J Neurosci. 2011 Jun 8; 31 (23): 8625-33.
St Onge JR, Abhari H, Floresco SB.
gwero
Dipatimenti ya Psychology ndi Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Kudalirika
Zosankha pakati pazinthu zina komanso zosatsimikizika za mpikisano zosiyana siyana zakonzedwa kuti zithetsedwe ndi lobes loyang'anizana ndi mesocorticolimbic dopamine (DA). Mu makoswe, njira zowonongeka za ntchito za DA kapena kutsekedwa kwa mphambano yamakono (PFC) yosokoneza chisankho chokhudzana ndi ngozi ndi mphotho. Komabe, sizikudziwika bwino momwe kufalitsa kwa PFC DA kumathandizira pazinthu izi. Tidakambirana nkhaniyi pofufuza zotsatira za mankhwala okhudzana ndi mankhwala a D1 ndi D2 amalandirira mu PFI (prelimbic) PFC pakusankha pakati pazing'ono, zina ndi zazikulu, koma zopindulitsa. Makoswe adaphunzitsidwa ntchito yowonongeka yomwe nkhumba imodzi inapereka phala limodzi limodzi ndi 100% mwinamwake, ndipo lina linapereka mapepala anayi, koma mwayi wodzalandira mphotho unachepa pamayeso osiyanasiyana (100, 50, 25, 12.5%). D1 blockade (SCH23390) m'kati mwa PFC inachepetsa chisankho chachikulu / choopsa. Mosiyana ndi zimenezi, D2 blockade (eticlopride) inachepetsera kusokonekera kwapadera komanso kuwonjezeka kwabwino. D1 agonist SKF81297 inachititsa kuwonjezeka pang'ono, kosafunikira kwenikweni kwa chiwindi chachikulu / choopsa. Komabe, kukakamizidwa kwa D2 kulandira (quinpirole) kunapangitsa kuti munthu akhale ndi vuto linalake lopanga chisankho, kugwiritsira ntchito mpata wochepetsetsa ndi kusankha kukasankha kuchoka kumbali kapena kuchitapo kanthu koopsa pamene sichikuthandizani, motero. Zomwe zapezazi zikusonyeza kuti PFC D1 ndi D2 amalandila amapanga zosokoneza, koma zowonjezera, zopereka zowonongeka. Poika malire abwino pakati pa ntchito ya D1 / D2 yolandira, DA angathandize kuwongolera ziweruzozi, kulimbikitsa kugwiritsa ntchito zinthu zomwe zilipo pakadali pano kapena kufufuza zopindulitsa kwambiri pamene zinthu zisintha.
Introduction
Kuthamangitsidwa kwa mesocorticolimbic dopamine (DA) kulumikizidwa ndi zoperewera zazikulu pakupanga zisankho zokhudzana ndi matenda ena amisala. Izi zikuphatikiza anthu omwe ali ndi schizophrenia (Hutton et al., 2002), matenda a Parkinson (Pagonabarraga et al., 2007), komanso zosokoneza bongo (Rogers et al., 1999). Mitundu yazinyama popanga zisankho yaulula kuti kusokonekera kwa kufalitsa kwa DA kumatha kusintha kwambiri zisankho pakati pazing'ono, zopindulitsa mosavuta komanso zazikulu, koma zotsika mtengo. Kutsekedwa kwadongosolo kwa ma D1 kapena D2 receptors kumachepetsa kukonda kudikirira kwa nthawi yayitali kapena kugwira ntchito molimbika kuti mulandire mphotho yayikulu, pomwe kufalikira kwa DA kumabweretsa kusiyanasiyana pakuyesayesa- kapena kuzengereza popanga zisankho, kukulitsa kapena kuchepetsa kukonda mphotho zazikulu zomwe zimadza ndi mtengo wokwera (Achibale et al., 1994; Kadinala et al., 2000; Denk et al., 2005; van Gaalen et al., 2006; Floresco et al., 2008a; Bardgett et al., 2009). Mofananamo, pamene makoswe amasankha pakati pazing'ono, zazikulu ndi zazikulu, komabe zimakhala zopanda phindu pa ntchito yowonongeka, machitidwe otsogolera a D1 kapena otsutsa a D2 amachepetsa zosankha zazikulu, zoopsa (St. Onge ndi Floresco, 2009). Mosiyana ndi zimenezo, D1 kapena D2 agonists kusankha zosankha zazikulu, zoopsa. Komabe, popeza kuti madera ambiri a ubongo akhala akuphatikizidwa mu chiweruzo cha mphoto / mphoto (mwachitsanzo, frontal lobes, ventral striatum, amygdala) (Floresco et al., 2008b), malo osatha omwe DA angakhale akuyendetsa zinthu izi sizikhala bwino .
DA imayendetsa ntchito zamtundu wankhanza zomwe zimayendetsedwa ndi zigawo zosiyanasiyana za prefreal cortex (PFC), monga kusintha kwa khalidwe, kugwira ntchito, kukumbukira (Williams ndi Goldman-Rakic, 1995; Granon et al., 2000; Chudasama ndi Robbins, 2004; Floresco et al., 2006), kawirikawiri mu mphepo yamtundu wa "U" yomwe imakhala yovuta kwambiri, kumene ntchito yaying'ono kapena yochuluka kwambiri ya DA imalepheretsa ntchito zina zapamwamba. Komabe, pakhala zowerengeka zochepa zopenda ndikufufuza zopereka za PFC DA ku mitundu yosiyanasiyana ya mtengo waphindu / kupanga mapindu. Kuchepetsa ntchito ya DA m'zinthu zosiyana siyana zomwe zimagwiritsidwa ntchito pochita khama (Schweimer et al., 2005; Schweimer ndi Hauber, 2006), komabe kutsekedwa kapena kukakamizika kwa PFC D1 receptors kumachepetsa zofuna zapadera, kuchepetsa malipiro (Loos et al., 2010 ). Ndipotu, palibe pulogalamu yomwe ikufufuza za zopereka zosiyanasiyana za PFC DA zotengera zokambirana.
Ntchito yatsopano yakhala ikudziwika kuti PFC ndi yapakati pazomwe zimakhala zovuta kwambiri, koma ntchito zina m'madera ena (zowoneka bwino, zowonongeka, zowonjezera) siziwoneka kuti zimathandizira kuchita izi (St. Onge ndi Floresco, 2010). Kuwonetseratu za PFC yapakatikati kunapangitsa kuti anthu azikhala ndi mwayi wopindula kwambiri, pamene zovuta zowonjezerazo zatsika pamapeto pa gawoli, koma kuchepetsa chisankho pamene mphotho zowonjezera zawonjezeka pa gawoli. Zotsatira za phunziroli zinatipangitsa kuganiza kuti PFC yapakati ikuphatikizira mfundo zokhudzana ndi kusintha mphotho zowonjezereka kuti zisonyeze kufunika kwazithunzi zomwe zimapangitsa kuti zisankho zitheke bwino. Chifukwa cha ntchito yovuta kwambiri imene DA imasewera pamaganizo ena (Floresco ndi Magyar, 2006), kafukufukuyu akufufuza zopereka za opouraal D1 / D2 ntchito yopanga chiopsezo pogwiritsa ntchito ntchito yowonongeka.
Zida ndi njira
Nyama.
Makoswe aamuna a Long-Evans (Charles River Laboratories) olemera 275-300 g koyambirira kwamaphunziro azikhalidwe adagwiritsidwa ntchito poyesa. Pakufika, makoswe adapatsidwa sabata la 1 kuti azolowere koloniyo ndipo chakudya chidangolekezera 85-90% yakulemera kwawo kodyetsa kwaulere sabata lowonjezera asanaphunzitsidwe zamakhalidwe. Makoswe anapatsidwa ad libitum mwayi wopeza madzi nthawi yonse yoyesera. Kudyetsa kumachitika m'nyumba zosungira makoswe kumapeto kwa tsiku loyesera, ndipo zolemera zamthupi zimayang'aniridwa tsiku ndi tsiku kuti zitsimikizike kuti muchepetse kuchepa panthawi yoletsa zakudya komanso kukonza kapena kunenepa kwambiri poyesa konseko. Kuyesedwa konse kunali kogwirizana ndi Canadian Council of Animal Care ndi Animal Care Committee ya University of British Columbia.
Zida.
Kuyezetsa machitidwe kunkachitika m'zipinda zogwirira ntchito za 12 (30.5 × 24 × 21 masentimita; Ophatikiza Ma Med) omwe amalowetsamo mabokosi ochepetsera mawu, omwe ali ndi fanesi kuti apereke mpweya wabwino ndi kusokoneza phokoso lopitirira. Chipinda chilichonse chinali ndi zitsulo ziwiri zokhazikika, zomwe zimakhala kumbali zonse za chakudya chofunikira chomwe chimakhala chakudya (45 mg; Bio-Serv) chomwe chinkaperekedwa kudzera m'zipangizo zamatabwa. Zipindazi zinkaunikiridwa ndi kuwala kwina kwa 100 mA komwe kunali pamwamba pa khoma moyang'anizana ndi levers. Zithunzi zinayi zojambulapo zapachilengedwe zinkaikidwa pambali pa chipinda chilichonse. Ntchito yowonongeka inalembedwa ndi chiwerengero cha mapulogalamu a photobeam omwe anachitika patsiku. Deta yonse yamayesero inalembedwa ndi makompyuta a IBM omwe amagwirizanitsidwa ndi zipinda kudzera mu mawonekedwe.
Maphunziro opondereza ena.
Mapulogalamu oyambirira omwe tinaphunzitsidwa nawo anali ofanana ndi a St. Onge ndi Floresco (2009), monga adasinthidwa kuchokera kwa Cardinal et al. (2000). Patsiku loyamba asanalowe m'chipinda, makoswe anapatsidwa ~ xNUMX shuga zopatsa mphoto m'nyumba zawo. Patsiku loyamba la maphunziro, zidutswa za 25-2 zidaperekedwa mu kapu ya chakudya ndi mapepala ophwanyika anaikidwa pa lemba nyama isanayidwe m'chipinda. Makoswe anaphunzitsidwa koyamba pa ndondomeko ya 3 yokhazikika pazomwe zimayambira pa 1 minesiti mu 60 min, choyamba pa levo imodzi, ndiyeno mobwerezabwereza kwa lever ina (counterbalanced kumanzere / pakati pakati pa nkhani). Makoswe anaphunzitsidwa pa ntchito yosavuta ya ntchito yonse. Zitsanzo za mayesero a 30 zinayamba ndi ndondomeko zotsitsimula ndikubwezeretsanso ndipo chipinda chogwirira ntchito chili mumdima. Zina zonse za 90, mayesero anayamba kuyambika ndi kuwala kwa nyumba komanso kuika chimodzi mwa ziwiya ziwiri kuchipinda. Ngati ngongoleyo idalephera kuyankha pa chiwindi mkati mwa 40 s, chiwindicho chinachotsedwa, chipindacho chinadetsedwa, ndipo chiyesocho chinasankhidwa ngati chopanda pake. Ngati makoswewo atayankhidwa mu 10 s, chiwindicho chinachotsedwa ndipo pulogalamu imodzi imaperekedwa ndi 10% mwayi. Ndondomekoyi idagwiritsidwa ntchito kuti zidziŵe makoswe ndi zovuta za ntchito yonse. M'mayesero onse awiri, lemba lakumanzere kapena lamanja linaperekedwa kamodzi, ndipo dongosolo mkati mwa mayeserowo linali losavuta. Makoswe adaphunzitsidwa ~50-5 d pambali ya 6 kapena mayesero opambana (ie; ≤80 omissions).
Ntchito yotsitsimula yokhazikika.
Ntchito yaikulu yomwe ikugwiritsidwa ntchito mu maphunzirowa yakhala ikufotokozedwa kale (Floresco ndi Whelan, 2009; Ghods-Sharifi et al., 2009; St. Onge ndi Floresco, 2009, 2010; St. Onge et al., 2010), ndipo poyamba adasinthidwa kuchokera ku zomwe adafotokozedwa ndi Cardinal ndi Howes (2005) (mkuyu. 1). Mwachidule, makoswe amalandira magawo a tsiku ndi tsiku omwe ali ndi mayesero a 72, omwe amagawanika muzitsulo za 4 za mayesero a 18. Sukulu yonseyi inatenga 48 min kuti ikwaniritse, ndipo nyama zidaphunzitsidwa 6-7 d sabata iliyonse. Chigawo chinayambira mu mdima ndipo maulendo onse awiri anachotsedwa (dziko loyendetsa dziko). Chiyeso chinayambira 40 s iliyonse ndi kuunikira kwa kuwala kwa nyumba ndipo, 3 mtsogolo, kulowetsa kamodzi kapena zonse ziwiri mu chipinda (mtundu wa mayesero amodzi ukuwonetsedwa mkuyu. 1). Chiwindi chimodzi chinasankhidwa ndi chiwindi chachikulu / choopsa, chimzake chaching'ono / chiwindi, chomwe chinatsalira nthawi zonse pophunzitsa (counterbalanced kumanzere / kumanja). Ngati makoswe sanayankhe mwa kukakamiza chiwindi mkati mwa 10 s kawonetsedwe ka lever, chipindacho chinasinthidwa ku dziko linalake mpaka chiyeso chotsatira (kutaya). Pamene chiwindi chinasankhidwa, maulendo onse awiri anachotsedwa. Kusankha kwaling'ono / kansalu kena kameneka nthawi zonse kumapereka pepala limodzi ndi 100% mwayi; Kusankha chiwindi chachikulu / choopsa kwapadera kunapatsidwa mapiritsi a 4 koma ndi mwinamwake. Pamene chakudya chinaperekedwa, nyumbayo idakalipo kwa wina wa 4 pambuyo poyankha, kenako chipindacho chinabwereranso ku dziko linalake. Ma pellets ambiri anaperekedwa kwa 0.5 s. Zithunzi za 4 zinali ndi mayesero osankhidwa a 8 omwe amatsitsimutsa kamodzi kokha (mayesero a 4 pa chiwindi chilichonse, mwa awiri awiri), kulola zinyama kuti ziphunzire za mwayi wokhala ndi mphotho yayikulu kapena yaying'ono pambali iliyonse. Izi zinkatsatiridwa ndi mayesero osankhidwa a 10, omwe maulendo onse awiri anaperekedwa ndipo nyamayo inasankha chiwindi chaching'ono / chaching'ono kapena chachikulu / choopsa. Kukhoza kupeza mapuloteni a 4 mutasindikizira chiwopsezo chachikulu / chowopsya mosiyanasiyana pamadoko ena: poyamba poyamba 100%, ndiye 50%, 25%, ndi 12.5%, motsatira, pambali iliyonse. Mpata wokalandira mphoto yayikuru pa yesero lirilonse linachokera kugawidwa kokayikitsa. Pogwiritsira ntchito izi, kusankhidwa kwa chiwindi chachikulu / chowopsa kungakhale kopindulitsa m'mizere iwiri yoyamba, ndipo kumakhala kovuta kumalo otsiriza, pamene makoswe amatha kupeza nambala yowonjezera ya mapepala a chakudya atatha kuyankha pa chiwindi pamtunda wa 25%. Choncho, pamapeto atatu a ntchitoyi, chisankho chachikulu chotsatira chimakhala ndi "chiwopsezo" chosafuna kulandira mphotho pamayesero ena. Makhalidwe oyambitsa chisankho ndi zochita zonse zogulitsa (photobeam breaks) zinalembedwanso. Makoswe amaphunzitsidwa pa ntchitoyo, monga gulu, iwo (1) anasankha chiwindi chachikulu / choopsa panthawi yoyamba yoyesera (100%) pokhapokha 80% ya mayesero apambali, ndipo (2) adasonyeza miyeso yoyamba ya maziko kusankha, kuyesedwa pogwiritsira ntchito ndondomeko yofanana ndi yomwe inafotokozedwa ndi Winstanley et al. (2005) ndi St. Onge ndi Floresco (2009). Mwachidule, deta yochokera ku magawo atatu otsatizanawa anafufuzidwa ndi njira zobwereza mobwerezabwereza ANOVA ndi ziwiri mkati mwazifukwa (tsiku ndi mayesero).
Chithunzi 1.
Ntchito yojambula. Zopindulitsa mtengo / zopindulitsa zomwe zimakhudzana ndi kuyankha pa chiwindi (A) ndi mawonekedwe a yesewero lokhazikika laulere (B) pa ntchito yotsitsimula.
Ntchito ya kusankhana kwakukulu.
Monga momwe tachitira kale (Ghods-Sharifi et al., 2009; Stopper ndi Floresco, 2011), tinatsimikiza kuti ngati chithandizo china chinachepetsanso chiwombankhanga chachikulu / chowopsa pa ntchito yowonongeka, magulu osiyana a nyama angaphunzitsidwe ndi kuyesedwa pa ntchito yayikulu yopanga chisankho kuti aone ngati zotsatirazi zinali chifukwa cha kusokonezeka pakati pa ziphuphu zapadera zomwe zimagwirizanitsidwa ndi levers ziwiri. Muzofufuzazi, makoswe adaphunzitsidwa kuti azikakamiza kugwira ntchito yowonongeka, monga momwe adagwirira ntchito yowonongeka, pambuyo pake adaphunzitsidwa ntchito yosankhana. Pano, makoswe anasankha pakati pa lemba imodzi yomwe inapereka mapepala amodzi ndi ena omwe amapereka mapalete anayi. Mphoto ziwiri ndi zazikulu zidaperekedwa mwamsanga atangomva yankho limodzi ndi 100% mwayi. Gawoli linali ndi zigawo zinayi za mayesero, ndi chigawo chilichonse chokhala ndi 2 chokakamizidwa-kusankha kutsatiridwa ndi mayesero osankhidwa a 10.
Opaleshoni.
Makoswe anachitidwa opaleshoni pokhapokha gululo likuwonetsa ndondomeko zoyenera pa masiku a 3 otsatizana. Ndondomekoyi itatha, makoswe anapatsidwa chakudya ad libitum ndipo, pambuyo pake 2, anachitidwa opaleshoni ya stereotaxic. Makoswe ankatsitsimutsidwa ndi 100 mg / kg ketamine hydrochloride ndi 7 mg / kg xylazine ndipo kenaka anapangidwa ndi zida za 23 zogwiritsira ntchito zosapanga dzimbiri zothandizira cannulae kumtunda woyambirira wa PFC (fupa lapaderali, anteroposterior, + 3.4 mm; 0.7 mm kuchokera ku bregma; komanso kusintha kwapadera, -2.8 mm kuchokera ku dura). Zingwe makumi atatu zowonjezera, zothamanga ndi mapeto a guide guide cannulae, zidakali m'malo mpaka infusions anapangidwa. Makoswe anapatsidwa osachepera 7 d kuti ayambenso kuchipatala asanayesedwe. Pa nthawi yopuma, nyama zinkagwiritsidwa ntchito osachepera 5 min tsiku ndi tsiku ndipo chakudya chinali chochepa kwa 85% ya kulemera kwao kwaulere. Zolemera za thupi zinali kupitilira kuyang'aniridwa tsiku ndi tsiku kuti zitsimikizire kuti pang'onopang'ono nthawi yochira imakhala yolemera kwambiri.
Protocol ya Microinfusion.
Pambuyo pochira kuchokera ku opaleshoni, makoswe amatha kubwezeretsedwa pang'onopang'ono kapena kupindula ntchito yayikulu ya chisankho kwa osachepera 5 mpaka mpaka, monga gulu, iwo amasonyeza makhalidwe abwino. Kwa 3 d musanayese tsiku loyesa kuyerekezera, tizilombo toyambitsa matenda tinachotsedwera ndipo ndondomeko yotsekemera inakonzedwa. Mankhwala osapanga osapangidwira anaikidwa mu guide guide cannulae kwa 2 min, koma palibe kulowetsedwa kunachitika. Ndondomekoyi inkapangika makoswe kuti azitha kupanikizika kuti athe kuchepetsa nkhawa pa tsiku la mayesero otsatira. Tsiku lotsatira akuwonetsetsa bwinobwino, gululo linalandira mayeso oyambirira a kuyesera kwa microinfusion.
Kukonzekera koyambirira kwagwiritsidwe ntchito pazoyesera zonse. Mankhwala otsatirawa amagwiritsidwa ntchito: Wotsutsa D1 R - (+) - SCH23390 hydrochloride (1.0 μg, 0.1 μg; Sigma-Aldrich), mdani wa D2 eticlopride hydrochloride (1.0 μg, 0.1 μg; Sigma-Aldrich), D1 receptor agonist SKF81297 (0.4 μg, 0.1 μg; Tocris Bioscience), ndi D2 agonist quinpirole (10 μg, 1 μg; Sigma-Aldrich). Mankhwala onse anali kusungunuka mu thupi 0.9% saline, sonicated mpaka kusungunuka, ndi kutetezedwa ku kuwala. Mazira omwe asankhidwa onse alembedwa bwino ndi gulu lathu ndi ena kuti azikhala okhudzidwa atapatsidwa intracerebrally (Seamans et al., 1998; Ragozzino, 2002; Chudasama ndi Robbins, 2004; Floresco ndi Magyar, 2006; Floresco et al., 2006; Haluk ndi Floresco, 2009; Loos et al., 2010).
Mavuto a antchito a D1 ndi a D2, agonists, ndi saline amaperekedwa mozungulira mu PFC yapakati kudzera pampu ya microsyringe yomwe imagwirizanitsidwa ndi PE tubing ndi 30 gauge cannulae yomwe inayambitsa 0.8 mm pamapeto pake, pamlingo wa 0.5 μl / 75 s. Mankhwala a cannulae adasiyidwa m'malo ena a 1 min kuti alolere kufalikira. Ngwewe iliyonse inakhala mu khola la nyumba ina kwa 10 min min isanafike kuyesedwa kwa khalidwe.
Magulu anayi amphaka adagwiritsidwa ntchito kuyesa zovuta zamagulu anayi (D1 antagonist, D2 antagonist, D1 agonist, D2 agonist). Dongosolo lazithandizo (saline, low low, mlingo wambiri) lidafananitsidwa ndi makoswe pagulu linalake lazachipatala. Kutsatira tsiku loyesa kulowetsedwa koyambirira, makoswe adalandira tsiku loyambira (osalowetsedwa). Ngati, kwa makoswe aliwonse, kusankha cholembera chachikulu / chowopsa patsikuli kupatuka ndi> 15% kuchokera pachiyambi cha preinfusion, khosweyo idalandiranso tsiku lina la maphunziro asanayesenso kulowetsedwa kwachiwiri. Tsiku lotsatira, makoswe adalandira kulowetsedwa kwachiwiri kofananira, kutsatiridwa ndi tsiku lina loyambira, ndipo pomaliza adalowetsedwa.
Histology.
Pambuyo pomaliza kuyesa khalidwe lonse, makoswe anaphedwa mu chipinda cha carbon dioxide. Ubongo unachotsedwera ndikukhazikitsidwa mu njira ya 4% formalin. Ubongowo unali wachisanu ndipo unadulidwa mu 50 μm magawo musanayambe kukwera ndi kudetsedwa ndi cresyl violet. Kuyika kunatsimikiziridwa mothandizidwa ndi ma atlas a neuroanatomical of Paxinos ndi Watson (1998). Malo omwe amavomerezedwa ndi odwala mkati mwa PFC aperekedwa m'magulu abwino a Chithunzi 2.
Chithunzi 2.
Histology. Zizindikiro za ziphuphu za ubongo zimasonyeza malo ovomerezeka a infusions kupyolera mu rostral-caudal kutalika kwa PFC yapakati pa makoswe onse.
Kusanthula deta.
Chidwi choyambirira cha chidwi chinali kuchuluka kwa zisankho zomwe zimayang'aniridwa ndi lever yayikulu / yowopsa pagawo lililonse la mayesero osankha mwaulere, ndikuphatikizira pakusiya mayesero. Pabwalo lililonse, izi zimawerengedwa pogawa kuchuluka kwa zisankho za lever wamkulu / wowopsa ndi mayeso onse opambana. Deta yosankhidwa ya gulu lirilonse la mankhwala idasanthuledwa pogwiritsa ntchito njira ziwiri mkati mwa ma ANOVA, ndimankhwala (saline, low dose, high dose) ndi block block (100, 50, 25, 12.5%) monga zomwe zili mkati. Mphamvu yayikulu yazobwezera pazosankhazi inali yayikulu pakuyesa konse kochotsera (p <0.05), kuwonetsa kuti makoswe amachotsera kusankha kwa lever wamkulu / wowopsa chifukwa mwayi wamphotho yayikulu udasinthidwa pamabuloko anayiwo. Izi sizidzatchulidwanso kwina. Ma latency oyankhira, magwiridwe antchito (photobeam break), ndi kuchuluka kwa zoyeserera zoyeserera zidawunikiridwa ndi ANOVA za njira imodzi.
Zam'mbuyo ZotsatiraZotsatira Gawo
Results
Magulu anayi a zinyama adaphunzitsidwa poyamba pazoyezetsa zosiyana ndipo adagawira limodzi mwa magulu anayi a mankhwala. Magulu awiri oyambirira a 16 aliyense, omwe adasankhidwa kuti azitsutsana ndi D1 ndi D2, amayenera kuwerengera 28 d ya maphunziro asanafike pochita ntchito mosasunthika ndi kulandira mayeso osokoneza bongo. Magulu awiri achiwiri a 14 ndi 14 makoswe a agulu a D1 ndi a D2 amafunikira pafupifupi a 34 d a maphunziro asanafike poyendetsa bwino ntchito. Mauthenga ochedwa latency, locomotor, ndi kuyesedwa kwa mayesero omwe amapezeka pamasiku oyesa magulu onse anayi akuwonetsedwa mu Table 1.
Gulu 1.
Kudzikonda, kusayesedwa kwa mayesero, ndi deta yolandirira deta yomwe imalandira zotsatirazi zothandizidwa ndi mankhwala kapena mankhwala osokoneza bongo mu PFC
Kutsutsana kwa D1 ndi D2 kulandira thandizo komanso kuchotsera mavuto
D1 blockade
Poyamba, makoswe 16 adaphunzitsidwa kuyesaku. Nyama imodzi idamwalira pakuchita opareshoni ndipo zambiri kuchokera kwa ena atatu zidachotsedwa chifukwa chakuyika zolakwika, zomwe zidapangitsa kuti omaliza n = 12. Kuwunika kwa zomwe zidasankhidwa kuwulula kuti kulowetsedwa kwa intra-PFC kwa wotsutsana ndi D1 SCH23390 kudapangitsa zotsatira zoyipa zamankhwala (F (2,22) = 3.26, p = 0.05) koma palibe chithandizo × block block yolumikizana (F (6,66) = 0.92, ns). Mlingo waukulu wa SCH23390 (1 μg) unachepetsa kwambiri kukonda cholembera chachikulu / chowopsa m'mabwalo atatu omaliza (p <0.05; mkuyu. 3A), pomwe mlingo wotsika (0.1 μg) sunatulutse kusintha kosadalirika pamakhalidwe abwino. Kutsekedwa kwa D1 sikunakhudze mayankhidwe oyankha (F (2,22) = 0.18, ns), kusiyidwa kwamayesero (F (2,22) = 0.54, ns), kapena kuwerengera oyendetsa (F (2,22) = 1.66, ns ).
Chithunzi 3.
Zotsatira zamankhwala osokoneza bongo a DA mu PFC yamankhwala pochotsera mwayi. Zambiri zimakonzedwa potengera kuchuluka kwa cholembera chachikulu / chowopsa pamayeso osankha mwaulere block block (x-axis). Zizindikiro zikuyimira + SEM. Nyenyezi zakuda zimatanthauzira zazikuluzikulu (saline vs mlingo waukulu, p <0.05). Nyenyezi zakuda zimatanthawuza kusiyana kwakukulu (p <0.05) pakati pazithandizo zamankhwala pazovuta zina. A, Infusions of the 1.0 μg dose of D1 antagonist SCH23390 accelerated probabilistic discounting, kuchepetsa chiopsezo kusankha. B, Mosiyana ndi izi, infusions ya 1.0 μg dose ya D2 antagonist eticlopride yabweza kuchotsera ndikuwonjezera chisankho chowopsa. C, agonist D1 SKF81297 adapangitsa kuwonjezeka pang'ono, kopanda tanthauzo pakusankha koopsa. D, Infusions of the 10 μg dose of the D2 agonist quinpirole anachotsa kuchotsera, kuchepa kusankha kowopsa panthawi yoyamba ndikupanga chisankho munthawi yomaliza.
D2 blockade
Poyamba, makoswe 16 adaphunzitsidwa kuyesaku. Nyama imodzi idamwalira pakuchita opareshoni ndipo zomwe zidafotokozedwazo zidachotsedwa chifukwa chakuyika zolakwika, zomwe zidapangitsa kuti omaliza n = 12. Kuwunika kwa zomwe adasankha kunavumbulutsanso chithandizo chamankhwala (F (2,22) = 3.76, p <0.05) koma palibe chithandizo × block block interaction (F (6,66) = 0.84, ns). Komabe, mosiyana ndi zovuta za D1 receptor blockade, kuchuluka kwakukulu kwa eticlopride (1 μg) kumakulitsa kwambiri kukonda kwa lever yayikulu / yowopsa pamagawo onse (p <0.05; mkuyu. 3B), wokhala ndi mlingo wochepa (0.1 μg ) ndikupanga kuwonjezeka pang'ono, koma kopanda tanthauzo posankha. Eticlopride sinakhudze mayankho ake (F (2,22) = 0.63, ns), kusiyidwa kwamayesero (F (2,22) = 1.45, ns), kapena kuwerengera oyendetsa (F (2,22) = 0.99, ns) . Chifukwa chake, kutsekedwa kwa ma D1 kapena D2 receptors mu medial PFC kudakhala ndi zotsatirapo zina pamtengo wotsika. Kuchepetsa zochitika za D1 kulandila kumathandizira kuchotsera mphotho zazikulu, zosatsimikizika, pomwe kutsutsana kwa D2 kulandila kuchotsera, kumawoneka ngati kukucheperachepera ndikuwonjezera kusankha kosawopsa, motsatana.
D1 ndi D2 zokopa zokhazokha ndi kuchotsa zovuta
Kulimbikitsa kwa D1
Poyamba, makoswe a 14 adaphunzitsidwa kuyesera. Nyama imodzi inafa panthawi ya opaleshoni ndipo deta yomwe idasankhidwa inali yosasankhidwa chifukwa deta yake yosankhidwa mwapadera inali 2 SD pansi pa tanthauzo la gulu lonselo, zomwe zinachititsa kuti n = 12 ikhale yomaliza. Pambuyo poyendetsa D1 agonist SKF81297 mu PFC yapakati, makoswe amayesera kusonyeza zotsatira zosiyana ndi zomwe zinayambitsa mdani wa D1, kuwonetsa kuwonjezeka kwakukulu kosankhidwa ndi chiwindi chachikulu / choopsa, ndipo zotsatira zake zimakhala zazikulu pambuyo pa chithandizo ndi m'munsi, 0.1 μg mlingo. Ngakhale chizoloŵezi chimenechi, kusanthula deta yosankhidwa sikunathenso kuwonetsa zotsatira za mankhwala (F (2,22) = 2.05, Ns) kapena chithandizo × Kuphatikizana (F (6,66) = 0.10, ns; Fig. 3C), ngakhale mwachindunji Kuyerekeza pakati pa mankhwala ochepa ndi mankhwala ochizira amchere kunasonyeza kusonyeza chiwerengero cha chiwerengero (p = 0.086). D1 agonist sinakhalanso ndi zotsatira pa yankho lakutembenuka (F (2,22) = 0.67, ns), zosayesedwa zamayesero (F (2,22) = 0.06, ns), kapena chiwerengero cha ogulitsa (F (2,22) = 0.36, ns).
Kulimbikitsa kwa D2
Apanso, makoswe a 14 adaphunzitsidwa kuyesaku. Zambiri kuchokera pa rat imodzi sizinapezeke chifukwa chosankha chake choyambirira sichinawonekere kuchotsera pambuyo pa 34 d yamaphunziro, pomwe zomwe zimakhudzana ndi khoswe wina zidachotsedwa chifukwa chakuyika kolakwika, zomwe zidapangitsa komaliza n = 12 mgululi. Kuchiza ndi D2 agonist quinpirole kunapangitsa kuti zisankho zikhale zapadera poyerekeza ndi zomwe zimachitika ndi wotsutsa wa DA wolandila kapena D1 agonist. Kuwunika kwa zosankha zosankhidwa sikunawonepo kanthu pachithandizo (F (2,22) = 0.05, ns), koma panali chithandizo chofunikira × kulumikizana (F (6,66) = 2.33, p <0.05, Dunnett's p <0.05). Kuwunika kosavuta kwaposachedwa kunawonetsanso kuti, pomwe kuchuluka kocheperako (1 μg) kwa quinpirole sikunakhudze konse pakusankha, kuchuluka kwakukulu (10 μg) kumatulutsa kutchulidwa "kofewa" kwa mphotho yotsitsa. Makamaka, mlingowu kwambiri (p <0.05) unachepetsa kusankha kwa chiwindi chachikulu / chowopsa pachigawo choyambirira cha 100%, koma chinawonjezera chisankho chowopsa panthawi yomaliza (12.5%) yokhudzana ndi infusions ya saline (mkuyu. 3D). Kuphatikiza apo, kutsatira infusions ya saline kapena 1.0 μg mlingo wa quinpirole, makoswe adawonetsa kuchotsera kwakukulu pamachitidwe akulu / owopsa chifukwa zovuta zopeza mphotho yayikulu zatsika pagawo limodzi (p <0.005). Mosiyana ndi izi, kuchuluka kwa chisankhochi sikunasinthe kwambiri pamiyala inayi mutalandira chithandizo ndi 10 μg ya quinpirole (p> 0.25). Quinpirole sizinakhudze mayankho olowera m'mayesero (F (2,22) = 0.84, ns) kapena kuchuluka kwa oyendetsa magalimoto (F (2,22) = 1.72, ns), ngakhale kuti kuchuluka kwakulirako kudakulitsanso magawo osankhidwa pamabwalo anayiwo (F ( 2,22) = 3.54, p <0.05 ndi Dunnett's, p <0.05; Gulu 1).
Kupindula / kutaya-kusintha kusintha
Kulowetsedwa kwa ma Don kapena D1 receptor agonists kapena otsutsana nawo mu PFC yamtundu uliwonse kumapangitsa kuti pakhale chisankho. Kuti tidziwe bwino momwe mankhwalawa adakhudzira njira zosankhira ndikusintha pakuchepa, tidachita zowunikira zowerengera zosankha. Makamaka, tinapanga kusanthula ndi kusankha kuti tiwone ngati kusintha kwamakhalidwe kumachitika chifukwa chosintha mwayi wosankha lever wowopsa pambuyo pakupeza mphotho yayikulu (magwiridwe antchito) kapena zosintha pakumverera koyipa (kutaya-kusintha magwiridwe antchito) (Bari et al., 2; Stopper ndi Floresco, 2009). Zinyama zomwe zidasankhidwa pantchitoyi zidawunikiridwa molingana ndi zotsatira zoyeserera zaulere zam'mbuyomu (mphotho kapena mphotho) ndikuwonetsedwa ngati chiŵerengero. Kuchuluka kwamayeso opambana-kuwerengera kudawerengedwa kuchokera pomwe khoswe adasankha cholembera chachikulu / chowopsa atasankha njira yowopsa pamayeso am'mbuyomu ndikupeza mphotho yayikulu (yopambana), yogawidwa ndi kuchuluka kwa ufulu wosankha mayesero omwe khoswe adalandira mphotho yayikulu. Mosiyana ndi izi, magwiridwe antchito osintha anawerengedwa kuchokera pomwe makoswe adasunthira kusankha kwa wocheperako / winawake wa lever atasankha njira yowopsa pamilandu yam'mbuyomu ndipo sanalandire mphotho (kutayika), yogawidwa ndi kuchuluka kwa mayesero osankha mwaulere kumabweretsa kutayika.
Chifukwa cha kusagwirizana kwa ntchitoyi, pazitsulo zinai panali zosachepera 4-5 pomwe nyama imodzi sinasankhe chiwindi chachikulu / choopsa (choncho, sichikanakhoza "kukhala" kapena "kusintha" pambuyo pa kupambana kapena kutayika) kapena sanapeze mphotho yayikuru nthawi zonse panthawi inayake (makamaka zigawo ziwiri zomaliza). Choncho, muzochitika zonsezi, zizindikiro zomwe zimagwiritsidwa ntchito poyerekeza ndi ziwerengerozi zingakhale zero chifukwa chimodzi mwazitsulo, zomwe zimatilepheretsa kuti tipeze chidziwitso cha deta. Pofuna kuthana ndi izi, kufufuza kunayesedwa pa mayesero onse pazitsulo zinayi, monga momwe tachita kale (Stopper ndi Floresco, 2011). Kusintha kwa ntchito yogonjetsa-ntchito kunagwiritsidwa ntchito monga chiwonetsero chachikulu cha kupeza mphoto yaikulu, yowopsya pamakhalidwe abwino otsatila, pamene kusintha kwa ntchito yosasinthika kunakhala ngati ndondomeko ya chisamaliro chosayenerera pa nthawi yonse ya mayesero gawo.
Popeza kuti chilichonse chamagulu anayiwo chimapangitsa kuti munthu akhale ndi machitidwe abwino, tinali ndi chidwi chofanizira momwe gawo lililonse limagwirira ntchito mankhwala amchere. Pakuwunika uku, tidagwiritsa ntchito zomwe tapeza pochiza ndi mankhwala othandiza kwambiri pamankhwala aliwonse ndi jakisoni wamagalimoto ofanana (a SKF81297, tidagwiritsa ntchito zomwe tidapeza titalandira chithandizo ndi m'munsi, 0.1 μg dose). Kufufuza kwamayesero opambana ndikukhala osasunthika kwawonetsa kuyanjana kwakukulu kwa njira zinayi zamayesero (win-stay vs lose-shift) × chithandizo (saline vs mankhwala) × receptor (D1 vs D2) × mtundu wa mankhwala (antagonist vs agonist ) (F (1,44) = 11.92, p <0.05; Mkuyu 4, Gulu 2). Monga tawonera ndikuwunika mayendedwe onse asankho, kulumikizana kwanjira zinayi izi kumayendetsedwa ndi chifukwa chakuti mankhwala aliwonse amathandizira pakukonda kukhalabe / kutaya-kusintha kosintha. Ponena za magwiridwe antchito opambana, poyang'aniridwa, makoswe adawonetsa chizolowezi (pakati pa 80 ndi 90%) kuti asankhe lever wowopsa atasankha lever pamlandu wapitawu ndikulandila mphotho, monga tawonera kale (Stopper ndi Floresco , 2011). Mosiyana ndi izi, nyama zimakonda kusunthira kwa lever yaying'ono / yotsatira kutsatira "kutayika" mutasankha cholembera chachikulu / chowopsa pa -25-30% ya mayeserowa poyang'aniridwa.
Chithunzi 4.
Zotsatira za PFC DA receptor zochitika pa kupambana-galasi (gray galasi) ndi kutaya-kusintha (zoyera). Kuti ziwoneke bwino ndi zofanana, detayi ikufotokozedwa pano potsata kusiyana pakati pa mavotolo omwe amapezeka pa mankhwala osokoneza bongo (machitidwe abwino amasonyeza kuwonjezeka kwa chiwerengero, kuchepa kwa chiwerengero cha mankhwala osokoneza bongo chifukwa cha mankhwala osokoneza bongo). Deta zazikulu zomwe zimagwiritsidwa ntchito pofufuza momwe izi zimapezedwera zimaperekedwa mu Table 2. Zosagonjetsa zowonjezereka zimalongosola kuchuluka kwa mayesero omwe makoswe amasankha chiwindi chachikulu / chowopsa pambuyo poti adzalandire mphotho yayikuru pachiyeso choyambirira. Kutaya-kusintha kosinthika kumawerengetsera kuchuluka kwa mayesero omwe makoswe amasinthira kusankha kwaling'ono / kansalu kena kamodzi kotsatila kopanda malire a chiwindi chachikulu / choopsa. Nyenyezi zimatanthauzira kusiyana kwakukulu kuchokera ku saline pa msinkhu wa 0.05. ns, osati zofunikira.
Gulu 2.
Kugonjetsa / kutaya-kusinthana kwa makoswe akugwira ntchito yowonongeka yopanda chithandizo mutatha kulowetsedwa kwa saline ndi mlingo wapamwamba kwambiri kapena wothandiza kwambiri wa antchito a D1 ndi D2 kapena agonist
Kuwunika kosavuta kwamayendedwe amachitidwe anayi kudawulula kuti wotsutsana ndi D1 SCH23390 sanakhudze magwiridwe antchito koma adakulitsa kwambiri zizolowezi zosintha (Dunnett's, p <0.05), kuwonetsa kuti kuchepa kwa chisankho chowopsa chothandizidwa ndi mankhwalawa Zitha kukhala zochititsa chidwi kuti gawo lina limakhudzidwa ndi mayankho olakwika (mwachitsanzo; mphotho). Mosiyana ndi izi, D2 blockade yokhala ndi eticlopride (1 μg) idakulitsa kwambiri mwayi wosankha njira yowopsa potsatira "win" (p <0.05), pomwe imayambitsa kuchepa kopanda tanthauzo pakuchepa kosintha. Chifukwa chake, kuwonjezeka kwa chisankho chowopsa choyambitsidwa ndi D2 blockade kumawoneka kuti kumachitika makamaka chifukwa chakulimbikitsidwa kupeza mphotho yayikulu posankha pambuyo pake.
D1 agonist SKF81297 (0.1 μg) idakulitsa magwiridwe anthawi zonse poyerekeza ndi saline (p <0.05), komanso anali ndi zotsatira zotsutsana ndi SCH23390, zomwe zimachepetsa chizolowezi chosintha pambuyo potaika kwa lever wamkulu / wowopsa (p <0.05) . Mosiyana ndi izi, quinpirole (10 μg) inali ndi zotsatira zotsutsana ndi agonist a D1 pazomwe zimapambana, zomwe zimachepetsa mwayi wosankha lever yayikulu / yowopsa pambuyo pa "win" (p ya zazikulu, komabe zosatsimikizika. Chithandizochi sichinakhudze kwambiri magawanidwe otaya nthawi. Zotsatira izi zikuwonetsa kuti kusinthasintha kwa D0.05 vs D1 receptor kumapangitsa kusintha kosiyanasiyana pamachitidwe osankhidwa omwe amawoneka kuti akusintha mosiyanasiyana pakukhala ndi mphotho yayikulu kapena kukhudzika kwa mayankho.
Kusankhidwa kwakukulu kopindulitsa
Kutsekedwa kwa ma D1 receptors kapena kukakamiza kwa D2 receptors kunachepetsa kukonda ndalama zazikuru, zosatsimikizika pazochitika zina zoyesedwa za ntchito yochotsera. Kuti tiwone ngati zotsatirazi zimayesedwa ndi kusokoneza pakati pa mphotho zapadera zosiyana, tinayesanso kuyesera, momwe magulu awiri osiyana a makoswe adaphunzitsidwa ntchito yosavuta. Mphungu inasankha pakati pa levers awiri yomwe imapereka imodzi kapena ma pellets, onse awiri ndi 100% mwayi. Mapiko khumi ndi asanu adaphunzitsidwa a 11 d ntchitoyi asanalandire mankhwala ochepa a SCH23390 (1 μg) kapena quinpirole (10 μg) ndi saline. Deta ya nyama imodzi inachotsedwa chifukwa cha malo osalungama, kusiya nambala ya 6 mu gulu la SCH23390 ndi 8 mu gulu la quinpirole.
D1 blockade
Kutsatira kulowetsedwa kwa saline, makoswe amawonetsa kukondera kwakukulu pamphoto yayikulu, posankha izi pamayeso pafupifupi 100% (mkuyu. 5A). Kutsatira kulowetsedwa kwa SCH23390 (1 μg), panalibe kusintha kulikonse pankhani yazitsulo zinayi (F (1,5) = 1.72, ns). Mosiyana ndi kusankha, tawona kuwonjezeka pang'ono pakayankhidwe kotsatira D1 blockade (saline = 0.81 ± 0.1 s, SCH23390 = 0.98 ± 0.1 s; F (1,5) = 7.18, p <0.05). Zochita za locomotor (F (1,5) = 4.86, ns) ndi zoyeserera zoyeserera (F (1,5) = 1.0, ns) sizinakhudzidwe ndi SCH23390. Chifukwa chake, ngakhale kulowetsedwa kwa muyeso uwu wa SCH23390 kunachepetsa kusankha kwa mphotho yayikulu pantchito yochotsera, izi sizikuwoneka kuti zikuyambitsa kuchepa konse kwa phindu lokhala ndi mphotho zazikulu.
Chithunzi 5.
Zotsatira za kusintha kwa DA mu PFC yapakati pa chisankho chachikulu. Makoswe amaphunzitsidwa kusankha pakati pa levers ziwiri zomwe zimapereka kaya mphoto ina kapena imodzi imodzi pamodzi pokhapokha makina osakaniza ndi 100% mwayi. A, D1 blockade (SCH23390, 1 μg) sizinasokoneze kwambiri makondwerero a mapiritsi akuluakulu anayi akuluakulu pamasewero osankhidwa mwaulere okhudzana ndi chithandizo chamchere. B, D2 kulandira mpweya (quinpirole, 10 μg) sizinasinthe malingana ndi mphoto yaikulu.
Kutsatsa D2 kulandira
Mbiri yofananira yofananira idawonedwa ndi makoswe omwe amalandila mulingo wokwera (10 μg) wa quinpirole mu PFC yamankhwala. Apanso, makoswe adasankha zisonga zinayi zam'mimba pamayeso onse osankha pambuyo poti infusions yamchere. Izi sizinasinthidwe ndikulimbikitsa kwa ma D2 receptors (F (1,6) = 0.53, ns; Mkuyu. 5B). Quinpirole nawonso sanakhudze kwambiri ma latency, locomotion, kapena omissions (zonse F values <1.76, ns). Dziwani kuti chithandizo chofananacho chidachepetsa kusankha kwa mphotho yayikulu pantchito yochotsera yomwe ikadachitika koyambirira, 100% kuthekera (Mkuyu 3B). Kutanthauzira komwe kungachitike pakusiyanaku ndikuti, mosiyana ndi makoswe omwe adaphunzitsidwa pakukula kwa mphotho, omwe adaphunzitsidwa pantchito yochotsera adaphunzira kuti kugwiritsa ntchito njira yayikulu / yowopsa kumachepa pagawo limodzi. Chifukwa chake, kuyimira kwawo phindu lalingaliro la mphotho yayikuluyo akuyembekezeka kukhala ovuta kwambiri kuposa makoswe ophunzitsidwa ntchito yosavuta motero, atha kusokonekera. Pamodzi, zotsatira za kuyesaku zikuwonetsa kuti ngakhale kutsekedwa kwa ma D1 receptors ndi kukondoweza kwa ma D2 receptors kumasintha kwakukulu zosankha pakati pazing'onozing'ono, zina ndi zazikulu, mphotho zomwe zingachitike, zotsatirazi sizikuwoneka kuti zikuchitika chifukwa cha zovuta zina zazikulu zakusankha pakati pa mphotho zazikulu ndi zazing'ono.
Kukambirana
Pano timalengeza kuti D1 ndi D2 receptors mu PFC yapakati zimakhudzidwa kwambiri pa zosankha pakati pa zowonjezereka ndi madalitso ena. Kuwonjezera pamenepo, ntchito yocheperapo kapena yoonjezera ya zonsezi zimapangidwa mosiyana, ndipo nthawizina zimayenderana, kusintha kwa chisankho, kutanthauza kuti aliyense azichita zinthu zosiyana, koma zowonjezereka motsatira njira zopangira zisankho.
Zotsatira za D1 / D2 receptor blockade
Kudziwa kwathu, ichi ndichiwonetsero choyamba kuti kubwezeretsedwa kwa D1 kapena D2 receptor mu PFC yapakati kumayambitsa kutsutsana pa khalidwe. Kafukufuku wakale wa mtundu umenewu watsimikizira kuti D1, koma osati D2, kutsutsana kumasokoneza ntchito monga kusamalira kapena kukumbukira (Williams ndi Goldman-Rakic, 1995; Seamans et al., 1998; Granon et al., 2000) kapena kuti onse awiri amalandila amachitiramo ntchito kuti athetse khalidwe lokhazikika kapena lachisokonezo kusiyana ndi zilango zowonongeka (Ragozzino, 2002; Floresco ndi Magyar, 2006). Zomwe tinazipeza zomwe SCH23390 ndi eticlopride zimakhudza zovuta zina pa chisankho zimasonyeza kuti kupanga bwino kumadalira kuwonetsetsa koyambirira kwa loyang'ana D1 ndi D2 ntchito yochereza, ndipo kusintha kumeneku kumapangitsa kusintha kosasokonezeka pakusankha zinthu zina kapena zosatsimikizika.
PFC D1 blockade inachepetsa kukonda njira yaikulu / yowopsa mwa njira yomwe amadalira, makamaka kwambiri pa nthawi zitatu zotsirizazo zimatseka. SCH23390 yowonjezereka kwambiri, yomwe ikufanana ndi zotsatira za pulojekitiyi pamene ikugwiritsidwa ntchito (St. Onge ndi Floresco, 2009). Chochititsa chidwi, kuchepetsa kupititsa patsogolo kwa DA mu maphunziro a anthu kudzera mu tyrosine kuwonongedwa kumathandizanso kuzipanga zisankho zowonongeka kwambiri pa Cambridge Gambling Task (McLean et al., 2004). Zotsatira zathu zimasonyeza kuti zotsatirazi zingakhale zogwirizanitsa mbali ndi kuchepetsedwa kwazithunzi za D1. Kusanthula mwachindunji kupitiriza kusonyeza kuti kuchepetsa kukonda njira yowonongeka kunagwirizanitsidwa ndi chizoloŵezi chowonjezeka chosankhira chochepa / chotsatira chotsatira potsatira chisankho chosapindulitsa, kutanthauza kuti zotsatira pa kupanga chisankho zingakhale zotsatira zawonjezeka kuwonetsa zolakwika. Momwemonso, kutsekedwa kwa ma D1 receptors mu prelimbic kapena anterior cingulate amachepetsa zokonda zapadera mphoto ngati mwamsanga (Loos et al., 2010) kapena yogwirizana ndi khama lalikulu (Schweimer ndi Hauber, 2006). Zomwe zikupezazi zikusonyeza kuti PFC D1 kuwonetseratu imakhudza kwambiri ndalama zowonjezera ndalama / zopindulitsa, zomwe zingathandize kuthetsa ndalama zomwe zingagwirizane ndi malipiro akuluakulu pofuna kuyesetsa kupeza phindu la nthawi yaitali.
Kusiyanitsa kwakukulu, PFC D2 receptor blockade inasankha kukonda njira yayikulu / yoopsa, kuchepetsa kusintha kwa chisankho choyenera monga mphotho zowonjezera zatsikira pa gawoli. Zowoneka kuti, zotsatirazi zikufanana ndi zomwe zinapangitsa kuti PFC ikhale ndi ntchito zofanana (St. Onge ndi Floresco, 2010). Komabe, sitimakhulupirira izi zikusonyeza kuwonjezeka kwakukulu kwa khalidwe "loopsa" pa se. M'malo mwake, zomwe tinazipeza kale zinatipangitsa kuganiza kuti PFC yapakati imakhala yofunikira kwambiri pakuwonetsetsa kusintha kwa mphotho zowonjezereka kusintha khalidwe molingana. Zotsatira zowonjezera zikuwonjezeka pa izi, povumbulutsa kuti ovomerezeka a D2 amapereka chithandizo chofunikira pa malamulo a PFC pankhaniyi. Kuwonjezeka kumeneku kwowoneka mwachangu kusankha koopsa kunayendetsedwa bwino kwambiri ndi chizoloŵezi chowonjezeka chosankha choyipa chotsatira mutalandira mphoto yaikulu pachiyeso choyambirira. Choncho, osati kuphatikizapo mfundo zokhudzana ndi mwayi wopezera madalitso akuluakulu pamayesero angapo, D2 blockade inapangitsa kulandira mphotho yayikuru kuti ikhale ndi zotsatira zowonjezera komanso zowonjezereka motsatira njira yotsatira. Izi zikugwirizana ndi kufufuza kwaposachedwa kwa anthu, kumene kutsutsana kwa D2 kunapanga zonse zosankha zomwe zimagwirizanitsidwa ndi mphotho yapamwamba yopindulitsa komanso kusintha komwe kumachitika ku PFC ntchito (Jocham et al., 2011). Zomwe zikupezekazi zikusonyeza kuti PFC D1 ndi D2 amalandila amapanga zosiyana, koma zowonjezerapo zopereka chisankho. Ntchito yothandizira D1 imalimbikitsa zosankha zazikulu, koma zosatsimikizika kapena zowonjezereka, pamene ovomerezeka a D2 amachepetsa zotsatira zomwe zimapangitsa kuti phindu lalikulu likhale lopanda chisankho, ndikuthandizira kusintha kusintha kwa nthawi yaitali pamene mwayi wopeza mphoto kusintha.
Zotsatira za kukakamizidwa kwa D1 / D2 kulandira
Intra-PFC infusions ya D1 receptor agonist SKF81297, mkati mwa mapewa omwe awonetsedwa kuti amachititsa kusiyana kwa mitundu ina ya kuzindikira (kuyang'anitsitsa, kugwira ntchito kukumbukira), sanasinthe mwachangu kusankha koopsa, ngakhale kuti mankhwalawa akuwonjezeka makamaka kwa lalikulu / kansalu koopsa, kotchuka kwambiri ndi mlingo wochepa. Kutanthauzira zachisokonezo ichi kuyenera kuyankhulidwa mosamala, chifukwa izi siziwonekere kuti SKF81297 ikhoza kukhala ndi mlingo woyenera wa mlingo womwe ndi wochepa kuposa momwe zingakhalire ndi ntchito zina zamaganizo. Komanso, 0.1 μg mlingoyo inasintha kwambiri njira zosankha, kuwonjezeka kwa ntchito yopambana komanso kuchepa kwa zizoloŵezi zowonongeka, kumene makoswe amatha kusankha chiwindi chachikulu / chowopsya motsatira mphotho zonse ndi mphotho zotsalira. Komabe, kuti kuchuluka kwa mlingo wa SKF81297 sunasinthe kwambiri kusonyeza kuti kusonkhezera kwakukulu kwa PFC D1 receptors sikungasokoneze kwambiri kupanga zisankho za zoopsa ndi mphotho. Mosiyana ndi zimenezi, mankhwala ofanana amachepetsa kusankha kwapadera, mphotho (Loos et al., 2010).
D2 agonist quinpirole inachititsa "kuwonongeka" koona pakupanga chisankho, ndikunyalanyaza phokoso lokhalitsa, ndi makoswe osawonetsetsa kuti palibenso kuzindikira bwino pa kusintha kwa mphotho zowonjezera. Kusankhidwa kwazitsulo zamagulu anayi kunachepetsedwa mu 100% chipika (pamene chinali chopindulitsa kwambiri), koma chinawonjezeka mu 12.5% chipika (pamene kulibe kopindulitsa). Potsata kukakamiza kwa D2, chisankho chachikulu / chosasintha sanasinthe monga saline (~73%), koma zinyama zinkanyalanyaza kusintha kwa izi. Choncho, kupyolera mwamphamvu kwa D2 kulandira mphamvu kumadodometsa kwambiri kuthekera kusinthira chisankho, mwachiwonekere kumayambitsa makoswe kuti agwiritse ntchito njira yowonjezereka yophatikizapo ponsepokha pokhapokha kukhala ndi chiyanjano ku lemba lalikulu / loopsya. Kupeza izi, kuphatikizapo zotsatira za eticlopride, akuwonetsa kuti mayendedwe a D2 (osati a D1) omwe amalandira mpata pakati pa PFC ali ndi zovuta kwambiri pankhaniyi, ndipo mwina kuwonjezeka kapena kuchepetsa ntchitoyi kungasokoneze ntchito.
Chosokoneza chisankho chomwe chimapangidwa ndi zida za quinpirole zofanana kwambiri ndi zomwe zimapangitsa kuchepetsa chakudya chokhudzana ndi kudya kwaulere (St. Onge ndi Floresco, 2009). Zofufuzazi zowonjezera zimayesa kuganiza kuti zikhoza kukhala zofanana. Zoonadi, kusintha kwa PFC DA efflux kunakonzedwa kuti kuwonetsere chakudya chokwanira kapena kuwalimbikitsa (Ahn ndi Phillips, 1999, Winstanley et al., 2006). Choncho, kusintha kwa malipiro omwe amapezeka panthawiyi kungazindikiridwe kwa PFC ndikugwirizana ndi kusintha kwa ma CD a mesocortical kuti, kudzera m'magwiridwe a D2 receptors, angagwiritsidwe ntchito kuti azindikire kusintha kwa mphoto zomwe zimapezeka panthawi yake ndikuthandizira kusintha chisankho chosankha. Izi zikutsatila kuti madzi osefukira a D2 amatha kusokoneza chizindikiro chodabwitsa ichi, chomwe chingawonongeke machitidwe ambiri oyenera.
Zopereka za Dissociable za PFC D1 ndi D2 receptors kuti apange chisankho choyenera
Funso lidalibe chifukwa chake kubwezeretsedwa kwa D1 kapena D2 receptors ayenera kuyesetsa kutsutsa paziopsezo, chifukwa DA wotsirizayo amachititsa onse mapulogalamu. Lingaliro lamakono la momwe mapulogalamuwa amalumikizira mosiyana PFC neural network zochita zingathandize kuzindikira nkhaniyi (Durstewitz et al., 2000; Seamans ndi Yang, 2004). Ovomerezeka a D1 aperekedwa kuti achepetse mphamvu ya zofooka zochepa, kuyimitsa makompyuta kuti ntchito imodzi ikhale yolamulira PFC. Kumbali ina, ntchito ya D2 imapangitsa kuti ziwonongeke, zomwe zimalola kuti PFC neural ensembles ikwaniritse zochitika zosiyanasiyana, kuyika zidazo mudziko la labile lomwe lingalole kusintha kwa ziwonetsero.
Pakati pa magawo osiyanasiyana a ntchito yochotsa ntchito yomwe imagwiritsidwa ntchito pano, zinyama zina ziyenera kusunga (mkati mwazomwe zingatheke) kapena kusintha (kutsekemera) chifaniziro chawo cha mtengo wapatali / choopsa. Choncho, zotsatira zotsutsana za kutsutsana kwa D1 / D2 zomwe zafotokozedwa pano zingathe kusonyeza kusiyana kwapadera kwa mapepala ameneŵa panthawi zosiyana za ntchitoyo. Ntchito ya D1 ikhoza kuimitsa kuimira kwa nthawi yaitali mtengo wa chinthu chowopsa mwachindunji, ndikusankhira zosankha ngakhale pamene kusankha kosokoneza kumabweretsa mphotho (kusunga "diso pa mphoto"). Kulepheretsa kulandira mankhwalawa kungapangitse zinyama kukhala zogonjetsa mphotho zopanda malire (mwachitsanzo, kuwonjezeka kwa zizoloŵezi zosasinthika), ndi kuchepetsa kusankha koopsa. Mofananamo, monga chochita chachikulu / choopsa chimabweretsa mphoto zochepa pamadoko, ma D2 receptors (mwinamwake pamtundu wina wosiyana) angapangitse kusintha kosinthika. Potero, kuchepetsa ntchito yawo kungasokoneze kusinthidwa kwa zizindikirozo ndi kusintha komwe kumafanana ndi zisankho zabwino. Chitsanzochi chingathenso kuwerengera zotsatira za kuwonjezeka kwa ntchito ya D1 ndi D2, zomwe ziyenera kuchititsa kuti pakhale njira yochulukirapo / yowonjezera yomwe ingapangidwe kapena kuyambitsa "hyperflexible" boma. Choncho, zomwe tapeza zikusonyeza kuti PFC DA tone imapereka chithandizo chovuta komanso chovuta ku chilango cha mphoto / mphoto. Poika malire abwino pakati pa ntchito ya D1 / D2 receptor, DA yosavuta imathandiza kuthandizira kukonza mtengo kapena zopindulitsa pakati pa zosankha za kukula kwakukulu ndi kusatsimikizika, kulimbikitsa kugwiritsidwa ntchito kwa nyengo yabwino kapena kufufuza zopindulitsa kwambiri pamene zinthu zisintha.
Mawu a M'munsi
Ntchitoyi inathandizidwa ndi thandizo lochokera ku Canada Institute of Health Research (MOP 89861) kupita ku SBFSBF ndi Michael Smith Foundation for Health Research Senior Scholar ndipo JRSO ndi amene analandira maphunziro a Natural Sciences ndi Engineering Research Council ku Canada ndi Michael Smith Foundation for Health Research.
Mndandanda wa makalata uyenera kuuzidwa kwa Dr. Stan B. Floresco, Dipatimenti ya Psychology ndi Brain Research Center, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, [imelo ndiotetezedwa]
Copyright © 2011 olemba 0270-6474 / 11 / 318625-09 $ 15.00 / 0
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