IZIMVO: Olunye uphononongo lokulutha oluchaza iindlela zokukhotyokiswa ziingcali ezimbini eziphambili zehlabathi. Qaphela ukuba uNora Volkow yintloko ye-NIDA, kwaye uye wathi ukuziphatha kakubi kubandakanya iindlela ezifanayo ezisisiseko kunye nokutshintsha kwengqondo njengeziyobisi.
ISIFUNDO ESIPHELELEYO-Neuropsychopharmacology. 2010 Januwari; 35(1): 217–238.
Ipapashwe kwi-intanethi ye-2009 Agasti 26. doi: 10.1038 / npp.2009.110
Abstract
Ukukhotyokiswa ziziyobisi sisifo esihlala sibuyelela esiye saphawulwa (1) kukunyanzelwa ukuba ufune kwaye uthabathe ichiza, (2) ukulahlekelwa lulawulo ekuthinteleni ukuthatha, kunye (3) nokuvela kwimeko yeemvakalelo engentle (umz., dysphoria, ixhala, irritability) ebonisa i-motivational withdrawal syndrome xa ukufikelela kwichiza kuthintelwe. Ukukhotyokiswa ziziyobisi kuye kwaqondwa njengengxaki ebandakanya izinto zokungabinamdla kunye nokunyanzeliswa ezivelisa umjikelo odityanisiweyo wokulutha owenziwe ngamanqanaba amathathu: 'ukuzinkcinkca/ukunxila', 'ukurhoxa/ukuchatshazelwa kakubi', kunye 'nokuxakeka / ukulangazelela' (ukufuna). Izifundo zezilwanyana kunye nezomntu zibonise iisekethe ezicacileyo ezidibanisa izigaba ezintathu zomjikelo wokulutha kunye nezinto eziphambili ze-ventral tegmental area kunye ne-ventral striatum njengendawo ekugxilwe kuyo kwinqanaba lokunxila / lokunxila, indima ephambili ye-amygdala eyandisiweyo ekurhoxisweni. / inqanaba elichaphazela kakubi, kunye nendima ephambili kwinqanaba lokuzixakekisa / lokulindela uthungelwano olusasazwa ngokubanzi olubandakanya i-orbitofrontal cortex-dorsal striatum, i-prefrontal cortex, i-basolateral amygdala, i-hippocampus, kunye ne-insula ebandakanyekayo ekunqweneleni kunye ne-cingulate gyrus, i-dorsolateral prefrontal, iikhombo zangaphambili ezingaphantsi kulawulo oluphazamisekileyo lokuthintela. Utshintsho lokulutha lubandakanya i-neuroplasticity kuzo zonke ezi zakhiwo ezinokuqala ngotshintsho kwinkqubo ye-mesolimbic dopamine kunye ne-cascade ye-neuroadaptations ukusuka kwi-ventral striatum ukuya kwi-dorsal striatum kunye ne-orbitofrontal cortex kwaye ekugqibeleni ukungasebenzi kakuhle kwe-prefrontal cortex, i-cingulate gyrus, kunye ne-automal adl . Ukuchazwa kwe-neurocircuitry yamanqanaba aguqukayo e-addiction syndrome zenza isiseko se-heuristic sokukhangela i-molecular, genetic, kunye ne-neuropharmacological neuroadaptations ezingundoqo kumngcipheko wokuphuhlisa nokugcina umlutha.
ISIKHOKELO SOMQONDO
Iinkcazo zokulutha: Ukusetyenziswa kweziyobisi, ukusetyenziswa kakubi, kunye nokuXhomekeka komjikelo wokulutha
Ukukhotyokiswa ziziyobisi sisifo esihlala sibuyelela esiye saphawulwa (1) kukunyanzelwa ukuba ufune kwaye uthabathe ichiza, (2) ukulahlekelwa lulawulo ekuthinteleni ukuthatha, kunye (3) nokuvela kwimeko yeemvakalelo engentle (umz., dysphoria, ixhala, ukucaphuka) okubonisa i-motivational withdrawal syndrome xa ukufikelela kwichiza kuthintelwe (kuchazwa njengoKuxhomekeke kwiZinto I-Diagnostic and Statistical Manual of Disabilities [DSM] ye-American Psychiatric Association; UKoob noLe Moal, i-1997; 1 Table). Ukusetyenziswa ngamathuba athile kodwa okulinganiselweyo kwechiza elinokusebenziseka kwahlukile ngokwezonyango ekusetyenzisweni kweziyobisi okwandileyo, ukuphulukana nolawulo lokunciphisa ukusetyenziswa kweziyobisi, kunye nokuvela kokunyanzeliswa kokufuna iziyobisi okungapheliyo okuphawula ukuba likhoboka. Ubume obubalulekileyo bomahluko phakathi kokusetyenziswa kweziyobisi, ukusetyenziswa kakubi kweziyobisi, kunye nokuxhomekeka kuye kwakhanyiswa yidatha ebonisa ukuba malunga ne-15.6% (izigidi ezingama-29) zabantu abadala base-US baya kuqhubeka nokusebenzisa iziyobisi ezingekho mthethweni okanye ezingekho mthethweni ngexesha elithile ebomini babo. , malunga ne-2.9% (5.4 yezigidi) eqhubeleka nokuxhomekeka kwiziyobisi kumachiza angekho mthethweni (Isibonelelo kunye ne-Dawson, 1998; Grant okqhubekayo, 2004). Ezotywala, i-51% (i-120 lezigidi) yabantu abangaphezulu kweminyaka eyi-12 ibingabasebenzisi bangoku, kwaye kwaba basebenzisi bangoku, i-7.7% (i-18 yezigidi) ifikelele kwiikhrayitheriya zokuSetyenziswa gwenxa kweZiyobisi okanye ukuxhomekeka kuTywala. Kwi-nicotine, ngo-2007, malunga ne-28.6% (i-70.9 yezigidi) abantu baseMelika abaneminyaka eyi-12 okanye ngaphezulu babesebenzisa imveliso yecuba ngoku (kwinyanga edlulileyo), kwaye kulaba basebenzisi bangoku, i-24.2% (i-60.1 yezigidi) yayiyi-cigarette yangoku; I-5.4% (i-13.3 yezigidi) itshaya iisiga; I-3.2% (i-8.1 yezigidi) isebenzise icuba elingenamsi; kunye ne-0.8% (2.0 yezigidi) etshaya icuba kwimibhobho (Ukusetyenziswa gwenxa kweziyobisi kunye noLawulo lweeNkonzo zeMpilo yeNgqondo, 2008).
Nangona uninzi lwesifundo sokuqala se-neurobiology yokukhotyokiswa kweziyobisi kugxininise kwimpembelelo ebukhali yeziyobisi zokusetyenziswa kakubi (okufana nokuthelekisa ukungasetyenziswa kweziyobisi nokusetyenziswa kweziyobisi), ugxininiso ngoku lutshintshela kulawulo olungapheliyo kunye notshintsho oluqatha kunye nexesha elide lwe-neuroadaptive. ebuchotsheni obukhokelela ekubuyeleni kwakhona. Injongo yophando lwangoku lokusetyenziswa kakubi kweziyobisi ze-neurobiological kukuqonda i-genetic / epigenetic, iselula, kunye neendlela zemolekyuli ezilamla inguqu ukusuka ngamaxesha athile, ukusetyenziswa kweziyobisi okulawulwayo ukuya ekuphulukaneni nolawulo lokuziphatha ngokufuna iziyobisi kunye nokuthatha iziyobisi kunye nokubuyela umva okungapheliyo nkqu. emva kokuzila ixesha elide, nto leyo eluphawu lokuba likhoboka.
Isakhelo esikhuthazayo ngokwasengqondweni esibonelela ngemithombo yokomelezwa kokulungileyo nokubi ekuthatheni iziyobisi kukucinga ukuba ukukhotyokiswa ziziyobisi kunemiba yazo zombini iingxaki zolawulo lwempembelelo kunye nokuphazamiseka okunyanzelekileyo (1 Table). Iziphazamiso zokulawula i-Impulse ziphawulwa kukukhula koxinzelelo okanye ukuvuseleleka ngaphambi kokwenza isenzo sokungxama kunye nolonwabo, ukoneliseka, okanye isiqabu ngexesha lokwenziwa kwesenzo. Iziphazamiso zokulawula impembelelo zinxulunyaniswa kakhulu neendlela zokuqinisa ezilungileyo (Umbutho we-Psychiatric Association, i-1994). Ngokwahlukileyo koko, ukuphazamiseka okunyanzelekileyo kubonakaliswa kukuxhalaba kunye noxinzelelo ngaphambi kokuziphatha okunyanzelekileyo okuphindaphindayo kunye nokukhululeka kuxinzelelo ngokwenza ukuziphatha okunyanzelekileyo. Iziphazamiso ezinyanzelekileyo zinxulunyaniswa kakhulu neendlela zokuqinisa ezingalunganga kunye nokuzenzekela.
Ukuwohloka komjikelo wokunyanzeliswa kunye nokunyanzeliswa kuvelisa umjikelo odibeneyo wokulutha owenziwe ngamanqanaba amathathu-ukuzinkcinkca/ukunxila, ukurhoxa/impembelelo embi, ukuzixakekisa / ukulangazelela-apho ukungxamiseka kuhlala kulawula kumanqanaba okuqala kunye nokungxama okudityaniswa nokunyanzeliswa kulawula kumanqanaba amva. Njengoko umntu esuka ekunyanzelweni ukuya ekunyanzelweni, utshintsho lwenzeka lusuka kuqinisekiso olulungileyo oluqhuba indlela yokuziphatha ekhuthazayo ukuya ekomelezeni okungalunganga kunye nokuzenzekela ngokuqhuba indlela yokuziphatha ekhuthazayo (I-Koob, i-2004; 1 Table). Ezi zigaba zintathu zicingwa njengokunxibelelana omnye komnye, ziba namandla ngakumbi, kwaye ekugqibeleni zikhokelela kwimeko ye-pathological eyaziwa ngokuba likhoboka (addiction).UKoob noLe Moal, i-1997; 2 Table). Utshintsho ukusuka ekusetyenzisweni kweziyobisi ngamaxesha athile ukuya kumlutha lubandakanya i-neuroplasticity kuzo zonke ezi zinto kwaye inokuqala ngokusetyenziswa kweziyobisi kubantu abasesichengeni okanye abantu ngamaxesha okukhula abasesichengeni (umzekelo, ukufikisa; Koob okqhubekayo, 2008b). Uphononongo lwangoku lujolise kwingqondo ye-neurocircuitry ebandakanyekayo kwinqanaba ngalinye lomjikelo wokulutha, ukuba itshintsha njani ngokunyuka kokuzibandakanya neziyobisi zokuxhatshazwa, kunye nendlela enxibelelana ngayo ukuvelisa imeko ye-pathological eyaziwa ngokuba likhoboka.
Imithombo yokuQiniswa: Inkuthazo, iNkqubo yoMchasi, iNkuthazo yeNkuthazo
Utshintsho kwinkuthazo yeziyobisi kunye nemivuzo yendalo yeyona nto iphambili kumlutha (1 Table). Ukusebenza kwangoko UWikler (1952) Ugxininise umsebenzi wotshintsho kwiinkqubo zokuqhuba ezinxulumene nokuxhomekeka (apha kubhekiselwa kubo njengomlutha. Izifundo zichaze utshintsho lokurhoxa njenge 'indlala' okanye imfuno ephambili kunye neziphumo zemorphine kwimeko efana 'nokuhlutha' okanye ukwaneliseka kweyona mfuno iphambili.Wikler, ngo-1952). Nangona u-Wikler waxoxa ukuba ukomelezwa okulungileyo kwagcinwa nakwizifundo ezixhomekeke kakhulu (umzekelo, uvuyo lwenaliti ye-opioid emithanjeni), umlutha uvelise umthombo omtsha wokwaneliseka, okomeleza okungalunganga (1 Table).
Ingqikelelo yenkuthazo yadityaniswa ngokungenakuphikiswa kunye ne-hedonic, i-affective, okanye imeko yeemvakalelo kutshintsho oluya kuba likhoboka likaSolomon inkqubo yethiyori yenkuthazo. USolomon kunye noCorbit (1974) ithunyelwe ukuba i-hedonic, i-affective, okanye i-emotional states, xa iqalisiwe, iguqulwa ngokuzenzekelayo yinkqubo ye-nervous central kunye neendlela ezinciphisa ubuninzi beemvakalelo ze-hedonic. Iimpendulo ezilungileyo ze-hedonic ekusetyenzisweni kweziyobisi zenzeka kungekudala emva kokubonakaliswa kwe-stimulus, zihambelana ngokusondeleyo kunye nokuqina, umgangatho, kunye nobude be-reinforcer, kwaye ubonise ukunyamezela kunye nokurhoxiswa kwe-hedonic (ukuyeka). Ngokwahlukileyo, iimpendulo ezingalunganga ze-hedonic zilandela iimpendulo ezintle ze-hedonic, zinovila ekuqaleni, zicotha ukwakha i-asymptote, zicotha ukubola, kwaye zibe zikhulu ngokutyhileka ngokuphindaphindiweyo. Indima yeenkqubo zabachasi iqala kwangethuba ekuthatheni iziyobisi, ibonakalisa utshintsho kumvuzo wobuchopho kunye neenkqubo zoxinzelelo, kwaye kamva yenze enye yezona zinto zikhuthazayo zokunyanzeliswa ekuthatheni iziyobisi ngendlela ye-motivational withdrawal syndrome.
Kolu qulunqo, ukubonakaliswa kwe-syndrome yokurhoxisa emva kokususwa kolawulo lweziyobisi ezingapheliyo, nokuba zibukhali okanye zithatha ixesha elide, kuchazwa ngokwemiba ekhuthazayo yokuxhomekeka njengokuvela kwimeko yeemvakalelo ezimbi (umzekelo, i-dysphoria, ixhala, ukucaphuka) xa ukufikelela. kwichiza kuthintelwe (UKoob noLe Moal, i-2001), kunokuba kwiimpawu ezibonakalayo zokuxhomekeka, ezihlala zithatha ixesha elifutshane. Ewe, abanye baye baxoxa ukuba uphuhliso lwemeko enjalo engathandekiyo inokuchaza ukuxhomekeka kumlutha (URussell, 1976; Baker okqhubekayo, 1987) kwaye eso simo sengqondo sibi sinegalelo kunyanzeliso ngeendlela zokuqinisa ezingalunganga (UKoob noLe Moal, i-2005).
Enye ingqikelelo yotshintsho olukhuthazayo olunxulunyaniswa nokulutha luthatyathwe kumsebenzi wokuqala wokomelezwa ngokwemeko, inkuthazo yenkuthazo, ulwazelelelo lokuziphatha, kunye nokufunda kwe-maladaptive stimulus-response, zonke ezithi zifakwe phantsi kwengqikelelo ekhuthazayo yokuqina kwenkuthazo. Iziyobisi ziqikelelwa ukuba zirhwaphilize iinkqubo zobuchopho ezibekwe endaweni yokuqondisa izilwanyana ukuba zikhuthaze ngobuchule bokugcina uhlobo. I-incentive salience hypothesis inexabiso elibalulekileyo le-heuristic njengento eqhelekileyo yokukhotyokiswa ziziyobisi kuba icutha ingqwalasela ekufuneni iziyobisi ngeendleko zembuyekezo yendalo. Uqwalaselo lwezonyango lokuba abantu abanengxaki yokusebenzisa iziyobisi bagxile ngokungaqhelekanga ekufuneni iziyobisi ngaphandle kwembuyekezo yendalo ihambelana nembono yenkuthazo.
Ukonyuka kwenkuthazo yenkuthazo eveliswa ngamachiza e-psychostimulant ineengcambu zakwangoko ekuququzeleleni ukomelezwa kwemeko kunye nokufumana iziyobisi (Robbins, 1976; Intaba, i-1970). Apha, ukufuna iziyobisi kulawulwa ngokulandelelana kocalucalulo olunxulumene neziyobisi olunokuthi lusebenze njengabaqinisekisi bemeko xa zivezwa njengesiphumo seempendulo zezixhobo (Everitt okqhubekayo, 2008). Abaninzi baye baxoxa ukuba ngokufunda ngokubambisana, imeko yenkuthazo eyongeziweyo ijolise ngokuthe ngqo kwi-stimuli enxulumene neziyobisi, ekhokelela ekunyanzelweni okunyukayo kokufuna kunye nokuthatha iziyobisi.uHyman okqhubekayo, 2006; IKalivas neVolkow, i-2005). Ukusebenza okusisiseko kwezakhiwo ze-neural ezibandakanyekayo ekugcineni imeko yenkuthazo iyaqhubeleka, ibenza abakhobokileyo babe sesichengeni sokubuyela umva ixesha elide.
Olunye uluvo lwenkuthazo lubandakanya uvakalelo lokuziphatha, oludla ngokulinganiswa njengokwanda kweempendulo zelocomotor kulawulo oluphindaphindiweyo lwechiza. I-paradigm yokuvuselela isimilo ibonelele ngempembelelo enkulu ekuphononongeni kungekuphela nje i-neurocircuitry ye-addiction kodwa kunye nemodeli ye-neuroplasticity enokuthi yenzeke ngexesha lotshintsho ukusuka ekusebenziseni iziyobisi ukuya ekubeni likhoboka. Apha, inguqu kwimo ye-incentive salience, echazwa 'njengokufuna' okudityaniswe nokusetyenziswa okunyanzelekileyo, ngokuchasene 'nokuthanda' okudityaniswe neempendulo ze-hedonic, kwacingelwa ukuba kwandiswe ngokuqhubekayo ngokuchaneka ngokuphindaphindiweyo kwiziyobisi zokusetyenziswa kakubi.URobinson noBerridge, i-1993).
Ukutshintshela kwi-Addiction: Iipateni zokuThatha iziyobisi, iiModeli zezilwanyana
Amachiza ahlukeneyo avelisa iipateni ezahlukeneyo ze-neuroadaptations kunye nokuvezwa kweziyobisi ezingapheliyo. Umzekelo, abantu abakhotyokiswe yi-opioid bahlangabezana neyona ndlela ininzi ye-DSM yokukhotyokiswa, kubandakanya ukunyamezelana kunye nokurhoxa (iimpawu zakudala ezinxulumene nokuxhomekeka komzimba) kunye neempawu ezininzi ezinxulumene nokurhoxa. Ipatheni yokuthatha iziyobisi nge-intravenous okanye ukutshaya iyavela, kubandakanya ukunxila, ukunyamezelana, ukunyuka kokutya, kunye ne-dysphoria enzulu, ukungonwabi ngokwasemzimbeni, kunye neempawu zokurhoxa ngexesha lokuziyeka. Ukuzixakekisa kakhulu ngokufumana i-opioids (ukufuna) kukhula okuhlala kwandulela imiqondiso ye-somatic yokurhoxa kwaye ayidityaniswanga kuphela kwizivuseleli ezinxulumene nokufumana ichiza kodwa kunye nezivuseleli ezinxulumene nokurhoxa kunye nemeko yokukhuthaza. Ipateni ikhula apho iyeza kufuneka lifunyanwe ukunqanda i-dysphoria enzima kunye nokungakhululeki kokuziyeka. Ezinye iziyobisi zokusetyenziswa kakubi zilandela umzekelo ofanayo kodwa zingabandakanya ngakumbi inqanaba lokuxilisa / ukuxilisa (psychostimulants) okanye ukusela ngaphantsi / ukuxiliswa kunye nokurhoxiswa / okungalunganga kuchaphazela kunye nezigaba zokukhathazeka / zokulindela (nicotine kunye ne-cannabinoids).
Uninzi lwenkqubela phambili yamva nje ekuqondeni i-neurobiology yokulutha lufunyenwe kuphononongo lweemodeli zezilwanyana zokulutha kwiziyobisi ezithile ezinjengezivuseleli, i-opioids, utywala, inikotini, kunye ne-Δ.9-tetrahydrocannabinol (Δ9-THC). Nangona ingekho imodeli yesilwanyana sokukhobokisa exelisa imeko yomntu ngokupheleleyo, iimodeli zezilwanyana ziyakuvumela ukuphandwa kwezinto ezithile zenkqubo yokukhotyokiswa ziziyobisi. Ezo zinto zinokuchazwa ngeemodeli zezigaba ezahlukeneyo zomjikelo wokulutha (jonga ngasentla; 2 Table).
Ukunyuka okuqhubelekayo kubuninzi kunye nobukhulu bokusetyenziswa kweziyobisi yenye yezinto eziphambili zokuziphatha ezibonisa ukuphuhliswa komlutha kwaye inobuso obuchanekileyo kunye neendlela ze-DSM: 'Into idla ngokuthathwa ngamanani amakhulu kunye nexesha elide kunokuba bekucetywayo. (Umbutho we-Psychiatric Association, i-1994). Iimodeli ezimbini zezilwanyana, enye ibandakanya iziyobisi ezilawulwa ngumfuniselo, kwaye enye ibandakanya iziyobisi ezizilawulayo, zisetyenziselwe ukuphonononga iziphumo zokulawulwa kweziyobisi ngokuphindaphindiweyo kwi-neuroplasticity kwii-neurocircuits ezichongiweyo ngasentla. Ukwazisa ngokuziphatha ngokuqhelekileyo kubandakanye ulawulo oluphindaphindiweyo ngumfuni wechiza, ngokuqhelekileyo i-psychostimulant, kwimeko ethile yokusingqongileyo kwaye umlinganiselo oxhomekeke kwisiqhelo yayiyisenzo sokuhamba. Apha, izilwanyana ezifumene ichiza zibonise ukonyuka okumangalisayo ngakumbi kumsebenzi we-locomotor ukuya kumngeni wedosi yechiza (ukuvuselela) kunolawulo olufumene imilinganiselo ephindaphindiweyo yenaliti yesithuthi.
Isakhelo, mhlawumbi esinembuyekezo yobuso engaphezulu yokwenza umzekelo wenguquko ukusuka kusetyenziso lweziyobisi ukuya ekubeni likhoboka leziyobisi, inokufunyanwa kwimodeli yezilwanyana yokufikelela ixesha elide kulawulo lweziyobisi. Apha, ukusebenzisa i-intravenous drug self-control, ukufikelela okwandisiweyo kumachiza kuhambelana nokunyuka kokuthatha iintsuku (Koob, 2009a). Oko kunyuswa kokuzilawula kwakho kuye kwajongwa ngotywala apho iimpuku zisela ngokugqithisileyo ngexesha lokurhoxa ngokungxamisekileyo kunye nexesha elide lokurhoxa ekuxhomekekeni ekuzixhomekekeni kusetyenziswa ukutya okungamanzi okungapheliyo okanye ukuvezwa komphunga ongapheliyo.UGilpin noKoob, ngo-2008). Izilwanyana ezenziwe ngokuxhomekeke etywaleni zifumana ngokuthembekileyo amanqanaba otywala egazi kwi-100-150
mg% uluhlu, olulingana namanqanaba asetyenziswa kakubi ngabasebenzisa kakubi utywala obuphakathi ukuya kobunzima. Utshintsho kwimpembelelo yokomelezwa kunye nenkuthazo yechiza iye yabonwa emva kokufikelela okwandisiweyo kunye nokungeniswa kokuxhomekeka kwaye ibandakanya ukwanda kokuphendula kolungelelwaniso oluqhubekayo (Koob, 2009a), ukonyuka kokubuyiselwa okubangelwa ngamachiza emva kokuphela, ukunciphisa i-latency ukuya kwixesha lenjongo kwimodeli yendlela yokufumana umvuzo weziyobisi (UDeroche-Gamonet okqhubekayo, 2004), kunye nokwanda kokuchasa isohlwayo apho isilwanyana siya kugcina isohlwayo esiphezulu sokufumana ichiza (UVanderschuren no-Everitt, i-2004). Ingaba ukusetyenziswa kweziyobisi okuphuculweyo kunye nokufikelela okwandisiweyo kubonisa uvakalelo lomvuzo (okanye inkuthazo yenkuthazo) okanye imeko yokusilela komvuzo, okanye zombini, kusaxoxwa (I-Vezina, 2004).
I-NEUROCIRCUITRY OF ADDICTION: UBUNGQINA BE-NEUROPSYCHOPHARMACOLOGICAL OVELA KUFUNDO NGEZILWANYANA
Ukuzinkcinkca/Inqanaba lokunxila
Ukuqonda kwethu i-neurobiological substrates yeziphumo zokuqinisa iziyobisi zokusetyenziswa kakubi kunokulandelelwa kumsebenzi wangethuba ekuchongeni inkqubo yomvuzo ebuchotsheni ngokufunyanwa komvuzo wokuvuselela ubuchopho bombane okanye ukuzivuselela ngaphakathi. Endala kunye neMilner (1954). Umvuzo wokuvuselela ubuchopho ubandakanya i-neurocircuitry ebuchosheni, kodwa ezona ndawo zinovakalelo kakhulu ezichazwe yizona ndawo zisezantsi zibandakanya umkhondo we-medial forebrain bundle edibanisa indawo ye-ventral tegmental (VTA) kwi-basal forebrain.Abadala kunye neMilner, 1954). Zonke iziyobisi zokuxhatshazwa, xa zilawulwa ngokukhawuleza, zinciphisa imida yokuvuselela ingqondo (okt, ukonyuka komvuzo; Kornetsky kunye Esposito, 1979) kwaye xa ilawulwa ngokungaguqukiyo yonyusa imivuzo ngexesha lokurhoxa (okt, ukunciphisa umvuzo; bona ngezantsi). Nangona ugxininiso oluninzi lwalugxininise ekuqaleni kwindima yeenkqubo zokunyuka kwe-monoamine kwi-medial forebrain bundle kumvuzo, i-norepinephrine yokuqala (I-Stein, 1962kwaye emva koko i-dopamine (I-Crow, 1973; Ubulumko, 1978), ezinye iinkqubo ze-nondopaminergic kwi-medial forebrain bundle ngokucacileyo zinendima ephambili ekulawulweni komvuzo wokuvuselela ubuchopho (Hernandez okqhubekayo, 2006). Ewe, umsebenzi omninzi ucebisa ukuba ukusebenza kwenkqubo ye-dopamine ye-midbrain ineendima ezininzi zokunika inkuthazo ekhuthazayo kwindalo esingqongileyo (URobinson noBerridge, i-1993) ukukhuthaza indlela yokuziphatha ejoliswe kwiinjongo (Salamone okqhubekayo, 2007) okanye ukusebenza ngokubanzi (Le Moal kunye noSimon, 1991). Kutshanje, i-hypothesis iphakanyiselwe ukuba ixesha lokubonakaliswa kwe-dopamine yeyona nto iphambili, kunye nekhosi ekhawulezayo kakhulu inendima ekhethekileyo kumvuzo kunye nokuxatyiswa kweziphumo eziqikelelweyo zokuziphatha kunye nokusebenza okuzinzile kokukhululwa kwe-dopamine enendima ekhethekileyo ukubonelela ngesiphumo esivumelayo kwiinkqubo ezithile ezinxulumene nokuziphatha (Schultz, 2007). Umsebenzi kwindawo yokomeleza iziyobisi zokusetyenziswa kakubi kweziyobisi ixhasa le ngcamango apho inkqubo ye-mesolimbic dopamine ibaluleke kakhulu kwiziphumo ezivuzayo zeziyobisi ze-psychostimulant kodwa inomsebenzi ovumela ngakumbi kuzo zonke iziyobisi zokuxhatshazwa.
Iipropathi ezivuzayo zeziyobisi ze-psychostimulant kudala zaziwa ukuba zixhomekeke ekusebenzeni kwenkqubo ye-mesolimbic dopamine, kodwa ukusebenza kwale nkqubo akubalulekanga kakhulu kwiziphumo zokuqinisa ezinye iziyobisi zokusetyenziswa kakubi.I-Koob, i-1992; Nestler, 2005; Hnasko okqhubekayo, 2005). Izilonda ezikhethiweyo ze-neurotoxin zenkqubo ye-mesocorticolimbic dopamine zivimba iziphumo zokuqinisa i-cocaine kunye ne-amphetamine (UMcGregor noRoberts, ngo-1993). Ngokwahlukileyo, izilonda ezithile ze-neurochemically ze-dopamine kwi-nucleus accumbens kunye ne-6-hydroxydopamine ayikwazanga ukubhloka i-heroin okanye i-ethanol self-administration, exhasa le ngcamango (UKoob noLe Moal, i-2006).
Ukusebenzisa ubuchule bokuzilawula ngokwangaphakathi (1 Table) kunye nemeko yendawo ye-intracranial (1 Table), i-opioids kunye notywala zibonakaliswe ukuba zilawulwa ngokuthe ngqo kwi-VTA. IiOpioids zikwavelisa indawo ekhethwayo enemeko xa itofwe kwi-VTA. I-opioids, i-phencyclidine, kunye ne-psychostimulants zilawulwa ngokuthe ngqo kwi-nucleus accumbens, kwaye i-psychostimulants ivelisa indawo ekhethiweyo xa itofwe kwi-nucleus accumbens. I-Cocaine kunye ne-phencyclidine zilawulwa ngokuthe ngqo kwi-cortex yangaphambili.McBride okqhubekayo, 1999). Inkqubo ye-mesolimbic dopamine ivulwe lulawulo olubukhali lwe-opioids, i-ethanol, i-nicotine, kunye ne-Δ9-THC (I-Di Chiara kunye ne-Imperato, i-1988).
I-intravenous nicotine self-administration ivalwe zizilonda ze-neurotoxin-specific ze-mesocorticolimbic dopamine system, kwaye isenzo se-neuropharmacological siye sacingelwa ukuba senziwe nge-nicotinic receptor activation yokukhululwa kwe-dopamine ngokuyintloko kwi-VTA kunye nakwi-presynaptically kwi-nucleus accumbens.Watkins okqhubekayo, 2000). Nangona kunjalo, umvuzo we-nicotine olinganiswe ngokukhethwa kwendawo emiselweyo ibonakala izimeleyo kwinkqubo ye-mesocorticolimbic dopamine (I-Laviolette okqhubekayo, 2002). Ezinye ii-substrates ezibandakanyekayo kumvuzo we-nicotine ziquka igalelo le-cholinergic kwi-pedunculopontine nucleus (IYeomans kunye neBaptista, ngo-1997). Kwi-VTA, ukusebenza kwe βI-2 subunit ye-nicotinic receptors ibonakala ibalulekile ekusebenzeni kwe-nicotine ye-dopamine neurons (Mameli-Engvall okqhubekayo, 2006). Izifundo ze-Neuropharmacological kwi-cannabinoids ziye zachaphazela zombini iindlela ze-cannabinoid kunye ne-opioid. I-Opioid kunye ne-CB ye-cannabinoid1 abachasi bavimba ukuzilawula ngomthambo we-Δ9-THC kwiinkawu ezinonomatse (Justinova okqhubekayo, 2003). Ngokufana nezinye iziyobisi zokuxhatshazwa, Δ9Ulawulo lwe-THC luvuselela ukukhutshwa kwe-dopamine kwi-nucleus accumbens shell (Tanda okqhubekayo, 1997).
Ke, zonke iziyobisi zoxhatshazo zisebenza inkqubo ye-mesolimbic dopamine, kodwa ubungqina obuninzi bubonisa ukuba ukomelezwa okuzimeleyo kwe-dopamine kwenzeka kwinqanaba le-nucleus accumbens, ecebisa amagalelo amaninzi ekusebenzeni kwesekethe ebalulekileyo yokuqinisa kule mimandla yengqondo (I-Koob, i-1992; Nestler, 2005).
I-nucleus esembindini ye-amygdala (CeA) nayo inomsebenzi ophambili kwizenzo zokuqinisa iziyobisi zokuxhatshazwa. I-Microinjections ye-dopamine D1 abachasi be-receptor kwi-CeA block cocaine yokuzilawula ngokwakho (Caine okqhubekayo, 1995; UMcGregor noRoberts, ngo-1993). Eyona ndawo inovakalelo ye γ-i-aminobutyric acid (GABA) kunye ne-opioid antagonism yokulawula utywala ngomlomo kwiigundane ezingaxhomekekanga yi-CeA (UHytia noKoob, ngo-1995; Heyser okqhubekayo, 1999). Izilonda ze-CeA zibhloka ukuzilawula kotywala ngomlomo (Moller okqhubekayo, 1997). I-Serotonin-3 antagonists ifakwe kwi-CeA block yomlomo we-ethanol self-administration kwiigundane ezingaxhomekekanga, isiphumo sicingelwa ukuba sinokubandakanya amandla e-serotonin-3 receptor antagonists ukuvala ukukhutshwa kwe-dopamine eyenziwe ngeziyobisi (UDyr kunye noKostowski, ngo-1995).
Isiphumo esikhulu esivela kwi-nucleus accumbens sikwi-ventral pallidum/substantia innominata. Ngokuhambelana ne-nucleus accumbens njengesiseko esibalulekileyo somvuzo weziyobisi, izilonda ze-ventral pallidum zisebenza ngokukodwa ekuthinteleni inkuthazo yokusebenza kwi-cocaine ye-intravenous kunye ne-intravenous heroin (Hubner noKoob, ngo-1990; URobledo noKoob, ngo-1993). Ukongeza, i-blockade ye-dopamine kunye ne-GABAA i-receptors kwi-ventral pallidum ivimbela imiphumo yokuqinisa utywala (Melendez okqhubekayo, 2004; Isilimela okqhubekayo, 2003). Ke, izinto ze-ventral pallidum zinokungabalulekanga kuphela ekuqhubekeni phambili komqondiso womvuzo weziyobisi kodwa zinokuhlengahlengiswa ngokuthe ngqo ngamachiza okuxhatshazwa.
I-dorsal striatum ayibonakali inendima enkulu ekuqiniseni iziphumo zokusetyenziswa gwenxa kweziyobisi kodwa ibonakala ngathi igaywe ngexesha lophuhliso lokufuna iziyobisi okunyanzelekileyo (Everitt okqhubekayo, 2008). 6-Izilonda ze-Hydroxydopamine ze-dorsal striatum azithinteli umsebenzi we-cocaine-ukwenziwa kwe-locomotor okanye ukuzilawula kwe-cocaine (URoberts, ngo-1992) kodwa uthintele i-amphetamine-induced ukuziphatha stereotyped (UKelly no-Iversen, ngo-1976; UCreese no-Iversen, ngo-1974). Ukusebenzisa ishedyuli yomyalelo wesibini (1 Table), izilonda ze-nucleus accumbens kunye ne-basolateral amygdala zithintele ukufunyanwa kokufuna i-cocaine (I-whitelaw okqhubekayo, 1996). Ngokukwanjalo, xa i-nucleus accumbens core yayikhethwe ngokukhethekayo kwicala elinye lengqondo kwaye idityaniswe ne-dopamine receptor blockade kwi-contralateral dorsal striatum, akukho siphumo sabonwa kwizilwanyana kwangoko emva kokufunyanwa, kodwa kuncipha kakhulu ukufuna i-cocaine kwabonwa kwiimpuku ezizinzileyo. ukuphendula kwishedyuli yomyalelo wesibini (Belin kunye ne-everitt, i-2008). Ezi ziphumo zibonisa ukuba i-dorsal striatum inokuba nendima encinci kwiziphumo zokuqinisa amachiza e-psychostimulant kodwa indima ephambili kwinguqulelo yokusetyenziswa okunyanzelekileyo (Everitt okqhubekayo, 2008).
Idatha eneempuku zokunkqonkqoza ikwabonelela ngokuqonda okuphambili kwindima ye-dopamine kwiziphumo ezinomvuzo zeziyobisi zokuxhatshazwa. Iimpuku eziguqulwe ngokwemfuza i-homozygous ngokungabikho kwe-dopamine D1 i-receptor ayiziphathi ngokwazo i-cocaine (Caine okqhubekayo, 2007). Nangona ingxelo yokuqala yokuba i-dopamine transporter (DAT) yokunkqonkqoza iimpuku yaqhubeka nokuzilawula i-cocaine (Rocha okqhubekayo, 1998) ubuze umsebenzi we-DAT kwiziphumo zokuqinisa i-cocaine, uphononongo lwakutsha nje lubonise ukuba izilwanyana eziguquguqukayo ezibonise i-DAT engazange ibophe i-cocaine kodwa eyayisebenza njenge-dopamine ephethe i-reuptake carrier ayizange ibonise umvuzo we-cocaine olinganiswa ngendawo ekhethiweyo (Chen okqhubekayo, 2006a). Ezi ziphumo zixhasa ingqikelelo yendima ebalulekileyo ye-DAT kwiziphumo zokuqinisa i-cocaine.
Kwisiseko solu kuhlanganiswa, isekethe yokuqala ye-neurobiological yomvuzo weziyobisi yacetywa (I-Koob, i-1992) eye yacaciswa yaza yandiswa (I-Koob kunye neNestler, 1997; Umzobo 1). Indawo yokuqala yesekethe yomvuzo yayiyi-medial forebrain bundle, eyenziwe yimicu ye-myelinated edibanisa i-bidirectionally i-olfactory tubercle kunye ne-nucleus accumbens kunye ne-hypothalamus kunye ne-VTA (ENauta naseHaymaker, ngo-1969) kwaye kubandakanywa neendlela ezinyukayo ze-monoamine ezifana ne-mesocorticolimbic dopamine system.
Isenzo sokuqala somvuzo weziyobisi sasicingelwa ukuba sixhomekeke ekukhutshweni kwe-dopamine kwi-nucleus accumbens ye-cocaine, i-amphetamine, kunye ne-nicotine; I-opioid peptide receptor activation kwi-VTA (i-dopamine activation) kunye ne-nucleus accumbens (ezimeleyo yokusebenza kwe-dopamine) ye-opiates; kunye neGABAA iinkqubo kwi-nucleus accumbens kunye ne-amygdala yotywala. I-nucleus accumbens ibekwe ngokweqhinga lokufumana ulwazi olubalulekileyo lwe-limbic oluvela kwi-amygdala, i-frontal cortex, kunye ne-hippocampus enokuthi iguqulelwe kwisenzo senkuthazo ngoqhagamshelwano lwayo kunye ne-extrapyramidal motor system. Ke ngoko, indima ebalulekileyo yokuqala ye-nucleus accumbens yasekwa kwiziphumo zokuqinisa amachiza, kunye nendima yenkxaso ye-CeA kunye ne-ventral pallidum.Iimpawu ze1 kwaye kunye ne2a2a).
Ukurhoxiswa / Negative Affect Stage
Iqumrhu le-neuroanatomical libize i-amygdala eyandisiweyo (Heimer kunye neAlheid, 1991) inokumela i-anatomical substrate eqhelekileyo edibanisa i-brain arousal-stress systems kunye ne-hedonic processing systems ukuvelisa iimeko zeemvakalelo ezimbi ezikhuthaza iindlela zokuqinisa ezingalunganga ezinxulumene nophuhliso lomlutha. I-amygdala eyandisiweyo yenziwe yi-CeA, i-nucleus yebhedi ye-stria terminalis (BNST), kunye nommandla wenguqu kwi-medial (shell) subregion ye-nucleus accumbens (Umzobo 2b). Ngamnye kule mimandla ine-cytoarchitectural kunye nokufana kweesekethe (Heimer kunye neAlheid, 1991). I-amygdala eyandisiweyo ifumana ii-afferents ezininzi ezivela kwi-limbic structures ezifana ne-basolateral amygdala kunye ne-hippocampus kwaye ithumela i-efferents kwi-medial part ye-ventral pallidum kunye ne-projectionion enkulu kwi-hypothalamus esecaleni, ngaloo ndlela ichaza ngakumbi iindawo ezithile zengqondo ezidibanisa i-classical limbic (emotional) izakhiwo ezinemveliso ye-extrapyramidal motor system (Alheid okqhubekayo, 1995). I-amygdala eyandisiweyo kudala icingelwa ukuba inendima ephambili kungekuphela nje kwimeko yoloyiko.Le Doux, ngo-2000) kodwa nakwicandelo leemvakalelo zokucutshungulwa kweentlungu (Neugebauer okqhubekayo, 2004).
Uguqulo lwemithambo-luvo lwangaphakathi kwinkqubo yokuvezwa kweziyobisi ezingapheliyo lubandakanya ukuncipha kokusebenza kwenkqubo ye-neurotransmitter kwi-neurocircuits ebandakanyeka kwiziphumo ezibukhali zokuqinisa iziyobisi zokusetyenziswa gwenxa kweziyobisi. Enye ingqikelelo ebalaseleyo yeyokuba iinkqubo ze-dopamine zichaphazeleka kwizigaba ezibalulekileyo zomjikelo wokulutha, njengokurhoxa, kwaye zikhokelela ekunciphiseni inkuthazo yesivuseleli esinxulumene neziyobisi kunye nokwanda kovakalelo kwisiyobisi esixhatshaziweyo (UMelis okqhubekayo, 2005; jonga izifundo zokucinga ngengqondo ngezantsi). Ukurhoxa kwengqondo ebantwini kunxulunyaniswa nokudinwa, ukuncipha kweemvakalelo kunye nokudodobala kwengqondo, kwaye kwizilwanyana kunxulunyaniswa nokuncipha kwenkuthazo yokusebenzela umvuzo wendalo.UBarr noPhillips, ngo-1999) kunye nokuncipha komsebenzi we-locomotor (Pulvirenti kunye noKoob, ngo-1993), iziphumo zokuziphatha ezinokubandakanya ukunciphisa umsebenzi we-dopaminergic. Izilwanyana ngexesha lokurhoxiswa kwe-amphetamine umboniso wehla ekuphenduleni kwishedyuli eqhubekayo yesisombululo esimnandi, kwaye oku kuncitshiswa kokuphendula kwatshintshwa yi-dopamine partial agonist terguride (I-Orsini okqhubekayo, 2001), ecebisa ukuba ithowuni ye-dopamine ephantsi inegalelo kukusilela kwenkuthazo ehambelana nokurhoxa kwengqondo. Ukuncipha komsebenzi we-mesolimbic dopamine system kunye nokuncipha kwe-serotonergic neurotransmission kwi-nucleus accumbens kwenzeka ngexesha lokurhoxiswa kweziyobisi kuzo zonke iziyobisi ezisetyenziswa kakubi kwizifundo zezilwanyana.IRossetti okqhubekayo, 1992; Weiss okqhubekayo, 1992, 1996).
Icandelo lesibini lenqanaba lokurhoxisa / elibi elichaphazela inqanaba liphakathi kwenkqubo ye-neuroadaptation apho iinkqubo ezahlukeneyo ze-neurochemical ezibandakanyekayo kumodareyitha woxinzelelo nazo zinokubandakanyeka ngaphakathi kwe-neurocircuitry yoxinzelelo lwengqondo kunye neenkqubo ezigwenxa kwiinzame zokoyisa ubukho obungapheliyo bokuphazamiseka. ichiza ukubuyisela ukusebenza eqhelekileyo nangona ubukho ichiza. Zombini i-hypothalamic-pituitary-adrenal axis kunye noxinzelelo lobuchopho / inkqubo ephazamisayo elamlwa yi-corticotropin-releasing factor (CRF) iyasebenza ngexesha lokurhoxa kulawulo olungapheliyo lwazo zonke iziyobisi ezinkulu ezinokubakho ukusetyenziswa kakubi, kunye nempendulo eqhelekileyo yehomoni ye-adrenocorticotropic ephezulu, i-corticosterone, kunye ne-amygdala CRF ngexesha lokurhoxiswa ngokukhawuleza (I-Koob, i-2008; I-Koob kunye neKreek, i-2007). Ukurhoxa ngokungxamisekileyo kuzo zonke iziyobisi zoxhatshazo kukwavelisa imeko ephazamisayo okanye efana nexhala apho iCRF kunye nezinye iinkqubo ezinxulumene noxinzelelo (kubandakanya iindlela ze-noradrenergic) zinendima ephambili.
Iziphumo zokuvuselela i-aversive zokurhoxiswa kweziyobisi zinokulinganiswa kusetyenziswa ukuchaswa kwendawo (isandla okqhubekayo, 1988), kunye nedosi ye-opioid ye-agonist ye-buprenorphine ngokuxhomekeka yanciphisa indawo yokuchasana eveliswa kukuhoxiswa kwe-opioid. Ulawulo olucwangcisiweyo lweCRF1 i-receptor antagonist kunye nolawulo oluthe ngqo lwe-intracerebral ye-peptide CRF1/ CRF2 umchasi naye wehlise i-opioid ebangela ukurhoxa kwendawo (Stinus okqhubekayo, 2005; Heinrichs okqhubekayo, 1995). Abachasi be-noradrenergic abasebenzayo abalawulwa ngokuthe ngqo kwi-BNST bathintele ukurhoxiswa kwe-opioid-induced place aversion, okubandakanya ukubaluleka kokuvuselelwa kwe-noradrenergic kwiimpendulo zoxinzelelo ezilandela ukurhoxiswa kweziyobisi ngokuqatha.IiDelfs okqhubekayo, 2000). Enyanisweni, amayeza eklasiki asetyenziselwa ukunyanga ukuhoxiswa komzimba kubaxhaphazi be-heroin kunye nezinxila ziquka α-iziyobisi zeadrenergic (umzekelo, i-clonidine) ezithintela ukukhutshwa kwe-noradrenergic kunye nokunciphisa ezinye iimpawu zotywala kunye nokuyeka i-heroin.
Omnye umviwa weziphumo ezigwenxa zokurhoxiswa kweziyobisi yidynorphin. Ubungqina obuninzi bubonisa ukuba i-dynorphin yonyuka kwi-nucleus accumbens ekuphenduleni ukusebenza kwe-dopaminergic kwaye, emva koko, ukuba ukusebenza ngokugqithiseleyo kweenkqubo ze-dynorphin kunokunciphisa umsebenzi we-dopaminergic. κI-opioid agonists i-aversive, kwaye i-cocaine, i-opioid, kunye nokuhoxiswa kwe-ethanol kudibaniswa nokunyuka kwe-dynorphin kwi-nucleus accumbens kunye / okanye i-amygdala.I-Koob, i-2008). Ngaphandle kwe-salvidorin A, eyi-a κ-i-agonist ixhatshazwa ngabantu, kodwa oku kunokubonakalisa iziphumo zayo ze-hallucinogenic kunokuba nayiphi na ipropati eyonwabisayo (Gonzalez okqhubekayo, 2006).
Enye impendulo eqhelekileyo phakathi kwenkqubo yokuhoxiswa ngokukhawuleza kunye nokuyeka ixesha elide kuzo zonke iziyobisi ezinkulu zokuxhatshazwa kukubonakaliswa kweempendulo ezinjengexhala. Umzekelo, ukurhoxa kulawulo oluphindaphindiweyo lwe-cocaine kuvelisa impendulo efana ne-anxiogenic kwi-maze ephakanyisiweyo kunye novavanyo olukhuselayo lokungcwaba, zombini zitshintshwa ngabachasi beCRF. Ngokukwanjalo, ukurhoxa kwe-ethanol kuvelisa isimilo esifana nexhala esijikwa lulawulo lwe-intracerebroventricular yeCRF.1/ CRF2 abachasi be-peptidergic, ulawulo lwenkqubo ye-molecule encinci yeCRF1 umchasi, kunye ne-microinjection ye-peptidergic CRF1/ CRF2 umchasi kwi-amygdala (Funk okqhubekayo, 2006; I-Koob, i-2008). Abachasi beCRF batofelwe nge-intracerebroventricularly okanye ngokwenkqubo kwakhona bathintela iimpendulo ezinokubakho zokuxhalaba ezibonwa ngexesha lokuyeka kangangexesha elide kwi-ethanol engapheliyo, kunye neziphumo zabachasi beCRF ziye zafakwa kwi-CeA.I-Koob, i-2008). Ukurhoxa okukhawulezileyo kwi-nicotine kuvelisa iimpendulo ezifana nexhala ezithi zijikwe kwakhona ngabachasi beCRF (Tucci okqhubekayo, 2003; George okqhubekayo, 2007).
Ke, ukurhoxa ngokungxamisekileyo kunxulunyaniswa notshintsho lwangaphakathi lwenkqubo olubonakaliswe ekunciphiseni komsebenzi we-dopaminergic kwinkqubo ye-mesolimbic dopamine kunye naphakathi kwenkqubo yokugaya iinkqubo ze-neurotransmitter ezidlulisa uxinzelelo kunye neziphumo ezinje ngoxinzelelo njengeCRF kunye nedynorphin. Ezinye iinkqubo ze-neurotransmitter ezaziwa ngokuba zibandakanyeka ekuphazamisekeni ngokweemvakalelo kwimiphumo ekhuthazayo yokuyeka iziyobisi ziquka i-norepinephrine, i-substance P, i-vasopressin, i-neuropeptide Y (NPY), i-endocannabinoids, kunye ne-nociceptin (I-Koob, i-2008).
Ukuzixakekisa / Ukulindela (Ukufuna) Inqanaba
Ukuzixakekisa / ukulindela okanye ukunqwenela inqanaba lomjikelo wokulutha kudala kucingelwa ukuba yeyona nto iphambili yokubuyela umva ebantwini kwaye ichaza umlutha njengengxaki engapheliyo yokubuyela umva. Nangona kudla ngokunxulunyaniswa nokwakhiwa kokunqwenela, ukunqwenela ngomntu ngamnye bekunzima ukulinganisa ngokwezonyango (Tiffany okqhubekayo, 2000) kwaye kaninzi ayidibanisi kakuhle nokubuyela umva. Nangona kunjalo, inqanaba lomjikelo wokulutha apho umntu aphinde abuyisele isimilo sokufuna iziyobisi emva kokuziyeka sihlala singumceli mngeni weendlela ze-neurobiological kunye nophuhliso lwamayeza kunyango. Imifuziselo yezilwanyana ezinqwenelekayo inokwahlulwa ibe yimimandla emibini: ukufuna iziyobisi okubangelwa siziyobisi okanye isivuseleli esidityaniswe nokuthatha iziyobisi, kunye nokufumana iziyobisi okubangelwa kukuxinezeleka okubukhali okanye imeko yeemvakalelo eshiyekileyo, ehlala ikwimeko yoxinzelelo, ebizwa ngokuba kukuzila ukudla ixesha elide. (jonga iTransition to addiction: iipatheni zokuthatha iziyobisi, icandelo lemizekelo yezilwanyana).
Ubungqina obuninzi obuvela kwizifundo zezilwanyana bubonisa ukuba ukubuyiselwa okubangelwa ngamachiza kufumaneka kwi-medial prefrontal cortex/nucleus accumbens/ventral pallidum circuit mediated by neurotransmitter glutamate.McFarland kunye Kalivas, 2001). Ngokwahlukileyo, ukubuyiselwa okubangelwa yi-cue kubonakala kubandakanya i-amygdala ye-basolateral njenge-substrate ebalulekileyo kunye ne-feed-forward mechanism enokwenzeka ngenkqubo ye-cortex yangaphambili ebandakanyekayo ekubuyiselweni kweziyobisi (I-everitt kunye neWolf, 2002; Weiss okqhubekayo, 2001). Umbutho we-stimuli yangaphambili engathathi hlangothi idibaniswe nokuhoxiswa kwe-opioid (ukuhoxiswa okusemgangathweni) kuxhomekeke kakhulu kwi-amygdala ye-basolateral (Schulteis okqhubekayo, 2000), kwaye ezo zivuseleli zinokuba nentsingiselo ekhuthazayo (Kenny okqhubekayo, 2006). Utshintsho lwe-neurocircuitry olunxulunyaniswa nokubuyiselwa kweziyobisi kunye ne-cue-induced reinstatement emva kokutshabalala zidityaniswe nendlela ye-glutamatergic esuka kwi-prefrontal cortex ukuya kwi-nucleus accumbens core, i-dopamine projection esuka kwi-VTA ukuya kwi-medial prefrontal cortex, kunye nentelekelelo ye-GABA esuka kwi-nucleus accumbens. kwi-ventral pallidum (IKalivas kunye ne-O'Brien, 2008).
Ngokwahlukileyo koko, ukubuyiselwa okubangelwa kukuxinezeleka kokuphendula okunxulumene neziyobisi kwiimodeli zezilwanyana kubonakala kuxhomekeke ekusebenzeni kwe-CRF kunye ne-norepinephrine kwizinto ze-amygdala eyandisiweyo (zombini i-CeA kunye ne-BNST; uphononongo, bona UShamham okqhubekayo, 2003; Shalev okqhubekayo, 2002). Ukuzila ixesha elide, okuchazwa kakhulu kwiimodeli zokuxhomekeka etywaleni, kubonakala kubandakanya ukusebenza ngokugqithisileyo kwe-glutamatergic kunye neenkqubo zeCRF, mhlawumbi kwi-amygdala eyandisiweyo, nangona ubukhulu becala oku kusafuneka kuphononongwe.nguWitte okqhubekayo, 2005; Valdez okqhubekayo, 2002).
Izifundo zabantu ezinomlutha we-cocaine zibonisa ukusebenza kakubi kwimisebenzi ebandakanya ingqalelo, ukuguquguquka kwengqondo, kunye nokulibaziseka kwesaphulelo somvuzo olamlwa yi-medial kunye ne-orbital prefrontal cortices, kunye nokuphazamiseka kwendawo, yomlomo, kunye nokuqondwa kwememori elamlwa yihippocampus, kunye ezi ntsilelo zinokuxela kwangaphambili iziphumo zonyango olubi (Aharonovich okqhubekayo, 2006; Bolla okqhubekayo, 2003). Izifundo zezilwanyana ezinxuseneyo ze-orbitofrontal, i-prefrontal cortex, kunye ne-hippocampus ekukhotyokisweni kusetyenziswa imodeli yezilwanyana sele iqalile ukubonisa ezinye zeentsilelo ezibonakaliswe kwizifundo zabantu. Icocaine elawulwa ngumvavanyi ivelise ukuphazamiseka ekufundeni okubuyela umva (umsebenzi ongaphambili we-orbital) kwiimpuku nakwiinkawu (I-Jentsch okqhubekayo, 2002; Schoenbaum okqhubekayo, 2004; Calu okqhubekayo, 2007). Mhlawumbi nokunyanzeliswa ngakumbi, izilwanyana zivumele ukufikelela okwandisiweyo, kodwa kungaphelelanga ekufikeleleni, kwi-cocaine yabonisa intsilelo kwimemori yokusebenza (umsebenzi oxhomekeke kwi-prefrontal-cortex), umsebenzi wokuhoya ozinzileyo (umsebenzi oxhomekeke kwi-prefrontal-cortex), kunye nomsebenzi wokuqaphela into. (umsebenzi oxhomekeke kwihippocampus; Briand okqhubekayo, 2008a, 2008b; George okqhubekayo, 2008). Kwisifundo esinye (Briand okqhubekayo, 2008a), ezi ntsilelo zayanyaniswa nokuncipha okukhulu kwe-dopamine D2 i-receptor mRNA kwi-medial kunye ne-orbital prefrontal cortices, ukujonga kwakhona kuhambelana nezifundo zomntu. Ke, izifundo zezilwanyana zisebenzisa iimodeli zolawulo olunyanzelekileyo lokuvuselela ziqala ukubonisa intsilelo ehambelana nokukhotyokiswa kwecocaine yomntu (jonga Izifundo zomntu: imaging kunye neuropsychopharmacology).
IZIFUNDO ZABANTU: UKUFAKA KUNYE NEUROPSYCHOPHARMACOLOGY
Njengoko kuphawuliwe ngasentla, ubungqina obuvela kwizifundo zangaphambi kweklinikhi kunye nezonyango zibonisa ukuba umlutha umele ulandelelwano lwe-neuroadaptations. Ngenxa yoko, inyathelo lokuqala lokungxama lijika libe sisinyanzelo kwaye libe (ekugqibeleni) elingapheliyo kwaye liphinde libuyele. Umsebenzi ovela kwizifundo zokucinga unike ubungqina bokuba olu tshintsho lubandakanya ukulungiswa kwakhona kweesekethe ze-neuronal eziqhuba (1) umvuzo kunye nokukhuthaza; (2) inkumbulo, ukulungiswa, kunye nendawo yokuhlala; (3) umsebenzi wolawulo kunye nolawulo lokuthintela; (4) ukuzibona kunye nokuzazi; kunye (5) nokusebenza ngoxinzelelo. Olu tshintsho luphenjelelwa kakhulu yimiba yemfuza, yophuhliso, kunye nokusingqongileyo kunye nokunxibelelana kwabo okuguquguqukayo, okuya kuthi kumisele ikhosi kunye nobungqongqo bomlutha.
Ngokufana nophando lwangaphambili, ukwahlula amanqanaba amathathu kwikhondo eliphindaphindiweyo lokukhobokisa ebantwini (ukunxila, ukurhoxa, kunye nokunqwenela/ukubuyela umva) kube luncedo. La macandelo alandelayo achaza ezi zigaba kunye nezinye zeesekethe ze-neuronal ezifanelekileyo eziphantsi kwazo.
Ukuzinkcinkca/Inqanaba lokunxila
Uninzi lweemeko zokulutha ziqalwa ngokusetyenziswa kakubi kwezinto ezifunwayo ngenxa yeempawu zabo ze-hedonic. Nangona kunjalo, ukulingwa kweziyobisi kukwaphumela kwiziphumo zokuqinisa ukuhambelana namaqela oluntu (uxinzelelo loontanga) kunye nokudluliselwa okulandelayo kwenkuthazo ekuthatheni ichiza ngenxa yeziphumo zalo zokuqinisa. Ngamaxesha athile, ukusetyenziswa kokuqala kwechiza kunokunxulumana neempawu zalo zonyango (ezifana ne-opiate analgesics yeentlungu okanye izivuseleli zokuhoya-ingxaki yokungakhathali). Njengoko kubonisiwe kwizifundo zangaphambi kweklinikhi, eyona nto iphambili yeziphumo zokuqinisa amachiza yamkelwa ngokubanzi ukubandakanya amandla abo okubangela ukwanda okukhulu kwe-extracellular dopamine kwimimandla ye-limbic (kubandakanya i-nucleus accumbens). Nangona ukuzilawula kwechiza ngokuqatha kuyimodeli elungileyo yezilwanyana yokunxila, ukusebenzisa imodeli yezilwanyana ukuvavanya unxibelelwano oluphathekayo lokunyuka kwe-dopamine okubangelwa ngamachiza kunzima. Izifundo zokucinga ngengqondo ebantwini ziye zaba luncedo ekuboniseni ukuba ukonyuka kweziyobisi kwi-dopamine kwi-striatum (kubandakanywa ne-ventral striatum apho i-nucleus accumbens ikhoyo) inxulunyaniswa nezichazi ezizimeleyo zomvuzo (umz., ulonwabo, ukuphakama, ukonwaba; Volkow okqhubekayo, 1996b). Ngaphaya koko, ezi zifundo zibonise ukuba utshintsho olukhawulezayo lwe-dopamine lunxulunyaniswa nembono yomvuzo, ngelixa ukonyuka okucothayo nokuzinzileyo kwe-dopamine akuziphembeleli ezi mpendulo.Ubabalo, 2000; IVolkow neSwanson, 2003).
Iipropathi ze-pharmacokinetic zamachiza, eziphembelela isantya sokuhanjiswa kwengqondo kunye nexesha lezenzo zabo, zizinto eziphambili zesakhono sabo sokulutha. Iipropati ze-Pharmacokinetic zimisela iidosi, iindlela zokulawula, kunye nokuphindaphinda kokusetyenziswa kweziyobisi ngaphakathi kwesiqendu sokuzinkcinkca. Umzekelo, uthelekiso lwengqondo ye-pharmacokinetics ye-cocaine kunye ne-methamphetamine ibonisa ukuba zombini zifikelela ebuchotsheni ngokukhawuleza (nangona i-cocaine ikhawuleza ngandlel' ithile kune-methamphetamine) kodwa loo cocaine iphuma ebuchotsheni ngokukhawuleza kakhulu kune-methamphetamine.Umzobo 3). Lo mahluko unceda ukuchaza ukuba kutheni i-cocaine ithathwa rhoqo emva kwe-30-60min ngexesha lokuzinkcinkca, kanti imethamphetamine ithathwa qho kwiiyure ezimbalwa (Fowler okqhubekayo, 2008). Ukubaluleka kwe-pharmacokinetics kukwanceda ukucacisa ukuba kutheni iziyobisi ezininzi ezisetyenziswa kakubi (ngaphandle kotywala) zitofwa, zitshaye, okanye zifuthwe. Ezi ndlela zivumela ukuhanjiswa ngokukhawuleza kwechiza kwingqondo kunokuba lithathwe ngomlomo (Volkow okqhubekayo, 2000). I-Pharmacokinetics ikwanceda ekuchazeni ukuba kutheni iziyobisi ezivuselelayo ezifana ne-methylphenidate okanye i-amphetamine, nazo zonyusa i-dopamine, aziqondwa njengezomeleza xa zithathwa ngomlomo njengoko kumiselwe ngonyango.I-Chait, 1994; Volkow okqhubekayo, 2001b).
Izifundo zeklinikhi zikwabonise ukuba ulindelo lweziphumo zechiza lunempembelelo enkulu kwiimpendulo ezinomvuzo kumachiza, kangangokuba indlela yokuziphatha kunye nempendulo yobuchopho bengingqi yengqondo kwichiza ithande ukuba namandla ngakumbi xa ichiza elinomvuzo lilindelwe xa lithelekiswa ne xa iyeza elifanayo lifunyenwe ngokungalindelekanga (Volkow okqhubekayo, 2003). Ukuxhomekeka kweziphumo ezivuzayo zechiza kumxholo kunye nolindelo lucebisa ukubaluleka kwezinye ii-neurotransmitters ezifana ne-glutamate, ehlengahlengisa ukuphinda kusebenze kweeseli ze-dopamine kunye nokukhutshwa kwe-dopamine kwi-nucleus accumbens, kwiziphumo ezinomvuzo zeziyobisi zokusetyenziswa kakubi.IKalivas neVolkow, i-2005).
Ukurhoxiswa / Negative Affect Stage
Impendulo elandela inqanaba lokunxila kweziyobisi yohluka ngokuphawulekayo kuwo wonke amachiza kwaye iphenjelelwa kukunganyangeki kunye nokuphindaphindwa kokusetyenziswa kwawo kakubi. Kwamanye amachiza afana ne-opiates, utywala, kunye ne-sedative hypnotics, ukuyeka ukusetyenziswa kweziyobisi kubasebenzisi beziyobisi ezingapheliyo kunokubangela isifo esinamandla, esibuhlungu sokuyeka umzimba ukuba, ukuba asilawulwa kakuhle kwaye xa sinzima, sinokubulala ngamanye amaxesha. Zonke iziyobisi zokuxhatshazwa zinxulunyaniswa ne-motivational withdrawal syndrome ebonakaliswa yi-dysphoria, ukucaphuka, ukuxinezeleka ngokweemvakalelo, kunye nokuphazamiseka kokulala okuqhubeka nokuba emva kokurhoxa ixesha elide. I-neurobiology yokurhoxa ngokungxamisekileyo yahlukile ekurhoxeni okwexesha elide okanye kwenkuthazo, kwaye zombini zinegalelo ekubuyeleni kwakhona. Izifundo ezimbalwa zokucinga zenziwe ngexesha lokuhoxiswa ngokukhawuleza. Olunye uphononongo olulinganisa utshintsho kwi-dopamine ngexesha lokurhoxa kwe-heroin aluphumelelanga ukubhala i-dopamine yehla kwi-nucleus accumbens eyayixelwe ngaphambili nge-microdialysis kwingqondo ye-rodent.wang okqhubekayo, 1997). Kolu phononongo, akucaci ukuba iziphumo zibonisa ukungabikho kokubandakanyeka kwe-striatal dopamine ngexesha lokurhoxa ngokuqatha kubaxhaphazi be-heroin okanye uvakalelo olulinganiselweyo lwetekhnoloji ye-positron emission tomography (PET).
Iinkqubo eziphantsi kokurhoxa ngokuqatha zinokuthi zibe ngamachiza athile kwaye zibonakalise uhlengahlengiso kwiithagethi zemolekyuli zala machiza. Umzekelo, ngeentsuku ezimbalwa zokuqala zokurhoxa kwe-cocaine, uvakalelo oluphuculweyo lwengqondo kwiziphumo zeziyobisi ze-GABA ezenzekayo ezinokubonisa ukuthotywa kwe-neurotransmitter ngokusetyenziswa okungapheliyo kwe-cocaine.Volkow okqhubekayo, 1998). Ngokufanayo, izifundo zokucinga ngengqondo zikwaveze ukwehla kwe-opioids engapheliyo ngexesha lokurhoxa kwe-cocaine, enokuthi ibe negalelo ekucaphukeni, kwi-malaise, kunye ne-dysphoria eyenzeka ngeli nqanaba lokurhoxa.Zubieta okqhubekayo, 1996).
Ngexesha lokurhoxa ixesha elide, nje ukuba iimpawu kunye neempawu zokurhoxa ngokungxamisekileyo ziye zaphela, izifundo zokucinga ziye zabhala i-hypofunction kwiindlela ze-dopamine, ezibonakaliswa ngokuncipha kwe-D.2 ukubonakaliswa kwe-receptor kunye nokunciphisa ukukhutshwa kwe-dopamine, enokuthi ibe negalelo kwi-anhedonia (okt, ukunciphisa uvakalelo kwi-stimuli evuzayo) kunye ne-amotivation echazwe ngabantu abasebenzisa iziyobisi ngexesha lokuyeka ixesha elide (Volkow okqhubekayo, 1997b, 2007; martinez okqhubekayo, 2004, 2005). Ukuncipha kokuphinda kusebenze kwakhona kwe-dopamine ekomelezeni isivuseleli kukwakho emva kokurhoxa ixesha elide etywaleni xa ukurhoxa emzimbeni kuthobile. Ngokuchaseneyo nokuncipha kobuntununtunu kwimbuyekezo (kubandakanywa nembuyekezo yeziyobisi), izifundo zokucinga ziye zanika ingxelo yokuba ngexesha lokukhutshwa kwetyhefu, uvakalelo olongeziweyo kwimikhombandlela ekwimeko nayo iyenzeka. Ukuyeka ukutshaya, umzekelo, kunokubangela ngokumangalisayo iimpendulo ze-neural kwizinto ezinxulumene nokutshaya (McClernon okqhubekayo, 2009). Ezi mpendulo zinemiqathango zigcina umjikelo wokuziyeka kunye nokubuyela umva obonisa ukuphazamiseka kokusetyenziswa kweziyobisi (Umntwana okqhubekayo, 1988).
Ukongeza, izifundo zokucinga ezivavanya amanqaku okusebenza kwengqondo zibonise ukuba abaxhaphazi beziyobisi abavavanyiweyo ngexesha lokukhutshwa kwexesha elide babonisa ubungqina bokuphazamiseka komsebenzi wemimandla engaphambili, kubandakanya imimandla ye-dorsolateral prefrontal, i-cingulate gyrus, kunye ne-orbitofrontal cortex, eqikelelwa ukuba ibe phantsi kolawulo lwabo lokuthintela kunye nokuphazamiseka. ukungxama kunye nokuba negalelo ekubuyeleni kwakhona (jonga eli candelo lilandelayo kwingxoxo).
Ukuzixakekisa / Ukulindela (Ukufuna) Inqanaba
Uvakalelo olwandisiweyo kwiimpawu ezimiselweyo, ezibandakanya iimeko zovakalelo, zixhokonxa inqanaba lokuzixakekisa ngokufihlakeleyo/ukulindela (ukufuna), eliphawulwa kukwanda kokunqwenela iziyobisi. Inene, uxinzelelo sisisusa esinamandla sokubuyela ekuthatheni iziyobisi ngokusebenza kweesekethe zobuchopho ezibandakanyekayo ekusetyenzweni komvuzo kunye nokuthathela ingqalelo kunye nemnemonic kwizikhumbuzo zokusetyenziswa kweziyobisi (Duncan okqhubekayo, 2007). Esi siganeko singapheliyo sokuphinda sibuye saziwa ngokubanzi njengenye yezona ngxaki zingumngeni ekulweni likhoboka leziyobisi. Abantu abasebenzisa iziyobisi banoxanduva lokubuyela ekuthatheni iziyobisi ixesha elide emva kokufumana iimpawu zokurhoxa kakhulu (Langleben okqhubekayo, 2008). Ukuhlengahlengiswa ngokuthe ngcembe komvuzo kunye neesekethe zenkumbulo, eziziswa kukusetyenziswa kakubi kweziyobisi okungapheliyo, kucingelwa ukuba kubaluleke kakhulu ekunyukeni kwezi mpendulo. Zombini i-dopamine kunye ne-glutamate zichongiwe kwizifundo zangaphambi kweklinikhi njengegalelo kutshintsho lwe-neuroplastic oluhambelana neempendulo ezikwimeko. Ngaphaya koko, utshintsho lweplastiki kwiCRF kunye ne-glucocorticoid receptors kusenokwenzeka ukuba zithathe inxaxheba ekuphuculweni kobuntununtunu boxinzelelo. Ebantwini, ukunqongophala kwee-radiotracers ezifanelekileyo zokuvavanya i-glutamate neurotransmission kunye nokunqongophala kwe-ligands ye-CRF okanye i-glucocorticoid receptors kuthintele izifundo zokunqwenela ikakhulu kwinkqubo ye-dopamine.
I-NEUROCIRCUITRY DYNAMICS KWINGUQULELO YOKUKHOBISA
I-neurocircuitry echazwe apha ngasentla yenza isiseko se-neuroplasticity ehambelana nokuphuhliswa komlutha. Isishwankathelo apha ngezantsi lutshintsho lwe-neuroadaptive olubandakanyekayo kwiisekethe ezimele izigaba zomjikelo wokulutha ochazwe ngasentla. Iisekethe ezintlanu zicingelwa ukuba zibandakanyeke ngokulandelelana, kubandakanywa (1) inkqubo ye-mesolimbic dopamine, (2) i-ventral striatum, (3) i-ventral striatum/i-dorsal striatum/i-thalamus circuits, (4) i-dorsolateral frontal cortex/i-cortex yangaphambili engaphantsi/iisekethe ze-hippocampus, kunye (5) ne-amygdala eyandisiweyo (Umzobo 4). Ubunzima obunxulumeneyo kunye nesalathiso solu tshintsho lwe-neuroadaptive lubonisiwe kumzobo wesekethe yelizwe elikhoboka (Umzobo 5).
Inkqubo ye-Dopamine ye-Mesolimbic: Iindlela ze-Incentive Salience, i-Salience Attribution
Enye ingqikelelo enkulu ekhokela i-neuroplasticity ehambelana nokulutha igxile kwinkqubo ye-mesolimbic dopamine. Ingqikelelo yeyokuba iziyobisi zokusetyenziswa gadalala, ngakumbi i-cocaine kunye ne-amphetamine, zonyusa ukukhutshwa kwe-dopamine ngendlela eyongezelelekileyo nengalawulekiyo kunesivuselelo sendalo, okukhokelela kutshintsho kwi-synaptic plasticity ngaphakathi kwenkqubo ye-dopamine kunye ne-dopamine-receptive neurons.Wolf, 2002). Olu tshintsho ekugqibeleni luthatha iindlela zokufunda eziqhelekileyo zokutshintsha i-neurocircuitry ukuya kwimibutho okanye uhlobo lokufunda umkhwa oluzingisileyo ebusweni beziphumo ezibalulekileyo ezibi (icandelo lokunyanzeliswa; I-everitt kunye neWolf, 2002; uHyman okqhubekayo, 2006).
Iimodeli zezilwanyana zokuvuselela isimilo zigxile kakhulu kwiziphumo zokunyuka kwe-locomotor-activating ye-psychomotor stimulant drug kwizilwanyana ezinembali yokuvezwa okuvuselelayo. Uphononongo olunjalo luveze i-neuroplasticity etyebileyo enxulunyaniswa neenkqubo ze-mesolimbic dopamine kunye nentelekelelo yesiphelo sayo kwi-ventral striatum (apho i-nucleus accumbens ikhona). Iziyobisi zokuxhatshazwa zibangela ukuguqulwa kwexesha elifutshane kunye nexesha elide lokudubula kwe-dopamine neurons kwi-VTA (Bonci okqhubekayo, 2003). Uphononongo lubonise ukuba ukudubula kwe-dopamine neurons kwi-VTA kubonakala kunxibelelene nempendulo ejongisiweyo kwisivuseleli seemvakalelo (Freeman okqhubekayo, 1985). Umntu omnye kwi vivo Ukuvezwa kwe-cocaine okanye i-amphetamine kudala amandla exesha elide (LTP) ye-AMPA-mediated neurotransmission ye-neurotransmission kwi-dopamine neurons (Ngaphandle koko okqhubekayo, 2001). Ukubanakho kweempendulo ze-synaptic AMPA kuye kwacingelwa ukwandisa izehlo zokudubula (UJones noBonci, ngo-2005). I-LTP eqhubekayo ehlala kwiinyanga ezi-3 zokuziyeka iye yanyanzelwa kwi-VTA kwiimpuku ezizilawula ngokwazo i-cocaine kodwa kungekhona kwiimpuku ezitofwayo (Chen okqhubekayo, 2008). Iziphumo ezifanayo zokungeniswa kwe-LTP yokuhanjiswa kwe-glutamate kwi-dopamine neurons ziye zabonwa nge-morphine kunye ne-nicotine.Isalali okqhubekayo, 2003).
Nangona kunjalo, ulawulo oluphindaphindiweyo olungapheliyo lwee-psychostimulants aluphumelelanga ukuvelisa uvakalelo lomsebenzi we-mesolimbic dopamine njengoko kulinganiswa ngu. kwi vivo microdialysis (I-Maisonneuve okqhubekayo, 1995). Ukongeza, ukufikelela okwandisiweyo kwi-cocaine kuyasilela ukuvelisa i-locomotor sensitization (UBen-Shahar okqhubekayo, 2004) kodwa ivelisa impendulo yokuziphatha ekhuthazayo (Ferrario okqhubekayo, 2005). Ngaphaya koko, abaxhaphazi be-cocaine yabantu babonise iimpendulo ezithotyiweyo ze-dopamine xa becelwa umngeni ngechiza elivuselelayo, elichaseneyo nelo bekuxelwe kwangaphambili kukukhuthazwa kokwandiswa komsebenzi we-mesolimbic dopamine.Volkow okqhubekayo, 1997b; martinez okqhubekayo, 2007).
I-Ventral Striatum: Iindlela zeNkuthazo yeNkuthazo, iSalience Attribution
Enye iplastiki ehambelana nokuziphatha kokuziphatha kukuqhubekeka kwe-nucleus accumbens excitatory synapses ebonwa emva kokuvezwa ngokuphindaphindiweyo kweziyobisi kulandelwa ixesha elongezelelweyo lokungabikho kweziyobisi (Kourrich okqhubekayo, 2007). Ukulawulwa okuphindaphindiweyo kwe-cocaine kwandisa i-glutamate neurotransmission kuphela kwiimpuku ezibonise uvakalelo lokuziphatha (gqobhoza okqhubekayo, 1996). Ukongeza, iimpuku ezivezwa yi-cocaine zibonise ukonyuswa kwe-LTP kwi-nucleus accumbens izilayi ngexesha lokurhoxa, mhlawumbi ebonisa ukwanda komsebenzi we-glutamatergic.Yao okqhubekayo, 2004). Ukunyuka komphezulu ukuya kwi-intracellular ratio ye-glutamate-1 receptors (GluR1) ibonwe kwiintsuku ezingama-21 emva kokutofa kwe-cocaine, iphakamisa ukuphuhla kancinci kwakhona kwe-AMPA receptors kumphezulu we-nucleus accumbens neurons, ngakumbi kwezo ziswele i-GluR2.IBoudreau kunye neWolf, 2005; Conrad okqhubekayo, 2008). Ukonyuka kwe-cell-surface ye-AMPA receptors kuxhomekeke ekusebenzeni kwe-dopamine D1 ii-receptors kunye neprotein kinase A yokubonisa (Chao okqhubekayo, 2002). Ngokusebenzayo, ukugqithiswa kwe-GluR1 kwi-nucleus accumbens iququzelele ukuphela kweempendulo ezifuna i-cocaine (Sutton okqhubekayo, 2003) kunye nokwandiswa komvuzo wokuvuselela ubuchopho, kubonisa ukuhla komvuzo kunye nokunciphisa ukuziphatha okukhuthazwayo (Todtenkopf okqhubekayo, 2006). Nangona kunjalo, ukuvezwa okukodwa kwi-cocaine ngexesha lokurhoxa okwandisiweyo kwavelisa uxinzelelo lwe-synaptic, olunokubonisa ukukhutshwa kwe-glutamate ephuculweyo ngexesha lokuvezwa kwakhona kwe-cocaine (Kourrich okqhubekayo, 2007). Okumangalisayo kukuba, ukonyuka kwentetho ye-AMPA ye-receptor ebonwe nge-cocaine ayenzeki kwiigundane ezivuselelwe i-amphetamine, ekhokelela kwi-hypothesis yeziphumo ezahlukeneyo zokusebenza koqikelelo lwe-glutamate kwi-nucleus accumbens ngexesha le-cocaine. vs ukurhoxiswa kwe-amphetamine (Nelson okqhubekayo, 2009).
Ngokuhambelana neziphumo ezitshintshiweyo ze-glutamate neurotransmission kwi-cocaine-sensitized rats, i-microdialysis kunye ne-microinjection izifundo zibonise ukuba emva kwe-cocaine engapheliyo, ukuncipha kwe-basal ye-glutamate kwenzeka kodwa ukukhululwa kwe-synaptic glutamate ngexesha lokubuyiselwa kokucinywa kokufuna iziyobisi kwiimpuku (IKalivas kunye ne-O'Brien, 2008; McFarland okqhubekayo, 2003). Le dysregulation ye-glutamate icingelwa ukuba ibangelwa kukwehla komsebenzi we-cystine-glutamate exchanger (Baker okqhubekayo, 2003) kunye ne-desensitization ye-metabotropic glutamate mGlu2 / 3 receptor. Amanqanaba asezantsi e-basal ye-glutamate, edityaniswe nokukhululwa okwandisiweyo kwe-synaptic glutamate ukusuka ekusebenzeni kwe-prefrontal cortex afferents ukuya kwi-nucleus accumbens, kucingelwa ukuba kubangele ukuqhubela phambili ekufuneni iziyobisi.Kalivas, 2004).
Ezi ziphumo zihlala ixesha elide ze-synaptic zivelisa zombini ukuhla kwe-glutamate neurotransmission ngexesha lolawulo olungapheliyo lwechiza kunye nokwanda okuzingileyo kokusebenza kwe-glutamatergic synaptic neurotransmission ngexesha lokubuyiselwa emva kokurhoxa. Olu tshintsho luguqukayo lunokukhuthaza uchulumanco lweselula, oluye lwacingelwa ukuba luyinxalenye ebalulekileyo yokwazisa kunye nokufunda okunxulumene neziyobisi kwimeko yokulutha (IKauer kunye neMalenka, i-2007; ingcuka okqhubekayo, 2004).
Njengoko bekucetyiswe ngaphambili ziimodeli zezilwanyana, ubukhulu bokukhutshwa kwe-striatal dopamine (ingakumbi kwindawo yayo ye-ventral) ebantwini inxibelelana kakuhle nempendulo ye-hedonic kuninzi lweziyobisi zokuxhatshazwa, kubandakanya i-amphetamine (Drevets okqhubekayo, 2001), icocaine (Volkow okqhubekayo, 1997aI-methylphenidate (Volkow okqhubekayo, 2002kunye nenikotini (USharma noBrody, ngo-2009). Ukunyuka kokuxhomekeka kweziyobisi, okukhawulezayo, kunye nokunyuka kwe-supraphysiological kwi-dopamine kunokwenzeka ukulinganisa utshintsho lwe-dopamine olubangelwa kukudubula kweseli ye-phasic dopamine eyenzeka ngokuphendula isivuseleli esinamandla, ngaloo ndlela ihlela amava echiza njengeyona ibaluleke kakhulu, isiphumo esinamava iyalela ingqalelo kwaye ikhuthaze ukuvuseleleka, ukufunda okumiselweyo, kunye nenkuthazo (Volkow okqhubekayo, 2004b). Ngokwesiseko seziphumo ezifunyenweyo kwizilwanyana zaselabhoratri, ukuvezwa rhoqo kwezi mpendulo zeziyobisi kubaxhaphazi beziyobisi kumiselwe ukuba kubangele ukuphinda kuhlaziywe i-dopamine-activating (umvuzo) imida yabaqinise bendalo.
Ke, umntu unokuba nombono wophuhliso lokudubula kwi-mesolimbic dopamine neurons eqala ngolawulo olunye lwechiza, iphuhla ibe yi-LTP kuqala kwi-VTA emva koko i-nucleus accumbens, kwaye nge-loops yempendulo emva koko ibandakanye i-dorsal striatum. Ngaphezu koko, utshintsho lwexesha elide kwi-CeA kunye ne-medial prefrontal cortex inokulandela, kwaye idityaniswe ne-dysregulation yeenkqubo zoxinzelelo lwengqondo (jonga ngezantsi) inokubonelela nge-drive enamandla ekuziphatheni kokufuna iziyobisi nakwiinyanga emva kokurhoxiswa kweziyobisi.Umzobo 4 kwaye and55).
I-Ventral Striatum/Dorsal Striatum/Thalamus: Ngokuzithandela ukuya kuMkhwa wokufuna iziyobisi
I-hypothesis yokuba i-dorsal striatal circuitry inendima ephambili kuphuhliso lokusetyenziswa okunyanzelekileyo kwe-cocaine ixhaswa yidatha ebonisa ukubaluleka kwe-dorsal striatum ekufundeni umkhwa wokuvuselela-impendulo (Yin okqhubekayo, 2005) kunye nezifundo ze-microdialysis ezibonisa ukuba ukufuna ixesha elide kwe-cocaine kukonyusa ukukhutshwa kwe-dopamine kwi-dorsal striatum kodwa hayi i-ventral striatum (Ito okqhubekayo, 2002). Ukuqhawulwa kwe-ventral striatum kwi-dorsal striatum kwiigundane ezizilawulayo kwi-cocaine kwishedyuli yesibini-odolo kuphela kubonise intsilelo kwizilwanyana ezinokuthathwa 'okunyanzelekileyo' okumiselwe kakuhle kodwa hayi kwizilwanyana ezisandula ukufumana ishedyuli yomyalelo wesibini (Belin kunye ne-everitt, i-2008). Ke, i-hypothesis yeyokuba ukukhotyokiswa kweziyobisi kubonisa utshintsho kulwakhiwo lokunxulumana ukuze luzenzekele okanye lube luqhelo kwaye lubandakanya ukuzibandakanya kancinci kancinci kweendlela ze-dorsal striatal.
Izifundo zezilwanyana zicebise ngamandla ukuba ngokubonakaliswa kweziyobisi okuphindaphindiweyo kokungathathi hlangothi okunxulunyaniswa nechiza ekugqibeleni kunokufumana amandla okunyusa i-dopamine ngokwabo. Izifundo zokucinga ngengqondo ziqinisekisile oku kubantu abakhobokileyo (Volkow okqhubekayo, 2008a; Heinz okqhubekayo, 2004). Ezi zifundo zibonise ukuba iindlela ezihambelana neziyobisi zenza ukuba i-dopamine inyuke kwi-dorsal striatum (i-caudate kunye ne-putamen), isiphumo esinxibelelene neengxelo zokuzinqwenela. Inyani yokuba ubukhulu bokwanda kwe-dopamine ebangelwe zii-cues yayanyaniswa nenqanaba lobunzima bomlutha iqaqambisa ukubaluleka kwezi mpendulo ze-dopamine ezilungiselelwe kwinkqubo yokukhotyokiswa ziziyobisi ebantwini.
Izifundo zeklinikhi zikwabonise ukuba ukonyuka kwe-striatal kade kubangelwa lulawulo olubukhali lwe-methylphenidate yomlomo akubangeli ukunqwenela kubaxhaphazi be-cocaine ngaphandle kokuba zidityaniswe neziyobisi ezihambelana neziyobisi.Volkow okqhubekayo, 2008a). Oku kunokwenzeka ukuba kubonisa inyani yokuba iziphumo ezinqwenelekayo ezivela kwi-dopamine eyonyuka ngokukhawuleza ephunyeziweyo ngokudubula kwe-phasic dopamine, ngokuchasene nokonyuka okucothayo kwe-dopamine okuphunyeziweyo ngokudubula kwe-tonic dopamine kunye novavanyo lwe-methylphenidate yomlomo. Ngapha koko, ukulawulwa kwe-intravenous ye-methylphenidate, ekhokelela ekunyukeni ngokukhawuleza kwe-dopamine, kubangela ukulangazelela okukhulu.
Izifundo zokucinga ngengqondo zikwabonisile ukuba, kwizifundo ezikhotyokiswe ziziyobisi, ezi nkqubo zibandakanya i-orbitofrontal cortex, ingingqi yengqondo echatshazelwa kuphawu olunamandla kunye nenkuthazo, ukuphazamiseka okukhokelela ekunyanzelweni, kwaye ngummandla wobuchopho onokuqikelelwa okunzima kwi-dorsal striatum. . I-cingulate gyrus nayo ibandakanyeka kwaye iyindawo yobuchopho echaphazelekayo ekulawuleni inhibitory kunye nesisombululo songquzulwano, ukuphazamiseka okubangela ukungahambi kakuhle (Volkow okqhubekayo, 2004b). Ngapha koko, kwi-cocaine-addicted, kodwa ingengabo abasebenzisa iziyobisi, ukulawulwa kwe-intravenous ye-methylphenidate, abathi abaxhaphazi be-cocaine babika ukuba baneziphumo ezifanayo nezo ze-cocaine, zisebenze i-orbital kunye ne-medial prefrontal cortices, kwaye oku kusebenze kunxulunyaniswa nokunqwenela i-cocaine.Volkow okqhubekayo, 2005). Ngokufanayo, kwizifundo ezikhotyokiswe yintsangu, kodwa hayi kubantu abangenaziyobisi, ulawulo oluqatha lwe-Δ9-THC isebenze i-obitofrontal cortex (Volkow okqhubekayo, 1996a). Ukwenza kusebenze i-obitofrontal cortex kunye ne-cingulate gyrus kukwabangelwa ziimpawu ezilungiselelweyo ezixela kwangaphambili umvuzo kunye nokuqalisa ukulangazelela (McClernon okqhubekayo, 2009). Okubangela umdla kukuba, le yimimandla elawula ukudutyulwa kweeseli ze-dopamine kunye nokukhululwa, ekuye kwabekwa ukuba ziyimfuneko kumaxabiso enkuthazo enkuthazo ephuculweyo yamachiza kubantu abakhotyokisiweyo (ukulinganisa i-hypothesis esekwe kwizifundo zezilwanyana; Volkow okqhubekayo, 1999). Xa zidityanisiwe, olu qwalaselo lucebisa ngamandla ukuba ukonyuka kwe-dopamine okunxulunyaniswa ne-conditioned cues ayizizo iimpendulo eziphambili, kodwa endaweni yoko sisiphumo sovuselelo lweeseli ze-dopamine, eyona nto inokwenzeka ukuba i-glutamatergic afferents evela kwi-prefrontal cortex kunye/okanye i-amygdala. Ngokwesiseko sezi ziphumo, ukusebenza kwe-obitofrontal cortex, kunye nokunyuka okuhambelanayo kwi-dopamine eveliswa lichiza, kuye kwacingelwa ukuba negalelo ekusetyenzisweni kweziyobisi okunyanzelekileyo okubonisa ukuzintyintya kweziyobisi kubantu abakhobokileyo.Volkow okqhubekayo, 2007).
Ewe, izifundo ze-neuroimaging zabantu zibonisa ukuba i-prefrontal cortex (i-orbitofrontal, i-medial prefrontal, i-prelimbic / i-cingulate) kunye ne-amygdala ye-basolateral ibaluleke kakhulu kwi-chiza- kunye ne-cue-induced nkanuko ebantwini.Franklin okqhubekayo, 2007). Kwimimandla yangaphambili (umzekelo, i-cingulate gyrus kunye ne-obitofrontal cortex), olu tshintsho luye lwanxulunyaniswa nokuncipha kwe-striatal dopamine D.2 ukufumaneka kwe-receptor kuqatshelwe kwizifundo ezikhobokisayo (Heinz okqhubekayo, 2004; Volkow okqhubekayo, 1993, 2001a, 2007). Olu nxulumano lunokubonisa ukuphazamiseka kwemimandla yengqondo engaphambili eyesibini kutshintsho kumsebenzi we-striatal dopamine, okanye kungenjalo inokubonisa ukuphazamiseka okuphambili kwemimandla engaphambili elawula umsebenzi weseli ye-dopamine. Ewe, uphononongo lwamva nje lwe-PET lubonelele ngobungqina bokuba imimandla yobuchopho yangaphambili ilawula ixabiso lemivuzo ngokumodareyitha ukonyuka kwe-dopamine kwi-ventral striatum, inkqubo yolawulo engasebenzi kakuhle kubantu abakhobokileyo.Volkow okqhubekayo, 2007).
Ke, i-concomitant dopamine kunye ne-glutamate neurotransmission kwi-dorsal striatum, ummandla obandakanyeka ekufundeni komkhwa kunye nokuqaliswa kwesenzo, ubandakanyeka kwiminqweno ye-cue/exhomekeke kumxholo. Ngaloo ndlela, i-dorsal striatum inokuba yinxalenye ebalulekileyo yokulutha (Volkow okqhubekayo, 2006). Uphando lweendlela ezintsha zokuthintela i-dopamine ene-cue-conditioned kunye neempendulo ze-glutamate yeyona nto kugxilwe kuyo kwiinzame zangoku zophuhliso lwamayeza.
Ithalamus ayizange ifundwe ngokubanzi kumxholo wokulutha. Nangona kunjalo, ngenxa yomsebenzi wayo odibeneyo kulawulo lokuvuswa kunye nokumodareyitha ingqalelo, lo mmandla uye wabandakanyeka ngakumbi kwinkqubo yokulutha. Ngokomzekelo, ukulawulwa kwe-intravenous yechiza elikhuthazayo kubaxhaphazi be-cocaine, kodwa kungekhona kulawulo, ukunyuka kwe-dopamine neurotransmission kwi-thalamus, umphumo ohambelana nokunqwenela (Volkow okqhubekayo, 1997a). Ngokwahlukileyo, xa kuthelekiswa nolawulo, abaxhaphazi be-cocaine babonisa i-hypoactivation ye-thalamus, mhlawumbi ibonisa i-noradrenergic kunye / okanye i-dopaminergic deficits, xa besenza umsebenzi wokuqonda.UTomasi okqhubekayo, 2007b). Ngokufanayo, i-thalamus yaxelwa ukuba ibonise ukusebenza kwe-actiated ngelixa yenza umsebenzi obonakalayo wokuqonda kubantu abatshayayo abavezwe kwi-nicotine (USharma noBrody, ngo-2009). Ezi ziphumo zibonisa ukuba ukungahambi kakuhle kwe-thalamic kubaxhaphazi be-cocaine kunokuba negalelo kungekuphela nje kukuphazamiseka kokusetyenzwa kweemvakalelo kunye nokuqwalaselwa kodwa kunye nokunqwenela. Okubangela umdla kukuba, utshintsho kukuhanjiswa kwe-dopamine kwithalamus kunye ne-striatum kubonakala ngathi kubandakanyeka ekuwohlokeni kokusebenza kwengqondo (umzekelo, ukuqwalaselwa okubonakalayo kunye nenkumbulo yokusebenza) elandela ngokungenakuphikiswa ixesha lokungalali.Volkow okqhubekayo, 2008b). Ke ngoko, uphando olongezelelekileyo olwakhela phezu kwedatha ekhoyo yangaphambili lufanelekile.
I-Dorsolateral Frontal Cortex, i-Inferior Frontal Cortex, i-Hippocampus: Ulawulo lwengqondo, uLwaniso olulibazisekileyo, kunye neMemori.
Ukulutha kukwabandakanya ukuphazamiseka kwiinkqubo zokulawulwa kwengqondo kunye neemvakalelo ezilawulwa yicortical, ezibangela ukuxatyiswa kwezixhobo zokuqinisa iziyobisi ngeendleko zokungaxabiseki kwabaqinisi bendalo, kunye nokusilela kulawulo lokuthintela iimpendulo zeziyobisi (I-Goldstein neVolkow, i-2002). Ngenxa yoko, inkqubo ye-prefrontal engasebenzi kakuhle kukholelwa ngokubanzi ukuba ibalulekile kwinkqubo yokulutha.
Elinye lamacandelo kwinkqubo enjalo lulawulo lwempembelelo, ephakathi kwezona zinto zinamandla zomngcipheko wokuqonda ukuphazamiseka kokusetyenziswa kweziyobisi. I-Cocaine ibonakala inefuthe elithe ngqo kwi-neurobiology ephantsi kolawulo lwempembelelo. Emva kwenaliti ye-cocaine ye-intravenous, abasebenzisi be-cocaine ngokwenene babonise ukuphucuka komsebenzi wokuthintela ukuphendula kwemoto kunye nokuhambelana nokunyuka kokusebenza kwi-dorsolateral yabo yasekunene kunye ne-cortices yangaphambili engaphantsi (IGaravan okqhubekayo, 2008). Ngenxa yokuba ezi ndawo zithathwa njengezibalulekileyo kulawulo lwempembelelo, olu qwalaselo lucebisa ukuba ezinye zeziphumo ezibi ze-cocaine zinokulamla ukuguqulwa okwethutyana kwe-hypofunction engapheliyo kulawulo lwe-impulse control circuitry.
Omnye umsebenzi obalulekileyo ohlala kwimimandla yangaphambili kukukwazi ukukhetha phakathi kwemivuzo emincinci kunye nekhawulezileyo xa kuthelekiswa nembuyekezo emikhulu kodwa erhoxisiweyo, enokulinganiswa kusetyenziswa umsebenzi wokulibaziseka wesaphulelo. Uphononongo lwakutsha nje lufumanise ukuba yomibini i-dorsolateral kunye ne-inferolateral frontal cortex grey miba ihambelana ngokungafaniyo nokukhetha ukwaneliseka kwangoko ngexesha lokwenziwa kwezigqibo (Bjork okqhubekayo, 2009). Oku kufunyanisiweyo kuphakamisa ukuba izinto ezingaqhelekanga kwingingqi ye-frontocortical zinokuba sisiseko sokungakwazi ukulibazisa ukwaneliseka, uphawu oluphawu lokukhobokisa kunye nezinye iziphazamiso zengqondo.
I-neural substrates yememori kunye nokufunda okusemgangathweni ziphakathi kweesekethe ezinkulu ezifumana i-neuroadaptations engaqhelekanga ekuphenduleni ukuvezwa kweziyobisi ezingapheliyo (Volkow okqhubekayo, 2004a). Iinkqubo ezahlukeneyo zokukhumbula ziye zacetywa ukuba zibandakanyeke kumlutha weziyobisi, kubandakanywa ukufunda okukhuthazwayo (nge-nucleus accumbens kunye ne-amygdala), ukufunda ngokuziqhelanisa (nge-caudate kunye ne-putamen), kunye nememori echazayo (nge-hippocampus; Mhlophe, 1996), eyona nto kugxilwe kuyo leli candelo.
Kule minyaka ilishumi idlulileyo, uphando oluninzi lwezilwanyana oluxhokonxayo lucebise ukuba iziyobisi ezikhobokisayo zinokuphazamisa i-neurogenesis kwihippocampus yabantu abadala (Canales, ngo-2007). Umonakalo kwi-subiculum ye-ventral ye-hippocampus yaboniswa ukuba ichaphazele ukuzilawula kwe-cocaine kwiimpuku (Caine okqhubekayo, 2001). Olo qwalaselo lubonelele ngengqiqo malunga nokubandakanyeka okunokwenzeka kwe-hippocampus engalawulekiyo kubukhoboka bomntu. Le ngqikelelo kukwandiswa kolwazi lwangoku kuba i-hippocampus ijongwa ngokubanzi njengento ebalulekileyo kwimeko yomxholo, oko kukuthi ekuqhutyweni kweengqikelelo zeemeko apho iinkumbulo zinokufikelelwa kwaye zithathwe. Enyanisweni, imemori echazayo sele iqatshelwe ixesha elide ukuba ibandakanyeka ekufundeni kunye nokudibanisa kweemeko ezichaphazelekayo okanye iimeko kunye namava okusebenzisa iziyobisi. Izifundo nge-PET kunye ne-imaging magnetic resonance imaging ibonise ukuba i-cue-elicited inkanuko, kunye nokunxila okugqithisileyo, kusebenze i-hippocampus kunye ne-amygdala (Volkow okqhubekayo, 2004a). Umzekelo, umnqweno ofunyanwa ngabasebenzisi be-cocaine ngelixa bevezwe kwisivuseleli esinxulumene neziyobisi sikhatshwa kukuhamba kwegazi okunyukayo kwindawo esasaziweyo ebandakanyeka kwiintlobo ezininzi zememori, kubandakanya i-amygdala (Umntwana okqhubekayo, 1999; Grant okqhubekayo, 1996; Iikhithi okqhubekayo, 2001kunye nehippampus (Iikhithi okqhubekayo, 2001).
Ke ngoko, iindlela ezintsha zokuphazamisa ukuhlanganiswa kwenkumbulo zinokunceda ukuphelisa ubudlelwane obuqinileyo phakathi komxholo kunye neziyobisi (Lee, 2008; Lee okqhubekayo, 2005). Okubangela umdla, β-i-blockers sele ibonise amandla athembisayo okuthintela iimpendulo ezisemgangathweni kuzo zombini iziqinisekiso zendalo kunye ne-aversive stimuli (Miranda okqhubekayo, 2003). Ngaphaya koko, iziphumo ezisuka kuphononongo lwamva nje zibonisa ukuba iimpendulo ezenziwe ngamachiza zinokuba novakalelo β-unyango lwe-blockade (Milton okqhubekayo, 2008). Ngokufanayo, uphando olongezelelweyo ngamachiza okuphucula i-GABA nalo lubonakala lufanelekile. Ukuvuselela i-GABAergic, enokuthi ithintele imeko ye-Pavlovian, ibonakala iphazamisa impendulo kwiziyobisi zokuxhatshazwa kwizilwanyana (Volkow okqhubekayo, 2004a) kwaye inokuba sisicwangciso esiluncedo sokunyanga umlutha ebantwini (UDewey okqhubekayo, 1998).
I-Amygdala eyandisiweyo: Iindlela zokuQinisekisa ezimbi
Ukusetyenziswa kweziyobisi okunyanzelekileyo okuchazwa kukwanda kokuthatha ichiza kunye nokufikelela okwandisiweyo kukhatshwa kukuphazamiseka okungapheliyo kwi-homeostasis yomvuzo wobuchopho kusetyenziswa imilinganiselo yokuvuselela ubuchopho imida yokuvuza. Uvezwa ngokwahlukileyo ekuzilawuleni kweziyobisi kuneziphumo ezimangazayo kwimida yomvuzo ekhula ngokuthe ngcembe (okt, ukuhla komvuzo) kufikelelo olwandisiweyo, kodwa hayi ekufikeleleni okulinganiselweyo, iigundane kwiiseshini zokuzilawula ezilandelelanayo.Ahmed okqhubekayo, 2002; Kenny okqhubekayo, 2006; Wee okqhubekayo, iziphumo ezingapapashwanga). Izilwanyana ezinokufikelela okwandisiweyo kwi-cocaine zinovakalelo ngakumbi kuthintelo lokuzilawula ngabachasi be-dopamine kunye nee-agonists ezingaphelelanga (U-Ahmed noKoob, i-2004; Wee okqhubekayo, 2007), kunye nedosi ye-opioid inxalenye ye-agonist buprenorphine ngokuxhomekeka ekunciphiseni ukuzilawula kwe-heroin ekufikeleleni okwandisiweyo, iigundane ezixhomekeke kwi-opioid (Chen okqhubekayo, 2006b), ecebisa ukuba ukuguqulwa kokusilela kwembuyekezo kunokwenza buthathaka iimpembelelo ezikhuthazayo zokukhotyokiswa ziziyobisi. Lo matshini unokuthoba inzuzo ye-methadone kunye ne-buprenorphine kunyango lwe-heroin.
Njengoko kuphawuliwe ngasentla, abachasi beCRF bathintele i-anxiogenic- kunye ne-aversive-efana neziphumo zokurhoxa kweziyobisi, kunye nokurhoxa kuzo zonke iziyobisi zokuxhatshazwa kusebenze iCRF kwi-CeA. Olu qwalaselo lukhokelele kuqikelelo lokuba ukusebenza kweCRF, ngakumbi i-extrahypothalamic CRF kwi-CeA, ibe negalelo kunyanzeliso lokuqhuba lorhulumente wenkuthazo ukusuka kumbono wokomelezwa ongalunganga (UKoob noLe Moal, i-2008). Ke, umntu unokuqikelela ukuba ukuvalwa kweenkqubo zoxinzelelo lobuchopho kwiimodeli zezilwanyana zokufikelela okwandisiweyo kumachiza kunokuthintela inkuthazo yokuthatha iziyobisi ngokugqithisileyo. Abachasi beCRF bathintele ngokukhethayo ukonyuka kokuzilawula kweziyobisi ezinxulumene nokufikelela okwandisiweyo kulawulo lwe-cocaine, inikotini (I-Koob, i-2008), heroin (IGreenwell okqhubekayo, 2009), kunye notywala (I-Koob, i-2008). Umzekelo omangalisayo wempembelelo ye-CRF kwi-amygdala eyandisiweyo yokuxhomekeka inokubonwa kwiimodeli zezilwanyana ze-ethanol yokuzilawula kwizilwanyana ezixhomekeke apho iCRF1/2 I-peptide antagonist efakwe kwi-amygdala ivimbe ukwanda kwe-ethanol yokuzilawula ngexesha lokurhoxiswa (Funk okqhubekayo, 2006; I-Koob, i-2008).
Nangona kuncinci ukuphuhliswa kakuhle, ubungqina bubonisa ukubandakanyeka kweenkqubo ze-norepinephrine kwi-amygdala eyandisiweyo kwisimo esikhuthazayo esibi kunye nokwandisa ukuzilawula okuhambelana nokuxhomekeka (Koob, 2009b). Ngokuhambelana nendima yedynorphin-κ inkqubo ye-opioid kwimiphumo ephazamisayo yokurhoxiswa kweziyobisi, a κ-umchasi we-opioid uthintele ukusela ngokugqithiseleyo okuhambelana nokurhoxiswa kwe-ethanol kwiigundane ezixhomekeke kwaye ngokukhethayo uthintele ukunyuka kwentsebenzo yenkqubela phambili kwiigundane kunye nokufikelela okwandisiweyo kwi-cocaine.Koob, 2009b; Wee okqhubekayo, 2009).
I-Neuropeptide Y ineempawu ezimangalisayo ze-anxiolytic-ezifana ne-amygdala kwaye icingelwe ukuba ibe nemiphumo echasene ne-CRF kwiimeko ezikhuthazayo zokurhoxa kwiziyobisi zokuxhatshazwa.Heilig okqhubekayo, 1994; UHeilig noKoob, ngo-2007). I-NPY elawulwa nge-intracerebroventricular ivalwe ukwanda kokuthathwa kwechiza okuhambelana nokuxhomekeka kwe-ethanol (Thorsell okqhubekayo, 2005a, 2005b). Ukutofwa kweNPY kwi-CeA (Gilpin okqhubekayo, 2008) kunye nenkcazo ephuculweyo ye-vector-enhanced ye-NPY kwi-CeA ikwathintele ukwanda kokuthathwa kwechiza okuhambelana nokuxhomekeka kwe-ethanol (Thorsell okqhubekayo, 2007).
Ke ngoko, ukonyuka kweCRF kwi-CeA okwenzeka ngokurhoxa ngokungxamisekileyo kumachiza kunokubaluleka kwenkuthazo kungekuphela nje kuxhala/iziphumo ezinjengokurhoxa ngokungxamisekileyo kodwa nokonyuka kokuthathwa kweziyobisi okuhambelana nokuxhomekeka. Ukuhoxiswa ngokukhawuleza kunokunyusa ukukhululwa kwe-norepinephrine kwi-BNST kunye ne-dynorphin kwi-nucleus accumbens, zombini ezinokuthi zibe negalelo kwimeko yeemvakalelo ezimbi ezinxulumene nokuxhomekeka. Ukuncipha komsebenzi we-NPY kwi-CeA nako kunokuba negalelo kwimeko yokuxhalaba ehambelana nokuxhomekeka kwe-ethanol. Ukusetyenziswa kweenkqubo zoxinzelelo lwengqondo (CRF, norepinephrine, dynorphin), kudityaniswe nokungasebenzi kweenkqubo zokulwa noxinzelelo lwengqondo (NPY) kwi-amygdala eyandisiweyo inokubangela ukungasebenzi kakuhle ngokweemvakalelo ngokubaluleka kokukhuthaza ukuba likhoboka. Uninzi lwezinye iinkqubo ze-neurotransmitter ziye zacatshangelwa ukulungelelanisa i-amygdala eyandisiweyo zombini kwi-domain-induction domain (vasopressin, i-substance P, i-orexin) kunye ne-antistress domain (i-nociceptin, i-endocannabinoids; ukuhlaziywa, bona I-Koob, i-2008). Ukungalawuleki okunjalo kunokuba negalelo elibalulekileyo kwiinkqubo eziphakathi kwenkqubo echasayo ezinceda ukugcina ukuxhomekeka kwaye zisete inqanaba lotshintsho olude lwemeko yeemvakalelo njengokuzila ixesha elide.
Uphando malunga neendlela zokomelezwa kakubi kubukhoboka bomntu lusikelwe umda kakhulu. Nge-cocaine, umzekelo, i-amygdala kunye ne-lateral orbitofrontal cortex zibonakaliswe ukuba zenziwe zisebenze ngokungalindelekanga kodwa bekungalindelekanga infusions ye-cocaine kubaxhaphazi abasebenzayo be-cocaine (Kufahl okqhubekayo, 2008), kodwa ukuyeka i-cocaine kwayanyaniswa nokunciphisa okukhulu kumsebenzi wemimandla ye-dopamine yokubonisa, kubandakanya i-amygdala (UTomasi okqhubekayo, 2007a). Ngokwahlukileyo koko, ukuyeka ukutshaya kwakunxulunyaniswa nokunyuka kwegazi le-cerebral kwi-amygdala eyandisiweyo, phakathi kweminye imimandla (wang okqhubekayo, 2007), ngelixa i-nicotine spray yempumlo yanciphisa ukuhamba kwegazi kwi-cerebral yengingqi kwi-amygdala yasekunene kunye ne-cortex yangaphambili yesikhashana yangaphambili yabantu abatshayayo abaphantsi kwe-12h yokungabikho kokutshaya (Zubieta okqhubekayo, 2001).
I-amygdala inokubaluleka ngokulinganayo ekuqhubeni umvuzo olungileyo (UMurray, 2007) kunye nexesha elilindelekileyo lokuvuza (IHolland kunye neGallagher, 2004), iyafana nokusetyenzwa komvuzo ongalunganga. Eyona nto inomdla kumxholo wophando lwengqondo yokucinga iya kuba kukuqonda umsebenzi we-amygdala ekuveliseni ixhala kunye neemvakalelo ezingalunganga ezibonwa rhoqo ngexesha lokuzila.
Ingxelo yamva nje iqaqambise ukubaluleka kumlutha wesekethe ye-interoceptive enokuthi inxibelelane ne-amygdala eyandisiweyo kunye ne-ventral striatum. Uphononongo lubonise ukuba abantu abatshayayo ngomonakalo kwi-insula yabo (kodwa bengatshayi abanezilonda ezingaphandle) bakwazi ukuyeka ukutshaya ngokulula kwaye ngaphandle kokufumana iminqweno okanye ukuphinda babuyele (Naqvi okqhubekayo, 2007). I-insula, ngakumbi imimandla yayo engaphambili, idityaniswa ngokuphindaphindiweyo kwimimandla emininzi ye-limbic (umzekelo, i-ventromedial prefrontal cortex, i-amygdala, kunye ne-ventral striatum) kwaye ibonakala inomsebenzi wokuqonda, ukudibanisa ulwazi oluzimeleyo kunye nolwazi lwe-visceral kunye nemvakalelo kunye nenkuthazo kunye nokubonelela ngengqondo. ukuqonda ezi ngcebiso (UNaqvi noBechara, 2009). Ewe, izifundo zokulimala kwengqondo zibonisa ukuba i-ventromedial prefrontal cortex kunye ne-insula zizinto eziyimfuneko kwiisekethe ezisasaziweyo ezixhasa ukwenza izigqibo ngokweemvakalelo (Clark okqhubekayo, 2008). Ngokuhambelana nale ngqikelelo, uninzi lwezifundo zokucinga zibonisa ukusebenza okwahlukileyo kwi-insula ngexesha lokunqwenela (UNaqvi noBechara, 2009). Ukuphinda kusebenze kwakhona kwalo mmandla wobuchopho kucetyisiwe ukuba kusebenze njenge-biomarker ukunceda uqikelelo lokubuyela kwakhona.
IINJONGO ZE-MOLECULAR ZE-NEUROPLASTICITY: UKUZINXIPHA/UKUXABISA, UKUNXA UKUNXA/KUCHAPHAZELEKAYO, KUNYE NE-PREOCCUPATION/UKULINDELA (UKUKHALA)
Ingqwalasela yophononongo lwangoku ikwi-neurocircuitry yokulutha. Nangona kunjalo, i-parallel kwi-neuroplasticity ye-neurocircuitry lutshintsho lwe-molecular olwenzeka kwezi zakhiwo ezifanayo. Ukuvezwa okungapheliyo kwi-opiates kunye ne-cocaine kukhokelela ekusebenzeni kwe-cyclic adenosine monophosphate impendulo-element ebopha iprotheni (CREB) kwi-nucleus accumbens kunye ne-CeA (UShaw-Lutchman okqhubekayo, 2002; Edwards okqhubekayo, 2007). I-CREB inokuba yi-phosphorylated ngeprotein kinase A kunye neprotheyini kinase elawulwa yimiba yokukhula, ibeka kwindawo yokudibanisa kwiindlela ezininzi ze-intracellular messenger ezingakwazi ukulawula ukubonakaliswa kofuzo. Ukusebenza kwe-CREB kwi-nucleus accumbens kunye neziyobisi ze-psychostimulant inxulunyaniswe neempawu ezikhuthazayo zokurhoxa kwengqondo, njenge-dysphoria, mhlawumbi ngokungeniswa kwe-opioid peptide dynorphin, ebophelela kuyo. κ-i-opioid receptors kwaye icingelwe ukuba imele indlela yokunyamezela kunye nokuxhomekeka (Nestler, 2005). Ukusebenza okuphindaphindiweyo kwe-CREB kukhuthaza ukubonakaliswa kwe-dynorphin kwi-nucleus accumbens, ethi yona inciphise umsebenzi we-dopaminergic, zombini ezinokuthi zibe negalelo kwimeko yeemvakalelo ezimbi. I-kinase elawula umqondiso we-Extracellular yenye into ephambili yokusayinwa kwe-intracellular ethathwa njengeyona nto iphambili kwiplastikhi ehambelana nokulawulwa ngokuphindaphindiweyo kwe-cocaine, ngokukodwa uvakalelo lokuziphatha, umvuzo we-cocaine, kunye nokunyuka kwexesha elixhomekeke kwi-cocaine-ukufuna emva kokurhoxiswa (okt, i-incubation effect; Lu okqhubekayo, 2006; Li okqhubekayo, 2008).
Olunye ujoliso lwemolekyuli yokulawula iplastiki ekhokelela ekubeni likhoboka le-dysregulation ye-cystine-glutamate exchange, ecingelwa ukukhuthaza ukubonakaliswa kwe-pathological glutamate ehambelana nezinto ezininzi zomjikelo wokulutha. Apha, ulawulo oluphindaphindiweyo lwe-cocaine blunts cystine-glutamate exchange, ekhokelela ekunciphiseni i-basal kunye nokwanda kwe-cocaine-induced glutamate kwi-nucleus accumbens eqhubeka ubuncinane kwiiveki ezi-3 emva konyango lokugqibela lwe-cocaine (Baker okqhubekayo, 2003). Eyona nto inyanzelisayo luqwalaselo olunokuthi unyango nalo N-i-acetylcysteine, ngokuvula i-cystine-glutamate exchange, inqanda ukunyuka kwe-cocaine kunye nokuziphatha, ukubuyisela amandla okwenza i-LTP kunye nokudandatheka kwexesha elide kwi-nucleus accumbens, kunye nokubuyiselwa okufihliweyo kwizilwanyana kunye nokuphinda kusebenze kwimeko yeziyobisi ebantwini.Moussawi okqhubekayo, 2009; LaRowe okqhubekayo, 2007; UMadayag okqhubekayo, 2007).
I-CREB kunye nezinye izithunywa ze-intracellular zingenza kusebenze izinto ezibhaliweyo, ezinokutshintsha ukubonakaliswa kofuzo kunye nokuvelisa utshintsho olude kwixesha elide kwi-protein expression, kwaye, ngenxa yoko, umsebenzi we-neuronal. Nangona ulawulo olungqongqo lweziyobisi zokusetyenziswa kakubi lunokubangela ukuba amalungu osapho lweFos protein lusebenze ngokukhawuleza (kwisithuba seeyure) ezifana no-c-iifos, i-FosB, i-Fra-1, kunye ne-Fra-2 kwi-nucleus accumbens, ezinye izinto ezibhaliweyo, i-isoforms ye-ΔFosB, uhlobo oluzinzile lwe-FosB, lubonakaliswe ukuba luqokelele ixesha elide (ientsuku) kunye nokulawulwa kweziyobisi ngokuphindaphindiweyo (Nestler, 2005). Izilwanyana ezine-ΔFosB esebenzayo zinovakalelo olubaxiweyo kwiziphumo ezivuzayo zeziyobisi zokusetyenziswa kakubi, kwaye i-ΔFosB inokuba 'yitshintshi' yemolekyuli ezinzileyo enceda ukuqalisa kunye nokugcina imeko yokulutha.McClung okqhubekayo, 2004). Nokuba (kwaye njani) ezo zinto zokukhutshelwa zinefuthe ekusetyenzisweni kweenkqubo zoxinzelelo lobuchopho, ezinje ngeCRF kunye nezo zichazwe apha ngasentla, ziya kuhlala zimisiwe.
ISISHWANKATHELO NEMIGQUBO
Isishwankathelo, imimandla yobuchopho emininzi kunye neesekethe ziphazamisekile kumlutha weziyobisi kwaye zinokuthi zibe negalelo ngokwahlukileyo kwi-phenotype entsonkothileyo ebonwa kubantu abakhobokileyo (Umzobo 5). Nangona ezinye zezi ziphazamiso zinokuthi zibekho kumlinganiselo omkhulu okanye ongaphantsi kuzo zonke iindidi zokukhotyokiswa ziziyobisi, olunye utshintsho lunokuba luthe ngqo kwiintlobo ezithile zamachiza. Umzekelo, ukwehla okuhlala ixesha elide kwi-DAT kwi-striatum kujongwa kwi-methamphetamine kodwa hayi etywaleni okanye kwiziyobisi ze-cocaine. Ngokwahlukileyo, ukuncipha kwi-dopamine D2 i-receptors kwi-striatum ijongwa kwizifundo ezikhotyokiswe kuzo zonke iziyobisi zokusetyenziswa kakubi eziphandiweyo, kunye nokwanda kokusebenza kweenkqubo zoxinzelelo lobuchopho ezifana neCRF ibonwe kwiimodeli zezilwanyana ngexesha lokurhoxa ngokukrakra kuzo zonke iintlobo zeziyobisi. Okubalulekileyo, ukungahambi kakuhle kwe-neuronal okubonakala kumntu okhobokekileyo kwaye kunokutyhilwa ngokucinga kunye / okanye izifundo ze-neuropsychopharmacological alubonakaliso lwendlela yokuvezwa kweziyobisi ezingapheliyo, kodwa kunye neenkwenkwezi ezithile zomntu zofuzo, uphuhliso, kunye nokusingqongileyo. iimpawu.
IZIKHOKELO ZOPHANDO LWEXESHA
Inkqubela phambili echazwe ngasentla ikhomba indlela eya kwizikhokelo zexesha elizayo zophando kwi-neurocircuitry ye-addiction kwisakhelo sengqiqo efanayo yokuzinkcinkca/ukunxila, ukurhoxa/impembelelo embi, kunye nokuzixakekisa/nolindelo. Izibonelelo ezityebileyo ze-neuroscience zanamhlanje ezisetyenziswa kwi-neurobiology yokulutha zinika ithuba lokungaqondi kuphela i-neurocircuitry yenkqubo yokulutha kodwa nokubonelela ngezitshixo zokuqonda ukuba sesichengeni kunye nokubonelela ngonyango lwesi sifo sitshabalalisayo.
Kwinqanaba lokuzinkcinkca/lokunxila kumjikelo wokulutha, indlela i-neuroplasticity eqala ngotshintsho lokudubula kwi-mesolimbic dopamine neurons ngexesha lokuvezwa kweziyobisi kuguqulelwa kukuzibandakanya kwe-dorsal striatum, ukuphazamiseka komsebenzi wangaphambili, kunye nokugaya iinkqubo zoxinzelelo lwengqondo kunye kukhokelela kwintsalela enamandla okuqhuba ekufuneni amachiza kwaneenyanga emva kokurhoxa kusafuneka kumiselwe. Umzekelo, loluphi unxulumano phakathi kokuba sesichengeni sokutsaleka kunye nokunyanzeliswa okulandelayo kwi-neuroplasticity yeesekethe ezichazwe ngasentla? Uphononongo olunjalo lwexesha elizayo lunokubandakanya iindlela zofuzo zemolekyuli ezisukela ekuzaleni okukhethiweyo ukuya kulawulo okanye ukuthotywa kweendlela zemolekyuli ngaphakathi kweesekethe ezithile zobuchopho kusetyenziswa itekhnoloji ye-RNA eneenwele ezimfutshane.
Kwinqanaba lokurhoxisa / elibi elichaphazelayo, ukubandakanyeka kweenkqubo zoxinzelelo lwengqondo, njengeCRF, kwiimodeli zezilwanyana kufuneka zandiswe kwezinye iinkqubo zokuxinzelela kwengqondo ezisebenzisanayo kwaye zihlolwe kwizifundo zabantu. Uninzi lwezinye iinkqubo ze-neurotransmitter ezisebenzisana nenkqubo yoxinzelelo lwengqondo ngoku zijongwa kuphela, njenge-dynorphin, i-NPY, i-substance P, i-nociceptin, kunye ne-orexin. Phantse kungaphononongwanga kweli nqanaba zizifundo zokucinga zabantu zeli candelo lomjikelo wokulutha kunye nokucinga komntu kwiinkqubo ze-neurotransmitter zobuchopho ezibandakanyeka kwimiba ekhuthazayo yokurhoxiswa kweziyobisi. Uphuhliso lwenoveli ye-radioactive ligands kwizifundo zokucinga zabantu ezibophelela kwii-receptors zezi nkqubo ze-neurotransmitter zingasentla ziya kuba lukhuthazo olukhulu endle.
Kwinqanaba lokuxakeka / lokulindela, izifundo ze-neuroimaging zabantu zibonisa ukuba i-prefrontal cortex (i-orbitofrontal, i-medial prefrontal, i-prelimbic / i-cingulate) kunye ne-amygdala ye-basolateral ibaluleke kakhulu kwi-chiza- kunye ne-cue-induced craving. Nokuba loo mibutho ibonakalisa ukuphazamiseka kwemimandla yobuchopho yangaphambili eyesibini kutshintsho lomsebenzi we-striatal dopamine, okanye ngenye indlela ibonakalisa ukuphazamiseka okuphambili kwemimandla engaphambili elawula umsebenzi weseli ye-dopamine, kusafuneka kumiselwe. Iindlela ezintsha kuphononongo lokudityaniswa kwakhona kwenkumbulo zinokunceda ukucacisa unxulumano olomeleleyo phakathi komxholo kunye neziyobisi. Ukubaluleka kokulutha kwisekethe ye-interoceptive ebandakanya i-insula kunye neminye imimandla ekunokwenzeka ukuba ijongane ne-amygdala eyandisiweyo kunye ne-ventral striatum isahlala isenziwa. Ukusebenza kwakhona kwezi sekethe zobuchopho kunokusebenza njenge-biomarker ukunceda ukuqikelela ukuphinda ubuyele kwaye uncede uqikelele ukusebenza konyango. Izifundo zasemva kokufa kwabantu, izifundo zelabhoratri yabantu, kunye nezifundo ze-neurocircuitry kwiimodeli zezilwanyana ezihambelanayo zinokuvelisa iziphumo ezithembisayo kwesi sizinda.
Okokugqibela, utshintsho lwemolekyuli kunye nofuzo oludlulisa utshintsho kumsebenzi we-neurocircuits kuzo zontathu izigaba zomjikelo wokulutha ochazwe ngasentla kuphela ngoku ziyacaciswa. Utshintsho kwiinkqubo zolawulo lothumelo, izinto ezikhutshelweyo, kunye nokulawulwa kofuzo kwinqanaba le-epigenetic kunokucacisa ukuba iisekethe zilawulwa njani, zihlala zingasebenzi kakuhle, kwaye zibonelela ngomngcipheko wokungalawuleki ekuqaleni okanye ixesha elide ekuyekeni. Ekugqibeleni, iithagethi ze-neurobiological ezicaciswe ngesakhelo se-neurocircuitry of addiction iya kubonelela ekujoliswe kuko ekuchongeni ubungozi bemfuza eluntwini, kunye nokuba sesichengeni sofuzo kwizifundo zabantu kunokuchonga iithagethi zenoveli eziza kuphononongwa kwinqanaba lobuchwephesha kwizifundo zezilwanyana.
Imibulelo
Le yinombolo yopapasho ka-20084 evela kwiZiko loPhando lweScripps. Ukulungiswa kwalo msebenzi kuxhaswe yi-Pearson Centre for Alcoholism and Addiction Research and National Institutes of Health izibonelelo ze-AA12602, AA08459, kunye ne-AA06420 evela kwiZiko leSizwe lokuSebenzisa kakubi uTywala kunye noTywala; I-DA04043, i-DA04398, kunye ne-DA10072 evela kwiZiko leSizwe lokuSetyenziswa gwenxa kweZiyobisi; I-DK26741 evela kwiZiko leSizwe leSifo seswekile kunye neDigestive and Kidney Diseases; kunye ne-17RT-0095 kwiNkqubo yoPhando lweSifo esiNxulumene neToba evela kwiState of California. Siyabulela uMichael Arends kunye noRuben Baler ngoncedo lwabo ngokulungiselela iphepha.
Ucaphulo
- Aharonovich E, Hasin DS, Brooks AC, Liu X, Bisaga A, Nunes EV. Ukusilela kwengqondo kuqaphela ukugcinwa konyango oluphantsi kwizigulana ezixhomekeke kwikhoboka. Ukusetyenziswa kotywala kotywala. 2006;81: 313-322. [PubMed]
- U-Ahmed SH, uKenny PJ, uKoob GF, uMarkou A. Ubungqina be-Neurobiological be-hedonic allostasis ehambelana nokunyuka kokusetyenziswa kwe-cocaine. Nat Neurosci. 2002;5: 625-626. [PubMed]
- U-Ahmed SH, uKoob GF. 1998. Utshintsho ukusuka kwimodareyitha ukuya kwi-intake yeziyobisi: utshintsho kwindawo yokubeka i-hedonic inzululwazi 282I-298-300.300Olu phononongo lubonise ukuba iimpuku zinikwe ukufikelela okwandisiweyo kwi-cocaine ekhuphukayo yokuthatha kunye nokubonisa ukuziphatha okuhambelana nokonyuka kwendawo yokumisela i-hedonic (umvuzo ophantsi) wechiza. [PubMed]
- U-Ahmed SH, uKoob GF. Utshintsho ekuphenduleni umchasi we-dopamine kwiimpuku kunye nokunyuka kokutya kwe-cocaine. Psychopharmacology. 2004;172: 450-454. [PubMed]
- Ahmed SH, Walker JR, Koob GF. Ukwanda okuzingileyo kwinkuthazo yokuthatha i-heroin kwiimpuku ezinembali yokunyuka kweziyobisi. Neuropsychopharmacology. 2000;22: 413-421. [PubMed]
- Alheid GF, De Olmos JS, Beltramino CA. 1995. Amygdala kunye ne-amygdala eyandisiweyoKu: Paxinos G (ed).Inkqubo yeNervous yempuku I-Academic Press: San Diego; 495–578.578.
- Allen TJ, Moeller FG, Rhoades HM, Cherek DR. Impulsivity kunye nembali yokuxhomekeka kweziyobisi. Ukusetyenziswa kotywala kotywala. 1998;50: 137-145. [PubMed]
- I-American Psychiatric Association 1994. I-Diagnostic and Statistical Manual of Disabilities4th edn.American Psychiatric Press: Washington, DC.
- I-American Psychiatric Association 2000. I-Diagnostic and Statistical Manual of Disabilities4th edn, uhlaziyo lombhaloAmerican Psychiatric Press: Washington, DC.
- Arroyo M, Markou A, Robbins TW, Everitt BJ. Ukufumana, ukugcinwa kunye nokubuyiselwa kokuzilawula kwe-cocaine ye-intravenous phantsi kweshedyuli ye-second-odolo yokomelezwa kwiigundane: iziphumo zeempawu ezimiselweyo kunye nokufikelela ngokuqhubekayo kwi-cocaine. Psychopharmacology. 1998;140: 331-344. [PubMed]
- I-Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, et al. I-Neuroadaptations kwi-cystine-glutamate exchange exchange underlie cocaine back. Nat Neurosci. 2003;6: 743-749. [PubMed]
- Baker TB, Morse E, Sherman JE. 1987. Inkuthazo yokusebenzisa iziyobisi: uhlalutyo lwe-psychobiological lwezibongozoKwi: River PC (ed).Utywala kunye ne-Addictive Behaviour(isihloko sothotho: Nebraska Symposium on Motivation, vol 34) .University of Nebraska Press: Lincoln, NE; 257–323.323.
- Baldwin HA, Rassnick S, Rivier J, Koob GF, Britton KT. Umchasi weCRF ubuyisela umva impendulo 'ye-anxiogenic' ekutsaleni i-ethanol kwimpuku. Psychopharmacology. 1991;103: 227-232. [PubMed]
- Barr AM, Phillips AG. Ukurhoxiswa kulandela ukubonakaliswa okuphindaphindiweyo d-i-amphetamine iyancipha ukuphendula kwisisombululo se-sucrose njengoko ilinganiswa neshedyuli yomlinganiselo oqhubekayo wokuqiniswa. Psychopharmacology. 1999;141: 99-106. [PubMed]
- Belin D, uEveritt BJ. 2008. Imikhwa yokufuna i-cocaine ixhomekeke kunxibelelwano lwe-serial oluxhomekeke kwi-dopamine edibanisa i-ventral kunye ne-dorsal striatum. Neuron 57432-441.441Olu phononongo lubonise ukuba intsebenziswano phakathi kwe-ventral kunye ne-dorsal striatum ibalulekile kuphuhliso lokuziphatha okunyanzelekileyo okufana ne-cocaine. [PubMed]
- U-Ben-Shahar O, u-Ahmed SH, u-Koob GF, u-Ettenberg A. Ukutshintsha ukusuka ekulawuleni ukuya ekusetyenzisweni kweziyobisi okunyanzelekileyo kuhambelana nokulahlekelwa kwe-sensitization. Res Resin. 2004;995: 46-54. [PubMed]
- Bjork JM, Momenan R, Hommer DW. Ukulibaziseka kwezaphulelo ezihambelanayo kunye nomxholo othe ngqo wecortex wangaphambili. Biol Psychiatry. 2009;65: 710-713. [PubMed]
- Bolla KI, Eldreth DA, London ED, Kiehl KA, Mouratidis M, Contoreggi C, et al. Ukungasebenzi kakuhle kwe-Orbitofrontal cortex kubaxhaphazi be-cocaine abangahlaliyo benza umsebenzi wokuthatha izigqibo. Neuroimage. 2003;19: 1085-1094. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Bonci A, Bernardi G, Grillner P, Mercuri NB. I-neuron equlethe i-dopamine: i-maestro okanye imvumi elula kwi-okhestra yokulutha. Iintlobo zeP Pharmacol Sci. 2003;24: 172-177. [PubMed]
- Boudreau AC, Wolf ME. Uvakalelo lokuziphatha kwi-cocaine lunxulunyaniswa nokunyuka kwe-AMPA receptor surface expression kwi-nucleus accumbens. J Neurosci. 2005;25: 9144-9151. [PubMed]
- Briand LA, Flagel SB, Garcia-Fuster MJ, Watson SJ, Akil H, Sarter M, et al. Utshintsho oluqhubekayo kumsebenzi wokuqonda kunye ne-prefrontal dopamine i-D2 receptors ezilandela ukwandiswa, kodwa kungasikelwanga mda, ukufikelela kwi-cocaine ezilawulayo. Neuropsychopharmacology. 2008a;33: 2969-2980. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Briand LA, Gross JP, Robinson TE. Ukuqondwa kwento ephazamisekileyo emva kokurhoxa ixesha elide ekuzilawuleni okwandisiweyo kwe-cocaine. Neuroscience. 2008b;155: 1-6. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Caine SB, Heinrichs SC, Coffin VL, Koob GF. Iziphumo ze-dopamine D-1 antagonist SCH 23390 microinjected kwi-accumbens, amygdala okanye striatum ekuzilawuleni kwe-cocaine kwi-rat. Res Resin. 1995;692: 47-56. [PubMed]
- Caine SB, Humby T, Robbins TW, Everitt BJ. Iziphumo zokuziphatha ze-psychomotor stimulants kwiimpuku ezinezilonda ze-dorsal okanye ze-ventral subiculum: i-locomotion, ukuzilawula kwe-cocaine, kunye nokuthintela kwangaphambili ukothuka. Behav Neurosci. 2001;115: 880-894. [PubMed]
- Caine SB, Thomsen M, Gabriel KI, Berkowitz JS, Gold LH, Koob GF, et al. Ukunqongophala kokuzilawula kwe-cocaine kwi-dopamine D1 receptor knock-out iimpuku. J Neurosci. 2007;27: 13140-13150. [Inkcazelo yamahhala ye-PMC] [PubMed]
- UCalu DJ, u-Stalnaker TA, uFranz TM, uSingh T, u-Shaham Y, uSchoenbaum G. Ukuhoxiswa kwi-cocaine self-administration kuvelisa ukusilela okuhlala ixesha elide kwi-orbitofrontal-dependent reversal learning kwiigundane. Funda iMem. 2007;14: 325-328. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Canales JJ. I-neurogenesis yabantu abadala kunye neenkumbulo zokukhotyokiswa ziziyobisi. I-Ar Ar Psychchiin Clin Neurosci. 2007;257: 261-270. [PubMed]
- Nxibelela LD. Ukuqiniswa kunye neziphumo ezizimeleyo ze-methylphenidate ebantwini. Behav Pharmacol. 1994;5: 281-288. [PubMed]
- Chao SZ, Ariano MA, Peterson DA, Wolf ME. I-D1 dopamine receptor stimulation yonyusa ukubonakala kwe-GluR1 kwi-nucleus accumbens neurons. J Neurochem. 2002;83: 704-712. [PubMed]
- I-Chen BT, i-Bowers MS, uMartin M, uHopf FW, u-Guillory AM, u-Carelli RM, et al. I-cocoaine kodwa ayisiyiyo indalo yomvuzo wokuzilawula okanye ukumilisela i-cocaine engapheliyo ivelisa i-LTP eqhubekayo kwi-VTA. Neuron. 2008;59: 288-297. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Chen R, Tilley MR, Wei H, Zhou F, Zhou FM, Ching S, et al. Uphelisiwe umvuzo we-cocaine kwiimpuku ngesithuthi se-cocaine-sensitive dopamine. Proc Natl Acad Sci USA. 2006a;103: 9333-9338.
- Chen SA, O'Dell L, Hoefer M, Greenwell TN, Zorrilla EP, Koob GF. 2006b. Ukufikelela okungenamkhawulo kwi-heroin self-administration: iimpawu ezizimeleyo ezikhuthazayo zokuxhomekeka kwi-opiate Neuropsychopharmacology 312692-2707.2707 (i-corrigendum: 31: 2802). [PubMed]
- Childress AR, McLellan AT, Ehrman R, O'Brien CP. 1988. Iimpendulo ezikwimeko eqhelekileyo kukuxhomekeka kwe-opioid kunye ne-cocaine: indima ekubuyeleni kwakhonaKu: Ray BA (ed).Imiba yokufunda ekuSetyenzisweni gwenxa kweZiyobisi(isihloko sochungechunge: NIDA Research Monograph, vol 84) .Iziko leSizwe lokuSetyenziswa gwenxa kweZiyobisi: Rockville, MD; 25–43.43.
- Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O'Brien CP. Ukusebenza kwe-Limbic ngexesha lokunqwenela i-cocaine. IJ Psychiatry. 1999;156: 11-18. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Clark L, Bechara A, Damasio H, Aitken MR, Sahakian BJ, Robbins TW. Iziphumo ezahlukeneyo zezilonda ze-insular kunye ne-ventromedial prefrontal cortex ekwenzeni izigqibo ezinobungozi. Ubunjani. 2008;131: 1311-1322. [Inkcazelo yamahhala ye-PMC] [PubMed]
- UCollins RJ, iiVeki JR, Cooper MM, iPI elungileyo, uRussell RR. Ukuqikelelwa koxanduva lokuxhatshazwa kweziyobisi usebenzisa i-IV yokuzilawula ngokwazo ngamagundane. Psychopharmacology. 1984;82: 6-13. [PubMed]
- Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, et al. Ukwenziwa kwe-accumbens GluR2-eswele i-AMPA receptors mediates incubation of cocaine craving. Uhlobo. 2008;454: 118-121. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Creese I, Iversen SD. Indima yeenkqubo ze-forebrain dopamine kwi-amphetamine-induced stereotyped behaviour kwi-rat. Psychopharmacology. 1974;39: 345-357.
- Crow TJ. I-Catecholamine-equkethe i-neurones kunye ne-self-stimulation yombane: 2. Ukutolikwa kwethiyori kunye neziphumo ezithile zengqondo. Psychol Med. 1973;3: 66-73. [PubMed]
- de Witte P, u-Littleton J, uParot P, uKoob G. I-Neuroprotective kunye nokuyeka ukukhuthaza iziphumo ze-acamprosate: ukucacisa indlela yokusebenza. CNS Iziyobisi. 2005;19: 517-537. [PubMed]
- UDelfs JM, uZhu Y, uDruhan JP, u-Aston-Jones G. Noradrenaline kwi-ventral forebrain ibaluleke kakhulu kwi-opiate ukuhoxiswa kwe-aversion. Uhlobo. 2000;403: 430-434. [PubMed]
- UDeroche-Gamonet V, uBelin D, uPiazza PV. Ubungqina bokuziphatha-okufana nokuziphatha kumlinganiso. Sayensi. 2004;305: 1014-1017. [PubMed]
- Dewey SL, Morgan AE, Ashby CR, Jr, Horan B, Kushner SA, Logan J, et al. Isicwangciso senoveli sonyango lwe-cocaine. Synapse. 1998;30: 119-129. [PubMed]
- UDi Chiara G, Imperato A. Izidakamizwa ezixhatshazwa ngabantu zikhetha ukwandisa i-synaptic i-dopamine i-concentrations kwinkqubo ye-mesolimbic yokuhamba ngokugqithisileyo. Proc Natl Acad Sci USA. 1988;85: 5274-5278.
- Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, et al. Ukukhutshwa kwe-dopamine eyenziwe yi-amphetamine kwi-ventral striatum yomntu ihambelana ne-euphoria. Biol Psychiatry. 2001;49: 81-96. [PubMed]
- UDuncan E, uBoshoven W, uHarenski K, uFiallos A, uTracy H, uJovanovic T, et al. Uphononongo lwe-fMRI lokusebenzisana koxinzelelo kunye ne-cocaine cues kumnqweno we-cocaine kumadoda axhomekeke kwi-cocaine. Am J Addict. 2007;16: 174-182. [PubMed]
- UDyr W, uKostowski W. Ubungqina bokuba i-amygdala ibandakanyeka kwimiphumo yokuthintela ye-5-HT3 abachasi be-receptor ekuseleni kotywala kwiimpuku. Utywala. 1995;12: 387-391. [PubMed]
- Edwards S, Graham DL, Bachtell RK, Self DW. Ukunyamezelana okuthe ngqo kwi-cocaine elawulwa yi-cAMP-exhomekeke kwiprotheyini ye-phosphorylation emva kokuzilawula okungapheliyo. Eur J Neurosci. 2007;25: 2201-2213. [PubMed]
- I-everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW. Uphononongo. Iindlela zeNeological ezisisiseko sokuba semngciphekweni wokuhlakulela umkhwa wokufuna iziyobisi kunye nokusebenzisa iziyobisi. Phil Trans Royal Soc London B Biol Sci. 2008;363: 3125-3135.
- Everitt BJ, Robbins TW. 2005. Iinkqubo ze-Neural zokuqiniswa kweziyobisi: ukusuka kwizenzo ukuya kwimikhwa yokunyanzeliswa Nat Neurosci 81481–1489.1489(erratum: 9(7): 979). [PubMed]
- Everitt BJ, Wolf ME. 2002. I-Psychomotor stimulant addiction: imbono ye-neural systems J Neurosci 223312–3320.3320(erratum: 22(16): 1a). [PubMed]
- Ferrario CR, Gorny G, Crombag HS, Li Y, Kolb B, Robinson TE. Iplastiki yeNeural kunye neyokuziphatha ehambelana notshintsho ukusuka kulawulo ukuya kusetyenziso olukhulayo lwecocaine. Biol Psychiatry. 2005;58: 751-759. [PubMed]
- Fowler JS, Volkow ND, Logan J, Alexoff D, Telang F, Wang GJ, et al. Ukuthatha ngokukhawuleza kunye nokubopha ixesha elide kwe-methamphetamine kwingqondo yomntu: ukuthelekisa ne-cocaine. Neuroimage. 2008;43: 756-763. [Inkcazelo yamahhala ye-PMC] [PubMed]
- UFranklin TR, u-Wang Z, u-Wang J, u-Sciortino N, u-Harper D, uLi Y, et al. Ukuvuselelwa kweLimbic kwimigudu yokutshaya icuba elizimeleyo ukurhoxiswa kwe-nicotine: isifundo se-fMRI sokuthambisa. Neuropsychopharmacology. 2007;32: 2301-2309. [PubMed]
- Freeman AS, Meltzer LT, Bunney BS. Ukudubula iipropathi ze-substantia nigra dopaminergic neurons kwiigundane ezihamba ngokukhululekileyo. Life Sci. 1985;36: 1983-1994. [PubMed]
- Funk CK, O'Dell LE, Crawford EF, Koob GF. 2006. I-Corticotropin-ikhupha into ngaphakathi kwinucleus ephakathi ye-amygdala mediates ephuculweyo yokulawula i-ethanol ekuzilawuleni okurhoxisiweyo, okuxhomekeke kwi-ethanol J Neurosci 2611324–11332.11332Olu phononongo lubonise ukuba ibhlokhi yee-receptors zeCRF kwindawo yombindi we-amygdala ithintela ukonyuka kotywala obunxulumene nokuxhomekeka kodwa hayi ukusela utywala kwizilwanyana ezingaxhomekekanga. [PubMed]
- UGaravan H, uKaufman JN, uHester R. Iziphumo ezibukhali ze-cocaine kwi-neurobiology yokulawula ukuqonda. Phil Trans Royal Soc London B Biol Sci. 2008;363: 3267-3276.
- George O, Ghozland S, Azar MR, Cotton P, Zorrilla EP, Parsons LH, et al. I-CRF-CRF1 inkqubo isebenze ilamla ukunyuka kwe-nicotine ekuzilawuleni ngokuzimeleyo kwiimpuku ezixhomekeke kwi-nicotine. Proc Natl Acad Sci USA. 2007;104: 17198-17203.
- UGeorge O, CD yeMandyam, Wee S, Koob GF. Ukufikelela okwandileyo kokuzilawula kwe-cocaine kuvelisa ukungaphumeleli kwimemori yokusebenza kwengqondo ye-cortex ehlala ihleli. Neuropsychopharmacology. 2008;33: 2474-2482. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Gilpin NW, Koob GF. Amagqabantshintshi: i-neurobiology yokuxhomekeka kotywala ngokugxila kwiindlela ezikhuthazayo. Utywala Res Health. 2008;31: 185-195. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Gilpin NW, Misra K, Koob GF. I-Neuropeptide Y kwi-nucleus ephakathi ye-amygdala icinezela ukunyuka okubangelwa ukuxhomekeka kotywala. Pharmacol Biochem Behav. 2008;90: 475-480. [Inkcazelo yamahhala ye-PMC] [PubMed]
- IGoldstein RZ, iVolkow ND. Iziyobisi kunye neziyobisi ezingaphantsi kwayo: Isiseko se-neuroimaging sokuzibandakanya kwe-cortex yangaphambili. IJ Psychiatry. 2002;159: 1642-1652. [Inkcazelo yamahhala ye-PMC] [PubMed]
- UGonzalez D, uRiba J, uBouso JC, uGomez-Jarabo G, uBarbanoj MJ. Ipateni yokusetyenziswa kunye neziphumo ezizimeleyo ze Isalin divinorum phakathi kwabasebenzisi bokuzonwabisa. Ukusetyenziswa kotywala kotywala. 2006;85: 157-162. [PubMed]
- UGrace AA. Imodeli ye-tonic / phasic yolawulo lwenkqubo ye-dopamine kunye neziphumo zayo zokuqonda utywala kunye nenkanuko ye-psychostimulant. Umlutha. 2000;95 (I-Suppl 2: S119-S128. [PubMed]
- Grant BF, Dawson DA. Ubudala bokuqala bokusetyenziswa kweziyobisi kunye nokudibanisa kunye ne-DSM-IV yokusetyenziswa kakubi kweziyobisi kunye nokuxhomekeka: iziphumo ezivela kwi-National Longitudinal Alcohol Epidemiologic Survey. J Ukuxhatshazwa kweSubst. 1998;10: 163-173. [PubMed]
- Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, Pickering RP. Ukuxhaphaka kweenyanga ezili-12 kunye neendlela kwi-DSM-IV yokusetyenziswa kakubi kotywala kunye nokuxhomekeka: eUnited States, 1991-1992 kunye no-2001-2002. Ukusetyenziswa kotywala kotywala. 2004;74: 223-234. [PubMed]
- Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, et al. Ukusebenza kweesekethe zememori ngexesha lokunqwenela i-cocaine. Proc Natl Acad Sci USA. 1996;93: 12040-12045.
- UGreenwell TN, uFunk CK, uCottone P, uRichardson HN, uChen SA, iRice K, et al. I-Corticotropin-ikhupha i-factor-1 i-receptor antagonists iyancipha i-heroin self-administration kwixesha elide, kodwa kungekhona iigundane zokufikelela okufutshane. Umlutha weBool. 2009;14: 130-143. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Isandla TH, i-Koob GF, i-Stinus L, i-Le Moal M. Iipropati eziphazamisayo ze-opiate receptor blockade: ubungqina bolamlo oluphakathi kuphela kwiigundane ezingenangqondo kunye ne-morphine. Res Resin. 1988;474: 364-368. [PubMed]
- Heb YENZA. 1972. Incwadi yezifundo zengqondo3rd edn.WB Saunders: Philadelphia.
- Heilig M, Koob GF. Indima ephambili ye-corticotropin-ekhulula into yokuxhomekeka kotywala. Iintlobo zeeurosci. 2007;30: 399-406. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Heilig M, Koob GF, Ekman R, Britton KT. I-Corticotropin-release factor kunye neuropeptide Y: indima ekudityanisweni kweemvakalelo. Iintlobo zeeurosci. 1994;17: 80-85. [PubMed]
- Heimer L, Alheid G. 1991. Ukudibanisa iphazili ye-basal forebrain anatomyKu: Napier TC, Kalivas PW, Hanin I (eds).I-Basal Forebrain: I-Anatomy yokuSebenza(isihloko sothotho: I-Advances in Experimental Medicine and Biology, vol 295) .Plenum Press: New York; 1–42.42.
- I-Heinrichs SC, i-Menzaghi F, i-Schulteis G, i-Koob GF, i-Stinus L. Ukunyanzeliswa kwe-corticotropin-releasing factor kwi-amygdala kunciphisa imiphumo ephazamisayo yokuhoxiswa kwe-morphine. Behav Pharmacol. 1995;6: 74-80. [PubMed]
- Heinz A, Siessmeier T, Wrase J, Hermann D, Klein S, Grusser SM, et al. 2004. Unxulumano phakathi kwe-dopamine D (2) i-receptors kwi-ventral striatum kunye nokusetyenzwa okuphakathi kotywala kunye nokunqwenela IJ Psychiatry 1611783-1789.1789 (erratum: 161: 2344). [PubMed]
- Hernandez G, Hamdani S, Rajabi H, Conover K, Stewart J, Arvanitogiannis A, et al. Ukuvuselela okuvuzayo ixesha elide kwi-rat medial forebrain bundle: i-neurochemical kunye neziphumo zokuziphatha. Behav Neurosci. 2006;120: 888-904. [PubMed]
- Heyser CJ, Roberts AJ, Schulteis G, Koob GF. Ulawulo oluphakathi lomchasi we-opiate kunciphisa ukuzilawula kwe-ethanol yomlomo kwiimpuku. Utywala lweeNkcazo zoTywala. 1999;23: 1468-1476. [PubMed]
- Induli RT. 1970. Ukuququzelela ukomelezwa kwemeko njengendlela yokuvuselela ingqondoKwi: Iindleko E, iGarattini S (eds).I-Amphetamines kunye neMichiza eNxulumeneyo IRaven Press: eNew York; 781–795.795.
- Hnasko TS, Sotak BN, Palmiter RD. Umvuzo weMorphine kwiimpuku eziswele i-dopamine. Uhlobo. 2005;438: 854-857. [PubMed]
- I-Holland PC, i-Gallagher M. Amygdala-unxibelelwano lwangaphambili kunye nokulindela umvuzo. Curr Opin Neurobiol. 2004;14: 148-155. [PubMed]
- Hubner CB, Koob GF. I-ventral pallidum idlala indima ekulaleni i-cocaine kunye ne-heroin yokuzilawula ngokwakho kwimpuku. Res Resin. 1990;508: 20-29. [PubMed]
- Hyman SE, Malenka RC, i-Nestler EJ. Iinkqubo ze-Neural zokulutha: inxaxheba yemfundo enxulumene nomvuzo kunye nememori. Annu Rev Neurosci. 2006;29: 565-598. [PubMed]
- Hyytia P, Koob GF. I-GABA-A receptor antagonism kwi-amygdala eyandisiweyo inciphisa ukuzilawula kwe-ethanol kwiigundane. Eur J Pharmacol. 1995;283: 151-159. [PubMed]
- Ito R, Diking JW, Robbins TW, Everitt BJ. Ukukhutshwa kweedopamine kwisithambiso esenziwa dorsal ngexesha lokufuna ikhokhasi phantsi kolawulo lwe-cue enxulumene neziyobisi. J Neurosci. 2002;22: 6247-6253. [PubMed]
- Jentsch JD, Olausson P, de la Garza R, II, Taylor JR. Ukonakaliswa kokufunda okubuyela umva kunye nokunyamezela impendulo emva kokuphindaphindiweyo, ukulawulwa kwe-cocaine okwethutyana kwiinkawu. Neuropsychopharmacology. 2002;26: 183-190. [PubMed]
- Jones S, Bonci A. Iplastiki ye-Synaptic kunye nokulutha kweziyobisi. Curr Opin Pharmacol. 2005;5: 20-25. [PubMed]
- Juni HL, Foster KL, McKay PF, Seyoum R, Woods JE, Harvey SC, et al. Iimpawu zokuqinisa utywala zixutywe yi-GABA (A1) receptors kwi-ventral pallidum. Neuropsychopharmacology. 2003;28: 2124-2137. [PubMed]
- Justinova Z, Tanda G, Redhi GH, Goldberg SR. Ukuzilawula ngokwakho kwe-delta9-tetrahydrocannabinol (THC) ngeziyobisi ze-squirrel monkeys. Psychopharmacology. 2003;169: 135-140. [PubMed]
- Kalivas PW. Iinkqubo zeGlutamate kumlutha wecocaine. Curr Opin Pharmacol. 2004;4: 23-29. [PubMed]
- I-Kalivas PW, i-O'Brien C. Iziyobisi njengesiyobisi esisiseko se-neuroplasticity. Neuropsychopharmacology. 2008;33: 166-180. [PubMed]
- Kalivas PW, Volkow ND. Isiseko se-neural of addiction: i-pathology of motivation and choice. IJ Psychiatry. 2005;162: 1403-1413. [PubMed]
- I-Kauer JA, i-Malenka RC. I-synaptic plasticic kunye nokulutha. Nat Rev Neurosci. 2007;8: 844-858. [PubMed]
- Kelly PH, Iversen SD. Okukhethiweyo kwe-6-OHDA-eyenziwe intshabalalo ye-mesolimbic dopamine neurons: ukupheliswa komsebenzi we-locomotor we-psychostimulant-induced in rats. Eur J Pharmacol. 1976;40: 45-56. [PubMed]
- Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF. Ukurhoxiswa okunemiqathango kuqhuba ukusetyenziswa kwe-heroin kwaye kunciphisa ubuntununtunu bomvuzo. J Neurosci. 2006;26: 5894-5900. [PubMed]
- I-CD ye-Kilts, i-Schweitzer JB, i-Quinn CK, i-Gross RE, i-Faber TL, i-Muhammad F, et al. Umsebenzi weNeural onxulumene nokunqwenela iziyobisi kumlutha wecocaine. Arch Gen Psychiatry. 2001;58: 334-341. [PubMed]
- Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L. Ukunyuka kwe-methamphetamine ukuzilawula ngokwakho kwiimpuku: idosi-isiphumo somsebenzi. Psychopharmacology. 2006;186: 48-53. [PubMed]
- Koob GF. Iziyobisi zokuxhatshazwa: i-anatomy, i-pharmacology, kunye nomsebenzi weendlela zomvuzo. Iintlobo zeP Pharmacol Sci. 1992;13: 177-184. [PubMed]
- Koob GF. 2004. Imbono ye-Allostatic yenkuthazo: iimpembelelo kwi-psychopathologyKu: Bevins RA, Bardo MT (eds).Izinto ezikhuthazayo kwi-Etiology yokusetyenziswa gwenxa kweziyobisi(isihloko sothotho: Nebraska Symposium on Motivation, vol 50) .University of Nebraska Press: Lincoln, NE; 1–18.18.
- Koob GF. I-neurocircuitry yokulutha: iziphumo kunyango. Clin Neurosci Res. 2005;5: 89-101.
- Koob GF. Indima yeenkqubo zoxinzelelo lwengqondo kubukhoboka. Neuron. 2008;59: 11-34. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Koob GF. I-suburates ye-Neurobiological yecala elimnyama lokunyanzeliswa ekulutha. Neuropharmacology. 2009a;56 (I-Suppl 1: 18-31. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Koob GF. 2009b. Iinkqubo zoxinzelelo zeBongo kwi-amygdala kunye noxilongo Res Resin(kwiphepha).
- Koob GF, Everitt BJ, Robbins TW. 2008a. Umvuzo, inkuthazo, kunye nokuluthaKu: Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N (eds).I-Neuroscience esisiseko3rd edn.Academic Press: Amsterdam; 987–1016.1016.
- Koob GF, Kandel D, Volkow ND. 2008b. I-Pathophysiology yokuluthaKu: Tasman A, Kay J, Lieberman JA, First MB, Maj M (eds).Psychiatry3rd edn, vol 1Wiley: Chichester; 354–378.378.
- Koob GF, Kreek MJ. Uxinzelelo, ukungasebenzi kakuhle kweendlela zokuvuza iziyobisi, kunye nokutshintshela ekuxhomekekeni kwiziyobisi. IJ Psychiatry. 2007;164: 1149-1159. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Koob GF, Le Moal M. 1997. Ukusetyenziswa kakubi kweziyobisi: hedonic homeostatic dysregulation inzululwazi 278I-52-58.58Olu phononongo lwethiyori lubonisa ukuba umlutha weziyobisi ubandakanya ukuncipha kwe-hedonic homeostatic dysregulation (i-dysregulation yomsebenzi womvuzo) oqhutywa zizo zombini ezincitshisiweyo zendlela yomvuzo kunye nokufunwa kweenkqubo zoxinzelelo lwengqondo. [PubMed]
- I-Koob GF, i-Le Moal M. Iziyobisi, iziyobisi, inkuthazo yomvuzo, kunye ne-allostasis. Neuropsychopharmacology. 2001;24: 97-129. [PubMed]
- I-Koob GF, i-Le Moal M. Ubuninzi beplastiki yomvuzo kunye 'necala elimnyama' leziyobisi. Nat Neurosci. 2005;8: 1442-1444. [PubMed]
- Koob GF, Le Moal M. Neurobiology of Addiction. I-Academic Press: London; 2006.
- I-Koob GF, i-Le Moal M. Ukulutha kunye nenkqubo yangaphakathi yobuchopho. I-Annu Rev Psychol. 2008;59: 29-53. [PubMed]
- Koob GF, Lloyd GK, Mason BJ. Ukuphuhliswa kwee-pharmacotherapies zokukhotyokiswa kweziyobisi: indlela yeRosetta Stone. I-Nat Rev iDisk Disc. 2009;8: 500-515. [Inkcazelo yamahhala ye-PMC] [PubMed]
- UKoob GF, uNestler EJ. I-neurobiology yeziyobisi. J Neuropsychiatry Clin Neurosci. 1997;9: 482-497. [PubMed]
- Kornetsky C, Bain G. 1990. Umvuzo wokuvuselela ubuchopho: imodeli ye-euphoria eyenziwe ngeziyobisiKu: Adler MW, Cowan A (eds).Uvavanyo kunye noVavanyo lweZiyobisi zokuSebenzisa kakubi(isihloko sothotho: IiNdlela zale mihla kwi-Pharmacology, vol 6) .Wiley-Liss: New York; 211–231.231.
- Kornetsky C, Esposito RU. Iziyobisi ze-Euphorigenic: iimpembelelo kwindlela yomvuzo wengqondo. I-Pro Pro. 1979;38: 2473-2476. [PubMed]
- Kourrich S, Rothwell PE, Klug JR, Thomas MJ. Amava eCocaine alawula iplastiki ye-synaptic ye-bidirectional kwi-nucleus accumbens. J Neurosci. 2007;27: 7921-7928. [PubMed]
- Kufahl P, Li Z, Risinger R, Rainey C, Piacentine L, Wu G, et al. Ukulindela kulungelelanisa iimpendulo zobuchopho bomntu kwi-cocaine ebukhali: isifundo esisebenzayo sokucinga ngemagnethi. Biol Psychiatry. 2008;63: 222-230. [PubMed]
- Langleben DD, Ruparel K, Elman I, Busch-Winokur S, Pratiwadi R, Loughead J, et al. Isiphumo esibukhali sedosi yokugcinwa kwe-methadone kwimpendulo ye-FMRI yobuchopho kwiimpawu ezinxulumene ne-heroin. IJ Psychiatry. 2008;165: 390-394. [PubMed]
- LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, et al. Ngaba umnqweno wecocaine uncitshisiwe N-i-acetylcysteine. IJ Psychiatry. 2007;164: 1115-1117. [PubMed]
- I-Laviolette SR, i-Alexson TO, van der Kooy D. Izilonda ze-tegmental pedunculopontine nucleus zivimba imiphumo evuzayo kwaye zibonakalise imiphumo ephazamisayo ye-nicotine kwindawo ye-ventral tegmental. J Neurosci. 2002;22: 8653-8660. [PubMed]
- Le Doux JE. Iisekethe zeemvakalelo kwingqondo. Annu Rev Neurosci. 2000;23: 155-184. [PubMed]
- Le Moal M, uSimon H. Mesocorticolimbic inethiwekhi ye-dopaminergic: iindima ezisebenzayo kunye nokulawula. Physiol Rev. 1991;71: 155-234. [PubMed]
- ULee JL. Ukumanyanisa inkumbulo kulamla ukomelezwa kweenkumbulo ngokufunda okongeziweyo. Nat Neurosci. 2008;11: 1264-1266. [PubMed]
- U-Lee JL, uDi Ciano P, uThomas KL, u-Everitt BJ. Ukuphazamisa ukudityaniswa kwakhona kweenkumbulo zeziyobisi kunciphisa indlela yokuziphatha yokufuna i-cocaine. Neuron. 2005;47: 795-801. [PubMed]
- Li YQ, Li FQ, Wang XY, Wu P, Zhao M, Xu CM, et al. I-Central amygdala ye-extracellular signal-regulated kinase pathway ibalulekile ekufakeni i-opiate craving. J Neurosci. 2008;28: 13248-13257. [PubMed]
- I-Logan GD, i-Schachar RJ, i-Tannock R. Ukunyanzeliswa kunye nokulawula inhibitory. Psychol Sci. 1997;8: 60-64.
- Lu L, Koya E, Zhai H, Ithemba BT, Shaham Y. Indima ye-ERK kwikhoboka lecocaine. Iintlobo zeeurosci. 2006;29: 695-703. [PubMed]
- Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Ukuva uM, et al. Iphindaphindwe NUlawulo lwe-acetylcysteine luguqula iziphumo ezixhomekeke kwiplastiki ye-cocaine. J Neurosci. 2007;27: 13968-13976. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Maisonneuve IM, Ho A, Kreek MJ. Ulawulo olungapheliyo lwe-cocaine 'binge' luguqula amanqanaba e-basal extracellular kwiimpuku zamadoda: i kwi vivo Ufundo lwegciwane J Pharmacol Exp Ther. 1995;272: 652-657. [PubMed]
- Mameli-Engvall M, Evrard A, Pons S, Maskos U, Svensson TH, Changeux JP, et al. Ulawulo lwe-hierarchical yeepateni ze-dopamine neuron-firing nge-nicotinic receptors. Neuron. 2006;50: 911-921. [PubMed]
- Markou A, Kosten TR, Koob GF. Ukufana kwe-Neurobiological kuxinzelelo kunye nokuxhomekeka kweziyobisi: i-hypothesis yokuzonyanga. Neuropsychopharmacology. 1998;18: 135-174. [PubMed]
- Martinez D, Broft A, Foltin RW, Slifstein M, Hwang DR, Huang Y, et al. 2004. Ukuxhomekeka kweCocaine kunye nokufumaneka kwe-d2 receptor kulwahlulo olusebenzayo lwe-striatum: ubudlelwane kunye nokuziphatha kokufuna i-cocaine. Neuropsychopharmacology 291190-1202.1202 (erratum: 29: 1763). [PubMed]
- Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, et al. Ukuxhomekeka kotywala kunxulunyaniswa nokuhanjiswa kwe-dopamine engacacanga kwi-ventral striatum. Biol Psychiatry. 2005;58: 779-786. [PubMed]
- Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang DR, Broft A, et al. Ukukhutshwa kwe-dopamine ye-amphetamine-eyenziwe yi-dopamine: ibonakaliswe ngokubonakalayo kukuxhomekeka kwe-cocaine kunye nokuqikelelwa kokhetho lokuzilawula ngokwakho i-cocaine. IJ Psychiatry. 2007;164: 622-629. [PubMed]
- UMcBride WJ, uMurphy JM, i-Ikemoto S. Ukwakhiwa kwendawo yeendlela zokuqinisa ubuchopho: i-intracranial self-administration kunye ne-intracranial place-conditioning studies. Behav Brain Res. 1999;101: 129-152. [PubMed]
- McClernon FJ, Kozink RV, Lutz AM, Rose JE. Iiyure ezingama-24 zokuyeka ukutshaya zenza ukuba i-fMRI-BOLD ivuleke kwiimpawu zokutshaya kwi-cerebral cortex kunye ne-dorsal striatum. Psychopharmacology. 2009;204: 25-35. [Inkcazelo yamahhala ye-PMC] [PubMed]
- McClung CA, Ulery PG, uPerrotti LI, uZachariou V, uBerton O, uNestler EJ. DeltaFosB: i-molecular switch for long-term adaptation in the brain. I-Mol Brain Res. 2004;132: 146-154.
- McFarland K, Kalivas PW. 2001. Umjikelo wokulamla we-cocaine-ukubuyiselwa kokuziphatha kokufuna iziyobisi J Neurosci 218655-8663.8663 Olu phononongo luseke indima ephambili ye-dorsal frontal cortex-nucleus accumbens-ventral pallidal circuit ekubuyiselweni kwe-cocaine. [PubMed]
- McFarland K, Lapish CC, Kalivas PW. Ukukhutshwa kwe-prefrontal glutamate kumbindi we-nucleus accumbens kulamla ukubuyiselwa kwakhona kwe-cocaine kwindlela yokuziphatha yokufuna iziyobisi. J Neurosci. 2003;23: 3531-3537. [PubMed]
- McGregor A, Roberts DCS. I-antagonism ye-Dopaminergic ngaphakathi kwe-nucleus accumbens okanye i-amygdala ivelisa iziphumo ezahlukileyo kwi-intravenous cocaine self-control phantsi kweshedyuli esisigxina kunye nenkqubela phambili yomlinganiselo wokuqiniswa. Res Resin. 1993;624: 245-252. [PubMed]
- Melendez RI, Rodd ZA, McBride WJ, Murphy JM. Ukubandakanyeka kwenkqubo ye-mesopallidal dopamine ekuqiniseni i-ethanol. Utywala. 2004;32: 137-144. [PubMed]
- UMelis M, uSpiga S, uDiana M. I-dopamine hypothesis yokukhotyokiswa kweziyobisi: imeko ye-hypodopaminergic. Int Rev Neurobiol. 2005;63: 101-154. [PubMed]
- Milton AL, Lee JL, Everitt BJ. Ukudityaniswa kwakhona kweenkumbulo ezinomdla kuzo zombini zendalo kunye nokomelezwa kweziyobisi kuxhomekeke kwi-β-adrenergic receptors. Funda iMem. 2008;15: 88-92. [PubMed]
- Miranda MI, LaLumiere RT, Buen TV, Bermudez-Rattoni F, McGaugh JL. Ukuvalwa kwe-noradrenergic receptors kwi-basolateral amygdala yonakalisa inkumbulo yokunambitha. Eur J Neurosci. 2003;18: 2605-2610. [PubMed]
- Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC. Imiba yengqondo yokungxama. IJ Psychiatry. 2001;158: 1783-1793. [PubMed]
- Moller C, Wiklund L, Sommer W, Thorsell A, Heilig M. Ukunciphisa ukuxhalaba kovavanyo kunye nokusetyenziswa kwe-ethanol ngokuzithandela kwiigundane ezilandela izilonda ze-amygdala eziphakathi kodwa ezingekho phantsi kwe-basolateral. Res Resin. 1997;760: 94-101. [PubMed]
- UMoussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, et al. NI-acetylcysteine ibuyisela i-cocaine-induced metaplasticity. Nat Neurosci. 2009;12: 182-189. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Murray EA. I-amygdala, umvuzo kunye nemvakalelo. Iintlobo zeCogn Sci. 2007;11: 489-497. [PubMed]
- Naqvi NH, Bechara A. Isiqithi esifihliweyo sesiyobisi: i-insula. Iintlobo zeeurosci. 2009;32: 56-67. [PubMed]
- Naqvi NH, Rudrauf D, Damasio H, Bechara A. 2007. Ukonakaliswa kwendawo yokufakelwa kuphazamisa ukutshaya inzululwazi 315531-534.534Olu phononongo lubonise ukuba umonakalo kwi-insula kubantu abatshayayo unxulunyaniswa nokuyeka ukutshaya, ukuseka ikhonkco phakathi kwe-insula kunye ne-nicotine addiction. [PubMed]
- Nauta JH, uHaymaker W. 1969. Iinuclei zeHypothalamic kunye noqhagamshelwano lwefiberKu: Haymaker W, Anderson E, Nauta WJH (eds).I-Hypothalamus UCharles C Thomas: Springfield, IL; 136–209.209.
- Nelson CL, Milovanovic M, Wetter JB, Ford KA, Wolf ME. Ukukhuthazwa kokuziphatha kwi-amphetamine akuhambi kunye notshintsho kwi-glutamate receptor surface expression kwi-rat nucleus accumbens. J Neurochem. 2009;109: 35-51. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Nestler EJ. 2005. Ngaba kukho indlela eqhelekileyo yeemolekyuli yokukhobokisa Nat Neurosci 8I-1445-1449.1449Olu phononongo lushwankathela umzimba womsebenzi obonisa indima yotshintsho lwemolekyuli elamla inguqulelo ukusuka ekuthatheni iziyobisi ukuya ekubeni likhoboka lotywala ngogxininiso olukhethekileyo kwingqokelela yento ekhutshelweyo ye-ΔFosB kwi-nucleus accumbens kulandela ukuba sesichengeni seziyobisi ezingapheliyo. [PubMed]
- Neugebauer V, Li W, Bird GC, Han JS. I-amygdala kunye neentlungu eziqhubekayo. Neuroscientist. 2004;10: 221-234. [PubMed]
- O'Dell LE, Koob GF. Isiphumo sokuvinjwa kweNicotine kwiimpuku kunye nokufikelela kwe-23-h engapheliyo kwi-intravenous nicotine self-administration. Pharmacol Biochem Behav. 2007;86: 346-353. [Inkcazelo yamahhala ye-PMC] [PubMed]
- I-Olds J, uMilner P. Ukuqiniswa okulungileyo okuveliswe ngokuvuselela kombane kwindawo ye-septal kunye neminye imimandla yobuchopho begundane. J Comp Physiol Psychol. 1954;47: 419-427. [PubMed]
- I-Orsini C, i-Koob GF, i-Pulvirenti L. I-Dopamine inxalenye ye-agonist ibuyisela ukurhoxiswa kwe-amphetamine kwiigundane. Neuropsychopharmacology. 2001;25: 789-792. [PubMed]
- Pierce RC, Bell K, Duffy P, Kalivas PW. I-cocaine ephindaphindiweyo yokwandisa ukuhanjiswa kwe-amino acid kwi-nucleus iqokelele kuphela kwiimpuku eziphuhlise uvakalelo lokuziphatha. J Neurosci. 1996;16: 1550-1560. [PubMed]
- Pulvirenti L, Koob GF. I-Lisuride inciphisa ukubuyiswa kwengqondo ngexesha lokurhoxa kwi-amphetamine engapheliyo yokuzilawula kwiimpuku. Neuropsychopharmacology. 1993;8: 213-218. [PubMed]
- URachlin H, uGreen L. Ukuzibophelela, ukhetho kunye nokuzibamba. J Uhlaziyo lwe-Behav. 1972;17: 15-22. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Robbins TW. Ubudlelwane phakathi kokuphucula umvuzo kunye neziphumo ezibambekayo zamachiza avuselela ingqondo. Uhlobo. 1976;264: 57-59. [PubMed]
- Roberts AJ, Heyser CJ, Cole M, Griffin P, Koob GF. Ukusela i-ethanol ngokugqithisileyo emva kwembali yokuxhomekeka: imodeli yezilwanyana ze-allostasis. Neuropsychopharmacology. 2000;22: 581-594. [PubMed]
- Roberts DCS. 1992. I-Neural substrates yokulamla ukomelezwa kwe-cocaine: indima yeenkqubo ze-monoamineKu: Lakoski JM, Galloway MP, White FJ (eds).I-Cocaine: I-Pharmacology, i-Physiology kunye ne-Clinical Strategies I-CRC Press: Boca Raton, FL; 73–90.90.
- URobinson TE, iBerridge KC. Isiseko se-neural sokukhanga izidakamizwa: intsholongwane yokukhuthaza ukunyanzela. Brain Res Rev. 1993;18: 247-291.
- Robledo P, Koob GF. Iindawo ezimbini ezicacileyo zenucleus accumbens zokuqikelela ngokwahlukileyo zilamla ukuzilawula kwe-cocaine kwimpuku. Behav Brain Res. 1993;55: 159-166. [PubMed]
- Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, et al. Ukuzilawula kweCocaine kwi-dopamine-transporter knockout mice. Nat Neurosci. 1998;1: 132-137. [PubMed]
- Rossetti ZL, Hmaidan Y, Gessa GL. Uthintelo oluphawulweyo lokukhutshwa kwe-mesolimbic dopamine: into eqhelekileyo ye-ethanol, i-morphine, i-cocaine kunye nokuyeka i-amphetamine kwiimpuku. Eur J Pharmacol. 1992;221: 227-234. [PubMed]
- URussell MAH. 1976. Yintoni ukuxhomekekaKu: Edwards G (ed).Iziyobisi kunye nokuxhomekeka kwiziyobisi Iincwadi zeLexington: Lexington, MA; 182–187.187.
- Saal D, Dong Y, Bonci A, Malenka RC. 2003. Iziyobisi zokuxhatshazwa kunye noxinzelelo zibangela uhlengahlengiso oluqhelekileyo lwe-synaptic kwi-dopamine neurons Neuron 37577-582.582 (erratum: 38: 359). [PubMed]
- Salamone JD, Correa M, Farrar A, Mingote SM. Imisebenzi enxulumene nomzamo we-nucleus accumbens dopamine kunye nemijikelezo ye-forebrain ehambelana nayo. Psychopharmacology. 2007;191: 461-482. [PubMed]
- I-Sanchis-Segura C, i-Spanagel R. Uvavanyo lokuziphatha lokuqiniswa kweziyobisi kunye neempawu zokulutha kwiigundane: isishwankathelo. Umlutha weBool. 2006;11: 2-38. [PubMed]
- USarnyai Z, uBiro E, uGardi J, uVecsernyes M, uJulesz J, uTelegdy G. I-Brain corticotropin-releasing factor ilamla ukuziphatha 'okunjengexhala' okubangelwa kukurhoxa kwecocaine kwiimpuku. Res Resin. 1995;675: 89-97. [PubMed]
- I-Schoenbaum G, i-MP ye-Saddoris, i-Ramus SJ, u-Shaham Y, i-Setlow B. Iigundane ezinamava e-Cocaine zibonisa ukusilela ekufundeni kumsebenzi obuthathaka kwizilonda ze-orbitofrontal cortex. Eur J Neurosci. 2004;19: 1997-2002. [PubMed]
- Schulteis G, Ahmed SH, Morse AC, Koob GF, Everitt BJ. Ukulungiswa kunye nokurhoxiswa kwe-opiate: i-amygdala idibanisa i-intuthral engathathi hlangothi kunye neentlungu zokoyisa umlutha weziyobisi. Uhlobo. 2000;405: 1013-1014. [PubMed]
- Schulteis G, Stinus L, Risbrough VB, Koob GF. I-Clonidine iibhloko zokufumana kodwa ayibonakalisi ukuhoxiswa kwe-opiate enemeko kwiigundane. Neuropsychopharmacology. 1998;19: 406-416. [PubMed]
- Schultz W. Imisebenzi emininzi ye-dopamine kwiikhosi zamaxesha ahlukeneyo. Annu Rev Neurosci. 2007;30: 259-288. [PubMed]
- U-Shaham Y, u-Shalev U, uLu L, u-Wit H, uStewart J. Imodeli yokubuyisela ukubuyiswa kweziyobisi: imbali, indlela yokusebenza kunye neziphumo eziphambili. Psychopharmacology. 2003;168: 3-20. [PubMed]
- Shalev U, Grimm JW, Shaham Y. 2002. I-Neurobiology yokubuyela kwi-heroin kunye nokufuna i-cocaine: uphononongo I-Pharmacol Rev 54I-1-42.42Olu hlaziyo lushwankathela i-neurocircuitry ehambelana neziyobisi-, i-cue-, kunye noxinzelelo-olunyanzeliswa ukuphindaphinda okugqitywe kumsebenzi obanzi kunye neemodeli zezilwanyana. [PubMed]
- USharma A, uBrody AL. In vivo umfanekiso wengqondo wokuvezwa komntu kwi-nicotine kunye necuba. I-Handb Exp Pharmacol. 2009;192: 145-171. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Shaw-Lutchman TZ, Barrot M, Wallace T, Gilden L, Zachariou V, Impey S, et al. Imephu yengingqi kunye neselula yempendulo ye-cAMP ye-elementi-mediated transcript ngexesha lokurhoxiswa kwe-naltrexone-precipitated morphine. J Neurosci. 2002;22: 3663-3672. [PubMed]
- USolomon RL, uCorbit JD. Ithiyori yenkqubo yemchasi yenkuthazo: 1. Amandla exeshana okuchaphazela. Psychol Rev. 1974;81: 119-145. [PubMed]
- I-Stein L. Iziphumo kunye nokusebenzisana kwe-imipramine, i-chlorpromazine, i-reserpine, kunye ne-amphetamine kwi-self-stimulation: isiseko se-neurophysiological esinokwenzeka sokudakumba. Kutshanje Adv Biol Psychiatry. 1962;4: 288-309. [PubMed]
- Stinus L, Cador M, Zorrilla EP, Koob GF. IBuprenorphine kunye neCRF1 umchasi uthintele ukufunyanwa kwe-opiate ukurhoxiswa-induced conditioned indawo inzondo kwiimpuku. Neuropsychopharmacology. 2005;30: 90-98. [PubMed]
- Ukusetyenziswa kakubi kweziyobisi kunye noLawulo lweeNkonzo zeMpilo yeNgqondo ngo-2008. Iziphumo ezivela kuPhando lweSizwe lwe-2007 ngokuSetyenziswa kweZiyobisi kunye neMpilo: Iziphumo zeSizwe(I-Ofisi yeeNkcukacha eziSetyenzisiweyo, i-NSDUH Series H-34, i-DHHS Publication No. SMA 08-4343). Rockville, MD.
- Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D, et al. Ukunyanzeliswa kokunyanzeliswa kokunyanzeliswa kwee-receptors ze-AMPA kunciphisa indlela yokuziphatha yokufuna i-cocaine. Uhlobo. 2003;421: 70-75. [PubMed]
- Tanda G, Pontieri FE, Di Chiara G. I-Cannabinoid kunye ne-heroin esebenzayo yosasazo lwe-mesolimbic dopamine ngokuqhelekileyo μ1 Indlela yokusebenza ye-opioid receptor. Sayensi. 1997;276: 2048-2050. [PubMed]
- Thorsell A, Rapunte-Canonigo V, O'Dell L, Chen SA, King A, Lekic D, et al. I-Viral Vector-induced amygdala I-NPY overexpression ibuyisela umva ukwanda kokusela utywala okubangelwa ukuvinjwa ngokuphindaphindiweyo kwiimpuku zeWistar. Ubunjani. 2007;130: 1330-1337. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Thorsell A, Slawecki CJ, Ehlers CL. Iziphumo ze-neuropeptide Y kunye ne-corticotropin-releasing factor on ethanol intake in Wistar rats: ukusebenzisana kunye ne-ethanol exposure engapheliyo. Behav Brain Res. 2005a;161: 133-140. [PubMed]
- Thorsell A, Slawecki CJ, Ehlers CL. Iziphumo ze-neuropeptide Y kwi-appetitive and consummatory behaviors ezinxulumene nokusela utywala kwiimpuku ze-Wistar ezinembali yokuvezwa kwe-ethanol. Utywala lweeNkcazo zoTywala. 2005b;29: 584-590. [PubMed]
- Tiffany ST, Carter BL, Singleton EG. Imingeni ekwenziweni, kuvavanyo kunye nokutolikwa kweminqweno eguquguqukayo efanelekileyo. Umlutha. 2000;95 (Inkxaso 2: s177–s187. [PubMed]
- I-Todtenkopf MS, i-Parsegian A, i-Naydenov A, i-Neve RL, i-Konradi C, i-Carlezon WA., i-Jr Umvuzo wobuchopho olawulwa yi-AMPA receptor subunits kwi-nucleus accumbens shell. J Neurosci. 2006;26: 11665-11669. [PubMed]
- Tomasi D, Goldstein RZ, Telang F, Maloney T, Alia-Klein N, Caparelli EC, et al. Ukuphazamiseka okuxhaphakileyo kwiipateni zokuvula ingqondo kumsebenzi wememori osebenzayo ngexesha lokuyeka i-cocaine. Res Resin. 2007a;1171: 83-92. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Tomasi D, Goldstein RZ, Telang F, Maloney T, Alia-Klein N, Caparelli EC, et al. Ukungasebenzi kakuhle kweThalamo-cortical kubaxhaphazi be-cocaine: iimpembelelo kwingqwalasela kunye nokuqonda. Psychiatry Res. 2007b;155: 189-201. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Tornatzky W, Miczek KA. Ukuzilawula kwe-cocaine 'ukuzinkcinkca': inguqu ukusuka kulawulo lokuziphatha kunye nokuzimela ukuya kwi-homeostatic dysregulation kwiimpuku. Psychopharmacology. 2000;148: 289-298. [PubMed]
- Tucci S, Cheeta S, Seth P, File SE. I-Corticotropin ekhupha into echasene nayo, α-Helical CRFI-9 − 41, ibuyisela umva i-nicotine-induced conditioned, kodwa ingaqinisekanga, ixhala. Psychopharmacology. 2003;167: 251-256. [PubMed]
- Tzschentke TM. Ukulinganisa umvuzo ngeparadigm emiselweyo yendawo: uphononongo olubanzi lweziphumo zeziyobisi, inkqubela phambili yamva nje kunye nemiba emitsha. Prog Neurobiol. 1998;56: 613-672. [PubMed]
- Ungless MA, Whistler JL, Malenka RC, Bonci A. Uvezimo olunye lwecocaine kwi vivo yenza amandla okubamba kwexesha elide kwi-dopamine neurons. Uhlobo. 2001;411: 583-587. [PubMed]
- Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, et al. Ukonyuka kokuzilawula kwe-ethanol kunye nokuziphatha okuxhalabileyo ngexesha lokurhoxiswa ngokukhawuleza kunye nokuyeka ixesha elide: ukulawulwa yi-corticotropin-releasing factor. Utywala lweeNkcazo zoTywala. 2002;26: 1494-1501. [PubMed]
- IVanderschuren LJ, i-everitt BJ. Ukufuna iziyobisi kuyanyanzeleka emva kokuzilawula ixesha elide kwecocaine. Sayensi. 2004;305: 1017-1019. [PubMed]
- I-Vezina P. Uvakaliso lwe-midbrain dopamine neuron reactivity kunye nokuzilawula kwe-psychomotor stimulant drug. Neurosci Biobehav Rev. 2004;27: 827-839. [PubMed]
- Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, et al. 2001a. Inqanaba eliphantsi lengqondo ye-dopamine receptors ye-D2 kubaxhaphazi be-methamphetamine: ukunxulumana nemetabolism kwi-orbitofrontal cortex. IJ Psychiatry 158Ngo-2015–2021.2021 Olu phononongo lubonisa unxulumano phakathi kokuncipha kokusebenza kwe-dopamine kubukhoboka kunye nokuncipha komsebenzi we-orbitofrontal cortex, ukuseka ikhonkco eliphambili phakathi komsebenzi wokubethelwa esichengeni kunye nokungasebenzi kakuhle kwe-orbitofrontal kubukhoboka. [PubMed]
- Volkow ND, Fowler JS, Wang GJ, Ding YS, Gatley SJ. Indima ye-dopamine kunyango kunye nokomeleza iziphumo ze-methylphenidate ebantwini: iziphumo zezifundo zokucinga. Eur Neuropsychopharmacol. 2002;12: 557-566. [PubMed]
- IVolkow ND, uFowler JS, uWang GJ, uHitzemann R, uLogan J, uScilyer DJ, et al. Ukufumaneka kwe-dopamine D2 receptor kunxulunyaniswa nokuncitshiswa kwangaphambi kwemetabolism kubaxhaphazi becocaine. Synapse. 1993;14: 169-177. [PubMed]
- Volkow ND, Fowler JS, Wang GJ. Ingqondo yomntu olikhoboka ijongwe ekukhanyeni kwezifundo zokucinga: iisekethe zobuchopho kunye nezicwangciso zonyango. Neuropharmacology. 2004a;47 (I-Suppl 1: 3-13. [PubMed]
- Volkow ND, Fowler JS, Wang GJ, Swanson JM. Dopamine ekusebenziseni iziyobisi gwenxa kunye neziyobisi: iziphumo ezivela kwizifundo zokucinga kunye nefuthe lonyango. Mol Psychiatry. 2004b;9: 557-569. [PubMed]
- UVolkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Valentine A, et al. Ubuchopho be-glucose metabolism kubasebenzisi be-marijuana abangapheliyo kwisiseko kunye nangexesha lokuxilwa kwentsangu. Psychiatry Res. 1996a;67: 29-38. [PubMed]
- Volkow ND, Swanson JM. Izinto eziguqukayo ezichaphazela ukusetyenziswa kweklinikhi kunye nokuxhatshazwa kwe-methylphenidate kunyango lwe-ADHD. IJ Psychiatry. 2003;160: 1909-1918. [PubMed]
- UVolkow ND, Wang G, Fowler JS, Logan J, Gerasimov M, Maynard L, et al. Iidosi zonyango ze-methylphenidate yomlomo zonyusa kakhulu i-extracellular dopamine kwingqondo yomntu. J Neurosci. 2001b;21: RC121. [PubMed]
- Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, et al. Ubudlelwane phakathi kweziphumo ezibambekayo ze-cocaine kunye nokuhlala kwe-dopamine transporter. Uhlobo. 1997a;386: 827-830. [PubMed]
- UVolkow ND, Wang GJ, Fowler JS, Franceschi D, Thanos PK, Wong C, et al. Abaxhaphazi be-Cocaine babonisa impendulo ephosakeleyo ekunxileni kotywala kwimimandla yengqondo ye-limbic. Life Sci. 2000;66:PL161-PL167. [PubMed]
- Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Ding YS, Logan J, et al. Ubudlelwane phakathi kwe-psychostimulant-induced 'high' kunye nokuhlala komthuthi we-dopamine. Proc Natl Acad Sci USA. 1996b;93: 10388-10392.
- Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B, Gatley SJ, et al. Umbutho we-methylphenidate-induced craving with change in right striato-orbitofrontal metabolism kubaxhaphazi be-cocaine: iimpembelelo kubukhoboka. IJ Psychiatry. 1999;156: 19-26. [PubMed]
- Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Gatley SJ, Dewey SS, et al. Uvakalelo olongeziweyo kwi-benzodiazepines kwizifundo ezisebenzayo zokusebenzisa kakubi i-cocaine: isifundo se-PET. IJ Psychiatry. 1998;155: 200-206. [PubMed]
- UVolkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, et al. 1997b. Ukuncipha kokuphendula kwe-striatal dopaminergic kwizifundo ezixhomekeke kwi-cocaine. indalo 386830-833.833 Olu phononongo lusebenzisa i-PET lubonise ukuhla kokukhululwa kwe-dopamine kwi-striatum kunye nokwehla 'okuphezulu' okuveliswe yi-methylphenidate, ebonisa ukuba inkqubo ye-striatal dopamine esengozini yokulutha. [PubMed]
- Volkow ND, Wang GJ, Ma Y, Fowler JS, Wong C, Ding YS, et al. Ukwenza kusebenze i-orbital kunye ne-medial prefrontal cortex nge-methylphenidate kwizifundo ezikhotyokiswe yi-cocaine kodwa zingekho kulawulo: ukubaluleka kubukhoboka. J Neurosci. 2005;25: 3932-3939. [PubMed]
- Volkow ND, Wang GJ, Ma Y, Fowler JS, Zhu W, Maynard L, et al. Ulindelo luphucula imetabolism yengqondo yengingqi kunye neziphumo zokuqinisa izivuseleli kubaxhaphazi be-cocaine. J Neurosci. 2003;23: 11461-11468. [PubMed]
- Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. I-Cocaine cues kunye ne-dopamine kwi-dorsal striatum: indlela yokunqwenela ukuba likhoboka le-cocaine. J Neurosci. 2006;26: 6583-6588. [PubMed]
- Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. Ukunyuka kwe-Dopamine kwi-striatum akufuni ukunqwenela kubaxhaphazi be-cocaine ngaphandle kokuba zidityaniswe ne-cocaine cues. Neuroimage. 2008a;39: 1266-1273. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, et al. I-Pound yehla ekukhutshweni kwe-dopamine kwi-striatum kwizinxila ezikhutshiweyo: ukubandakanyeka okunokwenzeka kwe-orbitofrontal. J Neurosci. 2007;27: 12700-12706. [PubMed]
- Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Wong C, et al. Ukungalali kunciphisa ukubophelela kwe [11C] raclopride ukuya kwi-dopamine D2/D3 receptors kwingqondo yomntu. J Neurosci. 2008b;28: 8454-8461. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Wang GJ, Volkow ND, Fowler JS, Logan J, Abumrad NN, Hitzemann RJ, et al. Ukufumaneka kwe-Dopamine D2 receptor kwizifundo ezixhomekeke kwi-opiate ngaphambi nangemva kokurhoxiswa kwe-naloxone-precipitated. Neuropsychopharmacology. 1997;16: 174-182. [PubMed]
- Wang Z, Faith M, Patterson F, Tang K, Kerrin K, Wileyto EP, et al. I-Neural substrates yeminqweno yecuba ebangelwa kukuyeka ukutshaya kubantu abatshayayo abangapheliyo. J Neurosci. 2007;27: 14035-14040. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Watkins SS, Stinus L, Koob GF, Markou A. Umvuzo kunye notshintsho lwe-somatic ngexesha lokuhoxiswa kwe-nicotine kwiigundane: imiphumo ephakathi kunye ne-peripherally mediated. J Pharmacol Exp Ther. 2000;292: 1053-1064. [PubMed]
- Wee S, Wang Z, Woolverton WL, Pulvirenti L, Koob GF. Isiphumo se-aripiprazole, inxalenye ye-D2 i-receptor agonist, kwinqanaba elonyukayo le-methamphetamine yokuzilawula ngokwakho kwiimpuku ezinokufikelela ixesha elide. Neuropsychopharmacology. 2007;32: 2238-2247. [Inkcazelo yamahhala ye-PMC] [PubMed]
- Wee S, Orio L, Ghirmai S, Cashman J, Koob GF. 2009. Ukuthintelwa kwe-kappa opioid receptors kunciphisa inkuthazo eyandayo ye-cocaine kwiimpuku kunye nokufikelela okwandisiweyo kwi-cocaine. Psychopharmacology(kwiphepha).
- Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, et al. 2001. Ukuziphatha okunyanzelekileyo kokufuna iziyobisi kunye nokuphinda ubuyele kwakhona: i-neuroadaptation, uxinzelelo, kunye nemekoKu: Quinones-Jenab V (ed).Isiseko sebhayoloji seCocaine Addiction(isihloko songcelele: Annals of the New York Academy of Sciences, vol 937)New York Academy of Sciences: New York; 1–26.26.
- Weiss F, Makaou A, Lorang MT, Koob GF. Amanqanaba e-basal extracellular dopamine kumanqanaba e-nusus ancitshiswa ngexesha lokurhoxiswa kwe-cocaine emva kokuzilawula okungenamkhawulo. Res Resin. 1992;593: 314-318. [PubMed]
- Weiss F, Parsons LH, Schulteis G, Hyytia P, Lorang MT, Bloom FE, et al. Ukuzilawula kwe-Ethanol kubuyisela ukusilela okunxulumene nokurhoxa kwi-accumbal dopamine kunye ne-5-hydroxytryptamine yokukhululwa kwiimpuku ezixhomekeke. J Neurosci. 1996;16: 3474-3485. [PubMed]
- NM emhlophe. Iziyobisi ezikhobokisayo njengabancedisi: izenzo ezininzi eziyingxenye kwiinkqubo zememori. Umlutha. 1996;91: 921-949. [PubMed]
- Whitelaw RB, Markou A, Robbins TW, Everitt BJ. Izilonda ze-Excitotoxic ze-amygdala ye-basolateral yonakalisa ukufunyanwa kwendlela yokuziphatha efunwa yi-cocaine phantsi kweshedyuli yesibini yokuqinisa. Psychopharmacology. 1996;127: 213-224. [PubMed]
- U-Wikler A. Uphononongo lwengqondo yesigulane ngexesha lokuziqhelanisa nokuzilawula kwakhona kwi-morphine. Psychiatr Q. 1952;26: 270-293. [PubMed]
- Ulumkile RA. I-Catecholamine yethiyori yomvuzo: uphononongo olubalulekileyo. Res Resin. 1978;152: 215-247. [PubMed]
- Ngcuka MNA. Umlutha: ukwenza unxibelelwano phakathi kweenguqu zokuziphatha kunye neplastiki ye-neuronal kwiindlela ezithile. Ungenelelo lweMol. 2002;2: 146-157.
- Wolf ME, Sun X, Mangiavacchi S, Chao SZ. Iingqondo zengqondo kunye neeplastiki. Neuropharmacology. 2004;47 (I-Suppl 1: 61-79. [PubMed]
- Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM, et al. Ukuchongwa kwe-PSD-95 njengomlawuli we-dopamine-mediated synaptic kunye nokuziphatha kweplastiki. Neuron. 2004;41: 625-638. [PubMed]
- Yeomans J, Baptista M. Zombini i-nicotinic kunye ne-muscarinic receptors kwindawo ye-ventral tegmental igalelo kumvuzo wokuvuselela ingqondo. Pharmacol Biochem Behav. 1997;57: 915-921. [PubMed]
- Yin HH, Ostlund SB, Knowlton BJ, Balleine BW. Indima ye-dorsomedial striatum kwimeko yesixhobo. Eur J Neurosci. 2005;22: 513-523. [PubMed]
- Zubieta JK, Gorelick DA, Stauffer R, Ravert HT, Dannals RF, Frost JJ. Ukonyuka kwe-opioid receptor ebophelelayo efunyenwe yi-PET kumadoda axhomekeke kwi-cocaine inxulumene nokunqwenela i-cocaine. Nat Med. 1996;2: 1225-1229. [PubMed]
- Zubieta J, Lombardi U, Minoshima S, Guthrie S, Ni L, Ohl LE, et al. Iziphumo zokuhamba kwegazi kwi-cerebral zengingqi ze-nicotine kubantu abatshayayo ubusuku bonke. Biol Psychiatry. 2001;49: 906-913. [PubMed]
;