Ulawulo olufutshane lwe-Cocaine kunye nokuZithiba luSensitize iimpembelelo zeCocaine kwi-Dopamine Transporter kunye nokwandisa ukufunwa kweziyobisi (2014)

Neuropsychopharmacology. I-2015 Feb; I-40 (3): 728-735.

Ipapashwe kwi-intanethi ngo-2014 Oct 8. Ipapashwe kwangaphambili kwi-intanethi 2014 Sep 12. doi: 10.1038 / npp.2014.238

PMCID: PMC4289961

Erin S Calipari,^1,² Cody A Siciliano,² UBenjamin A Zimmer,^2,³ kwaye USara R Jones^2,^*

Abstract

Nangona ii-paradigms zesiNtu zokwazisa, ezikhokelela ekwandisweni kokuziphatha kwe-cocaine-induced locomotor kunye ne-dopamine (DA) ephuphumayo kulandela iinaliti eziphindaphindiweyo ze-cocaine, zihlala zisetyenziswa njengemodeli yokufunda ukuba likhoboka leziyobisi, iziphumo ezifanayo kube nzima ukubonisa ukulandela i-cocaine. ukuzilawula. Kutshanje siye sabonisa ukuba ukufikelela kwangethuba (IntA) kwi-cocaine kunokubangela ukonyuka kwe-cocaine potency kumthuthi we-DA (DAT); nangona kunjalo, iiparadigms zokuvuselela ngokwesiko zihlala zibonisa iziphumo ezongeziweyo emva kwexesha lokurhoxa/lokuyeka. Ke ngoko, sigqibe kwelokuba ikhosi ye-IntA-induced sensitization ngokuphonononga iziphumo ze-1 okanye i-3 yeentsuku ze-IntA, kunye nexesha le-7 lokuziyeka emsebenzini we-DA, amandla e-cocaine, kunye nokomeleza. Apha sibonisa ukuba amandla e-cocaine anyuswa ngokulandelayo kangangeentsuku ezi-3 ze-IntA kwaye yongezwa ngakumbi emva kwexesha lokuyeka.

Ukongeza, i-IntA kunye nokuziyeka kuvelise ukukhutshwa okukhulu kwe-DA kubukho be-cocaine xa kuthelekiswa nawo onke amanye amaqela, ebonisa ukuba emva kokuyeka, zombini amandla e-cocaine okunyusa ukukhutshwa kwe-DA kunye nokuthintela ukufunyanwa kwi-DAT, iindlela ezimbini ezahlukeneyo zokunyusa amanqanaba e-DA, ziphuculwe. Okokugqibela, safumanisa ukuba i-IntA-induced sensitization yenkqubo ye-DA ikhokelele ekomeleleni kokusebenza kwe-cocaine, isiphumo esaye sandiswa emva kwexesha le-7 lokuziyeka. Ezi ziphumo zibonisa ukuba uvakalelo lwenkqubo ye-DA lunokuba nendima ebalulekileyo kumanqanaba okuqala okusetyenziswa gwenxa kweziyobisi kwaye kunokuqhuba ukwanda kokufunwa kwechiza kunye nokuthatha oko kubonisa inguqu yokusetyenziswa kweziyobisi okungalawulwayo. Idatha yabantu icebisa ukuba ukuphumla, ukwazisa, kunye namaxesha okuzikhwebula kunendima ebalulekileyo kwinkqubo yokuba likhoboka, iqaqambisa ukubaluleka kokusebenzisa iimodeli zangaphambi kweklinikhi ezidibanisa ezi ziganeko, kwaye icebisa ukuba iiparadigms ze-IntA zinokusebenza njengemizekelo yenoveli yokukhotyokiswa kwabantu.

INTSHAYELELO

Ukusetyenziswa kweziyobisi okuphindaphindiweyo ebantwini kuboniswe ukuba kubangele uvakalelo kwiimpawu ezixela kwangaphambili ukufumaneka kweziyobisi kunye nemiphumo yeziyobisi, ekucingelwa ukuba ziqhuba ukusetyenziswa kweziyobisi okuqhubekayo okukhokelela ekubeni likhoboka; Ke, ukuqonda inkqubo ye-neurochemical elamla ezi ziphathamandla kunokunika ukuqonda okubalulekileyo kwiindlela eziqhuba inkqubo yokulutha (UVezina kunye noLeyton, 2009). Iimodeli ze-rodent of sensitization ziye zacetyiswa ukuba zibe ngumzekelo wokuguqulela wokulutha (URobinson kunye no-Becker, 1986; Post, ngo-1980), kodwa ezi paradigms zisebenzisa iindlela ezingabonakaliyo zolawulo, kwaye i-neurochemical sensitization iye yaba nzima ukubonisa ngee-paradigms ezithintekayo, ezifana nokulawulwa kwe-intravenous self-administration, ukuba imodeli engcono yokuxhatshazwa kwabantu. Ngokomzekelo, ukuzilawula okwandisiweyo kwe-cocaine kubonakaliswe ngokuphindaphindiweyo ukunciphisa amandla e-cocaine kwi-dopamine transporter (DAT) kunye nokuvelisa ukunyamezela ukuziphatha okuhambelanayo (I-Calipari okqhubekayo, 2013a, 2013b, 2013c, 2013d; I-Calipari okqhubekayo, 2014a, 2014b; Ferris okqhubekayo, 2011, 2012, 2013a, 2013b; Oleson okqhubekayo, 2011; Ukhathazekile okqhubekayo, 1989). Iziphumo zokuziphatha kunye ne-neurochemical yokuvezwa kwe-cocaine ixhomekeke kwizinto ezininzi ezibandakanya, ukuphindaphinda kolawulo, ukuphumla, kunye nokuyeka (Jones okqhubekayo, 1996: UVezina kunye noLeyton, 2009; Bouayad-Gervais okqhubekayo, 2014; I-Calipari okqhubekayo, 2013a), ekhuthaza umsebenzi wamva nje ngokufikelela okungaphakathi (IntA) ukuzilawula ngokwakho ukujonga iziphumo ezivakalayo zecocaine (I-Calipari okqhubekayo, 2013d; igumbi okqhubekayo, 2012).

I-IntA yiparadigm yenoveli yokuzilawula ethintela ukuba i-cocaine ithathe ixesha elifutshane (imizuzu emi-5) yokufikelela rhoqo kwimizuzu engama-30 (imizuzu emi-XNUMX)igumbi okqhubekayo, 2012). I-IntA isandula kuboniswa ukuba ivelise ulwazelelelo lweziphumo ze-cocaine kwi-DAT, okokokokuqala ukuba ukuvalelwa kweziphumo ze-cocaine kwi-DAT kubonwe kusetyenziswa ulawulo olungalindelekanga.I-Calipari okqhubekayo, 2013d). Nangona lo msebenzi ubonise ukuba uvakalelo lweziphumo ze-cocaine kwi-DAT zenzeke nge-24 h kulandela i-IntA yeentsuku ezili-14, iprofayili yethutyana yezi ziphumo isaza kumiselwa. Ngaphaya koko, kwiiparadigms ze-cocaine eziziswe ngokwemveli, ukuphumla kunye nokuhluthwa yimiba ebalulekileyo yenkqubo yokwazisa, kwaye rhoqo, iimpendulo ze-cocaine ezivuselelweyo azichazwa de kube semva kwexesha lokuyeka (Pierce kunye neKalivas, i-1997; URobinson kunye no-Becker, 1986; Post, ngo-1980). Ke ngoko kunokwenzeka ukuba ukonyuka kwe-cocaine potency okwenzeka ngokukhawuleza emva kwe-IntA kunokufukama ngexesha lokuyeka.

Injongo yolu phononongo yayikukumisela iprofayile yethutyana yempembelelo ye-cocaine kwi-DAT ngexesha lamanqanaba okuqala e-IntA yokuzilawula, ukuvavanya iziphumo zexesha lokuziyeka kumandla e-cocaine kunye nokomeleza ukusebenza kwe-cocaine. Apha sibonisa ukuba iziphumo ze-IntA ekukhuthazeni zombini i-cocaine potency kunye ne-dopamine (DA) yokubonisa (I-Calipari okqhubekayo, 2013a, 2013d). Ezi ziphumo zabonwa emva nje kweentsuku ezi-3 zokuvezwa kulawulo lwe-IntA lwe-cocaine, kwaye ixesha leentsuku ezi-7 lokuziyeka libangele uvakalelo olungakumbi lweziphumo ze-cocaine. Utshintsho lwe-neurochemical lwalukhatshwa lutshintsho lwendlela yokuziphatha, apho ukonyuka kwe-IntA-eyenziwe kukuqinisa ukusebenza kwe-cocaine kuye kwaphuculwa ngakumbi emva kwexesha lokuyeka. Apha sibonisa ukuba i-IntA-induced sensitization luphawu lweziphumo ezininzi zokuziphatha kunye ne-neurochemical yokukhobokisa ebantwini, sicebisa ukuba iimodeli ze-IntA zinokusebenza njengemodeli efanelekileyo yokufunda utshintsho olwenzeka ngexesha lotshintsho lokukhobokisa kwe-cocaine.

IMPAHLA NENKQUBO

izilwanyana

Iimpuku zeMale Sprague-Dawley (375–400 g; Harlan Laboratories, Frederick, Maryland), zigcinwe kwi-12: 12 h umva umjikelo wokukhanya/umnyama (iiyure ezingama-0300 zicima izibane; iiyure eziyi-1500 zilayita) ngokutya namanzi. ad adum.

Ukuzilawula

Iimpuku zaye zafakwa i-anesthetized kwaye zafakwa kwi-catheter ye-jugular engapheliyo njengoko kuchaziwe ngaphambili (I-Calipari okqhubekayo, 2013d). Izilwanyana zazihlaliswe zodwa, kwaye zonke iiseshini zenzeke kwi-cage yasekhaya ngexesha lomjikelezo osebenzayo / omnyama (iiyure ze-0900-1500). Izilwanyana ziye zafumana i-paradigm yoqeqesho apho izilwanyana zanikwa ukufikelela kwi-fixed ratio enye (FR1) kwishedyuli ye-cocaine-paired lever, eyathi, ekuphenduleni, yaqalisa inaliti ye-cocaine ye-intravenous (0.75 mg / kg, ifakwe ngaphezulu kwe-4 s). Emva kwempendulo nganye / i-infusion, i-lever yachithwa kwaye ukukhanya kwe-stimulus kwakhanyiswa kwi-20-s timeout timeout. Iiseshoni zoqeqesho ziye zayekiswa emva kobuninzi be-20 okanye i-6 h, nokuba yeyiphi eyenzeke kuqala. Iikhrayitheriya zokufumana zibonakaliswe ngee-injection ze-20 ezilawulwa iintsuku ezimbini ezilandelelanayo kunye nezithuba ezihambelanayo ze-inter-infusion.

IntA

Ngexesha leseshini nganye ye-6-h, izilwanyana zazinokufikelela kwi-cocaine kwiindlela ze-12 zemizuzu emihlanu ezahlulwe ngamaxesha emizuzu engama-25. Ngaphakathi kweseshoni nganye ye-5-min, kwakungekho ixesha lokuphuma ngaphandle kwexesha lokunyuswa, kwaye isilwanyana sinokucinezela i-lever kwishedyuli ye-FR1 ukufumana i-1-s infusion ye-cocaine (0.375 mg / kg / inf). Izilwanyana zifumene i-1 okanye i-3 iintsuku ezilandelelanayo zokuzilawula kwe-IntA phambi kwe-voltammetry okanye i-threshold experiments. Iqela elihlukeneyo lezilwanyana liye lafumana iintsuku ze-3 zokuzilawula kwe-IntA elandelwa yi-7-day ukuziyeka ngexesha apho babengenakho ukufikelela kwi-lever self-administration.

Ulawulo

Zonke izilwanyana zafaniswa nezilwanyana ezilawulayo ezaye zenziwa utyando lwe-catheter kwaye zazihlala kwindawo efanayo kunye nezilwanyana ezizilawulayo.

I-In vitro IVoltmetry

Izilwanyana zabulawa ngenxa yovavanyo olukhawulezayo lwe-cyclic voltammetry ngentsasa elandelayo emva kweseshoni yokugqibela yokuzilawula (∼18 h), okanye ngosuku lwesixhenxe lokuziyeka. Izicubu zalungiswa njengoko kuchaziwe ngaphambili (I-Calipari okqhubekayo, 2013b; ISiciliano okqhubekayo, 2014). I-carbon fiber (i-Goodfellow Corporation, i-Coraopolis, i-PA) i-microelectrode (i-100-200 μM ubude, i-7 μM i-radius) kunye ne-bipolar evuselela i-electrode ifakwe kwi-core ye-NAc. Ukukhutshwa kwe-DA kukhutshwe yi-pulse eyodwa yombane (350 μA, 4 ms, monophasic) esetyenziswe kwi-tissue yonke i-5 min. I-DA ye-Extracellular yarekhodwa ngokusebenzisa i-waveform engunxantathu (-0.4 ukuya ku- +1.2 ukuya -0.4 V vs Ag/AgCl, 400 V/s). Nje ukuba impendulo ye-DA ye-extracellular izinzile, i-cocaine (0.03-30 μmol / l) yasetyenziswa ngokudibeneyo kwisilayi sobuchopho. Ukuvavanya i-kinetics ye-DA kunye namandla eziyobisi, amanqanaba avuselelweyo e-DA aye amodareyithwa kusetyenziswa iMichaelis-Menten kinetics. Kugxininiso lwe-cocaine-ijika lokuphendula, usetyenziso. K_m, umlinganiselo wobudlelwane obucacileyo be-DAT, wasetyenziselwa ukumisela utshintsho kwisakhono se-cocaine ukuthintela ukuthatha kwe-DA.

Ukukhusela

Kwiqela elahlukileyo lezilwanyana, inkqubo yomgubasi yayisetyenziselwa ukumisela utshintsho olwenziwe yi-IntA kulawulo lwe-cocaine. Inkqubo yomqobo yenziwa ngaphambi kwe-IntA kwaye kwakhona emva kweentsuku ezi-3 ze-IntA okanye ilandela iintsuku ezi-3 ze-IntA kunye nexesha leentsuku ezisi-7 zokuziyeka. Inkqubo ye-threshold yindlela yokuziphatha kwezoqoqosho ekuhloleni ukuthatha/ukufuna iziyobisi kunye nokomeleza ukusebenza ngempumelelo. Inkqubo ye-threshold ibandakanya ukunika iigundane ukufikelela kuluhlu oluhlayo lwe-11 yeyunithi yeedosi ze-cocaine (421, 237, 133, 75, 41, 24, 13, 7.5, 4.1, 2.4, kunye ne-1.3 μg/isitofu) ekhoyo kwishedyuli ye-FR1 okomeleza. I-dose nganye ifumaneka kwi-10 min, kunye nomgqomo ngamnye owenziwe ngokulandelelana kwiseshoni ye-110-min. Izilwanyana zenze le nkqubo ngeentsuku ze-3 ezilandelelanayo kwaye ukuphendula kwakulinganiselwe ukufumana amaxabiso asetyenzisiweyo. Ukugqitywa kwenkqubo kuvelisa i-dose yangaphakathi-iseshoni-ijika lokuphendula, eliboniswe kuMfanekiso 4a. Ngexesha lemigqomo yokuqala yenkqubo, xa idosi iphezulu, isilwanyana siyakwazi ukufumana inqanaba elikhethiweyo lokuthatha i-cocaine kunye nokuphendula okuncinci. Njengoko idosi yehliswa kuyo yonke imigqomo, isilwanyana kufuneka sandise ukuphendula ukuze sigcine ukuthathwa okungaguqukiyo, de idosi ibe sezantsi ngokwaneleyo kangangokuba amanqanaba akhethiweyo e-cocaine ayinakugcinwa kwaye ukuphendula kuyancipha. Iinguqu ekuphenduleni kwi-dose-response curve zinokuhlalutywa kusetyenziswa imigaqo yezoqoqosho yokuziphatha, njengoko kuchazwe ngezantsi.

Uhlalutyo lwezoqoqosho lokuziphatha lusetyenziselwe ukumisela iiparameters zexabiso eliphezulu elihlawulweyo (P_max) kunye nokusetyenziswa ngexabiso elinyanzeliswa kancinci (Q₀), njengoko kuchaziwe ngaphambili (Oleson okqhubekayo, 2011; U-Oleson noRoberts, ngo-2009; U-Oleson noRoberts, ngo-2012). Ngokufutshane, P_max kwaye Q₀ amaxabiso athatyathwe ngokwemathematika kusetyenziswa igophe lemfuno. Iigophe zemfuno zenziwe ngokuthatha kwesilwanyana esinye esilingana negophe kusetyenziswa i-equation: log(Q)=log(Q₀)+k × (e-α × Q₀ × C−1) (I-Hursh kunye neSilberberg, i-2008; Christensen okqhubekayo, 2008). Kule nxaki, P_max kwamiselwa ukuba ibe lixabiso leyunithi apho indawo yokuqala ephuma kuyo ithambeka lomsebenzi=−1 (UHursh noWinger, ngo-1995). Ixabiso k yayimiselwe ku-2 kuzo zonke izilwanyana, kanti Q₀ kwaye α, emele ukukhawuleza komsebenzi ekuphenduleni kwixabiso eliguqukayo, kuqikelelwa ukuba kufikeleleke ngokufanelekileyo (I-Hursh kunye neSilberberg, i-2008; Christensen okqhubekayo, 2008). La manyathelo achazwe ngokweenkcukacha apha ngezantsi.

Q₀: Q₀ ngumlinganiselo wenqanaba elikhethwa zizilwanyana lokusela icocaine. Oku kunokulinganiswa xa idosi iphezulu kwaye i-cocaine ifumaneka ngomzamo ophantsi, okanye ngexabiso elincinci elinyanzelisayo. Eli nqanaba likhethwayo lokusetyenziswa lisekwe kwimigqomo yokuqala yenkqubo ye-threshold.

P_max: Ixabiso lichazwa njengeempendulo ezikhutshwayo ukufumana i-1 mg ye-cocaine, ngoko ke njengoko idosi iyancipha kumgqomo ngamnye olandelelanayo wenkqubo ye-threshold, ixabiso liyanyuka. Njengoko iseshoni iqhubela phambili, izilwanyana kufuneka zandise ukuphendula kwi-lever esebenzayo ukuze kugcinwe ukuzinza okuzinzile. P_max lixabiso apho isilwanyana singasakhuphi iimpendulo ezaneleyo zokugcina ukutya kunye nokunciphisa ukusetyenziswa. Ngaloo ndlela, izilwanyana eziphakamileyo P_max iya konyusa ukuphendula ukugcina amanqanaba e-cocaine ekude kwidosi-yempendulo yejika; ngamanye amazwi baya kuhlawula ixabiso eliphezulu lecocaine. Umsebenzi wangaphambili ubonise ukuba P_max inxulumene kakhulu kunye namanqaku okuqhawula kwishedyuli yomlinganiselo oqhubekayo wokuqiniswa, eqinisekisa ukuba inkqubo ye-threshold ihlola ngokuchanekileyo ukuqinisa ukusebenza (Oleson okqhubekayo, 2011).

Ukubala K_i Iimilinganiselo

Iinhibition constants (K_i) zigqitywe ngokucwangcisa iiprofayili zempembelelo yomgca womgca kunye nokumisela i-slope ye-linear regression. I-K_i yabalwa ngenxaki K_m/ithambeka.

Statistics

IGraph Pad Prism (uhlobo 5, La Jolla, CA, USA) yasetyenziselwa ukuhlalutya iiseti zedatha kunye nokwenza iigrafu. Idatha inikezelwe njengentsingiselo ±SEM kunye nepesenti ngaphandle kokuba kuchazwe ngenye indlela. Isiseko sedatha yevoltammetry kunye ne-K_i ixabiso lithelekiswe kusetyenziswa uhlalutyo lwendlela enye yokwahluka (ANOVA). Xa iziphumo eziphambili zafunyanwa (P<0.05), ukungafani phakathi kwamaqela kwavavanywa ngokusebenzisa iTukey iposi uvavanyo. Ukukhutshwa kwedatha kunye nedatha efunyenwe emva kokuxutywa kwe-cocaine yayiphantsi kwe-ANOVA yeendlela ezimbini kunye neqela lovavanyo kunye nokuxinana kweziyobisi njengezinto. Umahluko phakathi kwamaqela wavavanywa kusetyenziswa iBonferroni iposi uvavanyo. Uhlalutyo lonxulumano lusetyenziselwe ukuvavanya umanyano lokukhutshwa kwe-DA kubukho bechiza kunye ne-cocaine potency, njengoko kulinganiswe ngazo zombini usetyenziso. K_m K_i. I-Pearson's coefficients yokulungelelanisa yayisetyenziselwa ukulinganisa amandla okulungelelaniswa. P_max kwaye Q₀ amaxabiso ahlalutywa kwangaphambili kunye nesithuba se-IntA sathelekiswa kusetyenziswa uMfundi odityanisiweyo t-uvavanyo. Konke p-amaxabiso e-<0.05 athathwe njengezibalo ezibalulekileyo.

IINKCUKACHA

Ukwandiswa koKhupho oluVunyiweyo lweDA kunye V_max ezilandela 3-Day IntA yongezwa yiXesha lokuzila

Indlela enye i-ANOVA ibonise isiphumo esiphambili seqela elizilawulayo ekukhutshweni okuvuselelweyo kwe-DA (F_{3, 27}= 6.17, p<0.01; Umzobo 1a). Nangona ukukhululwa akuzange kuphakanyiswe kakhulu emva kwe-1 okanye iintsuku ezi-3 ze-IntA cocaine self-administration, Tukey iposi Uhlalutyo lubonise ukuba ukukhutshwa okukhuthazwayo kuye kwaphakanyiswa emva kwe-IntA yeentsuku ze-3 kunye nexesha le-7 lokuziyeka xa kuthelekiswa nolawulo (q= 5.24, p<0.01), usuku olu-1 lwe-IntA (q= 4.99, p<0.01) kunye neentsuku ezi-3 ze-IntA (q= 4.16, p<0.05).

Umzobo 1

Ukufikelela okwethutyana (IntA) ukuzilawula kwe-cocaine kuguqula i-presynaptic dopamine system kinetics. (a) Ukukhutshwa kwe-dopamine (DA) kwi-μM phakathi kwamaqela. Izilwanyana ziye zazilawula ngokwazo kwi-IntA cocaine kangangeentsuku ezi-1 okanye ezi-3. Iqela elinye lanikwa ...

Indlela enye i-ANOVA ibonise isiphumo esiphambili seqela elizilawulayo V_max (F_{3, 27}= 11.24, p<0.0001; Umzobo 1b). Tukey iposi Uhlalutyo lubonise ukuba iqondo eliphezulu lokuthatha liye laphakanyiswa kwiqela le-IntA leentsuku ezi-3 xa kuthelekiswa nolawulo (q= 4.85, p<0.05) kunye nosuku olu-1 lwe-IntA (q= 4.31, p<0.05). Ngaphaya koko, ixesha lokuzila iintsuku ezisi-7 lilandela ixesha leentsuku ezi-3 zokuzilawula libangele ukwanda kokuthatha ngokumalunga nolawulo (q= 6.83, p<0.001) kunye nosuku olu-1 lwe-IntA (q= 6.37, p<0.001), nangona kunjalo, ukuthathwa kwakungahlukanga kakhulu kwiqela le-3-day self-administration elingenalo ixesha lokuziyeka.

Ukonyuka kwamandla e-Cocaine emva kwe-IntA yeentsuku ezi-3 yongezwa ngakumbi yiXesha leentsuku ezisi-7

Amanyathelo amabini aphindaphindiweyo i-ANOVA ibonakalise eyona mpembelelo iphambili yembali yokuzilawula kwi-cocaine potency (F_{4, 100}= 12.68, p<0.001; Umzobo 2a). Nangona kwakungekho mahluko ubalulekileyo phakathi kwe-1 yosuku lwe-IntA kunye nezilwanyana zokulawula, iBonferroni iposi Uhlalutyo lubonise ukuba ukuzilawula kwe-IntA ye-cocaine yeentsuku ezi-3 kubangele ukonyuka kwe-cocaine potency xa kuthelekiswa nezilwanyana zokulawula kwi-10 μM (t= 2.93, p<0.05) kunye ne-30 μM (t= 5.54, p<0.001) ugxininiso. Ukongeza, ukuzilawula kwe-IntA ye-cocaine yeentsuku ezi-3 kubangele ukonyuka kwe-cocaine potency xa kuthelekiswa nezilwanyana zosuku lwe-1 ze-IntA kwi-10 μM (t= 3.53, p<0.01) kunye ne-30 μM (t= 6.11, p<0.001) ugxininiso. Izilwanyana eziye zafumana ukuzilawula kwe-IntA ye-cocaine yeentsuku ezi-3, kunye nexesha leentsuku ezi-7 zokuziyeka zonyuse amandla e-cocaine xa kuthelekiswa nezilwanyana zokulawula kwi-10 μM (t= 4.60, p<0.001) kunye ne-30 μM (t= 11.44, p<0.001) ugxininiso; Izilwanyana ze-IntA zosuku olu-1 kwi-10 μM (t= 4.39, p<0.001) kunye ne-30 μM (t= 10.64, p<0.001) ugxininiso; kunye nezilwanyana zeentsuku ezi-3 ze-IntA kwi-30 μM (t= 5.35, p<0.001) ukugxila.

Umzobo 2

Ukufikelela okwethutyana (IntA) ukuzilawula kwakho kubangela uvakalelo kwiziphumo ze-neurochemical ye-cocaine. (a) Icocaine eyongezelekayo (0.3–30 μM) ithamo-igophe lokuphendula kwizilayi eziqulethe undoqo we-nucleus accumbens. Cocaine ...

K_i ngumlinganiselo woxinaniso lweziyobisi olunciphisa ukunyuswa ukuya kwi-50% yexabiso layo elingenakunqandwa; ngoko ke ukuncipha kwe K_i lubonisa ukwanda kwamandla. Indlela enye i-ANOVA iveze isiphumo esibalulekileyo seqela ku-K_i (F_{3, 28}= 13.96, p<0.0001; Umzobo 2b). Tukey iposi Uhlalutyo lwabonisa ukuba uK_i yancitshiswa kwiqela le-IntA leentsuku ezi-3 ngokunxulumene nolawulo (q= 5.58, p<0.01) kunye ne-IntA yosuku olu-1 (q= 4.18, p<0.05). Ithuba leentsuku ezisi-7 lokuzila ukutya libangele ukuhla okungaphezulu kwe-K_i ngokunxulumene nolawulo (q= 8.09, p<0.001) kunye ne-IntA yosuku olu-1 (q= 6.88, p<0.0001).

Ukonyuka kweCocaine-Indused kuKhupho lwe-DA kuyaphuculwa emva kwe-IntA kunye nokuyeka

Ukongeza ekumiseleni iziphumo ze-cocaine ngokuthe ngqo kwi-DAT elandela i-IntA kunye nokuyeka, siye savavanya iziphumo zokuzilawula kwe-cocaine kunyuso olubangelwa yi-cocaine ekukhutshweni okuvuselelweyo kwe-DA kumbindi we-NAc. Indlela ezimbini i-ANOVA iveze eyona mpembelelo iphambili yokuxinana kwecocaine ekukhutshweni okuvuselelweyo kwe-DA (F_{5, 26}= 38.31, p<0.001; Umzobo 3a). Ukongeza, bekukho isiphumo esiphambili sembali yokuzilawula kwakho ekukhutshweni okuvuselelweyo kweDA (F_{3, 26}= 7.19, p<0.001). Bonferroni iposi Uhlalutyo lubonakalise ukonyuka okubonakalayo kokunyuka okubangelwa yi-cocaine ekukhutshweni kwe-DA kulandela i-IntA kunye nokuyeka ukuya kwi-0.3 (p<0.001), 1 (p<0.001), 3 (p<0.001), kunye ne-10 μM (p<0.001) ugxininiso xa kuthelekiswa nezilwanyana zokulawula. Ukongeza, kukho ukonyuka kokukhutshwa kwe-cocaine eyenziwe yi-cocaine kulandela i-IntA kunye nokuziyeka xa kuthelekiswa ne-IntA yosuku olu-1 lokuzilawula kwi-0.3 (p<0.05), 1 (p<0.01), 3 (p<0.05), kunye ne-10 μM (p<0.05) ugxininiso. Okokugqibela, kukho ukonyuka kokukhutshwa kwe-cocaine eyenziwe yi-cocaine kulandela i-IntA kunye nokuziyeka xa kuthelekiswa ne-3 yeentsuku ze-IntA kwi-0.3 (p<0.05), 1 (p<0.01), kunye ne-3 μM (p<0.01) ugxininiso. Ngaphaya koko, bekukho unxibelelwano olubalulekileyo-nolawulo lwesiqu sakho (F_{15, 26}= 7.19, p<0.05).

Umzobo 3

Ukukhutshwa kwe-dopamine yeziyobisi (DA) kuyaphuculwa emva kokufikelela okuphakathi (IntA) kunye nokuyeka. (a) Ukukhutshwa okuvuselelweyo kwe-DA, kulinganiswe kuzo zonke izigxina ze-cocaine zolawulo, i-IntA yosuku lwe-1, i-IntA yosuku lwe-3, kunye ne-3 yosuku lwe-IntA kunye nexesha le-7 lokuziyeka. ...

I-Cocaine Potency ayinxulumananga neMilinganiselo yokuKhupha

Ukuze siqinisekise ukuba iyantlukwano ekukhululweni okuvuselelweyo ibingaqhubeki utshintsho olwenziwe yi-IntA kwi-cocaine potency kwi-DAT, sanxibelelanisa ukukhutshwa kwe-DA kubukho be-cocaine kunye no-K._i (Umzobo 3b). Sifumene ukuba ukukhutshwa okuvuselelweyo kubukho be-cocaine akuzange kuhambelane nokuthintelwa kokuthatha (Ulawulo, r=−0.48, NS; Ngeentsuku ezi-1, r=−0.55, NS; Kwiintsuku ezi-3, r=0.07, NS; Ngeentsuku ezi-7 zokuphumla, r=0.06, NS), ebonisa ukuba ubukhulu bokukhutshwa okukhutshiweyo ayisiyonto ebalulekileyo echaphazela inhibition yokuthatha kunye nokuba zombini ziyiziganeko ezihlukeneyo.

Ukonyuka koQiniso lokuSebenza kweCocaine kulandela i-IntA yongezwa emva kweXesha leentsuku ezisi-7

Ukumisela iziphumo ze-IntA-induced sensitization yenkqubo ye-DA kunye ne-cocaine potency ekomelezeni ukusebenza kwe-cocaine, iqela elahlukileyo lezilwanyana lenze inkqubo yomgubasi ngamaxesha amabini, kanye emva kokufunyanwa kwe-cocaine yokuphendula (Umzobo 4a, indawo yolawulo yasekhohlo, isilwanyana esimeleyo) kwaye kwakhona kulandela nokuba ziintsuku ezi-3 ze-IntA iyodwa okanye iintsuku ezi-3 ze-IntA kunye nexesha leentsuku ezisi-7 zokuziyeka (Umzobo 4a, iphaneli yasekunene, isilwanyana esimeleyo). Kwiqela le-IntA leentsuku ezi-3, loMfundi t-uvavanyo lubonakalise ukwanda okukhulu P_max iposi ye-IntA xa ithelekiswa nesiseko (t₉= 2.21, p<0.05; Umzobo 4b), ebonisa ukuba i-IntA yonyusa ukuqinisa ukusebenza kwe-cocaine. Ngokufanayo, uMfundi t-uvavanyo lubonakalise ukwanda okukhulu P_max emva kweentsuku ezi-3 ze-IntA kunye neentsuku ezisi-7 zokuyeka ukulala (t₆= 3.11, p<0.05; Umzobo 4c). Ukongeza, uMfundi t-Uvavanyo lubonakalise ukuba ukwanda kwe P_max Yayinkulu kakhulu kwiqela lokuziyeka leentsuku ezi-7, nto leyo ebonisa ukuba ukwanda kwe-IntA-induced ekomelezeni ukusebenza kwe-cocaine yokwandisa ixesha lokuziyeka (t₁₅= 2.25, p<0.05; Umzobo 4d).

Umzobo 4

Ukomelezwa kweCocaine kwandiswe kukufikelela kwangethuba (IntA) kwaye kuphuculwe ngakumbi ngokuziyeka. Iziphumo ze-IntA yeentsuku ezi-3 kunye neentsuku ezi-3 ze-IntA kunye neentsuku ezisi-7 zokuziyeka P_max (b-d) kunye nokusetyenziswa kwe-cocaine ngexabiso elincinci elinyanzelisayo (Q₀; e–g) ...

Ukusetyenziswa kwe-Cocaine kuyancitshiswa emva kwe-IntA kunye nokuyeka

Ukongeza ekumiseleni ukuqinisa ukusebenza kwe-cocaine, inkqubo ye-threshold nayo iyalinganisa Q_0, umlinganiselo wokusetyenziswa. Kwiqela le-IntA leentsuku ezi-3, akukho tshintsho Q₀ (Umzobo 4e), ebonisa ukuba nangona i-IntA inyuka P_max, ayitshintshi idosi ekhethiweyo ukuba isilwanyana siya kudla. Ngapha koko, yoMfundi t-uvavanyo lubonakalise ukuhla okukhulu Q₀ (t₆= 3.80, p<0.01; Umzobo 4f) kulandela iintsuku ezi-3 ze-IntA kunye neentsuku ezisi-7 zokuzila. Ukuthelekisa phakathi kweqela kubonise ukuba izilwanyana ezinikwe ixesha le-7 lokuziyeka zibonise ukunciphisa okukhulu Q₀ kunezilwanyana ze-IntA ngaphandle kokuzibamba (t₁₃= 1.78, p<0.05; Umfanekiso 4g). Kuye kwaboniswa ngaphambili ukuba xa ichiza lifumaneka kwimfuno ephantsi yempendulo, izilwanyana zilinganisa umthamo wazo owuthathayo ujikeleze inqanaba le-cocaine yengqondo ekhethwayo, ekucingelwa ukuba imiselwe ziziphumo ezizimeleyo zekhompawundi. Ngenxa yokuba iziphumo ze-cocaine zixhomekeke kwinkqubo ye-DA, uvakalelo lweziphumo ze-cocaine kwi-DA neurotransmission kubangela ukuba izilwanyana zijikeleze kwinqanaba elisezantsi.

Ngokudibeneyo, ezi datha zibonisa ukuba i-IntA iguqula iipropathi zokuqinisa i-cocaine ngokubhekisele kuzo zombini inkuthazo kunye nokusetyenziswa, kwaye ubungakanani bezi ziphumo buphuculwe lixesha lokurhoxa.

UKUQALA

Olu phononongo lubonisa ukuba ukuzilawula kwe-cocaine okwethutyana kubangela utshintsho olwahlukileyo lwe-neurochemical olungachaphazeli kuphela ukusebenza kwenkqubo ye-DA kodwa kunye namandla kunye nokomeleza ukusebenza kwe-cocaine. Kubekho umsebenzi omninzi ojolise ekulungelelaniseni ukuzilawula kweempuku kunye ne-pathology yabantu, kubandakanya ukunyuka, ukuphendulwa kwesohlwayo, kunye nokuphela / ukubuyisela / ukuphinda ubuyele kwi-paradigms (U-Ahmed noKoob, i-1999, 1998; Jonkman okqhubekayo, 2012; UShamham okqhubekayo, 2003). Apha siqaqambisa ukubaluleka kweprofayile yethutyana yokuzilawula kwe-cocaine kunye nokuqwalaselwa kwamaxesha okuziyeka xa ukhetha imodeli efanelekileyo yokuguqulela, njengoko iindlela zembuyekezo ezinxulumene nokuvezwa kweziyobisi zixhomekeke kakhulu kuzo zombini iipateni zokuzilawula kunye nokurhoxa. Kuba iimodeli zeempuku azikwazi ukubandakanya yonke imiba yokukhotyokiswa kweziyobisi ebantwini, kubaluleke kakhulu ukukhetha iimodeli ezibonisa ngokuchanekileyo imiba ecacileyo yeenkqubo. Iipateni ezingapheliyo zokuzilawula kwe-cocaine luphawu lweepatheni zokuthatha komntu kwaye imodeli ye-IntA ibonelela ngeparadigm yenoveli yezifundo ezinokubakho malunga nokwazisa okwenzeka ngaphakathi kwenkqubo yokuba likhoboka lomntu.

Kumsebenzi wethu wangaphambili, kwaye uninzi lwangoku olusamkelayo iimodeli zolawulo lwe-cocaine, ugxininiso lubekwe ekwandiseni umthamo wesilwanyana, ngengcinga yokuba ukuthathwa okuninzi kukhokelela kwiziphumo ezingaphezulu ze-neurochemical kunye neemodeli ezichaneke ngakumbi iprofayili yokusetyenziswa kakubi kwe-cocaine yomntu. Apha sibonisa ukuba akunjalo, njengoko kuphezulu, ukungenisa ngokuqhubekayo akuyomfuneko ukuvelisa iziphumo ezinamandla ze-neurochemical. Uvakalelo lwe-cocaine potency kwi-DAT, ebonwe kuphononongo lwangoku, luchasene nokuhla okubhalwe kakuhle kumandla e-cocaine emva kokuzilawula okwandisiweyo kwe-cocaine (Ukhathazekile okqhubekayo, 1989; Ferris okqhubekayo, 2011, 2012, 2013a, 2013b; I-Calipari okqhubekayo, 2013c, 2013d; I-Calipari okqhubekayo, 2014a) kwaye icebisa ukuba i-cocaine iyasebenza ngakumbi ekuphakamiseni i-DA kumbindi we-NAc emva kokusetyenziswa okufutshane, kwaye ixesha lokuyeka ukuya kwandisa iziphumo. Undoqo we-NAc ubandakanyeka ekubuyiselweni kweziyobisi ezifuna emva kwamaxesha okuziyeka (Millan okqhubekayo, 2011), kunye nokwanda kwe-cocaine potency kulo mmandla kunokukhuthaza ukunyuka okuvuzayo kunye nokomeleza iziphumo ze-cocaine, ezinokukhokelela kumngcipheko omkhulu wokunyanzeliswa okanye ukukhobokisa okufana ne-cocaine. Ewe, sibonisa ukuba inkuthazo yokuzilawula i-cocaine yonyuka kakhulu kulandela i-IntA. Ke, kunokwenzeka ukuba ukusetyenziswa okwethutyana kwe-cocaine ebantwini kukhokelela kwimpendulo ye-cocaine ekhuthazayo ekhuthaza inguqu ekusetyenzisweni okuzinzileyo kunye nokuba likhoboka.

Kuye kwacetyiswa ukuba abantu basebenzise i-cocaine ngendlela ephazamisayo, endaweni yokugcina amanqanaba azinzileyo, egxininisa ukubaluleka kokumisela i-neurochemical kunye nemiphumo yokuziphatha yemiphumo ye-cocaine xa ilawulwa ngendlela efanayo (Ibeveridge okqhubekayo, 2012). Iimodeli zangaphambili zeklinikhi zokukhotyokiswa kwe-cocaine usebenzisa iiparadigms zokuzilawula zixhomekeke ekufikeleleni ixesha elide kwi-cocaine kwiintsuku ezininzi. Ukunyuka ngexesha lokufikelela ixesha elide (LgA) ukuzilawula kudala kwamiselwa ukuba kufane nokutshintsha ukusuka ekusebenziseni iziyobisi kukuzonwabisa (UKoob noLe Moal, i-1997). Nangona kunjalo, ukutya okuzinzileyo kwe-cocaine okudityaniswa ne-LgA kunokungabonisi ngokuchanekileyo iipatheni zokuthatha komntu kwaye kuvelise iziphumo ezichasene ne-neurochemical, xa kuthelekiswa ne-IntA (I-Calipari okqhubekayo, 2013a). Apha sibonisa ukuba IntA ngeentsuku ezi-3 kuphela yayanele ukunyusa zombini amazinga okuthathwa kunye nokukwazi kwe-cocaine ukunqanda i-DAT. I-IntA iphinde yavelisa ukonyuka okuhambelanayo nokomeleza ukusebenza kwe-cocaine, icebisa ukuba ukusetyenziswa kwe-cocaine okungapheliyo kuqhuba ukusetyenziswa kweziyobisi okulandelayo, oko kunokubangela inkqubo ekhokelela ekubeni likhoboka. Oku kufunyanisiweyo, kudityaniswe nenkuthazo eyongeziweyo yokulawula i-cocaine emva kweentsuku ezi-7 zokurhoxa, icebisa ukuba izilwanyana ziba nobuntununtunu kwiziphumo ze-cocaine ngokubanzi kulandela i-IntA kunye nokurhoxa. Amandla e-cocaine eyongeziweyo kwi-NAc kusenokwenzeka ukuba aqhube ukomeleza ukomeleza ukusebenza kwe-cocaine kulandela i-IntA. Ewe, apha sibonisa ukuba ngamaxesha apho amandla e-cocaine anyuswa, P_max, umlinganiselo wokomeleza ukusebenza kakuhle, ukwandiswa. Ngapha koko, ngenxa yokuba umzamo isilwanyana sikulungele ukuchitha ukufumana ichiza (P_max) ukunyuka ngexesha lokuhoxiswa, olu hlengahlengiso lunokuba nendima ekubuyiseleni kwakhona emva kwexesha elongezelelweyo lokuziyeka.

Ngokubhekiselele ekubuyeleni, ukusetyenziswa okuphakamileyo kwe-cocaine ixesha elide akudli ngokubonwa kwiziyobisi ze-cocaine, kodwa endaweni yoko, abasebenzisi be-cocaine bajikeleza phakathi kwexesha eliphindaphindiweyo lokusetyenziswa kakubi kwe-cocaine elandelwa kukuyeka kunye nokuphinda ubuyele (Cohen noSas, ngo-1994). Le patheni yokusetyenziswa igxininisa ukubaluleka kokuqonda utshintsho lwe-neurochemical olwenzeka ngexesha lokurhoxiswa. I-IntA elandelwa lixesha le-7 leentsuku zokuziyeka kubangele uvakalelo olungakumbi (1) i-cocaine-induced augmentation yokukhululwa kwe-DA, (2) i-cocaine potency kwi-DAT, kunye (3) nokuqinisa ukusebenza kwe-cocaine, xa kuthelekiswa ne-IntA yodwa. . Iziphumo ze-cocaine ekukhutshweni kwe-DA ezikhutshiweyo azinxulumananga notshintsho ekuthinteleni ukuthatha, njengoko kubonisiwe kukungabikho konxibelelwano phakathi kwala manyathelo mabini. Ukonyuka okubangelwa yi-Cocaine ekukhutshweni kwe-DA kubonisiwe ngaphambili ukuba kwenzeke ngendlela exhomekeke kwi-synapsin, kwaye izimeleyo kubuchule be-cocaine bokuthintela i-DAT (Venton okqhubekayo, 2006). Apha sibonisa ukuba i-IntA yongeza zombini iziphumo ze-cocaine kwi-DAT kunye neziphumo zayo ekukhutshweni kwe-DA exocytotic, kunye nokukhululwa kwe-cocaine-induced kunye nokuphuculwa kwe-inhibition enokuthi isebenze ngokubambisana ukunyusa amanqanaba e-DA kunye nokuqhubela phambili inkuthazo eyongeziweyo yokulawula i-cocaine ngeli xesha. . Iziphumo zexesha lokurhoxa kwi-cocaine ye-neurochemical kunye neziphumo zokuziphatha ziyahambelana nabaninzi kwi vivo Izifundo, ezibonisa ukuba i-cocaine ye-cocaine sensitization paradigms kunye namaxesha okurhoxisa / ukuziyeka kubangela ukwanda kwe-DA evuselelayo kunye ne-cocaine-induced DA njengoko ilinganiswe yi-microdialysis.IKalivas kunye neDuffy, 1993; Iiparsons kunye nezoBulungisa, i-1993; URobinson kunye no-Becker, 1982; URobinson okqhubekayo, 1988). Ngaphaya koko, siye sabona ukomelezwa kwe-cocaine elandela i-IntA kunye nokurhoxa, kwaye kunokwenzeka ukuba utshintsho kwi-cocaine potency kunye nokwanda kwe-cocaine-induced ekukhutshweni kwe-DA okukhutshiweyo kunokuguqula ukuqhuba iziphumo zokuqinisa i-cocaine kunye nokubuyela umva emva kokurhoxa.

Ebantwini, imbali yokusetyenziswa gwenxa kweziyobisi imiselwe ukuba inxulunyaniswe nokusebenza okukhulu kwe-ventral striatum ngeempawu ezinxulumene neziyobisi, kwaye ixesha lokusetyenziswa gwenxa kweziyobisi lihambelana ngokufanelekileyo nobukhulu bokusebenza (Prisciandaro okqhubekayo, 2014). Apha sibonisa ukuba ukulandela imbali yeentsuku ezi-3 zokuzilawula kwe-IntA cocaine, ukukhutshwa kwe-DA akuzange kutshintshe. Nangona kunjalo, ixesha leentsuku ezi-7 zokuziyeka emva kwe-IntA ibangele ukukhululwa kwe-DA okwandisiweyo, ngokungabikho kwe-cocaine, xa kuthelekiswa nolawulo. Ukukhutshwa okwandisiweyo kwe-DA kunokwalatha ekonyukeni kwephuli ye-DA enokukhutshelwa, enokuphucula ukukhululwa ngexesha lemisitho yokubonisa i-phasic. Ukonyuka kokukhululwa ngexesha lokudubula kwe-phasic DA neuron ekuphenduleni isivuseleli kwindalo kunokukhokelela ekuphuculweni kobudlelwane bomvuzo we-cue, kwaye kube lula ukuphinda ubuyele emva kwamaxesha okuziyeka (Ostlund okqhubekayo, 2014).

Lo msebenzi ugxininisa ukubaluleka kokukhetha imodeli efanelekileyo yeklinikhi kunye nenguqulelo kwimiba ethile yokusetyenziswa gwenxa kweziyobisi. Nangona i-LgA inokusebenza njengemodeli engcono yonyamezelo olukhula emva kokutya okungapheliyo kwe-cocaine ebantwini, iimodeli ezingcono ze-IntA zokwazisa imiba ekhuthazayo yokusetyenziswa gwenxa kweziyobisi, kunye neempendulo ezivakalayo kwizityholo zokuqikelela ukufumaneka kweziyobisi. Zithathiwe kunye, ezi datha zibonisa ukuba ukuphumla kunye nokurhoxa kunendima ebalulekileyo ekumiseleni i-neurochemical kunye neziphumo zokuziphatha zokuzilawula kwe-cocaine. Kucetyiswa ukuba ebantwini, ukusetyenziswa kweziyobisi kwenzeka phantsi kweemeko zokufumaneka okulinganiselweyo, ezinokuthi zikhokelele abantu ukuba basebenzise ichiza ngokwepatheni ephakathi (Ahmed okqhubekayo, 2013), noncwadi lwabantu olukhoyo luyazixhasa ezi ngxelo. Ngaphaya koko, i-neurochemical kunye neziphumo zokuziphatha ze-cocaine ebantwini ziyavuselelwa ixesha elide, ukuya kuthi ga kwiminyaka, kulandela ukusetyenziswa kakubi kweziyobisi, kwaye kucingelwa ukuba ziqhuba imijikelo engapheliyo yokuphinda ubuyele kunye nolawulo lweziyobisi oluphawu lokukhotyokiswa okuvuselelayo (Prisciandaro okqhubekayo, 2014). Ke, ngenxa yokuba iprofayili yethutyana yolawulo lwe-cocaine kunye namaxesha okuziyeka ineziphumo ezinzulu kwi-neurochemical kunye neziphumo zokuziphatha zolawulo lwe-cocaine, iimodeli zokusetyenziswa kakubi kwe-cocaine kufuneka zizame ukuthathela ingqalelo ngokuchanekileyo iipatheni zolawulo lwe-cocaine ngabantu abasebenzisa i-cocaine. Ngokudibeneyo, idatha yomntu ibonisa ukuba ukuphumla, ukwazisa, kunye namaxesha okuziyeka kunye nokubuyela umva ayaguquka ukuqhubela phambili inkqubo yokulutha, iqaqambisa ukubaluleka kokuthathela ingqalelo le miba ekumiseleni eyona modeli ibalulekileyo yokuguqulelwa kwangaphambili.

INKXASO-MALI NOKUBHELWA

Lo msebenzi uxhaswe ngemali yezibonelelo ze-NIH R01 DA024095, R01 DA030161, R01 DA014030, P50 DA006634 (SRJ), T32 DA007246 kunye ne-F31 DA031533 (ESC), kunye ne-T32 AAA007565. Ababhali babhengeza ukuba akukho kungqubana kwemidla.

Imibulelo

Sithanda ukubulela uGqr Amanda Gabriele ngoncedo lwakhe ngezifundo zokuzilawula kwi-manuscript yangoku.

Ucaphulo

Ahmed SH, Koob GF. Inguqu ukusuka kokumodareyitha ukuya nokufumana kakhulu iziyobisi: utshintsho kwincopho ye-hedonic. Inzululwazi. I-1998; 282: 298-300. [PubMed]
Ahmed SH, Koob GF. Ukonyuka okuhlala ixesha elide kwindawo emiselweyo yokuzilawula kwe-cocaine emva kokunyuka kweempuku. I-Psychopharmacology (Berl) 1999; 146: 303-312. [PubMed]
U-Ahmed SH, uLenoir M, uGuillem K. I-Neurobiology yokulutha ngokuchasene nokusetyenziswa kweziyobisi eqhutywa kukungabikho kokuzikhethela. Curr Opin Neurobiol. 2013;23:581–587. [PubMed]
Beveridge TJR, Wray P, Brewer A, Shapiro B, Mahoney JJ, Newton TF. Ukuhlalutya iCocaine yoMntu iSebenzisa iipateni ukwazisa uPhuhliso lweModeli yokuXhasa iZilwanyana. Kupapashelwe iNtlanganiso yoNyaka yoXhomekeko lweZiyobisi kwiKholeji. Palm Springs, CA; 2012.
Bouayad-Gervais K, Minogianis EA, Lévesque D, Samaha AN. Ngo-2014Ulawulo lwe-cocaine oluziswa ngokukhawuleza lukhuthaza ukwanda kwenkuthazo yokuthatha ichiza: iminikelo yamanqanaba angaphambili okuphendula kunye nokuthatha i-cocaine Psychopharmacology (Berl) (kumaphephandaba). [PubMed]
Calipari ES, Beveridge TJ, Jones SR, Porrino LJ. Ukuzingisa ukuncipha komsebenzi osebenzayo wemimandla yengqondo ye-limbic kulandela ukufikelela okwandisiweyo kokuzilawula kwe-cocaine. I-Eur J Neurosci. 2013;38:3749–3757. [Inkcazelo yamahhala ye-PMC] [PubMed]
Calipari ES, Ferris MJ, Caron MG, Roberts DC, Jones SR. Ukuzilawula kweMethylphenidate kwandisa amandla kunye nokomeleza iziphumo zabakhuphi ngokusebenzisa indlela yokuthutha i-dopamine. Nat Commun. 2013;4:2720. [Inkcazelo yamahhala ye-PMC] [PubMed]
Calipari ES, Ferris MJ, Melchior JR, Bermejo K, Salahpour A, Roberts DC, et al. I-Methylphenidate kunye ne-cocaine yokuzilawula ngokwayo ivelisa utshintsho olwahlukileyo lwe-dopamine. Umlutha weBiol. 2014;19:145. [Inkcazelo yamahhala ye-PMC] [PubMed]
Calipari ES, Ferris MJ, Roberts DCS, Jones SR. Ukufikelela okwandisiweyo ukuzilawula kwe-cocaine kubangela unyamezelo kwi-dopamine-ephakamisa kunye ne-locomotor-evuselela iziphumo ze-cocaine. J Neurochem. 2013;128:224–232. [Inkcazelo yamahhala ye-PMC] [PubMed]
Calipari ES, Ferris MJ, Siciliano CA, Jones SR. Ukuzilawula kwe-cocaine okwethutyana kuvelisa uvakalelo lweziphumo ezivuselelayo kumthuthi we-dopamine. J Pharmacol Exp Ther. 2014;349:192–198. [Inkcazelo yamahhala ye-PMC] [PubMed]
Calipari ES, Ferris MJ, Zimmer BA, Roberts DCS, Jones SR. Ipateni yexeshana yokuthatha i-cocaine imisela unyamezelo ngokuchasene novelwano lweziphumo ze-cocaine kumthuthi we-dopamine. Neuropsychopharmacology. 2013;38:2385–2392. [Inkcazelo yamahhala ye-PMC] [PubMed]
Christensen C, Silberberg A, Hursh S, Huntsberry M, Riley A. Ixabiso elibalulekileyo le-cocaine kunye nokutya kwiigundane: iimvavanyo zemodeli ye-exponential yemfuno. I-Psychopharmacology. 2008;198:221–229. [PubMed]
Cohen Peter, Sas Arjan. Ukusetyenziswa kwe-cocaine e-Amsterdam kwi-nondeviant subcultures. I-Addict Res. 1994;2:71–94.
Ferris MJ, Calipari ES, Mateo Y, Melchior JR, Roberts DC, Jones SR. Ukuzilawula kwe-Cocaine kuvelisa ukunyamezela kwe-pharmacodynamic: iziphumo ezihlukeneyo kumandla we-dopamine transporter blockers, abakhuphi, kunye ne-methylphenidate. Neuropsychopharm. 2012;37:1708–1716. [Inkcazelo yamahhala ye-PMC] [PubMed]
Ferris MJ, Calipari ES, Melchior JR, Roberts DC, España RA, Jones SR. Ukunyamezela okumangalisayo kwi-cocaine emva kokuva ubunzima bokuqala kwizilwanyana ezisebenzisa iziyobisi. I-Eur J Neurosci. 2013;38:2628–2636. [Inkcazelo yamahhala ye-PMC] [PubMed]
Ferris MJ, Calipari ES, Yorgason JT, Jones SR. Ukuphonononga umgaqo ontsonkothileyo kunye neplastiki eyenziwe ngeziyobisi yokukhutshwa kwe-dopamine kunye nokuthathwa kusetyenziswa i-voltammetry kwizilayi zobuchopho. I-ACS Chem Neurosci. 2013;4:693–703. [Inkcazelo yamahhala ye-PMC] [PubMed]
Ferris MJ, Mateo Y, Roberts DC, Jones SR. Abathuthi be-dopamine abangeva ngeCocaine ngothutho lwesubstrate olungaguqukiyo oluveliswe kulawulo lwesiqu sakho. I-Biol Psychiatry. 2011;69:201–207. [Inkcazelo yamahhala ye-PMC] [PubMed]
I-Hurd YL, i-Weiss F, i-Koob GF, kunye ne-NE, i-Ungerstedt U. I-Cocaine yokuqinisa kunye ne-extracellular dopamine ephuphumayo kwi-nucleus accumbens ye-rat-i kwi vivo Uphononongo lweMicrodialysis. Ubuchopho Res. 1989;498:199–203. [PubMed]
Hursh SR, Silberberg A. Imfuno yezoqoqosho kunye nexabiso elibalulekileyo. I-Psychol Rev. 2008; 115: 186-198. [PubMed]
Hursh SR, Winger G. Imfuno eqhelekileyo yamachiza kunye nezinye iziqinisekiso. J Exp Anal Behav. 1995;64:373–384. [Inkcazelo yamahhala ye-PMC] [PubMed]
Jones SR, Lee TH, Wightman RM, Ellinwood EH. Iziphumo zolawulo olungenasiphelo kunye noluqhubekayo lwe-cocaine ekukhululweni kwe-dopamine kunye nommiselo wokuthathwa kwi-striatum: in vitro uvavanyo lwevoltammetric. I-Psychopharmacology (Berl) 1996; 126: 331-338. [PubMed]
Jonkman S, Pelloux Y, Everitt BJ. Iindima ezahlukeneyo ze-dorsolateral kunye ne-midlateral striatum ekufuneni i-cocaine. J Neurosci. 2012;32:4645–4650. [PubMed]
I-Kalivas PW, uDuffy P. Ixesha lexesha le-dopamine ye-extracellular kunye ne-sensitization yokuziphatha kwi-cocaine. I. Iitheminali ze-axon zeDopamine. J Neurosci. 1993;13:266–275. [PubMed]
I-Koob GF, i-Le Moal M. Ukuxhatshazwa kweziyobisi: dysregulation ye-hedonic homeostatic. Inzululwazi. I-1997; 278: 52-58. [PubMed]
Millan EZ, Marchant NJ, McNally GP. Ukuphela kokufuna iziyobisi. Behav Brain Res. 2011;217:454–462. [PubMed]
Oleson EB, Richardson JM, Roberts DC. Inoveli ye-IV ye-cocaine yokuzilawula ngokwakho kwiimpuku: iziphumo ezahlukileyo ze-dopamine, i-serotonin, kunye nonyango lwangaphambili lwechiza le-GABA ekusebenziseni i-cocaine kunye nexabiso eliphezulu elihlawulweyo. I-Psychopharmacology (Berl) 2011; 214: 567-577. [Inkcazelo yamahhala ye-PMC] [PubMed]
Oleson EB, Roberts DC. Uvavanyo lokuziphatha loqoqosho lwexabiso kunye nokusetyenziswa kwecocaine kulandela iimbali zokuzilawula ezivelisa ukonyuka komlinganiselo wokugqibela okanye ukutya. Neuropsychopharmacology. 2009;34:796–804. [Inkcazelo yamahhala ye-PMC] [PubMed]
Oleson EB, Roberts DC. Ukuzilawula kwe-Cocaine kwiigundane: iinkqubo ze-threshold. Iindlela Mol Biol. 2012;829:303–319. [PubMed]
Ostlund SB, Leblanc KH, Kosheleff AR, Wassum KM, Maidment NT. I-Phasic mesolimbic dopamine signing ifaka ikhowudi yokukhuthaza inkuthazo eveliswa kukubonakaliswa okuphindaphindiweyo kwe-cocaine. Neuropsychopharmacology. 2014;39:2441–2449. [Inkcazelo yamahhala ye-PMC] [PubMed]
I-Parsons LH, uJustice JB., Jr Serotonin kunye ne-dopamine sensitization kwi-nucleus accumbens, indawo ye-ventral tegmental, kunye ne-dorsal raphe nucleus elandela ulawulo oluphindaphindiweyo lwe-cocaine. J Neurochem. 1993;61:1611–1619. [PubMed]
Pierce RC, Kalivas PW. Imodeli ejikelezayo yokubonakaliswa kweemvakalelo zokuziphatha kwi-amphetamine-like psychostimulants. Res Brain Res Brain Res. 1997;25:192–216. [PubMed]
Thumela i-RM. Ukuvuselela okungapheliyo kuchasene nokuqhubekayo: isiphumo sexesha lexesha ekuphuhliseni uvakalelo okanye ukunyamezela. Ubomi beSayensi. 1980;26:1275–1282. [PubMed]
UPrisciandaro JJ, uJoseph JE, uMyrick H, uMcRae-Clark AL, uHenderson S, uPfeifer J, et al. Ngo-2014 Ubudlelwane phakathi kweminyaka yokusetyenziswa kwe-cocaine kunye nokusebenza kwengqondo kwi-cocaine kunye ne-inhibition inhibition cues Addiction (kwi-press). [Inkcazelo yamahhala ye-PMC] [PubMed]
URobinson TE, uBecker JB. Uvakaliso lokuziphatha lukhatshwa kukunyuswa kwe-amphetamine-evuselelwe ukukhutshwa kwe-dopamine kwizicubu ezibulalayo. in vitro. Eur J Pharmacol. 1982;85:253–254. [PubMed]
Robinson TE, Becker JB. Ukunyamezelwa kotshintsho kubuchopho kunye nokuziphatha okuveliswa ngulawulo lwe-amphetamine engapheliyo: uphononongo kunye nokuvavanywa kweemodeli zezilwanyana ze-amphetamine psychosis. Brain Res. I-1986; 396: 157-198. [PubMed]
Robinson TE, Jurson PA, Bennett JA, Bentgen KM. Ukuqhubeka uziva kwe-dopamine neurotransuction kwi-ventral striatum (i-nucleus accumbens) eveliswe ngamava angaphambili kunye (+) - amphetamine: isifundo esingumdibaniso wentsholongwane kwimigundwane ehamba ngokukhululekileyo. Brain Res. I-1988; 462: 211-222. [PubMed]
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J. Indlela yokubuyisela iziyobisi kwakhona: imbali, indlela kunye neziphumo eziphambili. I-Psychopharmacology (Berl) 2003; 168: 3-20. [UPubMed]
Siciliano CA, Calipari ES, Ferris MJ, Jones SR. Iindlela ze-Biphasic zesenzo se-amphetamine kwi-terminal ye-dopamine. J Neurosci. 2014;34:5575–5582. [Inkcazelo yamahhala ye-PMC] [PubMed]
Venton BJ, Seipel AT, Phillips PE, Wetsel WC, Gitler D, Greengard P, et al. I-Cocaine yonyusa ukukhutshwa kwe-dopamine ngokuhlanganisa ichibi elixhomekeke kwi-synapsin. J Neurosci. 2006;26:3206–3209. [PubMed]
I-Vezina P, i-Leyton M. I-conditioned cues kunye nokubonakaliswa kwe-stimulant sensitization kwizilwanyana nakubantu. I-Neuropharmacology. 2009;56 (Inkxaso 1: 160-168. [Inkcazelo yamahhala ye-PMC] [PubMed]
Zimmer BA, Oleson EB, Roberts DCS. Inkuthazo yokuzilawula yonyuka emva kwembali yamanqanaba obuchopho e-cocaine. Neuropsychopharmacology. 2012;37:1901–1910. [Inkcazelo yamahhala ye-PMC] [PubMed]