DeltaFosB ukungeniswa kwe-corbitx e-orbitofrontal cortex engakwazi ukukhuthaza ukusondeza ukukhathazeka ngaphandle kokunciphisa ukungasebenzi okubangelwa yi-cocaine. (2009)

IMIBUZO: Ucwaningo lubonisa ukuthi imbangela yekhandlela ye-DelatFosB kokubili ukuzwela nokwehliswa kwemisebenzi (ukubekezelelana). 
 
I-Pharmacol i-Biochem Behav. I-2009 Sep; 93 (3): 278-84. I-Epub 2008 Dec 16.
 
Winstanley CA, Green TA, Theobald DE, Renthal W, LaPlant Q, DiLeone RJ, Chakravarty S, Nestler EJ.

Umthombo

Umnyango Wezokwelapha, I-University of Texas Southwestern Medical Center, i-5323 Harry Hines Boulevard, i-Dallas, i-TX 75390-9070, e-United States. [i-imeyili ivikelwe]

abstract

Imiphumela ye umlutha izidakamizwa zishintsha ngokusetshenziswa okuphindaphindiwe: abantu abaningi bayakubekezelela imiphumela yabo ejabulisayo kodwa futhi banomthelela kakhulu kwi-sequelae engafanele (isib. ukukhathazeka, i-paranoia, nesifiso sezidakamizwa). Ukuqonda izindlela ezithinta ukubekezelelana nokuzwela okunjalo kungase kuhlinzeke ukuqonda okubalulekile ngesisekelo sokuxhomeka kwezidakamizwa futhi Ukuba umlutha wezithombe. Sesanda kubonisa ukuthi ukuphathwa kwe-cocaine okungapheli kunciphisa ikhono lomjovo omningi we-cocaine ukuthinta ukungabi nomphumela kwamagundane. Kodwa-ke, izilwane zishintsha kakhulu ngesikhathi sokuhoxiswa kwe-cocaine self-administration. Siphinde sibonise ukuthi ukulawulwa okungapheli kwe-cocaine kwandisa ukubonakala kwe-factor factor DeltaFosB ku-corbit (orbitofrontal cortex) ye-OFC. Ukumisa ukuphakama okwenziwe izidakamizwa ku-OFC DeltaFosB ngokusebenzisa ukuguqulwa kwegciwane lesandulela ngculazi kulingisa lezi zinguquko zokuziphatha: I-DeltaFosB evezwe ngaphezulu kwe-OFC ikhuthaza ukubekezelelana nemiphumela yesinselelo esinzima se-cocaine kodwa ikhuthaza izintuthwane kwi-sequelae engqondweni yokuxoshwa. Lapha sibika idatha yombhalo ekhombisa ukuthi i-DeltaFosB ekhulayo e-OFC ibuye ivuselele izilwane ezakhiweni ezivuselela i-cocaine. AI-nalysis yezicubu ze-nucleus accumbens ezithathwe kumagundane eziveza ngokweqile i-DeltaFosB e-OFC futhi iphathwe ngokungapheli nge-saline noma i-cocaine ayinikeli ukusekelwa kwe-hypothesis ethi ukwanda kwe-OFC DeltaFosB kungadala ukuzwela nge-nucleus accumbens. Le mininingwane iphakamisa ukuthi kokubili ukubekezelelana nokuzwela emiphumeleni eminingi ye-cocaine, noma kubukeka sengathi kuyizinqubo eziphikisanayo, kungenziwa ngokufana ngendlela efanayo yemvelo esifundeni esifanayo sobuchopho, nokuthi izinguquko ezibangelwa izidakamizwa ekubonakalisweni kofuzo ngaphakathi kwe-OFC zidlala indima ebalulekile ezicini eziningi ze- Ukuba umlutha wezithombe.

1. Isingeniso

TI-phenomena yokubekezelelana nokuzwela amanga enhliziyweni yamanje imibono mayelana nokulutha izidakamizwa. Ngokucubungula i-Manual Diagnostic and Statistical (i-American Psychiatric Association DSM IV) ye-criteria (1994) ye-disorder drug disorder, esinye sezibonakaliso eziyinhloko ukuthi umsebenzisi wezidakamizwa ubekezelela imiphumela emihle yesidakamizwa futhi kudinga ukuthi izidakamizwa eziningi zifeze okufanayo "Phezulu". Kodwa-ke, ukubekezelelana akuhambisani nokushesha okulinganayo kuwo wonke umphumela wezidakamizwa, okuholela ekugqithiseni okubulalayo njengoba abasebenzisi bekhula ngokudla kwezidakamizwa. Abasebenzisa izidakamizwa ezingapheli nabo bayakhuthazwa, kunokuba babekezele, ezinye izici zesipiliyoni semithi. Ngisho noma injabulo etholakala ekudleni kwezidakamizwa iyancipha, isifiso sokuthatha izidakamizwa sanda, futhi izidakamizwa ezidakamizwa zivame ukukhuthaza imiphumela emibi yesidakamizwa (isb., Ukukhathazeka, i-paranoia) kanye namandla amathrekhi ahambisana nezidakamizwa ukuqala izidakamizwa ukuhlehlisa nokuziphatha (I-Robinson ne-Berridge, i-1993). Ngokuqonda izindlela eziphilayo ezikhuthaza ukukhuthazwa nokubekezelela izidakamizwa, kulindeleke ukuthi izindlela zitholakale zishintshe noma zivimbele inqubo yokulutha.

Ngenxa yalokho, isimo se-locomotor sensibisi siye sacwaningwa ngokujulile, ikakhulukazi kumagundane we-laboratory (bheka (Pierce and Kalivas, 1997) ukubuyekezwa). Izidakamizwa ze-Psychostimulant ezifana ne-cocaine ne-amphetamine zandisa umsebenzi wokuqhubela phambili. Ngemuva kokuphatha okuphindaphindiwe, le mpendulo iyancipha futhi isilwane siba namandla kakhulu ngemuva kokuthola inselelo enkulu yezidakamizwa. Manje sekusekelwe kahle ukuthi ukukhuthaza ukuhlelwa kwamandla kngokuyisisekelo kuxhomeke ekushintsheni kokubonakaliswa kwe-dopaminergic ne-glutamatergic ngaphakathi kwe-nucleus accumbens (NAc) (bheka (UKalivas noStewart, i-1991; I-Karler et al., I-1994; I-Wolf, i-1998). Kuye kwatholakala ukuthi kukhona amaprotheni amaningi okubonakaliswa kwamangqamuzana angase afake isandla ekukhulumeni kwalokhu impendulo yemoto. Enye iprotheni enjalo isici sokubhalisa ΔFosB esanda ku-NAc ne-dorsal striatum ngemuva kokungapheli, kodwa hhayi okunamandla, ukuphathwa kwezidakamizwa eziningi eziluthayo (I-Nestler, i-2008). IUkunciphisa ama-NAc we-ΔFosB kwandisa ukuvuthwa kwe-locomotor ukwehlisa i-cocaine, ukwandisa indawo enesimo esifanele kunomuthi, futhi kukhuthaza i-cocaine self-administration (I-Colby et al., I-2003; Kelz et al., 1999). Ngakho-ke kubonakala sengathi ukufakwa kwe-ΔFosB ku-NAc kusiza ukuthuthukiswa kombuso onomlutha.

Kuye kwaqaphela ukuthi ukuchayeka ngokuphindaphindiwe kwezidakamizwa eziluthayo kuthinta imisebenzi ephakeme yokunakekelwa kwe-oda njengokuthatha izinqumo nokulawula ukucindezela, nokuthi lokhu kunomthelela obalulekile ekuphindeni emuva kokufuna izidakamizwa (U-Bechara, i-2005; I-Garavan ne-Hester, i-2007; UJentsch no-Taylor, i-1999). Ukwehluleka kokulawula okungaqondakali kuye kwaqashelwa emilutha yokuqeda i-cocaine, kanye nabasebenzisi bezinye izidakamizwa (isib.Hanson et al., 2008; Lejuez et al., 2005; Moeller et al., 2005; U-Verdejo-Garcia et al., 2007). Kuye kwacatshangwa ukuthi lokhu kungabonakali kubangelwa ukungazenzisi ku-corbit (orbitofrontal cortex) ye-OFC ehlonishwayo kubantu abanjalo (Kalivas noVolkow, i-2005; Rogers et al., 1999; I-Schoenbaum et al., I-2006; I-Volkow ne-Fowler, i-2000). Sesanda kuphawula ukuthi ukuphathwa kwe-cocaine okuphindaphindiwe kwandisa ama-ΔFosB ngaphakathi kwe-OFC, nokuthi ukulinganisa lokhu kuhlanganiswa ngokufaka igciwane le-adeno-elihambisanayo (AAV) elenzelwe ukudlulisa phambili i-ΔFosB ku-OFC (ukudluliselwa kwegciwane lesandulela ngculazi) kubonakala kusebenze ukuvimbela indawo izifunda (I-Winstanley et al., I-2007). Amazinga aphezulu e-OFC ΔFosB angakholelwa ekungeneni ekushintsheni okubangelwa izidakamizwa ekulawuleni umfutho.

Sesanda kuqeda uchungechunge lwezifundo ukuze sihlole le nqubo, futhi sinqume imiphumela yokuphathwa okunamandla nokungahleliwe kwe-cocaine ngezinyathelo ezimbili zokungafisi emagatsheni: izinga lokungapheli isikhathi (impulsive) ukuphendula ekusebenzeni isikhathi sokuphendula isikhathi esiyisihlanu ( I-5CSRT) nokukhethwa kokuncane okuncane phezu komvuzo obambezelekile obambezelekile emsebenzini wokubambezeleka-ukusaphulelo (I-Winstanley et al., I-2007). Sibonile ukuthi i-cocaine ephawulekayo yabe isabela ngokuziphendulela kwi-5CSRT kodwa isinciphise ukukhetha okungafuneki komvuzo omncane osheshayo ekuboniseni ukubambezeleka-ukukhipha isaphulelo, ukulinganisa imiphumela ye-amphetamine. Le ndlela yokuziphatha-ukwanda kwezenzo zokuziphendulela kodwa ukwehla kokuzikhethela-kuye kwahunyushwa njengokwanda kwesikhuthazo sokukhuthaza umvuzo (U-Uslaner no-Robinson, i-2006). Kodwa-ke, emva kokuphathwa ngokuphindaphindiwe kwe-cocaine, amagundane ayengasabonakali izinguquko ezinjalo ngokungahambi kahle, njengokungathi bebelokhu bebekezelela le miphumela engqondweni yomuthi. Lokhu kuhluke kakhulu kumpendulo yokuvakasha ehlonzweyo ku-cocaine egcinwe ngemuva kokuphathwa okungapheli okuxoxwe ngenhla. Ngaphezu kwalokho, ukubonakaliswa ngokweqile kwe-ΔFosB e-OFC kwakulingisa imiphumela yezokwelapha ezingapheliyo: imiphumela ye-cocaine ephawulekayo ekusebenzeni kokubili i-5CSRT kanye nemisebenzi yokubambezeleka-ukuphushulwa kwakunqanyuliwe kulezi zilwane, njengokungathi zase zithuthukise ukubekezelela izidakamizwa 'imiphumela.

Kodwa-ke, ngenkathi ukwandisa i-ΔFosB e-OFC ivimbela i-cocaine ephawulekayo ekukhulekeleni ukungathandeki, lokhu kukhwabanisa okwenyuka kwamambala kwandipha umthamo ngesikhathi sokuhoxiswa kusukela kuhulumeni obhekene nokufinyelela isikhathi eside wokulawula ubunikazi be-cocaine (I-Winstanley et al., I-2008). Ukusebenza kwengqondo yalezi zilwane kwakungasetshenziswanga kangako uma i-cocaine isebhodini, kodwa bebesengozini yokulawula ukungalawuleki ngesikhathi sokuhoxiswa. Ukukhwabanisa okufanayo-okwandisa i-DFFB e-OFC-kungakwandisa ukubekezelelana noma ukuzwela ezintweni zemiphumela ye-cocaine. Lapha sibheka idatha eyengeziwe yombhalo ebonisa ukuthi izilwane ezibonise impendulo ephikisayo inselelo enzima ye-cocaine ekuhlolweni kokungafuni ukulandela okulandelayo ngemuva kwe-ΔFosB e-OFC nazo zazishukunyiswa ezenzweni zokuvuselela i-cocaine. Ngakho-ke, ukubekezelelana nokuzwela ezicini ezihlukahlukene zemiphumela ye-cocaine kwagcinwa ezifundweni ezifanayo. Njengoba kunikezwe indima evezwe yi-NAc ekuxhumaniseni ukukhuthazwa kwezokuvakasha, nokungabikho kwemininingwane efaka i-OFC emtsetfweni wezimoto, sicabanga ukuthi ukwandisa i-ΔFosB e-OFC kungase kuthuthukise ukuphendula kwe-motor nge-cocaine ngokushintsha umsebenzi kule ndawo yokubulala. Ngakho-ke senza ukuhlolwa okuhlukile usebenzisa i-PCR yangempela-sikhathi ukuphenya ukuthi ukwandisa i-ΔFosB ku-OFC iguqulela inkulumo yesigcawu ku-NAc ngendlela ebonisa ukwandisa ukukhuthazwa kwezokuvakasha.

Iya ku:

I-2. Izindlela

Zonke izivivinyo zenziwa ngokuhambisana nesiqondiso se-NIH sokuNakekela nokuSebenza kwezilwane zaseBathole futhi zavunyelwa yiKomiti YezokuPhathwa Kwezilwane Nezokusetshenziswa eT-Southwestern.

I-2.1. Izihloko

Amantombazane ama Long Long Evans (isisindo sokuqala: 275-300 g; uCharles River, Kingston, RI) babehlelwe ngababili ngaphansi komjikelezo okhanyayo (ukukhanya kusuka ku-21.00-09.00) ekamelweni elilawulwa yi-colony. Izilwane ezenzweni zokuziphatha (n= 84) kwakukudla kuphela ku-85% yesisindo sokudla samahhala futhi sigcinwe ku-14 g we-rat chow ngosuku. Amanzi ayatholakala isikhangiso. Ukuhlolwa kokuziphatha kwenzeka phakathi kwe-09.00 ne-19.00 izinsuku ezinhlanu ngesonto. Izilwane ezazisetshenziselwa ukukhiqiza izicubu zobuchopho zemizamo ye-qPCR yayine ukufinyelela mahhala kokubili kokudla namanzi (n= 16). Lezi zilwane zazikwazi ukufinyelela kokubili kokudla namanzi.

2.2. Ukuhlinzwa

Amagundane athola ama-intra-OFC ama-AAV-GFP, AAV-ΔFosB, noma i-AAV-ΔJunD esebenzisa amasu ajwayelekile we-stereotaxic njengoba kuchaziwe (I-Winstanley et al., I-2007). Amagundane ayenziwe ngama-ketamine (Ketaset, 100 mg / kg injection (im) injection) kanye ne-xylazine (10 mg / kg im; kokubili izidakamizwa ezivela kuHenry Schein, eMelville, NY). Ama-AAV afakwe ngaphakathi kwe-OFC usebenzisa i-31 gauge steel injector engenazinsimbi (i-Small Parts, eFlorida, eU.SA) ehlanganiswe nopompo lwe-microfilm e-Hamilton nge-polyethylene tubing (Instech Solomon, ePennsylvania, eU.SA). Ama-vectors wegciwane afakwe ngesilinganiso se-0.1 μl / min ngokuvumelana nezixhumanisi ezilandelayo ezithathwe ku-atlas stereotaxic (I-Paxinos ne-Watson, i-1998): indawo 1 AP + 4.0, L ± 0.8, DV-3.4, 0.4 μl: indawo 2 AP + 3.7, L ± 2.0, DV -3.6, 0.6 μl: indawo 3 AP ± 3.2, L ± 2.6, DV -4.4, I-0.6 μl (bona (Hommel et al., 2003) ngemininingwane yokulungiselela i-AAV). I-AP (i-anteroposterior) ihlangene ithathwe kusukela ku-bregma, i-L (i-lateral) yokuxhumanisa kusukela ku-midline kanye ne-DV (i-dorsoventral) yokuxhumanisa kusuka ekugcineni. Izilwane zavunyelwa isonto elilodwa ukuba lilulame kusukela ekuhlinzekeni ngaphambi kokuhlolwa kokuziphatha (ukuhlola i-1) noma ukuphathwa kwezidakamizwa (ukuhlolwa kwe-2).

I-2.3. Umklamo wokuhlola

Idatha yokuqwashisa yokuzithokozisa itholakala ezilwaneni ezazithola uchungechunge lwezivivinyo zokuziphatha ukuze zilinganiswe i-sequelae engqondweni yokutholakala kwezidakamizwa ezingapheli, futhi le datha ishicilelwe ngaphambili (I-Winstanley et al., I-2007). Ngamafuphi, amagundane aqeqeshelwe ukwenza i-5CSRT noma umsebenzi wokubambezeleka-ukusaphutha. Bese behlukaniswe ngamaqembu amathathu afanelwe ukusebenza okuyisisekelo. I-adeno-ehlobene negciwane (AAV2) ngaphezulu-eveza i-APF (UZachariou et al., 2006) yafakwa ngokukhetha ku-OFC yeqembu elilodwa usebenzisa ama-standard standard stereotaxic (bheka ngezansi) ngaleyo ndlela ulinganisa ukufakwa kwaleli protheyini ngokuphathwa okungapheli kwe-cocaine. Iqembu lesibili latholwa i-intra-OFC infusions ye-AAV-ΔJunD. I-AAV-GFP (iphrotheni ye-fluorescent eluhlaza) isetshenziselwa iqembu lokulawula. Uma kusekelwe isisekelo sokusekela ngemuva kwe-post-operative, imiphumela ye-cocaine ephawulekayo (i-0, i-5, i-10, i-20 mg / kg ip) inqunywe ngomsebenzi. Ukuze kuhlolwe ukuthi ukuphathwa okungapheli kwe-cocaine kushintshela imiphumela engqondweni yokwehliswa okukhulu kwe-cocaine, izilwane zahlanganiswa kokubili ngaphakathi naphakathi kwamaqembu abo okuhlinzwa zibe amasethi amabili alinganayo. Iqembu elilodwa lalashwa nge-saline, enye enye nge-cocaine (2 × 15 mg / kg) ngezinsuku ezingu-21. Amasonto amabili ngemuva kokwelashwa okungapheli kwezidakamizwa kwaphela, izinselelo ezimbi kakhulu ze-cocaine zaphindaphindiwe ngomsebenzi. Ngesonto elilodwa kamuva, impendulo yezokuvakasha ku-cocaine yahlolwa.

I-2.4. Impendulo yokuziqhenya ku-cocaine

Umsebenzi wokuqapha indawo uhlolwe ngamakheji ngamunye (25 cm × 45 cm × 21 cm) usebenzisa uhlelo lomsebenzi we-photobeam (PAS: San Diego Instruments, San Diego, CA). Umsebenzi ekamelweni ngalinye lalinganiselwe ngama-photobamende e-7 ewela ububanzi bendawo, eceleni kwe-6 cm no-3 cm ukusuka emgodini. Idatha yahlanganiswa ngamabhangi we-5 usebenzisa uhlelo lwe-PAS (version 2, San Diego Instruments, San Diego, CA). Ngemuva kwe-30 iminithi, izilwane zajojelwa nge-cocaine (15 mg / kg ip) nomsebenzi wokuqapha oqashwe ngeminye imininingwana ye-60.

I-2.5. I-Quantification ye-MRNA

Amagundane athola injection ye-intra-OFC ye-AAV-GFP noma i-AAV-ΔFosB, elandelwa yi-21 injection yansuku zonke kabili ye-saline noma i-cocaine, njengoba nje kuchazwe ukuhlolwa kokuziphatha. Izilwane zasetshenziselwa i-24 h ngemuva komjovo wokugcina we-saline noma we-cocaine. Amagundane abulawe yi-decapitation. Ubuchopho bukhishwa ngokushesha futhi ama-1 aphakathi kwe-12 ama-punch punge ye-NAc atholakala futhi asheshe afriziwe futhi agcinwe ku-80 ° C kuze kube yilapho i-RNA ihlukaniswa khona. Izimpondo ezivela ku-OFC nazo zazisuswa ukuze zihlaziywe yi-DNA microarray eqinisekisile ukuphumelela kwegciwane lokudluliswa kwegciwane kule ndawo (bheka (I-Winstanley et al., I-2007) ngemiphumela eningiliziwe). I-RNA ikhishwe kuma-sampuli we-NAc usebenzisa isisetshenziswa se-RNA Stat-60 (i-Teltest, i-Houston, TX) ngokusho kwemiyalelo yomkhiqizi. Ukungcoliswa kwe-DNA kususwe nge-DNase yokwelapha (i-DNA-Free, ikhathalogu # 1906, Ambion, Austin TX). I-RNA ehlanjululwe yayiphindaphinda-ibhaliswe ku-cDNA (i-Superscript First Strand Synthesis, i-Catalog # 12371-019; i-Invitrogen). Ukubhalwa kwezakhi zofuzo zentshisekelo kwakunqunywa ngokusebenzisa i-real-time qPCR (SYBR Green; Applied Biosystems, Foster City, CA) eStratagene (La Jolla, CA) i-Mx5000p 96-kahle i-thermocycler. Zonke izimbambo zazijwayele ukuhlanganiswa ngu-Operon (Huntsville, AL; bheka Ithebula 1 ngokulandelana) futhi kuqinisekiswe ukulingana nokucacisa ngaphambi kokuhlolwa. Yonke idatha ye-PCR yayijwayelekile kumazinga we-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), engazange ishintshwe ukwelashwa kwe-cocaine, ngokusho kwefomula elandelayo: ΔCt =Ct(isakhi sofuzo) - Ct (GAPDH). Amazinga okukhulunyelwa okuguquguqukayo kokubili amagundane AAV-ΔFosB kanye ne-AAV-GFP athola i-cocaine, nama-AAV-ΔFosB amagundane athola u-saline okungapheli, abalwa ngaleso sikhathi ngokuphathelene nokulawula (i-AAV-GFP eqenjini elinikezwa i-saline chronic) kanje: ΔΔCt = ΔCt - ΔCt (iqembu lokulawula). Ngokuhambisana nomkhuba onconyiwe emkhakheni (U-Livak no-Schmittgen, i-2001), amazinga okukhuluma ahlobene nezilawuli abalwa besebenzisa inkulumo elandelayo: 2-DACt.

Ithebula 1  

Ithebula 1

Ukulandelana kweziqalo ezisetshenziselwa ukulinganisa amazinga e-cDNA nge-PCR yangempela-isikhathi.

I-2.6. Izidakamizwa

I-Cocaine HCl (Sigma, St. Louis, MO) yahlakazwa ku-0.9% saline ngevolumu ye-1 ml / kg futhi ilawulwa nge-ip injection. Amanani ayebalwa njengewosawoti.

I-2.7. Ukuhlaziywa kwedatha

Yonke idatha yahlaziywa isebenzisa isofthiwe ye-SPSS (SPSS, Chicago, IL). Idatha yokuqapha i-ANOVA ibe ne-multipletifactorial nge-operation (amazinga amabili: i-GFP vs i-FosB noma i-AJJD) nokuphathwa okungapheli (amazinga amabili, i-saline engapheli kanye ne-cocaine engapheli) phakathi kwezihloko zezihloko, kanye ne-bin isikhathi njengengaphakathi kwezihloko eziyinhloko. Idatha evela ekuhlolweni kwangempela kwesikhathi kwe-PCR yahlaziywa yi-ANOVA engavumelekile ngokuhlinzwa (amazinga amabili: GFP vs ΔFosB) nokwelashwa okungapheli (amazinga amabili, i-saline engapheli kanye ne-cocaine engapheli) njengezici ezihleliwe. Imiphumela emihle yalandelwa amasampula azimele t-ukuthi lapho kufanele khona.

Iya ku:

I-3. Imiphumela

Zama i-1

Ukuphathwa kwe-cocaine okungapheli kuveza ukuzwela emiphumeleni ye-hyperlocomotor ye-cocaine ephawulekayo eyenziwa yi-ΔFosB

Njengoba kungalindeleke, ukuqwashisa okunamandla kuhlonishwa ngokulawulwa kwezilwane ngemuva kokutholakala kwe-cocaine engapheli, nezilwane ziphathwa ngokungahambi kahle nge-cocaine ezibonisa ukwanda kokungapheleli ekuphenduleni inselelo enkulu ye-cocaine (I-Fig. 1A, ukwelashwa okungapheli: F1,34 = 4.325, p<0.045). Izilwane zizwakalisa ngokweqile i-ΔJunD, isakhi esiphikisayo esibi seJunD esisebenza njengephikisana ne-ΔFosBUZachariou et al., 2006), e-OFC ayengaqondanisi nokulawula izilwane (I-Fig. 1C, GFP vs ΔJunD, iqembu: F1, 56 = 1.509, NS). Kodwa-ke, izilwane ezingaphezu kwe-ΔFosB e-OFC ezazithola izijovo zokuphefumula eziphindwe kabili zivele "zizwela phambili": zikhombisa impendulo yokuthuthukisa i-cocaine ephawulekayo engaphenduliyo kusuka ekuphenduleni okuthintwayo kwabalingani babo abaphathwa nge-cocaine engapheli (I-Fig. 1B, GFP vs ΔFosB ukuhlinzeka × ukwelashwa okungapheli: F1, 56 = 3.926, p<0.052; I-osBFosB kuphela: ukwelashwa okungamahlalakhona: F1,22 = 0.664, NS). Izilwane ze-FosB zazingasebenzi kahle ngaphakathi kwe-15 min yokubeka emabhokisini okuvula (GFP vs ΔFosB, ukuhlinzwa: F1,56 = 4.229, p <0.04), kepha amazinga womsebenzi we-locomotor afaniswa nezilawuli kumzuzu we-15 ngaphambi kokuphathwa kwe-cocaine (ukuhlinzwa: F1, 56 = 0.138, NS).

I-Fig. 1  

I-Fig. 1

Ukunika amandla ukuzwela ukucocaine. I-cocaine enamandla yenza ukwanda okukhulu komsebenzi wokulawulwa kwezilwane ekulawuleni izilwane eziphathwa ngokungapheli nge-cocaine versus saline (iphaneli A). Ezizilwaneni ezingaphezu kwe-ΔFosB (iphaneli B), labo abazinikezwa i-saline ephindaphindiwe (Okuningi …)

Ngokucabangela ukuthi, uma unikezwa i-cocaine ngesikhathi se-5CSRT, izilwane ezifanayo zibonisa ikhono elithuthukisiwe lokuvimbela ekwenzeni izimpendulo zangasese ngaphambi kwesikhathi, lokhu kuhlaselwa kubonakala ngokucacile ekuqhumeni kokuvuthwa okungukuthi uhlobo lokunyakaza okuvame ukuqoshwa ekuhloliseni ukuhlolisisa. Nakuba umsebenzi othuthukisiwe ekuphenduleni izidakamizwa ezivusa amadlingozi kungabonisa iphrofayli ye-anxiogenic, i-intra-OFC engaphezu kwe-expression ye-ΔFosB ayikhulisi ukukhathazeka njengoba kulinganiswa ngokusebenzisa i-maze plus ephakeme noma ukuhlolwa kwensimu evulekile (idatha engaboniswa). Izilwane nazo zazijwayele ukufakwa kwezilwane ze-IP, futhi ama-saline injection awazange aguqule ukusebenza kwabo kokuzicabangela (I-Winstanley et al., I-2007), ngakho-ke lo mphumela wemoto awukwazi ukubhekwa ngokuphendula okujwayelekile kumjovo we-IP. Ngokufingqiwe, lokhu okutholakele kubonisa ukuthi ukufakwa kwe-ΔFosB ku-OFC kwanele (kodwa akudingekile) ukuze kutholakale umthengisi ohloniphekile ophendula i-cocaine, noma i-ΔFosB esifundeni esifanayo ibangela ukubekezela emiphumeleni ye-cocaine ekugqugquzelweni nasekufuseni (I-Winstanley et al., I-2007).

Zama i-2

Ukuphathwa kwe-cocaine okungapheli kwenza i-gene ikhulume nge-NAc

Uma i-molecule ethile e-NAc ibambe iqhaza ekuphenduleni kwangaphambi kokuzwela eboniswe eqenjini le-AAV-ΔFosB ephathwa ngamanoni, ngakho-ke singalindela ukubona impendulo efana ne-biochemical kulezi zilwane uma kuqhathaniswa nezilwane ku-AAV-GFP futhi Amaqembu e-AAV-ΔFosB aphethwe i-cocaine ngokungapheli. Ngaphezu kwalokho, izilwane ezinqenjini ze-AAV-GFP eziphathwe nge-saline akufanele zibonise le mpendulo njengoba lezi zilwane zingasetshenziselwa uketshezi lwe-cocaine. Leli phethini lemiphumela lizobonakala emthinini ophawulekayo wokuxhumana okuhlinzekwa, okusekelwa amasampula azimele ezimele t-kuqhathanisa izindlela zeqembu le-AAV-GFP ne-AAV-ΔFosB ephathwa ngamafutha, kanye namaqembu aphethwe i-AAV-ΔFosB ne-AAV-GFP ye-cocaine. Imiphumela emqoka yokwelapha izidakamizwa noma ukuhlinzwa kuzoqinisekisa ukuthi i-cocaine engapheli noma ukubonakaliswa okungaphezu kuka-ΔFosB e-OFC ingahle ilandise i-molecule ehlokisiwe ku-NAc, kodwa lokhu kungakwaneli ukuchaza impendulo yokuvakasha ezwelayo ebonwe eqenjini eliphathwayo le-AAV-ΔFosB . Izicubu ezivela kwesilwane esisodwa esathola i-intra-OFC infusions ye-AAV-GFP kanye nomjovo we-cocaine ophindaphindiwe awukwazanga ukuhlaziywa ngenxa yokuvunwa okungavamile kwe-RNA. Kulesi silingo, sagxile emajenini amaningana afakiwe ekukhunjweni kwe-cocaine (bheka Ingxoxo).

I-3.1. ΔFosB / FosB

Amazinga e-FosB mRNA ku-NAc awazange aguqulwe ngukuphathwa kwezidakamizwa ezingapheli (I-Fig. 2A, izidakamizwa: F1,14 = 1.179, ns) noma inkulumo ye-ΔFosB e-OFC (ukuhlinzwa: F1, 14 = 0.235, ns). Kodwa-ke, amazinga e-ΔFosB ayekhudlwana kakhulu ezilwaneni eziphathwa ngokungapheli nge-cocaine ngokuhambisana nemibiko yangaphambilini (Chen et al., 1997); I-Fig. 2B, izidakamizwa: F1,14 = 7.140, p<0.022). Kuyathakazelisa ukuthi inani le-ΔFosB mRNA ku-NAc yezilwane eziphathwe ngosawoti laliphansi kulabo lapho le nto yokubhalwa kwento ivezwe ngokweqile ku-OFC (umuthi: F1,14 = 9.362, p<0.011). Kodwa-ke, ukungabikho kokuhlangana kokuhlinzwa kwezidakamizwa × kukhombisa ukuthi ukwelashwa okungapheli kwe-cocaine kunomphumela ofanayo kuwo womabili amaqembu aphathwa yi-AAV-GFP ne-AAV-ΔFosB, kukhuphula ngokulinganayo amazinga e-ΔFosB ngezinga elifanayo (ukuhlinzwa kwezidakamizwa ×: F1, 14 = 0.302, ns).

I-Fig. 2  

I-Fig. 2

Izinguquko ku-mRNA ngaphakathi kwe-NAc yezilwane ngaphezulu-eziveza i-GFP noma i-ΔFosB e-OFC, futhi iphathwa ngokungapheli nge-saline noma i-cocaine. Idatha ikhombisa ushintsho oluthile lwezintambo ekukhulumeni njengengxenye yezindinganiso zokulawula. Idatha ebonisiwe ikhona (Okuningi …)

I-3.2. I-Arc / CREB / PSD95

Kwakungekho bufakazi bokuthi i-Arc eyengeziwe (i-cytoskeleton ehlobene nemisebenzi ehlobene neprotheyini) ekhuluma nge-24 h emva kokutholakala kwezidakamizwa zokugcina, futhi ayizange ikhulise i-ΔFosB emazingeni we-OFC ushintsho we-Arc mRNA ku-NAc (I-Fig. 2C, izidakamizwa: F1.14 = 1.416, ns; ukuhlinzwa: F1,14 = 1.304, ns). Ngokufanayo, akukho ukuguqulwa okwakubonwe ku-CREB (isici sempendulo yesampula ebopha amaprotheni) inkulumo (I-Fig. 2D, izidakamizwa: F1,14 = 0.004, ns; ukuhlinzwa: F1,14 = 0.053, ns). Kodwa-ke, ukuphathwa okungapheli kwe-cocaine kunyuke kakhulu amazinga e-mRNA we-PSD95 (i-postsynaptic ubukhulu bemaprotheni ye-95 kD) (I-Fig. 2E, izidakamizwa: F1,14 = 11.275, p <0.006), kepha lokhu kwanda bekufana kuwo womabili amaqembu e-AAV-GFP ne-AAV-ΔFosB (ukuhlinzwa: F1, 14 = 0.680, ns; ukuhlinzwa kwezidakamizwa: F1,14 = 0.094, ns).

I-3.3. D2/ GABAB/ GluR1 / GluR2

Izinga le-mRNA ye-dopamine D2 I-receptors yanda ngokulandela ukuphathwa okungapheli kwe-cocaine (I-Fig. 2F, izidakamizwa: F1,14 = 7.994, p<0.016), kepha lokhu kukhuphuka akuzange kuthintwe ukubonakaliswa okungaphezulu kwe-ΔFosB ku-OFC (ukuhlinzwa: F1, 14 = 0.524, ns; ukuhlinzwa kwezidakamizwa: F1,14 = 0.291, ns). amazinga e-mRNA we-GABAB i-receptor ibonise iphrofayli efanayo, ngamazinga akhula ngemali encane kodwa ephawulekayo ngokulandela ukuphindaphinda ngokuphindaphindiwe kwe-cocaine kungakhathaliseki ukuxhaphazwa kwamagciwane (I-Fig. 2G, izidakamizwa: F1,14 = 5.644, p <0.037; ukuhlinzwa: F1, 14 = 0.000, ns; ukuhlinzwa kwezidakamizwa: F1,14 = 0.463, ns). Kodwa-ke, amazinga we-AMPA glutamate receptor subunits GluR1 ne-GluR2 ayengathinteki nanoma yikuphi ukuxhaphazwa, nakuba kwakukhona umkhuba omncane wokwanda kwe-GluR2 elandela ukwelapha okungapheli kwe-cocaine (I-Fig. 2H, I-GluR1: izidakamizwa: F1,14 = 0.285, ns; ukuhlinzwa: F1, 14 = 0.323, ns; ukuhlinzwa kwezidakamizwa: F1,14 = 0.224, ns; I-Fig. 2I, I-GluR2: izidakamizwa: F1,14 = 3.399, p <0.092; ukuhlinzwa: F1, 14 = 0.981, ns; ukuhlinzwa kwezidakamizwa: F1,14 = 0.449, ns).

Ngokufingqa, nakuba ama-mRNA ashintshwe amazinga e-cocaine aguqulelwe ama-gene ahlolwe ku-NAc, asizange sibone ukunyuka okuhambisanayo kwalezi zakhi zofuzo ezinamakhofu aphathwa ngethusi kuveza i-ΔFosB e-OFC. Lokhu okutholakele kusikisela ukuthi lezi zakhi zofuzo azibandakanyekile ekuphenduleni okwenyuka kwezokuvakasha okuphawulwe kuleli qembu.

Iya ku:

I-4. Ingxoxo

Lapha sibonisa ukuthi i-ΔFosB evezwa ngokweqile kwizinhlayiya ze-OFC ezenza izenzo zokuvuselela i-cocaine, ezilingisa izenzo ze-cocaine zokuphatha okungapheli. Siye sabonisa ngaphambilini ukuthi ukusebenza kwalezi zilwane ezifanayo kwi-5CSRT nokubambezeleka-ukuphushulwa kwama-paradigms kungathinteka kancane yi-cocaine ephawulekayo, futhi ukuthi ukunyamezela okufanayo-okufana nomphumela kubonakala ngemva kokuchayeka kwe-cocaine ephindaphindiwe. Ngakho-ke, ukuzwela nokubekezelelana ngezenzo ezahlukene ze-cocaine kungabonwa ezilwaneni ezifanayo, kokubili ukuvumelanisa okuhlangene nge-molecule efanayo, i-DFFB, esebenza esifundeni esifanayo sobuchopho. Iqiniso lokuthi lezi zici zombili zingenziwa ngokufanayo ngokulingisa enye yezenzo ze-cocaine endaweni eyodwa ye-frontocortical igcizelela ukubaluleka kwezifunda ze-cortical ku-sequelae yokudla izidakamizwa ezingapheli. Ngaphezu kwalokho, le datha ibonisa ukuthi ukubekezelelana nokuzwela kubonisa ukuthi izici ezimbili zokuphendula izidakamizwa eziluthayo zibonakala zihluke kakhulu, kodwa zihlobene kakhulu.

Njengoba kunikezwe ukuthi ukukhuliswa kwe-ΔFosB ku-NAc kuhileleke ngokujulile ekuthuthukiseni ukwakhiwa kwe-locomotor, i-hypothesis eyodwa eyobe yikho ukuthi ngabe i-ΔFosB e-OFC ivuselela phambili izilwane ukuze i-cocaine ikhule ngamazinga e-FosB ku-NAc. Kodwa-ke, umphumela ongenayo utholakale: amazinga e-ΔFosB ku-NAc ayephansi kakhulu ezilwaneni ngaphezu kwe-ΔFosB e-OFC. Imiphumela yokuziphatha yalokhu kwehla ku-NAc ΔFosB kunzima ukuyihumusha, njengokuvimbela izenzo ze-FosB ngokubheka ngaphezulu kwe-ADJun kule ndawo kunciphisa imiphumela eminingi ye-cocaine emasimini (I-Peakman et al., 2003). Ukufana okukhona kukhona phakathi kwalezi ziboniso kanye nalabo abenziwe ngokubhekisela ohlelweni lwe-dopamine. Isibonelo, ukuchithwa kwe-dopamine encane ku-NAc kungadala ekuziphatheni kabi njengoba kuqondisa ukusetshenziswa kwe-dopamine agonists kule ndawo (Bachtell et al., 2005; I-Costall et al., I-1984; I-Parkinson et al., I-2002; I-Winstanley et al., I-2005b). Ngokufanayo, ukuthi amazinga e-cortic akhula we-ΔFosB anganciphisa ukuboniswa kwe-subcortical kufana nokuthola kahle ukuthi ukunyuka kwe-prefrontal ukudlulisa i-dopaminergic kuvame ukuhambisana nokunciphisa ngokuphindaphindiwe kwamazinga we-dopamine (I-Deutch et al., 1990; UMitchell noGratton, i-1992). Yeka ukuthi indlela enjalo yempendulo ingasebenza kanjani ama-molecule emangqamuzaneni okwangena kwamanje okwamanje, kodwa ingabonakalisa izinguquko emisebenzini evamile yamanethiwekhi athile we-neuronal abangelwa ushintsho ekubhalisweni kwegazi. Isibonelo, ukwandisa i-ΔFosB e-OFC kuholela ekwenzeni ukwenziwa komsebenzi wokuvimbela indawo, njengoba kuboniswe ukwanda kwamazinga we-GABAA receptor, mGluR5 receptor nempahla P, njengoba kutholakala ukuhlaziywa kwe-microarray (I-Winstanley et al., I-2007). Lolu shintsho kumsebenzi we-OFC lungathinta umsebenzi kwezinye izindawo zobuchopho, okungaholela ekushintsheni kwendawo ekuboniseni i-ΔFosB. Kungakhathaliseki ukuthi amazinga e-ΔFosB abonisa izinguquko ezihambelana nomsebenzi we-dopamine yinkinga efuna ukuphenywa okuqhubekayo.

Zonke izilwane zabonisa ukwanda okukhulu emazingeni e-ΔFosB mRNA ku-NAc elandelayo ukwelapha okungapheli kwe-cocaine, ngokuhambisana nemibiko yangaphambilini yamaningi weeprotheni (Chen et al., 1997; Ithemba ne-al., I-1992; Nye et al., 1995). Kodwa-ke, umbiko wamuva wathola ukuthi amazinga e-ΔFosB mRNA ayengasaphakanyiswa kakhulu i-24 h ngemuva kokwelashwa okungapheli kwe-amphetamine, nakuba ukunyuka okuphawulekayo kukhishwe i-3 h ngemuva kokujola kokugcina (U-Alibhai et al., 2007). Lokhu kungabangelwa ukuhlukana kwesidakamizwa se-psychostimulant esetshenziswa (i-cocaine vs amphetamine), kodwa kunikezwe ingxenye encane yokudla kwe-cocaine, kungaba nokulindela ukulindela ukuthi imiphumela yayo ekukhulumeni kwegeni izongena ngokusheshisa kakhulu kuneya-amphetamine, kunokuba kunesidingo. Isizathu esizwakalayo salo miphumela ehlukile yukuthi izilwane esifundweni samanje zijojowe ngomthamo olinganiselayo wezidakamizwa kabili nsuku zonke izinsuku ezingu-21 uma kuqhathaniswa nomjovo ophezulu owodwa wezinsizakalo zezinsuku ze-7 (U-Alibhai et al., 2007). Uhlelo olwandisiwe lwezokwelapha lungase luholele ekushintsheni okukhulunywa kakhulu lapha.

Nakuba izinguquko zesiginja sezakhi zofuzo ezibonwe ngaphakathi kwe-NAc elandela i-cocaine engapheli zivumelane ngokujwayelekile neziphumo ezibikezelwe ngaphambili, ubukhulu bemiphumela buyingcosana esifundweni samanje. Esinye sezizathu zokuthi lezi zilwane zahlatshwa ngo-24 h kuphela emva kokujola kokugcina kwe-cocaine, kanti iningi lezifundo ziye zasebenzisa izicubu zathola amasonto amabili kusukela ekugqibeleni izidakamizwa zokugcina. Ukuhlola ukuhlola isikhathi-ukusizwa kwendawo yokukhombisa ukukhombisa ukubonisa ukuthi izinguquko eziningi ezenziwe ngokubili kokuziphatha kanye nezakhi zofuzo / amaprotheni kubonakala kule nkathi yesikhathi esizayo. Nakuba sitshela ukwanda kancane kwe-mRNA ye-dopamine D2 i-receptor ku-NAc, ukuvumelanisa jikelele ukuthi amazinga okukhulumisana we-D2 noma D1 i-receptor ayishintshwa unomphela emva kokuthuthukiswa kokwakhiwa kwe-locomotor, nakuba kokubili kwanda futhi kwehla ku-D2 Inombolo ye-receptor ibike ngemuva nje kokuphela kobuso obushukumisayo (bheka (Pierce and Kalivas, 1997) ukuze uthole ingxoxo). Ukubheka kwethu ukuthi i-GluR1 ne-GluR2 mRNA ayishintshwanga ngemuva kokwelapha okungapheliyo kwe-cocaine kulezi zinsuku zangaphambili-ngokufanayo nombiko wangaphambilini (UFitzgerald et al., 1996), nakuba ukwanda kwe-GluR1 mRNA kutholakale esikhathini esilandelayo ngemva kwamaphesenti okuphulukiswa kwengqondo okungapheli (psychostimulant treatment)Churchill et al., 1999).

Kodwa-ke, sibonile ukunyuka okuncane kwe-PSD95 mRNA ku-NAc yezilwane eziphatheka kabi nge-cocaine. I-PSD95 iyi-molecule ye-scaffolding, futhi ingenye yamaphrotheni amakhulu ngaphakathi kwesimo se-postsynaptic se-synapses exitatory. Ihlanganisa ama-glutamate receptors amaningana kanye nama-protein ahlobene nokubonakaliswa ku-synapse, futhi ukwanda kwezwi le-PSD95 kucatshangwa ukuthi kubonisa umsebenzi owenziwe ukwandiswa kwe-synaptic nokunyuka okufakiwe nokuqiniswa kwama-receptors we-glutamate ku-synapses (van Zundert et al., 2004). Indima ye-PSD95 ekuthuthukiseni ukukhuthazwa kwezokuvakasha isikisiwe ngaphambili (Yao et al., 2004).

Ukwanda kwe-Arc expression kubuye kwaxhunyaniswa nokwandiswa komsebenzi we-synaptic. Kodwa-ke, ngenkathi ukwanda kwenkulumo ye-Arc ku-NAc kubonwe i-50 min ngemva kokujova nge-amphetamine (Klebaur et al., 2002), idatha yethu ibonisa ukuthi ukulawulwa okungapheli kwe-cocaine akukwenzelisi i-Arc ku-NAc ngokugcwele unomphela, nakuba ukunyuka kwe-Arc kuye kwaqaphela i-24 h ngemuva kokulinda okungapheli ngezidakamizwa ezicindezelayo (Larsen et al., 2007) ne-amphetamine (Ujike et al., 2002). Ukwanda kwe-CREB phosphorylation kubuye kubonwe ku-NAc ngemuva kwe-cocaine ejulile kanye nokuphathwa kwe-amphetamine (Kano et al., 1995; Konradi et al., 1994; Self et al., 1998), kodwa mhlawumbe akumangalisi ukuthi akukho ukwanda kwe-CREB mRNA okwakubhekwa ngemuva kokuphathwa okungapheli kwe-cocaine. Ukusayina ngokusebenzisa indlela ye-CREB kucatshangwa ukuthi kubaluleke kakhulu ezigabeni zokuqala zokuthatha izidakamizwa, ngezici zokubhalisa ezifana ne-ΔFosB eza ukulawula njengokugqilaza izidakamizwa (UMcClung noNestler, i-2003). Nakuba i-CREB ifakiwe emiphumeleni emivuzo ye-cocaine (I-Carlezon et al., I-1998), akubanga khona imibiko yokuthi ukukhuliswa kwe-CREB okwandayo kuthinta ukukhushulwa kwe-locomotor, nakuba ukwanda kwe-viral-mediated in anti-antagonist engapheli kakhulu ye-CREB, i-inducible cAMP yokuqala yokuphefumula amaprotheni noma i-ICER, yandisa ukungabi nokucindezeleka okubangelwa umjovo omningi we-amphetamine (I-Green et al., I-2006).

Ngokufingqa, nakuba iningi lezinguquko ezithathwe yizidakamizwa esizibonile zihambisana nezibikezelo ezivela ezincwadini, asizange sithole noma yiziphi izinguquko ekukhulumeni kofuzo ngaphakathi kwe-NAc engachaza ukuphendula okuthandekayo kwe-cocaine egcinwe ezilwaneni ezidakamizwa eziphathwe kabi nge-intra-OFC AAV-ΔFosB. Lokhu kuphakamisa ukuthi kungenzeka ukuthi i-ΔFosB ekwandiseni i-OFC ingase ingathinti ukuzwa kwezimoto nge-NAc, nakuba ezinye izakhi zofuzo, ezingafundiwe lapha, zingabandakanyeka. Ubufakazi obuningi bubonisa ukuthi ukuguquguquka kwe-prefrontal cortex (mPFC) yangaphakathi kungashintsha umsebenzi wokuhlaselwa futhi ngaleyo ndlela kubangele ukugqugquzela ukuziphatha kuya kuma-psychostimulants (I-steketee, i-2003; Steketee noWalsh, i-2005), nakuba engaziwa kancane ngendima yezindawo ezingaphezulu kwe-ventral prefrontal njenge-OFC. I-NAc ithola ezinye izilinganiso ezivela ku-OFC (Berendse et al., 1992). Kodwa-ke, ucwaningo lwamuva nolwazi oluningi oluthile lwaluveza ezimbalwa kakhulu ukuhlolwa kwe-OFC-NAc: i-label ye-NAc eyayiqhamuka kakhulu emaphethelweni e-NAc ahlonishwa ngokulandela ukujova kwe-anterograde tracer endaweni ye-lateral kanye ne-ventralateral ye-OFC, kanye ne-OFC enkulu kakhulu isifunda sithumela amaphrofayili amancane ku-NAc core (Schilman et al., 2008). I-central caudate-putamen ithola ukungabi namandla okukhulu kakhulu. Ngenxa yalokhu bufakazi obunjalo, iningi lezicubu ze-NAc ezihlaziywe ekusebenziseni kwethu kwe-PCR kwakungeke zilandelwe ngokuqondile yi-OFC, ukunciphisa amathuba ukuthi noma yikuphi ukuguqulwa kwesiginja sezakhi kuyotholakala ngempumelelo.

I-OFC yenza kakhulu ezindaweni ezizihlanganisa kakhulu ne-NAc, njenge-mPFC, i-basolateral amygdala (BLA), i-caudate putamen ne-subthalamic nucleus (STN). Kungakhathaliseki ukuthi izinguquko ku-OFC zingahle zilandele ngokungaqondile ukusebenza kwe-NAc ngokusebenzisa ithonya layo kulezi zindawo umbuzo ovulekile. Kuye kwaboniswa ukuthi umsebenzi ku-BLA uguqulwa ngemuva kwezilonda ze-OFC, nokuthi lokhu kubangele kakhulu ekulahlekeni kokufunda okuguquguqukayo okubangelwa umonakalo we-OFC (U-Stalnaker et al., 2007), kodwa noma yimiphi imiphumela ngaphakathi kwezindawo ezifana ne-NAc ayisazobikwa. Kungaba ngcono kakhulu ukugxila kwezinye izindawo ezixhunywe kakhulu kwi-OFC futhi ezibandakanyeka kakhulu ekulawuleni imoto. I-STN ihlose ngokukhethekile, njengoba nje izilonda ze-STN ne-OFC ziveza imiphumela efanayo ngokungahambi kahle nokufunda nge-Pavlovian (I-Baunez ne-Robbins, i-1997; I-Chudasama et al., I-2003; U-Uslaner no-Robinson, i-2006; I-Winstanley et al., 2005a), kodwa ukusondelana kwe-psycho-stimulant-stimulated sensitization kuhlotshaniswa nokwanda kwe-c-Fos ukukhulunywa kule ndawo (Uslaner et al., 2003). Ukuhlolwa kwesikhathi esizayo oklanyelwe ukuhlola ukuthi izinguquko ezenziwe izidakamizwa ekukhulumeni kwezakhi zofuzo ngaphakathi kwe-OFC zithinta kanjani ukusebenza kwezindawo eziphansi njenge-STN eziqinisekisiwe. I-OFC iphinde ithumele ukuhlelwa okuncane kumkhakha we-ventral tegmental (Geisler et al., 2007), isifunda esaziwa ukuthi sihileleke ngokujulile ekuthuthukiseni ukukhuthazwa kwezokuvakasha. Kungenzeka ukuthi i-FFBB e-OFC ingakhombisa ukukhushulwa kwe-locomotor ngale ndlela.

Ubuhlobo obuhle bokuhlobana phakathi kwezinguquko ezibangelwa izidakamizwa ekusebenziseni ukucabangela kanye nokwazisa ukuvakasha okwamanje akucaci kahle, futhi manje sigxile kwi-OFC. Njengoba kunikezwe lezi zitholakele, kungenzeka ukuthi izinguquko zesitatimende sofuzo ezihlotshaniswa nokuthuthukiswa kokwehliswa kwemvelo kwezinye izifunda zobuchopho zingase zibe nomthelela othile ekuphenduleni kwengqondo ku-cocaine. Izivivinyo ezihlola ukusebenzisana phakathi kwezizinda ze-cortical ne-subcortical emva kokuphathwa kwezidakamizwa eziluthayo kungenza kube lula ukukhanya ukuthi isimo esiluthayo senziwe kanjani futhi sigcinwe, futhi izindima ezithintekayo zidlalwa ngokuqwashisa nokubekezela kule nqubo.

Iya ku:

Okubhekwayo

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