Isiyobisi: Ukuncipha koMvuzo wokuNwabela kunye nokuLindelwa kokuLindelwa kokuQiniseka kokuQinisekiswa koKoyisa iSekethe yoLawulo lweBongo (2010)

Iimbangela zokuxhatshazwa koononopopayi zihlala kumvuzo wesiphaluka

IINKCUKACHA: Ukuphononongwa yintloko yeZiko leSizwe lokuSetyenziswa gwenxa kweziyobisi, uNora Volkow, kunye neqela lakhe. Olu hlaziyo luluhlu lwe-3 eziphambili ze-neurobiological dysfunctions ezichaphazelekayo kuzo zonke iziyobisi. Ngokuchaziweyo zezi: a) Ukuxhatshazwa: impendulo enomdla kakhulu ngenxa yokuncipha kwe-dopamine; b) Ukwazisa: ukuphucula i-dopamine impendulo kwiziqulatho zomlutha, okubangela okanye uxinzelelo; kwaye c) Ubuthathaka: buthathaka ukuzilawula kweesekethe ngenxa yokwehla kwevolumu kunye nokusebenza kwecortex yangaphambili. Olu tshintsho lwengqondo luye lwasasazwa nguMbutho waseMelika woNyango lweziyobisi (ASAM) kwezabo inkcazelo entsha yokulutha kukhutshwa ngo-Agasti, i-2011.

I-Volkow ND, i-Wang GJ, i-Fowler JS, uTomasi D, iTelang F, i-Baler R. Bioessays. 2010 Sep; 32 (9): 748-55.

ISikole seSizwe malunga nokuSetyenziswa kakubi kweziyobisi, i-NIH, iBetdada, i-MD 20892, eU.SA.

[imeyile ikhuselwe]

UKUFUNDA NGOKUGQIBELEYO-Isiyobisi: Ukuncipha koVavanyo loVavanyo kunye noKonyuka koLindelo lokuNqwenela ukuNqwenela ukuSebenzisa iSekethe yoLawulo lweBongo

Abstract

Ngokusekelwe ekufunyanweni kweengqondo zengqondo, sinika imodeli ngokubhekiselele kulokuba ukugqithiswa komlingo kubonakala ngokungalingani kwintsebenziswano yokucwangciswa kunye nokudibanisa phakathi kweesekethe kunye nemisebenzi eyahlukeneyo.

Izidumbu zibonisa:

(a) wehla ukuvalelwa kwemibhobho yomvuzo,

(b) ukuphuculiswa kweempawu zeememori ukulungelelanisa ukulindela kwiziyobisi kunye nezilwanyana zamachiza, ukunyanzeliswa kwengqondo kunye nokuphazamiseka kwemizwa,

(c) kunye nesekethe yolawulo ebuthathaka.

Nangona uvavanyo lokuqala kunye neziyobisi zokusetyenziswa kakubi kukhulu ngokuziphatha ngokuzithandela, ukusetyenziswa kweziyobisi ngokuqhubekayo kunokugqithisa izijikelezo ze-neuronal ezibandakanyekayo kwimpumelelo yokuzikhethela, ukuguqula ukusetyenziswa kwezidakamizwa ngokuziphatha okuzenzekelayo. Ikhono leziyobisi eziluthayo ukuba likhethe iingu-neurotransmitter phakathi kwama-neurons (kuquka i-dopamine, i-glutamate, ne-GABA) iguqula umsebenzi wee-circuits ezahlukeneyo ze-neuronal, eziqala ukuphazamiseka kwiinqanaba ezahlukeneyo zomzila wokulutha umlutha. Emva kokuchasana nezilwanyana, iziphumo zamachiza okanye ukuxinzelela oku kubangela ukukhutshwa komsebenzi wesitishi / ukuqhuba isiphaluka esichukumisayo esiphumela ekubanjweni kweziyobisi ezinyanzelisayo ezibonakalisa umlutha.

Internet: umlutha, izifo zobuchopho, i-dopamine, i-circuit circuit

intshayelelo

Iminyaka yokugqibela ye-25 yophando lwe-neuroscience iye yavelisa ubungqina bokuthi umlutha sisifo seengqondo, ukunika ingxabano enamandla yokuxhasa imilinganiselo efanayo yokunyango lwezonyango kumntu onomlutha njengalezo eziqhelekileyo kwezinye izifo ezinempembelelo enkulu karhulumente, iswekile. Enyanisweni, uphando malunga nomlutha luye lwaqala ukufumanisa ukulandelelana kweziganeko kunye ne-sequelae elihlala ixesha elide elinokubangela ukusetyenziswa kakubi kweziyobisi. Ezi zifundo zibonise ukuba ukusetyenziswa kwezidakamizwa ngokuphindaphindiweyo kunokujolisa njani kwiimodlekli eziphambili kunye nezijikelezo zengqondo, kwaye ekugqibeleni ziphazamise iinkqubo eziphezulu ezenza iimvakalelo, ukuqonda nokuziphatha. Siye safunda ukuba umlutha ubonakaliswa ngumjikelezo owandayo wokungasebenzi kwiingqondo. Ukukhubazeka ngokuqhelekileyo kuqala kwimimandla yendawo yokuqala yengqondo eqhuba umvuzo, kwaye iqhubela phambili kwezinye iindawo ezijongene nemisebenzi enzima yokuqonda. Ngaloo ndlela, ngaphezu komvuzo, abantu abanomlingo banokuphazamiseka okukhulu ekufundeni (imemori, imeko, ukuhlala), umsebenzi olawulayo (ukunyanzeliswa kwesisombululo, ukuthatha izigqibo, ukulibazisa ukuxhaswa), ukuqaphela ukuqonda (ukungena ngaphakathi) kunye nemvakalelo (imizwelo kunye noxinzelelo lwengqondo) imisebenzi.

Ukukhangela ikakhulu kwimiphumo yezifundo zobuchopho ezisebenzisa i-positron emission tomography (PET), sichaza iinkqubo eziphambili zengqondo ezichaphazelekayo ngokusetyenziswa kakubi kwezidakamizwa kwaye zenza umzekelo ohambelanayo, ngokubhekiselele kulokuba umlutha uvela njengemiphumela ukungqinisiswanga kolwazi ekusebenziseni kunye naphakathi kwezi zijikelezo. Ukuqonda ngokucacileyo oku kuhamba phambili (i-neuroplastiki) iinkqubo zobuchopho, kunye neemeko zesimo sezinto ezikhuselekileyo ezinobungozi, okubaluleke kakhulu ekuphuhliseni iindlela ezinqamlekileyo zokuthintela nokukhusela iindlela zokulwa nomlingo.

Ephakamileyo, kodwa emfutshane, i-dopamine iyaphunyezwa imfuneko

Umlutha, okokuqala nokuphambili, sisifo senkqubo yomvuzo wobuchopho. Le nkqubo isebenzisa i-neurotransmitter dopamine (DA) njengeyona mali yayo iphambili yokuhambisa ulwazi. Ubuchopho beDA budlala indima ebalulekileyo ekusetyenzisweni kolwazi malunga nokuqina [1, 2], enentliziyo yokukwazi ukulawula okanye ukuphawula umvuzo [3, 4], umvuzo wokulindela [5], inkuthazo, iimvakalelo, kunye neemvakalelo zolonwabo. Ukukhutshwa okwethutyana kwe-DA kwingqondo ye-ventral striatum iyimfuneko, nangona ingonelanga, umsitho kwiinkqubo ezintsonkothileyo ezenza uvakalelo lomvuzo: ukwanda kwe-DA kubonakala ngathi kuhambelana ngokuqinisekileyo nokuqina "okuphezulu" kwezifundo zinamava. Iimpendulo ezinemiqathango zenziwa kuphela xa i-DA ikhutshwa kaninzi njengale ibukhali, idlulayo, inyuka, ekuphenduleni iziyobisi okanye iindlela ezinxulumene neziyobisi.

Okuthakazelisayo, ngokuthe ngqo okanye ngokungathanga ngqo, zonke iziyobisi eziluthayo zisebenza ngokubangela ukunyuka okweqile kodwa ukunyuka kwexesha elide kwi-DA engaphandle kwinqanaba eliphambili lomvuzo (isilumko) kwinkqubo [6, 7], ngokukodwa, kwi-nucleus accumbens (Nac) ekhoyo kwi-ventral striatum. Ukunyuka kwe-DA okunjalo kufana, kwaye kwezinye iimeko zigqithise kakhulu, ukunyuka komzimba kubangelwa yimishukumiso engokwemvelo (ngokuqhelekileyo ibhekiswa njengabaqinisi bemvelo okanye imivuzo). Njengoko sasingalindela, iingcamango zobuchopho bomntu ngokusebenzisa i-positron emission tomography (PET), zibonise ngokucacileyo ukuba i-DA inyuselwa kwizigaba ezahlukeneyo zamachiza (umz. ezikhuthazayo (Umzobo 1A), [8, 9], iicicin [10], notywala [11]) ngaphakathi kwe-ventral striatum, zidibaniswa namava okuzimela (okanye aphakamileyo) ngexesha lokuxhatshazwa [12, 13, 14]. Ukususela kwizifundo ze-PET ezinokuthi ziqhutywe ngokuphaphazeleka kwezifundo zabantu, kunokwenzeka ukuba uceba ulwalamano phakathi kweengxelo ezizimeleyo zeziphumo zonyango kunye neenguqu ezinxulumene namazinga e-DA. Uninzi lweengxelo zixelile ukuba abo babonakalisa i-DA enkulu kunazo zonke emva kokutshatyalaliswa kweziyobisi [amphetamine, nicotine, utywala, i-methylphenidate (MPH)] kwakhona ingxelo enkulu kakhulu okanye ivuyo (Umzobo 1B).

Ukunyuka kwama-DA okuxhasayo kwi-striatum kuhambelana nomvakalelo "ophakamileyo." A: Umthamo wokusabalalisa (DV) wemifanekiso [¹¹C] i-raclopride enye yezifundo kwisiseko kwaye emva kokulawulwa kwe-0.025 kunye ne-0.1 mg / kg iv ...

Izilwanyana kunye nezifundo zabantu zibonise ukuba isantya apho isiza singena khona, senza, kwaye sishiya ingqondo (ie iphrofayili yayo ye-pharmacokinetic) idlala indima ebalulekileyo ekuqaliseni iziphumo zayo zokuqinisa. Enyanisweni, zonke iziyobisi zokusetyenziswa kakubi kwezilwanyana ezinokuthi i-pharmacokinetics yengqondo iye yalinganiswa ne-PET (cocaine, MPH, methamphetamine, kunye nicotine) ibonisa iphrofayili efanayo xa ulawulo lukhupha, ie, amanqanaba okuphakama kobuchopho bomntu afinyelelwa ngaphakathi kwe-10 min (Umzobo 2A) kwaye oku kufakwa ngokukhawuleza kudibaniswa ne "phezulu" (Umzobo 2B). Ngokusekelwe kulo mbutho, kulandela ukuba ukuqinisekiswa ukuba izilwanyana eziluthayo zifaka ingqondo ngokukhawuleza njengoko kunokwenzeka kufuneka kube yindlela efanelekileyo yokunciphisa amandla okuqinisa, ngoko ke ukuxhatshazwa kwayo. Senze uvavanyo ukuvavanya ngokuchanekileyo le ngcamango kunye nesiphumo esinomdla i-MPH, efana ne-cocaine, iphakamisa i-DA ngokunciphisa izithuthi zayo kwi-neuron ye-presynaptic (ie ngokuthintela abathunywa be-DA), ngaloo ndlela bephakamisa isibonakaliso se-DA. Enyanisweni, sifumene ukuba, nangona ukulawulwa kwe-MPH ngokugqithisileyo kudla ngokuqhelekileyo, i-MPH elawulwa ngomlomo, eyongeza i-DA kwi-striatum [15], kodwa nge-6- kwi-12-i-pharmacokinetics ye-slow slow, ayibonakali ngokubonakalayo njengokomeleza [16, 17]. Ngaloo ndlela, ukungaphumeleli kwe-MPH yomlomo okanye i-amphetamine [18] malunga naloo nto - ukukhupha phezulu kukubonakalisa ukunyanzeliswa kwabo okucothayo kwingqondo [19]. Ngako oko, kunengqiqo ukucebisa ukuba kukho ukulungelelaniswa okufutshane phakathi kwesantya apho isilwanyana sokusetyenziswa gadalala singene engqondweni, esenza isivinini apho i-DA ikhula kwi-striatum ye-ventral, kunye nemiphumo yayo yokuqinisa [20, 21, 22]. Ngamanye amagama, ukuba isichengisisi senze imiphumo yokuqinisa i-DA ngokukhawuleza. Kutheni kufanele ukuba njalo?

A: Imifanekiso yeengcamango zeengqondo zokuhambisa [¹¹C] methamphetamine ngamaxesha ahlukeneyo (imizuzu) emva kolawulo lwayo. B: Ixesha lomsebenzi wendlela yokuxubusha [¹¹C] methamphetamine kwi-striatum ecaleni kwinqanaba lexesha lexesha "eliphezulu" ...

Ngokusekelwe kubukhulu kunye nobude bokudubula i-neuronal, ukutyunjwa kwe-DA kunokuthatha iifom ezimbini zeziseko ezibalulekileyo: i-phasic okanye itoniki. Ukubonakaliswa kwe-Phasic kubonakaliswe ukuphakama okukhulu kunye nokugqithisa okufutshane, ngelixa ukubonakaliswa kwe-tonic ngokuqhelekileyo kunamaplitude aphantsi kunye nexesha elide elide okanye elilondoloziweyo. Ukwahlukana kubalulekile kuba kuvela ukuba ukubonakaliswa kwe-DA ye-phasic kuyimfuneko kwiziyobisi zokusetyenziswa gadalala ukudala "iimpendulo ezimiselweyo," enye yeyona ndlela yokuqala ye-neuroadaptations esilandelayo ukunyanzelisa ukuxhaswa (kubandakanywa neziyobisi). Enye yeempawu ezahlukileyo ezidibanisa ukubonakaliswa kwe-phasic kunye neemeko kukubandakanywa kwe-D2R kunye ne-glutamate n-methyl-di-aspartic acid (i-NMDA) i-receptors [23]. Ngakolunye uhlangothi, ukubonakaliswa kwe-DA ye-toni kudlala indima ekumoduleni kwimemori yokusebenza kunye nezinye iinkqubo ezilawulayo. Ezinye zeempawu ezahlula le ndlela yokubonisa ukususela kwi-phasic hlobo yinto esebenza ngokubanzi ngama-receptors asezantsi (DA D1 receptors). Nangona kunjalo, nangona kukho iindlela ezahlukeneyo ezibandakanyekayo, ukuchithwa kwezidakamizwa eziqhubekayo (kwaye utshintsho kwi-tonic ye-DA ukubonakaliswa ngolu hlobo) luye lwabandakanya kwiinguqu ze-neuroplastic eziphumela ekugqibeleni imeko [25] ngokuguqulwa kwe-NMDA kunye ne-alpha-amino-3-hydroxyl-5-methyl-4-isoxazone-propionate (AMPA) i-glutamate receptors [24].

Ubungqina bubonisa ukuba ukwanda kweziyobisi ngokukhawuleza kwi-DA kufana nokutshitshisa i-DA yeseli. Oku kunceda ukucacisa ukuba kutheni ukusetyenziswa okungapheliyo kweziyobisi kunokushukumisa iimpendulo ezinamandla ezinjalo kwisilwanyana ngokwawo, ukulindela kwayo kunye neengcinga ezininzi (abantu, izinto kunye neendawo) ezihambelana nokusetyenziswa kwazo. Nangona kunjalo, ngelixa iziphumo zokuqinisa ukusetyenziswa kakubi kweziyobisi ezixhomekeke kwi-DA ngokukhawuleza kunokwenzeka ukuba "ziyimfuneko" ekuphuhliseni umlutha, ngokucacileyo "alaneleyo." Ukuchithwa kwezidakamizwa okuphindaphindiweyo kubangela utshintsho kwi-DA umsebenzi wengqondo othabatha ixesha ukuphuhliswa kuba zibangelwa kwii-al-neodadaptations kwinqanaba le-neurotransmitter (umz glutamate [26] mhlawumbi kunye ne-γ-aminobutyiric acid (GABA)), ekugqibeleni, inokuchaphazela ezongezelelweyo izijikelezo zeengqondo ezilungiswe yi-DA. Ezi zijikelezo zijoliswe kumacandelo alandelayo.

Ukusetyenziswa gwenxa kweziyobisi ezingasigxina kwehlisa i-dopamine receptors kunye nomveliso we-dopamine: "Iphakamileyo" idibene

Inyaniso yokuba ukusebenzisa iziyobisi kufuneka kube yinto engapheliyo ngaphambi kokuba umlutha uthathe ingcambu ibonakaliso esicacileyo sokuba isifo sichazwa, kubantu abasengozini, ngokuphazamiseka ngokuphindaphindiweyo kwenkqubo yokuvuza. Ezi ziphazamiso zingagcina zikhokelela kwiziganeko ezingaphelelanga kwezinye izijikelezo (ukukhuthazwa / ukuqhuba, ukulawulwa kwemimiselo / umsebenzi olawulayo, kunye nememori / imimiselo) elandelwa yi-DA [27]. Phakathi kweengxaki ze-neuro-eziye zatshintshwa ngokuqhubekayo kwizifundo ezinomlutha ziyancitshiswa kakhulu kumanqanaba e-D2R (aphezulu) kunye nexabiso le-DA elikhishwe ngamaseli e-DA [28] (Ikhiwane. 3). Okubaluleke kakhulu, ezi ntlupheko zidibene nomsebenzi wezityalo ezingaphantsi komhlaba kwiindawo ze-prefrontal cortex (PFC) ezibalulekileyo ekusebenzeni kakuhle kwegunya (ie i-cingulate gyrus (CG) kunye ne-orbitofrontal cortex (OFC)) (Umzobo 4A). Lo mbono usishukumisele ukuba sikhombise ukuba le ngenye yeendlela ezidibanisa ukuphazamiseka kwezidakamizwa kwi-DA ukubonakalisa ukulawulwa kweziyobisi kunye nokungalawulwa kokulawulwa kwezidakamizwa ezibonakalisa umlutha [29]. Kananjalo, imeko ye-hypodopaminergic enokuthi ichaze imeko yomntu olikhoboka lokuncipha kwembuyekezo yendalo (umz. Ukutya, isini, njl. Njl.) Kunye nokuqhubekeka nokusetyenziswa kweziyobisi njengeendlela zokuhlawulela okwethutyana [30]. Ukubaluleka kokubaluleka kwalolu lwazi kukuba ukujongana nala maphulo (ngokunyusa amazinga e-D2R abulalayo kunye nokwandisa ukukhululwa kwe-DA kwimigangatho ye-striatum kunye neengingqi ze-prefrontal) kunokunika isicwangciso sekliniki ukuze kulungiswe umphumo wokulutha [31]. Ngaba kukho ubungqina bokuba ukuguqula imeko ye-hypodopaminergic ingaba nempembelelo emihle kwizinto ezinxulumene nokusetyenziswa kakubi kweziyobisi? Impendulo nguyebo. Izifundo zethu zibonisa ukuba ngokunyanzeliswa kwe-D2R, ngaphakathi ngaphakathi kwinkqubo yokuvuza yee-cocaine okanye i-rats-experienced experiences, sinokunciphisa kakhulu ukulawulwa kwe-cocaine [31] okanye utywala [32], ngokulandelanayo. Ngaphezu koko, kwiirandi, kunye nabahlukumezi base-methamphetamine [33], inqanaba elincinci lokuhlaselwa kwe-D2R linxulumene nokungafuneki, kwaye kwiigundane liqikelela iipatheni ezinyanzelisayo zokulawulwa kweziyobisi (jonga ngezantsi).

Imifanekiso yeBongo ye-DA D2 receptors (D2R) kwinqanaba le-striatum kwizifundo zolawulo kunye nabaxhaphazi beziyobisi. Imifanekiso ifumaneka kunye [¹¹C] raclopride. Uguqulwe ngemvume evela kuVolkow okqhubekayo. [U].

A: Izithombe ezitholakalayo nge-fluorodeoxyglucose (FDG) ukulinganisa ubuchopho be-metabolism ekulawuleni nasekuhlaseleni i-cocaine. Phawula ukuba imetabolism enciphise kwi-cortex ye-orbitofrontal (OFC) kumxhaphazi we-cocaine xa kuthelekiswa nokulawula. B: Ulungelelaniso phakathi ...

Ucwaningo lokucinga luye lwabonisa ukuba, kubantu, umlutha uhambelana nokunciphisa i-DA ekukhululweni kwi-ventral striatum nakweminye imimandla ye-striatum, kunye nezimpendulo ezimnandi ezinokusetyenziswa kweziyobisi kunye nabasebenzisi beziyobisi (Ikhiwane. 5) [34]. Oku kwakufumaniseki ukuba kwakungalindelekanga kuba bekuye kwaxilongwa ukuba umlutha wabonakalisa ubuzwe obunokubangela umvuzo (kwaye ke i-dopaminergic) iimpendulo kwiziyobisi. Kwisixhaphazi seziyobisi, ukunciphisa ukukhululwa kwe-DA kunokubonakalisa ukuphazamisa i-neurophysiology ngaphakathi kwesekethe yokuvuza (ie kwi-neurons ye-DA ekhupha i-DA kwi-striatum) okanye, ngokunye, ukuphazamiseka kwemimiselo yengxelo ye-circuit by prefrontal (ulawulo olulawulayo) okanye i-amygdalar (emoyeni) indlela (i-prefrontal-striatal, amygdalarstriatal glutamatergic pathways). Ekubeni i-dataminergic echaphazelekayo kwi-striatum, njengokuba ibonwe ngumxhaphazi ongasetyenziswayo, ayinakuziphendulela iimpawu ezibonisa ukuziphatha kakubi, njengomdla, ukuthanda, kunye nokuphindaphinda okubangelwa yimichiza yezilwanyana, kunokwenzeka ukuba iindawo ezikhethiweyo (njengoko kunye ne-amygdala) nazo zibandakanyeka apha, kuba ukuphazamiseka kwabo kuya kunceda okanye okungenani kuthonye iimpawu zokuziphatha.

I-MPH inyanzelise ukonyuka (kuvavanywa ukuthintela kwayo ukubophelela okungafaniyo kwe-raclopride okanye iBmax / Kd) kulawulo nakwiziselo ezinxilisayo. Utywala bubonisa ukwehla kokukhutshwa kwe-DA. Utshintshiwe ngemvume evela kwiVolkow okqhubekayo. [U].

Ukunciphisa i-dopamine receptor (i-DR2) amanqanaba awonakalisa ukulawulwa kokungafuneki ngecrotex ye-prefrontal

Kuye kucatshulwa ukuba ukulawulwa kakubi kokuziphatha kakubi kweziyobisi ezibonisa ukuba ngumlutha kunokuba kungenxa yeengxaki ezithile kwiindawo eziphambili zeengqondo [35]. Kukho ubungqina obuninzi obuxhasa le ngcamango, ngokuqala ngezifundo zezilwanyana ezihlola ukuxhamla phakathi kwe-D2R nokulawula ukuziphatha. Iingcamango ezintle zibonisa ngokucacileyo ukulungelelaniswa phakathi kwe-D2R ephantsi kunye nokungafuneki [36], kunye nokunyaniseka nokulawulwa kwezidakamizwa [37]. Kodwa yintoni inxulumano? Njengoko kuthethwe ngaye ngaphambili, kubahlukumezi beziyobisi, i-D2R engaphantsi kwe-DXNUMXR ihambelana kakhulu nengqondo ye-glucose engezantsi kwimimandla ephambili ye-PFC, njenge-OFC (echaphazelekayo kunye nokuphazamiseka okubangelwa ukuziphatha okunyanzelekileyo) kunye neCG (inxaxheba ekulawuleni kunye nokugqithiswa kwempazamo kunye nokuphazanyiswa kwawo kubangele ukungafuneki) (Umzobo 4B) [38, 39]. Ngaphezu koko, kwisifundo esasenza ngabantu ngabanye (i-SD ± yobudala, i-24 ± 3 iminyaka) imbali yentsapho yobunxila, kodwa abo babengenalo utywala, nathi safumanisa ubudlelwane obalulekileyo phakathi kwe-D2R yokuzala kunye ne-metabolism kwimimandla engaphambili (CG). , I-OFC, kunye ne-PFC) kunye nakwi-insula yangaphakathi (echaphazelekayo kwi-interoception, ukuzazi ngokwabo, kunye nokukhanga izidakamizwa) [40] (Ikhiwane. 6). Okuthakazelisayo kukuba, aba bantu babe ne-D2R ephezulu yokuhlaselwa ngaphandle kolawulo oluhambelana nolunye ulwalamano lwentsapho olunxilisayo, nangona bekungafani nxamnye ne-metabolism yangaphambili. Kwakhona, kulawulwayo, i-D2R yokubeletha ayizange ihambelane ne-metabolism yangaphambili. Oku kwasikhokelela ukuba sicacise ukuba i-D2R ephakamileyo kunazo zonke kwizifundo ezinobungozi obuphezulu bokunxiliswa kotywala zibavikela ekunqandeni utywala kwindawo ethile ngokuqinisa umsebenzi kwimimandla ye-prefrontal. Xa zidibaniswe, ezi nkcukacha zibonisa ukuba amanqanaba aphezulu e-D2R kwi-statum ayakukhusela ekusebenziseni kakubi iziyobisi kunye nokulutha ngokutsha ngokugcina iziphathamandla eziphantsi kolawulo, ie, ngokulawula iisekethe ezibandakanyeka ekuthintela iimpendulo zokuziphatha nokulawula iimvakalelo.

Iingingqi zengqondo apho i-DA D2 receptors (D2R) zihambelana kakhulu kunye nengqondo ye-metabolism kwizifundo kunye nomlando wentsapho yobunxila. Uguqulwe ngemvume evela kuVolkow okqhubekayo. [U].

Ngokufanayo, sasixhomekeka ukuba iindawo ze-prefrontal zibandakanyeka ekunciphiseni ukukhululwa kwe-DA (kunye nokuqiniswa) kuboniswe kwizifundo ezinobungozi njengoko zilawula i-DA yesebe yokudubula kwi-midbrain kunye ne-DA yokukhululwa kwi-striatum. Ukuvavanya le ngcamango sihlolisise ubudlelwane phakathi kwe-basic metabolism kwi-PFC kunye nokunyuka kwe-DA ekhulayo kubangelwa ukulawulwa kwe-MPH ekulawuleni nasekulawuleni izidakwa. Ngokuvisisana neengcamango, kwizidakamizwa asikwazanga ukufumana ubudlelwane obuqhelekileyo phakathi kokusekwa kwe-metabolism kunye ne-DA ekukhululweni kwi-striatum, ebonisa ukuba ukuphawulwa kwamanqaku kwi-DA ukukhululwa kwi-striatum ebonwayo kwizidakwa kubonakalisa ukulawula okungalunganga komsebenzi weengqondo kwiindawo zengqondo ze-prefrontal [34].

Ngaloo ndlela, sifumene ubudlelwane phakathi komsebenzi osisiseko osisiseko kwi-PFC kunye nokunciphisa i-D2R ebulalayo kwizifundo ezinobungozi, kunye naphakathi komsebenzi we-PFC kunye nokukhishwa kwe-DA ekulawuleni okungabikho kubantu abanomlutha. Le mibutho ixhomekeke kwiintsebenziswano eziqinileyo phakathi kweengxoxo ze-PFC kunye neengxaki ezingezantsi kwi-DA umvuzo kunye nenkqubo yokukhuthaza, mhlawumbi ngenxa yempembelelo ye-PFC ngokungathandabuzeki nokunyanzelisa. Nangona kunjalo, aba bahluleka ukuphendula ngeengxaki zokuziphatha ezongezelelweyo, ezifana nemiphumo yeziphumo ezichaphazelekayo nezidakamizwa ekukhuseleni ukukhanga, okuya kubakhokelela kwimemori kunye nezifundo zokufunda.

Inkumbulo enemiqathango kunye neendlela zokuziphatha ezizenzekelayo zithatha indawo "phezulu" njengomqhubi

Ukuvuselela ngaphezu kweeseli ze-DA kwi-ventral striatum ekugqibeleni kusekwa uqhagamshelwano olutsha olusebenzayo kwingqondo phakathi kwesenzo sokwaneliseka, kunye neziganeko ezixhomekeke kuyo (umzekelo, ukusingqongileyo, ukulungelelanisa iziyobisi, njl.), Ukubeka entsha , imibutho enamandla enokufunda engabangela ukuziphatha. Ekugqibeleni, imemori nje okanye ukulindela kwesilwanyana kunokubangela ukuziphatha okuphazamisayo okubonisa abantu abanomdla. Ngokusetyenziswa kwezidakamizwa ngokuphindaphindiweyo, ukuqhutyelwa kweeseli ze-DA kwi-striatum kuqala ukutshintsha i-neurochemistry engundoqo yokufunda inxulumano. Oku kuququzelela ukuhlanganiswa kwememori ye-maladaptive ehambelana nesilwayo, esinceda ukuchazela ubuchule bazo zonke iintlobo ze-stimuli ezihambelana neziyobisi (ekufundeni okufunyenweyo kokufumana umvuzo wezonyango xa zichazwe kule miyalelo) [41] ngokukhawuleza ukudala ii-DA zitshisa. Kwaye ngenxa yendima ye-DA ekukhuthazeni, le-DA ikwandisa ukuqhubela phambili umqhubi wokuqhuba umvuzo [42]. Enyanisweni, xa iinkokhwe zibonakaliswa ngokuphindaphindiweyo kwi-stimulus engathathi hlangothi edibeneyo kunye neziyobisi (imimiselo), inokunyusa ukunyuka kwe-DA kunye nokubuyisela ukulawulwa kwezidakamizwa [43]. Izimpendulo ezinjalo zilungelelaniswa nekliniki kwizifo zokusebenzisa izidakamizwa kuba zijongene nokuphakama okukhulu komntu onomlutha wokuphinda abuyele emva nangemva kwexesha elide lokuxutywa kwe-detoxification. Ngoku, ubuchule bokucinga ngobuchopho buvumela ukuba sivavanye ukuba ukubonakaliswa kwabantu kwiinkcazo ezinxulumene neziyobisi kunokubangela ukukhanga izidakamizwa njengokuba kuboniswa kwizilwanyana zasebhoratri.

Ngokusetyenziswa kwezidakamizwa ngokuphindaphindiweyo, ukuqhutyelwa kweeseli ze-DA kwi-striatum kuqala ukutshintsha i-neurochemistry engundoqo yokufunda inxulumano. Oku kuququzelela ukuhlanganiswa kwememori ye-maladaptive ehambelana nesilwayo, esinceda ukuchazela ubuchule bazo zonke iintlobo ze-stimuli ezihambelana neziyobisi (ekufundeni okufunyenweyo kokufumana umvuzo wezonyango xa zichazwe kule miyalelo) [41] ngokukhawuleza ukudala ii-DA zitshisa. Kwaye ngenxa yendima ye-DA ekukhuthazeni, le-DA ikwandisa ukuqhubela phambili umqhubi wokuqhuba umvuzo [42]. Enyanisweni, xa iinkokhwe zibonakaliswa ngokuphindaphindiweyo kwi-stimulus engathathi hlangothi edibeneyo kunye neziyobisi (imimiselo), inokunyusa ukunyuka kwe-DA kunye nokubuyisela ukulawulwa kwezidakamizwa [43]. Izimpendulo ezinjalo zilungelelaniswa nekliniki kwizifo zokusebenzisa izidakamizwa kuba zijongene nokuphakama okukhulu komntu onomlutha wokuphinda abuyele emva nangemva kwexesha elide lokuxutywa kwe-detoxification. Ngoku, ubuchule bokucinga ngobuchopho buvumela ukuba sivavanye ukuba ukubonakaliswa kwabantu kwiinkcazo ezinxulumene neziyobisi kunokubangela ukukhanga izidakamizwa njengokuba kuboniswa kwizilwanyana zasebhoratri.

Lo mbuzo uphando kwi-abusers cocaine. Benzisa iPET kunye [¹¹C] i-raclopride, izifundo ezimbini ezizimeleyo zibonise ukuba ukuboniswa kwevidiyo ye-cocaine (yezifundo zokubhema i-cocaine) kodwa kungekhona kwividiyo engekho nto (kwimiba yendalo) kwandiswe i-DA yokuhlula kwizifundo zabantu ezinomlutha we-cocaine (Ikhiwane. 7) kwaye ukunyuka kwe-DA kudibaniswe neengxelo ezizimeleyo zesifiso sezilwanyana [44, 45]. Ukuphakama kwe-DA kwenyuka kubangelwa ukugqithiswa kwevidiyo ye-cocaine, ngokugqithiseleyo ukukhupha izidakamizwa. Ngaphezu koko, ubukhulu be-DA bonyuka bunxulumene nokukhawulelana nomlingo, ukugqamisa ukubaluleka kweempendulo ezimiselweyo kwi-kliniki syndrome of addiction.

A: Umlinganiselo wemifanekiso yeDV ye- [¹¹C] i-raclopride kwiqela labahlukumezi be-cocaine abakhuthazayo (n = 17) ihlolwe ngelixa lijonga (B) i-video engekho nto (imibala yendalo), kwaye ngelixa lijonga (C) ividiyo kunye neengoma ze-cocaine (izifundo ezifumana nokulawula i-cocaine). Ukuguqulwa kunye ...

Kubalulekile ukugxininisa, nangona kunjalo, nangona amandla okucingwa kwale mibutho ye-maladaptive, sisandula ukuhlanganisa ubungqina obutsha obubonisa ukuba abahlukumezi be-cocaine bahlala banamandla okuba banqwenele ukukhanga. Ngoko ke, izicwangciso zokomeleza umgaqo-nkqubo we-fronto-striater ungabonelela ngeenzuzo zokwelapha [46].

Ukubeka konke ndawonye

Ezinye zezona zinto zikhohlakeleyo izidakamizwa zezidakamizwa zinqwenela kakhulu ukuthabatha iziyobisi ezinokuzikhumbuza nangemva kweminyaka yokuziyeka, kunye nekhono lokuxhatshazwa kwabasebenzi abanomlwelwe ukuvimbela ukufuna izidakamizwa xa kukhangeka ukuthanda kwabo naphezu kwemiphumo emibi eyaziwayo.

Sicetyise imodeli yomlutha [47] echaza ubuninzi beli gulane ngokuphakamisa inethiwekhi yezijikelezo ezine ezidibeneyo, ezo zinto zidibeneyo zisebenza ngokuchasene nezixhobo zokuziphatha: (a) umvuzo, kubandakanywa iinuclei eziliqela kwi-basal ganglia, ngakumbi i-ventral striatum, i-Nac yayo ifumana igalelo ukusuka kwendawo yendawo ye-ventral kwaye idlulisela ulwazi kwi-pallidum ye-ventral (VP); (b) ukukhuthazwa / ukuqhuba, e-OFC, i-cortex e-subcallosal, i-rorsal striatum kunye ne-motor cortex; (c) imemori nokufunda, ekhoyo kwi-amygdala kunye ne-hippocampus; kunye (d) nokucwangcisa nokulawula, ezikwimeko ye-correx ye-dorsolateral, i-CG yangaphambili kunye ne-cortex engaphantsi. Ezi zijikelezo ezine zifumana ukungabikho ngokuthe ngqo kwi-neurons ze-DA kodwa zixhamene kunye ngokucwangcisa ngqo okanye ngokungangqaliyo (ikakhulukazi i-glutamatergic).

Izijikelezo ezine kulo mzekelo zisebenza kunye kunye nemisebenzi yazo ishintsha ngamava. Ngamnye udibaniswa nomxholo obalulekileyo, ngokulandelanayo: i-saliency (umvuzo), urhulumente wangaphakathi (ukukhuthazwa / ukuqhuba), imihlangano efundwayo (imemori, imeko) kunye nokulungiswa kwemibango (ukulawula). Ukongezelela, ezi zijikelezo zidibanisa neesekethe ezithintekayo nomoya (kubandakanywa nokuxhaswa koxinzelelo) [48] kunye nokungena ngaphakathi (okubangela ukuqwashisa izilwanyana kunye nesimo sengqondo) [49]. Siye sicetyiswa ukuba umzekelo womsebenzi kumnatha wesiphaluka amane ochazwe apha uchaphazela indlela umntu oqhelekileyo enza ukhetho phakathi kwezinye iindlela ezikhuphisanayo. Ezi zigqibo zithatyathwa ngokufanelekileyo ngomvuzo, imemori / imimiselo, iinjongo, kunye nezicwangciso zokulawula kwaye ezi zinto zilandelelwe ngamasekethe aphantsi kwengqondo kunye nolwazi oluqaphelayo (Umzobo 8A).

Umzekelo ukuphakamisa inethiwekhi yezijikelezo ezine ezixhomekeke kumlingo: umvuzo (obomvu: okhoyo kwi-nucleus accumbens ye-ventral astriatum kunye ne-VP); iinjongo (eziluhlaza: ezifumaneka kwi-OFC, i-coralx subcallosal, i-dorsal striatum, kunye ne-cortex); imemori (igolide: ikhona ...

Impendulo kwi-stimulus ichaphazelekayo yesikhashana sayo, oko kukuthi umvuzo wayo ulindelekile. Ngaloo ndlela, umvuzo wokulindela uqhutyelwa inxalenye ye-DA neurons eyenza i-ventral striatum kunye neempembelelo ze-glutamatergic ezivela kwi-OFC (ekwabela ixabiso le-saliency njengomsebenzi womxholo) kunye ne-amygdala / i-hippocampus (ephikisanayo nezimpendulo zeememori). Ixabiso le-stimulus linzima (xa kuthelekiswa) nxamnye nelinye i-stimuli, kodwa iguquka njengento yemfuno zangaphakathi zomntu, ezixhaswa ngumoya (kubandakanywa nokuxhaswa koxinzelelo) kunye nokuqwashisa okungaqhelekanga. Ngokukodwa, ukunyuswa koxinzelelo kuphucula ukubaluleka kwezilwanyana ngexesha lolo xesha linciphisa umgaqo-nkqubo we-amygdala [50]. Ukongezelela, ekubeni ukungaxilanga kweziyobisi ezingapheliyo kudibaniswa nokukhuthaza ukunyanzeliswa kwezimpendulo ezixininisa le nto ichaza ukuba kutheni ukucinezeleka kunokubangela ukuba izidakamizwa ziphindwe rhoqo kwiimeko zempilo. Unamandla ngakumbi kwixabiso le-saliency le-stimulus, inxalenye eyenziwe ngamava awakhunjulwe ngaphambili, ngakumbi ukuqhutyelwa kwesekethe yokukhuthaza kunye namandla ngakumbi ukufumana. Isigqibo sokuqonda (okanye kungenjalo) ukufumana ukuvuselelwa kuqhutyelwa inxalenye yi-PFC kunye neCG, enokulinganisela ukulinganisela phakathi kwexesha elichanekileyo kunye neziphumo ezingalindelekanga, kunye ne-cortex engaphantsi (Broadmann Area 44), osebenza ukuvimbela impendulo engaphambili yokusebenza [51].

Ngokwale mzekelo, kwisifundo esinomlutha (Umzobo 8B), ixabiso le-saliency yeziyobisi zokusetyenziswa kakubi kunye neengcombolo zalo ezihambelanayo ziphuculiswa ngendleko yeminye imivuzo (yemvelo). Oku kuya kuchaza ukunyusa okunyanisekileyo ukufuna iziyobisi. Nangona kunjalo, ukuxilongwa kweziyobisi ezinzulu kwakhona kuhlaziya umgca wembuyekezo, okubangela ukunciphisa ubuchule besiphaluka somvuzo ukuvuselela [52], ekunceda ekuchazeni ukunciphisa ukubaluleka kwabangenayo izidakamizwa kumachiza kumntu onomlutha. Esinye isizathu sokwenza umgangatho ophuculweyo weziyobisi kukungabikho kweempendulo ze-DA kwizidakamizwa zokusetyenziswa kakubi (ukunyamezela) xa kuthelekiswa nomkhuba oqhelekileyo okhoyo kwimbuyekezo yemvelo kwaye oku kubangela ukunyaniseka [53].

Ukongezelela, ukuchasana nesimo esiqhotyoshelweyo sanele ukwandisa imivuzo [54]; Ngaloo ndlela, siza kuqikelela ukuba kumntu onomlutha, ukuchasana kwimeko kunye nemigqaliselo emiselweyo kuya kubangela ukwanda kweemvakalelo zabo ekunciphiseni imivuzo yemvelo. Ukungabikho komncintiswano ngabanye abaqinisekisiweyo, ukufunda okumgangatho ophakamileyo kuphakamisa ukufumana iziyobisi ukuya kumgangatho wokuqhuba umqhubi omkhulu. Sifumanisa ukuba izidakamizwa (okanye uxinzelelo) zikhokelela ekunyusweni kwe-DA ngokukhawuleza kwi-Nac kwi-striatum ye-ventral nakwi-storum ye-dorsal eqhuba i-motivation ukuthatha isibisi kwaye ayikwazi ukuchasene ngokufanelekileyo ne-PFC engasebenzi. Ngaloo ndlela, ekusebenziseni iziyobisi kunye nokuxhatshazwa kokuphuculwa kwezibonakaliso ze-DA kuya kubangela ukuchithwa okuhambelana nokuqhubela phambili / ukuhamba kunye neememori zeememori, ezenza ukuba i-PFC (i-prefrontal inhibition isebenze ngokusebenza okukhulu kwe-amygdala) [50], ukuvimbela amandla e-PFC ukulawula isiphaluka se-motivation / drive. Ngaphandle kokulawulwa kwe-inhibitory control, i-positive-feedback loop isungulwe, nto leyo ibangela ukunyanga kweziyobisi. Ngenxa yokuba intsebenziswano phakathi kweesekethe ziyi-bidirectional, ukusetyenziswa kwenethiwekhi ngexesha lokuxhatshazwa kunceda ukuqinisa ngakumbi ixabiso le-saliency yezilwanyana kunye nesimo sengxaki kwizilwanyana.

izigqibo

Ngamafutshane, siphakamisela imodeli ukuba i-akhawunti ixhomekeke kumlingo ngolu hlobo: Ngethuba lokuxhatshazwa, ixabiso eliphuculweyo lenkcazo yesigxina kwimemori yesiphaluji liqhuba umxhelo wokulindela kwaye landisa umxhasi wokudla izidakamizwa, ukunqoba ukulawulwa kwe-inhibitory eyenziwa yi-PFC esele ingasebenzi. Nangona ukwanda kwe-DA okwenziwe ngamachiza kuphawulwe ngokukhawuleza kwizifundo ezinokusetyenziswa kweziyobisi, iziphumo zemithi yezilwanyana ziba nezimpendulo ezimiselweyo ngokwabo, ziqhube phambili ukuqhuba isichengisiso sokuthabatha iziyobisi kwaye zithande i-feedback-feedback loop ngoku ingagxininiswa, ngenxa yokunqanyulwa wesiphaluka sokulawula i-prefrontal. Ngexesha elifanayo, umlutha unokuphinda uhlaziye kwakhona iisekethe eziqinisekisa ukuqonda kunye nolwazi oluqaphelayo (olumele yimithunzi emnyama)Umzobo 8B) ngeendlela, ukuba ziza kulungelelaniswa, ziza kuqhubeka zitshintshe ukulinganisela kude nokulawulwa kwemimiselo kunye nokuthanda nokunyanzeliswa kweziyobisi.

Siyamkela ngokukhawuleza ukuba le ndlela ifanelekileyo: siyaqonda ukuba ezinye iindawo zengqondo kufuneka zibandakanyeke kwezi zijikelezo, loo mmandla omnye unokuba negalelo kwiisekethe eziliqela, kwaye ezinye iisekethe nazo zibandakanyeka kumlutha. Ukongeza, nangona lo mzekelo ugxininisa kwi-DA, kubonakala kwiinkalo zeengqungquthela eziguqulwayo kwiimpawu zogutamatergic zidibanisa ezininzi izilungelelwaniso ezibhekiselwe kwi-addiction kwaye esixoxe ngazo apha. Kuyabonakala nakwiindiza zengqungquthela ukuba ezinye i-neurotransmitters zibandakanyeke kwimiphumo yokuqinisa iziyobisi kuquka i-cannabinoids kunye ne-opioids. Ngelishwa, kude kube kutshanje, ufikelelo olunqongophele kubagijimi bee-radiyo kwi-PET imaging liye linciphisa amandla okuphanda ukubandakanyeka kwamanye ama-neurotransmitter kwimbuyekezo yezidakamizwa kunye nokulutha.

izifinyezo

AMPA: α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
CG: ukucinga i-gyrus
CTX: i-cortex
D2R: uhlobo lwe-dopamine 2 / 3 receptor
DA: dopamine
FDG: i-fluorodeoxyglucose
GABA: γ-aminobutyiric acid
HPA: hypothalamic pituitary axis
mph: methylphenidate
Nac: nucleus accumbens
NMDA: n-methyl-d-aspartic acid
OFC: i-cortex
PET: positron emission tomography
PFC: i-correx
VP: pallidum

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