Umlutha: ngaphaya kwe-dopamine umvuzo wesekethe (2011)

I-DA kunye neMvuzo yeziyobisi eAcute

Zonke iziyobisi ezinokukhokelela ekwandiseni umlutha we-DA kwi-NAc, ephunyezwa ngokusebenzisana kwabo kunye neethagethi ezahlukeneyo zeemolekyuli ziiklasi ezahlukeneyo zamachiza (6) (1 Table). Ebantwini, uphando lwe-PET lubonise ukuba amayeza amaninzi [7, 8, i-nicotine (9), Utywala10), kunye nentsangu (11)] ukwandisa i-DA kwi-dorsal kunye ne-ventral striatum (apho i-NAc ikhona). Ezi zifundo zisebenzise i-radiotracer ebophelela kwi-DA D2 receptors (D2Rs) kodwa kuphela xa ezi zingahlali yi-DA (okt, [¹¹C]raclopride). Ngokuthelekisa ukubophelela emva kwe-placebo nasemva kwechiza, ezi zifundo ziqikelela ukuncipha kokufumaneka kwe-D2R okubangelwa lichiza, ezihambelana nokunyuka kwe-DA (12). Uninzi lophononongo luxele ukuba abathathi-nxaxheba ababonisa ukonyuka okukhulu kwe-DA kunye nechiza bakwaxela kakhulu "phezulu" okanye "euphoria" (iref ehlaziyiweyo. 13).

Uphononongo lwe-PET lukwabonise ukuba isantya esingena ngaso ichiza kwaye sishiye ingqondo (iprofayili ye-pharmacokinetic) ibalulekile kwiziphumo zalo zokuqinisa. Ngokukodwa, uphando lwe-PET lwe-brain pharmacokinetics yamachiza abhalwe nge-positron emitters abonisa ukuba amanqanaba aphezulu ebuchotsheni bomntu afikeleleka kwimizuzu eyi-10 emva kokulawulwa kwe-iv kwaye oku kuthatyathwa kwechiza ngokukhawuleza kuhambelana nokuphezulu (13) (Ikhiwane. 1). Ewe, kwinqanaba elilinganayo le-cocaine efikelela ebuchotsheni (evavanyiweyo njengenqanaba elilinganayo le-DA transporter blockade), xa icocaine yangena ngokukhawuleza ebuchosheni (itshayiwe kunye nolawulo lwe-iv), yaphakamisa ukuphakama okuthe kratya kunaxa yangena ingqondo kancinci kancinci ( wancwina) (14). Oku kuhambelana nezifundo zangaphambi kweklinikhi ezibonisa ukuba ngokukhawuleza ukungena kwechiza ebuchotsheni, kokukhona kunamandla okuqinisa iziphumo zalo (15). Oku mhlawumbi kubonakalisa inyani yokuba ukunyuka okukhawulezileyo kunye nokukhulu kwe-DA okubangelwa ngamachiza kulinganisa ukunyuka okukhawulezayo kunye nokukhulu kwe-DA okuhambelana nokudubula kwe-DA okuhambelana nobuchopho kunye nokudlulisa ulwazi malunga nomvuzo kunye nokunyaniseka (16).

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Umzobo 1.

I-Pharmacokinetics yeziyobisi ezikhuthazayo kwingqondo yomntu kunye nobudlelwane "abaphezulu." (A) Imifanekiso yeAxial yobuchopho yosasazo lwe [¹¹C] icocaine, [¹¹C]MP, kunye [¹¹C]methamphetamine ngamaxesha ahlukeneyo (imizuzu) emva kolawulo lwayo. (B) Ijika lomsebenzi wexesha loxinaniso lwe [¹¹C] icocaine, [¹¹C]MP, kunye [¹¹C]methamphetamine kwi-striatum ecaleni kwekhosi yethutyana yabanamava aphezulu emva kwe-iv ulawulo lwala machiza. Qaphela ukuba ukuthathwa kwengqondo ngokukhawuleza kula machiza kuhambelana nekhondo lexeshana eliphezulu, elicebisa ukuba phezulu kunxulunyaniswa "nomlinganiselo wokunyuka kwe-DA." Ngokwahlukileyo, ukucaciswa kwabo kubonisa imbalelwano ephezulu ye-cocaine kunye neye-methamphetamine kodwa ingeyiyo yeMP. Umahluko phakathi kwe-MP kunye ne-cocaine unokubonisa umahluko kwizinga labo lokucoceka kunye nokuba phakathi kwe-MP kunye ne-methamphetamine inokubonisa iindlela zabo ezahlukeneyo zokwenza. Ngokukodwa, ngenxa yokuba i-MP kunye ne-cocaine yonyusa i-DA ngokuvimba abathuthi be-DA, ukonyuka kwe-DA kupheliswa kukusebenza kwe-autoreceptor, ethintela ukukhutshwa kwe-DA. Kwi-cocaine, isantya sayo esikhawulezayo sokucaciswa (i-20-min-half-life in brain) iphumela ekubeni i-autoreceptor isebenze ixesha elifutshane, ngelixa i-MP, ukucocwa kwayo kancinci (i-60-min-half-life) ikhokelela ekuthinteleni ixesha elide lokukhululwa kwe-DA. ngama-autoreceptors, aphelisa ukuphakama nangona ichiza lisesengqondweni. Ngokwahlukileyo, i-methamphetamine, eyi-DA releaser, ayinandaba ne-autoreceptor activation; ngoko ke, ukonyuka kweDA akupheliswanga yile ndlela, kubalwa ixesha elide elihlala liphezulu. Ilungiswe ukusuka kwisalathiso. 18. Copyright (1995) American Medical Association. Onke Amalungelo Agciniwe. Iprintwe kwakhona kwiref. 43. Copyright (2008), ngemvume evela Elsevier.

Ukonyuka kwe-DA okubangelwa ziziyobisi kwi-NAc kwenzeka kubantu abangakhobokiyo kunye nakwizifundo ezikhobokileyo, nto leyo ephakamisa umbuzo wendlela abanxulumana ngayo nokulutha.

Ukuqala, kukho ubungqina obandayo bokuba indima ye-DA ekuqiniseni intsonkothe ​​ngakumbi kunokubhala nje ikhowudi yomvuzo nge-se (ulonwabo lwe-hedonic) kwaye eso sivuseleli esibangela ukwanda okukhawulezayo nokukhulu kwe-DA kukwadala iimpendulo ezicwangcisiweyo kwaye zenze inkuthazo yenkuthazo yokuzifumana (17). Ngokumisela imeko, ukuvuselela okungathathi hlangothi okudityaniswe nomxhasi (oko kukuthi, umncedi wendalo, iziyobisi) ufumana amandla ngokwawo okunyusa i-DA kwi-striatum (kubandakanywa ne-NAc) ngokulindela umvuzo, kwaye oku kuhambelana nokufuna iziyobisi (17). Kwizilwanyana eziqeqeshelwe ukulindela ukuqiniswa kwendalo (ukutya) xa kubonakaliswe kwi-stimulus conditioned (CS), i-neurons ye-DA iyayeka ukuphendula kwi-primary reinforcer kwaye, endaweni yoko, iphendule kwi-CS.16). Ubungakanani benkqubo efanayo eyenzekayo ekuphenduleni iziyobisi zokuxhatshazwa akucaci, nangona kunjalo, ngenxa yokuba iziyobisi, ngezenzo zabo ze-pharmacological, zingenza ngokuthe ngqo i-DA neurons (okt, nicotine) okanye ukwandisa ukukhululwa kwe-DA (okt, amphetamine)1 Table).

Ukuphendula oku, sithelekise ukonyuka kwe-DA okubangelwa sisiyobisi esivuselelayo i-methylphenidate (MP) phakathi kwezifundo ezikhotyokiswe yi-cocaine kunye nolawulo. Njengecocaine, iMP yonyusa iDA ngokuvimba abathuthi beDA; omabini amachiza anosasazo olufanayo kwingqondo yomntu kwaye aneempembelelo zokuziphatha ezifanayo xa enikwe iv (18). Kwimixholo ye-cocaine-addicted (n = 20, i-detoxified 3-6 wk), sibonise ukuthotywa okuphawulweyo kwe-MP-induced DA ukunyuka kwi-striatum (i-50% ephantsi) kunye nokunyuka kweengxelo ezizimeleyo eziphezulu, xa kuthelekiswa nolawulo olungasebenzisi kakubi iziyobisi (n = 23). Iziphumo ezifanayo zaxelwa emva kokulawulwa kwe-iv amphetamine (elinye iyeza elivuselelayo) kutsha nje abaxhaphazi be-cocaine (i-detoxified 2 wk), ekwabonise ukukhutshwa kwe-DA kwi-striatum kunye neengxelo ezizimeleyo ze-euphoria (19). Ngenxa yokuba ukudideka kwezi zifundo kwakunokwenzeka ukuba ukurhoxiswa kweziyobisi kubangelwe iimpendulo ze-DA ezithintelweyo, siye saphinda olu phononongo kwizifundo ezisebenzayo ze-cocaine (n = 19, akukho tyhefu) (20). Kubaxhaphazi abasebenzayo be-cocaine, utshintsho lwe-DA lwe-MP aluzange lwahluke kwi-placebo kwaye utshintsho lwe-DA lwalungaphantsi kwe-80% kunolawulo.n = 24); iingxelo zokuzixela eziphezulu nazo zathotywa (Ikhiwane. 2). Ukuphawulwa okuphawulweyo kwe-DA yokubulawa konyuka okwesibini kwiMP okanye kwi-amphetamine kubhaliwe nakwizinxila ezikhutshiweyo (zihlaziywe kwi-ref. 13). Ukuba, njengoko kukholelwa ngoku, i-DA eyenzelwe iziyobisi yonyuka kumvuzo weziyobisi we-NAc, kutheni le nto abantu abakhotyokiswe yi-cocaine, ababonisa ukuthotywa okuphawulwayo kokunyuka kwe-DA okubangelwa ziziyobisi, bathathe ichiza ngokunyanzelekileyo?

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Umzobo 2.

Utshintsho lwe-DA olunyanzelwa yi-IV MP kulawulo nakwizifundo ezikhotyokiswe yi-cocaine. (A) I-avareji yesakhono sokubhida esingenakubekelwa indawo (BP_ND) imifanekiso ye [¹¹C]raclopride kwizifundo ezisebenzayo ze-cocaine-addicted (n = 19) kunye nolawulo (n = 24) kuvavanywa emva kwe-placebo nasemva kwe-iv MP. (B) Ukufumaneka kwe-D2R (BP_ND) kwi-caudate, putamen, kunye ne-ventral striatum emva kwe-placebo (blue) nasemva kweMP (bomvu) kulawulo nakwizifundo ezikhotyokiswe yi-cocaine. I-MP yanciphisa i-D2R kulawulo kodwa hayi kwizifundo ezikhotyokiswe yi-cocaine. Qaphela ukuba abaxhaphazi be-cocaine babonisa zombini ukuncipha kokufumaneka kwe-D2R yesiseko (umlinganiselo we-placebo) kwaye yehla ekukhululweni kwe-DA xa inikwe i-iv MP (elinganiswa njengokuncipha kokufumaneka kwe-D2R ukusuka kwisiseko). Nangona umntu unokubuza ubungakanani bokufumaneka kwe-D2R ephantsi kwisifundo esikhotyokiswe yi-cocaine kuthintela ukukwazi ukubona ukwehla ngakumbi kwi-MP, into yokuba izifundo ezikhotyokiswe yi-cocaine zibonisa ukuncitshiswa kokufumaneka kwe-D2R xa bevezwe kwi-cocaine cues.Ikhiwane. 3) ibonisa ukuba iziphumo ezincitshisiweyo zeMP kwi [¹¹C]i-raclopride ebophelelayo ibonisa ukuhla kokukhululwa kwe-DA.

I-DA kunye neMiqathango kwiiNtlobo zeziyobisi

Inkcazo inokuvela kwinkqubo yokulungiswa kwemeko, enye ye-neuroadaptations yokuqala elandela ukuvezwa kweziyobisi kwaye ibandakanya i-DA phasic signaling (ikakhulukazi i-D1Rs) kunye neenguqu ze-synaptic kwi-NMDA kunye ne-AMPA receptors (imodyuli ye-glutamate) (21, 22). Ezi mpendulo zinemeko kukholelwa ukuba ziphantsi komnqweno onzulu wechiza (umnqweno) kunye nokusetyenziswa okunyanzelekileyo okwenzekayo xa abantu abakhotyokisiweyo bevezwa kwizikhokelo zeziyobisi.

Ukuvavanya ukuba iziyobisi ezikwimeko yeziyobisi zinokunyusa i-DA kwizifundo ezikhotyokiswe yi-cocaine, siye savavanya abantu abasebenzisa iziyobisi ze-cocaine (n = 18) xa abafundi bebukele ividiyo engathathi hlangothi (imifanekiso yendalo) vs.23). Iimpawu ze-Cocaine zonyuse kakhulu i-DA kwi-dorsal striatum, kwaye ubukhulu bolu nyuso bunxulunyaniswa namava okunqwenela (Ikhiwane. 3); iziphumo ezifanayo zixelwe yenye ilabhoratri (24). Izifundo ezinokonyuka okukhulu kwe-DA kwi-dorsal striatum nazo zinawona manqaku aphezulu kwimilinganiselo yobungqongqo bomlutha. Ngenxa yokuba i-dorsal striatum ibandakanyeka ekufundeni ngokuziqhelanisa, olu nxulumano lunokubonisa ukomelela kwemikhwa njengoko kuqhubeka ukukhotyokiswa. Oku kuphakamisa ukuba ukuphazamiseka okusisiseko kumlutha kunokuba ziimpendulo ezibangelwa yi-DA ezikhokelela kwimikhwa ekhokelela ekusetyenzisweni kweziyobisi okunyanzelekileyo. Kangangokuba kwizifundo ezikhotyokiswe yi-cocaine, ukonyuka kwe-DA okubangelwa ziimpawu ezikwimeko kubonakala ngathi kukhulu kunezo ziveliswa lichiza elikhuthazayo, oku kuphakamisa ukuba iimpendulo ezikwimeko ethile zinokuqhuba umqondiso we-DA obangela kwaye ugcine inkuthazo yokuthatha ichiza. Ukuya kuthi ga kwinqanaba lokuba iyeza (naxa iziphumo zalo zokuphucula i-DA zincitshisiwe) liqikelela umvuzo, isenzo solawulo lwalo (umzekelo, inaliti, ukutshaya) inokuba yinto enemeko kwaye, ngenxa yoko, inokunyusa i-DA. Ke, nangona iziyobisi zinokukhokelela ekukhululweni kwe-DA kwi-striatum (umqondiso womvuzo), ngolawulo oluphindaphindiweyo kwaye njengoko imikhwa ikhula, kubonakala ngathi kukho utshintsho kunyuko lwe-DA ukusuka kwichiza ukuya kwi-CS, njengoko kuxeliwe kubaxhasi bendalo.16). Izifundo zangaphambi kweklinikhi zibonakalise ukuba uqikelelo lwe-glutamatergic ukusuka kwi-prefrontal cortex ukuya kwi-VTA/SN kunye ne-NAc zilamla ezi mpendulo zinemeko.5).

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Umzobo 3.

Utshintsho lwe-DA olubangelwa ziimeko ezibekwe kwimixholo esebenzayo ye-cocaine. (A) I-avareji yesakhono sokubhida esingenakubekelwa indawo (BP_ND) imifanekiso ye [¹¹C]raclopride kwizifundo ezikhotyokiswe yi-cocaine (n = 17) ivavanyiwe ngelixa ujonge ividiyo engathathi hlangothi (imifanekiso yendalo) kwaye ngelixa ujonge ividiyo ye-cocaine-cues (izifundo ezilawula i-cocaine). (B) Ukufumaneka kwe-D2R (BP_ND) kwi-caudate, putamen, kunye ne-ventral striatum yevidiyo engathathi hlangothi (blue) kunye nevidiyo ye-cocaine-cues (bomvu). Iimpawu ze-cocaine zehlise i-D2R kwi-caudate kunye ne-putamen. (CUlungelelwaniso phakathi kotshintsho kwi-D2R (ebonisa ukonyuka kwe-DA) kunye neengxelo ezizimeleyo zokunqwenela i-cocaine ebangelwa yividiyo ye-cocaine-cues. Ilungiswe ukusuka kwisalathiso. 23.

I-DA kunye ne-Inhibitory Control in Addiction

Amandla okuthintela iimpendulo ezinamandla kunokwenzeka ukuba abe negalelo kumandla omntu wokuzibamba ekusebenziseni iziyobisi, kwaye ngenxa yoko ukuba sesichengeni kwakhe ekubeni likhoboka (25).

Izifundo ze-PET zibonise ukuba izifundo ezikhobokileyo zinokuncitshiswa okubonakalayo kwe-D2R efumaneka kwi-striatum eqhubeka iinyanga emva kokuchithwa kwexesha elide (kuhlaziywe kwi-ref. 13). Ukuphanda ukubaluleka kokusebenza kokunciphisa i-D2R yokubulala, siye savavanya ubudlelwane babo kunye nemilinganiselo yesiseko se-brain glucose metabolism (umakishi wokusebenza kwengqondo). Sibonisile ukuba ukuncitshiswa kwe-striatal D2R kunxulunyaniswa nokuncipha kwemetabolism kwi-orbitofrontal cortex (OFC), i-anterior cingulate gyrus (ACC), kunye ne-dorsolateral prefrontal cortex (DLPFC) (26-28) (Ikhiwane. 4). Ngenxa yokuba i-OFC, i-CG, kunye ne-DLPFC zibandakanyeka kuphawu olubalulekileyo, ulawulo oluthintelayo / ukulawulwa kweemvakalelo, kunye nokwenza izigqibo, sasibeke ukuba ukulawulwa kwabo okungafanelekanga yi-DA kwizifundo ezikhotyokisiweyo kunokuba sisiseko sexabiso lenkuthazo eyongeziweyo yeziyobisi kwindlela yabo yokuziphatha kunye nokuphulukana nolawulo. ngaphezu kokuthatha iziyobisi (29). Ukongeza, ngenxa yokuba ukonakaliswa kwe-OFC kunye ne-ACC kunxulunyaniswa nokuziphatha okunyanzelekileyo kunye nokungabinamdla, sibeke phantsi ukuba ukumodareyitha okungahambi kakuhle kwe-DA kule mimandla kunokuba sisiseko sokunyanzeliswa kunye nokunyanzeliswa kokutya kweziyobisi okubonwa kumlutha.30, 31). Ewe, kubaxhaphazi be-methamphetamine, i-D2R ephantsi yokubetha yayanyaniswa nokungabinamdla (32), kunye ne-D2R ephantsi yokubulala yayinxulunyaniswa nokungabinamdla kunye nolawulo olunyanzelekileyo lwe-cocaine kwiimpuku (33).

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Umzobo 4.

Unxulumano phakathi kokufumaneka kwe-D2R yokubulala kunye nemetabolism kwimimandla yobuchopho yangaphambili. (AImifanekiso ye-Axial yobuchopho yolawulo kunye nesifundo esikhotyokiswe yi-cocaine kwimifanekiso esisiseko yokufumaneka kwe-D2R kwi-striatum (efunyenwe nge- [¹¹C]raclopride) kunye ne-brain glucose metabolism kwi-OFC (efunyenwe kunye [¹⁸F]FDG). (BUnxulumano phakathi kwe-D2R yokubulala kunye ne-metabolism kwi-OFC kwi-cocaine-addicted kunye ne-methamphetamine-addicted subjects. Iprintwe kwakhona kwiref. 13, Copyright (2009), ngemvume evela Elsevier.

Kwakhona kunokwenzeka ukuba ubuthathaka bokuqala bokusetyenziswa kweziyobisi kwenzeka kwimimandla yangaphambili kwaye ukusetyenziswa kweziyobisi okuphindaphindiweyo kubangela ukuhla kwe-D2R yokubulala. Ewe, kuphononongo olwenziwa kwizifundo ezithe, ngaphandle komngcipheko omkhulu wokusela utywala (imbali yosapho entle yokusela utywala), bebengengabo butywala, sibonise ngaphezulu kokufumaneka kwe-D2R ye-striatal eqhelekileyo eyayanyaniswa nemetabolism eqhelekileyo kwi-OFC, ACC, kunye ne-DLPFC. (25). Sikutolike oku ukucebisa ukuba umsebenzi oqhelekileyo we-prefrontal unokuba ukhusele ezi zifundo ekusebenziseni kakubi utywala.

I-DA kunye neNkuthazo kubukhoboka

I-DA ikwabandakanyeka kwinkuthazo (okt, amandla, ukuzingisa, umzamo wokusukela ukuqinisa isivuseleli) ngolawulo lwayo lwemimandla ekujoliswe kuyo, kubandakanya i-NAc, i-ACC, i-OFC, i-DLPFC, i-amygdala, i-dorsal striatum, kunye ne-ventral pallidum (34).

Inkuthazo eyandisiweyo yokuthenga iziyobisi luphawu lokukhotyokiswa. Abantu abakhotyokiswe ziziyobisi baya kuhamba ngendlela egqithisileyo ukuze bafumane iziyobisi, nokuba oko kuya kuba nemiphumo emibi kakhulu (2). Ukufuna iziyobisi kunye nokusetyenziswa kweziyobisi kuba yeyona nto iphambili yenkuthazo, ethi ithathe indawo yeminye imisebenzi (35). Ke ngoko, isifundo esikhobokileyo siyavuswa kwaye siyakhuthazeka xa sifuna ukufumana ichiza kodwa sithande ukurhoxiswa kwaye singabi namdla xa sivezwe kwimisebenzi enganxulumananga neziyobisi. Olu tshintsho luye lwaphononongwa ngokuthelekisa iipateni zokuvula ingqondo ezenzekayo kunye nokuvezwa kwimikhombandlela enemeko kunye nezo zenzeka ngaphandle kwezi mpawu.

Ngokuchaseneyo nokuncipha komsebenzi wangaphambili oxelwe kubaxhaphazi be-cocaine e-detoxified xa ingavuselelwa ngamachiza okanye iziyobisi (zihlaziywe kwi-ref. 13), le mimandla yangaphambili iyasebenza xa abaxhaphazi be-cocaine bevezwa kumnqweno ovuselela inkanuko (nokuba ziziyobisi okanye iindlela) (36-39). Ngokufanayo, abaxhaphazi be-cocaine bafunda kwakamsinya emva kwesiqendu se-cocaine binging babonise ukonyuka kwe-metabolic kwi-OFC kunye ne-ACC (kwakhona ne-dorsal striatum) eyayinxulunyaniswa nokunqwenela (40).

Ngaphaya koko, xa sithelekisa impendulo kwi-IV MP phakathi kwezifundo ezikhobokekileyo kunye ne-cocaine, sibonise ukuba i-MP yonyusa imetabolism kwi-ventral ACC kunye ne-medial OFC (isiphumo esihambelana nokunqwenela) kuphela kwizifundo ezikhobokileyo, ngelixa iyancipha imetabolism kule mimandla abantu abangasebenzisanga mlutha (41). Oku kuphakamisa ukuba ukusebenza kwale mimandla yangaphambili kunye nokuvezwa kweziyobisi kunokuchaneka ngokuthe ngqo kumlutha kwaye kunxulunyaniswa nomnqweno owongeziweyo wechiza. Ngaphaya koko, kuphononongo olwalandelayo apho siye sakhuthaza abantu abakhotyokiswe yi-cocaine ukuba bathintele ukunqwenela ngenjongo xa bevezwe kwimikhwa yeziyobisi, sibonise ukuba izifundo eziye zaphumelela ekunqandeni inkanuko yehla i-metabolism kwi-OFC ye-medial (iinkqubo zexabiso elikhuthazayo lokuqinisa) kunye ne-NAc (uqikelelo. ibuyiselo) (42).

Ezi ziphumo ziqinisekisa ukubandakanyeka kwe-OFC, i-ACC, kunye ne-striatum kwinkuthazo eyongeziweyo yokuthenga ichiza kubukhoboka.

IiNkqubo zeModeli yokuXhasa

Njengoko kushwankathelwe apha ngasentla, iisekethe ezininzi zobuchopho zifanelekile kwi-neurobiology yokulutha. Apha, sigxininise ezine kwezi zijikelezo: umvuzo / ukunyaniseka, ukukhuthaza / ukuqhuba, ukulungiswa / imikhwa, kunye nokulawula inhibitory / umsebenzi wokulawula (Ikhiwane. 5). Umjikelo wolawulo lwemood (unegalelo kulawulo loxinzelelo lokuphinda usebenze) kunye nesekethe ye-interoception (inegalelo kulwazi lokunqwenela iziyobisi kunye neemvakalelo) nazo zithatha inxaxheba kumlutha, kodwa ukuzibandakanya kwabo kwingqondo yomntu akuzange kuphandwe kakhulu. Iziphumo zokuphazamiseka kwezi sekethe lixabiso lenkuthazo eyongeziweyo yechiza (okwesibini ukuya kwimibutho efundiweyo ngokusebenzisa imeko kunye nemikhwa) ngeendleko zabanye abaqinisekisi (okwesibini ukuya kukuncipha kovakalelo lwesekethe yomvuzo) kunye nokukwazi ukuthintela izenzo zangabom. ezinxulumene nomnqweno onamandla wokuthatha ichiza (elikwinqanaba lesibini ukuya kokungasebenzi kakuhle) okukhokelela ekuthatheni iziyobisi kumlutha (35).

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Umzobo 5.

Imodeli ephakamisa inethiwekhi yeesekethe ezisebenzisanayo eziphantsi komlutha: umvuzo (i-nucleus accumbens, i-VTA, kunye ne-ventral pallidum), i-conditioning / imemori (i-amygdala, i-OFC ye-medial yokunikezelwa kwe-saliency, i-hippocampus, kunye ne-dorsal striatum yemikhwa), ulawulo lwesigqeba (DLPFC, ACC). , i-cortex yangaphambili engaphantsi, kunye ne-OFC esecaleni), kunye nenkuthazo / i-drive (i-OFC ye-medial ye-attribution of saliency, i-ventral ACC, i-VTA, i-SN, i-dorsal striatum, kunye ne-motor cortex). Nac, i-nucleus accumbens. (A) Xa ezi zisekethe zilinganisiwe, oku kubangela ulawulo olululo lwe-inhibitory kunye nokwenza izigqibo. (B) Ngexesha lokulutha, xa ixabiso lokulindela eliphuculweyo lechiza kumvuzo, inkuthazo, kunye neesekethe zememori zoyisa isekethe yolawulo, oku kuthanda i-loop-feedback loop eqaliswe kukusetyenziswa kwechiza kwaye iqhutyelwe kukuvuselelwa kwenkuthazo/ ukuqhuba kunye neesekethe zememori. Ezi zijikelezo ziphinde zidibanise neesekethe ezibandakanyekayo ekulawuleni isimo sengqondo, kubandakanywa ukunyanzeliswa kwengcinezelo (ebandakanya i-amygdala kunye ne-hypothalamus) kunye ne-interoception (ebandakanya i-insula kunye ne-ACC kwaye igalelo ekuqapheliseni ukunqwenela). Ii-neurotransmitters ezininzi zibandakanyeka kwezi neuroadaptations, kubandakanywa i-glutamate, i-GABA, i-norepinephrine, i-corticotropic-releasing factor, kunye ne-opioid receptors. I-CRF, i-corticotropic-releasing factor; NE, i-norepinephrine. Ilungiswe ngemvume evela kwiref. 35; Imvume egqithiswe ngeZiko lokuCoca iCopyright, Inc.

Nangona kunokwenzeka ukuba i-DA itshintshe indlela yokuziphatha engafanelekanga kwi-addiction, kuyenzeka ukuba ezinye iinguqu ze-DA zinokubonisa iinzame zokubuyekeza iintsilelo kwezinye ii-neurotransmitters, ngakumbi ngenxa yokuba i-DA imodareyithwa yi-glutamate (i-GABA ayikaphandwa kancinci). Iitheminali zeCorticostriatal glutamatergic zinoxanduva lokufunda izimilo ezisekwe kakuhle kunye nokutshintsha ezi ndlela zokuziphatha xa zingasaguquguqukiyo, kwaye i-neuroadaptations kolu qikelelo (kunye ne-amygdalostriatal glutamate pathways) kunye nokusetyenziswa kweziyobisi okuphindaphindiweyo (kubandakanya ukulawulwa kakubi kokukhululwa kwe-glutamate synaptic) kubandakanyeka. kwinkuthazo ephuculweyo yokufuna iziyobisi eyenzeka kumlutha (5). Ukonakaliswa kwi-glutamate-induced neuroplasticity kunye nokuvezwa kweziyobisi ezingapheliyo kukwanokuthi kubandakanyeke kukusilela komsebenzi wangaphambili okuxelwe kubantu abakhobokileyo okukhokelela kuthintelo kulawulo lokuthintela kunye nokungakwazi ukuguqula izimilo ezingalunganga kunye nokufunda kwiziphumo ezibi zokusetyenziswa kweziyobisi.

Le modeli icebisa indlela yonyango ephindaphindwayo yokukhobokisa ukucutha iipropathi zokuqinisa iziyobisi, ukuphucula iipropathi ezinomvuzo zabaxhasi bendalo, inqanda imibutho efundiweyo enemeko, iphucule inkuthazo yemisebenzi enganxulumananga neziyobisi, kunye nokomeleza ulawulo lokuthintela.