Umlutha Wezidakamizwa njenge-Pathology ye-Neuroplasity Staged (2007)

1. ¹Iminyango ye-Neurosciences, i-Medical University yaseNingizimu Carolina, uCharleston, SC, eU.SA
2. ²UMnyango Wezokwelapha, iPhililadelphia VA Medical Center, iYunivesithi yasePennsylvania, Philadelphia, PA, eU.SA

Ukuxhumana: UDkt P Kalivas, Iminyango ye-Neurosciences, i-Medical University yaseNingizimu Carolina, i-173 Ashley Ave, i-BSB 410, i-Charleston, i-SC 29425, e-USA. I-Tel: + 1 843 792 4400; Ifeksi: + 1 843 792 4423; Imeyili: [i-imeyili ivikelwe]

abstract

I-NEUROPLASTICITY NEMIGABA YOKUPHILA

Kulokhu kubuyekezwa, i-neuroplasticity izobe isetshenziswe ngezigaba ezimbili: okokuqala, izinguquko ezicishe zibe yinto esheshayo emsebenzini we-neuronal oqhubeka amahora kuze kube amasonto ekuzigwemeni kwezidakamizwa, futhi okwesibili, izinguquko ezinomsoco ezihlala njalo kusukela emasontweni kuya ekubeni nezinguquko ezihlala njalo. I-neuroplasticity yesikhashana ihambelana nezinguquko ezidingekile ezithintekayo ekuthuthukiseni ukuziphatha okusha, kanti ukuqina kwe-neuroplasticity okuzinzile kufana nolwazi oluzinzile olubuyiselwa ukuqondisa ukwenziwa kokuziphatha okufundiwe. Ngenxa yokulutha, lezi zigaba ngokuvamile zichazwa njengokuthuthukisa ukulutha (okungukuthi, ukufunda ukuba umlutha), kanye nesimo esiqinile esiphezulu sokukhulelwa ukubuyela emuva ngemuva kokuyeka ukuphuza izidakamizwa. Ukuthuthukiswa kwezidakamizwa kuvame ukutholakala ngokusetshenziswa komphakathi ngokuphindaphindiwe, futhi kuhilela izinguquko eziningi ezifushane esikhathini samakhemikhali ezobuchopho kanye ne-physiology esekelwe ikakhulukazi kwi-pharmacology ye-molecular of the drug ngokwayo (I-Nestler, i-2005). Ngaphakathi Umfanekiso 1a, lesi sigaba sibhekwa njengokusetshenziswa komphakathi. Isigaba sesibili senziwa ngokuhlambalaza izidakamizwa eziphindaphindiwe futhi sisekelwe ekuguquleni izinguquko emzimbeni we-synaptic wezicubungula zobuchopho ezilawula ukuqonda kwengqondo nokuziphendulela ngokomzwelo ekubambeni okubalulekile kwezemvelo. Lokhu kuboniswe ku Umfanekiso 1a njengezigaba ezimbili zokubuyela emuva. Isigaba sokuqala sokuphindaphindiwe sichazwa ngokuphindaphindiwe, okwesibili njengokuphindaphindiwe. Ukuphindaphinda okulawulwayo kubhekisela enkambisweni yokwenza izinqumo ezicacile lapho umlutha ekhetha ngokucophelela ukuphindaphinda. Isibonelo, umuntu angakhetha phakathi kokusiza ingane yakhe ngomsebenzi wesikole noma ukuphuza ingilazi yewayini. Kulesi sigaba, umlutha uvame ukukhetha ukukhetha umphakathi. Ekuphindaphindiwe, umlutha awukwenzi ukhetho olufanele. Isibonelo, nakuba ukusiza izingane zabo ngomsebenzi wesikole kungase kube yinto yokuhlela kusihlwa, ukuvezwa kwezimo ezihlukahlukene zemvelo noma ukucindezeleka ukuthi umuntu uhlangene nokusetshenziswa kwezidakamizwa okuphindaphindiwe kwenza kusebenze izidakamizwa, futhi isinqumo esaziwayo asikaze senziwe, lo muntu ivuselela ngokuzenzekelayo.

Ngokusobala, ukuphindaphinda ngokweqile kuyisigaba esibi kakhulu, njengoba sizobona, sinemigomo engase ibe neuropathological yokuthuthukisa ukungenelela kwe-pharmacotherapeutic. Njengoba kuboniswe ku Umfanekiso we-1, sizosikisela ekupheleni kwalokhu kubuyekezwa okususelwe ekutheni i-neuropathology yokuphindaphinda isimo se-neuroplasticity esinezinzile, indima eyinhloko ye-psychopharmacology ekuphatheni umlutha ukuthuthukisa izidakamizwa ezikhuthaza ukulawulwa ngokuphindaphindiwe. Ngamanye amazwi, phakathi kwama-pharmacotherapies abaluleke kunazo zonke kuzoba yizo ezenza izinqumo ezisebenzayo, zivumele umlutha wokukhetha ukungathathi umuthi. Ngokuphambene nalokho, ukuguqulwa kusuka ekuphindaphindiwe okusetshenziselwa ukusetshenziselwa ukusetshenziswa komphakathi noma ekuziqhenyeni kungcono ukuphathwa ngokuhlanganiswa kwemithi kanye nokungenelela kokuziphatha okuqinisa nokusekela izinqumo ezifanele (I-Centroni et al, 2005). Isibonelo, ukungenelela kokuziphatha kungabuka ezinkambeni zakudala ezifana nokuqeqeshwa kokuqedwa kanye nokwelashwa kokuziphatha kwengqondo, ukuthola umsebenzi ozinzile noma ukuhlangana nabathandekayo.

Izinyathelo Zokulutha Umlutha Nezinyathelo Zemivuzo Ejwayelekile Yokufunda

Umfanekiso 1b uzama ukudweba ukuqonda kwethu kwamanje kwememori yomvuzo wezinto eziphilayo kanye nezinqubo zokufunda ezigabeni zokulutha umlutha (Kelley, 2004; I-LaLumiere ne-Kalivas, i-2006). Ngakho-ke, ukutholakala kwezinkumbulo nokuthuthukisa izimpendulo zokuziphatha ezithinta izidingo ezibalulekile kubhekiselwa ekuthengeni futhi kufana nokusetshenziswa kwezidakamizwa zenhlalo. Umlingani ozobuyela emuva ekulawulweni kabusha ukubuyiswa kwezinkumbulo zokumemezela, okungukuthi, izinkumbulo ezichazwe futhi zisetshenziselwa ukwenza izinqumo ezifanele. Okokugcina, ukuphindaphinda ngokucindezela kungabhekwa njengokulingana nomkhuba noma izinkumbulo zenqubo. Ukubuyisa izinkumbulo zenqubo akuchazwiswanga, futhi kuqondisa ukukhishwa okungaqondakali kwezimo zokuziphatha ezihamba phambili. Lezi zimo ziziphatha kahle futhi ziqhubeka kahle kakhulu ngaphandle kokwenza izinqumo eziqhubekayo (isib. Ukugibela ibhayisikili, noma ukuvula umnyango wesiqandisisi uma ulambile).

Kuye kwaba nenqubekela phambili enkulu kule minyaka eyishumi edlule ekuqondeni kwethu izingxenye ezisemqoka zengqondo kanye nezindlela zezingcingo ezidlala indima ebalulekile ekukhunjweni okugqugquzelayo, futhi ukuziphatha okufundiwe kwenziwa. Kuyathakazelisa ukuthi okuningi kwalolu lwazi luye lwavela ngenqubo yokutholakala kwe-iterative phakathi kwabacwaningi abacwaninga izindlela zokufunda ezivuthiwe kanye nalabo abafundela izidakamizwa njengezifo ekufundeni okujwayelekile. Umfanekiso 1b sibonisa ukuthi i-circuits eyinhloko yobuchopho kanye ne-neurotransmitters ehambelanayo ibalazwe kanjani kwizigaba zokulutha umlutha. Ngakho-ke, ukufundela ukuba ngumlutha ngokusebenzisa ukusetshenziswa kwezidakamizwa kwezenhlalo kuhilela kakhulu amaseli e-dopamine endaweni ye-ventral tegmental (VTA) ekhulula i-dopamine endaweni ye-prefrontal cortex (PFC), i-amygdala ne-nucleus accumbens (NA) (IBerridge noRobinson, i-1998; Kelley, 2004; I-Schultz, i-2004; Ohlakaniphile, 2004; UJonathan noBonci, i-2005). Ukulandelana okunengqondo okusekelwa yizilwane zezilwane ukuthi ukufuna izidakamizwa kufundiswa kahle, ukuthembela ekuziphatheni kwe-glutamatergic kusuka ku-PFC kuya ku-NA kuvela (Pierce and Kalivas, 1997; Ikhadineli no-Everitt, i-2004; Wolf et al, 2004). Ngakho-ke, ukuphindaphinda okulawulwa ngokuqinile kuxhomeke ekutholeni izinkumbulo ezihlobene nezidakamizwa kanye nokuhlanganiswa kwalezi zinkumbulo ezibikezelayo ngokubaluleka kwe-glutamatergic kusuka ku-PFC kuya ku-NA. Ngesikhathi i-glutamate iqhubeka nokudlala indima enkulu ekuphoqeleleni ukuphindaphinda kulo modeli, isifunda se-glutamatergic sishintsha kusuka emaphandleni amaningi okumemezela, aphezulu okuphatha amakhemikhali abandakanya ukukhiqiza okuhlanganisa ama-classic-generate-thalamic motor generator pattern, kanye nezinkumbulo zenqubo ezenza ukubandakanyeka okungenasici ukuziphatha kahle okufundiwe (Barnes et al, 2005; Everitt noRobbins, i-2005).

Okusele kwalokhu kubuyekezwa kuhilela ukuhlakazeka okujulile kwe-neuroplasticity ehambisana nezigaba zokulutha umlutha, nokuhlanganiswa kwalokhu kwe-neuroplasticity kumathemba okuthuthukiswa kwezidakamizwa ezintsha zokuguqula izidakamizwa ekuphoqeleleni ukubuyela emuva.

I-ACQUISITION OF ADDICTION NGOKUPHAKATHI KWOKUPHATHWA KWEZINDLELA ZOMDLALO

Njengoba kuhlongozwe ku Umfanekiso we-1, ukutholakala kwezidakamizwa eziphindaphindiwe (ukusetshenziswa kwezidakamizwa) kuhilela ukukhululwa ngokuphindaphindiwe kwe-dopamine kusuka kwamaseli e-VTA kuya ku-PFC, isakhiwo esibulalayo (kuhlanganise ne-NA), ne-amygdala. Lesi sifunda siboniswe ku Umfanekiso 2a. I-Akin ngesisusa esiyingozi esiyingozi, zonke izidakamizwa eziluthayo zikhulisa i-dopamine ukukhululwa ngaphakathi kwalesi sigaba, noma yizinqubo ezihlukahlukene zesenzo se-molecule (I-Jay, i-2003; Kelley, 2004; I-Nestler, i-2005). Lokhu kubambisana phakathi kokwanda kwe-dopamine yokudlulisela kanye nokuziphatha kokufunda ukuthola umvuzo kuye kwaholela ekuqondeni ukuthi i-dopamine ukukhululwa kuyisenzakalo esiyinhloko sokusiza ukufunda. Ngakho-ke, izifundo eziningi zibonisa ukuthi ukuvimbela ukudlulisa i-dopamine kwehlisa ukugqugquzela nokufunda, kuyilapho ukugqugquzela i-dopamine kuvame ukukhuthaza ukutholakala kokuziphatha okufundile. Ukukhululwa kwe-dopamine kuye kwacatshangwa ukuba kuqhutshwe umcimbi ngobuqili, kudala umqondo wangaphakathi ukuthi lokhu kuyisenzakalo esibaluleke kakhulu esidinga ukuthuthukiswa kokuphendula okuziphatha (IBerridge noRobinson, i-1998). Ukuhlukaniswa okubalulekile kukhona phakathi kwe-dopamine ekhishwe izidakamizwa eziluthayo vs isisusa esiyingozi esithinta imvelo, futhi lezi zihlukaniso zicatshangwa ukuthi zibalulekile ekuthuthukiseni ukufuna izidakamizwa ezilawulwayo.

Umfanekiso 2b ibonisa ukuhlukaniswa okubili okukhulu phakathi kokukhululwa kwe-dopamine kulandela ukugqugquzelwa kwezinto eziphilayo ezishukumisayo vs okulandelayo ukuchayeka emthini wokulutha. Okokuqala, ukukhululwa kwe-dopamine ngezidakamizwa eziluthayo kunamapulitude amakhulu nobude obungaphezu kokufinyeleleka ngokusebenzisa izindlela zomzimba. Kulula nje, imithi yokwelapha izidakamizwa idonsa i-dopamine ukukhululwa ngaphandle kwemingcele yemvelo ngokunqoba izindlela ezijwayelekile ze-homeostatic zokulawula i-dopamine release. Isibonelo, ama-psychostimulants afana ne-amphetamine avimbela ukuqedwa kwe-dopamine kusuka ku-synapses, futhi kwezinye izimo kukhuthazwa i-presynaptic i-dopamine release (Seiden et al, 1993), kanti ezinye izidakamizwa ezifana ne-nicotine noma i-opioids zenza ukuguqulwa kwempendulo yamaseli e-dopamine, okwenza ukwanda komsebenzi we-cell dopamine. Ngakho-ke, i-nicotine ikhuthaza ukudluliselwa kwe-glutamate e-VTA, kuyilapho ama-opioid anciphisa ukukhishwa kwe-GABA okuvimbelayo kwi-dopamine neurons (UNader no-van der Kooy, i-1997; U-Laviolette no-van der Kooy, i-2004; Pierce noKumaresan, i-2006). Ingqikithi yesibili enkulu eboniswe kuyo Umfanekiso 2b phakathi kokukhululwa kwezidakamizwa ezenziwa yizidakamizwa futhi okukhiqizwa yizinto eziphilayo, ukuthi ukubekezelelana kuyaholela ekukhululweni kwe-dopamine nge-organic biological, kanti izidakamizwa ezidakamizwa zikhulula i-dopamine njalo lapho isidakamizwa sithathwa. Kubasebenzisi abangapheli, ukuguqulwa kwegazi kuyadingeka ngenxa yokubekezelelana, kodwa ngesilinganiso esanele, i-dopamine iyanda ngokwethembeka. Okungafani nalokhu kubandakanya amabhayingi ane-psychophetimulants-like-like psychostimulants, okungabangela ukuphulukiswa okwesikhashana kwe-dopamine nabasebenzisi abangapheliyo abaye babika ukungahloniphi okwedlulele noma ukubekezela emisebenzini esebenzayo yomuthi ngokusebenzisa izindlela ezingaziwa okwamanje (Martinez et al, 2007). Ngakho-ke, ngenxa yemivuzo yezinto eziphilayo, uma umuntu efunde ukuziphatha okuphumelelayo kakhulu ukuthola umvuzo, ukukhululwa kwe-dopamine ukusiza ukufunda okuqhubekayo akudingekile futhi akukwenzeka (I-Deutch no-Roth, i-1990; I-Schultz, i-2004). Noma kunjalo, kubalulekile ukuqaphela ukuthi i-dopamine iyaqhubeka ibonakalisa ukufika komvuzo ngesimiso esimisiwe (I-Schultz, i-1998). Isibonelo, ngenkathi ukulethwa kokudla kokudla ngokuphendulela kwesimiso esifanele kungase kungasetshenziselwa ukudlulisa i-dopamine kwisilwane esiqeqeshwe, ukubukeka kwesidakamizwa esasihlotshaniswa nokulethwa kokudla kuyokwandisa ukuqhuma kwesitokisi se-dopamine, cishe ukulungiselela isilwane ukuqala ukudla okuguquguqukayo -mpendulo yokusekela. Ngakho-ke, ngaphakathi kwemingcele yemvelo, i-dopamine isebenza imisebenzi emibili, (i-1) ukwenza lula ukuqala kokufunda ngokuphendula okuguquguqukayo ekubambeni okubalulekile, kanye ne-2 ukukhomba ukutholakala kolwazi oludingekayo ukuze kwenziwe ukuphendula okuziphatha okuguquguqukayo lapho izimo zemvelo zibikezela ukuthi ukudla kuseduze. Ngokuphambene nalokho, konke ukuphathwa komuthi wokulutha izidakamizwa kuhlotshaniswa nokukhululwa okukhulu kwe-dopamine engalindelwa ukukhuthaza ukufunda okusha (okungukuthi, izinhlangano ezintsha phakathi kwedakamizwa nemvelo) noma ukuqinisa ukuqala kokufunda, kanye nokukhomba umlutha yenza ukuziphatha okufuna izidakamizwa (okusho ukubuyela emuva). Ezilwaneni zezilwane, izikhala zingase zithuthukise impendulo ezithuthumayo ngaleyo ndlela zikhiqize impendulo ehloniphekile emkhakheni owunikiwe we-stimulant. Ngale ndlela, ukusetshenziswa kwezidakamizwa eziphindaphindiwe ngokuphindaphindiwe kukhuthaza ubudlelwane obandayo phakathi kwezidakamizwa nezenzakalo zokuphila, kuyilapho okwenziwe yizinto eziphilayo ezibaluleke kakhulu. Lokhu kungabika ukuthi kungani ukusetshenziswa okuphindaphindiwe kwesidakamizwa kubangela ukuziphatha okufuna izidakamizwa ukuba kuhambisane nazo zonke izici zokuphila kwansuku zonke njengoba umuntu eba ngaphansi kakhulu.

Njengoba kuboniswe ngenhla, izidakamizwa ezihlukene zokuhlukunyezwa zikhulula i-dopamine ngezinqubo ezahlukene ze-molecular. Enye yezenzo ze-ethanol kusebenze uhlelo lwe-opioid olungapheli ukuze uma i-opiate receptors ivinjelwe umphikisi onjengo-naltrexone, ukwanda kwe-dopamine okubangelwa utshwala akukwenzeka futhi umvuzo uvinjelwe (UGonzales no-Weiss, i-1998). Ngakho-ke, ukubonakaliswa kokuziphatha kwepulasitiki emilonyeni yabantu kungase kuhluke ngokwemithi. Ku-heroin umlutha, isibonelo, ukusetshenziselwa izidakamizwa eziphindaphindiwe kubangela ukubekezelelana okuphawulekayo ngezikhala ezifakiwe ezikhiqiza izimpendulo eziphambene nezidakamizwa noma ukuhoxiswa (I-O'Brien, 1975; O'Brien et al, 1977). Izidakamizwa ezidakamizwa ze-cocaine ziveza ukukhanga kwe-cocaine nokusebenza komzimba (Izingane et al, 1999) ngokukhululwa kwe-dopamine esimisiwe (I-Volkow et al, 2006). Ngokuvamile, emilonyeni yabantu, ukubekezelelana yi-neuroadaptation okuvame ukugcinwa ngisho nasezinhlakalweni ze-cocaine (O'Brien et al, 2006). Lokhu kubangela ukukhula okwenyuka kwezidakamizwa ezizimele ukufeza imiphumela yezidakamizwa ezitholakale ekuqaleni.

I-Dopamine-I-Neuroplasticity Ebonakalayo Incike Ekuthuthukiseni Ukuvuselelwa Okulawulwa Nokucindezela

I-D1 ne-delta-FosB yokufaka uphawu lokusakaza

Ukukhululwa kwe-dopamine ngezidakamizwa ezibalulekile noma izidakamizwa eziluthayo kuveza izinguquko endleleni ama-neurons afaka ngayo i-neurotransmission yokuzijabulisa nokuvimbela. Imiphumela ye-dopamine receptor activation iyinkimbinkimbi futhi ihlukaniswa phakathi kokusebenza kwe-D1-like vs I-D2-like receptors kuye ngokuthi ubukhona bezindawo zangaphambi no-postsynaptic endaweni yezifunda zendawo yenuclei enikeziwe. Kunezibuyekezo eziningi ezinhle kakhulu ezichazwa isimo samanje samanje mayelana nokubonakaliswa kwe-dopamine njengoba kuphathelene nokulutha nokulondeka kokufunda (I-Berke no-Hyman, i-2000; Nicola et al, 2000; U-El-Ghundi, i-2007). Ngezinhloso zethu, Umfanekiso we-3 ibonisa ezinye izenzakalo eziyinhloko eziqondiswe ngokuqondile ngukusebenza komsebenzi we-receptor we-D1 okucatshangwa ukuthi iyimfuneko evelele yokuthuthukisa izinguquko eziqhubekayo emzimbeni we-neuronal owenza ukusungulwa kokuziphatha okuguquguqukayo kwimicimbi efanelekile, kanye nokuziphatha okungafuneki kwezidakamizwa. Okubaluleke kakhulu, lokhu kuphazamiseka kokufaka uphawu kuhilela ushintsho ekubhalisweni kwegazi kanye nokulungiswa kwe-chromatin okucatshangelwa ukuba kuguquke ekusetshenzisweni kwezenhlalo kuze kube nokuphindaphindiwe okulawulwayo nokuphoqelelwa. Ngakho-ke, ukukhuthazwa kwama-receptors e-D1 ku-striatum ne-cortex kwandisa i -AMP, i-protein kinase (i-PKA) encike enkampanini, kanye namaprotheni ahlanganisa izimpendulo ze -AMP (i-CREB) ekhuthaza ukubhalwa kwezakhi eziningi zezakhi zofuzo ezibandakanya ukulutha, njenge-cfos, deltaFosB, Homer, ne-preprodynorphin (U-Hurd no-Herkenham, i-1993; Nestler et al, 2001; UMcClung noNestler, i-2003; I-Benavides ne-Bibb, i-2004). Okubaluleke kakhulu, ukuphakama kwe-CREB ku-NA futhi, kancane kancane, i-VTA iye yaxhunyaniswa nokuqiniswa kwezidakamizwa ezincishisiwe (I-Carlezon et al, 1998; I-Nestler, i-2005). Nakuba akuzona zonke izidakamizwa eziluthayo zibonakala zandisa i-CREB ku-accumbens (Pandey et al, 2004), ukuphazamiseka okukhulu kwe-CREB kule-accumbens kuvimbela imiphumela emihle ye-psychostimulants, i-opioids, nemivuzo yezinto eziphilayo, kanti ukucindezeleka okukhulu kwe-CREB mutant okukhuthaza kakhulu ukukhuthaza umuthi (I-Barrot et al, 2002; Lu et al, 2003; UMcClung noNestler, i-2003). Ngokuthakazelisayo, ezinye izifundo zibonisa ukuthi i-CREB iyadingeka ngemiphumela emihle yezidakamizwa eziluthayo nokuqiniswa kwezinto eziphilayo (Jin et al, 2005; Walters et al, 2005; Choi et al, 2006), kubonisa ukuthi nakuba ukulawulwa okunzima kwe-CREB kuyadingeka ekuziphatheni okugqugquzelayo, ukuguqulwa okuphindaphindiwe kwe-CREB kudala ukubekezelelana emiphakathini yokuqinisa imizamo yokuvuza. Ezinye izakhi zofuzo ezilawulwa yi-CREB, njenge-preprodynorphin, i-NAC-1, ne-Homer, ngokungangabazeki zenza iqhaza le-CREB ekwandiseni umphumela wokunciphisa inani lomvuzo wezidakamizwa. Isibonelo, i-dynorphin eyanda inqabela umsebenzi wamaseli e-dopamine nokukhululwa kwe-presynaptic dopamine (I-Carlezon et al, 1998; Chefer et al, 2000; Hyman et al, 2006), futhi ukucindezeleka ngokweqile kwe-NAC-1 noma i-Homer1c ekuhlanganyeleni kuvimbela ukuthuthukiswa kwezimo zokuziphatha ezithintekayo nge-cocaine ephindaphindiwe (Mackler et al, 2000; I-Szumlinski et al, 2006). Okubalulekile, amabili kulawa maprotheni, preprodynorphin kanye ne-NAC-1 abonisa ukuguqulwa okuqhubekayo ngokuzila, okubonisa ukuvinjelwa okuhlala isikhathi eside komvuzo wezidakamizwa (U-Hurd no-Herkenham, i-1993; Cha et al, 1997). Ngeshwa, njengoba kucatshangwe ngokuningiliziwe ngezansi, ukuhlaziywa kwemivuzo yezidakamizwa kungase kwandise nemiphumela emibi.

Kulezi zakhi zofuzo ezilawulwa yi-CREB, ukwanda komlawuli we-transcriptional, i-deltaFosB, iqinisekisiwe ngokukhethekile (Nestler et al, 2001). Ukwanda kwamakhomishri amaningi wokubhala kanye nama-genes asheshe okuqala ngezidakamizwa eziluthayo noma isisusa sokugqugquzela izinto eziphilayo, njenge-cfos, i-Arc, i-Homer1a, ne-narp, iyancipha ngemva kokuvezwa okuphindaphindiwe. Ngokuphambene, i-deltaFosB iqoqa emasimini e-dopamine-terminal e-cortex nase-striatum (Nestler et al, 2001; UMcClung noNestler, i-2003). Lokhu kuqoqa kwenzeka ekuphenduleni ukuphathwa okungapheli kwazo zonke izidakamizwa zokuhlukunyezwa ezivivinywa kuze kube yimanje, kanye nokuphendula ngokuphindaphindiwe kokugqugquzelwa kwezinto eziphilayo. Ngakho-ke, ukuqoqwa kwe-deltaFosB cishe kubalulekile ekufundeni nasekuthuthukiseni ukuziphatha okugqugquzelayo ngokujwayelekile. Endabeni yezidakamizwa eziluthayo, ukuphazanyiswa kwezemithi noma izakhi zofuzo kwalokhu kuvimbela ukuthuthukiswa kwezinhlobo ezithile zokuphuza izidakamizwa ezihambisana nokulutha umlutha, ezifana nezenzo zokuziphatha ezithintekayo (Nestler et al, 2001; UMcClung noNestler, i-2003). I-akin kumagciwane okulawulwa yi-CREB, ezinye zezinhlobo zomzimba ezilawulwe ngokuqondile yi-DeltaFosB zingase zihlawuliswe futhi zikwazi ukukhawulela ukuqiniswa kwezidakamizwa, futhi mhlawumbe ukufuna izidakamizwa (I-Nestler, i-2005). Ngakho-ke, ukungeniswa kwe-Cdk5 kuphazamisa i-phosphatase elawulwa yi-Dopamase DARPP-32, ngaleyo ndlela ivimbele iphosphorylation yayo futhi isebenze yi-PKA (I-Benavides ne-Bibb, i-2004). Kodwa-ke, ukungeniswa kwamanye amagciwane nge-deltaFosB cishe kukhuthaza umvuzo wezidakamizwa futhi iningi lezifundo libonisa ukuthi ukucindezeleka kwe-deltaFosB kwandisa umvuzo wezidakamizwa (Kelz et al, 1999; I-Colby et al, 2003; Zachariou et al, 2006). Izibonelo ze-deltaFosB umthethonqubo wegenesheni ozogqugquzela umvuzo wezidakamizwa kufaka ukufakwa kweGluR2 kugobolondo le-accumbens (Todtenkopf et al, 2006), nokususwa kwezwi le-dynorphin (Zachariou et al, 2006). Okubaluleke kakhulu, ukungeniswa kwe-deltaFosB kanye nemikhiqizo yegeni elawulayo kubonakala sengathi ihamba kancane futhi ijwayelekile ngesikhathi sokuziyeka. Ngakho-ke, nakuba kubalulekile ekuthengeni izidakamizwa zokuziphatha, i-deltaFosB ngokwalo ayiyona isibonelo sokungaxhumani kwezidakamizwa ezizinzile ngokuqondile ekuxhumaniseni ukukhishwa kwe-regulated or compulsive replapse. Ngempela, kuyinto engapheliyo ye-deltaFosB inkulumo eyenza ukuthi ibe ngumuntu omele ukwelapha amaprotheni aqondisa ukuguqulwa kokusetshenziswa komphakathi ukuze aphinde asebenzise ukusetshenziswa kwezidakamizwa (Nestler et al, 2001). Ngakho-ke, kuyilapho i-deltaFosB ilawula i-gene expression ngokwayo, i-neuroplasticity elawulwa yizi zakhi zingase zizinze kakhulu ngesikhathi sokuzilahla. Isibonelo, ukwenyuka okuqhubekayo ku-dendritic spine density kuye kwabikwa ekuqoqeni amangqamuzana e-spiny ngenkathi evinjelwe kakhulu ekulawulweni okungapheli kwengqondo ye-psychostimulant (URobinson noKolb, 2004), futhi lokhu kukhuphuka kuhlanganiselwe nge-deltaFosB ukugqugquzela kwe-Cdk5 (Norrholm et al, 2003).

Ngokufingqiwe, ukuvuselelwa kwe-D1, CREB, ne-deltaFosB ukufaka uphawu lokusakazwa kuyadingeka ngokucacile ukushayela i-neuroplasticity engaphansi kokubili kokufunda okugqugquzelayo nokuthuthukiswa kwezidakamizwa (I-Nestler, i-2001; Hyman et al, 2006). Kodwa-ke, izindima zokuguquguquka kwezidakamizwa kulokhu kuqhutshwa ekusetshenzisweni kwezidakamizwa noma ekukhuseleni ukubuyela emuva kuyinkimbinkimbi. Isibonelo, i-neuroplasticity yesikhashana futhi ehlala njalo eyenziwe ngokusebenza kwe-CREB ivame ukuboniswa ukuthi isebenze umsebenzi wokunciphisa ukunciphisa i-dopamine noma i-glutamate yokudlulisela ku-accumbens, kanti i-deltaFosB ekhulayo ilawula ukukhuluma ngendlela yezakhi zofuzo ngendlela ephindaphindiwe (ukwanda kwe-Cdk5 ) nokusekela umvuzo wezidakamizwa (ukwanda kwe-GluR2; kunciphise i-dynorphin). Lezi zindlela eziguquguqukayo ngokuvamile zizonciphisa inani elilinganiselwe lokugqugquzela izidakamizwa ezishukumisayo, futhi lokhu kungabangela ngokungaqondile ukubhekana nokulimala okuqhubekayo ukuphindela ekufuneni izidakamizwa. Ngakho-ke, ngokusebenza ngendlela evumelanayo yokudalula yonke imivuzo, imiphumela eqhubekayo yamangqamuzana yesikhashana esingaba khona se-D1-CREB yokusabalalisa (isib., Ukwanda kwe-dynorphin, i-NAC1, ne-Homer1c) kukhuthaza ukufuna izidakamizwa ukuze uthole imivuzo yezinto eziphilayo.

I-Brain-Effected Neurotrophic Factor Ukulawulwa Kwezingqalasizinda Ze-Synaptic ku-Addiction

Olunye ushintsho oluthile lwe-dopamine emaprotheni synthesis obonakala ngokubaluleke kakhulu ekusungulweni kwe-neuroplasticity ye-physiological kanye ne-drug-induced neuroplasticity yi-neurotrophic factor (i-BDNF) etholakala ebuchosheni. I-BDNF iseklasini lama-genes okuqala okulawulwa kwengqondo e-psychostimulant, okufaka i-Arc, c-fos, ne-zif / 268 (I-Dunais ne-McGinty, i-1994; I-Moratalla et al, 1996). Kodwa-ke, i-BDNF ne-Arc zibonakala ziyingqayizivele ngoba i-mRNA yabo ihanjiswe kakhulu futhi ihanjiswe kuma-dendrites ngomsebenzi weselula (Umphathi kanye noWorley, i-2001). Ngentshisekelo ethile, futhi ngokusobala ehluke kwizakhi zofuzo ezilawulwa yi-deltaFosB, kanye nezinye izakhi ezisekelwe emisebenzini eziphethwe yi-psychostimulants, izinguquko eziqhubekayo ku-BDNF ziqoqa ngezikhathi ezengeziwe zokuziyeka (Grimm et al, 2003; Lu et al, I-2004a; Filip et al, 2006). Futhi, ukukhuthaza ama-receptors e-BDNF ku-amygdala, i-NA, noma i-VTA ikhuthaza (Ama-Horger et al, 1999; Lu et al, I-2004b; Graham et al, 2007; Pu et al, 2006), kanti i-microinjection ye-BDNF ku-PFC inqabela ukufuna izidakamizwa (Berglind et al, 2007), okubonisa ukuthi ngokuvumelana nokusebenza kwe-deltaFosB, i-BDNF isebenza indima ebalulekile yomzimba ekusekeleni i-neuroplasticity esetshenziselwa izidakamizwa eziluthayo ukuze ekugcineni isungulwe kabusha futhi iphoqelelwe ukuphindaphinda.

I-BDNF iyaziwa ngokugqugquzela amafomu we-plastic syntaptic plastic excitatory, njenge-early-and-phase-term potential potentiation (LTP), futhi iphinde ikhuthaze ukwakheka kwemigodi ye-dendritic (I-Bramham noMessaoudi, i-2005). Izindlela ezisekelwe ngokujwayelekile ezithuthukisweni zokudlulisa ama-excitatory zihlukahlukene, futhi zibandakanya ukwandisa ukukhishwa kwe-vesiple ye-synagtic, ukukhululwa kwe-glutamate ekhulayo, nokukhuthaza ukufaka uphawu kwe-NMDA ngemuva kokuhamba kwesikhathi. Njengoba kunikezwe lezi zindlela zamaselula, akumangazi ukuthi i-BDNF iye yafakwa ekutheni i-neuroplasticity ehambisana nezinqubo ezijwayelekile zokufunda nezinkumbulo. Ngokuphathelene nokulutha kwezidakamizwa, i-BDNF ixhumanisa ukukhishwa okuqhubekayo kokudluliselwa kwe-excitatory kumaseli e-dopamine ku-VTA okukhulunywe ngokuphindaphindiwe kokuphathwa kwe-cocaine (Pu et al, 2006), kanye nokukhululwa kwe-orexin (Borgland et al, 2006), ingafaka isandla ochungechungeni oluthokozelisayo lokubheka kwe-LTP enezinkinga ezitholakala kumaseli e-Vop dopamine ngemva kokuphathwa okukodwa kwezidakamizwa eziluthayo (ukubuyekezwa kwalokhu okutholakele nokuthi bangabamba kanjani ekufakweni kwezinhlobo zokuhlala ezingapheliyo ezithintekayo, bheka UJonathan noBonci, i-2005). Okubaluleke kakhulu, izinga le-BDNF ku-VTA, kanye ne-NA ne-amygdala, landa kancane ngesikhathi sokuzigcina (Grimm et al, 2003). Lokhu kwanda okuqhubekayo kuye kwacutshungulwa ukuba kukhuliswe ukwanda okuqhubekayo kokufuna izidakamizwa okwenzeka ngenkathi kuhoxiswa kwe-cocaine, okungenzeka kwenzeke, ngokwengxenye, ngokukhulisa i-dopamine D3 receptor expression (Guillin et al, 2001; Le Foll et al, 2005). Iqiniso lokuthi i-BDNF iphakanyiswe ukuphathwa kabi kwezidakamizwa futhi ihlala iphakanyiswe ezindaweni ezithile zobuchopho ngemva kokuyeka ukuyeka ukuphawula lokhu kudlalwa njengephrothethi ye-neuroplasticity engase ibe nomthelela ekutholeni ukufunwa kwezidakamizwa, nokukhishwa kwezidakamizwa emva kwandiswa izikhathi zokuziyeka.

Ukwelashwa Kwe-Neuroplasticity Ehambisana Ne-Molecular Site yeDrug Action

Ezinye izinhlobo eziguquguqukayo zesikhumba esithathwe yizidakamizwa eziluthayo nazo zichazwe. Noma kunjalo, ngokungafani nomgwaqo we-D1-CREB-deltaFosB, lezi zenzakalo zokubonisa ziqondene ngqo nezidakamizwa ngabanye. Isibonelo, izinguquko ezithuthumayo ze-dopamine zihlotshaniswa nama-psychostimulants afana ne-amphetamine (Daws et al, 2002), Izinguquko zeGABA-A receptor ziye zaqaphela ngemuva kokuphuza utshwala obungapheli (Charlton et al, 1997), futhi i-nicotine igxeka ama-receptors we-nicotinic (I-Mansvelder no-McGehee, i-2000). Lezi zinguquko ezithize izidakamizwa zenza ama-nuances abalulekile ekudambiseni umuthi ngamunye, ikakhulukazi, ukuhoxiswa kwezidakamizwa kunezici eziyingqayizivele eklasini ngalinye lomuthi. Futhi, izinguquko ezithile eziphathelene nezidakamizwa zithonya abajikelezayo ababucayi ngomvuzo ovamile kanye nokufunda izidakamizwa. Ngokuvamile, imiphumela eqondene nezidakamizwa ayikho ngaphezu kokubuyekezwa okwamanje okugxile kulokho okubonakala sengathi yizici ezivamile zepulastiki yobuchopho ezabelwana yiziningi noma zonke izidakamizwa zokuhlukumeza kanye nesimiso esijwayelekile, nazo zabiwe nesisusa sokugqugquzela eziphilayo.

Isifingqo se-Neuroplasticity esekelwe ukutholakala kokusetshenziswa kwezidakamizwa kanye nokuguqulwa ekusetshenzisweni kwezidakamizwa kwezenhlalakahle ukuze kulawulwe futhi kuphoqeleke ukuphindaphinda

Umfanekiso we-4 ibonisa izigaba ezahlukene zesimo se-neuroplasticity ehlobene nokusetshenziswa okuphindaphindiwe kwezidakamizwa eziluthayo nokuzigwema okulandelayo. Kubalulekile ukuqaphela ukuthi ukuhlolwa okwenziwe ngokuphathwa okuphindaphindiwe kwe-psychostimulant, futhi ngezinga elingaphansi kwe-opioids, kunikeza iningi lwazi olusekelwe emaphethini abonisiwe Umfanekiso 4a. Kunezigaba ezintathu ezijwayelekile ezihlongozwayo. Isigaba sokuqala sihlanganisa ukungeniswa kwezakhi zofuzo ezisekelwe emisebenzini ngokuphathwa okunamandla, nokuthuthukiswa kokubekezela kulokhu kukhishwa ngokulandela ukuphathwa okuphindaphindiwe. Amaphrotheni kulesi sigaba afaka c-fos, i-Arc, i-Homer1a, i-narp, ne-zif / i-268. Okubaluleke kakhulu, emva kwesikhathi sokuzilahla, ukubekezelelana kwezimali nokuxhaswa futhi lezi zinhlelo zamaprotheni ziphinde ziphinde zithathwe ukwelashwa okunamandla kwengqondo, ngokuvamile emazingeni noma ngamaphethini okukhuluma ahluke kulokho okubangelwa ukutholakala kwezidakamizwa zokuqala. Lezi zinhlelo zamaprotheni zicatshangwa ukuthi zibalulekile ekuqaliseni i-neuroplasticity edingekayo ukuze zithole ukuziphatha okusha, kanye nokuvuselela ukuziphatha okufundiwe, kuhlanganise nokufuna izidakamizwa.

Isigaba sesibili sibonakala ngamaprotheni abamazwi abo athula kancane kancane noma anciphisa ngokuchayeka kwezidakamizwa eziphindaphindiwe, futhi abhekana nezikhathi ezihlukahlukene zokuziyeka. Ama-subcategories amabili aboniswa Umfanekiso 4b. Owokuqala ufaka phakathi ushintsho lwamaprotheni oluhlala isikhathi eside amahora amaningi kuye ekuzileni futhi luhambisana noshintsho olusondelene kakhulu nesiza samangqamuzana omuthi. Esinye isigaba esincane sifanekiselwa ukuqoqwa kwe-deltaFosB, lapho amazinga aphakeme angabekezelela izinsuku noma amasonto. Lesi sigaba sokugcina sicatshangwa ukuthi sinomthelela ekutholakaleni kokufunda okugqugquzelwayo, kepha okubalulekile, ekuphenduleni ukusetshenziswa kwezidakamizwa okuphindaphindwayo, i-deltaFosB icatshangelwe ukuthi ilamule inguquko yokusetshenziswa kwezidakamizwa zenhlalo ekusetshenzisweni kokubuyela emuva (I-Nestler, i-2005).

Isigaba sesithathu sinamaprotheni aphakanyisiwe noma anciphise emva kokuyeka ukuhlala isikhathi eside. Ama-subcategories amabili abhekwa ngawo Umfanekiso 4c. Owokuqala uboniswa yi-BDNF eqoqa ezindaweni ezithile zobuchopho emva kokuphatha okuphindaphindiwe kwe-psychostimulant futhi lokhu kuqoqa kuqhubeka nokukhula kwesikhathi sokuziyeka (Grimm et al, 2003; Lu et al, I-2004a). Isigaba esilandelayo sizocatshangelwa ngokuningiliziwe ngezansi, futhi iqukethe amaprotheni angashintshi ngokuphawulekayo ngesikhathi sokuphathwa kwezidakamizwa, kodwa aphakanyisiwe noma anciphise ngesikhathi sokuzilahla. Kucatshangwa ukuthi lesi sigaba sinezenzakalo ze-neuroplastiki okungenzeka ukuthi zibhekene nesimo sokungakwazi ukubuyela emuva. Iningi lalezi zinguquko ezihlala njalo azibonakalwanga ukuthi zenzeke ekuphenduleni okuphindaphindiwe ezenzakalweni zokugqugquzela eziphilayo futhi zingase zibe yizinto ezibonakalayo ze-neuropathology of addiction.

UKUPHILA NEUROPLASTICITY ONGAKUVUMELELA UKUTHUTHUKISWA KWEZINDLELA

Njengoba kuchazwe ngenhla, uma ukuziphatha okuklanyelwe ukuthola umvuzo noma ukugwema imiphumela emibi kuye kwafundwa, indima ye-dopamine ishintshe kusuka ekugqugquzelweni kokufunda okusha kuya kokunye okuvumela ukusetshenziswa kolwazi olufundiwe ukwenza ngokuphumelelayo impendulo yokuziphatha eguquguqukayo (I-Schultz, i-2004). Ngokuphambene nalokho, ukudluliselwa kwe-glutamate kusuka ku-cortex ne-allocortex (isb., I-amygdala ne-hippocampus) esiteshini sokuhamba ngezimoto (kuhlanganise ne-NA) kubonakala njengokubaluleke kakhulu ekusebenzeni ukuziphatha okufundiwe (Kalivas noVolkow, i-2005). Ngaphezu kwalokho, kucatshangwa ukuthi njengoba ukuziphatha kuqhutshwa kaningi, indima ye-glutamate ye-corticofugal ephuma ku-PFC ne-amygdala ibe yi-NA, ibonakala ingabaluleki kakhulu ekuthatheni i-glutamate ephuma ezindaweni ezihamba phambili ze-cortical kuya kwi-dorsal striatum (Everitt noRobbins, i-2005). Ngale ndlela, ukuziphatha kuvela ekubeni yinkqubo yokumemezela okubandakanya imisebenzi ye-prefrontal executive ibe yindlela yokuziphatha evamile esebenzisa insimbi yokusebenza yememori (Barnes et al, 2005). Ngokwemvelo, lokhu kuguquka kusuka ekumemezelweni kwe-declarative kuya ekuziphatheni okuzenzakalelayo kungashintsha ngokuvumela ukuziphatha okufundiwe kahle ukuqhubeka kahle ngaphandle kokubandakanyeka okuzimele, futhi uma ukuguqulwa okubaluleke kakhulu noma isimo sishintsha, imisebenzi ephezulu igxila ekuphazamiseni umkhuba njengengxenye yokuthuthukisa ukuziphatha okusha ezifanele ukuguqulwa kwemvelo. Endabeni yokufuna izidakamizwa, lolu shintsho olusuka ku-prefrontal circuitry ukujwayela ukuhamba ngezimoto olujikelezayo lubonisa ukulahlekelwa ukulawulwa nokuphindaphinda. Okubalulekile ukukhubazeka kokulutha umlutha, amandla okuba yi-prefrontal, ama-declarative circuitry angenelela futhi aphazamise umkhuba wokufuna izidakamizwa awunzima, okwenza kube nzima ngesinqumo esiyinhloko sokungena ekudleni izidakamizwa (Everitt noRobbins, i-2005; Kalivas noVolkow, i-2005). Ukuqonda i-neurophysiology eqinisa lolu shintsho olubi lwe-maladaptive kusuka ekulawulweni oludinga ukufuna izidakamizwa, futhi ukukhubazeka ekuvuseleleni ukulawula izidakamizwa ekudleni izidakamizwa kudinga ukuqonda ukuhlala kwamaselula okuqhubekayo okusebenza ngokuphindaphindiwe kwezidakamizwa. Ngokuyinhloko, lokhu kuhilela ukukhomba izinguquko ekudluliseni kwe-glutamate kanye nokuvela kobuzenzisi obuvumela ukuthi izidakamizwa ziqhubeke ngaphandle kokungenelela okuqaphelayo (UJentsch no-Taylor, i-1999; I-Goldstein noVolkow, i-2002).

Ukukhuthazela Neuroplasticity ku-Cortical Glutamate Circuitry: I-Human Neuro ukucabanga

Iningi le-neuroplasticity e-circuits cortical liye laboniswa ngqo kumilutha ngokusebenzisa izindlela ezihlukahlukene ze-neuroimaging. Ngakho-ke, kuncishiswa ngokujwayelekile emigqeni ye-prefrontal cortical ye-metabolism yamaselula kanye nokugeleza kwegazi kumuntu onomlutha wezidakamizwa ezihlukahlukene, kusukela ku-cocaine kuya ku-opioid utshwala (I-Goldstein noVolkow, i-2002). Lokhu kufaka phakathi izifunda ezifana ne-cortex yangaphakathi ye-cingulate ne-ventral. Unikezwe ubudlelwane phakathi kokusebenza kwe-anterior cingulate nokubandakanya iziphathamandla ezithintekayo eziphilayo (Ukukhokha et al, 2002), futhi phakathi kokusebenza kwe-cortex ye-orbital ye-ventral kanye nokukwazi ukushintsha ukuziphatha okufundile ekuziphatheni okusha okuguquguqukayo (Kolb et al, 2004), lobu buzenzisi bubekwe uphawu oluqinile lwekhono lokunciphisa ukufuna izidakamizwa. Ukunciphisa i-coral neurons yangaphambili kubuye kwabikwa ezilutha zezidakamizwa ze-cocaine (Franklin et al, 2002), kodwa awaziwa ukuthi lezi zibonakaliso ezisebenzayo nezibonakaliso zokungazenzisi zaziyizici ezisengozini ngaphambi kokuba kusetshenziswe i-cocaine noma imiphumela yokusetshenziswa okungapheli okuvuselelayo. Ngokuthakazelisayo, uma kutholakale ukucubungula ngaphambili okuhlotshaniswa nokusetshenziswa kwezidakamizwa okuvimbela isifiso sezidakamizwa, kusebenze ukukhishwa kwamandla ku-PFC, kufaka phakathi ama-cortices anterior cingulate kanye ventral orbital (I-Goldstein noVolkow, i-2002; Wilson et al, 2004; Kalivas noVolkow, i-2005). Ezingxenyeni eziningi, ukunyuka komsebenzi ku-PFC kuye kwahambisana kahle nokufisa kwesifiso sokwenza umuthi. Ngakho-ke, umehluko emisebenzini ye-prefrontal emkhatsini wesisekelo kanye namazinga avuselelwe izidakamizwa zezidakamizwa kunkulu kunalokho okwenzeka kusihloko sokulawula ngokuphendula izikhala ezihambisana nomvuzo wezinto eziphilayo, njengento ebonakalayo yokubukela ngokocansi. Ngaphezu kwalokho, okuhambisana nokulutha umlutha okuvezwe yingxenye ngokuphendula okunciphisisiwe emivuzo yezinto eziphilayo, lapho izidakamizwa ze-cocaine zinikezwe isisusa socansi, ukusebenza kwe-prefrontal kwakunzima kakhulu uma kuqhathaniswa nezilawuli (Igalari et al, 2000). Imizamo yokulwa nesifiso ekuphenduleni i-cocaine cues nayo ibike ukwandisa umsebenzi we-lobe wangaphambili (Izingane et al, 2007), ephakamisa ukuthi umsebenzi ongaphelele ongaphambili ungabandakanyeka ekuhlulekeni ukulwa nokubuyela emuva.

Olunye olumangalisa ukufundwa kwezibalo ezibonisa ukunciphisa impendulo kumvuzo wezinto eziphilayo eziluthayo kuwukunciphisa ukusebenza kwe-dopamine receptor ekuphenduleni ukulinganisa okuphansi kwama-psychostimulants (I-Volkow et al, 2004, 2005). Ngakho-ke, ukukhululwa kwe-dopamine eyenziwe nge-methylphenidate ngaphakathi kwe-striatum kuphelelwe yisikhathi ku-cocaine izidakamizwa ezihlobene nezihloko zokulawula. Kanti futhi, kungakhathaliseki ukuthi izidakamizwa ezixhashazwayo zihlukunyezwa kangakanani, izigqila zibonisa amazinga amancane we-D2 receptors ku-striatum (I-Volkow et al, 2004). Kuzo zonke izidakamizwa ze-D2 ezincishisiwe ezibonisa ukungaboni kahle kokudluliselwa kwe-dopamine, akumangazi ukuthi izidakamizwa zibika ukunciphisa phezulu noma ukuzijabulisa ekuphenduleni i-methylphenidate ezihlobene nezihloko zokulawula. Ngokuphambene nalokho, kanti i-methylphenidate yenza abantu babe nezifiso eziqinile eziluthayo, azikho izifiso eziqhathaniswa nezihloko. Noma kunjalo, izihloko zokulawula ezingasebenzisi izidakamizwa ziyahlukahluka ngokusho kwe-D2 ye-receptor. Labo abanesisindo se-D2 esincane babika imiphumela emihle, ejabulisayo esuka ku-methylphenidate, kuyilapho labo abanezinga eliphezulu le-D2 bengathandi imiphumela ye-stimulant (I-Volkow et al, 2002). Lokhu okutholayo ngezifundo zabantu ezijwayelekile kufaniswa nokuthola okufanayo ezinkambeni ezingezona zomuntu (I-Nader ne-Czoty, i-2005).

Ukuhlanganiswa ndawonye, ​​lezi zifundo ze-neuroimaging zikhomba ukuguquka okuqhubekayo emasiteshini ase-mesocorticolimbic. Ngakho-ke, esimweni esisezingeni eliyisisekelo, umlutha uqobo awukhohlisi ekuthandeleni izinto eziphilayo, njengoba kuboniswe yizinhlangothi ezimbili, (1) ukunciphisa umsebenzi ku-PFC, futhi (2) kunciphise amazinga okuhlukumeza ama-Dopamine D2 receptors. Mhlawumbe okubaluleke ngokwengeziwe ekukhulekeleni kokulutha, umthamo wokwenza izinto eziphilayo ezifanelekile ukuze kusebenze i-PFC kuphelelwe amandla. Ngokufanayo, ukukhululwa kwe-dopamine kwe-pharmacologically ku-pharmacologist kanye ne-subjective sensation ye-high noma injabulo ayizinhle. Kodwa-ke, ukuchithwa okuhlobene nezidakamizwa kubonakala kusebenze i-PFC ngokulutha ngendlela ehambisana nesifiso semithi. Ukuhlanganiswa ndawonye, ​​le datha yedatha yokuhlinzeka nge-neurocircuitry isetshenziselwa izici eziyinhloko zokulutha; ukuphendula ngokweqile, okungalawuliwe kwezidakamizwa, nokuphendula okungalungile noma okungafaneleki kwe-stimuli ebalulekile.

Ukukhuthazelela I-Neuroplasticity kwi-Cortical Glutamate Circuitry: Izilwane zezilwane

Ukuze uqonde ukuthi isisombululo sisebenza kanjani nokuthi lezi zinguquko zihamba kanjani futhi zithemba ukuthi zizokwenza kanjani ukuguqula noma ukuphikisana nezinguquko, kubalulekile ukusebenzisa izibonelo zezilwane, ezivumela ukuhlaziywa komsebenzi okwengeziwe. Okubaluleke kakhulu, izilwane ziziphathisa izidakamizwa ezilutha kubantu, futhi ukuguquka kwesifunda okutholakala ekuthengeni izidakamizwa ekufuneni izidakamizwa ekusebenziseni izidakamizwa ku-glutamate kubonakala ezifundweni zezilwane.

Imodeli esetshenziswa kakhulu kunazo zonke yokuphindaphindiwe ihilela ukuqeqeshwa kwamagundane ekuziphatheni izidakamizwa, ukubeka isilwane ekuqothulweni ngokuphoqeleka ngokuqeqeshwa kokuqedwa noma ngaphandle kokuqothulwa, bese kuveza kabusha izilwane kumongo wezidakamizwa, okushiwo ngokukhethekile ukuhanjiswa kwezidakamizwa, ukucindezeleka noma umuthi uqobo (Epstein et al, 2006). Ukuphendula lezi zici, isilwane esiqeqeshwe izidakamizwa sizohlanganyela ekufuneni izidakamizwa ngisho nangaphandle kokuthola izidakamizwa.

Izifundo zakuqala zokuphindaphinda ezilwaneni zihilela ukusetshenziswa kwamagundane ancike opiate aphathwe nge-naloxone noma naltrexone. Umvuzo we-opiate uvinjelwe futhi ngemuva kokuphendula okukhudlwana kokuqala, ukwehla okusheshayo kwenzeka (UDavis noSmith, 1974). Muva nje, ukuzithobela utshwala kwatholakala ukuthi kusebenze uhlelo oluphephile lwe-opioid okhiqiza ukukhululwa kwe-dopamine ku-NA nokuphuza utshwala obufuna isilwane (UGonzales no-Weiss, i-1998). Amagundane aqeqeshwe ukuzitholela utshwala bese anikwa i-naltrexone izobonisa ukuphela kokunyuka kwama-dopamine ku-NA nokuqeda utshwala ukuziphatha. Le model yokuqothula eqondile iboniswa abantu abadakwa ngokweqile ababika umthamo wokuphuza noma ongasabikho uma uphathwa nge-naltrexone (I-Volpicelli et al, 1995).

Muva nje, ukungasebenzi kwe-brain nuclei ehlukahlukene ne-GABA agonists noma izinhlanganisela ezivimbela izinyathelo zesenzo, i-nuclei yobuchopho edingekayo ekwenzeni izidakamizwa imephu (McFarland neKalivas, i-2001; Bheka, i-2002; McFarland et al, 2004). Imiphumela yalezi zifundo ezenziwa kule minyaka eyishumi edlule zihambisana ngokuphawulekayo nezifundo zabantu ezibalwe ngenhla. I-striatum ye-dorsolateral yisifunda somqondo esiye saboniswa ukuthi siyisibopho kungakhathaliseki ukuthi sinomthelela wokuphikisa izidakamizwa, noma ukutholakala noma ukungabikho kokuqeqeshwa kokuqedwa. Lokhu kubonisa ukubandakanyeka kwemikhuba yokuhamba kwemikhumbi ekuziphatheni okuqeqeshiwe kahle njengokufuna izidakamizwa. Kuyathakazelisa ukuthi ngaphandle kokuba izilwane ziqeqeshelwe ukuqothula, ukufuna izidakamizwa ezenziwe ngokubeka izilwane emuva kumongo wezidakamizwa akuthinteki ngokuvimbela noma yisiphi esinye isakhiwo sobuchopho esifundana kakhulu nokufunda okugqugquzelayo noma ukufunwa okubangelwa ukucabangela ekuhloleni kwezinkinga zezidakamizwa (isib. Izindawo we-PFC, i-amygdala, noma i-NA) (Ama-Fuchs et al, 2006). Kodwa-ke, uma isilwane sithola ukuqeqeshwa kokuqothulwa, ukufuna izidakamizwa okubangelwa ama-cues, ukucindezeleka, noma izidakamizwa ngokwayo zenza isifunda esithuthukisiwe kakhulu, equkethe izigaba ezivezwe emibonweni yabantu yokulutha. Isibonelo, uma i-experimenter yendawo ivimbela noma yikuphi i-nuclei esechungechungeni sesichungechunge esine-projection ye-dopamine kusuka ku-VTA kuya kwi-PF, i-glutamate evela ku-PFC kuya ku-NA noma i-GABA / peptide ekubonisweni kusukela ekuhlanganyeleni kuya kwi-ventral pallidum (VP), ukufuna izidakamizwa esilweni sokucima kuvinjelwe. Ngakho-ke, ukuqeqeshwa kokuqedwa kuhlanganisa izindawo eziphathelene nobuchopho ezihileleke ekucubunguleni okungaphezulu kokumemezela ngokomzwelo nokuziphatha kwezidakamizwa (McFarland neKalivas, i-2001; Bheka, i-2002; McFarland et al, 2004), okufakazela ukushicilelwa kokuziphatha kwe-executive behavioral. Ngokuhambisana nokuqeqeshwa kokuqedwa kokuletha ukulawulwa kokuziphatha, inani lokufuna izidakamizwa (isib. Ukucindezela kwesibindi) okubangelwa umongo wezidakamizwa ezilwaneni ezingapheli kuphakeme kunokufuna izidakamizwa ezenziwe ezilwaneni ezicishiwe (Ama-Fuchs et al, 2006). Ngokubambisana, idatha yesifunda neyokuziphatha ibonisa ukuthi isifunda esithuthukisiwe kakhulu esihlotshaniswa nokufuna izidakamizwa ezifundweni ezicishayo kusebenza ukulawula ukufuna izidakamizwa. Ukusekela lokhu kungenzeka, ukuqeqeshwa kokuqedwa kudala ama-GluR1 kanye ne-GluR2 i-glutamate receptor subunits ku-NA yamagundane aqeqeshwe yi-cocaine (I-Sutton et al, 2003). Ngokufanayo, ukuqeqeshwa kokuqedwa kwezilwane ezesabekayo kuhilela ukusetshenziselwa i-cortex ye-infralimbic ukuthi amaphrojekthi aya ku-NA (Sierra-Mercado et al, 2006). Ngakho-ke, njengoba ukungenelela kwengqondo kubantu abangamlutha abazama ukubuyisela ukulawula okuphezulu kwezigameko zokufuna izidakamizwa, ukuqeqeshwa kokuqedwa kwezilwane kuhlanganisa isifunda se-prefrontal esithuthukisiwe esenza isimiso sokufuna izidakamizwa siphendule iziqu, ukucindezeleka, noma izidakamizwa ngokwazo.

Ukufana kwezigaba ze-prefrontal phakathi kwezilwane eziqeqeshwe izidakamizwa kanye nezidakamizwa zomuntu kubonakala ngokuphakama okuphawulekayo kokudluliswa kwe-glutamate ngesikhathi sokufuna izidakamizwa kuphelile. Ngakho-ke, amagundane aqeqeshwe ukuzinakekela i-cocaine noma i-heroin abonisa ukunyuka okuphawulekayo ekukhululweni kwe-synaptic glutamate e-NA ekuphenduleni izidakamizwa noma ukufuna izidakamizwa ezibangelwa ukucindezeleka (McFarland et al, 2003, 2004). Ngaphezu kwalokho, lokhu kuphakama kuqedwe ngokuvinjelwa kwe-PFC, futhi akukwenzeka ku-saline noma i-coedine ye-yoked noma i-heroin yokulawula. Ngamanye amazwi, kungakhathaliseki ukuphathwa kwezidakamizwa eziphindaphindiwe, uma izilwane zingahlanganyeli ekuzifuneni izidakamizwa akukona ukukhululwa kwe-synaptic glutamate. Ngakho-ke, ukulawulwa kwezidakamizwa eziwodwa kuphela okwanele ukwenza kusebenze i-prefrontal accumbens glutamate pathway, kunalokho le ndlela ibhalwa izilwane ezifunda umsebenzi wokufuna izidakamizwa. Okubaluleke kakhulu, akukho ukwanda kwe-glutamate okwakunakekelwa ngesikhathi sokudla ukudla ezilwaneni eziqeqeshwe ukuba zikwazi ukuphatha ukudla, okubonisa ukuthi lesi sifo se-neuroplasticity asikwenywanga ngokufunda ukufuna imivuzo yezinto eziphilayo (McFarland et al, 2003). Ukusekela ukubaluleka kokudonswa kwe-glutamate ukukhishwa kokushayela izidakamizwa, ukuphathwa kwe-intra-accumbens ye-glutamate izithinteli kuvimbela ukufuna izidakamizwa, njengoba kwenza ukungasebenzi kwe-PFC (I-Cornish ne-Kalivas, i-2000; U-Di Ciano no-Everitt, i-2001). Muva nje, ezinye ze-molecular neuroplasticity ezithinta ukuhlukunyezwa kwe-prefrontal glutamate projection kuya ku-NA iye yafundwa. Ngaphezu kwalokho, ezinye imiphumela eqhubekayo yokukhululwa kwe-glutamate ngesikhathi sokufuna izidakamizwa kuye kwaphenywa.

I-Neuroplasticity Efakazela Ukudluliswa Kwe-glutamate Ehlukanisiwe

Njengoba ukukhululwa kwe-glutamate okukhungathekile kuqhubeka, i-plasticity efanayo yamapulangwe nayo iyaqhubeka. Isihluthulelo phakathi kwalezi zimo ezinamakhemikhali ukuhlaselwa kwe-cystine-glutamate exchange (xc-) (Baker et al, 2003). I-xc- isinyathelo sokulinganisa isilinganiso lapho amangqamuzana athola khona i-cystine ukwenza i-glutathione ye-intracellular antioxidant, futhi ivele ngokushintshanisa ukukhishwa kwe-cystine eyodwa ukuze kukhululwe i-molecule eyodwa ye-glutamate ye-intracellular engxenyeni ye-extracellular (UMcBean, i-2002). Ngokuvamile, le-glutamate ye-nononaptic ikhululwa imiphumela kumazinga esikhaleni esingekho emthethweni esanele ukuvuselela ama-autoreceptors (i-mGluR) ye-metabotropic-glutamate engavinjelwe, futhi ngaleyo ndlela inciphisa ukukhululwa kwe-synaptic glutamate (I-Moran et al, 2005). Kodwa-ke, ukunciphisa i-xc- ku-NA ngemuva kokwenza i-cocaine engapheli kususa lokhu kuvimbela kwe-tonic, ukwandisa amathuba okukhululwa kwe-synaptic glutamate. Lokhu ukunciphisa ithoni kuhlangene nokubonakaliswa okunciphise ngokusebenzisa i-presynaptic mGluRs, okucatshangwa ukuthi ibangelwa ukukhula kwe-phosphorylation ye-receptor (Xi et al, 2002), nokusungulwa kweprotheyini okuthiwa i-activator ye-G-protein yokubonisa i-3 (AGS3), ekhonza ukukhawulela ukusayina kwe-receptor nge-Giα isigaba sama-proteins GUbumnyama nabakwaLanier, i-2003; Bowers et al, 2004; Yao et al, 2005). Lobudlelwano buboniswe ku Umfanekiso we-5.

Ukukhululwa okuphindaphindiwe okukhulunywe kabi kwe-synaptic glutamate ngezikhathi eziphindaphindiwe izidakamizwa ezifuna izidakamizwa kucatshangwa ukuthi kunezibalo eziningana zokuguqulwa kwe-postsynaptic. Okuyinhloko phakathi kwalezi zinguquko ezisekelwe kahle ekudeni kwamandla omzimba we-dendritic obonakala ku-NA nasezindaweni eziphambili ze-cortical ngemva kokuphathwa kwezidakamizwa eziluthayo ngokuphindaphindiwe (URobinson noKolb, 2004). Kuyacaca ukuthi ukusebenzisa i-glutamate kuma-neurons emasikini kushintshela ubukhulu bomzimba, okwandisa noma ukwehla kuye ngokuthi inani le-glutamate receptor stimulation futhi mhlawumbe i-subtypes ivuselelwe (Lippman noDunaevsky, i-2005; Richards et al, 2005). Ngakho-ke, mhlawumbe akumangalisi ukuthi kuye ngokuthi yisiphi isidakamizwa esingasetshenziswa njalo, kukhona ukwanda (psychostimulants) noma kunciphise (ama-opioids) ngokuqina komgogodla (URobinson noKolb, 1999, 2004; Jedynak et al, 2007). Izindlela ezisetshenziswayo zesisindo ze-neuroplasticity eqondisa umjikelezo we-morphology yindawo ekhulayo yokucwaninga okukhulu kakhulu. Kodwa-ke, ukulawulwa kwe-actin cytoskeleton engakwazi ukuzinza noma ukuguqula umthambo we-spine morphology yiyona eyinhloko ye-candidate yenqubo engase iguqule ukushintsha komgogodla wesibindi (URao noCraig, i-2000; Lisman, 2003; U-Blanpied no-Ehlers, i-2004; I-Matus, i-2005). Ngakho-ke, kukhona ukwanda okuqhubekayo ku-actin ngebhayisikili ngemuva kokuhoxiswa ekuphathweni okungapheli kwengqondo ye-psychostimulant (Konke et al, 2006). Ukwanda kwe-actin ngebhayisikili kwenzeka, okungenani ingxenye, kusukela ekunciphiseni kweLim kinase, okuqondisa ngokucacile ukusetshenziswa kwe-F-actin depolymerization, kanye nokuvuthwa komgogodla (Meng et al, 2002; Soosairajah et al, 2005). Ngaphandle kokuguqulwa komzimba we-spine morphology esinye isisusa sokwenyuka kwe-actin ngebhayisikili kungaba ukuguqulwa kokuthengiswa kwamaprotheni engxenyeni ye-postsynaptic (I-Kasai et al, 2003). Nakuba kungenjalo umphumela wokwenyuka kwe-actin yokuhamba ngebhayisikili, ushintsho olubaluleke kakhulu ekuthungiseleni kwe-receptor ye-postsynaptic ukunyuka okuqhubekayo kwe-membrane ukufakwa kwe-AMPA glutamate receptors (I-Mangiavacchi ne-Wolf, i- 2004; Sun et al, 2005; I-Boudreau ne-Wolf, i-2005). Kodwa-ke, ngokumangazayo, ukwanda kwama-receptors we-AMPA kuhlotshaniswa nokuhluleka ukudala ukucindezeleka kwesikhathi eside (okuvame ukuhambisana nama-receptors anciphise ama-AMPA) (Martin et al, 2006). Nakuba lokhu kutholakala kusanda kuphikiswa ekutadisweni okubonisa ukuthi emva kokuhoxiswa kwe-cocaine kunomthelela ophawulekayo wamanje we-AMPA ekuhlanganiseni amaseli e-spiny (Kourrich et al, 2007). Ngokuvamile, i-electrophysiological correlates yokulutha komzimba ekuqongeni kwamaseli a-spiny njengamanje iyindawo yokudideka ezincwadini (I-Kalivas no-Hu, i-2006).

Ngokuthakazelisayo, ukuvuselela i-BDNF receptors kukhuthaza ukuhamba nge-actin ngebhayisikili futhi kuhlunga ukuqina komgogodla (I-Bramham noMessaoudi, i-2005), ebonisa ukuthi ukuphakama okuqhubekayo okukhulunywe ngaye kwe-BDNF ngesikhathi sokuhoxiswa kungafaka isandla ngokuqondile ekuguqulekeni okuqhubekayo ekudlulisweni kwe-excitatory. Ngokuphikisana nalesi sizathu, ukuvuselela ama-BDNF receptors kule-accumbens kukhuthaza ukufuna i-cocaine (Graham et al, 2007), umphumela futhi wenziwa ngokuvimbela ibhayisikili ye-actin e-NA (Konke et al, 2006). Kodwa-ke, ucwaningo lwamuva luveze ukuthi ukukhululwa kwe-BDNF ekuhlanganyeleni emva kokulawulwa kwe-PFC kuvimbela kokubili izidakamizwa ezibangelwa i-cocaine ezifuna nokukhululwa kwe-glutamate ehambisana nokufuna i-cocaine (Berglind et al, 2007). Kwacatshangwa ukuthi i-BDNF eyayiqondiswa kwi-PFC yayithunyelwa ngokulandelana futhi ikhululwe ku-NA ukukhiqiza lo mphumela wokuziphatha (I-altare et al, 1997). Ngakho-ke, ukukhululwa okungapheli kwe-BDNF kusuka ezikhundleni ze-prefrontal kuya e-NA kungenza umphumela ohlukile kunezingqinamba ezincane ze-pharmacy.

Nakuba ukukhuthazwa kwe-neuroplasticity e-NA nase-striatum kungabonakalisa ubuzenzisi obubheke emilonyeni yezidakamizwa, kucatshangwa ukuthi ukuqina kwe-neuroplasticity nakho kwenzeka ngqo kwi-PFC. Ngempela, ukuphathwa kwe-psychostimulant okuphindaphindiwe kwandisa i-dendritic umgogodla wezinzwa kumaseli we-prefrontal pyramidal (URobinson noKolb, 2004). Ngokuphambene namaseli e-spiny ku-accumbens lapho ukunyuka komgogodla okwenziwe khona kuhlotshaniswa nekhanda elingaphansi lokungena ngaphakathi (excitability)Zhang et al, 1998), amangqamuzana e-prefrontal pyramidal avela ukuthi avuselelwe kalula (Dong et al, 2005). Lokhu kufana nokunyuka okukhulu kwe-glutamate ekhishwa ngama-syntaptically ku-NA okhiqizwa ngesikhathi sokufuna izidakamizwa, futhi kungenzeka ukuthi, ngokuyinxenye, ihlobene nama-cellular neuroadaptations njengokunciphisa ukusayina ngokusebenzisa i-Gi-coupled receptors ngenxa ye-AGS3 ephakanyisiwe (I-Kalivas et al, 2005). Ngakho-ke, ngenkathi izinguquko ze-D2 zamukeli we-prefrontal cell ukudubula zingabonakali emva kokuhoxiswa kwe-cocaine engapheli, imiphumela ye-Gs-coupled receptors ehlanganisiwe i-GXIUMI iyathuthukiswa (Nogueira et al, 2006). Lokhu kungabangela ukukhuphuka nokulahlekelwa kwekhanda lokubambisana elibikwe kwi-prefrontal neurons ngemuva kwe-cocaine engapheli (I-Trantham et al, 2002), njengoba ukuvuselelwa kwe-D1 ukwamukela ukugqugquzela i-AMPA ukwamukela i-membrane (Sun et al, 2005). Ukuthi i-D1 receptor stimulation in the PFC iyadingeka ukubuyisela izidakamizwa kuhambisana nalokhu kungenzeka (Ama-Capriles et al, 2003; Ilanga noRebec, i-2005).

Isifinyezo se-Neuroplasticity esekelwe ekusetshenzisweni kokubuyiswa okulawulwayo nokucindezela

Njengoba kubonisiwe Umfanekiso 4c, izinhlobo ze-neuroplasticity ezikhuthazelayo ngesikhathi sokuzilahla zihlinzeka nge-neuroplastic substrates ezigxile ekutheni zihlale zihlaselwa ngokweqile. Ukuxhaswa kwezifundo ezihlukahlukene kwandisa ukwedluliswa kwe-prefrontal glutamate ku-NA njengomxhumanisi obaluleke kakhulu wokufuna izidakamizwa. Ngokufanayo, ukuguqulwa okuphawulekayo ekubonisweni kwe-postsynaptic glutamate, kufaka phakathi izinguquko ze-morphological kuma-neurons abulalayo cishe okufaka isandla ekushintsheni. I-plasticity yamaselula esekela kokubili ubuzenzisi obubonakalayo ngesikhathi sokuqala kanye nokuphendula okunamandla kwe-PFC kanye nemiphumela eya ku-NA ngesikhathi sokufuna izidakamizwa noma izidakamizwa kuqale ukucaciswa futhi, njengoba kuchazwe ngezansi, yakha izindawo ezintsha ezithathwe ezenzweni zokuthuthukisa ama-pharmacotherapies ekuphatheni umlutha.

IMISEBENZI YOKUPHAKATHI NOKUSETSHENZISWA KWEZINDLELA

Njengoba sikhulisa ukuqonda kwethu ngezinqubo zesifunda kanye nezamaselula lapho ukutholakala kwezidakamizwa okuphindaphindiwe kwandisa ukukhubazeka ukuphindaphinda, izinhloso ezintsha zokwelashwa ezibonakalayo zingabonakala. Ukuthi ukuguqulwa kwesimo sengcupheni phakathi kokuphindaphindiwe okulawulwa futhi okuphoqeleka kunika ama-rationales ekuthuthukiseni imishanguzo emisha, kanye nokuqonda ukwandisa kwezindlela ukuthi imithi ingathuthukisa imiphumela yezokwelapha kwengqondo.

Ukuguqula Ukuphoqeleka Ukubuyela Ekugcineni

Ukusebenzisa ama-pharmacotherapies ukwenza lula amandla omlutha ukubandakanya izinqubo ezengeziwe zokumemezela, izinqumo zokubuyela emuva kubalulekile ekunciphiseni ukuphindaphinda. Njengoba kuchazwe ngenhla, ukuguqulwa kokuphindaphinda kube umkhuba osuselwa ekutheni inkumbulo yokusebenza engazi lutho ihilela ukulahlekelwa kwemithetho yokulawula. Ngezinye izidakamizwa zokuhlukunyezwa lokhu kubonakala ngokulahlekelwa kwengqondo emisebenzini ehlobene nokunakwa, ukungabi nesifiso nokukwazi ukuguqula ukuziphatha ngokusekelwe kolwazi olusha. Ngokusekelwe kulokho okutholwe, ukusimamisa ngokwemithi noma ukuphikisana neuroprolasticity okhiqizwa yi-PFC ukulawula umkhuba wokuhlaselwa kwabantu kubonakala sengathi kuyindlela ewusizo. Njengoba kuvezwe ngenhla, izinguquko zamangqamuzana zihilela ukuhlaselwa okubonakalayo komvuzo wezinto eziphilayo ngokunciphisa ukudluliswa kwe-dopamine, kanye nokwenyuswa kwe-prefrontal ekutholeni ukuhanjiswa kwe-glutamate ukuqhubekela phambili ekudleni izidakamizwa. Ngakho-ke, izidakamizwa eziguqula ukudluliswa kwe-dopamine, ukudluliswa kwe-glutamate noma ukudluliswa kwe-GABA kungabakhona abangaba khona. Ngaphezu kwalokho, ukuhlaziywa kwe-GABA kusukela e-NA kuhloswe nge-neuropeptides ehlukahlukene (McGinty, 2007), futhi lawa ma-peptide, kanye nabanye abakwe-corticolimibic nabo bayagunyazwa ukuthuthukiswa kwezidakamizwa.

I-Dopaminergics

Ukudluliswa kwe-Dopamine kunezinguquko zokuhlukahluka kuye ngokuthi yi-subtype ye-receptor. Ngakho-ke, kunciphisa ukuboniswa kwe-receptor ye-D2 (I-Volkow et al, 2004), ukukhuphuka okungenzeka ku-D1 ukusayina (I-Kalivas et al, 2005), nokuphakama okumeziwe kuma-receptors e-D3 ngenxa yokunyuka okuqhubekayo ku-BDNF (Neisewander et al, 2004). Lokhu kwenza kube nzima ukubikezela indlela yokudlulisela phambili ukudluliswa kwe-dopamine. Kodwa-ke, kukhona idatha enhle kakhulu yokunqanda ukusekela ukusetshenziswa kwezingxabano ze-D3 ukuvimbela ukufuna izidakamizwa (Xi et al, 2006).

I-Glutamatergics

Ngokwe-neuroplasticity echazwe ngenhla, ukuvimbela ukukhululwa kwe-synaptic glutamate ehambisana nokufuna izidakamizwa kubonakala kuyindlela enhle kakhulu yokunciphisa isisusa sokubuyela emuva. Kodwa-ke, akunakwenzeka ukusebenzisa izitha ezigcwele ze-ionotropic glutamate receptors ngenxa yemiphumela engavumelekile. Ngakho-ke, izindlela ezihlukahlukene zezokwelapha zivela ukuze zilungele ukudlulisa esikhundleni sokuvimbela ukudluliswa kwe-glutamate. Ezinye zalezi zinhlanganisela sezivele zifake izivivinyo zomtholampilo futhi zibonisa ukusebenza kahle. Isibonelo, i-acamprosate ne-topiramate inezinyathelo ezibuthakathaka njengabaphikisi be-AMPA abamukelayo (U-Myrick no-Anton, i-2004; I-Cubells, i-2006). I-Topiramate ibike ukuthi inganciphisa ukuphindaphinda ku-cocaine izidakamizwa (Kampman et al, 2004). Futhi, i-modafinil futhi N-acetylcysteine ​​okwenza ukwandisa i-glutamate ye-extracellular futhi ngaleyo ndlela ivuselele ukuvinjelwa kwe-synagtic ye-synaptic glutamate kuye kwabonisa ukusebenza kahle kwe-cocaine okuphindaphindiwe noma ukukhanga okukhishwe, ngokulandelana (Dackis et al, 2005; LaRowe et al, 2007). Amalebhu amathathu azimele abikile (Dackis, i-2004; Malcolm et al, 2006; Hart et al, 2007) ukuthi i-modafinil iyanciphisa i-cocaine phezulu ngokukhuphula i-glutamate ye-extracellular futhi isebenze i-MGluR engavimbayo njengoba kuchazwe ngenhla. Ngaphezu kwalokho, ezinhlobonhlobo zokuqapha, ama-gGRRNUMX / 2 agonists aboniswe ukuvimbela ukufuna izidakamizwa (Baptista et al, 2004; Peters and Kalivas, 2006).

I-GABAergics

Amamodeli we-cocaine ne-heroin abonisa ukuthi ukwehlisa i-GABA ukukhululwa kwi-VP yi-NA afferents kuhlotshaniswa nokufuna izidakamizwa (I-Caille ne-Parsons, i-2004; I-Tang et al, 2005). Ukusekela ukubaluleka kwalesi simo, izidakamizwa ezithuthukisa ukuhanjiswa kwe-GABA zibonise isithembiso ekuhlolisweni kwe-preclinical and clinical, vigabatrin (inhibitor ye-GABA transferase), i-gabapentin (inqubo engacacile), ne-baclofen (i-GABAb agonist). Umfundi ubhekiselwa ekubukeni kwamuva nje kokusetshenziswa kwe-GABAergics ekwelapheni ukulutha kwezidakamizwa (I-O'Brien, 2005; I-Vocci ne-Ling, i- 2005).

I-Peptidergics

Ama-neuropeptide amaningi ahlukaniswe ne-GABA ekubonweni kusuka ku-NA, kuhlanganise neurotensin, i-substance P, i-dynorphin, ne-CART (McGinty, 2007). Nakuba ulwazi lwethu lokuthi la ma-peptide abamba iqhaza kanjani noma ukungabi nokulawula izidakamizwa ezixhunywe yi-accumbens kuya ku-pallidum ukubonakala kungampofu, kuye kwaboniswa ukuthi ukuvimbela i-enkephalin receptors ku-VP kuvimbela ukufuna i-cocaine ezinhlobonhlobo zezilwane (I-Tang et al, 2005), umphumela mhlawumbe unika amandla ekusebenziseni kwe-naltrexone ekulutha kwe-ethanol (I-Vocci ne-Ling, i- 2005).

iziphetho

Yize kube khona ukuthuthuka okubalulekile ekuqondeni kwethu ukuxilongwa kwe-neuroplasticity okugxila ekuthuthukiseni umlutha kanye nokukhubazeka okuqhubekayo ukubuyela emuva, sisezingeni eliphansi kakhulu ukuze sikwazi ukusebenzisa lolu lwazi olusha ukuphatha izidakamizwa. Nakuba sinezizathu ezithile zokuqokwa kwamakhemikhali ekulawuleni i-neurotransmission emkhatsini we-neurons ezijikelezweni eziboniswa ukuthi zibalulekile, kunzima ukuphatha i-neuroplasticity ekhishwa ekuboniseni kwe-intracellular okubaluleke kangaka ekugqiliseni. Ukusebenzisa lolu lwazi olusha kulindeleke ukuthuthukiswa kwamakhemikhali akhethe amaprotheni ahlosiwe ezindleleni zokubonisa, futhi okubaluleke kakhulu, kusho ukuletha izinhlanganisela. Noma kunjalo, izinhlobo ze-neuroplasticity ezikhonjisiwe kuze kube yimanje zikhomba indlela eya esikhathini esizayo zokwelashwa ezizobe zitholakala njengoba ezobuchwepheshe bezethulo ziguqukela.

amanothi

QAPHELA

UDkt O'Brien usebenze njengomxhumanisi eminyakeni emithathu edlule e-Alkermes, Cephalon, Forest naseMcNeil Laboratories. UDkt Kalivas akanalutho angaludalula.

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