I-DeltaFosB induction kwi-orbitofrontal cortex inokubangela ukukhuthaza ukukhuthaza ngaphandle kokunciphisa ukungasebenzi okubangelwa yi-cocaine. (2009)

IINKCUKACHA: Uvavanyo lubonisa ukuba imbangela ye candat yase DelatFosB zombini ukukhuthazwa kunye nokuchithwa (ukunyamezela). 
 
Pharmacol Biochem Behav. 2009 Sep; 93 (3): 278-84. Epub 2008 Dec 16.
 
I-Winstanley CA, i-Green TA, i-Theobald DE, i-Renthal W, i-LaPlant Q, i-DiLeone RJ, i-Chakravarty, i-Nestler EJ.

imvelaphi

ISebe leZengqondo, iYunivesithi yaseTexas Southwestern Medical Centre, i-5323 uHarry Hines Boulevard, i-Dallas, i-TX 75390-9070, e-United States. [imeyile ikhuselwe]

Abstract

Imiphumela ye umlutha Ukusetyenziswa kwezidakamizwa ngokusetyenziswa ngokuphindaphindiweyo: abaninzi abantu bayakwazi ukunyamezela iimiphumo zabo ezonwabisayo kodwa banokukhathazeka ngakumbi kwi-sequelae engafanelekanga (umz., ukuxhalaba, i-paranoia, kunye nesifiso seziyobisi). Ukuqonda iindlela ezixhomekeke ekunyamezelweni nasekukhuthazweni okunjalo kunokunika ingqiqo ebalulekileyo kwisiseko sokuxhomekeka kweziyobisi kunye likhoboka. Satshanje sibonise ukuba ukulawula okungapheliyo kwe-cocaine kuncitshiswe amandla okwenza i-cocaine engummangaliso ukuphazamisa impembelelo kwiirati. Nangona kunjalo, izilwanyana ziba nzima xa zihoxiswa kwi-cocaine. Siphinde sibonise ukuba ukulawulwa okungapheliyo kwe-cocaine kwandisa ukubhaliswa kwe-DeltaFosB ye-transcription kwi-cortex ye-orbitofrontal (OFC). Ukumisa ukuphakanyiswa kwezidakamizwa ku-OFC DeltaFosB ngokuguqula i-gene-mediated-transfered ukutshintshwa kwezi zitshintsho zendlela yokuziphatha: I-DeltaFosB ebonakaliswe ngokubanzi kwi-OFC yenza ukuba kube nokunyamezela kwimiphumo yomngeni omkhulu we-cocaine kodwa iyancenga iifiti kwi-sequelae ecacnitive yokuhoxiswa. Apha sibika ingxelo yesaveli ebonisa ukuba ukwandisa i-DeltaFosB kwi-OFC ikwazisa izilwanyana kwiindawo ezihamba phambili zokukhuthaza i-cocaine. AI-nalysis ye-nucleus eqokelela izicwili ezithathiweyo kwiigundane ngaphezulu kwe-DeltaFosB kwi-OFC kwaye inyangwa ngokungapheliyo nge-saline okanye i-cocaine ayiboneleli ngenkxaso ye-hypothesis eyonyusa i-OFC DeltaFosB enokubangela uvakalelo nge-nucleus accumbens. Ezi datha zicebisa ukuba zombini ukunyamezelana kunye novakalelo kwiziphumo ezininzi zecocaine, nangona kubonakala ngathi ziyinkqubo ephikisayo, zinokubangelwa ngokufanayo ngendlela efanayo kwibhayoloji kwingingqi efanayo yobuchopho, kunye notshintsho olwenziwe ngamachiza kwimbonakalo yemfuza ngaphakathi kwe-OFC idlala indima ebalulekileyo kwimiba emininzi likhoboka.

1. intshayelelo

TIintsingiselo zokunyamezela kunye nokunyaniseka kuxoxwe kwintliziyo yeengcamango zangoku malunga nokusetyenziswa kweziyobisi. Ngokuqwalasela i-Manual Diagnostic and Statistical Manual (i-American Psychiatric Association Association DSM IV) (i-1994) ye-disorder drug disorder, esinye sezibonakaliso eziphambili kukuba umsebenzisi weziyobisi uyaxhomekeka kwimiphumo eyonwabisayo yesichengiso kwaye ufuna ukuba izidakamizwa ezininzi ziphumelele "Phezulu". Nangona kunjalo, ukunyamezela akuhlakuli ngokukhawuleza kuzo zonke iziphumo zeziyobisi, okukhokelela ekugqibeleni kokubulawa kwabantu njengoko abasebenzisi bebenzela ukwandisa izidakamizwa zabo. Abasebenzisi beziyobisi abangapheliyo banokuthi baqinisekiswe, kunokunyamezela, ezinye iinkalo zamava eziyobisi. Nangona ukuzonwabisa okufunyenwe kwiidakamizwa kuthatha ngokunyuka, umnqweno wokuthatha izidakamizwa ukwanda, kunye nezilwanyana ezidakisayo zivame ukuphazamiseka kwimiphumo emibi yechiza (umz., Ukuxhalaba, i-paranoia) kwakunye namandla okubambisa izidakamizwa ekubangela ukusetyenziswa kweziyobisi ukuhlaziya nokuziphatha (URobinson noBerridge, i-1993). Ngokuqonda iindlela eziphilayo ezikhuthaza ukunyanzelisa nokunyamezela izilwanyana, ithemba ukuba iindlela ziya kufumaneka okanye zivimbele inkqubo yokulutha.

Ngenxa yoko, inzululwazi ye-locomotor sensitization iye yaphandwa ngamandla, ngokukodwa kwimijondolo yebhoratri (jonga (Pierce kunye neKalivas, i-1997) ukuhlaziywa). Iziyobisi ze-Psychosululant ezifana ne-cocaine kunye ne-amphetamine zandisa ukwenziwa komsebenzi. Emva kokulawulwa ngokuphindaphindiweyo, le mpendulo iyancatshiswa kwaye isilwanyana siya kuba nzima kakhulu emva kokusasazeka kweziyobisi. Ngoku ngoku kusekwe ngokuqinisekileyo ukuba u-sensorisation sensitization crkuxhomekeke ekutshintsheni kwi-dopaminergic kunye ne-glutamatergic ngaphakathi kwe-nucleus accumbens (NAc) (jonga (UKalivas noStewart, i-1991; Karler et al., 1994; Wolf, 1998). I-plethora yeproteins yokubonakalisa i-molecular iye yachongwa ukuba ingaba negalelo ekuboniseni le mpendulo yemoto. Enye iprotheyini enjalo yinto yokubhalwa kwephepha ΔFosB eyonyuka kwi-NAc kunye ne-dorsal striatum emva kokungapheliyo, kodwa kungekho nzima, ukulawulwa kwezidakamizwa ezininzi eziluthayo (Nestler, 2008). MnaUkunciphisa ama-NAc ama-ΔFosB ukwandisa ukukhuthaza abantu ukuba baqhube i-cocaine, ukwandiswa kwendawo ekhethwe yinto ekhethiweyo kwiziyobisi, kunye nokuququzelela i-cocaine ukuzilawula (Colby et al., 2003; UKelz et al., 1999). Ngoko ke kuya kubonakala ukuba ukufakelwa kwe-ΔFosB kwi-NAc kuququzelela ukuphuhliswa kwimeko engumlutha.

Kuye kwaqaphela ukuba ukugqithiswa ngokuphindaphindiweyo kwiziyobisi eziluthayo kuchaphazela imisebenzi ephezulu yokujonga izinto ezinjengezenzo zokwenza izigqibo kunye nokulawulwa komgudu, kwaye oku kubaluleke kakhulu ekuphinda kubuyiselwe ukufuna izidakamizwa (Bechara, 2005; I-Garavan ne-Hester, i-2007; UJentsch noTylor, i-1999). Ukuphulukana nokulawulwa kokunyanzeliswa kuye kwaphawulwa kwizilwanyana ezinobuthi be-cocaine, kunye nabasebenzisi bezinye iziyobisi (umzekelo (Hanson et al., 2008; Lejuez et al., 2005; Moeller et al., 2005; U-Verdejo-Garcia et al., 2007). Kuye kwacatshulwa ukuba le ntshukumo ibangelwa ukunyaniseka kwi-cortex ye-orbitofrontal cortex (OFC) ephawulwe ngala maninzi (IKalivas neVolkow, i-2005; Rogers et al., 1999; Schoenbaum et al., 2006; I-Volkow neFowler, i-2000). Sitshanje ukuba i-cocaine yokuphatha ngokuphindaphindiweyo yandisa ama-ΔFosB ngaphakathi kwe-OFC, kwaye ukulinganisa oku kutyalwa nge-virus ye-adeno-echaphazelekayo (AAV) eyenzelwe ukudlulisa i-ΔFosB kwi-OFC (i-genetic mediation-mediated transfer gene) ibonakala ukuba isebenzise inqobo iisekethe (Winstanley et al., 2007). Amanqanaba aphezulu e-OFC ΔFosB ngoko ke anokwenza igalelo ekutshintshweni kwezidakamizwa ekulawuleni.

Sandule ukugqiba uchungechunge lwezifundo ukuvavanya le ngcamango, kwaye ukugqiba imiphumo yokulawula okungahambiyo kwaye okungapheliyo kwe-cocaine kwiimilinganiselo ezimbini zokungahambisani nempembe kwizinga: inqanaba lexesha elingakapheliyo (impulsive) ekuphenduleni kwindlela yokuphendula isithuba sexesha eli- 5CSRT) kunye nokukhethwa komncinci omncinci phezu komvuzo wokulibaziseka omkhulu kumsebenzi wokulibaziseka (ukuphuculwa komsebenzi (Winstanley et al., 2007). Siye sabona ukuba i-cocaine ephawulekayo yanda ukuphendula ngokukrakra kwi-5CSRT kodwa isinciphisa ukhetho oluchanekileyo lomvuzo omncinci kwixesha lokulibazisa-ukuphuhlisa i-paradigm, ukulinganisa imiphumo ye-amphetamine. Le ndlela yokuziphatha-ukwanda kwezenzo ezingenangqondo kodwa kuncipha ekukhethweni okungafuneki-kuguqulelwe njengenyusa ekukhuthazeni umvuzo (Uslaner noRobinson, 2006). Nangona kunjalo, emva kokulawulwa ngokuphindaphindiweyo kwe-cocaine, iirhwe zange zingabonakali utshintsho oluthatywayo ngokungathandabuzeki, njengokungathi ziye zanyamezela kule miphumo engqondweni. Oku kwahluke kakhulu kumpendulo wokuphucula umonakalo kwi-cocaine egcinwe emva kokuphathwa okungapheliyo okuxoxwa ngasentla. Ukongezelela, ukubonakaliswa kwangaphezulu kwe-DFB kwi-OFC imilisa imiphumo yonyango lwama-cocaine angapheliyo: iziphumo ze-cocaine ebonakalayo ekusebenzeni kwe-5CSRT kunye nemisebenzi yokulibaziseka. iziphumo.

Nangona kunjalo, ngelixa ukwandisa i-FosB kwi-OFC ivimbela i-cocaine ephawulekayo ekunyuseni ukunyaniseka, oku kukhangela ngokufanayo kwandisa ukunyanzeliswa ngexesha lokuhoxiswa ukusuka kwi-cocaine-self-administration regimeWinstanley et al., 2008). Ukusebenza kwengqiqo kwezi zilwanyana kwakungekho ncitshiswe xa i-cocaine ibingene ebhodini, kodwa bekungasengozini yokulawulwa kweengxaki ngexesha lokuhoxiswa. Ukwenyuka okufanayo -AFosB kwi-OFC-ngoko kunokunyusa ukunyamezela okanye ukuqonda kwimimandla yefuthe le-cocaine. Lapha sichaza ulwazi olongezelelweyo lwedatha lubonisa ukuba izilwanyana ezibonisa impendulo ephosakeleyo kumngeni onzima we-cocaine kwiimvavanyo zokunyamezela ezilandelayo emva kokubonakaliswa kwe-ΔFosB kwi-OFC nazo ziye zaziswa kwizenzo ezikhuthazayo ze-cocaine. Ngaloo ndlela, ukunyamezela nokukhuthazwa kwimiba eyahlukeneyo yemiphumo ye-cocaine yabonwa kwizifundo ezifanayo. Njengoko i-NAc inendima ebhengeziweyo ye-NAc ekujonganeni nokukhuthazwa kweentengo, kunye nokungabikho kwedatha echaphazela i-OFC kwimimiselo yommiselo, siqikelelwe ukuba ukwandisa i-DFF kwi-OFC inokuphucula impendulo yemoto kwi-cocaine ngokuguqula umsebenzi kule ndawo yokuzala. Ngoko ke senza uvavanyo oluhlukeneyo usebenzisa i-PCR yangempela-time ukuphenya ukuba ukwandisa i-DFB kwi-OFC iguqula umzobo we-gene kwi-NAc ngendlela ebonisa ukuphucula ukukhuthaza abantu.

Yiya e:

2. Iindlela

Zonke iilingo zenziwa ngokuhambelana ngqo neNcwadana ye-NIH yoLondolozo kunye nokusetyenziswa kwezilwanyana zeLebhanari kwaye zavunyelwa yiKomiti yokuNakekela iZilwanyana kunye neKomiti yokuSebenzisa kwi-UT eNtshona-ntshona.

2.1. I zifundo

Amadoda amaninzi ama-Evans ama-rats (ubunzima bokuqala: 275-300 g; uMfula waseCharles, i-Kingston, RI) babehlala ngeebini ngaphantsi komjikelezo wokukhanya ojikelezayo (izibane ukusuka kwi-21.00-09.00) kwigumbi elilawulwa yiimoya. Izilwanyana kwiindlela zokuziphatha (n= I-84) ukutya kwakukuncitshiswe kwi-85% yesisindo sokunceda ngokukhululeka kwaye kugcinwe kwi-14 ye-rat chow ngosuku. Amanzi ayatholakala ad adum. Uvavanyo lokuziphatha luyenzeka phakathi kwe-09.00 kunye ne-19.00 iintsuku ezintlanu ngeveki. Izilwanyana ezazisetyenziselwa ukuvelisa izicubu zengqondo yezilingo ze-qPCR zazinokufikelela ngokukhululekileyo kokutya kunye namanzi (n= 16). Ezi zilwanyana zazinokufikelela ngokukhululekileyo kokutya kunye namanzi.

2.2. Ukuhlinzwa

Amagundane athola i-intra-OFC iinjongo ze-AAV-GFP, AAV-ΔFosB, okanye i-AAV-ΔJunD usebenzisa iindlela eziqhelekileyo zokusetyenziswa kwe-stereotaxic njengoko kuchazwe (Winstanley et al., 2007). Amagqabi ayenziwe nge-ketamine (Ketaset, 100 mg / kg ye-intramuscular (im) injection) kunye ne-xylazine (i-10 mg / kg im; zombini iziyobisi ezivela ku-Henry Schein, eMelville, NY). Ii-AAV zangeniswa kwi-OFC usebenzisa i-31 gauge injector injector (i-Small Parts, eFlorida, eU.SA) ifakwe kwiPamilton microinfusion ipom nge-polyethylene tubing (Instech uSolomon, ePennsylvania, eU.SA). Iimvenge zentsholongwane zatshintshwe kwisantya se-0.1 μl / min ngokulandelelaniswa kwezi zilandelayo ezivela kwi-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, 0.6 μl (bona (Hommel et al., 2003) ukwenzela iinkcukacha ze-AAV ukulungiselela). I-AP (i-anteroposterior) ilungelelaniswa ithathwe kwi-bregma, i-L (i-lateral) idibanisa ukusuka kwi-midline kunye ne-DV (i-dorsoventral) idibanisa ukusuka kwi-dura. Izilwanyana zavunyelwa ngeveki ukuba zibuyele ekutyunjweni phambi kokuba kuhlolwe uvavanyo (ukuhlola i-1) okanye ukulawulwa kweziyobisi (ukuzama kwe2).

2.3. Uyilo lo vavanyo

Idatha yokukhuthaza ukukhuphaza ifunyenwe kwizilwanyana eziye zafumana uchungechunge lweemvavanyo zokuziphatha ukulinganisa i-sequelae ecognitive ye-drug incordance, kwaye ezi nkcukacha zipapashwe ngaphambili (Winstanley et al., 2007). Ngamafutshane, iiliti zaqeqeshwa ukwenza i-5CSRT okanye umsebenzi wokulibaziseka. Baye ke bahlukana baba ngamaqela amathathu afana nomsebenzi wokuqala. Intsholongwane ye-adeno-echaphazelekayo (AAV2) ngaphezulu-ebonisa i-APF (Zachariou et al., 2006) yafakwa ngokukhethekileyo kwi-OFC yeqela elinye usebenzisa ubuchule obuphambili bokuhlinzwa (jonga ngezantsi) ngaleyo ndlela ufanise ukutyalwa kweprotheni ngokulawulwa kwe-cocaine engapheliyo. Iqela le sibini lafumana i-intra-OFC e-AAV-ΔJunD. I-AAV-GFP (iprotheni ye-green fluorescent) yayisetyenziselwa iqela lokulawula. Emva kokuba kusekelwe isiseko esisezantsi sokusebenza, imiphumo ye-cocaine ephawulekayo (0, 5, 10, 20 mg / kg ip) yazinqunywa ngomsebenzi. Ukuvavanya ukuba ulawulo olungapheliyo lwe-cocaine lushintsha imiphumo engqiqweni ye-cocaine, iilwanyana zazingqinelana phakathi kwaye phakathi kwamaqela abo otyando abe ngamaqela alinganayo. Elinye iqela laliphathwa ngokungapheliyo nge-saline, enye enye i-cocaine (2 × 15 mg / kg) kwiintsuku ze-21. Kwiiveki ezimbini emva kokuba unyango olungapheliyo lwamayeza luphelile, imingeni ye-cocaine enzima yaphinda iphindwe ngomhla. Emva kweveki kamva, impendulo yokuhlawula i-cocaine yahlolwa.

2.4. Impendulo ye-locomotor kwi-cocaine

Umsebenzi we-locomotor wavavanywa kumagareji ngamnye (25 cm × 45 cm × 21 cm) usebenzisa inkqubo ye-photobeam (PAS: Ii-San Diego Instruments, eSan Diego, CA). Umsebenzi kwinqanaba ngalinye lalinganiswa ne-7 photobeams ewela ububanzi bekhosi, i-6 cm kunye ne-3 cm ukusuka kwisiteji. Idatha yahlanganiswa kwi-5 min bins usebenzisa i-software ye-PAS (i-2, i-San Diego Instruments, iSan Diego, CA). Emva kwe-30 min, izilwanyana zafakwa ngecocaine (i-15 mg / kg ip) kunye nomsebenzi woqhagamshelwano olongeziweyo kwi-60 min minye.

2.5. Ukukhishwa kweMRNA

Amagundane athola i-intra-OFC injections ye-AAV-GFP okanye i-AAV-ΔFosB, ilandelwa yi-21 injini yansuku zonke ye-saline okanye i-cocaine, njengokuba kuchazwe ukuhlolwa kokuziphatha. Izilwanyana zazisetyenziswa i-24 h emva kwe-injini yokugqibela okanye i-cocaine injection. Amagqabi abulawa yi-decapitation. Ubuchopho bukhishwe ngokukhawuleza kwaye i-1 mm ephakamileyo ye-12 i-puncter gauge ye-NAc yafunyanwa kwaye yanyuswa ngokukhawuleza kwaye igcinwe kwi-80 ° C ide i-RNA iyodwa. Iiplanga ezivela kwi-OFC nazo zazisuswa ukuze zihlaziywe yi-DNA microarray eqinisekisile impumelelo yokuguqula i-viral-mediated transfusion kule ndawo (jonga (Winstanley et al., 2007) kwiziphumo ezingakumbi). I-RNA yakhishwa kwiisampula ze-NAc usebenzisa i-RNA Stat-60 reagent (iTeltest, Houston, TX) ngokwemiyalelo yomenzi. I-DNA engcolileyo isuswe nge-DNase unyango (i-DNA-Free, ikhathalogu # 1906, Ambion, Austin TX). I-RNA eyahlanjululwa yabuyisela kwakhona kwi-cDNA (i-Superscript yokuqala ye-Strand Synthesis, i-Catalog # 12371-019; i-Invitrogen). Iinguqu zengqungquthela zenzalo zazingqiniswanga zisebenzisa ixesha langempela qPCR (SYBR Green; Applied Biosystems, Foster City, CA) kwiStratagene (La Jolla, CA) Mx5000p 96-well thermocycler. Zonke izibhengezo zenziwe ngeziko-Operon (Huntsville, AL; bona 1 Table ukulandelelana) kwaye iqinisekiswe ukulungelelaniswa kunye nobume phambi kokulinga. Yonke idatha ye-PCR yayimiselwe kumanqanaba e-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), engatshintshi ngonyango lwe-cocaine, ngokolu hlobo lulandelayo: ΔCt =Ct(uhlobo lomdla) - Ct (GAPDH). Amanqanaba okubonakalisa amanyathelo ama-AAV-ΔFosB kunye nee-AAV-GFP iinkozi ezithe zafumana i-cocaine, kunye neerati ze-AAV-ΔFosB ezafumana i-saline engapheliyo, zabe zibalwa ngokumalunga nolawulo (i-AAV-GFP iqela elinikwa i-saline elingasigxina) ngale ndlela: ΔΔCt = ΔCt - DCt (iqela lokulawula). Ngokuhambisana nesenzo esicetywayo kwintsimi (Livak noSchmittgen, 2001), amanqanaba okuthetha ngokumalunga nolawulo aye kubalwa esebenzisa eli binzana elilandelayo: 2-DACt.

1 Table  

1 Table

Ukulandelelana kwamagqabi asetyenziselwa ukulinganisa amazinga e-cdna ngokusebenzisa i-PCR yangempela-time.

2.6. Zi yobisi

I-Cocaine HCl (Sigma, iSt. Louis, MO) yachithwa kwi-0.9% i-saline kumthamo we-1 ml / kg kwaye ilawulwa nge-injection ye-ip. Amanani ayebalwa njengetyuwa.

2.7. Uhlalutyo lwedatha

Yonke idatha yahlaziywa isebenzisa isofthiwe ye-SPSS (SPSS, Chicago, IL). Idatha ye-locomotor yayithotyelwe kwi-ANOVA eninzi kunye nokuhlinzwa (amanqanaba amabini: GFP vs ΔFosB okanye i-JAJ) kunye nokunyanga okungapheliyo (amazinga amabini, i-saline engapheliyo kunye ne-cocaine engapheliyo) phakathi kwezinto eziphathekayo, kunye nexesha lokuhamba njengento ephantsi kwezifundo. Ulwaziso oluvela kwiziphumo ze-PCR zangempela-mali lwahlaziywa yi-ANOVA engavumelekanga kunye nokuhlinzwa (amanqanaba amabini: GFP vs ΔFosB) kunye nokunyanga okungapheliyo (amanqanaba amabini, i-saline engapheliyo kunye ne-cocaine engapheliyo) njengezinto ezichanekileyo. Iziphumo eziphambili zalandelwa ziziimodeli ezizimeleyo t-iindawo ezifanelekileyo.

Yiya e:

3. Iziphumo

Zama 1

Ukulawulwa kwe-cocaine engapheli kuvelisa ukukhunjulwa kwimiphumo ye-hyperlocomotor ye-cocaine ephawulekayo eyenziwa yi-DFosB

Njengoko kulindeleke ukuba, ukukhuthazwa kweentengo ezinamandla kwimbonakaliso kwizilwanyana emva kokunyanzeliswa kwe-cocaine, kunye nezilwanyana ziphathwa ngokungapheliyo nge-cocaine ezibonisa ukwanda kokungabi nongxaki ekuphenduleni umngeni we-cocaine mngeni (Umzobo 1A, unyango olungapheliyo: F1,34 = 4.325, p<0.045). Izilwanyana zichaza ngaphezulu ΔJunD, esona siguquko siphambili seJunD esisebenza njenge-ΔFosB echasayo (Zachariou et al., 2006), kwi-OFC babengabonakali kwizilwanyana ezilawulayo (Umzobo 1C, GFP vs ΔJunD, iqela: F1, 56 = 1.509, NS). Nangona kunjalo, izilwanyana ezigqithiseleyo -AFosB kwi-OFC ebeyifumene iilen injini ephindaphindiweyo yabonakala "isengaphambili": yabonisa impendulo yokuphucula i-cocaine eyayingabonakaliyo ukusuka kwindlela yokuphendula yabantwana babo abaphatha ngayo i-cocaine engapheliyo (Umzobo 1B, GFP vs ΔFosB ukuhlinzwa ngonyango olungapheliyo: F1, 56 = 3.926, p<0.052; ΔFosB kuphela: unyango olungapheliyo: F1,22 = 0.664, NS). Izilwanyana ze-FosB zazingekho kakuhle kwi-15 min yokufakwa kwiibhokisi zokuhlawula (GFP vs ΔFosB, ukuhlinzwa: F1,56 = 4.229, p <0.04), kodwa amanqanaba omsebenzi we-locomotor athelekiswa nolawulo kwi-15 min ngaphambi kolawulo lwecocaine (utyando: F1, 56 = 0.138, NS).

Ikhiwane. 1  

Ikhiwane. 1

Ukuxhotyiswa kwe-locomotor ukucocaine. I-cocaine eqhelekileyo yenze ukwanda okukhulu kwintsebenziswano ekulawuleni izilwanyana eziphathwa kakubi nge cocaine ngokubhekiselele kwi-saline (ipaneli A). Kwizilwanyana ezingaphezu kwe-ΔFosB (ipaneli B), abo bazinikezelwa ngokuninzi (Kaninzi …)

Ukuqwalasela ukuba, xa kunikezwa i-cocaine ngexesha le-5CSRT, izilwanyana ezifanayo zibonisa amandla anokunyaniseka okubambelela ekwenzeni iimpendulo zeemoto zangaphambi kwexesha, ukuxhatshazwa kwezinto ezibonakalayo kubonakala ngokukodwa kwi-locomotion ye-ambulatory, oko kukuthi uhlobo lokunyakaza olubhaliswe kwizifundo zokukhuthaza abantu. Nangona umsebenzi ophuculweyo ekuphenduleni izidakamizwa ezikhuthazayo unokubonisa iprofayili yecalagenic, i-intra-OFC ebonakaliswe ngaphezu kwe-ΔFosB ayinakwandisa ukuxhalaba njengoko ilinganiswe ngokusebenzisa umqolo ophakamileyo ophezulu okanye ukuvavanywa kwintsi evulekile (idatha engaboniswa). Izilwanyana nazo zazixhomekeke kwizijova ze-IP, kwaye iilject zangasese azizange zitshintshe ukusebenza kwazo (Winstanley et al., 2007), ngoko le miphumo yemoto ayinakuthi ithathelwe ukuphendula ngokubanzi kwi-injection ye-IP. Ezi sishwankathelo, ezi ziphumo zibonisa ukuba ukufakelwa kwe-FosB kwi-OFC kwanele (kodwa kungabaluleki) ukuba umntu ocebileyo aphendule i-cocaine, nangona i -ΔFosB kwindawo efanayo iya kubangela ukunyamezela kwimiphumo ye-cocaine kwi-motivation and impulsivity (Winstanley et al., 2007).

Zama 2

Ukulawulwa kwe-cocaine engapheliyo ihambelana nomzimba we-NAc

Ukuba i-molecule ethile e-NAc yayinomdla kwiempendulo ezandulelekileyo ezibonwe kwiqela le-AAV-ΔFosB ephathwa ngetyuwa, ngoko siyakulindela ukubona iimpendulo ezifanayo kunye nezilwanyana kwi-AAV-GFP kunye Amaqela e-AAV-ΔFosB ayiphatha ngokungapheliyo nge-cocaine. Ukongezelela, izilwanyana kwiqela le-AAV-GFP elaphathwa nge-saline akufanele libonise le mpendulo njengoko ezi zilwanyana zingabonakali kwi-cocaine. Lo mzekelo weziphumo uza kubonakaliswa kwiziyobisi ezinzulu zokusebenzisana, ukuxhaswa ngamasampuli azimele ezizimeleyo t-kukuthelekisa iindlela zeAAV-GFP kunye neAAV-ΔFosB namaqela aphathwa ngetyuwa, kunye neqela le-AAV-ΔFosB kunye neAAV-GFP yokuphathwa kwecocaine. Iziphumo eziphambili zonyango lweziyobisi okanye utyando luya kuqinisekisa ukuba i-cocaine engapheliyo okanye ukubonakaliswa kwangaphezulu kwe-FosB kwi-OFC inokuyilungisa i-molecule ekujoliswe kuyo kwi-NAc, kodwa lo mbono awunelisekanga ukuchazela impendulo yokuphucula i-AAV-ΔFosB . Iisisisi ezivela kwisilwanyana esasifumana i-intra-OFC e-AAV-GFP kunye neenkokhelo eziphindaphindiweyo ze-cocaine azikwazi ukuhlaziywa ngenxa yokuveliswa okungaqhelekanga kwe-RNA. Kulo vavanyo, sigxininise kwiijethi eziliqela eziye zabandakanyeka ekukhutshelweni kweentengo ze-cocaine (jonga Ingxoxo).

3.1. ΔFosB / FosB

Amanqanaba e-FosB mRNA kwi-NAc ayengagqitywanga ngonyango olungapheliyo (Umzobo 2A, iziyobisi: F1,14 = 1.179, ns) okanye ibonakaliso ye-ΔFosB kwi-OFC (ukuhlinzwa: F1, 14 = 0.235, ns). Nangona kunjalo, amazinga e-ΔFosB aphezulu kakhulu kwizilwanyana eziphathwa ngokungapheliyo ngecocaine ngokuhambelana neengxelo zangaphambili (Chen et al., 1997); Umzobo 2B, iziyobisi: F1,14 = 7.140, p<0.022). Into enomdla kukuba, isixa se-ΔFosB mRNA kwi-NAc yezilwanyana eziphathwe ngetyuwa sasisezantsi kwezo zinto zibhalwe ngaphezulu kwi-OFC (iziyobisi: F1,14 = 9.362, p<0.011). Nangona kunjalo, ukungabikho kwesiyobisi × ukusebenzisana kotyando kubonisa ukuba unyango lwecocaine olungapheliyo lwaluneziphumo ezifanayo kuwo omabini amaqela aphathwe ngeAAV-GFP kunye neAAV-ΔFosB, ngokunyusa amanqanaba e-osBFosB kwinqanaba elifanayo (iziyobisi × utyando: F1, 14 = 0.302, ns).

Ikhiwane. 2  

Ikhiwane. 2

Utshintsho kwi-MRNA ngaphakathi kwe-NAc yezilwanyana ngaphezu kwe-GFP okanye i-ΔFosB kwi-OFC, kwaye iphathwa ngokungapheliyo nge-saline okanye i-cocaine. Iinkcukacha zibonisa utshintsho olusondeleyo lwentlobo kubonakaliso njengengxenye yemilinganiselo yokulawula. Idatha ibonisiwe (Kaninzi …)

3.2. I-Arc / CREB / PSD95

Kwakungabikho ubungqina bokunyuka kweArc (i-protoste-related protein protein) ebonisa i-24 h emva kokugqithiswa kweziyobisi, kwaye ayizange ikhule ΔFosB kwi-OFC utshintsho lwamanqanaba e-Arc mRNA kwi-NAc (Umzobo 2C, iziyobisi: F1.14 = 1.416, ns; utyando: F1,14 = 1.304, ns). Ngokufanayo, akukho tshintsho ebonwe kwi-CREB (into ephendulayo yeCAMP ebopha iprotheni) ibinzana (Umzobo 2D, iziyobisi: F1,14 = 0.004, ns; utyando: F1,14 = 0.053, ns). Nangona kunjalo, ukulawula okungapheliyo kwe-cocaine kunyuke kakhulu kwinqanaba le-MRNA ye-PSD95 (iprotheni ye-postsynaptic yobuninzi be-95 kD) (Umzobo 2E, iziyobisi: F1,14 = 11.275, p <0.006), kodwa olu nyuso lwalufana kuwo omabini amaqela e-AAV-GFP kunye ne-AAV-ΔFosB (utyando: F1, 14 = 0.680, ns; utyando otyando: F1,14 = 0.094, ns).

3.3. D2/ GABAB/ GluR1 / GluR2

Amanqanaba e-MRNA ye-dopamine D2 i-receptors yanda emva kokulawulwa kwe-cocaine engapheliyo (Umzobo 2F, iziyobisi: F1,14 = 7.994, p<0.016), kodwa oku kunyuka akuzange kuchaphazele ukubonakaliswa okungaphezulu kwe-osBFosB kwi-OFC (utyando: F1, 14 = 0.524, ns; utyando otyando: F1,14 = 0.291, ns). amanqanaba e-MRNA yeGABAB i-receptor ibonise iphrofayili efanayo, kunye namanqanaba okwandiswa yincinci encinci kodwa ebonakalayo ngokulandela ngokuphindaphindiweyo kwi-cocaine kungakhathaliseki ukunyanzelwa kwe-viral (Umzobo 2G, iziyobisi: F1,14 = 5.644, p <0.037; utyando: F1, 14 = 0.000, ns; utyando otyando: F1,14 = 0.463, ns). Nangona kunjalo, amanqanaba e-AMPA ama-glutamate receptor subunits GluR1 kunye ne-GluR2 awazange athathwe naluphi na ukuphathwa, nangona kwakukho umkhonto omncinci wokwanda kwe-GluR2 elandela ukwelashwa kwe-cocaine engapheliyo (Umzobo 2H, I-GluR1: iziyobisi: F1,14 = 0.285, ns; utyando: F1, 14 = 0.323, ns; utyando otyando: F1,14 = 0.224, ns; Umzobo 2I, I-GluR2: iziyobisi: F1,14 = 3.399, p <0.092; utyando: F1, 14 = 0.981, ns; utyando otyando: F1,14 = 0.449, ns).

Isishwankathelo, nangona unyango olungapheliyo lwe-cocaine lushintshile amanqanaba e-MRNA kwimibolo yegesi evivinywe kwi-NAc, asizange sibone ukwanda okwenziweyo kwezi ntlobo zegeni kwiirats zonyango ezigqithisileyo. Ezi ziphumo zibonisa ukuba ezi zakhi zofuzo azibandakanyeki kwimpendulo eyongezelelweyo yokuphucula iphawulwayo kweli qela.

Yiya e:

4. Ingxoxo

Lapha sibonisa ukuba ukubonakaliswa kwangaphezulu kwe-DFB kwi-OFC ezinengqiqo ezinokuthi zenze izinto ezikhuthazayo ze-cocaine, zilinganisa izenzo ze-cocaine. Siye sabonisa ngaphambili ukuba ukusebenza kwezi zilwanyana ezifanayo kwi-5CSRT kunye nokukhawuleza-ukuphuculwa kwama-paradigms kuncinci kuchatshazelwa yi-cocaine ephawulekayo, kwaye ukuba ukunyamezela okufanayo kufana nokugqithiswa emva kwe-cocaine. Ngaloo ndlela, ukuqonda kunye nokunyamezela kwiindlela ezahlukeneyo ze-cocaine ziyakubonwa kwizilwanyana ezifanayo, kunye nezilungelelaniso ezidibeneyo nge-molecule efanayo, i-DFF, esebenza kwindawo efanayo yengqondo. Iqiniso lokuba zombini iziganeko zingenziwa ngokufanayo ngokulinganisa enye yezenzo ze-cocaine kwendawo enye ye-frontocortical igxininisa ukubaluleka kwemimandla yendawo ye-cortical kwi-sequelae yesidlo esingunaphakade.. Ukongezelela, ezi nkcukacha zibonisa ukuba ukunyamezela kunye nokukhuthaza kubonakalisa ezimbini ezibonakalayo zichasene, kodwa zihambelana ngokusondeleyo, imiba yempendulo kwiimichiza eziluthayo.

Ngenxa yokuba ukwandiswa kwegama le-FosB kwi-NAc ibandakanyeka ngokukodwa ekuphuhliseni ukwenziwa kweentengiso, enye ingcamango ecacileyo yayiya kuba i-FosB e-OFC ibangela ukuba izilwanyana zisebenzise i-cocaine ngokunyuka kwamazinga e-FosB kwi-NAc. Nangona kunjalo, isiphumo esingenanto sathotyelwa: amazinga e-DFFB kwi-NAc ayengaphantsi kakhulu kwizilwanyana ezingaphezu kwe-ΔFosB kwi-OFC. Imiphumo yokuziphatha yale nciphiso kwi-NAc ΔFosB inzima ukuyichazela, njengokuba i-DFF yezenzo ze-FosB ngokubhekiselele kwi-ΔJunD kule ndawo inciphisa imiphumo eminingi ye-cocaine kwimichiza (Peakman et al., 2003). Ukufana okunye kukho phakathi kwezi mboniso kunye nezo zenziwe ngokubhekiselele kwinkqubo ye-dopamine. Ngokomzekelo, ukuchithwa kwe-dopamine encinci kwi-NAc kunokukhokelela ekungathandabuzeki njengokuba kunokuhambisa i-dopamine agonists kule ndawo (Bachtell et al., 2005; Costall et al., 1984; Parkinson et al., 2002; Winstanley et al., 2005b). Ngokufanayo, into yokuba ukwandiswa kwamanqanaba e-ΔFosB kunokunciphisa ukubonakaliswa kwamagqabantshintshi kufana nokufumanisa kakuhle ukuba ukunyuka kwi-prefrontal yokudlulisa i-dopaminergic kudla ngokuhamba kunye nokunciphisa ngokukhawuleza kwinqanaba le-dopamine yokuzala.UDeutch et al., 1990; UMitchell noGraton, i-1992). Ingaba indlela yokuphendula ingasebenza ngayo iamolekyu zokungena kwamaselula okwangoku ayikho into ecacileyo, kodwa ingabonakalisa utshintsho kwimisebenzi eqhelekileyo yamanethiwekhi athile e-neuronal obangelwa utshintsho kwi-gene transcription. Ngokomzekelo, ukwandisa i-DFBB kwi-OFC kukhokelela ekugqibeleni umsebenzi wokungavimba kwendawo, njengoko kuboniswe ukwanda kwamanqanaba e-GABAA i-receptor, mGluR5 i-receptor kunye ne-P, njengoko ifunyenwe uhlalutyo lwe-microarray (Winstanley et al., 2007). Olu tshintsho kumsebenzi we-OFC lunokuyichaphazela umsebenzi kwezinye iindawo zengqondo, okuya kubangela ukuba utshintsho lwengingqi lubonakalise i-ΔFosB. Ingaba amazinga e-FosB abonakalisa utshintsho oluthile kumsebenzi we-dopamine ngumba obangela ukuba uphando olongezelelweyo.

Zonke izilwanyana zibonise ukwanda okwenziwe kumazinga e-FosB mRNA kwi-NAc elandela ukwelashwa kwe-cocaine engapheliyo, ngokuhambisana neengxelo zangaphambili zamanqanaba eeprotheni (Chen et al., 1997; Hope et al., 1992; Nye et al., 1995). Nangona kunjalo, ingxelo yangoku ifumene ukuba amanqanaba e-DFFBMRNA awazange aphakanyiswe kakhulu kwi-24 h emva kokunyanga kwama-amphetamine angapheliyo, nangona ukwanda okwenziwe kubonwe i-3 h emva kokufakelwa kwe-injection yokugqibela (U-Alibhai et al., 2007). Ukungahambelani kubangelwa ngenxa yecatshulwa kwisistim se-psychostimulant esisetyenziswayo (i-cocaine vs amphetamine), kodwa kunikezwe ubuncinane bomi-cocaine, kuya kuba nengqiqo ukulindela ukuba imiphumo yazo kwiimpawu zemizimba iza kulungelelana ngokukhawuleza kunezo i-amphetamine, kunokuba yenzeke. Isizathu esicacileyo sazo zeziphumo ezahlukeneyo kukuba izilwanyana kwizifundo ezikhoyo zijojowe ngeqondo elilinganayo lezonyango kabini ngeentsuku ze-21 xa kuthelekiswa nejokelelo elilodwa eliphezulu le-dose kwiintsuku ze-7 (U-Alibhai et al., 2007). I-regimen eyongezelelweyo yonyango inokubangela ukuba utshintsho oluthile lubekwe apha.

Nangona ukutshintshwa kwegama lomzimba kuboniswe ngaphakathi kwe-NAc elandela i-cocaine engapheliyo kuvumelana ngokubanzi kunye neziphumo ezichazwe ngaphambili, ubukhulu bemiphumo yincinci kwisifundo samanje. Esinye sezizathu zokuba zezi zizilwanyana zanikelwa ngo-24 kuphela emva kokuba ijocaine yokugqibela ijojoine, ngelixa uninzi lwezifundo zisebenzise izicubu zathatha iiveki ezimbini ukususela ekugqibeleni izidakamizwa zokugqibela. Uphando oluhlola ixesha lokwenza ulwaphulo lweentengo lubonakalisa ukuba utshintsho oluthe lwabizwa kuzo zombini ukuziphatha kunye ne-gene / protein expression luboniswa kule ngongoma yexesha elizayo. Nangona sichaza ukwanda kweMRNA kwiDopamine D2 i-receptor kwi-NAc, isivumelwana ngokubanzi kukuba amaqondo e-D2 okanye iD1 i-receptor ayiguqukanga ngokusisigxina emva kokuphuhliswa kwe-locomotor sensitization, nangona zombini iyakhula kwaye iyancipha kwi-D2 Inombolo ye-receptor ibiwe kungekudala emva kokuphela kolawulo olusishukumisayo (jonga (Pierce kunye neKalivas, i-1997) kwingxoxo). Ukubona kwethu ukuba i-GluR1 kunye ne-GluR2 mRNA ayitshintshi emva kokunyanga okungapheliyo kwe-cocaine kule nkqubo yexesha elidlulileyo ngokufanayo kunye nengxelo yangaphambili (UFitzgerald et al., 1996), nangona ukunyuka kwe-GluR1 mRNA kuye kwafunyanwa kwixesha elide emva kokupheliswa kwonyango olusisigxina (psychostimulant treatment)UChurchill et al., 1999).

Nangona kunjalo, siye sabona ukwanda okwenyuka kwi-PSD95 mRNA kwi-NAc yezilwanyana eziphathwa kakubi ngecocaine. I-PSD95 iyimelakhi ye-scaffolding, kwaye enye yeeprotheyini ezinkulu kwi-postsynaptic ukuxinwa kwe-synapses. I-anchor receptors ezininzi kunye neepalini zokubonakalisa iiprotheni, kunye nokwanda kwegama lika-PSD95 kucatshangelwa ukuba kubonakalise umsebenzi owandisiweyo we-synaptic kunye nokunyusa ukunyuswa kunye nokuzinza kwama-glutamate receptors kwi-synapses (van Zundert et al., 2004). Inxaxheba kwi-PSD95 ekuphuhliseni ukukhuthazwa kweentengiso kuphakanyisiwe ngaphambili (Yao et al., 2004).

Ukwandiswa kwegama lika-Arc liye laxhunyaniswa nokwandiswa komsebenzi we-synaptic. Nangona kunjalo, ngelixa ukunyuka kwegama le-Arc kwi-NAc kuye kwagcinwa i-50 min emva kokujova nge-amphetamine (Klebaur et al., 2002), idatha yethu ibonisa ukuba ukulawulwa okungapheliyo kwe-cocaine akuyi kulungelelanisa iArc kwi-NAc ngokusisigxina, nangona ukwanda kweArc kuye kwagcinwa i-24 h emva kokungapheliyo kwezilonda ezixinzelelekileyo (I-Larsen et al., 2007) kunye ne-amphetamine (Ujike et al., 2002). Ukwanda kwe-CREB i-phosphorylation ijongwa kwakhona kwi-NAc emva kwe-cocaine enobuchule kunye nolawulo lwe-amphetamine (Kano et al., 1995; Konradi et al., 1994; Self et al., 1998), kodwa mhlawumbi akumangalisi ukuba akukho kunyusa kwi-CREB mRNA ebonwa emva kokulawulwa kwe-cocaine engapheliyo. Ukubonakaliswa ngendlela ye-CREB kucatshangelwa ukuba kubaluleke kakhulu kwiinqanaba zokuqala zokusetyenziswa kweziyobisi, kunye neziganeko zokubhalwa kwezinto ezifana ne-DFB iza ukulawula njengokuba umlutha uyaqhubeka (McClung noNestler, 2003). Nangona i-CREB ibandakanywe kwimiphumo emivuzo ye-cocaine (I-Carlezon et al., 1998), akubangakho ingxelo yokuba ukwandiswa kwegama le-CREB kuthintela ukukhuthazwa kweentengo, nangona ukwanda kwe-viral-mediated ku-anti-antagonist of CREB, i-inducible cAMP iprotheni yokuqala okanye i-ICER, iyandisa ukwanda komonakalo obangelwa ngumjovo ophezulu we-amphetamine (Green et al., 2006).

Isishwankathelo, nangona uninzi lweenguqu ezibangelwa yiziyobisi esizibonayo zihambelanayo neziprofeto ezivela kwiincwadi, asizange sithole nayiphi na inguqu kwi-NAc engachaza ukuba impendulo yokuvakalisa i-cocaine ebonakalayo kwizilwanyana ezinobuthi nge-intra-OFC AAV-ΔFosB. Oku kuphakamisa ukuba amathuba okwandisa i-DFF kwi-OFC ayinakuchaphazela ukukhuthaza imoto nge-NAc, nangona ezinye iizakhi zegesi, ezingakhange zifundwe apha, zinokuthi zibandakanyeke. Ubungqina obubonakalayo bubonisa ukuba ukulungelelaniswa kwe-cortex ye-prefrontal (i-mPFC) inokutshintsha umsebenzi we-bereatal kwaye ngaloo ndlela igalelo ekuphatheni ukukhuthaza ukuziphatha kwabafundi beengqondo (ISteteete, i-2003; Steketee noWalsh, i-2005), nangona kungaphantsi kwaziwa malunga nendima yemimandla engaphezulu ye-ventral njenge-OFC. I-NAc ifumana iziphumo ezithile kwi-OFC (UBerendse et al., 1992). Nangona kunjalo, uphando olutshanje nolusondeleyo lubonakaliswe kakhulu ezimbalwa ngokuthe ngqo kwe-OFC-NAc izicwangciso: i-ilec ye-NAc yeyona nto iboniswe ngokulandelelanayo emva kweengxube ze-anterograde tracer kwiindawo ze-OFC ezisemgangathweni kunye ne-ventrolateral. Ummandla uthumela izicwangciso ezingancinci kwi-NAC yengundoqo (USchilman et al., 2008). I-central caudate-putamen ifumana ubuninzi obukhulu bokugcina. Ngenxa yokobu bungqina bobuninzi, ubuninzi bee-TC ezihlaziyiweyo kwiimpendulo zethu ze-PCR aziyi kulandelwa ngqo yi-OFC, ukunciphisa amathuba ukuba nayiphi inguqu kwimbonakalo yomzimba iza kubonwa ngempumelelo.

I-OFC yenza iprojekti kakhulu kwimimandla edibeneyo ngokunxulumene ne-NAc, efana ne-mPFC, i-amygdala ye-basolateral (BLA), i-caudate putamen kunye ne-subthalamic nucleus (STN). Ingaba utshintsho kwi-OFC lunokumisela ngokuthe ngqo ukusebenza kwe-NAc ngokusebenzisa impembelelo yalo kule mimandla ngumbuzo ovulekile. Kuye waboniswa ukuba umsebenzi kwi-BLA utshintshwe emva kwezilonda ze-OFC, kwaye ukuba oku kunceda kakhulu ekulahlekeni kokufunda okutshintshiswe ngumonakalo we-OFC (UStalnaker et al., 2007), kodwa nayiphi na imiphumo kwimimandla efana ne-NAc ayisayi kubikwa. Kungaphumelela ngakumbi ukugxila ingqalelo kwezinye iindawo ezixhomekeke kakhulu kwi-OFC kwaye nazo zichaphazeleka kakhulu ekulawuleni imoto. I-STN ijolise ngokuthe ngqo, njengoko kungekhona nje ukuba izilonda ze-STN ne-OFC zivelisa imiphumo efanayo kunye nokufundwa kwePavlovian (IBaunez kunye neRobbins, i-1997; UChudasama et al., 2003; Uslaner noRobinson, 2006; UWinstanley et al., 2005a), kodwa ukukhutshulwa kweentengo zengqondo kwintsebenziswano yenzelwa ukunyuswa kwenkcazo ye-c-Fos kule ndawo (Uslaner et al., 2003). Uvavanyo olulandelayo olwenzelwe ukuhlola indlela ukuguqulwa kwezidakamizwa ekutshintshweni kwemizimba kwi-OFC kuthintela ukusebenza kweendawo ezinjenge-STN zivumelekile. I-OFC iphinde ithumele umboniso omncinci kummandla wezentengiso (Geisler et al., 2007), ummandla owaziwayo ochaphazelekayo ngokukodwa ekuphuhliseni ukwenziwa kweentengiso. Kungenzeka ukuba ukubonakaliswa kwangaphezulu kwe-FosB kwi-OFC kungakhokelela ekukhuliseni ukuqhutyiswa kwendlela.

Ubume obuchanekileyo bobudlelwane phakathi kweenguqu ezibangelwa yiziyobisi ekusebenzeni kwengqondo kunye nokukhuthazwa kwamanani okwangoku kungabonakali kakuhle, kwaye ngoku siye sigxile kwi-OFC. Ukubonelelwa kwezi ziphumo, kunokwenzeka ukuba utshintsho kwimbonakalo yezofuzo ezihambelana nokuphuhliswa kweentengiso zengingqi kwezinye iindawo zengqondo zingabangela impembelelo ekuphenduleni ingcamango kwicocaine. Iingcaphephe ezihlolisisa ukusebenzisana phakathi kweendawo ezikhuselekileyo kunye neengqamaniso ezilandelayo emva kokulawulwa kweziyobisi ezinomlingo zingakhangela ukukhanya okutsha malunga nendlela ulwaphulo lomhlaba olwenziwa ngayo kwaye lugcinwe, kwaye iindima ezibandakanyekayo zidlalwa ngokukhuthaza nokunyamezela kule nkqubo.

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