J Neurosci. 2011 Jun 8;31(23):8625-33.
St Onge JR, Abhari H, Floresco SB.
imvelaphi
ISebe lePsychology kunye neZiko loPhando lweBrain, kwiYunivesithi yaseBritish Columbia, eVancouver, eBritish Columbia V6T 1Z4, eKhanada
Abstract
Ukhetho phakathi kwemivuzo ethile kunye nokungaqinisekiyo kobukhulu obahlukeneyo kuye kwacetywa ukuba kulamlwe zizo zombini iilobes zangaphambili kunye nenkqubo ye-mesocorticolimbic dopamine (DA). Kwiimpuku, ukuguqulwa kwenkqubo yomsebenzi we-DA okanye ukungasebenzi kwe-medial prefrontal cortex (PFC) kuphazamisa ukwenziwa kwezigqibo malunga nemingcipheko kunye nemivuzo. Nangona kunjalo, akucaci ukuba usasazo lwe-PFC DA lunegalelo njani kwezi nkqubo. Siwusombulule lo mbandela ngokuphonononga iziphumo zokunyangwa kwe-pharmacological ye-D1 kunye ne-D2 receptors kwi-medial (prelimbic) PFC ekukhetheni phakathi kwemivuzo emincinci, ethile kunye nemikhulu, kodwa enokwenzeka. Iimpuku zaqeqeshwa kumsebenzi wokunciphisa okunokwenzeka apho i-lever enye yazisa ipellet enye nge-100% enokwenzeka, kwaye enye yahambisa iipellets ezine, kodwa amathuba okufumana umvuzo ehlile kwiibhloko zovavanyo (100, 50, 25, 12.5%). I-blockade ye-D1 (i-SCH23390) kwi-PFC ye-medial iyancipha ukukhetha ukhetho olukhulu / olunobungozi. Ngokwahlukileyo, i-D2 blockade (eticlopride) yehlise isaphulelo esinokwenzeka kunye nokwanda kokukhetha okuyingozi. I-agonist ye-D1 SKF81297 ibangele ukunyuka okuncinci, okungabalulekanga kokukhetha kwi-lever enkulu / enobungozi. Nangona kunjalo, i-D2 receptor stimulation (i-quinpirole) ibangele ukukhubazeka okwenyani ekuthathweni kwezigqibo, ukubethelela i-curve yesaphulelo kunye nokukhetha okukhethiweyo kude okanye kukhetho oluyingozi xa lunenzuzo enkulu okanye encinci, ngokulandelanayo. Ezi ziphumo zibonisa ukuba i-PFC D1 kunye ne-D2 receptors zenza i-dissociable, kodwa iyancedisana, igalelo kwimigwebo yomngcipheko / umvuzo. Ngokubetha ibhalansi elungileyo phakathi komsebenzi we-D1/D2 we-receptor, i-DA inokunceda ukucokisa ezi zigwebo, ikhuthaze nokuba kusetyenziswe iimeko ezifanelekileyo ngoku okanye ukuphononongwa kwengeniso eninzi xa iimeko ziguquka.
intshayelelo
Ukuphambuka kwenkqubo ye-mesocorticolimbic dopamine (DA) inxulunyaniswe nokusilela okunzulu ekwenzeni izigqibo ezinxulumene nezifo ezithile zengqondo. Oku kubandakanya abantu abane-schizophrenia (Hutton et al., 2002), isifo sikaParkinson (Pagonabarraga et al., 2007), kunye nomlutha ovuselelayo (Rogers et al., 1999). Imifuziselo yezilwanyana yokwenza izigqibo ibonakalise ukuba ubuqhetseba bosulelo lwe-DA lunokutshintsha ngokunzulu ukhetho phakathi kwamancinci, kulula ukufumana imbuyekezo kunye nemivuzo emikhulu, kodwa enexabiso elingaphezulu. Ukuvalwa okucwangcisiweyo kwe-D1 okanye i-D2 receptors kunciphisa ukhetho lokulinda ixesha elide okanye ukusebenza nzima ngakumbi ukufumana umvuzo omkhulu, ngelixa ukonyuka kokuhanjiswa kwe-DA kuneziphumo ezahlukileyo kumzamo- okanye ekuthatheni izigqibo okusekwe kukulibaziseka, ukwandisa okanye ukunciphisa ukhetho kwimivuzo emikhulu ezayo iindleko ezinkulu (Cousins et al., 1994; Cardinal et al., 2000; Denk et al., 2005; van Gaalen et al., 2006; Floresco et al., 2008a; Bardgett et al., 2009). Ngokufanayo, xa iimpuku zikhetha phakathi kwezincinci, ezithile kunye nezinkulu, kodwa imbuyekezo enobungozi kumsebenzi wesaphulelo onokwenzeka, ulawulo olucwangcisiweyo lwabachasi be-D1 okanye i-D2 lunciphisa ukhetho olukhulu, olunomngcipheko. (I-St. Onge kunye neFloresco, i-2009). Ngokuchaseneyo, i-D1 okanye i-D2 i-agonists ikhetha ukhetho olukhulu, olunobungozi. Nangona kunjalo, ngenxa yokuba imimandla emininzi yobuchopho iye yabandakanyeka kumngcipheko/kumgwebo womvuzo (umzekelo, i-lobes yangaphambili, i-ventral striatum, i-amygdala) (uFloresco et al., 2008b), imimandla yesiphelo apho i-DA inokuthi isebenze ukuphembelela ezi nkqubo ihlala ingacacanga. .
I-DA imodareyitha imisebenzi emininzi yengqiqo edibeneyo yimimandla eyahlukeneyo ye-prefrontal cortex (PFC), efana nokuguquguquka kokuziphatha, imemori yokusebenza, kunye neenkqubo zokuqaphela (uWilliams noGoldman-Rakic, i-1995; i-Granon et al., i-2000; i-Chudasama kunye ne-Robbins, i-2004; Floresco et al., 2006), rhoqo kwigophe elimilise “u-U”, apho umsebenzi omncinci okanye omninzi kakhulu weDA uphazamisa imisebenzi ethile yesigqeba. Nangona kunjalo, bekukho izifundo ezimbalwa ezithelekisa igalelo losasazo lwe-PFC DA kwiindlela ezahlukeneyo zeendleko / zenzuzo yokwenza izigqibo.. Ukunciphisa umsebenzi we-DA kwi-cingulate yangaphambili kuguqula izigqibo ezisekwe kwimigudu (Schweimer et al., 2005; Schweimer kunye noHauber, 2006), ngelixa ukuvalwa okanye ukuvuselela i-medial PFC D1 receptors kunciphisa ukhetho lwemivuzo emikhulu, elibazisiweyo (Loos et al., 2010) ). Ngokucacileyo, akukhange kubekho zifundo ziphanda ngegalelo leezamkeli ezahlukeneyo ze-PFC zeDA ekwenzeni izigqibo ezisekwe emngciphekweni.
Umsebenzi wakutsha nje uchonge i-PFC ye-prelimbic medial njengommandla obalulekileyo kulamlo lwesaphulelo esinokwenzeka, ngelixa umsebenzi kwezinye iindawo ezingaphantsi (i-anterior cingulate, i-orbitofrontal, i-insular) ayibonakali igalelo kule ndlela yokuziphatha (i-St. Onge kunye ne-Floresco, i-2010). Ukungasebenzi kwe-PFC yangaphakathi kunyuse ukhetho lwemivuzo emikhulu, enokwenzeka xa amathuba okuwafumana ehla ngeseshoni, kodwa ancipha ukhetho xa amathuba okuvuza enyuka ngaphezulu kweseshoni. Iziphumo zolu phononongo zisikhokelele ekubeni sigqibe kwelokuba i-PFC yangaphakathi isebenza ukudibanisa ulwazi malunga nokutshintsha amathuba okuvuza ukuze kuhlaziywe umboniso wexabiso oququzelela ukwenziwa kwezigqibo ngokufanelekileyo. Ukunikezelwa kwendima ebalulekileyo edlalwa yi-mesocortical DA kwezinye iindlela zokuqonda (Floresco kunye neMagyar, 2006), uphononongo lwangoku luphande igalelo le-prefrontal D1/D2 receptor umsebenzi ekwenzeni izigqibo ezisekwe emngciphekweni kusetyenziswa umsebenzi wokunciphisa onokwenzeka.
Impahla nenkqubo
Izilwanyana.
Iimpuku ze-Male Long-Evans (iCharles River Laboratories) ezinobunzima be-275-300 g ekuqaleni koqeqesho lokuziphatha zazisetyenziselwa ukulinga. Ekufikeni, iigundane zanikwa i-1 iveki ukuba zivumelane nekholoni kwaye ukutya kwakunqatshelwe kwi-85-90% yesisindo sazo sokutya mahhala kwiveki eyongezelelweyo ngaphambi kokuqeqeshwa kokuziphatha. Iimpuku zanikwa i-ad libitum ukufikelela emanzini ngexesha lovavanyo. Ukutya kwenzeka kwiikheji zekhaya leempuku ekupheleni kosuku lovavanyo, kwaye ubunzima bomzimba babujongwa imihla ngemihla ukuqinisekisa ukwehla kobunzima obuzinzileyo ngexesha lokuthintelwa kokutya kunye nokugcinwa okanye ukufumana ubunzima kulo lonke uvavanyo. Lonke uvavanyo lwaluhambelana neKhansile yaseKhanada yoLondolozo lweZilwanyana kunye neKomiti yoLondolozo lwezilwanyana kwiYunivesithi yaseBritish Columbia.
Izixhobo.
Uvavanyo lokuziphatha lwenziwa kumagumbi asebenzayo angama-12 (30.5 × 24 × 21 cm; iMed Associates) evalelwe kwiibhokisi ezithomalalisa isandi, nganye ixhotyiswe ngefeni ukunika umoya kunye nokufihla ingxolo engaphandle. Igumbi ngalinye lifakwe iileveli ezimbini ezirhoxiswayo, enye ibekwe kwicala ngalinye lendawo yokutya esembindini apho ukuqinisa ukutya (45 mg; Bio-Serv) kwahanjiswa nge-pellet dispenser. Amagumbi ayekhanyiswa sisibane esisodwa se-100 mA sendlu ebekwe kwindawo ephezulu eludongeni olujongene nezixhobo. Iiphotobeam ezine ze-infrared zaxhonywa kumacala egumbi ngalinye. Umsebenzi we-Locomotor uboniswe ngenani lekhefu le-photobeam eyenzeka ngexesha leseshoni. Yonke idatha yovavanyo irekhodwe yikhompyuter ye-IBM eqhagamshelwe kumagumbi nge-interface.
Uqeqesho lwe-Lever-pressing.
Iiprothokholi zethu zokuqala zoqeqesho zazifana nezo zeSt. Onge kunye neFloresco (2009), njengoko ziguqulelwe kwiCardinal et al. (2000). Kusuku olungaphambi kokuba luvezwe okokuqala emagumbini, iimpuku zanikwa ~ama-25 eepilisi zomvuzo weswekile kwindlwana yazo yasekhaya. Ngosuku lokuqala loqeqesho, iipelisi ezi-2-3 zahanjiswa kwindebe yokutya kunye neepelisi ezichotshoziweyo zafakwa kwi-lever ngaphambi kokuba isilwanyana sibekwe kwigumbi. Iigundane zaqala ukuqeqeshwa phantsi kwe-fixed-ratio ye-1 ishedyuli kwi-criterion ye-60 presses kwi-30 min, okokuqala kwi-lever enye, kwaye iphinda iphindwe kwenye i-lever (i-counterbalanced left / right phakathi kwezifundo). Iimpuku zaye zaqeqeshwa kuhlelo olulula lomsebenzi opheleleyo. Ezi seshoni zovavanyo ze-90 zaqala nge-levers ehoxisiweyo kunye negumbi elisebenzayo ebumnyameni. Rhoqo nge-40s, ulingo lwaluqaliswa ngokukhanyisa isibane sendlu kunye nokufakwa kwesinye sezitshixo ezimbini kwigumbi. Ukuba i-rat ayiphumelelanga ukuphendula kwi-lever ngaphakathi kwe-10, i-lever yarhoxiswa, igumbi laba mnyama, kwaye uvavanyo lwafunyanwa njengento engenziwanga. Ukuba i-rat iphendule ngaphakathi kwe-10 s, i-lever ihoxisiwe kwaye i-pellet enye yahanjiswa kunye ne-50% yamathuba. Le nkqubo yayisetyenziselwa ukuqhelanisa iimpuku kunye nobume obunokwenzeka bomsebenzi opheleleyo. Kuzo zonke izibini zezilingo, i-lever yasekhohlo okanye yasekunene yaboniswa kanye, kwaye umyalelo phakathi kwezibini zezilingo wawungenamkhethe. Iigundane zaqeqeshelwa ∼5–6 d kwikhrayitheriya ye-80 okanye izilingo ezingaphezulu eziyimpumelelo (okt; ≤10 omissions).
Umsebenzi wesaphulelo onokwenzeka.
Umsebenzi ophambili osetyenziswa kwezi zifundo uchazwe ngaphambili (uFloresco noWhelan, 2009; Ghods-Sharifi et al., 2009; St. Onge noFloresco, 2009, 2010; ISt. Onge et al., 2010), kwaye yatshintshwa ekuqaleni ukusuka kuleyo ichazwe nguCardinal and Howes (2005) (Fig. 1). Ngokufutshane, iigundane zifumene iiseshini zemihla ngemihla ezibandakanya izilingo ze-72, zahlulwe kwiibhloko ze-4 zezilingo ze-18. Iseshoni yonke ithathe i-48 min ukugqiba, kwaye izilwanyana zaqeqeshwa 6-7 d ngeveki. Iseshoni yaqala ebumnyameni zombini iilevers zirhoxisiwe (imeko yovavanyo). Ulingo lwaqala rhoqo nge-40 s ngokukhanyiswa kwesibane sendlu kwaye, i-3 s kamva, ukufakwa kwesinye okanye zombini iilever kwigumbi (ifomathi yolingo olunye iboniswe kwiFig. 1). I-lever enye yayityunjwe i-lever enkulu / enobungozi, enye i-lever encinci / i-lever ethile, eyahlala ihambelana ngexesha lonke loqeqesho (i-counterbalanced left / right). Ukuba i-rat ayizange iphendule ngokucinezela i-lever ngaphakathi kwe-10 ye-lever presentation, i-chamber yabuyiselwa kwimeko ye-intertrial kuze kube yilingo elilandelayo (ukushiywa). Xa kukhethwe i-lever, zombini iilever zarhoxa. Ukukhetha i-lever encinci / ethile ihlala ihambisa i-pellet enye kunye ne-100% yamathuba; ukhetho lwe-lever enkulu / enobungozi ihanjiswe iipellets ezi-4 kodwa ngokunokwenzeka okuthile. Xa ukutya kuhanjiswa, ukukhanya kwendlu kwahlala kwenye i-4 emva kokuba impendulo yenziwe, emva koko igumbi libuyele kwi-intertrial state. Iipellet ezininzi zahanjiswa nge-0.5 s ngaphandle. Iibhloko ze-4 zazibandakanya izilingo ze-8 zokukhetha ngenkani apho i-lever enye kuphela yavezwa (izilingo ze-4 kwi-lever nganye, i-randomized in pairs), evumela izilwanyana ukuba zifunde malunga nobudlelwane obunokwenzeka bokufumana umvuzo omkhulu okanye omncinci kwibhloko nganye. Oku kwalandelwa yizilingo ze-10 ezikhethiweyo, apho zombini iilevers zavezwa kwaye isilwanyana sakhetha nokuba yincinci / ethile okanye i-lever enkulu / enobungozi. Ithuba lokufumana iipelisi ze-4 emva kokucinezela i-lever enkulu / enobungozi yahluka kwiibhloko: ekuqaleni yayiyi-100%, ngoko i-50%, i-25%, kunye ne-12.5%, ngokulandelanayo, kwibhloko nganye elandelelanayo. Amathuba okufumana umvuzo omkhulu kulingo ngalunye athatyathwe kulwabiwo olusetiyo lwamathuba. Ukusebenzisa ezi zinto zinokwenzeka, ukukhetha i-lever enkulu / enobungozi kuya kuba luncedo kwiibhloko ezimbini zokuqala, kwaye kube yingozi kwibhloko yokugqibela, ngelixa iigundane zinokufumana inani elilinganayo leepellets zokutya emva kokuphendula nakweyiphi i-lever ngexesha le-25% yebhloko. Ke ngoko, kwiibhloko zovavanyo ezintathu zokugqibela zalo msebenzi, ukhetho lwenketho yomvuzo omkhulu luhamba “nomngcipheko” wendalo wokungafumani mvuzo kulingo olunikiweyo. I-Latencies ukuqalisa ukhetho kunye nomsebenzi jikelele we-locomotor (ikhefu le-photobeam) nazo zarekhodwa. Iigundane zaqeqeshwa kulo msebenzi de, njengeqela, (1) bakhetha i-lever enkulu / enobungozi ngexesha lebhloko yokuqala yesilingo (i-100% enokwenzeka) ubuncinane kwi-80% yezilingo eziyimpumelelo, kwaye (2) ibonise amanqanaba asisiseko azinzile. ukhetho, luhlolwe kusetyenziswa inkqubo efana naleyo ichazwe nguWinstanley et al. (2005) kunye neSt. I-Onge kunye neFloresco (2009). Ngamafutshane, idatha evela kwiiseshoni ezintathu ezilandelelanayo zahlaziywa ngokuphindaphindiweyo-imilinganiselo ye-ANOVA kunye nezinto ezimbini ngaphakathi kwesifundo (imini kunye nebhloko yesilingo).
Umzobo 1.
Uyilo lomsebenzi. Iindleko/inzuzo yeemeko ezingalindelekanga ezinxulunyaniswa nokuphendula nakweyiphi na i-lever (A) kunye nefomathi yolingo olunye lokhetho lwasimahla (B) kumsebenzi wesaphulelo onokwenzeka.
Umsebenzi wocalucalulo lobungakanani bemivuzo.
Njengoko siye senza ngaphambili (Ghods-Sharifi et al., 2009; Stopper and Floresco, 2011), siye samisela i-priori ukuba unyango oluthile luye lwanciphisa ngokukhethekileyo ukhetho lwe-lever enkulu / enobungozi kumsebenzi wesaphulelo onokwenzeka, amaqela ahlukeneyo ezilwanyana. iya kuqeqeshwa kwaye ivavanywe kumsebenzi wocalucalulo lobungakanani bomvuzo ukufumanisa ukuba le mpembelelo ibibangelwe kukuthintelwa kocalucalulo phakathi kobukhulu bomvuzo obunxulunyaniswa nezi zixhobo zimbini. Kolu vavanyo, iimpuku zaqeqeshelwa ukucinezela izixhasi ezinokurhoxiswa njengakumsebenzi wesaphulelo onokwenzeka, emva koko zaqeqeshwa kumsebenzi wocalucalulo. Apha, iimpuku zakhetha phakathi kwelever enye ehambisa ipellet enye kunye nenye ehambisa iipellets ezine. Yomibini imivuzo emincinci kunye nemikhulu ihanjiswe ngokukhawuleza emva kwempendulo enye kunye ne-100% enokwenzeka. Iseshoni yayiquka iibhloko ezine zezilingo, kunye nebhloko nganye equkethe i-2 yokukhetha ngenkani elandelwa yi-10 izilingo zokuzikhethela.
Ukuhlinzwa.
Amagundane aphantsi kotyando emva kokuba iqela libonise iipateni ezizinzile zokukhetha iintsuku ze-3 ezilandelelanayo. Emva kokuba umlinganiselo wokuzinza uphunyeziwe, iigundane zanikwa i-ad libitum yokutya kwaye, i-2 d kamva, yenza utyando lwe-stereotaxic. Iigundane zifakwe i-anesthetized kunye ne-100 mg / kg i-ketamine hydrochloride kunye ne-7 mg / kg ye-xylazine kwaye emva koko ifakwe kunye ne-23 gauge ye-stainless steel guide cannulae kwingingqi ye-prelimbic ye-PFC ephakathi (ikhakhayi elicaba; i-anteroposterior, +3.4 mm; 0.7 mm ukusuka kwi-bregma kunye ne-dorsoventral, -2.8 mm ukusuka kwi-dura). Izithinteli zegauji ezingamashumi amathathu, ezigungxulwa ekupheleni kwesikhokelo se-cannulae, zahlala zihleli de kwenziwe ukufakwa. Iimpuku zanikwa ubuncinci iintsuku ezisi-7 ukuba ziphinde ziphile kuqhaqho phambi kovavanyo. Ngeli xesha lokubuyisela, izilwanyana zaphathwa ubuncinane ubuncinane be-5 iminithi nganye kwaye ukutya kwakunqatshelwe kwi-85% yesisindo sazo sokutya simahla. Ubunzima bomzimba buhlala bubekwe esweni imihla ngemihla ukuqinisekisa ukulahleka kwesisindo esizinzileyo ngeli xesha lokubuyisela.
Microinfusion protocol.
Ukulandela ukuchacha kuqhaqho, iimpuku ziye zaphinda zaphinda zaqeqeshwa nokuba kwisaphulelo esinokwenzeka okanye ubungakanani bomvuzo umsebenzi wocalucalulo ubuncinane kangange-5 d kwaye de, njengeqela, babonise amanqanaba azinzileyo okuziphatha okukhethileyo. Kwiintsuku ezi-3 ngaphambi kosuku lokuqala lovavanyo lwe-microinfusion, i-obdurators yasuswa kwaye inkqubo yokufakelwa kwe-mock yenziwa. I-injection yensimbi engenasici ifakwe kwi-cannulae yesikhokelo kwi-2 min, kodwa akukho kufakwa. Le nkqubo ihlalise iimpuku kwindlela yokufaka infusions ukunciphisa uxinzelelo kwiintsuku zovavanyo ezilandelayo. Ngosuku emva kokubonisa isaphulelo esizinzileyo, iqela lafumana usuku lokuqala lovavanyo lwe-microinfusion.
Uyilo lwangaphakathi lwezifundo lusetyenziselwe yonke imifuniselo. Ezi ziyobisi zilandelayo zisetyenzisiwe: umchasi we-D1 u-R-(+)-SCH23390 i-hydrochloride (1.0 μg, 0.1 μg; Sigma-Aldrich), i-D2 ephikisana ne-eticlopride hydrochloride (1.0 μg, 0.1 μg; i-Sigma-Aldrich receptor), i-D1 receptor I-SKF81297 (0.4 μg, 0.1 μg; Tocris Bioscience), kunye ne-D2 agonist quinpirole (10 μg, 1 μg; Sigma-Aldrich). Zonke iziyobisi zachithwa kwi-physiological 0.9% saline, i-sonicated de yachithwa, kwaye ikhuselwe ekukhanyeni. Iidosi ezikhethiweyo zonke zibhalwe kakuhle liqela lethu kunye nabanye ukuba baziphathe kakuhle xa benikwa intracerebrally (Seamans et al., 1998; Ragozzino, 2002; Chudasama and Robbins, 2004; Floresco and Magyar, 2006; Floresco et al., I-2006 i-Haluk kunye ne-Floresco, i-2009 Loos et al., i-2010).
I-infusions ye-D1 kunye ne-D2 antagonists, i-agonists, kunye ne-saline zalawulwa ngokudibeneyo kwi-PFC ye-medial ngepompo ye-microsyringe exhunywe kwi-tubing ye-PE kunye ne-30 ye-gauge cannulae ephuma kwi-0.8 mm edlulileyo ekupheleni kwesikhokelo, ngesantya se-0.5 μl / 75 s. I-cannulae ye-injection ishiywe kwindawo yokongeza i-1 min ukuvumela ukusasazwa. Impuku nganye yahlala kwindlwana yayo yasekhaya enye imizuzu eyi-10 ngaphambi kovavanyo lokuziphatha.
Amaqela amane ahlukeneyo eegundane asetyenziselwa ukuvavanya imiphumo nganye yeekhompawundi ezine (umchasi we-D1, umchasi we-D2, i-agonist ye-D1, i-agonist ye-D2). Umyalelo wonyango (i-saline, idosi ephantsi, idosi ephezulu) yayichasene neempuku kwiqela elithile lonyango. Ukulandela usuku lokuqala lovavanyo lokuxiliswa, iigundane zafumana usuku loqeqesho olusisiseko (akukho ukunyuswa). Ukuba, kuyo nayiphi na impuku eyedwa, ukhetho lwesixhobo esikhulu/esiyingozi ngolu suku lujikwe nge> 15% kwisiseko saso sangaphambi kokugalelwa, impuku ifumene usuku olongezelelweyo loqeqesho phambi kovavanyo lokufakwa okwesibini. Ngosuku olulandelayo, iimpuku zafumana ukufakelwa okwesibini okuchaseneyo, kulandelwa lolunye usuku olusisiseko, kwaye ekugqibeleni ukufakwa kokugqibela.
Histology.
Emva kokugqitywa kwalo lonke uvavanyo lokuziphatha, iigundane zabulawa kwigumbi le-carbon dioxide. Ubuchopho bususwe kwaye bulungiswe kwisisombululo se-4% se-formalin. Ubuchopho benziwe ngumkhenkce kwaye banqunyulwa kumacandelo e-50 μm ngaphambi kokuba ifakwe kwaye ifakwe i-cresyl violet. Ukubekwa kwaqinisekiswa ngokubhekiselele kwiatlasi ye-neuroanatomical yePaxinos kunye neWatson (1998). Iindawo ze-infusions ezamkelekileyo kwi-PFC ephakathi zinikezelwa kwiiphaneli ezifanelekileyo zoMfanekiso 2.
Umzobo 2.
I-Histology. I-Schematic yamacandelo e-coronal yobuchopho begundane ebonisa uluhlu lweendawo ezamkelekileyo zokungena kwi-rostral-caudal ye-PFC ephakathi kuzo zonke iigundane.
Uhlalutyo lwedatha.
Umlinganiselo ongundoqo oxhomekeke kwinzala yayiyipesenti yokhetho olujoliswe kwisixhobo esikhulu/ esinomngcipheko kwibhloko nganye yolingo lokhetho lwasimahla, umba wovavanyo olushiyiweyo. Kwibhloko nganye, oku kubalwa ngokwahlula inani lokukhetha i-lever enkulu / enobungozi ngenani elipheleleyo leemvavanyo eziyimpumelelo. Idatha ekhethiweyo kwiqela ngalinye leziyobisi zahlalutywa kusetyenziswa iindlela ezimbini ngaphakathi kwe-ANOVAs, kunye nonyango (i-saline, i-dose ephantsi, i-dose ephezulu) kunye nebhloko yesilingo (100, 50, 25, 12.5%) njengezinto ezingaphakathi kwesifundo. Impembelelo ephambili yebhloko yedatha ekhethiweyo yayibalulekile kuzo zonke iimvavanyo zokunciphisa (p <0.05), ebonisa ukuba iigundane ezikhethiweyo ezikhethiweyo ze-lever enkulu / enobungozi njengoko amathuba okuba umvuzo omkhulu utshintshile kwiibhloko ezine. Esi siphumo asisayi kukhankanywa ngokubhekele phaya. I-latency yokuphendula, umsebenzi we-locomotor (i-photobeam breaks), kunye nenani lokushiya ulingo lwahlalutywa nge-ANOVA yendlela enye.
Icandelo ElidlulileyoNeCandelo
iziphumo
Amaqela amane ezilwanyana aqale aqeqeshwa kuvavanyo olwahlukileyo kwaye abelwa kwelinye lamaqela amane amachiza. Amaqela amabini okuqala e-16 nganye, echongelwe i-D1 kunye ne-D2 yokuvavanya i-antagonist, idinga umyinge we-28 d yoqeqesho ngaphambi kokufikelela ekusebenzeni okuzinzile kokukhetha kunye nokufumana iimvavanyo ezichasene ne-microinfusion. Amaqela amabini amabini e-14 kunye ne-14 yeegundane ze-D1 kunye ne-D2 i-agonists zifuna umyinge we-34 d yoqeqesho ngaphambi kokufikelela ekusebenzeni okuzinzile kokukhetha. I-latency yokuphendula, i-locomotor, kunye nedatha yokushiya isilingo esifunyenwe ngeentsuku zovavanyo kuwo onke amaqela amane ziboniswe kwiThebhile 1.
Ithebula 1.
I-Locomotion, ukukhutshwa kwesilingo, kunye nedatha ye-latency yokuphendula efunyenwe emva kokungena kwe-saline okanye iziyobisi kwi-PFC ephakathi
I-D1 kunye ne-D2 ye-receptor antagonism kunye nesaphulelo esinokwenzeka
D1 ibhloko
Ekuqaleni, iimpuku ezili-16 zaqeqeshelwa olu vavanyo. Esinye isilwanyana safa ngexesha lotyando kwaye idatha evela kwabanye abathathu yapheliswa ngenxa yokungachanekanga kokubekwa, okubangelwa ekugqibeleni n = 12. Uhlalutyo lwedatha ekhethiweyo lubonise ukuba i-intra-PFC infusions ye-D1 antagonist SCH23390 ibangele umphumo obalulekileyo wonyango. (F (2,22) = 3.26, p = 0.05) kodwa akukho unyango × ukusebenzisana kwebhloko (F (6,66) = 0.92, ns). I-dose ephezulu ye-SCH23390 (1 μg) iyancipha kakhulu ukhetho kwi-lever enkulu / enobungozi kwiibhloko ezintathu zokugqibela (p <0.05; Umzobo 3A), kanti i-dose ephantsi (0.1 μg) ayivelisanga utshintsho oluthembekileyo ekuziphatheni okukhethiweyo. I-blockade ye-D1 yayingenayo impembelelo kwi-latencies yempendulo (F (2,22) = 0.18, ns), ukukhutshwa kwesilingo (F (2,22) = 0.54, ns), okanye ukubala kwe-locomotor (F (2,22) = 1.66, ns ).
Umzobo 3.
Iziphumo zokukhohlisa kwe-DA receptor kwi-PFC yangaphakathi kwisaphulelo esinokwenzeka. Idatha icwangciswe ngokwepesenti yokukhetha i-lever enkulu / enobungozi ngexesha lovavanyo lokukhetha ngokukhululekileyo ngebhloko enokwenzeka (x-axis). Iimpawu zibonisa intsingiselo + SEM. Iinkwenkwezi ezingwevu zibonisa umphumo obalulekileyo obalulekileyo (i-saline vs idosi ephezulu, p <0.05). Iinkwenkwezi ezimnyama zichaza umehluko omkhulu (p <0.05) phakathi kweemeko zonyango ngexesha elithile elinokwenzeka ibhloko isiphumo esiphambili. A, Ukufakwa kwe-1.0 μg idosi ye-D1 echasene ne-SCH23390 isaphulelo esikhawulezileyo esinokwenzeka, ukunciphisa ukhetho olunobungozi. B, Ngokwahlukileyo koko, i-infusions ye-1.0 μg idosi ye-D2 antagonist eticlopride yanciphisa isaphulelo kunye nokhetho oluyingozi. C, I-agonist ye-D1 SKF81297 yenza ukunyuka okuncinci, okungabalulekanga ekukhetheni okuyingozi. D, I-Infusions ye-10 μg idosi ye-D2 i-agonist quinpirole yaphelisa isaphulelo, ukunciphisa ukhetho olunobungozi ngexesha lebhloko yokuqala kunye nokwanda kokhetho ngexesha lebhloko yokugqibela.
D2 ibhloko
Ekuqaleni, iimpuku ezili-16 zaqeqeshelwa olu vavanyo. Esinye isilwanyana safa ngexesha lotyando kwaye idatha evela kwabanye abathathu yapheliswa ngenxa yokubekwa ngokungafanelekanga, okubangelwa ekugqibeleni n = 12. Uhlalutyo lwedatha ekhethiweyo lubonise umphumo obalulekileyo wonyango (F (2,22) = 3.76, p. <0.05) kodwa akukho unyango × ukusebenzisana kwebhloko (F (6,66) = 0.84, ns). Nangona kunjalo, ngokungafaniyo nemiphumo ye-D1 receptor blockade, i-dose ephezulu ye-eticlopride (1 μg) yandisa kakhulu ukhetho lwe-lever enkulu / enobungozi kuzo zonke iibhloko (p <0.05; Umzobo 3B), kunye nedosi ephantsi (0.1 μg) ) ukuvelisa ukhetho oluncinci, kodwa olungabalulekanga. I-Eticlopride yayingenayo impembelelo kwi-latencies yempendulo (F (2,22) = 0.63, ns), ukukhutshwa kwesilingo (F (2,22) = 1.45, ns), okanye ukubala kwe-locomotor (F (2,22) = 0.99, ns) . Ke ngoko, ukuvalwa kwe-D1 okanye i-D2 receptors kwi-PFC yangaphakathi ibe neziphumo ezichaseneyo ngokomgangatho kwisaphulelo esinokwenzeka. Ukunciphisa umsebenzi we-receptor we-D1 ukonyusa isaphulelo semivuzo emikhulu, engaqinisekanga, ngelixa ukuchasana kwe-D2 receptor kuncitshiswe isaphulelo, kubonakaliswa njengokuhla okubonakalayo kunye nokunyuka kukhetho olunobungozi, ngokulandelelana.
I-D1 kunye ne-D2 yokuvuselela i-receptor kunye nesaphulelo esinokwenzeka
D1 ukuvuselela
Ekuqaleni, iimpuku ezili-14 zaqeqeshelwa olu vavanyo. Esinye isilwanyana safa ngexesha lotyando kwaye idatha evela kwigundane enye yayingabandakanywanga ngenxa yokuba idatha yakhe yokukhetha isiseko yayiyi-2 SDs ngaphantsi kwentsingiselo yeqela lonke, okubangelwa ekugqibeleni n = 12. Ukulandela ulawulo lwe-D1 agonist SKF81297 kwi-PFC ephakathi. , iigundane zivame ukubonisa impembelelo echasene neyo eyenziwa ngumchasi we-D1, ebonisa ukunyuka okuphakathi kokukhetha i-lever enkulu / enobungozi, kunye nesi siphumo sibe sikhulu ngamanani emva konyango kunye ne-dose ephantsi, i-0.1 μg. Ngaphandle kolu tyekelo, uhlalutyo lwedatha ekhethiweyo aluzange lubonakalise umphumo obalulekileyo wonyango (F (2,22) = 2.05, ns) okanye unyango × ukusebenzisana kwebhloko (F (6,66) = 0.10, ns; Umzobo 3C) , nangona uthelekiso oluthe ngqo phakathi kwe-dose ephantsi kunye neemeko zonyango lwe-saline lubonise umkhwa wokubaluleka kwamanani (p = 0.086). I-agonist ye-D1 nayo yayingenayo impembelelo kwi-latencies yokuphendula (F (2,22) = 0.67, ns), ukukhutshwa kwesilingo (F (2,22) = 0.06, ns), okanye ukubala kwe-locomotor (F (2,22) = 0.36 NONE
D2 ukuvuselela
Kwakhona, iimpuku ezili-14 zaqeqeshelwa olu vavanyo. Idatha esuka kwigundane enye yayingabandakanywanga ngenxa yokuba idatha yakhe yokukhetha isiseko ayibonakalisi isaphulelo esibalaseleyo emva kwe-34 d yoqeqesho, ngelixa idatha ephathelele enye i-rat yacinywa ngenxa yokubekwa okungachanekanga, okubangelwa ekugqibeleni n = 12 kweli qela. Unyango nge-D2 agonist i-quinpirole ibangele isiphumo ekukhethweni okwahlukileyo xa kuthelekiswa noko kubangelwa yi-DA receptor antagonist okanye i-agonist ye-D1. Uhlalutyo lwedatha yokukhetha alubonakalisi umphumo obalulekileyo wonyango (F (2,22) = 0.05, ns), kodwa kwakukho unyango olubalulekileyo × ukusebenzisana kwebhloko (F (6,66) = 2.33, p <0.05, Dunnett's p <0.05). Iziphumo ezilula eziphambili ezihlalutya ngakumbi zibonise ukuba, ngelixa i-dose ephantsi (i-1 μg) ye-quinpirole yayingenayo impembelelo ekukhetheni, i-dose ephezulu (10 μg) ivelise "i-flattening" ecacileyo ye-curve yesaphulelo. Ngokukodwa, le dose ibaluleke kakhulu (p <0.05) iyancipha ukhetho lwe-lever enkulu / enobungozi kwi-block yokuqala ye-100%, kodwa yandisa kakhulu ukhetho olunobungozi ngexesha lokugqibela (12.5%) ngokubhekiselele kwi-saline infusions (Fig. 3D). Ngaphezu koko, ukulandela ukunyuswa kwe-saline okanye i-1.0 μg idosi ye-quinpirole, iigundane zibonise isaphulelo esibalulekileyo sokhetho olukhulu / olunobungozi njengoko amathuba okufumana umvuzo omkhulu wehla ngeseshoni (p <0.005). Ngokwahlukileyo, umlinganiselo wokukhetha olu khetho awuzange utshintshe kakhulu kwiibhloko ezine emva kokunyanga nge-10 μg ye-quinpirole (p> 0.25). I-Quinpirole yayingenayo impembelelo ekukhutshweni kovavanyo (F (2,22) = 0.84, ns) okanye ukubala kwe-locomotor (F (2,22) = 1.72, ns), nangona i-dose ephezulu yandisa kakhulu i-latencies yokukhetha kwiibhloko ezine (F ( 2,22) = 3.54, p <0.05 kunye noDunnett, p <0.05;
Win-stay/lose-shift analysis
Ukunyuswa kwe-D1 ekhethiweyo okanye i-D2 i-receptor agonists okanye i-antagonist kwi-PFC yangaphakathi nganye ibangele imiphumo eyahlukileyo yokwenza izigqibo. Ukufumana ulwazi olungakumbi malunga nokuba olu nyango luchaphazele njani iipatheni zokhetho kunye nesiphumo sotshintsho kwisaphulelo, senze uhlalutyo olongezelelweyo lwedatha ekhethiweyo. Ngokukodwa, senze uhlalutyo lokukhetha ngokhetho lokuchonga ukuba ngaba utshintsho kwindlela yokuziphatha lubangelwe lutshintsho olunokubakho lokukhetha i-lever enobungozi emva kokufumana umvuzo omkhulu (ukuphumelela ukuhlala) okanye utshintsho kwimvakalelo engalunganga yengxelo (ukulahlekelwa yi-shift. ukusebenza) (Bari et al., 2009; Stopper and Floresco, 2011). Ukhetho lwezilwanyana ngexesha lomsebenzi lwahlalutywa ngokwesiphumo sovavanyo ngalunye lwangaphambili lokuzikhethela (umvuzo okanye ukungabikho komvuzo) kwaye lubonakaliswe njengomlinganiselo. Umlinganiselo wolingo lokuhlala ubalwa ukusuka kwinani lamaxesha apho impuku ikhethe i-lever enkulu/enobungozi emva kokukhetha ukhetho olunomngcipheko kulingo olwandulelayo nokufumana umvuzo omkhulu (uloyiso), lwahlulwe ngenani lilonke lokhetho olukhululekileyo. izilingo apho impuku ifumene umvuzo omkhulu. Ngokwahlukileyo, ukusebenza kwe-shift-shift kubalwa ukusuka kwinani lamaxesha amagundane atshintshe ukhetho kwincinci / i-lever ethile emva kokukhetha ukhetho olunobungozi kulingo olwandulelayo kwaye aluzange luvuzwe (ilahleko), lwahlulwe ngenani elipheleleyo lezilingo ezikhethiweyo. okukhokelela kwilahleko.
Ngenxa yobume obunokwenzeka bomsebenzi, kuyo yonke imifuniselo emine bekukho ubuncinci iimeko ezi-4-5 apho isilwanyana esinye singakhange sikhethe i-lever enkulu/enobungozi (kwaye ke ngoko, asikwazanga “ukuhlala” okanye “ukushifta” emva kokuphumelela. okanye ilahleko) okanye akafumananga mvuzo mkhulu kwaphela ngexesha lebhloko enokwenzeka (ingakumbi iibhloko ezimbini zokugqibela). Ngaloo ndlela, nakweyiphi na kwezi meko, idinomineyitha kwi-equation esetyenziselwa ukubala ezi ratios iya kuba ngu-zero ubuncinane enye yeebhloko, ezisithintele ekuqhubeni uhlalutyo lwebhloko ngebhloko yale datha. Ukoyisa oku, uhlalutyo lwenziwa kuzo zonke izilingo kuzo zonke iibhloko ezine, njengoko besenzile ngaphambili (Stopper kunye noFloresco, 2011). Utshintsho kwintsebenzo ye-win-stay lusetyenziswe njengesalathiso esiqhelekileyo sempembelelo ekufumaneni umvuzo omkhulu, onobungozi ekuziphatheni okulandelayo, ngelixa utshintsho kwintsebenzo elahlekileyo lusebenza njengesalathiso sobuntununtunu bengxelo kulo lonke ixesha lovavanyo. iseshoni.
Ngenxa yokuba i-compounds nganye kwezine yenza imiphumo eyahlukileyo kwindlela yokuziphatha ekhethiweyo, sasinomdla ngokukodwa ekuthelekiseni ngokuthe ngqo iziphumo zekhompawundi nganye enxulumene nonyango lwe-saline. Kolu hlalutyo, sisebenzise idatha efunyenwe ngokulandela unyango kunye needosi ezisebenzayo zechiza ngalinye kunye nenaliti yemoto ehambelanayo (ye-SKF81297, sisebenzise idatha efunyenwe emva konyango ngedosi esezantsi, ye-0.1 μg). Uhlalutyo lwezilingo zokuhlala kunye nokulahlekelwa kwe-shift lubonise ukusebenzisana kweendlela ezine zohlobo lwesilingo (ukuphumelela-ukuhlala vs ukulahlekelwa yi-shift) × unyango (i-saline vs ichiza) × i-receptor (D1 vs D2) × uhlobo lweziyobisi (umchasi vs i-agonist ) (F (1,44) = 11.92, p <0.05; Umzobo 4, iThebhile 2). Njengoko kwaphawulwa ngohlalutyo lwendlela yokuziphatha ekhethiweyo, oku kusebenzisana kweendlela ezine kwaqhutywa yinyaniso yokuba ichiza ngalinye lenze isiphumo esahlukileyo kwi-win-stay/ lost-shift tendencies. Ngokubhekiselele ekusebenzeni kokuphumelela, phantsi kweemeko zolawulo, iigundane zibonise ukuthambekela okunamandla (phakathi kwe-80 kunye ne-90%) ukukhetha i-lever enobungozi emva kokukhetha le lever kwisilingo esandulelayo kunye nokufumana umvuzo, njengoko sibonile ngaphambili (i-Stopper kunye ne-Floresco , 2011). Ngakolunye uhlangothi, izilwanyana zivame ukutshintshela kwincinci / i-lever ethile elandela "ilahleko" emva kokukhetha i-lever enkulu / eyingozi kwi-~25-30% yezi zilingo phantsi kweemeko zokulawula.
Umzobo 4.
Iimpembelelo ze-PFC DA receptor manipulations kwi-win-stay (imivalo engwevu) kunye nokulahleka kwe-shift (imivalo emhlophe). Ukucaca kunye neenjongo zokuthelekisa, idatha inikwe apha ngokwemilinganiselo yamanqaku phakathi komlinganiselo ofunyenwe kumachiza ngokuchasene nonyango lwe-saline (amaxabiso afanelekileyo abonisa umlinganiselo owongeziweyo, amaxabiso angalunganga ayancipha emva kokunyangwa kweziyobisi ngokunxulumene nokulawulwa kokungena). Idatha eluhlaza esetyenziswe kuhlalutyo olupheleleyo apho la maxabiso afunyenwe khona aboniswe kwiThebhile 2. I-Win-stay ratios index umlinganiselo wezilingo apho iigundane zikhethe i-lever enkulu / enobungozi emva kokufumana umvuzo omkhulu kulingo lwangaphambili. I-Lose-shift ratios index umlinganiselo wezilingo apho iimpuku zitshintshe ukhetho kwi-lever encinci / ethile emva kokukhetha okungavuzwanga kwelever enkulu / enobungozi. Iinkwenkwezi zibonisa umahluko omkhulu ukusuka kwi-saline kwinqanaba le-0.05. ns, ayibalulekanga.
Ithebula 2.
Win-stay/lose-shift ratios yeempuku ezenza umsebenzi wokunciphisa onokwenzeka emva kokugalelwa kwetyuwa kunye nedosi ephezulu okanye eyona isebenzayo ye-D1 kunye ne-D2 antagonist okanye i-agonists
Uhlalutyo olulula lweziphumo eziphambili zentsebenziswano yeendlela ezine luveze ukuba umchasi we-D1 SCH23390 akazange achaphazele ukusebenza kokuwina-ukuhlala kodwa anyuse kakhulu ukulahleka kokutshintsha (uDunnett's, p <0.05), ebonisa ukuba ukuncipha kokhetho olunobungozi olubangelwa olu nyango. Isenokubalelwa ngokuyinxenye kuvakalelo olwandisiweyo kwingxelo engakhiyo (okt; ukushiywa komvuzo). Ngokwahlukileyo, i-D2 blockade kunye ne-eticlopride (1 μg) yandisa kakhulu amathuba okukhetha ukhetho olunobungozi emva kokuphumelela "(p <0.05), ngelixa kubangela ukuhla okungabalulekanga ekulahlekeni kwe-shift tendencies. Ke ngoko, ukonyuka kokhetho oluyingozi olubangelwe yi-D2 blockade lubonakala lubalelwa ikakhulu kwimpembelelo eyongeziweyo yokufumana umvuzo omkhulu kukhetho olulandelayo.
I-agonist ye-D1 SKF81297 (0.1 μg) yandisa kakhulu i-win-stay performance ngokubhekiselele kwi-saline (p <0.05), kodwa nayo yaba nefuthe elichasayo le-SCH23390, ukunciphisa ukutyekela kokutshintsha emva kokulahlekelwa kwi-lever enkulu / enobungozi (p <0.05) . Ngokwahlukileyo, i-quinpirole (i-10 μg) yayinempembelelo echaseneyo ye-agonist ye-D1 kwi-win-stay tendencies, iyancipha kakhulu amathuba okukhetha i-lever enkulu / enobungozi emva kokuphumelela "(p <0.05), ebonisa ukunciphisa uvakalelo ekufumaneni. yemivuzo emikhulu, kodwa engaqinisekanga. Olu nyango aluzange lube nempembelelo ebalulekileyo kwimilinganiselo yokulahleka kokuhlala. Ezi ziphumo zibonisa ukuba i-D1 vs D2 imodyuli ye-receptor yenza utshintsho oluhlukileyo ekusebenzeni okukhethiweyo okubonakala kubonakaliswe ngotshintsho olwahlukileyo kwimpembelelo yokufumana umvuzo omkhulu okanye uvakalelo olubi lwengxelo.
Ukuvuza ucalucalulo lobungakanani
Ukuvalwa kwee-receptors ze-D1 okanye uvuselelo lwee-receptors ze-D2 kunciphisa ukhetho lomvuzo omkhulu, ongaqinisekanga ngexesha leebhloko ezithile zesilingo somsebenzi wesaphulelo. Ukuvavanya ukuba ingaba ezi ziphumo zibangelwa kukuphazamiseka ngokubanzi ekucaluleni phakathi kwemivuzo yobukhulu obahlukeneyo, senze olunye uvavanyo, apho amaqela amabini ahlukeneyo eempuku aqeqeshelwa umsebenzi olula. Iimpuku zikhethe phakathi kweelever ezimbini ezihambisa i-pellets enye okanye ezine, zombini nge-100% enokwenzeka. Iigundane ezilishumi elinesihlanu zaqeqeshelwa i-11 d kulo msebenzi ngaphambi kokufumana i-microinfusions ephikisanayo ye-dose ephezulu ye-SCH23390 (1 μg) okanye i-quinpirole (10 μg) kunye ne-saline. Idatha yesilwanyana esinye isuswe ngenxa yokubekwa ngokungafanelekanga, ishiya i-n yokugqibela ye-6 kwiqela le-SCH23390 kunye ne-8 kwiqela le-quinpirole.
D1 ibhloko
Ukulandela i-saline infusions, iigundane zibonise i-bias enamandla kakhulu kumvuzo omkhulu, ukukhetha olu khetho malunga ne-100% yezilingo (Fig. 5A). Ukulandela i-infusions ye-SCH23390 (1 μg), akukho tshintsho ekukhetheni ukhetho lwe-pellet ezine (F (1,5) = 1.72, ns). Ngokwahlukileyo kukhetho, siye sabona ukunyuka okuncinci kweempendulo ezilandela i-blockade ye-D1 (i-saline = 0.81 ± 0.1 s, SCH23390 = 0.98 ± 0.1 s; F (1,5) = 7.18, p <0.05). Umsebenzi we-Locomotor (F (1,5) = 4.86, ns) kunye nokukhutshwa kwesilingo (F (1,5) = 1.0, ns) akuzange kuchaphazeleke yi-SCH23390. Ke ngoko, nangona ukufakwa kweli dosi ye-SCH23390 kuncitshiswe ukhetho lomvuzo omkhulu ngexesha lomsebenzi wesaphulelo onokwenzeka, esi siphumo asibonakali sinxulumene nokuncipha ngokubanzi kwixabiso elizimeleyo lemivuzo emikhulu.
Umzobo 5.
Iziphumo ze-DA receptor modulation kwi-PFC yangaphakathi kucalucalulo lobungakanani bomvuzo. Iimpuku zaqeqeshwa ukuba zikhethe phakathi kweentsimbi ezimbini ezihambisa umvuzo we-pellet ezine okanye enye ngokukhawuleza emva kokushicilela okukodwa kunye ne-100% enokwenzeka. A, i-D1 blockade (SCH23390, 1 μg) ayizange iphazamise kakhulu ukhetho lomvuzo omkhulu weepellet ezine ngexesha lolingo lokukhetha lwasimahla olunxulumene nonyango lwe-saline. B, i-D2 receptor stimulation (quinpirole, 10 μg) nayo ayizange itshintshe ukhetho lomvuzo omkhulu.
Ukuvuselela i-D2 receptor
Iprofayili efanayo yokuzikhethela yabonwa kwiigundane ezifumana umthamo ophezulu (10 μg) we-quinpirole kwi-PFC ephakathi. Kwakhona, iimpuku zakhetha ukhetho lwe-pellet ezine phantse kulo lonke ulingo lokhetho lwasimahla emva kokufakwa kwe-saline. Olu khetho aluzange lutshintshwe ngokukhuthazwa kwe-D2 receptors (F (1,6) = 0.53, ns; Umzobo 5B). I-Quinpirole nayo yayingenayo impembelelo ebalulekileyo kwi-latencies, i-locomotion, okanye i-omissions (zonke ixabiso le-F <1.76, ns). Qaphela ukuba unyango olufanayo luye lwanciphisa ukhetho lomvuzo omkhulu kumsebenzi wesaphulelo onokwenzeka ngexesha lokuqala, i-100% yebhloko enokwenzeka (Fig. 3B). Ingcaciso enokubakho yalo mahluko kukuba, ngokungafaniyo neempuku eziqeqeshelwe ucalucalulo lobungakanani bomvuzo, abo baqeqeshelwe umsebenzi wokwenza isaphulelo bafunde ukuba usetyenziso olunxulumeneyo lwenketho enkulu/eyingozi iyancipha ngeseshoni. Ke, ukumelwa kwabo kwexabiso elihambelanayo lokhetho olukhulu lomvuzo kuya kulindeleka ukuba kube ne-labile ngaphezulu kuneempuku eziqeqeshelwe umsebenzi olula kwaye, ngenxa yoko, zichaphazeleka ngakumbi. Ngokudibeneyo, iziphumo zolu vavanyo zibonisa ukuba nangona i-blockade ye-D1 receptors kunye nokuvuselela i-D2 receptors ilutshintsha kakhulu ukhetho phakathi kwemivuzo emincinci, ethile kunye nemikhulu, enokwenzeka, ezi ziphumo azibonakali ngathi zibangelwa kukuphazamiseka okubaluleke ngakumbi ekukwazini ukucalula. phakathi kwemivuzo emikhulu nemincinci.
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Apha sinika ingxelo yokuba i-D1 kunye ne-D2 ii-receptors kwi-PFC ephakathi zinempembelelo ebalulekileyo kukhetho phakathi kokunokwenzeka ngokuchasene nemivuzo ethile. Ngaphaya koko, ukuncipha okanye ukwandisa umsebenzi wento nganye kwezi zamkeli zivelise ukwahluka, kwaye ngamanye amaxesha ngokuchaseneyo, utshintsho kukhetho, lubonisa ukuba ngamnye wabo wenza ulawulo olwahlukileyo, kodwa oluhambelanayo lokumodareyitha kwezi nkqubo zokwenza izigqibo.
Iziphumo ze-D1 / D2 receptor blockade
Kulwazi lwethu, lo ngumboniso wokuqala wokuba i-blockade ye-D1 okanye i-D2 receptor kwi-PFC ephakathi ibangela iziphumo ezichasayo ekuziphatheni. Izifundo zangaphambili zolu hlobo zibonakalise nokuba i-D1, kodwa ingeyiyo i-D2, inkcaso iphazamisa imisebenzi efana nengqalelo okanye inkumbulo yokusebenza (uWilliams noGoldman-Rakic, 1995; Seamans et al., 1998; Granon et al., 2000) okanye zombini ama-receptors asebenza ngokubambisana ukuququzelela ukutshintshwa-ukutshintshwa okanye ukuziphatha kakubi kude nabajezi bemeko (i-Ragozzino, i-2002; i-Floresco kunye ne-Magyar, i-2006). Iziphumo zethu zokuba i-SCH23390 kunye ne-eticlopride zenze iziphumo ezichaseneyo ekukhethweni zibonisa ukuba ukwenza izigqibo eziqhelekileyo kuxhomekeke kwibhalansi ebalulekileyo ye-lobe yangaphambili ye-D1 kunye nomsebenzi we-D2 receptor, kwaye ukuguqula le bhalansi kubangela utshintsho olungenakulinganiswa ekukhetheni imivuzo ethile / engaqinisekanga.
Ukuvalwa kwe-PFC D1 kuncitshiswe ukhetho olukhulu / olunomngcipheko ngendlela exhomekeke kwidosi, kakhulu ngexesha leebhloko ezintathu zokugqibela ezinokwenzeka. I-SCH23390 yandisa isaphulelo esinokwenzeka, esifana nemiphumo yale khompawundi xa ilawulwa ngenkqubo (iSt. Onge kunye neFloresco, 2009). Okubangela umdla kukuba, ukunciphisa ukuhanjiswa kwe-DA kwizifundo zabantu nge-tyrosine yokuncipha kwakhona kukhokelela ekuthatheni izigqibo ezikumgangatho ophantsi kunye nomgangatho ophantsi kwiCambridge Gambling Task (McLean et al., 2004). Iziphumo zethu zibonisa ukuba ezi ziphumo zinokulamlwa ngokuyinxenye ngokunciphisa i-prefrontal D1 activation. Uhlalutyo lokukhetha ngokhetho lubonise ngakumbi ukuba oku kuncitshiswa kokukhetha ukhetho olunobungozi kwakudityaniswe notyekelo olwandisiweyo lokukhetha ukhetho oluncinci / oluthile olulandela ukhetho olunobungozi olungavuzwa, lubonisa ukuba iziphumo zokwenziwa kwezigqibo zinokuba sisiphumo sokunyuka. ubuntununtunu kwingxelo engakhiyo. Ngendlela efanayo, i-blockade ye-D1 receptors kwi-prelimbic okanye i-anterior cingulate inciphisa ukhetho lwemivuzo emikhulu xa ilibaziseka (Loos et al., 2010) okanye idibene neendleko ezinkulu zomzamo (iSchweimer kunye noHauber, i-2006). Ngokudibeneyo, ezi ziphumo zibonisa ukuba umqondiso we-PFC D1 unempembelelo enkulu kuvavanyo lweendleko / izibonelelo, ukuququzelela ukukwazi ukoyisa iindleko ezinokunxulunyaniswa nemivuzo emikhulu kumzamo wokwandisa iinzuzo zexesha elide.
Ngokwahlukileyo koko, i-PFC D2 ibhlokhi ye-receptor yonyusa ukhetho lokhetho olukhulu / olunomngcipheko, lucotha ukutshintshwa kokhetho lokukhetha njengoko amathuba okuvuza ehlile ngeseshoni. Ngokucacileyo, esi siphumo sifana neso esibangelwa yi-PFC yokungasebenzi phantsi kweemeko ezifanayo zomsebenzi (iSt. Onge kunye neFloresco, i-2010). Nangona kunjalo, asikholelwa ukuba oku kubonisa ukwanda ngokubanzi "kwingozi" yokuziphatha nganye. Endaweni yoko, iziphumo zethu zangaphambili zikhokelele ekubeni sigqibe kwelokuba i-PFC yangaphakathi idlala indima ebalulekileyo ekubekeni iliso kutshintsho kumvuzo onokwenzeka ukulungelelanisa indlela yokuziphatha ngokufanelekileyo. Iziphumo zangoku ziyanda kule nto, zityhila ukuba ii-receptors ze-D2 zenza igalelo elibalulekileyo kulawulo lwePFC kulo mba wokwenza izigqibo. Oku kunyuka okubonakalayo ekukhetheni okuyingozi kuqhutywa ngokubonakalayo ngakumbi kukunyuswa kokukhetha ukhetho olunobungozi emva kokufumana umvuzo omkhulu kulingo lwangaphambili. Ke, endaweni yokudibanisa ulwazi malunga nethuba lokufumana umvuzo omkhulu kuzo zonke izilingo ezininzi, i-D2 blockade ibangele ukwamkelwa komvuzo omkhulu ukwenza impembelelo enkulu kwaye ekhawulezileyo kwisalathiso sokhetho olulandelayo. Oku kuhambelana nophononongo lwakutsha nje ebantwini, apho inkcaso ye-D2 inyuse zombini ukhetho lokukhetha oluhambelana nomvuzo onokwenzeka kunye notshintsho oluhambelanayo nomsebenzi we-PFC we-ventromedial (Jocham et al., 2011). Ngokudibeneyo, ezi ziphumo zibonisa ukuba i-PFC D1 kunye ne-D2 ii-receptors zenza ngokwahlukileyo, kodwa igalelo elihambelanayo ekwenzeni izigqibo. Umsebenzi we-D1 receptor ukhuthaza ukhetho lwemivuzo emikhulu, kodwa engaqinisekanga okanye enexabiso elingaphezulu, ngelixa i-D2 i-receptors ithomalalisa impembelelo ekhawulezileyo enokuthi ibe nkulu, imbuyekezo enokwenzeka yokuzikhethela, iququzelela ukukwazi ukulungisa indlela yokuziphatha kwixesha elide xa amathuba okufumana le mivuzo. utshintsho.
Iziphumo ze-D1 / D2 receptor stimulation
I-Intra-PFC infusions ye-D1 receptor agonist SKF81297, ngaphakathi kwemilinganiselo yedosi ebonakaliswe ukuba yenze iziphumo ezahlukileyo kwezinye iindlela zokuqonda (ingqalelo, inkumbulo yokusebenza), ayizange itshintshe kakhulu ukhetho olunobungozi, nangona olu nyango lwanda kancinci ukhetho olukhulu / i-lever enobungozi, ebaluleke kakhulu ngedosi ephantsi. Ukutolikwa kwesi siphumo se-null kufuneka kusondezwe ngononophelo, njengoko ezi ziphumo ze-non-monotonic zedosi/impendulo zibonisa ukuba i-SKF81297 inokuba noluhlu lwedosi olusebenzayo oluncinci kuneminye imisebenzi yokuqonda. Ngaphezu koko, idosi ye-0.1 μg iye yatshintsha ngokuphawulekayo iipateni zokhetho, yandisa ukusebenza kwe-win-stay kunye nokunciphisa ukulahleka kwe-shift, apho iimpuku zinokuthi zikhethe i-lever enkulu / enobungozi emva kwemivuzo kunye nokushiya umvuzo. Nangona kunjalo, inyani yokuba ukonyuka kweedosi ze-SKF81297 khange kulutshintshe kakhulu ukhetho lubonisa ukuba ukuvuselelwa kwe-PFC D1 receptors akuphazamisi kakhulu ukwenziwa kwezigqibo malunga nemingcipheko kunye nemivuzo. Ngokwahlukileyo, unyango olufanayo lunciphisa ukhetho lwemivuzo emikhulu, elibazisekileyo (i-Loos et al., 2010), ibonelela ngenkxaso eyongezelelekileyo yokuba iintlobo ezahlukeneyo zeendleko / zenzuzo yokwenza izigqibo zinokwahlulwa ngokwemithi.
I-D2 i-agonist quinpirole ibangele "ukonakala" okwenyani ekuthatheni izigqibo, ngokuphawulekayo ukuthoba ijika lesaphulelo, kunye neempuku ezibonisa isaphulelo esibonakalayo kwiinguqu ezinokwenzeka zomvuzo. Ukukhetha ukhetho lwe-pellet ezine kwancitshiswa kwi-block ye-100% (xa yayinenzuzo kakhulu), kodwa yanda kwi-block ye-12.5% (xa incinci inzuzo). Ukulandela ukuvuselela kwe-D2, umlinganiselo opheleleyo wokhetho olukhulu / olunobungozi aluzange lutshintshe ngokumalunga ne-saline (∼73%), kodwa izilwanyana zazingenaluvelwano ngokupheleleyo kwiinguqu kula mathuba. Ngaloo ndlela, ukusetyenziswa kwe-receptor ye-D2 ngokugqithiseleyo kuphazamise kakhulu ukukwazi ukulungelelanisa ukhetho, ngokucacileyo kubangela ukuba iigundane zisebenzise isicwangciso esilula sokutshintsha kwiibhloko ngelixa zigcina i-bias ngokubhekiselele kwi-lever enkulu / enobungozi. Oku kufunyanisiweyo, kudityaniswe neziphumo ze-eticlopride, icebisa ukuba amanqanaba anxulumene ne-D2 (kunokuba i-D1) ithoni ye-receptor kwi-PFC yangaphakathi inempembelelo ebalulekileyo kulo mbandela wokwenza izigqibo, kwaye mhlawumbi ukwandisa okanye ukunciphisa lo msebenzi kunokuphazamisa ukusebenza..
Iphethini yokukhetha engafanelekanga eveliswa yi-quinpirole ithwala ukufana okuphawulekayo koko kubangelwa ukunciphisa ukukhuthaza ukutya ngokutya okukhululekile kwexesha elide (iSt. Onge kunye neFloresco, i-2009). Ezi ziphumo zongezelelayo zenza ukuba kuhendwe ukuqikelela ukuba zisenokuba ziziganeko ezinxulumeneyo. Ewe, iinguqu kwi-medial PFC DA efflux ziye zacetywa ukuba zibonise umvuzo wokutya ngokubanzi okanye uphawu lwenkuthazo (Ahn kunye noPhillips, 1999; Winstanley et al., 2006). Ke ngoko, utshintsho kwisixa somvuzo ofunyenwe ekuhambeni kwexesha lunokusayinwa kwi-PFC ngokuguquguquka okuhambelanayo kumanqanaba e-mesocortical DA okuthi, ngezenzo kwi-D2 receptors, isetyenziselwe ukufumanisa utshintsho kwisixa somvuzo ofunyenwe ngokuhamba kwexesha kunye nokuququzelela utshintsho kwi. ukhetho lokukhetha. Oku kulandela ukuba ii-receptors ze-D2 ezikhukulayo zinokuphazamisa olu phawu luguqukayo, olunokuthi ekugqibeleni luvelise iipateni ezizinzileyo zokhetho.
Iminikelo engabonakaliyo ye-PFC D1 kunye ne-D2 receptors ekwenzeni izigqibo ezisekelwe kumngcipheko
Umbuzo uhlala ungowokuba kutheni i-blockade ye-D1 okanye i-D2 i-receptors kufuneka ibe neziphumo ezichasayo ekukhetheni okuyingozi, kuba i-DA engapheliyo yenza ukuba zombini ii-receptors zisebenze. Ithiyori yangoku malunga nendlela ezi zamkeli ezichaphazela ngayo ngokwahlukileyo umsebenzi wenethiwekhi ye-neural ye-PFC inokubonelela ngengqiqo kulo mba (Durstewitz et al., 2000; Seamans and Yang, 2004). Ii-receptors ze-D1 ziye zacetywa ukunciphisa impembelelo yamagalelo abuthathaka, ukuzinzisa umsebenzi wenethiwekhi ukuze umboniso omnye ulawule imveliso ye-PFC. Ngakolunye uhlangothi, umsebenzi we-D2 unciphisa iimpembelelo zokuthintela, uvumela i-PFC ye-neural ensembles ukuba iqhubele phambili i-stimuli / umelo oluninzi, ibeka uthungelwano lwe-thesis kwindawo ene-labile ngakumbi enokuvumela utshintsho kumelo..
Ngexesha lezigaba ezahlukeneyo zomsebenzi wesaphulelo onokwenzeka osetyenziswa apha, izilwanyana kwiindawo ezithile kufuneka zigcine (ngaphakathi kwebhloko enokwenzeka) okanye ziguqule (kwiibhloko ezinqamlezayo) ukumelwa kwazo kwexabiso elihambelanayo lokhetho olukhulu/lomngcipheko. Ngaloo ndlela, iziphumo ezichasayo ze-D1 / D2 antagonism echazwe apha ingabonisa igalelo elihlukeneyo la ma-receptors ngexesha lezigaba ezahlukeneyo zomsebenzi. Umsebenzi we-D1 unokuzinzisa ukumelwa kwexabiso lexesha elide lexesha elide lokhetho olunobungozi phakathi kwebhloko ethile, ukugcina ukukhetha okukhethiweyo naxa ukhetho oluyingozi lukhokelela kumvuzo oshiyiweyo (ukugcina "iliso emvuzweni"). Ukuthintela ezi zamkeli kuya kwenza izilwanyana zibe novelwano ngakumbi ekuvuzeni okushiyiweyo (okt, ukonyusa utyekelo lokulahleka), kunye nokunciphisa ukhetho oluyingozi. Ngokwahlukileyo, njengoko ukhetho olukhulu / olunobungozi luvelisa imivuzo embalwa kwiibhloko, ii-receptors ze-D2 (mhlawumbi kwiindawo ezahlukeneyo ze-neuronal) zinokuququzelela ukuguqulwa kokubonakaliswa kwexabiso. Ngaloo ndlela, ukunciphisa umsebenzi wabo kuya kuphazamisa uhlaziyo lwezi ngxelo kunye nokutshintsha okuhambelanayo kukhetho lokukhetha. Lo mzekelo unokuthi kwakhona uphendule ngokuyinxenye ngemiphumo yokunyuka kwe-D1 kunye ne-D2 umsebenzi we-receptor, oya kulindeleka ukuba ikhokele ekukhetheni okuthe gqolo kwenketho enkulu / enobungozi okanye ibangele "i-hyperflexible" state, ngokulandelanayo. Ke, iziphumo zethu zibonisa ukuba ithoni ye-PFC yeDA yenza igalelo elibalulekileyo nelintsonkothileyo kumngcipheko / kwizigwebo zomvuzo. Ngokubetha ibhalansi elungileyo phakathi komsebenzi we-D1/D2 we-receptor, i-DA ye-mesocortical inokunceda ukucokisa izigqibo zeendleko/inzuzo phakathi kokhetho lobukhulu obahlukeneyo kunye nokungaqiniseki, ukukhuthaza nokuba kusetyenziswe iimeko ezifanelekileyo ngoku okanye ukuphononongwa kwenzuzo ngakumbi xa iimeko zitshintsha.
Imihlathi
Lo msebenzi uxhaswe yinkxaso-mali evela kwiCanadian Institutes of Health Research (MOP 89861) ukuya kwiSBFSBF yiMichael Smith Foundation yoPhando lwezeMpilo uMfundi oMkhulu kwaye uJRSO ngumamkeli wokufunda kwiNzululwazi yezeNdalo kunye neBhunga loPhando lobuNjineli yaseCanada kunye noMichael. Smith Foundation kuPhando lwezeMpilo.
Imbalelwano kufuneka ibhekiswe kuDkt. Stan B. Floresco, iSebe lezeNgqondo kunye neZiko loPhando lweBrain, iYunivesithi yaseBritish Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, [imeyile ikhuselwe]
I-Copyright © 2011 ngababhali 0270-6474 / 11 / 318625-09 $ 15.00 / 0
Ucaphulo
1. ↵
1. Ahn S,
2. Phillips AG
(1999) I-Dopaminergic correlates ye-sensory-specific satiety kwi-medial prefrontal cortex kunye ne-nucleus accumbens ye-rat. J Neurosci 19: RC29, (1-6).
I-Abstract / Umbhalo opheleleyo
2. ↵
1. Bardgett ME,
2. UDepenbrock M,
3. I-Downs N,
4. Amanqaku M,
5. Luhlaza L
(2009) I-Dopamine imodareyitha ukwenza izigqibo ezisekelwe kumgudu kwiigundane. Behav Neurosci 123: 242-251.
I-CrossRefMedline
3. ↵
1. UBhari A,
2. Ukhozi DM,
3. Mar AC,
4. Robinson ES,
5. Robbins TW
(2009) Iziphumo ezidityanisiweyo ze-noradrenaline, i-dopamine, kunye ne-serotonin ibhlokhi yokuthatha umsebenzi wokuyeka ukusebenza kwiimpuku. I-Psychopharmacology 205: 273-283.
I-CrossRefMedline
4. ↵
1. UKhadinali RN,
2. Howes NJ
(2005) Iziphumo zezilonda ze-nucleus accumbens core ekukhetheni phakathi kwemivuzo emincinci ethile kunye nemivuzo emikhulu engaqinisekanga kwiimpuku. BMC Neurosci 6:37.
I-CrossRefMedline
5. ↵
1. UKhadinali RN,
2. Robbins TW,
3. Everitt BJ
(2000) Iziphumo ze-d-amphetamine, i-chlordiazepoxide, i-alpha-flupenthixol kunye neendlela zokuziphatha ekukhetheni ukuqiniswa okulibazisekayo kunye nokungabhalwanga kwiimpuku. I-Psychopharmacology 152: 362-375.
I-CrossRefMedline
6. ↵
1. Chudasama Y,
2. Robbins TW
(2004) Ukumodareyitha kweDopaminergic yengqwalasela ebonakalayo kunye nenkumbulo yokusebenza kwi-rodent prefrontal cortex. I-Neuropsychopharmacology 29: 1628-1636.
I-CrossRefMedline
7. ↵
1. Abazala MS,
2. Wei W,
3. Salamone JD
(1994) I-Pharmacological characterization of performance on the concurrent lever pressing/ feed choice procedure: iziphumo ze-dopamine antagonist, cholinomimetic, sedative and stimulant drug. I-Psychopharmacology 116: 529-537.
I-CrossRefMedline
8. ↵
1. Idenki F,
2. Walton ME,
3. Jennings KA,
4. Tjile T,
5. Rushworth MF,
6. Bannerman DM
(2005) Ukubandakanyeka okwahlukileyo kweenkqubo ze-serotonin kunye ne-dopamine kwizigqibo zeendleko-inzuzo malunga nokulibaziseka okanye umzamo. I-Psychopharmacology 179: 587-596.
I-CrossRefMedline
9. ↵
1. Durstewitz D,
2. Abaselwandle uJK,
3. Sejnowski TJ
(2000) Iimodeli ze-Neurocomputational zememori yokusebenza. I-Nat Neurosci 3 (Suppl): 1184-1191.
I-CrossRefMedline
10. ↵
1. Floresco SB,
2. UMagyar O
(2006) Uhlengahlengiso lwe-Mesocortical dopamine lwemisebenzi yolawulo: ngaphaya kwenkumbulo yokusebenza. I-Psychopharmacology 188: 567-585.
I-CrossRefMedline
11. ↵
1. Floresco SB,
2. UWhelan JM
(2009) Ukuphazamiseka kwiindlela ezahlukeneyo zeendleko / zenzuzo yokwenza izigqibo ezibangelwa ukubonakaliswa okuphindaphindiweyo kwe-amphetamine. I-Psychopharmacology 205: 189-201.
I-CrossRefMedline
12. ↵
1. Floresco SB,
2. UMagyar O,
3. Ghods-Sharifi S,
4. Vexelman C,
5. Tse MT
(2006) Ii-subtypes ezininzi ze-dopamine receptor kwi-medial prefrontal cortex ye-rat ilawula ukusetwa kwe-shifting. I-Neuropsychopharmacology 31: 297-309.
I-CrossRefMedline
13. ↵
1. Floresco SB,
2. Tse MT,
3. Ghods-Sharifi S
(2008a) Ulawulo lwe-Dopaminergic kunye ne-glutamatergic yomzamo kunye nokulibaziseka-okusekelwe kwizigqibo. I-Neuropsychopharmacology 33: 1966-1979.
I-CrossRefMedline
14. ↵
1. Floresco SB,
2. I-St Onge JR,
3. Ghods-Sharifi S,
4. Winstanley CA
(2008b) Iisekethe zeCortico-limbic-striatal zithobela iindlela ezahlukeneyo zokwenza izigqibo ngeendleko-benefit. I-Cogn Affect Behav Neurosci 8: 375-389.
I-CrossRefMedline
15. ↵
1. Ghods-Sharifi S,
2. I-St Onge JR,
3. Floresco SB
(2009) Igalelo elisisiseko yi-amygdala ye-basolateral kwiindlela ezahlukeneyo zokwenza izigqibo. J Neurosci 29: 5251-5259 .
I-Abstract / Umbhalo opheleleyo
16. ↵
1. Granon S,
2. I-Passetti F,
3. UThomas KL,
4. UDalley JW,
5. Everitt BJ,
6. Robbins TW
(2000) Uphuculo kunye nokuphazamiseka kokusebenza kwengqwalasela emva kokufakwa kwe-D1 dopaminergic receptor agents kwi-rat prefrontal cortex. J Neurosci 20: 1208-1215.
I-Abstract / Umbhalo opheleleyo
17. ↵
1. Haluk DM,
2. Floresco SB
(2009) I-ventral striatal dopamine modulation yeendlela ezahlukeneyo zokuguquguquka kokuziphatha. I-Neuropsychopharmacology 34: 2041-2052.
I-CrossRefMedline
18. ↵
1. Hutton SB,
2. Murphy FC,
3. Joyce EM,
4. URogers RD,
5. UCuthbert I,
6. Barnes TR,
7. McKenna PJ,
8. Sahakian BJ,
9. Robbins TW
(2002) Ukusilela ekwenzeni izigqibo kwizigulane ezine-episode yokuqala kunye ne-schizophrenia engapheliyo. Schizophr Res 55:249–257.
I-CrossRefMedline
19. ↵
1. UJocham G,
2. Klein TA,
3. Ullsperger M
(2011) Iimpawu zokufunda zokuqinisa i-Dopamine-mediated kwi-striatum kunye ne-ventromedial prefrontal cortex ziphantsi kokhetho olusekelwe kwixabiso. J Neurosci 31: 1606-1613.
I-Abstract / Umbhalo opheleleyo
20. ↵
1. Lihle M,
2. UPattij T,
3. Janssen MC,
4. Counette DS,
5. Schoffelmeer AN,
6. Smit AB,
7. Spijker S,
8. van Gaalen MM
(2010) I-Dopamine receptor D1 / D5 i-gene expression in the medial prefrontal cortex iqikelela ukhetho olungxamisekileyo kwiigundane. Cereb Cortex 20:1064–1070.
I-Abstract / Umbhalo opheleleyo
21. ↵
1. McLean A,
2. Rubinsztein JS,
3. Robbins TW,
4. Sahakian BJ
(2004) Iziphumo zokuncipha kwe-tyrosine kumavolontiya aqhelekileyo anempilo: iimpembelelo zokudakumba kwe-unipolar. I-Psychopharmacology 171: 286-297.
I-CrossRefMedline
22. ↵
1. Pagonabarraga J,
2. UGarcía-Sánchez C,
3. Llebaria G,
4. UPascual-Sedano B,
5. UGironell A,
6. Kulisevsky J
(2007) Uphononongo olulawulwayo lokuthatha izigqibo kunye nokuphazamiseka kwengqondo kwisifo sikaParkinson. Mov Disord 22:1430–1435.
I-CrossRefMedline
23. ↵
1. I-Paxinos G,
2. Watson C
(1998) Ingqondo yegundane kwi-stereotaxic coordinates (Academic, San Diego), Ed 4.
24. ↵
1. Ragozzino ME
(2002) Iziphumo ze-dopamine D (1) i-receptor blockade kwindawo ye-prelimbic-infralimbic kwi-flexibility yokuziphatha. Funda kuMem 9:18–28 .
I-Abstract / Umbhalo opheleleyo
25. ↵
1. URogers RD,
2. Everitt BJ,
3. I-Baldacchino A,
4. Blackshaw AJ,
5. Swainson R,
6. UWynne K,
7. Baker QAPHELA,
8. Hunter J,
9. UCarthy T,
10. Booker E,
11. London M,
12. Deakin JF,
13. Sahakian BJ,
14. Robbins TW
(1999) Iintsilelo ezidityanisiweyo kwisigqibo sokwenza izigqibo zabaxhaphazi abangapheliyo be-amphetamine, abaxhaphazi be-opiate, izigulane ezinomonakalo ogxile kwi-cortex yangaphambili, kunye namavolontiya aqhelekileyo aphelelwe yi-tryptophan: ubungqina beendlela ze-monoaminergic. I-Neuropsychopharmacology 20: 322-339.
I-CrossRefMedline
26. ↵
1. Schweimer J,
2. Hauber W
(2006) I-Dopamine D1 receptors kwi-anterior cingulate cortex ilawula ukwenza izigqibo ezisekelwe kwimigudu. Funda iMem 13:777–782 .
I-Abstract / Umbhalo opheleleyo
27. ↵
1. Schweimer J,
2. Saft S,
3. Hauber W
(2005) Ukubandakanyeka kwe-catecholamine neurotransmission kwi-rat anterior cingulate ekwenzeni izigqibo ezinxulumene nomzamo. Behav Neurosci 119: 1687-1692.
I-CrossRefMedline
28. ↵
1. Abaselwandle uJK,
2. Yang CR
(2004) Iimpawu eziphambili kunye neendlela zokuguqulwa kwe-dopamine kwi-prefrontal cortex. IProg Neurobiol 74:1-58.
I-CrossRefMedline
29. ↵
1. Abaselwandle uJK,
2. Floresco SB,
3. Phillips AG
(1998) I-D1 receptor modulation ye-hippocampal-prefrontal cortical circuits edibanisa imemori yendawo kunye nemisebenzi yokulawula kwi-rat. J Neurosci 18: 1613-1621.
I-Abstract / Umbhalo opheleleyo
30. ↵
1. I-St Onge JR,
2. Floresco SB
(2009) Ukumodareyithwa kweDopaminergic yokwenziwa kwezigqibo ezisekwe kumngcipheko. I-Neuropsychopharmacology 34: 681-697.
I-CrossRefMedline
31. ↵
1. I-St Onge JR,
2. Chiu YC,
3. Floresco SB
(2010) Iziphumo ezahlukileyo ze-dopaminergic manipulations kukhetho oluyingozi. I-Psychopharmacology 211: 209-221.
I-CrossRefMedline
32. ↵
1. I-St Onge JR,
2. Floresco SB
(2010) Igalelo le-cortical yangaphambili ekwenzeni izigqibo ezisekelwe kumngcipheko. Cereb Cortex 20:1816–1828.
I-Abstract / Umbhalo opheleleyo
33. ↵
1. Isithinteli CM,
2. Floresco SB
(2011) Iminikelo ye-nucleus accumbens kunye nemimandla yayo kwiinkalo ezahlukeneyo zokwenza izigqibo ezisekelwe kumngcipheko. I-Cogn Affect Behav Neurosci 11: 97-112.
I-CrossRefMedline
34. ↵
1. van Gaalen MM,
2. van Koten R,
3. Schoffelmeer AN,
4. Vanderschuren LJ
(2006) Ukubandakanyeka okubalulekileyo kwe-dopaminergic neurotransmission ekwenzeni izigqibo ngokungxamayo. I-Biol Psychiatry 60: 66-73.
I-CrossRefMedline
35. ↵
1. UWilliams GV,
2. Goldman-Rakic PS
(1995) Ukumodareyithwa kwemimandla yememori yi-dopamine D1 receptors kwi-prefrontal cortex. Indalo 376:572–575.
I-CrossRefMedline
36. ↵
1. Winstanley CA,
2. Theobald DE,
3. UDalley JW,
4. Robbins TW
(2005) Ukusebenzisana phakathi kwe-serotonin kunye ne-dopamine kulawulo lokhetho olungxamisekileyo kwiigundane: iimpembelelo zonyango zokuphazamiseka kokulawulwa kwempembelelo. I-Neuropsychopharmacology 30: 669-682.
I-Medline
37. ↵
1. Winstanley CA,
2. Theobald DE,
3. UDalley JW,
4. UKhadinali RN,
5. Robbins TW
(2006) Ukwahlulwa kabini phakathi kwe-serotonergic kunye ne-dopaminergic modulation ye-medial prefrontal kunye ne-orbitofrontal cortex yokhetho olunganyanzelekanga. Cereb Cortex 16:106–114 .
I-Abstract / Umbhalo opheleleyo
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