwanyana ezimnyama (ezimnyama) ngokuthelekiswa nokulawulwa kwezesondo (ezimhlophe) zokulawula (i-Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Idatha liqela lithetha i-± SEM. *p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo olungenalwazi. #p <0.05, umahluko obalulekileyo xa kuthelekiswa ne-saline kunye ne-D2R ye-Ant yezilwanyana ezinamava. Ummeli wemifanekiso yeNaive Sal (C), Ex Sal (D), Exp D1R Intsimbi (E), kunye ne-Exp D2R Intsimbi (F). ac, Ukukhishwa kwangaphambili. Ibha ye-Scale, 100 μm.

Ukulawula ukusabalala kwe-D1R okanye i-D2R abachasene kwi-storum ye-dorsal, i-DFNB ibonakaliswe kwingingqi ngokukhawuleza ihlasele i-NAc kwaye idibene ne-ventricle, emva kokungeniswa kwe-FosB kwi-dorsal striatum yi-psychostimulants and opiates kuxhomekeke kwi-D1R umsebenzi (Zhang et al., 2002; Muller no-Unterwald, i-2005). Amava ezesondo akhulisa inani le-DFosB-ir e-storum ye-rorsal kwi-male-treated cats (i-Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), iqinisekisa ingxelo yethu yangaphambili (Pitchers et al., 2010b). Ukongezelela, akukho D1R okanye i-D2R inxamnye neengxaki ze-NAc ezithintekayo ngokwesini-zenze i-DFNB kwi-dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir cells; Exp-D2R: 83.9 ± 4.4 ir cells; p <0.001 ngokuthelekiswa nolawulo lweNaive-Sal). Ezi ziphumo zibonisa ukuba ukusasazeka kwe-infusions infusions yayijolise ikakhulu kwi-NAc.

Umxhasi we-D1R e-NAc uvimba u-Amph umvuzo

I-D1R ikhuselekile kwi-NAc ngexesha lokuxhatshazwa kunye nolwazi oluvaliweyo lwezesondo-olwenziwe luphuculweyo lwe-Amph, lwavanywa i-7 d emva kokunyuswa kwe-NAc yokugqibela kunye nokuhlolwa kokulingana (F(3,29) = 2.956, p = 0.049). Izilwanyana ezithandana ngesondo ezafumana i-saline kwi-NAc ngexesha leeseshoni zokuqhathanisa zichithe ixesha elikhulu kakhulu kwiCandelo le-Amph-paired xa kuthelekiswa nabesilisa abathandana ngesondo (Ikhiwane. 6A, p = 0.025), eqinisekisa iziphumo ezingentla. Ngokwahlukileyo, izilwanyana ezithandana ngesondo ezafumana i-intra-NAc D1R inxamnye ngexesha lokuqhathanisa ayenzanga i-CPP ye-Amph. Abazange bahluke ngokulawulwa ngokwesondo, kwaye bachitha ixesha elincinci kwiCandelo lama-Amph eliqhathaniswa ne-saline (Ikhiwane. 6A: p = 0.049) okanye umxhasi we-D2R (Ikhiwane. 6A: p = I-0.038) yabangela abantu abathandana ngokwesondo. I-D2R inxamnye neengxaki zokugonywa azizange zithinte i-Amph ukufumana umvuzo njengoko izilwanyana ezinokuzibandakanya ngokwesini kunye ne-NAc D2R ukuchasana kwamanye amazwe zakha i-Amph-CPP ebalulekileyo xa kuthelekiswa nokulawulwa kwe-saline ye-saline (Ikhiwane. 6A: p = 0.040) kunye ne-D1R engqubanayo nezilwanyana (Ikhiwane. 6A: p = I-0.038), kwaye ayizange ihluke kwindoda yesilisa enobulili.

Umzobo 6.     

Umzobo 6.     

Ukukhusela i-D1 i-receptors kwi-NAc isusa i-Amph ukufumana umvuzo kwaye yandisa iintlobo zeentlobo ze-dendritic kwizilwanyana ezibulili. A, Isixa sithuba esichithwe kwiCandelo le-Amph-paired ngexesha lokuvavanywa kokuvavanya kunconywe (amanqaku e-CPP, imizuzwana) yokwabelana ngesondo (umhlophe, n = I-6) kunye nezilwanyana (ezimnyama) ezifumene i-saline (n = 7), umxhasi we-D1R (n = 9), okanye umxhasi we-D2R (n = 8). Idatha liqela lithetha i-± SEM. *p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo lwe-saline engenamsebenzi. #p <0.05, umahluko obalulekileyo ukusuka kwi-D1R Imbovane yezilwanyana ezinamava. B, Inani leentlobo ze-dendritic (nge-10 μm) ngokuzibandakanya ngokwesondo (umhlophe, n = I-7) kunye nezilwanyana (ezimnyama) ezifumene i-saline (n = 8), umxhasi we-D1R (n = 8), okanye umxhasi we-D2R (n = 8). Idatha liqela lithetha i-± SEM. *p <0.05, umahluko obonakalayo xa kuthelekiswa nolawulo lwe-saline engenamsebenzi. #p <0.05, umahluko obonakalayo kulawulo olunetyuwa olunamava.

I-D1R yonyango ekhuselekileyo ikhusela amava e-zesini-ayenze i-NAc spinogenesis

Uhlalutyo lwesisindo somnxeba kwi-NAc yezilwanyana ezifanayo kubonisa ukuba ukusebenza kwe-D1R ngexesha lokuxhatshazwa kwakudingeka ukunyuka kwe-NAc kwintlungu emva kwamava ezesondo kunye ne-7 ye-sex rewarding abstinence (Ikhiwane. 6B; F(3,26) = 41.558, p <0.001). Ngokukodwa, ulawulo lwe-saline olunamava ngokwesondo kunye nezilwanyana ezichasene ne-D2R zazinenani elikhulu kakhulu leentsiba xa kuthelekiswa nolawulo lwe-saline naive (Ikhiwane. 6B: p <0.001) iqinisekisa iziphumo zethu zangaphambili (Pitchers et al., 2010a) kunye neziphumo kunye ne-GFP yokulawula ii-vectors vectors ezichazwe ngasentla. Ngokwahlukileyo, i-D1R echasene ngesondo-isilwanyana esasifakile asizange sichasane nokulawulwa kwezilonda zesini (i-saline)Ikhiwane. 6B). Kwakukho umphumo osisiphumo se-D2R ukunyuswa kwamanyathelo njengoko i-D2R ifaka izilwanyana zabonisa ubunzima obukhulu beentsipho ngaphezu kolawulo lwe-saline (Ikhiwane. 6B: p = 0.02), kodwa manani aphezulu kakhulu emincinci xa kuthelekiswa nokulawulwa kobulili bezesondo kunye ne-D1R ephathwe ngamadoda afanelekileyo (p <0.001; Ikhiwane. 6B). Ngaloo ndlela, i-D1R ikhuselekile kwi-NAc ngexesha lokuxhatshazwa kuvinjelwe imiphumo yamava ezesondo kunye nomvuzo wokuziyeka kwi-NAc spinogenesis.

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Kwisifundo esilandelayo, sibonise ukusikwa kwe-cross-sensitization phakathi komvuzo wendalo kunye neziyobisi, xa umvuzo wendalo ulandelwa lixesha lokuziyeka. Ngokukodwa, sibonise ukuba ngamava ngokuziphatha ngokwesondo, kulandelwa ngu-7 okanye i-28 yokuziyeka, kubangela ukuba i-Amph ivuselelwe. Ezi ziphumo zifana nendima ebalulekileyo yoxinzelelo kwiidakamizwa zokusetyenziswa gadalala kwi-incubation ye-aspiratory drug (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ukongezelela, i-AFosB yenzelwe umvuzo wemvelo kwi-NAc ibaluleke kakhulu kwimpembelelo yokumelana nemvelo yembuyekezo yokuziyeka ekunikeni umvuzo we-psychostimulant, mhlawumbi nge-spinogenesis kwi-NAc ngexesha lokuhlaziya umvuzo. Siye sabonisa ukuba i-ΔFosB ukuqokelela kwi-NAc emva kwamava ezesondo ihlala ixesha elide kwaye ixhomekeka kwi-NAc D1R umsebenzi ngexesha lokubambana. Ngaloo ndlela, le D1R-mediated ΔFosB ukulungiswa kwemali kwi-NAc iboniswe ukuba ibaluleke kakhulu ekuzuzeni umvuzo we-Amph kunye nokwandisa umthamo wentsholongwane kwi-NAc, nangona ezi ziphumo zamava ezesondo zixhomekeke kwixesha lokuziyeka kwisini somvuzo (Pitchers et al., 2010a). Ekugqibeleni, sibonise ukuba i-NAc spinogenesis inokufaka isandla ekuphuhlisweni kokuqala kwexesha elifutshane lokubonakalisa i-Amph ukufumana umvuzo kodwa akubalulekanga ekubonakalisweni komvuzo wokuphucula izidakamizwa, njengoko ukunyuka kwengqondo kwintsimi e-NAc kwakudlulileyo kwaye kugcinwa emva kwe-7, kodwa akukho 28 d, ixesha lokuziyeka.

Kuye kwaziwa ixesha elide ukuba i-dopamine ikhishwa kwi-NAc ngexesha lokuziphatha komvuzo, kubandakanya ukuziphatha ngokwesondo. Emva kokwethulwa kwesifazana esamkelekileyo, i-dopamine ye-extracellular kwi-NAc yanda kwaye ihlala iphakanyisiwe ngexesha lokuqhathaniswa (Fiorino et al., 1997). Uphononongo lwangoku lubonisa ukuba ukungena kwi-NAC ngexesha lokuxhatshaza akuzange kube nefuthe ekuqaliseni okanye ekusebenzeni ngokwesondo, okuhambelana nombono wokuthi i-dopamine ayibandakanyekanga kwimbonakalo yokuziphatha ngomvuzo ngamnye, kodwa ngenxa yesibonakaliso sobungozi bokukhuthaza abantu ngesondo (EBerridge noRobinson, i-1998). Enyanisweni, kubhekiselele ukulandelwa komvuzo wesondo kubangela ukuba kusebenze i-neurons kwi-systemlialic dopamine umvuzo wenkqubo, kubandakanywa neeseli ze-dopaminergic kwingingqi ye-ventral kunye nenjongo yazo, i-NAc (Balfour et al., 2004). Ukuphindaphinda ukuziphatha ngokwesondo kudala i-DFBB kwi-NAc, leyo idibanisa nokuvuselelwa kwimeko yokuziphatha ngokwesondo (Pitchers et al., 2010b). Iziphumo zangoku zibonisa ukuba ukukhishwa kwe-FFB-ukuxhaswa kwe-FosB kukuxhomekeke kwi-D1R kusebenze kwi-NAc ngexesha lokuxhatshazwa. Oku kufunyaniswayo kuyahambelana nezifundo zangaphambili ezibonisa ukuba ukuphathwa kwengqondo ngokuphindaphindiweyo kwandiswe ngokuphindaphindiweyo ΔFosB kwi-NAc spin neurons ezibonisa iD1R (ULee et al., 2006; UKim et al., 2009) kwaye ukuba u-ΔFosB ukulungiswa kwemigaqo kuxhomekeke kwi-D1R kusebenze (Zhang et al., 2002). Ukongezelela, iimpendulo zamachiza ezinokwenziwa, eziqhelekileyo ezifunyenwe kwisilwanyana esikwazi ukufumana iziyobisi, zingaveliswa ngokungabikho kwezidakamizwa zangaphambili phambi kwe-DFNB kwi-D1R ebonisa i-neurons kwi-striatum (UKelz et al., 1999). THayi, umvuzo wendalo kunye neziyobisi ukwandisa ΔFosB kwi-NAc ngokusebenzisa indlela yokuxhomekeka kwe-D1R ukukhuthaza ukuziphatha komvuzo.

Ukongezelela, iziphumo ezikhoyo zibonisa ukuba i-DFF ibaluleke kakhulu kumlamli okhuselekileyo phakathi kokuvalelwa kwemvelo kunye nomvuzo we-psychostimulant. Njengoko kuphawuliwe, imisebenzi ye-FFB kwi-NAc iye yaxutyushwa ngaphambili kwiimpendulo zonyango ezinqwenelekayo, njengoko i-DFF ibonisa ngokugqithiseleyo kwi-NAc eyenza usebenze ngokuqeshisa ukuba i-cocaine emva kokulawulwa kwangaphambili okanye ngokuphindaphindiweyo (UKelz et al., 1999), ukwandisa uvakalelo kwi-cocaine ne-morphine CPP (UKelz et al., 1999; Zachariou et al., 2006), kwaye ibangela ukulawulwa kwezinto eziphantsi kwee-cocaine (Colby et al., 2003). Uphononongo lwangoku lubonisa ukuba ukukhutshwa kwe-D1R okanye i-DFNB umsebenzi kwi-NAc ngexesha lokuqhathaniswa nokuqhelana nezobulili-kubangelwa ukukhuthaza u-Amph ukuvuza.

Uphononongo lwangoku lubonise ukuba ixesha lokuziyeka ekunikeleni umvuzo wesondo kuyafuneka ukuba kuqinisekiswe u-Amph ukuvuza kunye ne-NAc spinogenesis. Sifumanisa ukuba i-ΔFosB ngexesha lexesha lokuziyeka lichaphazela umsebenzi we-neuronal ngokutshintshela ukubonakalisa i-gene intetho ukuze kuqalwe i-spinogenesis kwaye utshintshe amandla ase-synaptic. Enyanisweni, ukuvimba ukukhutshwa kwe-DFB kwi-NAc ngexesha lokuqhathaniswa kukuthintela ukunyuka koxinzelelo lwe-spin kwi-NAc efunyenwe emva kokuhlaselwa. Ukongezelela, ukunyuswa kwe-D1R kumchasene kwi-NAc ngaphambi kweseshoni yokubambisana kwathintela ukunyuka kwe-sexist-incured increase in ΔFosB kunye nokunyuka koxinzelelo.

I-FosB yinto engumqondiso wendlela yokubhala engakwazi ukwenza njengomqhubi we-transcript okanye ukucindezela ukuphazamisa ukubonakaliswa kwezinto ezininzi zegciwane ezijoliswe ekujoliswe kuyo kunye nefuthe lentsholongwane kunye nesandla se-synaptic kwi-NAc (Nestler, 2008). Ngakumbi ngakumbi, ΔFosB isebenzisa i-kinase-5 exhomekeke kwi-cyclic (Bibb et al., 2001; Kumar et al., 2005), nuclear nyukliya κ B (NF-κB) (Russo et al., 2009b), kunye ne-GluA2 yunithi ye-glutamate AMPA receptor (Vialou et al., 2010) kunye rIphawula ngokubhalwa kweso sithuthi se-gene c-fos (Pitchers et al., 2010b) kunye ne-histone methyltransferase G9 (Maze et al., 2010). Ci-kinase-dependent kinase-5 ilawula iiprotokeletal proteins kunye neurite (Taylor et al., 2007). Ngaphezu koko, ukusebenza kwe-NF-κB kwandisa inani leentlobo ze-dendritic kwi-NAc, kanti ukuvinjelwa kwe-NF-κB kunciphise i-spinal dendritic spines kwaye ibingele ukwanda kwe-cocaine kwintsiba (Russo et al., 2009b). Ngako oko, umvuzo wecala uya kwandisa i-DFF kwi-NAc, enokuthi iguqule i-NAc spine density ngokusebenzisa iithagethi ezininzi (oko kukuthi, i-kinase-dependent kinase-5, i-NF-κB) kwaye umphumo wokugqibela unomvuzo wokusetyenziswa kwezidakamizwa, njengoko kwakucatshulwa Russo et al. (2009a) kwizenzo ze-cocaine ephindaphindiweyo.

Ukuqwalaselwa okungalindelekanga kwiphando langoku kukuba ukunyuka koxinzelelo kwintlambo ye-NAc kwakunokukhawuleza, kwaye akusabonakali kwi-28 d emva kwamava ezesondo. Ngako oko, ukunyuka kwentsholongwane kwintlambo kwakunxulumene nokuqala kokuhlaziywa kwe-Amph nokuphucula kwaye kunokuba negalelo ekuphuhlisweni kokuqala okanye ukubonakaliswa kwexesha elifutshane leempendulo ze-Amph. Nangona kunjalo, ukunyuka koxinzelelo kwintlambo kwakungadingeki ukuphikelela kwe-Amph ukufumana umvuzo emva kokuzila ixesha elide. Ngaphambili siye sabonisa ukuba amava ezesondo enza i-short-term (7, kodwa ingekho i-28, iintsuku emva kokutshatyalaliswa kokugqibela) ukwanda kwe-NMDA yamagumbi okufumana i-NR-1 kwi-NAc, ebuye yabuyela kumanqanaba okuqala emva kwexesha elide lokuzilahla (Pitchers et al., 2012). Oku kukhulisa i-NMDA yokufumana i-receptor ibonakaliswe ukuba ibonakalise isondo-sululwazi esisetyenziselwe ukulala (Huang et al., 2009; Brown kunye al., 2011; Pitchers et al., 2012), kwaye icetyiswa ukuba kungenzeka ukuba amava olwabelana ngesondo-okubangele ukukhula komgudu kuxhomekeke kwimisebenzi yokwamukela i-NMDA (Hamilton et al., 2012).

Ekugqibeleni, ukuphonononga okwangoku kukhombise ukukhuphaza umonakalo wembuyekezo yonyango ngomvuzo wendalo (ngokwesini) kunye nokuxhomekeka kwawo kwixesha lokuzilahla. Ukongezelela, le plastiki yokuziphatha yayingqinelana ne-DFFB nge-activation ye-D1R kwi-NAc. Ngoko ke, idatha ibonisa ukuba ukulahlekelwa ngumvuzo wemvelo emva kokufumana amava kunokubangela ukuba abantu basengozini ekuphuhliseni umlutha weziyobisi kwaye omnye umlamli wolu xhatshazo olusakhulayo ngu-DFF kunye neethagethi zalo ezingezantsi.

Imihlathi

  • Ifumene ngo-Oktobha 16, 2012.
  • Uhlaziyo olufunyenwe ngoDisemba 12, 2012.
  • Yamkelwa ngoDisemba 23, 2012.

  • Lo msebenzi wawuxhaswa yi-Institutes of Health Research (LMC) yaseCanada, isiZiko seSizwe seMpilo yengqondo (i-EJN), kunye neNzululwazi yeZendalo kunye neBhunga loPhando lweCandelo laseKhanada (iKKP kunye neLMC). Siyabulela uDkt. Catherine Woolley (iYunivesithi yaseNyakatho-ntshona) ngoncedo ngoncedo lwe-diOlistic yobhaliso.

  • Ababhali bavakalisa ukuba akukho mfuno yemali ekhuphisanayo.

  • Ubunikazi kufuneka bhekiswe kuDkt. Lique M. Coolen, kwiSebe lePhysical and Biophysics, kwiNyuvesi yaseMinissippi yeZonyango, kwi-2500 North State Street, i-Jackson, i-MS 39216. [imeyile ikhuselwe]

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Amaqaku acacisa eli nqaku

ISIFUNDO ESIPHELELEYO - ICANDELO LENGXOXO:

Kwisifundo esilandelayo, sibonise ukusikwa kwe-cross-sensitization phakathi komvuzo wendalo kunye neziyobisi, xa umvuzo wendalo ulandelwa lixesha lokuziyeka. Ngokukodwa, sibonise loo mava ngokuziphatha ngokwesondo, kulandelwa ngu-7 okanye i-28 yokuziyeka, kubangela ukuhlaziywa kwe-Amph.

Ezi ziphumo zifana nendima ebalulekileyo yexesha lokuziyeka ekusebenziseni iziyobisi kakubi kwi-incubation ye-drug desire (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ukongezelela, umvuzo wendalo? I-FosB kwi-NAc ibaluleke kakhulu kwimiphumo yokumelana ne-cross-sensitizing yempatho yemvelo yokuziyeka ukungabikho komvuzo we-psychostimulant, mhlawumbi ngokusebenzisa i-spinogenesis kwi-NAc ngexesha lokuhlaziya umvuzo.

Ngaba sibonise oko? Ukuqokelela kwe-FosB kwi-NAc emva kwamava ezesondo ihlala ixesha elide kwaye ixhomekeke kumsebenzi we-NAc we-D1R ngexesha lokulingana. Ngaloo ndlela, le D1R-idibeneyo? Ukulungiswa kwe-FosB kwi-NAc kuboniswe ukuba ibaluleke kakhulu kumvuzo ophuculweyo we-Amph kunye nokwandiswa koxinzelelo lwengqondo kwi-NAc, nangona ezi ziphumo zamava ezesondo zixhomekeke kwixesha lokuziyeka kwisinikelo somzimba (i-Pitchers). kunye al., 2010a). Ekugqibeleni, sibonise ukuba i-NAc spinogenesis inokufaka isandla ekuphuhlisweni kokuqala kwexesha elifutshane lokubonakalisa i-Amph ukufumana umvuzo kodwa akubalulekanga ekubonakalisweni komvuzo wokuphucula izidakamizwa, njengoko ukunyuka kwengqondo kwintsimi e-NAc kwakudlulileyo kwaye kugcinwa emva kwe-7, kodwa akukho 28 d, ixesha lokuziyeka.

Kuye kwaziwa ixesha elide ukuba i-dopamine ikhishwa kwi-NAc ngexesha lokuziphatha komvuzo, kubandakanya ukuziphatha ngokwesondo. Emva kokwakheka kwesifazana esamkelekileyo, i-dopamine ye-extracellular kwi-NAc yanda kwaye ihlala iphakanyisiwe ngexesha lokuqhathaniswa (Fiorino et al., 1997). Uphononongo lwangoku lubonisa ukuba ukungena kwi-NAC ngexesha lokuxhatshaza akuzange kube nefuthe ekuqaliseni okanye ekusebenzeni ngokwesondo, okuhambelana nombono wokuthi i-dopamine ayibandakanyekanga kwimbonakalo yokuziphatha ngomvuzo ngamnye, kodwa ngenxa yesibonakaliso sobungozi bokukhuthaza abantu ngesondo (IBerridge noRobinson, i-1998). Enyanisweni, kubhekiselele ukulandelelana komvuzo wesondo kubangela ukuba kusebenze i-neurons ngaphakathi kwindlela yokubuyisela i-dopamine ye-mesolimbic, kubandakanywa neeseli ze-dopaminergic kwingingqi ye-ventral kunye nejoliswe kuyo, i-NAc (i-Balfour et al., I-2004).

Ukuphindaphinda ukuziphatha ngokwesondo kukhuthaza i-FosB kwi-NAc, leyo idibanisa nokunyanzeliswa kwimeko yokuziphatha ngokwesondo (Pitchers et al., 2010b). Iziphumo zangoku zibonisa ukuba ukuxhatshazwa kwe-FosB, ngokuqinisekileyo, kuxhomekeke kusebenze kwe-D1R kwi-NAc ngexesha lokulingana. Oku kufunyaniswayo kuyahambelana neengxelo zangaphambili ezibonisa ukuba ukuphathwa kwengqondo ngokuphindaphindiweyo kwenyuka ngokuqhubekayo? I-FosB kwi-NAc spin neurons ebonisa i-D1R (ULee et al., 2006; Kim et al., 2009) kwaye loo nto? Ukulungiswa kwe-FosB kuxhomekeke kusebenziso lwe-D1R (iZhang et al., 2002). Ukongezelela, iimpendulo zamachiza ezisisiseko, eziqhelekileyo ezifunyenwe kwisilwanyana esinamava, zingaveliswa ngokungabikho kwezidakamizwa ezidlulileyo ngokugqithiseleyo? I-FosB kwi-D1R ibonisa i-neurons kwi-striatum (uKelz et al., 1999). Ngako oko, imivuzo yemvelo kunye neziyobisi yanda? I-FosB kwi-NAc ngokusebenzisa indlela yokuxhomekeka kwe-D1R ukukhuthaza ukuziphatha komvuzo.

Ngaphezu koko, iziphumo ezikhoyo zibonisa ukuba? I-FosB ngumlamli obaluleke kakhulu we-cross-sensitization phakathi kwamava omvuzo wemvelo kunye nomvuzo we-psychostimulant. Njengoko kuphawuliwe, umsebenzi we-FosB kwi-NAc uye waxutyushwa ngaphambili kwiimpendulo zonyango ezinzulu, njengokuba u-FosB ogqithiseleyo kwi-NAc uvuselela ukusebenziselwa ukuqhubela i-cocaine emva kokulawulwa kwangaphambili okanye ngokuphindaphindiweyo (uKelz et al., 1999), ukwandisa uvakalelo kwi-cocaine kunye ne-morphine CPP (uKelz et al., 1999; iZachariou et al., 2006), kwaye ibangela ukulawulwa kwezinto eziphantsi kwecocaine (Colby et al., 2003). Uphononongo lwangoku lubonisa ukuba ukukhutshwa kwe-D1R okanye umsebenzi weFosB kwi-NAc ngexesha lokutshatyalaliswa kwezesondo ekupheliseni ubulili obuphulukisiwe ekuphuculeni i-Amph ukuvuza. Tke, umvuzo wendalo kunye neziyobisi awuguquleli kuphela kwindlela efanayo ye-neural, bayaguquka kwi-molecular mediators (Nestler et al., 2001; Wallace et al., 2008; iiHedges et al., 2009; i-Pitchers et al., 2010b), kwaye mhlawumbi kwi-neurons efanayo kwi-NAc (Frohmader et al., 2010b), ukuphazamisa intuthuko yokukhuthaza kunye "nokufunwa" kwezi zombini iintlobo zembuyekezo (IBerridge noRobinson, i-1998).

Uphononongo lwangoku lubonise ukuba ixesha lokuziyeka ekunikeleni umvuzo wesondo kuyafuneka ukuba kuqinisekiswe u-Amph ukuvuza kunye ne-NAc spinogenesis. Sifumanisa loo nto? I-FosB ngexesha lexesha lokuzilahla lichaphazela umsebenzi we-neuronal ngokutshintshela ukubonakalisa i-gene intetho ukuze uqalise i-spinogenesis kwaye utshintshe amandla ase-synaptic. Kanjalo, ukuvimbela ukutyalwa kwe-FosB kwi-NAc ngexesha lokuxhatshazwa kuthintela ukunyuka kwentsholongwane kwintlambo kwi-NAc efunyenwe emva kokunciphisa umvuzo. Ngaphezu koko, iukuxubusha komdlali we-D1R ukuya kwi-NAc ngaphambi kweseshoni yokubambana nganye kuye kwathintela ukwanda kwe-sex-incured increase?. I-FosB yinto ebhaliweyo engakwazi ukwenza njengomshicileli wokubhala okanye ukunyanzelisa ukuphazamisa ukubonakaliswa kweengqikithi zemiqolo ekujoliswe kuyo ekutshintsheni amandla kunye nokuqina kwe-synctic kwi-NAc (Nestler, 2008). Ngokukodwa, i-FosB isebenzisa i-kinase-5 (i-Bibb et al., I-2001; i-Kumar et al., I-2005), into enyukliya? B (NF-? B) (Russo et al., 2009b), kunye ne-GluA2 yunithi ye-glutamate AMPA receptor (i-Vialou et al., 2010) kwaye igxininisa ukubhalwa kwe-gene yangaphambili ye-gene c-fos (Pitchers et al., 2010b) kunye ne-histone methyltransferase G9 (Maze et al., 2010). I-cyclicdependent kinase-5 ilawula iiprotokeletal proteins kunye neurite outgrowth (Taylor et al., 2007). Ngaphezu koko, ukusebenza kwe-NF-? B kwandisa inani leentlobo ze-dendritic kwi-NAc, kanti ukuvinjelwa kwe-NF-? B kwehla kwimiqolo ye-basal dendritic kwaye ibimbela ukunyuka kwe-cocaine ekwenzeni imiphunga (Russo et al., 2009b). Ngako ke, umvuzo wezocansi ukwandisa? I-FosB kwi-NAc, enokuthi iguqule i-NAc spine density ngokusebenzisa iithagethi ezininzi (okt, i-kinase-5-dependent cyclic, NF-? B) akwaye ukuba isiphumo sesiqhelo siphumo somhlaza, njengoko kwakucatshulwa nguRusso et al. (2009a) kwizenzo ze-cocaine ephindaphindiweyo

Ukuqwalaselwa okungalindelekanga kwiphando langoku kukuba ukunyuka koxinzelelo kwintlambo ye-NAc kwakunokukhawuleza, kwaye akusabonakali kwi-28 d emva kwamava ezesondo. Ngako oko, ukunyuka kwentsholongwane kwintlambo kwakunxulumene nokuqala kokuhlaziywa kwe-Amph nokuphucula kwaye kunokuba negalelo ekuphuhlisweni kokuqala okanye ukubonakaliswa kwexesha elifutshane leempendulo ze-Amph. Nangona kunjalo, iukunyanzeliswa komnxeba kwakungadingeki ukuphikelela kwe-Amph ukufumana umvuzo emva kwexesha elide lokuzilahla. Ngaphambili siye sabonisa ukuba amava ezesondo enza i-short-term (7, kodwa ingekho i-28, iintsuku emva kokutshatyalaliswa kokugqibela) ukwanda kwe-NMDA yamagumbi okufumana i-NR-1 kwi-NAc, ebuye yabuyela kumanqanaba okuqala emva kwexesha elide lokuzilahla (Pitchers et al., 2012). Oku kukhulisa i-NMDA yokufumana i-receptor ibonakaliswe ukuba ibonakaliswe ngesifo se-synapses esicacileyo esingaxhamli ngesini (i-Huang et al., I-2009; i-Brown et al., I-2011; i-Pitchers et al., I-2012), kwaye ibonisa ukuba kwenzeka Ukukhula komnxeba kuxhomekeke kwimisebenzi yokwamukela i-NMDA (Hamilton et al., 2012).

Ekugqibeleni, uphando olukhoyo lugqamisa ukugqithiswa kwemiphumo yemithi ngomvuzo wendalo (ngokwesini) kunye nokuxhomekeka kwayo kwixesha lokuzilahla. Ngaphezu koko, le plastiki yokuziphatha yayingqinelana nayo? I-FosB nge-activation ye-D1R kwi-NAc. Ngoko ke, idata ibonisa ukuba ukulahlekelwa ngumvuzo wendalo emva kokufumana amava kunokubangela ukuba abantu banobungozi bokuphuhliswa kokusetyenziswa kweziyobisi kwaye omnye umlamli wale nengozi yenyuka yi-FosB kunye neethagethi zayo ezingezantsi.