Synapse. 2008 May;62(5):358-69.
UPerrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ.
Umthombo
UMnyango Wezengqondo, i-University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
abstract
I-transaction factor I-DeltaFosB iyanqwabelana futhi iphikelele ebuchosheni ngokuphendula ukugqugquzela okungapheli. Lokhu kuhlangana ngemuva kokuchayeka okungapheli kwezidakamizwa zokuhlukunyezwa kuboniswe ngaphambili yi-Western blot kakhulu ezindaweni ezi-striatal, kufaka phakathi i-dorsal striatum (caudate / putamen) nama-nucleus accumbens. Esifundweni samanje, sisebenzise i-immunohistochemistry ukuchaza ngokunemba okukhulu kwe-anatomical ukutholwa kwe-DeltaFosB kulo lonke ubuchopho be-rodent ngemuva kokulashwa kwezidakamizwa okungapheli. Siphinde sengeza ucwaningo lwangaphambilini olubandakanya i-cocaine, i-morphine, ne-nicotine emithini eyengeziwe yokuhlukumeza, i-ethanol ne-Delta (9) -tetrahydrocannabinol (Delta (9) -THC, isithako esisebenzayo insangu). Sibonisa lapha ukuthi ukuphatha, kodwa hhayi okubi kakhulu, ukuphathwa kwezidakamizwa ezine zokuhlukumeza, i-cocaine, i-morphine, i-ethanol, ne-Delta (9) -THC, efaka ngamandla i-DeltaFosB ezindaweni ezihlanganisiwe ze-nucleus yale nombolo bekusobala ukuthi izidakamizwa ezahlukile. Izidakamizwa futhi ziyehluka ngezinga labo lokungeniswa kweDeltaFosB ku-dorsal striatum. Ngaphezu kwalokho, yonke le mishanguzo emine ibanga i-DeltaFosB ku-preortal cortex, ngemiphumela emkhulu ebonwa yi-cocaine ne-ethanol, nazo zonke lezi zidakamizwa zenza i-DeltaFosB ngezinga elincane e-amygdala. Ngaphezu kwalokho, zonke izidakamizwa zabanga i-DeltaFosB ku-hippocampus, futhi, ngaphandle kwe-ethanol, iningi lalokhu kufakwa kwabonwa ku-dentate. Amazinga aphansi we-DeltaFosB lokungeniswa abonwe kwezinye izindawo zobuchopho ekuphenduleni ekwelashweni okuthile kwezidakamizwa. Lokhu okutholakele kunikeza ubufakazi obengeziwe bokuthi ukwenziwa kwe-DeltaFosB ku-nucleus accumbens kuyisenzo esivamile cishe sazo zonke izidakamizwa zokuhlukumeza nokuthi, ngaphezu kwe-nucleus accumbens, isidakamizwa ngasinye senza i-DeltaFosB ngendlela eqondene nesifunda ebuchosheni.
ISINGENISO
Ukuchayeka kakhulu ku-cocaine kubangela ukungena kwesikhashana kwezinto ezibhalwe phansi i-c-Fos ne-FosB ezifundeni ezi-striatal (i-Greybiel et al., 1990; Ithemba et al., 1992; i-Young et al., I-1991), ngenkathi kuchayeka kakhulu emiphumeleni yemithi ekuqongeleleni ama-isoforms azinzile we-ΔFosB, i-splice splice eguquguqukayo yohlobo lwe-fosB (Hiroi et al., 1997; Ithemba et al., 1994; Moratalla et al., 1996; Nye et al., 1995). Lapho iqhutshwa, i-ΔFosB iyaphikelela kulezi zindawo amasonto amaningana ngenxa yokuqina okungatheni kwamaprotheni. Ucwaningo lwakamuva luye lwabonisa ukuthi ukuqina kwe-ΔFosB kuqondiswa ngokungabikho kwezizinda ezitholakalayo ezitholakala ku-C-termini ye-FosB yobude obugcwele nawo wonke amanye amaprotheni omndeni we-Fos (uCarle et al., 2007) nangokwe-phosphorylation ye-ΔFosB ku-N yakhe -terminus (Ulery et al., 2006). Ngokuphikisana nalokho, ukuphathwa kwezidakamizwa okungamahlalakhona akukuguquli ukuphazanyiswa kwe-fosB premRNA ku-ΔfosB mRNA noma ukuqina kwe-mRNA (Alibhai et al., 2007), okubuye kukhombise ukuthi ukunqwabelana kwamaprotheni we-ΔFosB kuyindlela ebaluleke kakhulu ebandakanyekayo.
Ubufakazi obukhulayo bukhombisa ukuthi ukungena kwe-ΔFosB ezifundeni ze-striatal, ikakhulukazi, i-ventral striatum noma i-nucleus accumbens, kubalulekile ekulameni izici zokulutha. Ukuqunjelwa ngokweqile kwe-ΔFosB kulezi zindawo zamagundane angenasici we-bitransgenic, noma ngokudluliselwa kohlobo olungelutho lwegciwane, kukhulisa umuzwa wesilwane ekutholeni nasekuvuseleleni okuhle kwe-cocaine ne-morphine, kanti ukubonakaliswa komphikisi omubi kakhulu we-ΔFosB (kubizwa ngokuthi Δc- IJun) inemiphumela ehlukile (uKelz et al., 1999; McClung noNestler, 2003; Peakman et al., 2003; Zachariou et al., 2006). I-ΔFosB overexpression nayo ikhonjisiwe ukukhulisa isisusa sokukhuthaza i-cocaine (Colby et al., 2003). Ngaphezu kwalokho, i-ΔFosB ithonywa ngokukhethekile yi-cocaine ezilwaneni ezisakhula, ezingaba nomthelela ekwandeni kwabo kokulutha (i-Ehrlich et al., 2002).
Ngaphandle kwalobu bufakazi, imibuzo ebalulekile isasele. Noma ukuphathwa okungapheli kwezinye izidakamizwa eziningi zokuhlukumeza, kufaka phakathi i-amphetamine, i-methamphetamine, i-morphine, i-nicotine, ne-phencyclidine, kubikwe ukuthi kufaka i-ΔFosB ezifundeni ze-striatal (Atkins et al., 1999; Ehrlich et al., 2002; McDaid et al. I-2006b; i-Muller ne-Unterwald, i-2005; i-Nye et al., I-1995; i-Nye kanye ne-Nestler, i-1996; uPich et al. 1997; uZachariou et al., 2006), kuncane noma akukho lwazi olutholakalayo mayelana nezenzo ze-ethanol ne-Δ9-tetrahydrocannabinol (I-N9-THC, isithako esisebenzayo insangu). Izifundo ezimbili zangaphambilini ziveze ukuthi i-FosB-like immunoreacaction ifakwa ku-hippocampus nakwezinye izindawo zobuchopho ngesikhathi sokuhoxa kwe-ethanol, kepha kuhlala kungaziwa ukuthi lokhu kugonywa kumelela ΔFosB noma i-FosB ephelele (Bachtell et al., 1999; Beckmann et al., 1997 ). Ukutadisha kwe-ethanol ne (Δ9-THC kubaluleke kakhulu, ngoba lezi yizidakamizwa ezimbili ezisetshenziswa kakhulu ekuhlukumezeni e-US namuhla (SAMHSA, 2005) .Ngaphezu kwalokho, yize izidakamizwa zokuhlukumeza noma zokuhlukumeza zikhonjiswe ukuthi zifaka i-ΔFosB ezinye izifunda zobuchopho ezihlukanisiwe, okuthi, ngaphezu kwezibalo ze-nucleus kanye ne-dorsal striatum, zifake phakathi i-cortex yokuqala, i-amygdala, i-ventral pallidum, indawo ye-ventral tegmental, kanye ne-hippocampus (Liu et al., 2007; McDaid et al., 2006a, 2006b; Nye I-et al., 1995; Perrotti et al., 2005), akukaze kube khona ukuhlelwa kwemephu okuhleliwe kokufakwa kwe-ΔFosB ebuchosheni ngokuphendula ukuvezwa kwezidakamizwa okungamahlalakhona.
Inhloso yocwaningo olukhona kwakuwukusebenzisa izinqubo ze-immunohistochemical ukubala ukulethwa kwe-ΔFosB kulo lonke ubuchopho ngemuva kokuphathwa okungapheli kwezidakamizwa ezine zokuhlukunyezwa: i-cocaine, i-morphine, i-ethanol, ne-Δ9-THC.
IZIMPAHLA NEZINDLELA
Izilwane
Zonke izivivinyo zenziwa kusetshenziswa amagundane angamaduna weSprague Dawley (uCharles River, eKingston, 250-275 g). Izilwane zahlaliswa ezimbili ekhejini ngalinye futhi zahlaliswa ngaphansi kwezimo zegumbi lesilwane isonto elilodwa ngaphambi kokuqala kokuhlolwa. Babenokuthola mahhala ukudla namanzi. Ucwaningo lwenziwe ngokuya ngezinqubomgomo ezibuyekezwe yi-Institutional Animal Care and Use Committee Committee e-University of Texas Southwestern Medical Center eDallas.
Izidakamizwa zokwelapha
I-cocaine engapheli
Amagundane (n = 6 ngeqembu ngalinye) athole imijovo ephindwe kabili nsuku zonke ye-cocaine hydrochloride (15 mg / kg ip; I-National Institute on Drug Abuse, Bethesda, MD) ichithwe ku-0.9% usawoti wezinsuku ze-14. Amagundane wokulawula (n = 6 ngeqembu ngalinye) athola imijovo ye-ip ye-0.9% usawoti ngaphansi kwenqubo efanayo engapheli. Yonke imijovo inikezwe ezindlini zezilwane. Le ndlela yokwelashwa ikhonjiswe ukuthi ikhiqize ukuguqulwa kokuziphatha okuhle nokuphathelene nezinto eziphilayo (bheka iThemba et al., 1994).
Cocaine ukuzilawula
Izilwane (n = 6 ngeqembu ngalinye) zaqeqeshelwa ukucindezela i-lever ye-45 mg sucrose pellet. Ngemuva kwalokhu kuqeqeshwa, lezi zilwane zondliwe i-ad libitum futhi yafakwa ngaphansi kwe-pentobarbital anesthesia ene-catheter engapheli (i-Silastic tubing, Green Rubber, Woburn, MA) njengoba kuchaziwe ngaphambili (Sutton et al., 2000). I-catheter idlule ngendlela ephumelelayo ukuphuma komgwaqo nge-22-gauge cannula (Plastics One, Roanoke, VA), yafakwa usimende we-cranioplastic, futhi yavikeleka nge-mesh yokuhlinza iMarlex (Bard, Cranston, RI). Ukuzilawula kwakwenzelwa kumagumbi okuhlola asebenzayo (amaMed Associates, iSt. Alban, VT) ayehluke ngokuphelele endaweni yezilwane yasendlini futhi esegumbini elihlukile. Igumbi ngalinye lalifakwe ku-cubicle enesisindo somsindo efakwe umhlangano wokumpompa we-Razel Model A (Stamford, CT) kanye nesirinji yengilazi ye-10 ml exhunywe kwi-fluid swivel (Instech, Plymouth Meeting, PA) nguT Teflon . Ishubhu likaTygon laxhuma iswibela nomhlangano we-catheter wesilwane futhi lavalelwa isiphethu sensimbi. Igumbi ngalinye elisebenzayo laline-levers ezimbili (i-4 × 2 cm2, ebekwe 2 cm phansi phansi). Ngesikhathi sokuqeqeshwa kokuzilawula, umshini wokuxhuma we-20 g lever-ku-lever esebenzayo ulethe ukumiliselwa kwe-cocaine (i-0.5 mg / kg ngokufakwa kwe-0.1 ml) ngokwesikhathi sokumiswa kwe-5-s. Ukumakwa kwalandelwa yisikhathi sokuphuma kwe-10, lapho isibani sendlu sicishiwe futhi ukuphendula akuzange kube nemiphumela ehleliwe. Ukukhanya kwesibani sendlu kukhombisa ukuphela kwesikhathi sokuphela kwesikhathi. Ukucindezela kwe-lever ku-lever engasebenzi akuzange kube nemiphumela. Izilwane ezizenzela i-cocaine ngesikhathi sama-14 nsuku zonke izivivinyo ze-4-h (izinsuku ze-6 / isonto) phakathi komjikelezo wazo omnyama; isilinganiso esimaphakathi sokudla nsuku zonke kwakungu ~ 50 mg / kg. Iqembu lezilwane ezinamajazi laliphathwa ngendlela efanayo kuphela lapho bethola imidwebo ye-cocaine lapho ozakwabo abazisebenzelayo bethola izidakamizwa. Iqembu lezilwane ezilawula usawoti zivunyelwe ukucindezela izingcingo ze-saline infusions. Le ndlela yokwelashwa ikhonjiswe ukuthi ikhiqize izilungiso zokuziphatha nezokuziphatha eziqinile (bona i-Sutton et al., 2000).
I-morphine engapheli
Ama-pellets ama-Morphine (ngalinye liqukethe i-75 mg ye-morphine base; I-National Institute on Drug Abuse) ifakwa i-sc kanye ngosuku ngezinsuku ze-5 (n = 6). Lawula amagundane ahlinzwe nge-sham izinsuku ze-5 zilandelana (n = 6). Le ndlela yokwelashwa ikhonjiswe ukuthi ikhiqize izilungiselelo eziguqukayo zokuziphatha nezokuziphatha (bheka uNye noNestler, 1996).
Δ9-THC
I-Δ9-THC yachithwa ku-1: 1: Isixazululo se-18 se-ethanol, emulphor, ne-saline. Amagundane afakwa ejwayiniwe kabili ngosuku nsuku zonke nge-Δ9-THC, noma imoto yezinsuku ze-15. Umthamo wokuqala we-Δ9-THC wawungu-10 mg / kg kanti umthamo wawuphindwe kabili ezinsukwini ezintathu ukuze kube nomthamo wokugcina we-160 mg / kg. Sisebenzise amagundane e-Δ9-THC, ngoba le nqubo yokwelashwa ikhonjisiwe ukukhiqiza ukuthambekela kokuziphatha okuhle nokuphathelene ne-biochemical kule hlobo (Sim-Selley noMartin, 2002).
I-Ethanol
U-Ethanol (osuka esitokisini se-95%; i-Aaper, iShelbyville, KY) waphathwa ngendlela yokudla uketshezi oluphelele olunempilo. Le nqubo ejwayelekile yokudla kwe-ethanol ifaka ukuphathwa kwe-7% [isisindo / ivolumu (wt / vol)] ethanol ekudleni okusekwe lactalbumin / dextrose kwezinsuku ze-17, phakathi naleso sikhathi amagundane ngokuvamile adla i-ethanol ku-8-12 g / kg / ngosuku kanye finyelela amazinga we-ethanol wegazi aze afike ku-200 mg / dl (uCriswell noBreese, 1993; uFrye et al., 1981; Knapp et al., 1998). Ukudla bekuphelele ngokomsoco (ngokugxilwa kwamavithamini, amaminerali, nezinye izakhamzimba ezithathwe kuma-ICN Research Diets kanye nokulinganisela okulinganiselwe (nge-dextrose) kumagundane aphathwe i-ethanol kanye namagundane okulawula. Ukuqhathaniswa kokudla kutholwe ngokunikeza amagundane wokulawula ukudla aphathwe ukudla umthamo wokudla olingana nesilinganiso sokudla okuphakathi kwamagundane aphethwe yi-ethanol ngosuku olwedlule. Womabili la maqembu athola isisindo ngesikhathi sokuvezwa kwe-ethanol (engakhonjiswanga). Le ndlela yokwelashwa iboniswe ukuthi ikhiqiza ukuvumelana kokuziphatha okuhle nokuphathelene nezinto eziphilayo (bheka i-Knapp et al., 1998).
Immunohistochemistry
Ishumi nesishiyagalombili ukuya kwe-24 h ngemuva kokwelashwa kwabo kokugcina, izilwane zahlatshwa umxhwele ngokujulile nge-chloral hydrate (i-Sigma, iSt. Louis, MO) futhi zagcotshwa ngenkani nge-200 ml ye-10 mM phosphate-buffered saline (PBS) yalandelwa yi-400 ml ye-4% paraformaldehyde e I-PBS. Ama-Brains asusiwe futhi agcinwa ubusuku bonke kwi-4% paraformaldehyde e-4 ° C. Ngakusasa ekuseni, ubuchopho badluliselwe kwi-20% glycerol kusisombululo se-0.1 M PBS se-cryoprotection. Izingxenye zeCoronal (40 µm) zazisikwa kuyi-microtome eqandayo (Leica, Bannockburn, IL) zabe sezicutshungulwa ukuze kwenziwe i-immunohistochemistry. I-ΔFosB ne-FosB immunoreactivities zitholakele zisebenzisa ama-antisera amabili ahlukene e-polyclonal. I-antiserum eyodwa, ephakanyiswe ngokumelene ne-FosB C-terminus engekho ku-ΔFosB (aa 317-334) ibona i-FosB ebude obugcwele, kepha hhayi i-ΔFosB (Perrotti et al., 2004). Elinye i-antiserum, i-anti paner FosB, lakhuliswa endaweni engaphakathi ye-FosB futhi libona bobabili i-FosB ne-ΔFosB (sc − 48; Santa Cruz Biotechnology, Santa Cruz, CA).
Ukudonswa okunjenge-FosB kwavezwa kusetshenziswa indlela eyinkimbinkimbi ye-avidin-biotin peroxidase. Ngale nqubo, izingxenye zobuchopho zaqale zaphathwa nge-0.3% H2O2 ukubhubhisa i-endoxia peroxidases bese iyashiselwa i-1 h ku-0.3% Triton X-100 kanye ne-3% evamile ye-serum yembuzi ukunciphisa i-nonspecific labeling. Izingxenye zamathishu zase zishiswa ubusuku bonke endaweni yokushisa yegumbi ku-1% i-serum yembuzi ejwayelekile, i-0.3% iTriton X-100 ne-pan-FosB antibody (1: 5000). Izingxenye zagezwa, zabekelwa i-1.5 h ku-1: 200 dilution of biotinylated goat-antirabbit immunoglobulin (DakoCytomation, Carpinteria, CA), yageza, yabekwa i-1.5 h ku-1: 200 dilution of avidin-biotin tata from the Elite kit (Vector kit Laboratories, Burlingame, CA). Umsebenzi wePeroxidase wabonwa ngokuphendula nge-diaminobenzidine (Vector Laboratories). Kwakusetshenziswa amaslayidi anamakhodi ukubala inani lamaseli we-FosB-immunoreactive. Ikhodi ayizange yephulwe kuze kube yilapho kuhlaziywa ukuhlolwa komuntu okuphelele.
Lapho ukutholwa kokungasebenzi kwe-FosB kufana nokutholwa, ukufakwa amalebula okuphindwe kabili kwe-ForesB nge-FosB-ezithile (C-terminus; 1: 500) antibody ne-pan-FosB antibody (sc UM 48; 1: 200) I-ΔFosB. Kusetshenziswe umthetho olandelwayo (Perrotti et al., 2005). Amaphrotheni aboniswa kusetshenziswa i-CY2 ne-CY3 fluorophore-labels secondary antibodies (UJackson ImmunoResearch Laboratories, West Grove, PA). Ukucaciswa kwasendaweni okwenziwe ngamaphrotheni kwenziwa kwi-microscope eyimfihlo (i-Axiovert 100; i-LSM 510 enama-wavelength ekhipha i-META we-488, i-543, kanye ne-633; i-Zeiss, Thornwood, NY). Izithombe ezethulwe lapha zithathwe kulolu hlelo futhi zibonisa isigaba se-1 µm-thick ngokusebenzisa indiza ye-Z.
Ukuhlaziywa kwesitatimende
Ukungeniswa okuphawulekayo kwamaseli e-ΔFosB + kuhlolwe kusetshenziswa ukuhlolwa kwe-t noma ama-ANOVA wendlela eyodwa kulandelwa ukuhlolwa kweNewman-Keuls njengokuhlaziywa kweposi. Konke ukuhlaziywa kwalungiswa ngokuqhathanisa okuningi. Idatha ivezwa njengeyize ± SEM. Ukubaluleka kwesitatimende kuchazwe njenge-P <0.05.
IZIPHUMA
Ukwenziwa kwe-ΔFosB ebuchosheni
Ukuqhathanisa ngqo amaphethini wokungeniswa kwe-ΔFosB ebuchosheni baphendukela ezinhlotsheni ezahlukahlukene zezidakamizwa zokuhlukumeza, saphatha izidakamizwa ezine ze-prototypical, i-cocaine, i-morphine, i-ethanol, ne-Δ9-THC, futhi sahlola i-ΔFosB expression 18-24 h ngemuva kokuvezwa kokugcina kwezidakamizwa . Sisebenzise ama-regimens aphathelene nokwelashwa ngezidakamizwa okujwayelekile, okukhonjiswe ezincwadini ukukhiqiza indlela yokuziphatha nokulandelana kwe-biochemical yokuchayeka kwezidakamizwa okungapheli (bheka isigaba sezinto zokwakha nezindlela). Amazinga we-ΔFosB ahlukaniswa yi-immunohistochemistry, ngokugxila ezifundeni ze-midbrain kanye nasezingqondweni zobuchopho ezifakiwe emvuzweni wezidakamizwa nokulutha. Lokhu kwenziwa kwebalazwe okuhle kwe-ΔFosB lokungeniswa kwenziwa nge-anti-pan-FosB, eqaphela zombili i-ΔFosB ne-FosB egcwele. Kodwa-ke, Siyazi ukuthi konke ukungaziphathi okubonakalayo, kulowo nalowo muthi, kungenxa ye-ΔFosB kuphela, ngoba i-antibody ekhetha i-FosB ebude obugcwele (bheka isigaba se-Material and Methods) asitholanga amaseli amahle. Ngaphezu kwalokho, konke ukugonywa okutholwe yi-pan-FosB antibody kulahlekile ku-fosB knockout mice, okuqinisekisa ukucaciswa kwaleli gciwane emikhiqizweni yohlobo lwefosB ngokungafani namanye amaprotheni omndeni wakwaFos. Lezi zilawuli zikhonjiswa i-cocaine kuMdwebo 1, kodwa yayibonwa yazo zonke ezinye izidakamizwa (azikhonjiswanga). Lokhu okutholakele akumangazi, ngoba ngesikhathi se-18-24 h isikhathi esisetshenziswe kulolu cwaningo konke okugcwele kwe-FosB, okuvezwe ukuphathwa kwezidakamizwa kokugcina, kulindeleke ukuthi kungcolise, kushiye stableFosB ezinzile kakhulu okuwukuphela kohlobo lwe-fosB umkhiqizo osele (bona u-Chen et al., 1995; Ithemba et al., 1994).
I-Fig. 1
I-anti-FosB (pan-FosB, iSanta-Cruz) noma i-anti-FosB (C-terminus) antibody ngokusebenzisa i-nucleus accumbens yezilwane eziphathwe nge-cocaine ebukhali noma engapheli kanye negundane lokulawula. Amabala we-pan-FosB antibody (Okuningi…)
Ukufingqwa kokutholwayo okuphelele kwalolu cwaningo kunikezwe kuThebula I. Umuthi ngamunye wezidakamizwa ezine utholakele ukufaka i-ΔFosB ebuchosheni, yize bekunamaphethini ahlukile wokuqalwa okubonakalayo kumuthi ngamunye.
Ithebula I
Ukwenziwa kwe-ΔFosB ebuchosheni ngezidakamizwa zokuhlukumeza
Ukwenziwa kwe-ΔFosB ezifundeni zezwekazi
Ukuqalwa okumangazayo kwe-ΔFosB kubonakale kuma-nucleus accumbens nase-dorsal striatum (caudate / putamen), lapho zonke izidakamizwa ezine zayenga khona iprotheni (i-Fig. 2-Fig. 4). Lokhu kuboniswa ngobuningi kuMdwebo 5. Ukungeniswa kwe-ΔFosB kwabonwa ekuqeshweni okungaphansi kwegobolondo kanye namagobolondo okuqongelelwa kwe-nukli, ngokufakwa okungatheni komthetho kubonwe enkabeni iningi lemithi. Ukungeniswa okuqinile kwe-ΔFosB kwabuye kwaqashelwa lapho kugcinwa khona izidakamizwa iningi lezidakamizwa. Okuhlukile kwakungu-Δ9-THC, okungazange kukhuthaze kakhulu i-ΔFosB ku-nucleus accumbens igobolondo noma i-dorsal striatum naphezu kwezitayela eziqinile (bheka i-Fig. 4; Ithebula I). Ngokuthabisako, i-ethanol ikhiqize ukwazisa okukhulu kwe-ΔFosB ku-nucleus accumbens core kuqhathaniswa nolunye unyango.
I-Fig. 2
Ukungeniswa kwe-ΔFosB ku-rat nucleus accumbens ku-rat rat (A) noma ngemuva kokwelapha okungamahlalakhona nge-ethanol (B), morphine (C), noma i-cocaine (D). Amaleveli we-FosB-like immunoreactivity ahlaziywa yi-immunohistochemistry esebenzisa i-pan-FosB antibody. (Okuningi …)
I-Fig. 4
Ukwenziwa kwe-ΔFosB ebuchosheni begundane ngemuva kokwelashwa okungapheli kwe-Δ9-THC. Amaleveli we-FosB-like immunoreactivity ahlaziywa yi-immunohistochemistry esebenzisa i-pan-FosB antibody ephethe (A, C, E) kanye nezilwane ezingama-chronic9-THC (B, D, F) ezingapheli. Inothi (ngaphezulu…)
I-Fig. 5
Inani le-ΔFosB lokungeniswa ezifundeni ezibulalayo ngemuva kwe-morphine engapheli, i-Δ9-THC, i-ethanol, ne-cocaine. Amagrafu ebha akhombisa inani elisho lamaseli e-osBFosB + alawula izilwane nasezilwaneni ezifakwe i-morphine engapheli, (more…)
Ukwenziwa kwe-ΔFosB ngokuchayeka kwezidakamizwa okungajwayelekile ngokuzithandela
Ngokungeniswa okumangazayo kwe-ΔFosB ezifundeni zezwe, besinesifiso sokuthola ukuthi amandla esidakamizwa okufaka amaprotheni kulezi zifunda ayehlukahluka njengomsebenzi wokuvezwa kwezidakamizwa ophoqelelwa ngokuchasanayo. Ukuze siphendule lo mbuzo, safunda iqembu lamagundane elizisebenzelayo i-cocaine yezinsuku ze-14 futhi saqhathanisa nokungeniswa kwe-ΔFosB kulezi zilwane nalezo ezathola ukumiswa kwe-cocaine kanye naleyo ethola usawoti kuphela. Njengoba kukhonjisiwe kuMdwebo 6, i-cocaine elawulwa i-cocaine ngamandla ku-nucleus accumbens (zombili izifunda ezingumongo kanye nezigobolondo) kanye ne-dorsal striatum, enamazinga alinganayo okuqalwa abonwa ngomuthi olawulwa wodwa olawulwa ngokwedlule. Ubungako lokungeniswa kwe-ΔFosB obonwa kula maqembu amabili ezilwane bukhulu kunalokho okubonwe ngomjovo we-ip we-cocaine (bona i-Fig. 5), ngokunokwenzeka ngenxa yamanani amakhulu we-cocaine ekuhlolweni kokuzibusa (imithamo yansuku zonke: 50 mg / kg iv vs 30 mg / kg ip).
I-Fig. 6
Inani le-ΔFosB lokungeniswa ezifundeni ezibulalayo ngemuva kokuzibusa okungapheli kwe-cocaine. Amagrafu ebha akhombisa inani elishoyo lamaseli e-osBFosB + alawula izilwane nasezilwaneni ezifakwe ekwelashweni kwe-cocaine, emgodini kanye (nokuningi…)
Ukwenziwa kwe-ΔFosB kwezinye izindawo zobuchopho
Ngaphandle kwesakhiwo esibucayi, ukuphathwa okungapheli kwezidakamizwa zokuhlukumeza okubangelwa i-ΔFosB kwezinye izindawo zobuchopho (bheka Ithebula I). Kufanele sigcizelele ukuthi idatha evezwe kuThebula I iyisilinganiso, futhi ayimeleli ukulinganisa okuqondile kokungeniswa kwe-ΔFosB, njengoba kwenziwa ezifundeni ezibulalayo (I-Fig. 5 ne-Fig. 6). Noma kunjalo, siyaqiniseka ngokungeniswa kwe-ΔFosB kulezi zifunda ezingezona ezokubeletha: I-ΔFosB cishe ayitholakali kulezi zifunda ngaphansi kwezimo ezingaphansi, ukuze ukutholwa okungaguquguquki kwe-ΔFosB ngemuva kokuvezwa kwezidakamizwa okungapheli kubaluleke kakhulu ngokwezibalo (P <0.05 ngu-χ2).
Ukungeniswa okuqinile yizo zonke izidakamizwa kwabonwa ku-cortex yokuqala, kanti i-morphine ne-ethanol kubukeka sengathi kukhiqiza imiphumela enamandla kakhulu ezingqekweni eziningi (i-Fig. 4 ne-Fig. 7). Zonke lezi zidakamizwa ezine zibuye zabangela amazinga aphansi we-ΔFosB lokungeniswa kombhede we-stria terminalis (BNST), i-substitial nucleus of the posterior limb of the anterior commissure (IPAC), futhi kulo lonke i-amygdala tata (Fig. 8). Imiphumela eyengeziwe, eqondene nezidakamizwa ezithile, nayo yabonwa. I-cocaine ne-ethanol, kepha hhayi i-morphine noma i-Δ9-THC, kubonakale sengathi kukhuthaza amazinga aphansi we-ΔFosB ku-septum yamuva, ngaphandle kokungeniswa okubonwe ku-medial septum. Zonke izidakamizwa zibanga i-ΔFosB ku-hippocampus futhi, ngaphandle kwe-ethanol, iningi lalokhu kungeniswa kwabonwa ku-dentate gyrus (Ithebula I ne-Fig. 9). Ngokuphambene, i-ethanol ibambe i-ΔFosB encane kakhulu ku-dyrate gyrus futhi esikhundleni salokho yafaka amazinga aphezulu weproteyini ku-CA3-CA1 subfields. I-cocaine, i-morphine, ne-ethanol, kepha hhayi i-X9-THC, yabangela amazinga aphansi wokufakwa kwe-ΔFosB ku-periaqueductal grey, kuyilapho i-cocaine kuphela eyenga ΔFosB endaweni ye-ventral yehlukano, ngaphandle kokuqanjwa kubonwe ku-sub-stantia nigra (bheka Ithebula I ).
I-Fig. 7
Ukungeniswa kwe-ΔFosB ku-prefrontal cortex ku-rat rat (A) noma ngemuva kokwelashwa okungalapheki nge-ethanol (B), morphine (C), noma i-cocaine (D). Amaleveli we-FosB-like immunoreactivity ahlaziywa yi-immunohistochemistry esebenzisa i-pan-FosB antibody. Kufakwa ilebula (okuningi…)
I-Fig. 8
Ukwenziwa kwe-ΔFosB ku-basal lateral and central medial nuclei ye-amygdala ye-control rat (A) noma kumagundane anikezwe ukwelashwa okungapheli kwe-ethanol (B), morphine (C), noma i-cocaine (D). Amaleveli we-FOS-like immunoreactivity ahlaziywa yi-immunohistochemistry (Okuningi…)
I-Fig. 9
Ukungeniswa kwe-ΔFosB ku-hippocampus yesilinganiso sokulawula (A) noma kumagundane anikezwe ukwelashwa okungapheli kwe-ethanol (B), morphine (C), noma i-cocaine (D). Amaleveli we-FosB-like immunoreactivity ahlaziywa yi-immunohistochemistry esebenzisa i-pan-FosB antibody. Kufakwa ilebula (okuningi…)
UKUKHULUMA
Ucwaningo oluningi luye lwabonisa ukuthi ukuphatha okungapheli kwezindlela eziningana zezidakamizwa zokuhlukumeza, kufaka phakathi i-cocaine, amphetamine, methamphetamine, i-morphine, i-nicotine, ne-phencyclidine, okwenza i-transcript factor, i-ΔFosB, ku-nucleus accumbens kanye ne-dorsal striatum (bona isigaba seSingeniso sereferensi; sibukeziwe kuMcClung et al., 2004; Nestler et al., 2001). Ukwenziwa kwe-ΔFosB ezifundeni ezinobuso nakho kuye kwaqashelwa ngemuva kokusetshenziswa okungapheli kwemivuzo yemvelo, njengokuziphatha kwesondo (Werme et al., 2002). Ngaphezu kwalokho, kunemibiko eminingana yamazinga aphansi we-ΔFosB lokungeniswa kwezinye izindawo zobuchopho, kufaka phakathi i-preortal cortex, i-amygdala, i-ventral pallidum, indawo ye-ventral tegmental, kanye ne-hippocampus (Liu et al., 2007; McDaid et al., 2006a, I-2006b; Nye et al., 1996; Perrotti et al., 2005), ephendula ezinye zalezi zidakamizwa zokuhlukumeza, noma kunjalo, akukaze kube nokuhlelwa kwemephu okuhlelekile kokufakwa kwezidakamizwa kwe-ΔFosB ebuchosheni. Ngaphezu kwalokho, ngaphandle kokuphenywa kwezidakamizwa eziningi zokuhlukunyezwa, izinto ezimbili ezihlukunyezwa kakhulu, i-ethanol ne-Δ9-THC, kuze kube manje azihloliswanga ikhono lazo lokusebenzisa i-ΔFosB. Inhloso yocwaningo olukhona kwakuwukwenza imephu yokuqala ye-ΔFosB ebuchosheni ngokuphathwa okungapheli kwezidakamizwa ezine zokuhlukunyezwa: i-cocaine, i-morphine, i-ethanol ne-Δ9-THC.
Ukutholwa okukhulu ocwaningweni lwethu ukuthi i-ethanol ne-Δ9-THC, njengazo zonke ezinye izidakamizwa zokuhlukumeza, zenza amazinga aphezulu we-ΔFosB abanzi ngaphakathi kobunzima be-striatal. Le miphumela ibuye isungule i-ΔFosB yokungeniswa kulezi zifunda njengendlela ejwayelekile, evamile yokuzivumelanisa nezimo cishe kuzo zonke izidakamizwa zokuhlukumeza (McClung et al., 2004). Iphethini lokungeniswa ngaphakathi kwe-striatal complex yehlukile ngandlela thize emithini ehlukahlukene. Zonke i-ΔFosB ezibambe ngamandla i-inFosB kumongo we-nucleus accumbens, kanti zonke izidakamizwa-ngaphandle kwe-Δ9-THC-eziyengelwe kakhulu i-ΔFosB ku-nucleus accumbens igobolondo ne-dorsal striatum futhi, futhi bekukhona ukuthambekela okuqinile kwe-Δ9-THC lezi zifunda zakamuva. Ama-nucleus accumbens core kanye negobolondo yizindawo ezibalulekile zemivuzo yobuchopho, eziye zaboniswa njengabalamuli ababucayi bezenzo ezivuzayo zezidakamizwa zokuhlukumeza. Ngokufanayo, i-dorsal striatum ihlobene nemvelo ephoqelekile noma efana nomkhuba wokusetshenziswa kwezidakamizwa (Vanderschuren et al., 2005). Ngempela, ukutholwa kwe-ΔFosB kulezi zifunda kukhonjiswe ukwandisa izimpendulo ezinomvuzo ku-cocaine kanye ne-morphine, kanye nokukhulisa izimpendulo emvuzweni wemvelo njengokuziphatha kokugijimisa amasondo nokudla ukudla, kanye (Colby et al., 2003; Kelz et al., 1999; Olausson et al., 2006; Peakman et al., 2003; Werme et al., 2003; Zachariou et al., 2006). Kudingeka omunye umsebenzi ukuthola ukuthi i-ΔFosB ingeniswa yini kulezi zifunda ivumelanisa nezimo ezifanayo zomsebenzi ekuzweleni komuntu nemiphumela evuza yezinye izidakamizwa zokuhlukumeza.
Ukwenziwa kwe-ΔFosB ezifundeni ezi-striatal akuwona umsebenzi wokuthatha umuthi okwejwayelekile. Ngakho-ke, sikhombisile ukuthi ukuzilawula kwe-cocaine kubangele isilinganiso esifanayo se-ΔFosB kuma-nucleus accumbens kanye ne-dorsal striatum njengoba kubonwe ezilwaneni ezathola imijovo elingana, eboshwe ejezini lomuthi. Le miphumela ikhombisa ukuthi i-ΔFosB yokungeniswa ku-striatum imelela isenzo se-pharmacologic sezidakamizwa zokuhlukumeza, ngaphandle kokulawulwa kwesilwane ekuvezweni kwezidakamizwa. Ngokuphikisanayo, sikhombise kamuva nje ukuthi ukuzilawula kwe-cocaine kubangela amazinga amaningi aphakeme we-ΔFosB ku-cortex ye-orbitofrontal kuqhathaniswa nokuphathwa kwe-cocaine ye-joen (Winstanley et al., 2007). Lo mphumela ubucacile nge-cortex ye-orbitofadal, ngoba amazinga afanayo wokufakwa kwe-ΔFosB abonwe ku-cortex yangaphambi kwalawa ngaphansi kwalezi zimo zokwelashwa ezimbili. Ngakho-ke, yize ukungeniswa kwe-ΔFosB kungahlobene nokulawulwa okuzenzakalelayo kokudla izidakamizwa ezifundeni ezi-striatal, kubukeka sengathi kuthonywe yizinto ezinogqozi ezikhungweni ezithile eziphakeme zecortical.
Siphinde futhi siveze imininingwane elandelanayo yokuthi yonke le mishanguzo emine yokuhlukumeza iveza i-ΔFosB ezindaweni eziningana zobuchopho ngaphandle kwenkimbinkimbi ye-striatal, yize ijwayele ngezinga elincane. Lezi ezinye izindawo zobuchopho zifaka i-cortex yokuqala, i-amygdala, i-IPAC, i-BNST kanye ne-hippocampus. Ukufakwa kwezidakamizwa kwe-ΔFosB ku-cortex yangaphambili ne-hippocampus kungahle kuhlobane neminye imiphumela yezidakamizwa zokuhlukumeza ekusebenzeni kwengqondo, yize lokhu kusamele kuphenywe ngqo. I-amygdala, i-IPAC, ne-BNST konke kufakwe emthonjeni wokulawula izimpendulo zomuntu ozithandayo. Lokhu kuphakamisa ukuthi kungenzeka ukuthi i-ΔFosB ingeniswe kulezi zifunda ngemuva kokuphathwa okungapheli komuthi wokuhlukunyezwa kuhlanganisa ukulawulwa kwezidakamizwa kokuziphatha okungaphezu komvuzo. Kungakujabulisa ukuhlola la mathuba ophenyweni oluzayo.
Izidakamizwa ezine zokuhlukumeza ezifundwe lapha zikhiqize nemiphumela ethile eqondene nezidakamizwa. I-Cocaine ihehe i-ΔFosB ngokuhlukile endaweni ye-ventral tegmental, njengoba kubikwe ngaphambilini (Perrotti et al., 2005). Ngokunjalo, i-cocaine ne-ethanol ngokukhethekile zabangela amazinga aphansi we-ΔFosB ku-septum yamuva. I-Δ9-THC yayihlukile kwimiphumela emincane kakhulu ekungenisweni kwe-ΔFosB, uma iqhathaniswa nezinye izidakamizwa zokuhlukunyezwa, kuyi-nucleus accumbens igobolondo ne-dorsal striatum, njengoba kushiwo ngaphambili. I-Δ9-THC nayo ihlukile kulokho kuchayeka okungapheli kwalo muthi, ngokungafani nabo bonke abanye, ayizange iholele emazingeni aphansi we-ΔFosB ku-periaqueductal grey. Ngokubhekwa kwendima ye-hippocampus ne-septum ekusebenzeni kwengqondo, kanye neqhaza lalezi zifunda kanye nokumpunga okuphathelene nokulawula izimpendulo zezilwane ezimweni ezicindezelayo, ukumiswa kwesifunda kanye nokuphathelene nezidakamizwa kwe-ΔFosB kulezi zifunda kungalamula izici ezibalulekile ze isenzo sezidakamizwa ebuchosheni.
Ngokufingqa, i-ΔFosB lokungeniswa ezifundeni zomvuzo wobuchopho iboniswe kabanzi njengendawo evumelanayo engaguquki yezidakamizwa zokuhlukumeza. Swedlulise lo mbono ngokubonisa lapha ukuthi izidakamizwa ezimbili ezengeziwe futhi ezihlukumezeke kabanzi, i-ethanol ne-Δ9-THC, nazo zenza i-ΔFosB kulezi zindawo zobuchopho.. Siphinde sikhombe ezinye izindawo eziningi zobuchopho, ezithinteka ekusebenzeni kwengqondo nezimpendulo zokucindezelwa, ezibonisa amazinga ahlukahlukene we-ΔFosB ukuphendula ukuvezwa kwezidakamizwa okungapheli. Ezinye zalezi zimpendulo, njengokufakwa kwe-ΔFosB ezifundeni ezithokomele, zivame kuzo zonke izidakamizwa zokuhlukumeza ezifundwe lapha, kanti izimpendulo kwezinye izindawo zobuchopho zichazwa kakhulu ngomuthi. Lokhu okutholakele manje kuzoqondisa ukuphenywa kwesikhathi esizayo ukubonakalisa iqhaza lokufakwa kwe-ΔFosB kulezi zindawo zobuchopho. Zibuye zisize ekuchazeni umsebenzi ongaba khona wabaphikisi be-ΔFosB njengokwelashwa okuvamile kwama-syndromes okulutha kwezidakamizwa.
I-Fig. 3
Ukungeniswa kwe-ΔFosB ku-rat caudate putamen ku-rat rat (A) noma ngemuva kokwelapha okungamahlalakhona nge-ethanol (B), morphine (C), noma i-cocaine (D). Amaleveli we-FosB-like immunoreactivity ahlaziywa yi-immunohistochemistry esebenzisa i-pan-FosB antibody. (Okuningi …)
Ukuvuma
Umxhasi wesibonelelo senkontileka: I-National Institute on Drug Abuse.
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