Eur J Neurosci. 2019 Apr 9. doi: 10.1111 / ejn.14418.
Kawa AB1, Valenta AC2, Kennedy RT2, Robinson TE1.
Abstract
Ipateni yexeshana yokusetyenziswa kweziyobisi (i-pharmacokinetics) inefuthe elinzulu kwisakhono se-cocaine ezilawulayo ukuvelisa ukuziphatha okufana nokulutha kwiimpuku, kunye nokutshintsha ingqondo. Ukujonga ngakumbi lo mba, sithelekise iziphumo zoFikelelo olude (LgA) lwe-cocaine self-administration, esetyenziswa ngokubanzi ukwenza imodeli yenguqu kwikhoboka, kunye noFikelelo oluNgaphakathi (IntA), ekucingelwa ukuba ibonakalisa ngcono ipateni yokusetyenziswa kweziyobisi. ebantwini, kwisakhono senaliti enye, ezilawulayo ye-cocaine yokwandisa i-dopamine (DA) ephuphumayo kumbindi we-nucleus accumbens (usebenzisa i-vivo microdialysis), kunye nokuvelisa ukuziphatha okufana nokulutha. Amava e-IntA ayesebenza ngakumbi kune-LgA ekuveliseni ukuziphatha okufana nokulutha- ukonyuka okuxhomekeke kumava eziyobisi kwinkuthazo ye-cocaine evavanywa kusetyenziswa iinkqubo zoqoqosho zokuziphatha, kunye nokubuyiselwa okubangelwa yi-cue-ngaphandle kokusetyenziswa kweziyobisi kuncinci.. Kwakungekho mahluko weqela kumanqanaba esiseko e-DA kwi-dialysate [DA], kodwa inaliti ye-IV ye-cocaine yonyuka [i-DA] kumbindi we-nucleus iqokelelana ukuya kumlinganiselo omkhulu kwiimpuku ezinamava e-IntA yangaphambili kunezo I-LgA okanye i-LimA yamava, kwaye amaqela amabini okugqibela awazange ahluke. Ngapha koko, inkuthazo ephezulu ye-cocaine yayanyaniswa nempendulo ephezulu ye- [DA]. Ke, i-IntA, kodwa hayi i-LgA, ivelise zombini inkuthazo kunye ne-DA yokwazisa. Oku kuhambelana noluvo lokuba inkqubo ye-hyper-responsive dopaminergic inokuba negalelo kutshintsho ukusuka kwiipateni eziqhelekileyo zokusetyenziswa kweziyobisi ukuya kwiipateni eziyingxaki ezichaza umlutha. Eli nqaku likhuselwe lilungelo lokushicilela. Onke amalungelo agciniwe.
IINKCUKACHA: ukuba likhoboka icocaine; i-dopamine; ukufikelela okwethutyana; uvakalelo
PMID: 30968487
UKUQALA
Injongo yolu phononongo yayikukuthelekisa amandla exesha elide le-LgA kunye ne-IntA cocaine namava okuzilawula ukuvelisa i-addiction-like behaviour (enxulumene ne-ShA), kunye nendlela oku okuphembelele ngayo isakhono se-cocaine ezilawulayo ekutshintsheni amanqanaba e-DA engaphandle i-nucleus accumbens ingundoqo kwi-vivo. Iziphumo eziphambili bezi: 1. Njengoko bekulindelekile, i-LgA ibe nesiphumo sokusetyenziswa kwe-cocaine iyonke kune-IntA. 2. Zombini i-IntA kunye ne-LgA zivelise ukunyuka kokuthatha ngokunyuka kwamava okuzilawula. 3. Amava e-IntA (kodwa hayi i-LgA) anyuse inkuthazo ye-cocaine, njengoko kubonisiwe kukuncipha kwe-α kunye nokunyuka kwe-PMax. 4. Iimpuku ze-IntA zibonise ukubuyiswa okukhulu okubangelwa yi-cocaine kuneempuku ze-LgA. 5. Amava e-LgA (kodwa hayi i-IntA) anyuse izinga elikhethiweyo lokuthatha i-cocaine xa kungekho nzame ifunekayo (Q0). 6. Kwakungekho mahluko weqela kumanqanaba asisiseko e-DA kwi-dialysate, kodwa inaliti ye-IV ye-cocaine yonyusa i-DA kumbindi we-nucleus accumbens ukuya kumlinganiselo omkhulu kwiimpuku ezinamava e-IntA yangaphambili kunezo zine-LgA okanye i-ShA. amava, yaye la maqela mabini okugqibela akazange ahluke. 7. Kuwo onke amaqela inkuthazo ephezulu yecocaine yayanyaniswa nempendulo enkulu yeDA. 8. Kwakungekho nantlukwano yeqela kwi-dialysate concentrations ye-glutamate, i-GABA, i-ACh, i-DOPAC okanye i-HVA, nangona i-cocaine yanda i-3-MT ukuya kumlinganiselo omkhulu kwi-IntA kune-ShA okanye iigundane ze-LgA, ezihambelana nemiphumo ye-DA.Amava e-IntA ayesebenza ngakumbi ekuveliseni ukuziphatha okufana nokulutha kune-LgA amava
Ukusukela ekuqalisweni kwayo ngo-1998 (Ahmed & Koob, 1998) inkqubo ye-LgA yamkelwe ngokubanzi ukuba ibonise inguquko kwi-cocaine likhoboka le-cocaine kwiimpuku, kuba kwakucingelwa ukuba iyasebenza kakhulu ekuveliseni inani lokuziphatha okufana nokulutha, ngokumalunga no-ShA. (uphononongo bona, Ahmed, 2012; Edwards and Koob 2013). Kwiphepha labo lika-1998 u-Ahmed no-Koob babika ukuba i-LgA, kodwa ingeyiyo i-ShA, ibangele ukunyuka kokuthatha. Ukusukela ngelo xesha kuye kwaxelwa ukuba, ngokunxulumene ne-ShA, iimpuku ezinamava e-LgA zikhuthazwa ngakumbi ukuba zifune i-cocaine (uPaterson & Markou, 2003; Wee okqhubekayo., 2008), thatha icocaine eninzi ebusweni beziphumo ezibi (Xue okqhubekayo., 2012; Bentzley okqhubekayo., 2014; kwakhona bona iVanderschuren & Everitt, 2004), kwaye ubonise ukubuyiselwa okukhulu kwindlela yokuziphatha yokufuna i-cocaine emva kokuphela (iMantsch okqhubekayo., 2004, 2008; Ahmed & Cador, 2006; Kippin okqhubekayo., 2006). Njengoko kubonisiwe kwisicatshulwa esicatshulwe kwiNtshayelelo evela ku-Ahmed (2012), kuye kwacetyiswa ukuba eyona nto ibalulekileyo efunekayo ekuveleni kokunyuka kunye nokunye ukuziphatha okufana nokulutha. isixa kweziyobisi ezisetyenzisiweyo. Njengoko kubekwe nguEdward noKoob (2013), “ukuba sesichengeni seziyobisi ngokugqithisileyo kuhlala kuyinto eyimfuneko ekuqhubeni ukukhula kobukhoboka”. Nangona kunjalo, iziphumo ezichazwe apha zongeza kuncwadi olukhulayo olubonisa ukuba oku akunjalo.
Ulawulo lwe-IntA lukhokelela ekusetyenzisweni okungaphantsi kwe-cocaine kune-LgA. Ukanti njengoko kuxeliwe apha, i-IntA ikwavelise ukunyuka kokutya kwaye yayisebenza ngakumbi kune-LgA ekwandiseni inkuthazo ye-cocaine kunye nokuvelisa ukubuyiselwa okubangelwa yi-cue-indeed yokuziphatha yokufuna i-cocaine. Ezi ziphumo ziyahambelana nenani lezifundo zamva nje ezixela ukuba i-IntA ivelisa ukunyuka kokutya, inkuthazo ephezulu ye-cocaine, ukuqhubeka nokufuna i-cocaine ebusweni besiphumo esibi, ukuqhubeka nokufuna i-cocaine xa ingafumaneki, kunye ne-cue enkulu- ukubuyiselwa esikhundleni (Zimmer okqhubekayo., 2012; Kawa okqhubekayo., 2016; Allain & Samaha, 2018; Allain okqhubekayo., 2018; UJames okqhubekayo., 2018; Kawa & Robinson, 2018; Imvumi okqhubekayo., 2018). Ngokudibeneyo, ezi zifundo zifumanise ukuba ukusetyenziswa kwesixa esikhulu se-cocaine ehambelana ne-LgA akuyomfuneko kuphuhliso lokuziphatha okufana nokulutha kunye nezinye izinto ze-pharmacokinetic zibonakala zibaluleke ngakumbi (Allain okqhubekayo., 2015). Ukusilela kwamava e-LgA ukunyusa inkuthazo ye-cocaine kwesi sifundo sikhoyo asihambelani nezifundo ezininzi zangaphambili zisebenzisa nokuba zizalathisi zokuziphatha ezifanayo.
Amava e-IntA ayesebenza ngakumbi ekuveliseni ukuziphatha okufana nokulutha kune-LgAamava
Ukusukela ekuqalisweni kwayo ngo-1998 (Ahmed & Koob, 1998) inkqubo ye-LgA yamkelwe ngokubanzi ukuba ibonise inguquko kwi-cocaine likhoboka le-cocaine kwiimpuku, kuba kwakucingelwa ukuba iyasebenza kakhulu ekuveliseni inani lokuziphatha okufana nokulutha, ngokumalunga no-ShA. (uphononongo bona, Ahmed, 2012; Edwards and Koob 2013). Kwiphepha labo lika-1998 u-Ahmed no-Koob babika ukuba i-LgA, kodwa ingeyiyo i-ShA, ibangele ukunyuka kokuthatha. Ukusukela ngelo xesha kuye kwaxelwa ukuba, ngokunxulumene ne-ShA, iimpuku ezinamava e-LgA zikhuthazwa ngakumbi ukuba zifune i-cocaine (uPaterson & Markou, 2003; Wee okqhubekayo., 2008), thatha icocaine eninzi ebusweni beziphumo ezibi (Xue okqhubekayo., 2012; Bentzley okqhubekayo., 2014; kwakhona bona iVanderschuren & Everitt, 2004), kwaye ubonise ukubuyiselwa okukhulu kwindlela yokuziphatha yokufuna i-cocaine emva kokuphela (iMantsch okqhubekayo., 2004, 2008; Ahmed & Cador, 2006; Kippin okqhubekayo., 2006). Njengoko kubonisiwe kwisicatshulwa esicatshulwe kwiNtshayelelo evela ku-Ahmed (2012), kuye kwacetyiswa ukuba eyona nto ibalulekileyo efunekayo ekuveleni kokunyuka kunye nokunye ukuziphatha okufana nokulutha. isixa kweziyobisi ezisetyenzisiweyo. Njengoko kubekwe nguEdward noKoob (2013), “ukuba sesichengeni seziyobisi ngokugqithisileyo kuhlala kuyinto eyimfuneko ekuqhubeni ukukhula kobukhoboka”. Nangona kunjalo, iziphumo ezichazwe apha zongeza kuncwadi olukhulayo olubonisa ukuba oku akunjalo.
Ulawulo lwe-IntA lukhokelela ekusetyenzisweni okungaphantsi kwe-cocaine kune-LgA. Ukanti njengoko kuxeliwe apha, i-IntA ikwavelise ukunyuka kokutya kwaye yayisebenza ngakumbi kune-LgA ekwandiseni inkuthazo ye-cocaine kunye nokuvelisa ukubuyiselwa okubangelwa yi-cue-indeed yokuziphatha yokufuna i-cocaine. Ezi ziphumo ziyahambelana nenani lezifundo zamva nje ezixela ukuba i-IntA ivelisa ukunyuka kokutya, inkuthazo ephezulu ye-cocaine, ukuqhubeka nokufuna i-cocaine ebusweni besiphumo esibi, ukuqhubeka nokufuna i-cocaine xa ingafumaneki, kunye ne-cue enkulu- ukubuyiselwa esikhundleni (Zimmer okqhubekayo., 2012; Kawa okqhubekayo., 2016; Allain & Samaha, 2018; Allain okqhubekayo., 2018; UJames okqhubekayo., 2018; Kawa & Robinson, 2018; Imvumi okqhubekayo., 2018).
Ngokudibeneyo, ezi zifundo zifumanise ukuba ukusetyenziswa kwesixa esikhulu se-cocaine ehambelana ne-LgA akuyomfuneko kuphuhliso lokuziphatha okufana nokulutha kunye nezinye izinto ze-pharmacokinetic zibonakala zibaluleke ngakumbi (Allain okqhubekayo., 2015). Ukusilela kwamava e-LgA ukunyusa inkuthazo ye-cocaine kuphononongo lwangoku akuhambelani nezifundo ezininzi zangaphambili zisebenzisa izalathisi zokuziphatha ezifanayo zokuziphatha ezinokunyuka kuzo zombini i-LgA kunye ne-IntA, kodwa ngezizathu ezahluke kakhulu - ngenxa yonyamezelo kwisiphumo esinqwenelekayo se-cocaine. imeko yeLgA kunye nenkuthazo-sensitization kwimeko ye-IntA (Kawa okqhubekayo., 2016; Kawa & Robinson, 2018). Ewe kunjalo, umbono wokuba izinto ezigqibeleleyo kunye nezikhuthazayo zokuziphatha zisengqondweni (kunye neurobiologically) dissociable isetyenzisiwe apha (Zimmer). okqhubekayo., 2012; Bentzley okqhubekayo., 2014) okanye uvavanyo lweProgressive Ratio (PR) (Paterson & Markou, 2003; Wee okqhubekayo., 2008). Nangona kunjalo, iziphumo ze-LgA ezichazwe kwezi zifundo zazivame ukuhlolwa kuphela ngexesha elinye kwaye xa kuthelekiswa ne-ShA, kwaye ayizange ibandakanye phakathi kokuthelekisa izifundo. Kwizifundo ezilinganisa indlela inkuthazo utshintshile ngokwanda kwamava e-LgA (Bentzley okqhubekayo., 2014) iziphumo bezithobekile ngokumalunga notshintsho olwenzeka emva kwe-IntA. Iziphumo zethu ziyahambelana nezinye iingxelo zokuba amava e-LgA awanyusi inkuthazo ye-cocaine, njengoko ivavanyiwe nokuba yimilinganiselo yezoqoqosho yokuziphatha (Oleson & Roberts, 2009) okanye iimvavanyo zePR (Liu okqhubekayo., 2005; Quadros & Miczek, 2009; Willuhn okqhubekayo., 2014 ezongezelelweyo). Ukongezelela, kuye kwaxelwa ukuba utshintsho kwi-motivation eveliswa ngamava e-LgA ludlula kakhulu, luhlala iintsuku ezimbalwa emva kweseshoni yokugqibela yokuzilawula (uBentzley). okqhubekayo., 2014; UJames okqhubekayo., 2018), ngelixa ukunyuka kwenkuthazo eveliswa ngamava e-IntA kuhlala ixesha elide - kubonakala emva kweentsuku ze-50 zokuziyeka (uJames okqhubekayo., 2018). Isishwankathelo, ubungqina bokuba i-LgA yonyusa inkuthazo ye-cocaine ixubene ngandlel' ithile, ngelixa i-IntA ibisoloko ixelwa ukuba yenze njalo.
Xa ivunyelwe ukuba izilawulele i-cocaine phantsi kweshedyuli esezantsi ye-Fixed Ratio (FR) yokomelezwa, iimpuku zidla ngokutsala impendulo yazo ukuze zifezekise ingqondo ekhethwayo ye-cocaine, eziyikhusela kuluhlu olubanzi lweedosi (Gerber & Wise, 1989; Ahmed & Koob, 1999; Lynch & Carroll, 2001). Eli nqanaba lokusetyenziswa likhethwayo lilinganiswe apha nge-metric Q0 - inqanaba elikhethiweyo lokusebenzisa xa ixabiso lingekho. I-Q0 ngokuqinisekileyo imele inqanaba lengqondo ye-cocaine evelisa isiphumo esinqwenelekayo esifanelekileyo, kangangokuba akukho cocaine ingcono okanye ingaphantsi. Abanye baye babhekisela kwi-Q0 njenge "hedonic set-point" (iBentzley okqhubekayo., 2013), nangona "indawo yokuhlalisa" inokuthi ifaneleke ngakumbi (jonga iBerridge, i-2004). Ngokuqinisekileyo, akunakwenzeka ukwazi ukuba i-Q0 ngokwenene ibonisa iziphumo ze-hedonic ezizimeleyo kwiigundane. Nangona kunjalo, amava e-LgA ayalonyusa inqanaba elikhethiweyo lokusetyenziswa kwe-cocaine, njengoko kubonisiwe kukukhula kokuthatha (Ahmed & Koob, 1998), kunye nokunyuka kwe-Q0, njengoko kuxeliwe apha nangabanye (Oleson & Roberts, 2009; Bentzley okqhubekayo., 2014; UJames okqhubekayo., 2018). Iziphumo zangoku zibonisa, ke ngoko, ukuba amava e-LgA avelisa unyamezelo kuyo nayiphi na impembelelo enqwenelekayo ye-cocaine ikhuselwa njengoko kunyuka amaxabiso, ngaphandle kotshintsho kwinkuthazo ye-cocaine. Ngokwahlukileyo, i-IntA yonyusa inkuthazo ye-cocaine ngaphandle kotshintsho oluhambelanayo kwiziphumo ezinqwenelekayo zecocaine. Nangona kuqikelelwa kakhulu, oku kunokubonakalisa ukwahlukana phakathi kwe-cocaine "ukufuna" kunye "nokuthanda" (Robinson & Berridge, 1993; Berridge & Robinson, 2016). Ikwacebisa ukuba icocaine icetyiswa rhoqo (umzekelo, uNicola & Deadwyler, 2000; Sharpe & Samson, 2001; Oleson et al., 2011; Guillem okqhubekayo., 2014).
Akukho namava e-LgA okanye e-IntA atshintshileyo i-basal dopamine
Ukuncipha kwamanqanaba e-DA esisiseko kuye kwaxelwa xa uvavanyo lwenzeka kwakamsinya emva kokuyekiswa kwedosi ephezulu kunye / okanye iinkqubo zokuzilawula nge-cocaine (Mateo et al., 2005; Ferris okqhubekayo., 2011). Nangona kunjalo, kuphononongo lwangoku akukho namava e-LgA okanye e-IntA ayenayo nayiphi na impembelelo kwi-basal DA kwi-dialysate. Kwakhona, sifake i-13C6 dopamine kwi-aCSF, eyasivumela ukuba sibale iqhezu lokutsalwa kwisampulu nganye, kwaye ngoko ke siqikelela ngokuchanekileyo ngakumbi i-basal DA. Kwakungekho yantlukwano yeqela kwiqhezu lokutsalwa, ngaloo ndlela someleza isigqibo sethu sokuba akukho LgA okanye i-IntA eyatshintsha i-basal DA (ngokunxulumene ne-SHA). Esi siphumo siyahambelana nezinye iingxelo zokuba amava e-LgA awatshintshi isiseko sokugxilwa kweDA kwi-dialysate, ngokumalunga neempuku ze-ShA (Ahmed okqhubekayo., 2003) okanye iigundane ezingenayo iziyobisi (Calipari okqhubekayo., 2014). Ukongeza, amanqanaba esiseko e-DA awazange ahambelane nayo nayiphi na imilinganiselo yethu yokuziphatha efana nomlutha, ehambelana nezinye izifundo (Hurd okqhubekayo., 1989; U-Ahmed okqhubekayo., 2003).
I-IntA, kodwa hayi i-LgA, ivuselela ukuphuphuma kwe-cocaine evusa i-cocaine
Kubekho izifundo ezimbalwa kakhulu kwiziphumo ze-neurobiological zamava e-IntA, kwaye ezo zikhoyo zibandakanyeke zonke ex vivo amanyathelo. Uninzi olufanelekileyo kwisifundo esikhoyo ziingxelo zikaCalipari et al. (2013, 2015) ukuba amava e-IntA akhuthaza ukukhutshwa kwe-DA kwi-nucleus accumbens core kwizilayi zezicubu, ngokumalunga neempuku ezi-naïve okanye iimpuku ezinembali ye-ShA, kwaye zinyusa amandla e-cocaine okuthintela ukufunyanwa kwe-DA. Eyona njongo iphambili yovavanyo lwangoku yayikukumisela ukuba ngaba uvakalelo olufanayo lwe-DA neurotransmission lukhona ekuvukeni, ukuziphatha kweempuku. Ukulandela amava e-IntA exesha elide ukunyuselwa kwe-cocaine enye, enikwe ngokungabikho kwe-cocaine cue, kuvelise ukonyuka okukhulu kwe-DA ye-extracellular kumbindi we-accumbens kunokulandela amava e-LgA okanye e-ShA, kwaye la maqela mabini okugqibela awahlukanga. Ngaphaya koko, ubukhulu bempendulo ye-DA yaqikelela inkuthazo ye-cocaine, njengoko ivavanyiwe ngamanyathelo amaninzi, kubandakanya i-PMax, i-α, kunye nokufuna i-cocaine ngosuku lovavanyo lwe-microdialysis. Ukongeza, impendulo ye-DA kwi-cocaine yayiyeyona inkulu kwiimpuku ezihlangabezana neyona ndlela yokukhobokisa. Ezi ziphumo zibonakalisa ukuba i-IntA, inkqubo yokulawula i-cocaine esebenza ngokukodwa ekuveliseni impembelelo yenkuthazo kunye nokuziphatha okufana nokulutha, ikwavuselela impendulo ye-dopaminergic kwi-cocaine. Okokugqibela, i-IntA ikwaxelwe ukuba isebenza ngakumbi ekuveliseni inani lezinye iziphumo ze-neurobiological ezinxulumene nophuhliso lokuziphatha okufana nokulutha, kubandakanya ukungasebenzi kakuhle kwe-mGluR2/3 receptor function (Allain okqhubekayo., 2017), amanqanaba aphezulu eBDNF (Gueye okqhubekayo., 2018), kunye nomsebenzi owandisiweyo kwi-orexin/hypocretin neurons (uJames okqhubekayo., 2018).
Ngokuchaseneyo ne-dopaminergic sensitization eveliswa ngamava e-IntA, kukho inani leengxelo zokuba i-LgA yenza okwahlukileyo - yehlisa umsebenzi we-DA, ngokunxulumene ne-ShA. Umzekelo, ukulandela i-LgA, okanye ezinye iinkqubo zedosi ephezulu ye-cocaine, ukukwazi kwe-cocaine ukunqanda ukuthatha kwe-DA, okanye ukuvuselela umbane ukukhupha ukukhutshwa kwe-DA kumbindi we-accumbens, kuyancipha kwizilayi zethishu, njengoko i-cocaine ekhutshwe yi-DA ephuphumayo ilinganiswa nayo. microdialysis kwi vivo (Ferris okqhubekayo., 2011; I-Calipari okqhubekayo., 2013, 2014; Siciliano okqhubekayo., 2016). Kungabonakala kumangalisa, ke ngoko, ukuba kuphononongo lwangoku, inaliti ye-IV ye-cocaine yonyusa i-DA ukuya kwinqanaba elifanayo kwiimpuku ezinamava e-LgA okanye e-ShA- oko kukuthi, kwakungekho bungqina bokunyamezelana. Akukacaci ukuba yintoni ebangela lo mahluko – umz., ex vivo vs. kwi vivo imilinganiselo, umceli mngeni we-IP we-cocaine owenziwe ngumfuniselo vs. Isitofu se-IV esizilawulayo, ubuchule bokulinganisa, okanye omnye umahluko wendlela. Nangona kunjalo, iziphumo zangoku ziyahambelana nolunye uphononongo kwiziphumo zamava e-LgA kwi-DA elinganiswe nge-microdialysis. kwi vivo. U-Ahmed (2003) uxele ukuba, xa kuthelekiswa ne-ShA, i-LgA ayizange inciphise impendulo ye-DA kwi-nucleus accumbens ukuya kwiinaliti ze-IV ze-cocaine, okanye i-cocaine selfa. Ke, kubonakala ngathi amava e-LgA awahlali ewunciphisa umsebenzi we-DA. Kufuneka kwakhona kuqatshelwe ukuba iziphumo zinokwahluka kakhulu njengomsebenzi wexesha elingakanani emva kokuyekiswa kweempuku zokuzilawula zivavanywa (umz., Ferrario okqhubekayo., 2005; Siciliano okqhubekayo., 2016). Ukongeza, uWilluhn et al. (2014) ingxelo yokuba ubukhulu bempendulo ye-phasic ye-DA ebonwe emva kwempumlo eyazisa i-cocaine ngokuqhubekayo yehla ngokunyuka kwamava e-LgA, njengoko kulinganiswe ngokukhawuleza kwe-voltammetry ye-cyclic. Nangona kunjalo, le mpendulo ye-phasic ye-DA inyuke malunga ne-5 sec emva kwe-nosepoke, ekungekudala kakhulu ukuba ibonise iziphumo ze-pharmacological ze-cocaine (Stuber okqhubekayo., 2005; Aragona okqhubekayo., 2008), kwaye ke, isenokungahambelani nezifundo ezixoxwe ngasentla.
Iyure enye emva kwesitofu se-cocaine i-cue eyayinxulunyaniswa ne-cocaine yaboniswa kwaye sasilindele ukubona impendulo ye-DA enemeko. Kodwa i-cocaine cue yayingenasiphumo kulo naliphi na iqela, kuwo nawuphi na umlinganiselo we-neurochemical. Akukacaci ukuba kutheni le nto bekunjalo, kuba i-cue ngokuqinisekileyo yayineempawu ezikhuthazayo, njengoko kubonisiwe luvavanyo lokubuyisela i-cue. Nangona kunjalo, ukuba bekukho ixesha elifutshane kakhulu (imizuzwana) kunye nokuphendula okuncinci kunokuba kungabonakali kwisithuba se-3 min yesampulu esetyenzisiweyo apha, kunye nezinye iindlela zobuchule zingafuneka ukuba kufundwe iziphumo ze-IntA kwiimpendulo ezinemeko ezinjalo.
Kuye kwacetyiswa ukuba ukukhotyokiswa buphawu a iHypoI-dopaminergic, imeko ye-anhedonic, kunye nenkuthazo enyanzelekileyo yokufuna kunye nokuthatha icocaine evela kumnqweno wokoyisa le ntsilelo yeDA (Dackis & Gold, 1985; Koob & Le Moal, 1997, 2001; Blum okqhubekayo., 2015; Volkow okqhubekayo., 2016). Iingxelo zokuba amava okuzilawula kwe-LgA cocaine anciphisa umsebenzi we-DA atolikwe njengenkxaso yolu luvo, ngakumbi xa kucingwa ukuba i-LgA yayicingelwa ukuba yeyona modeli yotshintsho engqondweni nakwindlela yokuziphatha ekhokelela kutshintsho olusuka kwiipateni eziqhelekileyo zokusetyenziswa kweziyobisi ukuya kusetyenziso olwandayo. ibonakalisa ukuba likhoboka. Nangona kunjalo, njengoko kuqwalaselwe ngasentla, ubungqina bokuba i-LgA ivelisa imeko ye-hypodopaminergic iyalingana, njengoko bubungqina bokuba yonyusa inkuthazo ye-cocaine. Ukongeza, amaphononongo asebenzisa inkqubo yolawulo lwakutsha nje ye-IntA ixhasa ithiyori eyahlukileyo. Inkqubo ye-IntA yaqala yaphuhliswa ngenxa yokuba kucingelwa ukuba ingumzekelo ongcono weendlela zokusetyenziswa kwe-cocaine ebantwini, ngakumbi ngexesha lokutshintshela ekubeni likhoboka (Zimmer). okqhubekayo., 2012; Allain okqhubekayo., 2015). Kukho ubungqina obuninzi bokuba i-IntA ivelisa i-incentive-sensitization, kwaye isebenza ngakumbi kune-LgA ekuveliseni ukuziphatha okufana nokulutha (Kawa okqhubekayo., 2016; Allain okqhubekayo., 2017, 2018; Allain & Samaha, 2018; UJames okqhubekayo., 2018; Kawa & Robinson, 2018). Nangona ubungqina bunqongophele, kwaye kufuneka umsebenzi omninzi, ubungqina obukhoyo bubonisa ukuba amava e-IntA nawo anika umva umsebenzi weDA (Calipari okqhubekayo., 2013, 2015), kubandakanywa ukukwazi kwe-cocaine ukunyusa i-DA ye-extracellular kwi vivo, njengoko kuchaziwe apha.
Ukuqukumbela, izifundo ezisebenzisa inkqubo ye-IntA zihambelana ngakumbi nombono wokuba inkuthazo ye-pathological yokufuna kunye nokuthatha i-cocaine ekukhotyokisweni kungenxa, ubuncinci ngokuyinxenye, hyper-Imeko ephendulayo ye-dopaminergic, ehambelana nombono wokukhuthaza umlutha (Robinson & Berridge, 1993; Berridge & Robinson, 2016). Ewe kunjalo, i-syndrome entsonkothileyo njengomlutha ayinakuncitshiswa kutshintsho kwinkqubo enye ye-neurotransmitter, okanye inkqubo enye yengqondo, kwaye kuya kuhlala kubonwa ukuba yeyiphi eminye imisebenzi ye-neuropsychological eguqulwa ngamava e-IntA (umz., Allain). okqhubekayo., 2017; Gueye okqhubekayo., 2018; UJames okqhubekayo., 2018). Nangona kunjalo, ubungqina obukhulayo malunga nokubaluleka kwezinto ze-pharmacokinetic ekukhuthazeni ukuphuhliswa kokulutha bubonisa ukuba oku kufuneka kuthathelwe ingqalelo ngakumbi kwiimodeli zangaphambili zokulutha (Allain). okqhubekayo., 2015).
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