Isiyaluyalu: Isifo Sokufunda Nememori (2005)

Ukulutha umlutha kuchazwa ngokuthi ukusetshenziswa kwezidakamizwa eziphoqelekile naphezu kwemiphumela emibi. Izinhloso zomuntu onomlutha ziyancipha ukuthola, ukusebenzisa, nokubuyiselwa kwezidakamizwa, naphezu kokuhluleka kwemisebenzi yokuphila, ukugula kwezempilo, ingozi yokuboshwa, nezinye izinkinga. Isici esibalulekile sokulutha umlutha ukuphikelela kwakhe okunenkani (1, 2). Nakuba abanye abantu bangase bayeke ukusetshenziselwa ukubhema ugwayi, utshwala noma izidakamizwa ezingekho emthethweni, ngenxa yocingo elikhulu labantu ababhekene nosengozini ngenxa yezici zomzimba nezifo (3-5), ukulutha umlutha kufakazela isimo se-recalcitrant, esingasiguli, nokubuyiselwa (2). Inkinga eyinhloko ekwelapheni umlutha wukuthi ngisho nangemva kokuhlala isikhathi eside esingalawa izidakamizwa, ngemva kokuphela kwesimiso sokuhoxiswa kokugcina, ingozi yokuphindaphindiwe, evame ukugxilwa yizici ezihlobene nezidakamizwa, ihlala iphezulu kakhulu (6, 7). Uma kwakungenjalo, ukwelashwa kungahle kuhlanganise nokukhiya abantu abanomlutha kude endaweni evikelayo kuze kube yilapho izimo zokuhoxiswa zihamba kahle, zinikeze isixwayiso esiqinile mayelana nokuziphatha kwesikhathi esizayo, futhi senze ngakho.

Izingqinamba zememori ngokuvamile zicatshangwa njengezimo ezibandakanya ukulahleka kwenkumbulo, kodwa kuthiwani uma ubuchopho bukhumbula kakhulu noma bunamandla kakhulu ukuloba izinhlangano zezinkinga zomzimba? Phakathi neminyaka eyishumi edlule, ukuthuthukiswa kokuqonda indima ye-dopamine ekufundeni okuhlobene nomvuzo (8) baye benza icala eliphoqelela "imfundo yokuhlukumezeka" yokulutha ngokweqile okuhambisana nokubheka isikhathi eside mayelana nokuziphatha kwabantu abanomlutha (6). Lo msebenzi, kanye nokuhlaziywa kamuva kwamakhompiyutha we-dopamine (9, 10), uye wafaka izindlela zokuthi izidakamizwa nezidakamizwa ezihlobene nezidakamizwa zithole amandla angashukumisayo. Ngesikhathi esifanayo, uphenyo lwamaseli kanye namakhemikhali luveze ukufana phakathi kwezenzo zezidakamizwa eziluthayo kanye nezinhlobo ezijwayelekile zokufunda nokukhumbula (11-14), ne-caveat ukuthi ulwazi lwethu lwamanje lwendlela inkumbulo efakwe ngayo (15) nokuthi liphikelela (15, 16) akuphelelanga nanoma yisiphi isimiso sememori yamammalia. Lapha ngiphikisana ngokuthi ukulutha umlutha kubhekisela ekusetshenzisweni kwamathambo ezinqubo ze-neural zokufunda kanye nenkumbulo ukuthi ngaphansi kwezimo ezivamile kudala ukuziphatha okuqhubekayo okuhlobene nokuphishekela imivuzo kanye nezici ezibikezelayo (11, 17-20).

Ukuqotshwa kwezinhlelo ze-Neural ezihlobene nokuphishekela imivuzo

Ukusinda komuntu ngamunye nezinhlobo zezinto eziphilayo kudinga ukuthi izinto eziphilayo zithole futhi zithole izinsizakusebenza ezidingekayo (isb., Ukudla nendawo yokuhlala) namathuba okukhwelana naphezu kwezindleko nobungozi. Lezo zinhloso zemvelo eziphathelene nokusinda zisebenza “njengemivuzo,” okungukuthi, zilandelwa ngethemba lokuthi ukusetshenziswa kwazo (noma ukupheleliswa) kuzoveza imiphumela efiselekayo (okungukuthi, “kuzokwenza izinto zibe ngcono”). Ukuziphatha okunemigomo evuzayo kuvame ukuphikelela ngokuqinile esiphethweni futhi kukhuphuke ngokuhamba kwesikhathi (okungukuthi, kuyaqinisa impela) (21). Izinkulumo zangaphakathi ezishukumisayo, njengokulamba, ukoma, nokuvuswa kocansi, ukwandisa ukubaluleka kokubambisana okuphathelene nemigomo kanye nezinhloso zomgomo ngokwabo futhi kwandise injabulo yokusetshenziswa (isb., Ukudla kunambitheka kangcono uma umuntu elambile) (22). Amaphuzu angaphandle ahlobene nemiklomelo (ukugqugquzela okukhuthazayo), njengokubona noma iphunga lokudla noma iphunga lomfazi wesister, angaqala noma aqinise amazwe ashukumisayo, okwandisa amathuba okulandelana okunzima futhi okulukhuni okuqhubekayo okuziphatha, okufana nokuhlinzekela noma ukuzingela ukudla, kuzothathwa isiphetho esiphumelele, ngisho nalapho ubhekene nezingqinamba. Ukulandelana kokuziphatha okuhilelekile ekutholeni imivuzo oyifunayo (isb., Ukulandelana okuhilelekile ekuzingeleni noma ekusebenziseni imisebenzi) kuphelelwa yisikhathi. Ngenxa yalokho, ukulandelana kwezinyathelo eziyinkimbinkimbi kungenziwa ngokushelelayo nangempumelelo, njengoba nje umgijimi efunda imizila kuze kube yilapho esebenza ngokuzenzekelayo kodwa eguquguqukayo ngokwanele ukuze aphendule eziningi. Lezi zikhombisi-ndlela zokuziphendulela ezinjalo ezenziwe ngokuzenzakalela, nazo zingahle zenziwe kusebenze ngamaphuzu wokubikezela umvuzo (19, 23).

Izidakamizwa eziluthayo zifaka amaphethini wokuziphatha okukhumbuza labo abafakwe imiklomelo yemvelo, nakuba amaphethini wokuziphatha ahlobene nezidakamizwa ahlukaniswa amandla awo ukuze athathe cishe zonke ezinye izinjongo. Njengemivuzo yemvelo, izidakamizwa zifunwa ngokulindela imiphumela emihle (kungakhathaliseki ukuthi yiqiniso eliyingozi), kodwa njengabantu ngabanye bawela ekujuleni kwezidakamizwa, ukufuna izidakamizwa kuthatha amandla anjalo angakhuthaza abazali ukuba banganaki izingane, abantu abahlala benomthetho abagcina ubugebengu , kanye nabantu abanezinkinga eziphuza utshwala noma ezihlobene nogwayi ukuqhubeka bephuza nokubhema (24). Ngokuthatha izidakamizwa eziphindaphindiwe kulandela ukulungiswa kwe-homeostatic okukhiqiza ukuxhomeka, okubhekene nokuphuza utshwala kanye ne-opioids kungaholela ekucindezelweni kokuxoshwa kwezidakamizwa nokuyeka izidakamizwa. Ukurhoxiswa, ikakhulukazi isici esithintekayo, kungabhekwa njengesizwe esishukumisayo (25) futhi ngaleyo ndlela ingabhalwa ukulamba noma ukoma. Nakuba ukugwema noma ukuqedwa kwezimpawu zokuhoxiswa kwandisa ukugqugquzela ukuthola izidakamizwa (26), ukuxhomeka nokuhoxiswa akuchazi umlutha (7, 19). Ezilwaneni zezilwane, ukubuyiselwa kwezidakamizwa zokuziphathisa izidakamizwa emva kokuphela kwezidakamizwa kushukunyiswa kakhulu ngokuphindaphinda kwesidakamizwa kunokuba kuhoxiswe (27). Mhlawumbe nakakhulu, ukuthembela nokuhoxiswa akukwazi ukuchaza ukuphikelela kokuphindaphindiwe kokubuyela emuva engozini ngemuva kokuxoshwa kwe-detoxification (6, 7, 19).

Ukubuyela emuva ngemuva kokuxoshwa kwe-detoxification kuvame ukugxila ngamagama, njengabantu, izindawo, izindawo, noma imizwa yomzimba ehlotshaniswa nokusetshenziswa kwezidakamizwa ngaphambilini (6, 7) futhi futhi ngokucindezeleka (28). Ukucindezeleka nokucindezeleka kwama-hormone afana ne-cortisol anezimo zomzimba emikhondweni yokuvuza, kodwa kuyathakazelisa ukubona ukuthi ukucindezeleka okuhlanganyela nezidakamizwa eziluthayo kunamandla okuqala ukukhululwa kwe-dopamine (28) futhi ukwandise amandla we-synapses e-excitatory ku-dopamine neurons endaweni ye-ventral tegmental (29). Ama-cues asebenze ukufuna izidakamizwa (11, 30), ukufuna izidakamizwa (19, 31), kanye nokusetshenziswa kwezidakamizwa. Izibukeli ezifuna izidakamizwa / zokusebenzisa izidakamizwa ezisetshenziswe yizici ezihlobene nezidakamizwa kumele ziguquguquke ngokwanele ukuze ziphumelele ezweni langempela, kodwa ngesikhathi esifanayo, kumele zibe nekhwalithi ephakeme kakhulu futhi ezenzakalelayo uma zizosebenza kahle (19, 23, 31). Ngempela ukusebenza kwe-cue-dependent of the automated drug seeking has been hypothesized ukuze idlale indima enkulu ekuphindeni kabusha (18, 19, 23).

Ukuzikhandla kwezidakamizwa ngokuzenzekelayo yisimo sokumelwa kokudinga izidakamizwa; Iziphakamiso ezizithobayo zingase zifinyeleleke kuphela noma zibonelele kakhulu uma izidakamizwa zingatholakali kalula noma uma umuntu onomlutha enza imizamo yokunciphisa ukusetshenziswa (19, 23, 31). Kungumbuzo ovulekile ukuthi ngabe ukufisa izidakamizwa ezithandwayo, ngokuphambene nezinyathelo ezithintekayo, izinqubo ezizenzekelayo, kudlala indima ebalulekile ekufuneni izidakamizwa nokuthatha izidakamizwa (32). Ngempela, abantu ngabanye bangase bafune futhi bazenzele izidakamizwa ngisho ngenkathi bexazulula ngokucophelela ukuthi bangalokothi benze njalo.

Ezisethweni zokubhubhisa, ukuphathwa kwezidakamizwa (33, 34) kanye nezinkulumo ezihlobene nezidakamizwa (35-37) ziye zaboniswa ukukhiqiza izidakamizwa zezidakamizwa kanye nezimpendulo zomzimba ezifana nokuvuselelwa kwesimiso somzwelo ozwela. Nakuba ukuvumelanisa ngokugcwele kungakabikho ukuvela, izifundo ezisebenzayo ze-neuroimaging izifundo ziye zabika ukuqhutshwa komsebenzi ngokuphendula izidakamizwa eziphathelene nezidakamizwa ku-amygdala, i-cingulate yangaphambili, i-orbital prefrontal ne-dorsolateral prefrontal cortex, kanye ne-nucleus accumbens.

I-Dopamine Hypothesis

Umsebenzi omningi, kuhlanganise nokuhlolwa kwemithi, izilonda, ezithintekayo, kanye neziqu ze-microdialysis, uye wafakazela ukuthi izindawo ezivuzayo zezidakamizwa eziluthayo zixhomeke ekwenzeni kwabo ukwandisa i-dopamine ngama-synapses eyenziwe yi-midbrain ventral tegmental area neurons kwi-nucleus accumbens (38-40), okuyinto ethatha striratum ventral, ikakhulukazi ngaphakathi nucleus accumbens igobolondo esifundeni (41). I-Ventral tegmental indawo ye-dopamine yokuhlolisisa kwezinye izindawo ezinjenge-prefrontal cortex kanye ne-amygdala nazo zidlala indima ebalulekile ekwakheni ukuziphatha kwezidakamizwa (42).

Izidakamizwa ezithathelisayo zimelela imindeni ehlukahlukene yamakhemikhali, ivuselele noma ivimbele ukuhloswa okuhlukile kwamangqamuzana okuqala, futhi ibe nezenzo eziningi ezingavumelani ngaphandle kwendawo ye-ventral tegmental / nucleus accumbens circuit, kodwa ngokusebenzisa izindlela ezahlukene (isib. Bheka izikhombo 43, 44), konke ekugcineni kwandisa i-synaptic dopamine ngaphakathi kwe-nucleus accumbens. Naphezu kwendima ebalulekile, i-dopamine ayiyona indaba yonke yazo zonke izidakamizwa eziluthayo, ikakhulukazi i-opioids. Ngaphezu kokubangela ukukhululwa kwe-dopamine, i-opioids ingasebenza ngokuqondile kwi-nucleus accumbens ukukhiqiza umvuzo, kanti i-norepinephrin ingadlala indima emiphumeleni emihle ye-opioids kanye (45).

Umsebenzi wakamuva ekuziphatheni komzimba, ngokomzimba, ekhompyutheni, nakwemangqamuqalile isiqalile ukucacisa indlela isenzo se-dopamine esikhungweni se-nucleus accumbens, i-prefrontal cortex, nezinye izakhiwo zangaphambili zingase ziphakanyise izikhuthazo zokuthatha izidakamizwa kuze kufike lapho kulawulwa khona izidakamizwa ilahlekile. Ama-caveats amabili abalulekile ekubukezeni lolu cwaningo ukuthi njalo ukhohlisayo ukukhulisa lokho esikufunda ezilwaneni ezivamile ze-laboratory ezibhekene nezimo eziyinkimbinkimbi zomuntu ezinjengokulutha umlutha nokuthi akukho mhlobo wezilwane eziwumlutha ophelele ozala isifo somuntu. Lokho kuthiwa, iminyaka embalwa edlule yenze intuthuko ebalulekile ekuphenyweni kwe-pathogenesis yokulutha.

I-Dopamine Action: I-Hypothesis Yokubikezela-Iphutha Lokubuyisela

Ukuhlolwa kwe-dopamine kusuka endaweni ye-ventral tegmental kuya kwi-nucleus accumbens yiyona ingxenye eyinhloko ye-circuitry rewardry circuitry. Lesi sifunda sinikeza imali ejwayelekile yokulinganisa imivuzo ehlukahlukene ebuchosheni (21, 46). Ngaphakathi kwendawo ye-ventral / se-nucleus accumbens circuit, i-dopamine iyadingeka ukuze kube nesimiso semvelo, njengokudla namathuba okubambisana, ukuvuza; Ngokufanayo, i-dopamine iyadingeka ukuze izidakamizwa eziluthayo zikhiqize umvuzo (22, 39, 40, 47). Umehluko ocacile kakhulu phakathi kwezinhloso zemvelo yemvelo, njengokudla, nezidakamizwa eziluthayo ukuthi lezi zinsuku azikho ikhono lokusebenzisa izidingo eziphilayo. Kodwa-ke, ngoba izidakamizwa zomlutha kanye nemivuzo yemvelo ikhulula i-dopamine ku-nucleus accumbens nezinye izakhiwo zangaphambili, izidakamizwa eziluthayo zilingisa imiphumela yemiphumela yemvelo futhi zingabangela ukuziphatha (9, 22, 23). Ngempela, kuye kwacatshangelwa ukuthi izidakamizwa eziluthayo zinezinzuzo zokuncintisana ngaphezu kweningi lemvelo ngenxa yokuthi zingaveza amazinga amakhulu kakhulu okukhululwa kwe-dopamine nokuvuselela okuqhubeka isikhathi eside.

Yiluphi ulwazi olufakwe nge-dopamine? Ukuqala kokusebenza kwe-dopamine kwakuwukuthi kwenziwa njengesignali ye-hedonic (ukubonisa injabulo), kodwa lo mbono ubekwa umbuzo ngokuvinjelwa kwemithi, i-lesion (48), nezifundo zofuzo (49) lapho izilwane zaqhubeka zathanda ("ukuthanda") imivuzo efana ne-sucrose naphezu kokuncipha kwe-dopamine. Ngaphezu kwalokho, izenzo ze-nicotine zihlale ziyimfihlakalo kule akhawunti, ngoba i-nicotine iyalutha kakhulu futhi ibangela ukukhishwa kwe-dopamine kepha ikhiqiza okuncane uma kukhona ukuthokoza.

Esikhundleni sokwenza isignali ye-hedonic, i-dopamine ibonakala ikhuthaza ukufunda okuhlobene nomvuzo, ibopha izinto ze-hedonic zomgomo wokufisa nokuthatha isenzo, ngaleyo ndlela kudala ukuziphatha okuhlobene nomvuzo okulandelayo (48). Kwichungechunge olubalulekile lokuhlola olubandakanya ukurekhoda kusuka ezinkimbini zokuqapha, u-Schultz nozakwabo (8, 50-52) uphenye izimo lapho i-midbrain i-dopamine neurons ishisa ngokuphathelene nomvuzo. Lezi zivivinyo zinikeze ulwazi olubalulekile olujwayelekile mayelana nemigomo ye-dopamine kodwa hhayi ngezenzo ezahlukene ze-dopamine ku-nucleus accumbens, i-dorsal striatum, i-amygdala, ne-prefrontal cortex. Schultz et al. wenza amarekhodi avela ku-dopamine neurons ngenkathi izinkawu zilindele noma zidla ijusi elimnandi, isisusa esivuzayo. Izimbongolo zaziqeqeshwe ukulindela ijusi ngemuva kwesikhathi esinqunyiwe esilandela ukubonwa okubukwayo noma okubonakalayo. Lokho okwakubonakala kwaba indlela eguquguqukayo yokudubula kwama-dopamine neurons njengoba izinkawu zafunda izimo lapho imivuzo ivela khona. Ezimvu izimpukane, i-dopamine neurons ibonisa iphethini yokudubula efana ne-basal (tonic); okuvelele kulolu hlobo lwe-basal yi-stsic short sts activity yomsebenzi we-spike, isikhathi esinqunywe yilokho okwenzeka ngaphambili kwesilwane ngemiklomelo. Ngokuyinhloko, umvuzo ongalindelekile (ukulethwa kwejusi) ukhiqiza ukwanda okwesikhashana kokudubula, kodwa njengoba i-monkey ifunda ukuthi izimpawu ezithile (ithoni noma ukukhanya) zibikezela lo mvuzo, isikhathi salo msebenzi wokushintsha kwesigaba. I-dopamine neurons ayisabonakali ukuphazamiseka kwe-phasic ekuphenduleni ukulethwa kwejusi, kodwa benza kanjalo ngaphambili, ngokuphendula isisusa sokubikezela. Uma kuvezwa isenzo esivame ukuhambisana nomvuzo kodwa umvuzo uvaliwe, kukhona isikhashana ekudubula kwe-tonic ye-dopamine neurons ngenkathi umlindleko wawuzolindeleke. Ngokuphambene nalokho, uma umvuzo ufika ngesikhathi esingalindelekile noma udlula ukulindela, ukuphazamiseka kokuphazamiseka kokuphazamiseka kubonakala. Kuye kwacatshangelwa ukuthi lezi ziphazamiso ze-phasic kanye nama-pauses zihlanganisa isignali yokubikezela-iphutha. Izimpawu zomsebenzi we-Tonic azikho ukuphambukela ekulindeni, kepha ukuphazamiseka kwe-phasic kubonisa iphutha elihle lokubikezela umvuzo (okungcono kunokulindeleke), ngokusekelwe emlandweni odiziziwe wokudilizwa komvuzo, futhi ukumisa kusayine iphutha elibikezelayo lokubikezela (okubi kunalindelekile) (9, 53). Yize kuvumelana nokunye okuningi okubhekwayo, okutholakele kwalokhu kuhlolwa okudingekayo akuzange kuphindwe ngokuphelele kwamanye ama-laboratories futhi akwenzelwanga nemiklomelo yezidakamizwa; ngakho-ke, ukusetshenziswa kwazo ezidakamizweni eziluthayo kuhlala kuyinkinga. Kubalulekile ukuthi wazi ukuthi lo msebenzi ungabikezela inzuzo eyengeziwe yezidakamizwa kunemivuzo yemvelo. Ngenxa yezenzo zabo eziqondile zokwenziwa kwemithi, amandla abo okukhulisa amazinga e-dopamine ekusetshenzisweni kwawo ngeke abole ngokuhamba kwesikhathi. Ngakho-ke, ubuchopho babuyothola kaningi isibonakaliso sokuthi izidakamizwa “zingcono kunokulindelekile.”

IBerridge noRobinson (48) kukhombisile ukuthi i-dopamine ayidingeki ezintweni ezijabulisayo (ze-hedonic) ze-sucrose, okuthi, kuphenyo lwabo, ziqhubeke "zithandwa" ngamagundane aphelelwe yi-dopamine. Esikhundleni salokho baphakamise ukuthi i-nucleus accumbens dopamine transmission mediates the assignment of "incentive salience" to umvuzo and cices related-condices, such that these cues can kamuva drivate a state of "want" for the goal object as separate from "ukuthanda". Ngokubona kwabo, isilwane sisengakwazi "ukuthanda" okuthile ngokungabikho kokudluliswa kwe-dopamine, kepha isilwane asikwazi ukusebenzisa lolu lwazi ukugqugquzela isimilo esidingekayo ukuze sikuthole. Kukonke, kungaphethwa ngokuthi ukukhishwa kwe-dopamine akuyona ukumelwa kwangaphakathi kwezakhiwo ze-hedonic zento; izivivinyo zikaSchultz et al. phakamisa esikhundleni salokho ukuthi i-dopamine isebenza njengesiginali-yephutha lesibikezelo elakha isimilo ukuze lithole imivuzo ngokuyimpumelelo.

Lo mbono we-dopamine umsebenzi uhambisana namamodeli okusebenzisa ulwazi ngokuqinisa ukufunda (9, 53, 54). Amamodeli wokufunda aqinisayo asuselwa ekucabangeni kokuthi inhloso yesidalwa ukufunda ukwenza ngendlela ezokwandisa imivuzo yesikhathi esizayo. Lapho kusetshenziswa amamodeli anjalo kudatha yomzimba echazwe ekuqaleni, ukuhlaba ikhefu nokuthwebula okuyimpoqo kwama-dopamine neurons kungacatshangwa njengokumelwa kwangaphakathi kwamaphutha okubikezela umvuzo lapho izenzo ezihleliwe noma zangempela zenkawu ("umenzeli") "zigxekwa" amasiginali wokuqinisa (okungukuthi, imivuzo eba ngcono, ibe yimbi kakhulu, noma njengoba kubikezelwe). Ukukhishwa kwe-Dopamine kungakha ukufundwa komvuzo wokuvuselela ukwenza ngcono ukubikezela ngenkathi kubuye kufundise isenzo sokuvuselela isenzo, okungukuthi, impendulo yokuziphatha kuzikhuthazo ezihlobene nomvuzo (8, 9). Njengoba kunikezwe ukuthi kungenzeka ukuthi izidakamizwa eziluthayo zidlula ukunqunywa kwemvelo ekuthembekeni, ngobuningi, nokuphikelela kwamazinga e-synoptic dopamine, imiphumela ebikezelwe yalezi zicabango izoba yinkimbinkimbi enkulu yokubaluleka kwamaphuzu okubikezela ukulethwa kwezidakamizwa. Ngesikhathi esifanayo, okuningi kuhlale kungacacile. Isibonelo, ezinkambeni ezifundwa nguSchultz nozakwabo, ukuqhuma okufushane kanye nokuphambana nokudubula kwe-dopamine neurons kusetshenziswe njengesignali-iphutha lokubikezela. Kodwa-ke, izidakamizwa ezifana ne-amphetamine zingasebenza amahora amaningi futhi ngaleyo ndlela ziyophazamisa wonke amaphethini avamile okukhululwa kwe-dopamine, kokubili i-tonic ne-phasic, ukukhiqiza isignali engavamile yokuhlola i-dopamine. Imiphumela ye-dopamine kinetics ephathelene nezidakamizwa ekuziphatheni okuhlobene nomvuzo iqala ukucwaningwa (55).

Indima ye-Prefrontal Cortex

Ngaphansi kwezimo ezivamile, izinto eziphilayo zixabisa imigomo eminingi, okwenza kubalulekile ukukhetha phakathi kwabo. Isici esibalulekile sokulutha umlutha ukunciphisa umzimba ekukhethweni kwezinhloso kulabo abahlobene nezidakamizwa. Ukumelelwa kwemigomo, isabelo sokubaluleka kubo, nokukhethwa kwezinyathelo ngokusekelwe kokulinganisa okwenziwe kuxhomeke ku-prefrontal cortex (56-59). Ukufezwa ngokuphumelelayo kokuziphatha okuqondiswe ngamagoli, kungakhathaliseki ukuthi kusetshenziselwa ukudla (noma ngezikhathi zanamuhla, ukuyothenga) kokudla noma ukudlala ukudlala i-heroin, kudinga ukulandelana okuyinkimbinkimbi nokwandiswa kwezenzo okumelwe zigcinwe naphezu kwezithiyo neziphazamiso. Ukulawulwa kwengqondo okuvumela ukuziphatha okuqondiswe umgomo ukuqhubekela esiphethweni esiyimpumelelo kucatshangwa ukuthi kuncike ekulondolozeni okusebenzayo kwezimvo ngaphakathi kwe-prefrontal cortex (56, 59). Ngaphezu kwalokho, kuye kwacatshangelwa ukuthi ikhono lokuvuselela ulwazi ngaphakathi kwe-correx ye-prefrontal njengokuba imigomo emisha ingakhethwa futhi ukugwema ukugwenywa kugcwele ukukhishwa kwe-phasic dopamine (8, 60).

Uma i-phasic dopamine ukukhululwa inikeza isibonakaliso sokubamba kwi-prefrontal cortex, izidakamizwa eziluthayo zizoveza isignali enamandla kodwa ehlanekezela kakhulu ephazamisa ukufunda okujwayelekile okuhlobene ne-dopamine ku-prefrontal cortex, naku-nucleus accumbens ne-dorsal striatum (9, 19). Ngaphezu kwalokho, kumuntu onomlutha, ukuguquguquka kwe-neural ukuphindaphindiwe, ukuqhunyiswa kwebhola lokudonswa kwe-dopaminergic ngokweqile (61) kunganciphisa izimpendulo kumvuzo wemvelo noma izici ezihlobene nomvuzo ezenza kube nzima ukuvuselela i-dopamine, uma kuqhathaniswa nezidakamizwa ezibangelwa ngqo ukukhululwa kwe-dopamine; okungukuthi, isisindo semvelo singase siphumelele ukuvula indlela yokucubungula i-prefrontal yomuntu onomlutha futhi ngaleyo ndlela ayiphumeleli ekuthandeni ukhetho lwemigomo. Ukuphakama kwesimo esinjalo kungaba ukumelela kwezwe, ukukhululeka ngokweqile ekubhekiseni izidakamizwa ezihlobene nezidakamizwa futhi kude nokunye okukhethayo, ngaleyo ndlela kubangele ukulahlekelwa kokulawulwa kokusetshenziswa kwezidakamizwa eziveza ukulutha. Kuyathakazelisa ukuphawula ukuthi izifundo zokuqala ze-neuroimaging zibike amaphethini angavamile okwenziwa ku-cortex e-cingulate kanye ne-orbital prefrontal cortex ezifundweni eziluthayo (62-64).

Nakuba uphenyo oluningi lwe-neurobiological luyadingeka ukuze kuqondwe imiphumela yezimpawu ze-tonic ne-phasic dopamine, izindlela izidakamizwa eziluthayo eziphazamisayo ngazo, nemiphumela esebenzayo yalokhu kuphazanyiswa, ukuqonda kwamanje indima ye-dopamine kokubili ukuvuselela-ukuvuza nokufunda nokuvuselela -ukufunda okusebenzayo kunemiphumela eminingana ebalulekile ekuthuthukiseni ukulutha izidakamizwa. Amagama athi ukubikezela ukuthi ukutholakala kwezidakamizwa kuzothatha isisindo esikhulu sokugqugquzela, ngokusebenzisa izenzo ze-dopamine ku-nucleus accumbens ne-prefrontal cortex, nokuphindaphinda izidakamizwa zokuziphatha kwezidakamizwa kuzohlanganiswa ngamandla nge-dopamine izenzo ku-prefrontal cortex nase-dorsal striatum (9, 18, 19, 23, 65).

Imiphumela Yembono Yezinhlawulo Ezihlobene Nezidakamizwa

Isikhuthazo-umvuzo kanye nesikhuthazo-isenzo sokufunda sihlobanisa izinkomba ezithile, ezenzeka ngaphakathi kwezimo ezithile, ezinemiphumela ethile efana "nokufuna" umklomelo, ukuthatha isenzo ukuthola umvuzo, nokusetshenziswa komvuzo. (Isici esibalulekile somongo ukuthi ngabe inkomba ihanjiswa kakhulu noma ngaphansi komvuzo [66]; isibonelo, ukubhekana nokubhekwa kwezidakamizwa ebhokisathri kunomphumela ohlukile wesenzo kunokubhekana nokufana okufanayo emgwaqweni.) Ukufunda ukubaluleka kokuqamba nokuxhuma lolo lwazi ngokuphendula okufanele kudinga ukugcinwa kwamaphethini athile olwazi ebuchosheni. Lolu lwazi olulondoloziwe kufanele lunikeze izethulo zangaphakathi zokuvuselela okuhlobene nomvuzo, ukulinganisa kwayo, kanye nokulandelana kwezinyathelo ezenzakalelayo ukuze isiqephu singabangela impendulo yokuziphatha ephumelelayo futhi ephumelelayo (19). Okufanayo kufanele kube yiqiniso emaceleni aversive ukuthi ingozi yesignali.

Uma i-hypothesis yokubikezela-iphutha yesenzo se-dopamine ilungile, i-dopamine ye-phasic iyadingeka ukuze ubuchopho buyekeze ukubikezela kokubikezela kwamagama. Uma i-dopamine-gating hypothesis yomsebenzi we-prefrontal cortex ilungile, i-dopamine ye-phasic iyadingeka ukuvuselela ukukhethwa komgomo. Kunoma yikuphi, Nokho, i-dopamine inikeza ulwazi olujwayelekile mayelana nesimo esishukumisayo senyama; i-dopamine neurons ayicacisi ulwazi oluningiliziwe mayelana nemigomo ehlobene nomvuzo, izinhlelo, noma izenzo. Ukwakhiwa kwesistimu ye-dopamine-inani elincane kakhulu lamagciwane esitholakala emkhatsini we-midbrain engase avuke ngokubambisana futhi afake kabanzi kulo lonke i-forebrain, ne-neurons elilodwa elingenakulinganiswa kakhulu-alinakho ukugcina ulwazi oluqondile (67). Esikhundleni salokho, le ndlela yokwakha "efana ne-spray" ilungele ukuxhumanisa izimpendulo ezenzakalweni ezibalulekile kuzo zonke izijikelezo eziningi zobuchopho ezisekela ukuvezwa okuqondile kolwazi lwezinzwa noma ukulandelana kwezenzo. Imininingwane eqondile mayelana nesikhuthazi nokuthi ikubikezelani (isb. Ukuthi umhubhe othile, isiko elithile, noma iphunga elithile — kepha hhayi iphunga elihlobene kakhulu — libikezela ukulethwa kwezidakamizwa) kuncike ezinhlelweni zezinzwa nezinkumbulo eziqopha imininingwane yesipiliyoni ngokuthembeka okuphezulu. Imininingwane ethile mayelana nezinkomba, ukuhlolwa kokubaluleka kwazo, nezimpendulo zezimoto ezifundwayo kuncike kumasekethe asekela ukunemba kwe-point-to-point neurotransmission eqondile futhi asebenzise ama-neurotransmitter ajabulisayo njenge-glutamate. Ngakho-ke, ukuxhumana okuhlangene phakathi kwe-glutamate ne-dopamine neurons kuzakhiwo ezahlukahlukene ezisebenza njenge-nucleus accumbens, i-prefrontal cortex, i-amygdala, ne-dorsal striatum (68, 69) okuletha ulwazi oluthile lokuqondisa noma ukulandelana kwezinyathelo ezithile nolwazi mayelana nesimo esishukumisayo sezinto eziphilayo kanye nesibindi sokubakhuthaza kwezimo emvelweni. Izidingo zokusebenza zokurekhoda ulwazi oluningiliziwe mayelana nezimo ezihlobene nomvuzo nezimpendulo zesenzo cishe zifana nalezi zindlela ezingezansi zememori yesikhathi eside ezihambisanayo, okulandela ngqo ukucabanga ukuthi ukulutha umlutha kubonisa ukuthunjwa kwezintambo zezinkumbulo ezihlobene nomvuzo (11, 19).

Robinson neBerridge (30, 70) uhlongozwa umbono ohlukile-ukugqugquzela ukukhuthaza ukukhuza umlutha. Kulo mbono, ukuphathwa kwezidakamizwa nsuku zonke kuveza ukubekezela kwezinye izidakamizwa kodwa ukuthuthukiswa okuqhubekayo-noma ukukhuthaza-kwabanye (71). Isibonelo, kumagundane, ukujova kwansuku zonke kwe-cocaine noma i-amphetamine kuveza ukwanda okuqhubekayo komsebenzi wokwakha. Ukuhlonza isisindo esimnandi sokulutha umlutha ngoba ukugqugquzela kuyinkqubo ehlala isikhathi eside futhi ngoba ezinye izinhlobo zokukhuthaza zingabonakaliswa ngendlela exhomekeke esimweni (72). Ngakho-ke, ngokwesibonelo, uma amagundane ethola umjovo we-amphetamine nsuku zonke ekhejini lokuhlola kunamakheji abo asekhaya, akhombisa isimilo sokuqina se-locomotor lapho ebekwa futhi kulelo kheji lokuhlola. Umbono wokukhuthaza ukugqugquzela ukuthi njengoba nje nokuziphatha kwe-locomotor kungenziwa kukhuthazwe, ukuphathwa kwezidakamizwa okuphindaphindwayo kuvuselela uhlelo lwe-neural olunikeza amandla okukhuthaza (ngokungafani nenani le-hedonic noma "ukuthanda") kwizidakamizwa nezinkomba ezihlobene nezidakamizwa. Lokhu kuzikhuthaza kungaholela "ekufuneni" okukhulu kwezidakamizwa ezingenziwa zisebenze ngokuhambisana nezidakamizwa (30, 70). Ngokuyinhloko, ukubukwa kokukhuthaza ukuvuselela kuhambisana nombono wokuthi i-dopamine isebenza njengesignali yokubikezela iphutha lokuvuza (9). Kungase kubonakale kungenakuphikisana ukuthi ukukhuthazwa kwezikhuthazo ezihlobene nezidakamizwa kuthuthukiswa kubantu abanomlutha. Ngaphezu kwalokho, akukho ukuphikisana ukuthi ikhono lalezi zici zokuqalisa ukufuna izidakamizwa noma ukufuna izidakamizwa kuxhomeke ekusebenzisaneni kokufunda. Iphuzu lokungavumelani kungakhathaliseki ukuthi indlela yokwazisa i-neural yokunakekelwa, njengamanje eqondakalayo kusukela ezinhlobonhlobo zezilwane, idlala indima ebalulekile ekuluthweni komuntu. Ezilwaneni zezilwane, ukuziphatha okukhuthazwayo kokuhlelwa kokuqala kuqaliswa endaweni ye-ventral tegmental bese kuboniswa ku-nucleus accumbens (73, 74), mhlawumbe ngokusebenzisa ngcono izimpendulo ze-dopamine. Njengoba kunikezwe ukuthi i-homogeneity ehambisana nengxenye ye-ventral tegmental projection kuya kwi-nucleus accumbens noma i-prefrontal cortex kanye nekhono lalezi zilinganiso zokusebenzisana ne-neurons eminingi, kunzima ukuchaza ukuthi ukuphendula okunjalo okuqinisekisiwe (i-sensitized) izixhumanisi ezihlobene ngaphandle kokubiza izindlela zokukhumbula inhlangano. Naphezu kwezincwadi zokuhlola ezididekile, ubufakazi obamuva obuvela ekucwaningweni kwamagundane okugaya izakhi zofuzo ezingenayo ukusebenza ama-AMPA glutamate receptors athola ukuhlukaniswa phakathi kokwehliswa kwe-cocaine eyenziwa yi-locomotor (okugcinwe kumagundane wokugodla) nokufunda okuhlangene; okungukuthi, amagundane ayengasabonakali impendulo yokuhlelwa kwempahla uma efakwe kumongo owawuhlotshaniswa ngaphambili ne-cocaine, futhi abangekhombise ukukhethwa kwendawo efanelekile (75). Okungenani lezi zivivinyo ziqokomisa indima ebalulekile yezinhlelo zokufunda zokuxhumana zokufaka ikhodi ethize izigcawu zezidakamizwa nokuxhuma lezi zici ethize izimpendulo (19, 23). Noma ngabe ukuboniswa kufanele kuboniswe kubantu (okungazange kwenzeke ngokuzwakalayo), akucaci ukuthi indima yayo ingaba ngaphezu kokuthuthukisa izindlela zokufunda ezixhomeke ku-dopamine ngokukhulisa ukukhululwa kwe-dopamine ezimweni ezithile. Ekugcineni lezo zindlela zokufunda ezibophezela ukufaka ikhomishini yezinto ezicacile kakhulu, eziqine kakhulu izidakamizwa kanye nokuzixhumanisa nezimo ezithile zokuzibulala izidakamizwa kanye nezimpendulo zomzwelo.

Ekugcineni, incazelo yokulutha umlutha kudinga inkolelo yokuphikelela kwayo. Imibuzo eminingi ihlala ngokuphathelene nezinqubo ezenzeka ngayo izinkumbulo zesikhathi eside noma iminyaka yonke (15, 16, 76). Kusukela kulo mbono, izimpendulo zengqondo ye-dopamine ezizwakalayo ezibangelwa izidakamizwa nezidakamizwa zingase ziholele ekuhlanganiseni okuthuthukisiwe kwezinkumbulo ezihlobene nezidakamizwa, kodwa ukuphikelela kokulutha komzimba kubonakala sengathi kusekelwe ekulungiseni izivumelanisa nezicubungula ezicatshangelwa ukuthi ziyisici inkumbulo ye-associative yesikhathi eside (15, 16).

Izindlela zeMeluleki NeziMlutha Zokulutha Umlutha kanye neMemori Yesikhathi Eside

Njengoba kushiwo yingxoxo engenhla, izindlela zamangqamuzana namaselula okulutha kumazinga okuziphatha nawamasistimu ekugcineni kufanele achaze i-1) ukuthi iziqephu eziphindaphindwayo zokukhishwa kwe-dopamine zihlanganisa kanjani izindlela zokusebenzisa izidakamizwa ekusebenziseni okuphoqelelwe, i-2) ukuthi ingozi yokuphinda ibuyele kumuthi- isimo samahhala singaqhubeka iminyaka, no-3) ukuthi izindlela ezihlobene nezidakamizwa zikulawula kanjani ukuziphatha. Izinqubo zokusayina zangaphakathi ezikhiqiza i-synaptic plasticity ziyindlela ekhangayo yokhetho lokulutha ngoba zingaguqula amasiginali abangelwa yizidakamizwa, njengokukhishwa kwe-dopamine, kube izinguquko zesikhathi eside ekusebenzeni kwe-neural futhi ekugcineni kube ukulungiswa kwamasekethe we-neuronal. I-Synaptic plasticity iyinkimbinkimbi, kepha ingahlukaniswa ngokwehlukana kube izindlela ezishintsha amandla noma "isisindo" sokuxhuma okukhona nalezo ezingadala ukwakheka kwe-synapse noma ukuqeda nokulungiswa kwesakhiwo sama-dendrites noma ama-axon (15).

Njengoba kuye kwachazwa, ukucaciswa kwezidakamizwa nezidakamizwa zabo nokulandelana okuqondene nokuziphatha kuphakamisa ukuthi okungenani ezinye zezindlela ezibhekiswe ekuluthweni kufanele zibe yizici ezihambisanayo kanye nezihlanganisi. Izindlela ezifanele kakhulu zokuzikhethela ukushintsha amandla e-synaptic, okubili okuhambisanayo nokuhlanganiswa kwe-synapse, kungukuthi kungakapheli isikhathi eside nokucindezeleka isikhathi eside. Lezi zinqubo ziye zaxilongwa ukuba zidlale indima ebalulekile ezinhlobonhlobo ze-plasticity ezithembele ekuhlangenwe nakho, kufaka phakathi izinhlobo ezahlukene zokufunda nokukhumbula (77, 78). Izinqubo ezinjalo ze-plasticaplasticity zizoholela ekuhleleni kabusha kwamaseli we-neural ngokushintsha i-gene ne-protein expression kuma-neurons athola izimpawu ezithuthukisiwe noma ezinciphile ngenxa yesikhundla eside noma ukucindezeleka isikhathi eside. Ukuba khona kwesikhathi eside kanye nokucindezeleka kwesikhathi eside kuye kwaba yindlela ebalulekile yokukhethwa kwezidakamizwa zokuguqulwa kwezidakamizwa umsebenzi wesifunda se-neural ezenziwa ukuba zibe nezidakamizwa (11). Kukhona ubufakazi obuhle bokuthi izindlela zombili zenzeka ku-nucleus accumbens nezinye izinhloso ze-mesolimbic dopamine neurons ngenxa yokulawulwa kwezidakamizwa, futhi ubufakazi obukhulayo bubonisa ukuthi bangadlala indima ebalulekile ekuthuthukiseni umlutha. Ingxoxo eningiliziwe yalezi zitholakele zidlula ububanzi balobu buhlolo (ngokubuyekezwa, bheka izinkomba 11, 79-81). Izindlela zamakhemikhali ezithatha isikhathi eside kanye nokucindezeleka kwesikhathi eside zihlanganisa ukulawulwa kwesimo se-phosphorylation samaprotheni ayisihluthulelo, ukuguqulwa kokutholakala kwe-glutamate receptors ku-synapse, nokulawulwa kwezwi lesakhi (78, 82).

Umbuzo wokuthi izinkumbulo ziyaqhubeka kanjani (15, 16, 76) ihambisana kakhulu nokulutha umlutha futhi engakaphendulwanga okwanelisayo, kodwa ukuphikelela ekugcineni kucatshangwa ukuthi kuhilela ukuhlelwa kabusha kwe-synapses nama-circuits. Imiphumela yokuqala eyakhayo ibonise ukuthi i-amphetamine ne-cocaine ingaveza ukuguqulwa kwemvelo kuma-dendrites ngaphakathi kwe-nucleus accumbens ne-prefrontal cortex (83, 84).

Indlela yokubaluleka ebalulekile yokulungiswa ngokomzimba kwama-dendrites, axons, kanye nama-synapses ukuguqulwa kwezidakamizwa ekukhulumeni kwegenesheni noma ekuhumusheni kwamaprotheni. Ngenkathi yokudlula isikhathi, izinhlobo ezimbili zokulawulwa kwezakhi zofuzo zingaba nomthelela kwimemori yesikhathi eside, kufaka phakathi izinqubo zokukhumbula inqubo yokulutha: 1) ukuhlala isikhathi eside noma phansi-isimiso somqondo wegesi noma amaprotheni ne-2 ) ukuphazamiseka okuncane kwezakhi zofuzo (noma ukuhumusha kwamaprotheni) okuholela ekuguqulweni ngokomzimba kwe-synapses (okungukuthi, ukuguquguquka kwemvelo okuholela ekuguqulweni kwamandla ase-synaptic, isizukulwane sesigcino esisha, noma ukusika izi-synapses ezikhona), kanjalo, ekuhleleni kabusha izifunda. Zombili izinhlobo zokuguquguquka kwesiginja segeni ziye zabonwa ngokuphendula ukugqugquzela i-dopamine kanye nezidakamizwa eziluthayo ezifana ne-cocaine (85, 86).

Ukuguqulwa kwamangqamuzana okude kunazo zonke okwamanje okuyaziwa ukuthi kuzokwenzeka ekuphenduleni izidakamizwa eziluthayo (nezinye izinyathelo) ku-nucleus accumbens ne-dorsal striatum kuphakanyisiwe-ukulawulwa kwezinhlobo ezizinzile, ezenziwe ngemuva kwe-posttranslationally ye-factor factor ΔFosB (85). Ngomunye umkhawulo wesimiso se-temporal sithatha isikhathi (imizuzu kuya emahoreni) ukubonakaliswa kwenani elikhulu lezakhi zofuzo cishe kuxhomeke ekusebenziseni i-dopamine D₁ i-receptors kanye ne-transcription factor factor CREB, isakhi se-AMP-response se-cyclic esibopha amaprotheni (86). I-CREB isebenze yi-protein kinase eminingi, kufaka phakathi i-protein kinase encike e-AMP ne-Ca eziningana²⁺- amaprotheni kinase-dependent ezifana ne-calcium / calmodulin encike kumaprotheni kinase uhlobo IV (87, 88). Ngoba i-CREB ingasabela kokubili kwe-AMP ne-Ca²⁺ izindlela futhi ngakho-ke kungenza njengomtshina wengozi, ukusebenza kwayo kubonwe njengomuntu ozobamba iqhaza ekusebenzeni isikhathi eside nasenkumbulo yokuhlangana. Eqinisweni, iqembu elikhulu locwaningo kokubili ezinganeni ezingenalutho kanye namagundane lisekela indima ebalulekile ku-CREB kwimemori yesikhathi eside (ukubuyekezwa, bheka izinkomba 87 futhi 88).

Njengoba kunikezwe inkolelo yokulutha umlutha njengokwakheka kwempilo yengqondo yesikhathi eside, kunikezwa indima eyakheke kahle ye-CREB ezinhlotsheni eziningi zememori yesikhathi eside (87, 88), futhi unikezwe ikhono le-cocaine ne-amphetamine ukuze kusebenze i-CREB (88-90), kuye kwaba nesithakazelo esikhulu ekwenzeni okungenzeka kwe-CREB ekuhlanganiseni izinkumbulo ezihlobene nomvuzo (11, 19). Ubufakazi obuqondile bendima enjalo namanje buthaka. Nokho, kukhona ubufakazi obunamandla obuxhumanisa i-cocaine ne-amphetamine yokuvuselela i-dopamine D₁ ireptor-CREB indlela yokubekezela nokuthembela. I-gene egxile kakhulu ekuhloswe yi-CREB okungase ihileleke ekubekezelelweni nasekuxhasweni yi-gay prodynorphin (91-93), ehlanganisa ama-peptide e-opioid e-opioid endogenous apiopid opioid receptor agonists. I-Cocaine noma i-amphetamine iholela ekuvuseleleni i-dopamine ye-D₁ i-receptors kwi-neurons ku-nucleus accumbens ne-dorsal striatum, eholela ekudaleni i-CREB phosphorylation nokusebenza kwe-prodynorphin yezwi legalo (93). Ama-peptide e-dynorphin avela athunyelwa kuma-neonons abathintekayo aphindaphindiwe, okuvimbela ukukhululwa kwe-dopamine kuma-terminals of midbrain dopamine neurons, ngaleyo ndlela ukunciphisa ukuphendula kwezinhlelo ze-dopamine (91, 94). D₁ Ukwandiswa kwe-receptor okukhulunywe ngayo ku-dynorphin kungahle kuthathwe ngokuthi i-homeostatic evumelaniswe nokuvuselela ngokweqile kwe-dopamine ye-target neurons ku-nucleus accumbens ne-dorsal striatum ebuyisela emuva ekunciphiseni ukukhululwa kwe-dopamine (91). Ngokuvumelana nalo mbono, ukucindezeleka okukhulu kwe-CREB ku-nucleus accumbens okukhulunywe yi-vector ye-viral kwandisa i-prodynorphin yezakhi zegesi futhi kunciphisa imiphumela emihle ye-cocaine (95). Imiphumela emihle ye-cocaine ingabuyiselwa kulo mfanekiso ngokuphathwa komphikisi we-kappa receptor (95).

Ukulungiswa kwe-homeostatic njengokungeniswa kwe-dynorphin, okunciphisa ukuphendula kwezinhlelo ze-dopamine, kuzobonakala sengathi idlala indima ekuxhomekeni nasekuhoxisweni (26, 96). Njengoba kunikezwe indima elinganiselwe yokuthembela ekutheni i-pathogenesis yokulutha (6, 11, 19, 27, 40), ezinye izifundo ziye zagxila ekusebenziseni izindlela ezingamakhemikhali ezingase zibe negalelo ekuthuthukiseni umvuzo wezidakamizwa (ukubuyekezwa, bheka izinkomba 12, 13). I-candidate efundela phambili kakhulu kuze kube yimanje yiyona factor factor ΔFosB. Ukwehliswa kwesikhathi eside kwe-ΔFosB ku-model ye-transgenic ye-glue engabonakali kwandise imiphumela emihle ye-cocaine, futhi ukugqama okukhulu kwe-CREB nokubonakaliswa kwesikhashana kwe-ΔFosB kunomphumela ohlukile wokunciphisa umuthi wezidakamizwa (97). Ngaphezu kwalokho, iphrofayli ehlukile ngokungafaniyo yesiginja segciwane embukisweni wegundane yenziwa ngokubonakaliswa kwesikhathi eside kwe-ΔFosB, uma kuqhathaniswa ne-CREB noma inkulumo yesikhashana ye-ΔFosB (97). Imiphumela yalezi zithole ukuthi okungenani izakhi zofuzo ezivezwe ngaphansi kwe-CREB, njenge-pro-dynorphin gene (93), zibandakanyeka ekubekezelelweni nasekuthembekeni futhi ukuthi izakhi zofuzo ezivezwe ngaphansi kwe-ΔFosB zingase zibe ukhetho lokuthuthukisa izimpendulo zokuthola imivuzo kanye nezinkulumo ezihlobene nomvuzo. Ukuhlaziywa kuyinkimbinkimbi ngobuchwepheshe bokuhlola obukhona ngoba zonke izindlela zokudala i-CREB ngokweqile ngokweqile zidlula isikhathi esijwayelekile (amaminithi) we-CREB phosphorylation ne-dephosphorylation ngaphansi kwezimo ezivamile. Ngakho-ke, indima ye-CREB ekuhlanganiseni izinkumbulo ezihlobene nomvuzo ezihlobene nomvuzo akufanele zilahlwe ngesisekelo sobufakazi obukhona. Imizamo emisha yokuthuthukisa izindlela zokulutha izilwane (98, 99) ingase ibonakale isebenziseka kakhulu emizamweni yokukhuluma ngokusetshenziswa kwezidakamizwa-inducible expression ye-genetic synaptic, ukulungisa kabusha kwe-synaptic, nokuziphatha okufanele.

iziphetho

abstract  |  Ukuqotshwa kwezinhlelo ze-Neural ezihlobene nokuphishekela imivuzo  |  Imiphumela Yembono Yezinhlawulo Ezihlobene Nezidakamizwa  |  Izindlela zeMeluleki NeziMlutha Zokulutha Umlutha kanye neMemori Yesikhathi Eside  |  iziphetho  |  Okubhekwayo

I-dopamine hypothesis yesenzo sezidakamizwa ithola imali engaphansi kweminyaka engamashumi amabili edlule (38-40). Ngaleso sikhathi, i-dopamine yayicatshangelwa ngokuyinhloko njengesignali ye-hedonic, futhi ukulutha ngokweqile kwakuqondwa ikakhulukazi ngokwemigomo ye-hedonic, ngokuxhomeka nokuhoxiswa kubonakala njengabashayeli abakhulu bokuthatha izidakamizwa ngokuphoqelela. Imizamo yakamuva yamuva emazingeni ahlukene okuhlaziywa inikeze isithombe esicacile nakakhulu kakhulu sokusebenza kwesenzo se-dopamine nokuthi singayikhiqiza kanjani umlutha, kodwa ulwazi olusha kanye nokwakhiwa okusha kwemibono kuye kwaphakamisa imibuzo eminingi njengoba baphendule. Kulesi sibuyekezo ngacabanga ukuthi lokho esikwaziyo mayelana nokulutha komlutha kuze kube yimanje kuyathathwa kangcono ngombono wokuthi ubhekisela ekusetshenzisweni kwemvelo kwamasu okufunda okuhlobene nomvuzo kanye nenkumbulo. Noma kunjalo, kufanele futhi kucace ukuthi izingcezu eziningi ze-puzzle azikho, kufaka phakathi ezinye izinto ezinkulu, njengendlela ecacile lapho izidakamizwa ezihlukahlukene ziphazamisa ukubonakaliswa kwe-tonic nokuphazamiseka kwe-dopamine kuma-circuits ahlukene, imiphumela esebenzayo yalokhu kuphazanyiswa, futhi izindlela zamaselula namakhemikhali lapho izidakamizwa eziluthayo zilungisa kabusha i-synapses nezifunda. Lezi zinselelo nokho, i-neuroscience eyisisekelo neyomtholampilo iye yakhiqiza isithombe esinembile kakhulu futhi esinamandla sokulutha kunalokho esasineminyaka embalwa edlule.

Utholile u-Aug. 19, i-2004; ukubuyekezwa kwamukelwe ngo-Nov. 15, i-2004; yamukele uDis. 3, 2004. Kusuka eMnyangweni we-Neurobiology, i-Harvard Medical School, eBoston; ne-Office of the Provost, i-Harvard University. Ikheli lekheli bese uphinde ucele uDkt Hyman, i-Office of the Provost, iMahton Hall, i-Harvard University, i-Cambridge, i-MA 02138; [i-imeyili ivikelwe] (e-mail).

Okubhekwayo

abstract  |  Ukuqotshwa kwezinhlelo ze-Neural ezihlobene nokuphishekela imivuzo  |  Imiphumela Yembono Yezinhlawulo Ezihlobene Nezidakamizwa  |  Izindlela zeMeluleki NeziMlutha Zokulutha Umlutha kanye neMemori Yesikhathi Eside  |  iziphetho  |  Okubhekwayo