Mphatso Zachilengedwe ndi Zamankhwala Zochita pa Common Neural Plasticity Njira ndi DFF monga Mkhalapakati Wofunika (2013)

Kafukufukuyu anafufuza zotsatira za mphotho ya kugonana pa DeltaFosB ndi zotsatira za DeltaFosB pa chiwerewere ndi mphotho. Kusintha kwa ma molekyulu komwe kumadziwika kuti kumachitika ndikumwa mankhwala osokoneza bongo kumapezeka kuti kumafanana ndi komwe kumachitika ndi kugonana. Mwa kuyankhula kwina, DeltaFosB inasintha chifukwa cha zofuna zogonana, komabe mankhwala osokoneza bongo amachitanso chimodzimodzi. Izi zimamaliza mkangano wokhudza momwe kugwiritsa ntchito mankhwala osokoneza bongo kumasiyana ndi zizolowezi zamakhalidwe, komanso momwe zizolowezi zamakhalidwe zimangokhala zokakamiza (zilizonse zomwe zikutanthauza). Maseketi omwewo, njira zomwezo, kusintha kwama cell komweko, machitidwe omwewo ogwirizana - ndimasiyana pang'ono.

J Neurosci. 2013 Feb 20;33(8):3434-3442.

PHUNZIRO LONSE

Pitchers KK , Vialou V , Nestler EJ , Laviolette SR , Lehman MN , Coolen LM.

gwero

Dipatimenti ya Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 3K7, Canada, department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, ndi Madipatimenti a Neurobiology ndi Anatomical Sayansi ndi Physiology ndi Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216.

Kudalirika

Mankhwala osokoneza bongo amachititsa kuti mitsempha ya m'magazi isamagwire bwino ntchito m'njira yachilengedwe yopezera mphotho, makamaka nucleus accumbens (NAc), zomwe zimapangitsa kuti munthu akhale ndi khalidwe loledzera. Umboni waposachedwapa ukusonyeza kuti mphotho zachilengedwe zingayambitse kusintha kofanana mu NAc, zomwe zikusonyeza kuti mankhwala osokoneza bongo amatha kuyambitsa njira zopezera phindu zomwe zimagawidwa ndi mphotho zachilengedwe, ndikulola kuti pakhale mgwirizano wapadera pakati pa mphotho zachilengedwe ndi mphotho zamankhwala.

Mu phunziroli, timasonyeza kuti kugonana kwa abambo amphongo pakutsatiridwa ndifupipafupi kapena nthawi yayitali yoperewera kugonana kumayambitsa mphotho ya amphetamine, yomwe imasonyezedwa ndi malo opatsirana amodzi (0.5 mg / kg) amphetamine. Komanso, kuyambira, koma osati nthawi yayitali, yowonjezera mphoto ya amphetamine inali yogwirizana ndi kuwonjezeka kwapadera kwa mitsempha ya dendritic ku NAc. Pambuyo pake, gawo lofunika kwambiri pa cholembera ΔFosB mu zochitika zogonana zowonjezera mphotho ya amphetamine komanso kuwonjezeka komwe kumagwiritsidwa ntchito m'mitsempha ya dellritic pa NAc neurons inakhazikitsidwa pogwiritsira ntchito tizilombo toyambitsa matenda kuchokera kwa wodwalayo. Komanso, zinasonyezedwa kuti mphotho yothandizira kugonana, ΔFosB, ndi spinogenesis zimadalira kugwiritsira ntchito dopamine D1 kulandirira ku NAC. Kusamalidwa kwa mankhwala kwa D1 receptor, koma osati D2 receptor, mu NAc panthawi ya chiwerewere anatsutsa ΔFosB kulowetsedwa ndikuletsa kuwonjezeka kwa spinogenesis ndi kulimbikitsa mphoto ya amphetamine.

Zonsezi zikusonyeza kuti mankhwala osokoneza bongo ndi machitidwe achilengedwe a mphotho amagwira ntchito pa njira zodziwika bwino za maselo ndi maselo zomwe zimawongolera kufooka kwa chizolowezi cha mankhwala osokoneza bongo, ndipo kuti kufooka kumeneku kumayendetsedwa ndi ΔFosB ndi zolinga zake zotsatizana.

Introduction

Makhalidwe a mphotho ndi madokotala amaphatikizapo njira yodziwika bwino ya neural pathway, masolimbic dopamine (DA) dongosolo, momwe khunyu accumcums (NAc) ili ndi gawo lalikulu (Kelley, 2004). Mankhwala osokoneza bongo amachititsa kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda,Hyman et al., 2006; Kauer ndi Malenka, 2007; Kalivas, 2009; Chen et al., 2010; Koob ndi Volkow, 2010; Wolf, 2010a; Mameli ndi Luscher, 2011). Zikugodometsedwa kuti mankhwala osokoneza bongo ndi madalitso a chilengedwe sagwiritsa ntchito neurons yomweyi m'masolambic system, ndipo motero mankhwalawa amachititsa kusintha ndikusintha dera ili (Cameron ndi Carelli, 2012). Komabe, zakhala zikuonekeratu kuti madalitso achilengedwe ndi mankhwala omwe amagwiritsidwa ntchito ndi mankhwala amachititsa masolimbic dongosolo m'njira zofanana ndi zosiyana zomwe zimaloleza kugwirizana pakati pa mphotho zachilengedwe, mphotho yapadera ya kugonana, komanso zotsatira za mankhwala osokoneza bongo (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Khalidwe logonana limapindulitsa kwambiri ( Tenk et al., 2009 ),

Zofukufukuzi zikusonyeza kuti zochitika zapachilengedwe ndi zakumwa mankhwala zimagwirizanitsa njira zofala za pulasitiki za neural, zomwe zimakhudza chiopsezo cha kugwiritsa ntchito mankhwala osokoneza bongo.

Cholinga cha kafukufukuyu chinali kudziwa njira zamaselo zomwe zimayambitsa pulasitiki yomwe imayambitsa kugonana, zomwe zimapangitsa kuti mphotho ya mankhwala ikhale yowonjezereka. Makamaka, ntchito ya transcription factor ΔFosB idafufuzidwa chifukwa imakhudzidwa ndi zotsatira za mphotho zachilengedwe komanso zamankhwala ( Nestler et al., 2001 ; Werme et al., 2002 ; Olausson et al., 2006 ; Wallace et al., 2008 ; Hedges et al., 2009 ; Pitchers et al., 2010b ). Kuphatikiza apo, ntchito ya dopamine D1 receptors (D1R) ya neural plasticity yomwe imayambitsa kugonana idawunikidwa chifukwa NAc ΔFosB induction ndi kuchuluka kwa msana pambuyo pa psychostimulant administration zimawonetsedwa mu ma neuron okhala ndi D1R ( Lee et al., 2006 ; Kim et al., 2009 ) ndipo zimadalira D1R activation ( Zhang et al., 2002 ).

Pano, tinagwiritsa ntchito mavotolo ogwirizana ndi mavairasi a DFB, diOlistic ma labeling, ndi machitidwe apamtima kuti ayesere kuganiza kuti zotsatira zowonongeka za kugonana zotsatiridwa ndi mphotho yolepheretsa kupititsa patsogolo Amph kupindula ndizogwirizana ndi Kudalitsidwa kwa D1R kwa ΔFosB mu NAc ndi kuwonjezereka kwina kwa msana wa NAc. Zonsezi, zomwe zapeza zimapereka umboni wakuti madalitso a chilengedwe ndi mankhwala amagawana njira zofala za pulasitiki ya neural, ndi ΔFosB monga mkhalapakati wovuta.

Zida ndi njira

Nyama.

Amuna akuluakulu (225-250 g pofika) ndi akazi (210-220 g) Kupopera makoswe a Dawley (Charles River Laboratories) ankalowetsamo ku Plexiglas osagwiritsidwa ntchito pamagulu amodzimodzi pazomwe akuyesera, pansi pa kutentha ndi kutentha komanso pa 12 / 12 h Kuwala / mdima ndi chakudya ndi madzi momasuka. Amayi omwe amawathandiza kuti azitha kukambirana nawo amatha kukhala osakanikirana ndipo amalandira implants omwe ali ndi 5% estradiol benzoate (Sigma-Aldrich) ndi jekeseni wa 500 μg wa progesterone (mu 0.1 ml ya mafuta a sesame; Sigma-Aldrich) 4 h asayesedwe. Ndondomeko zonse zinavomerezedwa ndi Komiti Yogwiritsira Ntchito Zanyama Zogwiritsira Ntchito Zilombo za Yunivesite ya Western Ontario ndi Yunivesite ya Michigan ndikugwirizana ndi Canada Council on Animal Care ndi malangizo a National Institutes of Health okhudza zinyama zofufuza.

Chiwerewere.

Magawo ogonana anachitika kumayambiriro kwa mdima (pakati pa maola awiri ndi asanu ndi limodzi kuyambira nthawi ya mdima itayamba) pansi pa kuwala kofiira kofiyira, m'mabokosi oyera oyesera (60 × 45 × 50 cm). Makoswe aamuna adagonana kuti atulutse umuna mkati mwa magawo anayi kapena asanu ogonana tsiku lililonse. Magawo asanu adasankhidwa chifukwa tawonetsa kale kuti njira imeneyi imayambitsa kutsogozedwa kwa nthawi yayitali kwa khalidwe logonana ( Pitchers et al., 2010b ), kuzindikira zochitika za Amph locomotor ( Pitchers et al., 2010a ), ndi mphotho ( Pitchers et al., 2010a ). Kutulutsa umuna kunasankhidwa ngati mapeto a gawo lililonse logonana chifukwa kale tidawonetsa kuti ndikofunikira pa zotsatira za kugonana pa Amph locomotor sensitization ( Pitchers et al., 2010a ), zomwe sizinachitike pamene nyama zinkaloledwa kukwatirana ndi akazi popanda kuwonetsa umuna. Makhalidwe a kugonana (monga kuchedwa kufika pa kukwera koyamba, kutuluka m'mimba ndi kutuluka kwa umuna, ndi chiwerengero cha kukwera ndi kutuluka kwa umuna) zinalembedwa monga momwe tafotokozera kale ( Pitchers et al., 2010b ). Pa zoyeserera zonse, magulu odziwa za kugonana adafanizidwa ndi machitidwe a kugonana (chiwerengero chonse cha kutuluka kwa umuna ndi kutuluka kwa umuna panthawi iliyonse yokumana). Pambuyo pa gawo lachisanu la kukwatirana, amuna adakhalabe ndi akazi omwewo ndipo sanaloledwe kukwatirana panthawi yogonana ya 1, 7, kapena 28 d. Zinyama zomwe sizinali zodziwa za kugonana zinasamalidwa ndikusungidwa m'zipinda zomwezo ndi amuna odziwa za kugonana. Kuphatikiza apo, zowongolera zopanda nzeru zinayikidwa m'mabokosi oyesera oyera kwa ola limodzi mkati mwa masiku 5 otsatizana, popanda mwayi wopeza mkazi wolandila.

FosB expression.

Nyama zinapatsidwa mankhwala oletsa ululu kwambiri (sodium pentobarbital; 390 mg/kg; ip) ndipo zinalowetsedwa mkati mwa mtima ndi 50 ml ya 0.9% saline, kutsatiridwa ndi 500 ml ya 4% paraformaldehyde (Sigma-Aldrich) mu 0.1 m phosphate buffer (PB) ya nthawi ndi mayeso a DR antagonist. Ubongo unachotsedwa ndipo unakonzedwanso kwa ola limodzi kutentha kwa chipinda mu fixative yomweyo, kenako unasungidwa pa 4°C mu 20% sucrose ndi 0.01% sodium azide mu 0.1 m PB. Pa mayeso a DR antagonist, ubongo unachotsedwa ndikudulidwa pakati motsatira sagittal axis. Theka limodzi linasungidwa mu PB ndipo linagwiritsidwa ntchito pa DiOlistics, ndipo linalo linakonzedwa kuti likhale ΔFosB. Zigawo za coronal (35 μm) zinadulidwa ndi microtome yozizira (Microm H400R), zomwe zinasonkhanitsidwa m'magulu anayi ofanana mu yankho la cryoprotectant (30% sucrose ndi 30% ethylene glycol mu 0.1 m PB) ndikusungidwa pa −20°C. Zigawo zoyandama zokha zinatsukidwa kwambiri ndi 0.1 m PBS, pH 7.35, pakati pa kulowetsedwa, ndipo masitepe onse anali kutentha kwa chipinda. Zigawo zinawonetsedwa ku 1% H 2 O 2 (mphindi 10) ndi yankho la kulowetsedwa (ola limodzi; PBS yokhala ndi 0.1% BSA, Fisher; ndi 0.4% Triton X-100, Sigma-Aldrich). Zigawozo zinalowetsedwa usiku wonse mu pan-FosB rabbit polyclonal antibody (1:5K; sc-48 Santa Cruz Biotechnology), yomwe idatsimikiziridwa kale ( Perrotti et al., 2004 , 2008 ; Pitchers et al., 2010b ). Antibody ya pan-FosB idakwezedwa motsutsana ndi dera lamkati lomwe FosB ndi ΔFosB zimagawana, ndipo kale idadziwika kuti ikuwonetsa maselo a ΔFosB nthawi yomwe idagwiritsidwa ntchito mu kafukufukuyu (> tsiku limodzi pambuyo pa stimulus) ( Perrotti et al., 2004 , 2008 ; Pitchers et al., 2010b ). Kenako, magawo adayikidwa mu biotin-conjugated goat anti-rabbit IgG (ola limodzi; 1:500 mu PBS+; Vector Laboratories), avidin-biotin-horseradish peroxidase (ola limodzi; ABC elite; 1:1000 mu PBS; Vector Laboratories), ndi 0.02% 3,3′-diaminobenzidine tetrahydrochloride (mphindi 10; Sigma-Aldrich) ndi 0.02% nickel sulfate mu 0.1 m PB yokhala ndi hydrogen peroxide (0.015%). Zigawo zinayikidwa pa Superfrost plus glass slides (Fisher) ndipo zinaphimbidwa ndi dibutyl phthalate xylene.

Ziwerengero za maselo a ΔFosB-IR zinawerengedwa mu chipolopolo cha NAc ndi pakati mkati mwa madera ofunikira owunikira (400 × 600 μm) monga momwe tafotokozera kale ( Pitchers et al., 2010b ). Magawo awiri anawerengedwa pa gawo lililonse la NAc, avareji pa nyama iliyonse. Mu kuyesa kwa nthawi, ziwerengero za maselo a ΔFosB-IR zinafotokozedwa ngati kusintha kwa gulu lolamulira lopanda chidziwitso pa nthawi yoyenera ndipo zinayerekezeredwa pakati pa magulu odziwa bwino ntchito ndi osadziwa chidziwitso pa gawo lililonse pa nthawi iliyonse pogwiritsa ntchito mayeso a t osaphatikizidwa okhala ndi mulingo wofunikira wa p < 0.05. Mu kuyesa kwa ΔJunD-AAV ndi DR antagonist, njira ya ANOVA ya njira ziwiri kapena imodzi, motsatana, ndi njira ya Holm-Sidak zinagwiritsidwa ntchito. Kuphatikiza apo, maselo a ΔFosB-IR anawerengedwa mu dorsal striatum (dera lowunikira: 200 × 600 μm), nthawi yomweyo dorsal ku NAc komanso pafupi ndi lateral ventricle, m'zinyama zonse mu kuyesa kwa DR antagonist. Mayeso a ANOVA ndi t a njira imodzi adagwiritsidwa ntchito poyerekeza pakati pa magulu.

Diolistics.

Pa nthawi ndi kuyesa kwa ΔJunD viral vector, makoswe adathiridwa madzi mkati mwa mtima ndi 50 ml ya saline (0.9%), kutsatiridwa ndi 500 ml ya 2% paraformaldehyde mu 0.1 m PB. Ubongo unagawika m'magawo (100 μm coronal) pogwiritsa ntchito vibratome (Microm) ndipo magawo anasungidwa mu 0.1 m PB ndi 0.01% sodium azide pa 4°C. Kuphimba tinthu ta tungsten (1.3 μm diameter, Bio-Rad) ndi lipophilic carbocyanine dye DiI (1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate; Invitrogen) kunachitika monga momwe tafotokozera kale ( Forlano ndi Woolley, 2010 ). Tinthu tating'onoting'ono ta tungsten tokutidwa ndi DiI tinaperekedwa m'thupi pa 160–180 psi pogwiritsa ntchito Helios Gene Gun system (Bio-Rad) kudzera mu fyuluta yokhala ndi kukula kwa 3.0 μm pore (BD Biosciences) ndipo tinaloledwa kufalikira kudzera mu nembanemba ya neuronal mu 0.1 m PB kwa maola 24 pomwe kuwala kunatetezedwa pa 4°C. Kenako, zidutswazo zinaikidwa mu 4% paraformaldehyde mu PB kwa maola atatu kutentha kwa chipinda, kutsukidwa mu PB, ndikuyikidwa m'zipinda zotsekedwa ndi chimango (Bio-Rad) ndi gelvatol yokhala ndi anti-fading agent 1,4-diazabicyclo(2,2)octane (50 mg/ml, Sigma-Aldrich) ( Lennette, 1978 ).

Ma neuron okhala ndi zilembo za DiI adajambulidwa pogwiritsa ntchito maikulosikopu ya Zeiss LSM 510 m confocal ( Carl Zeiss ) ndi laser ya helium/neon 543 nm. Pa nyama iliyonse, ma neuron 2-5 m'chigawo chilichonse cha NAc, kapena mu chipolopolo (kutengera malo okhudzana ndi zizindikiro, kuphatikiza lateral ventricle ndi anterior commissure) mu zoyeserera za ΔJunD-AAV ndi DR antagonist, adagwiritsidwa ntchito kupeza dera lofunika pa dendrite yachiwiri kuti ayese kuchuluka kwa msana. Pa neuron iliyonse, ma dendrite 2-4 adasanthulidwa kuti ayese kutalika kwa dendritic yonse ya 40-100 μm. Zigawo za dendritic zidajambulidwa pogwiritsa ntchito cholinga cha 40× madzi-immersion pa 0.25 μm intervals motsatira z -axis, ndipo chithunzi cha 3D chidamangidwanso ( Zeiss ) ndipo chidasinthidwa (Autoquant X, Media Cybernetics) pogwiritsa ntchito adaptive (blind) ndi theoretical PSF setting monga momwe pulogalamuyo ikufunira. Kuchuluka kwa msana kunayesedwa pogwiritsa ntchito Filament module ya pulogalamu ya Imaris (mtundu 7.0, Bitplane). Manambala a misana ya dendritic anafotokozedwa pa 10 μm, avareji ya neuron iliyonse kenako pa nyama iliyonse. Kusiyana kwa ziwerengero kunadziwika pogwiritsa ntchito ma ANOVA awiri mu nthawi yoyesera pakati pa nyama zosadziwa kugonana ndi zodziwa zambiri nthawi iliyonse (zifukwa: zokumana nazo zogonana ndi NAc subregion) ndi mu ΔJunD experiment (zifukwa: zokumana nazo zogonana ndi vector ya kachilombo), ndi ANOVA ya njira imodzi mu DR antagonist experiment. Kuyerekeza kwa magulu kunapangidwa ndi njira ya Holm-Sidak yokhala ndi mulingo wofunikira wa p < 0.05.

Malo okonda malo.

Kapangidwe ka CPP koyesera kanali kofanana ndi komwe kanafotokozedwa kale ( Pitchers et al., 2010a ), pogwiritsa ntchito chipangizo chopanda tsankho cha zipinda zitatu (Med Associates), ndi kapangidwe kopanda tsankho, ndi mayeso ophatikizana a d-Amph sulfate (Amph; Sigma-Aldrich; 0.5 mg/ml/kg sc owerengedwa potengera maziko aulere) mu chipinda chophatikizana ndi saline mu chipinda chopanda tsankho masiku ena, ndipo adachitika mkati mwa theka loyamba la gawo lowala. Zinyama zowongolera zidalandira saline m'zipinda zonse ziwiri.

Zigoli za CPP zinawerengedwa pa nyama iliyonse monga nthawi yomwe inagwiritsidwa ntchito (m'masekondi) m'chipinda cholumikizidwa panthawi yoyeserera pambuyo pake kupatula mayeso oyambirira. Ma ANOVA a njira imodzi ndi njira ya Holm-Sidak zinagwiritsidwa ntchito poyerekeza magulu omwe anali mu nthawi yoyesera. Mayeso a t osaphatikizidwa okhala ndi tanthauzo loyikidwa pa p < 0.05 adagwiritsidwa ntchito poyerekeza Naive-Sal ndi Naive Amph mkati mwa nthawi iliyonse mu nthawi yoyesera, komanso mkati mwa chithandizo chilichonse cha ma virus vector mu kuyesa kwa ΔJunD. Mu kuyesa kwa nthawi, ma ANOVA a njira imodzi ndi njira ya Holm-Sidak zinagwiritsidwa ntchito poyerekeza magulu omwe anali ndi vuto logonana (Exp-Sal, 7 d Exp Amph ndi 28 d Exp Amph), ndipo mayeso a t osaphatikizidwa adagwiritsidwa ntchito poyerekeza magulu awiri osadziwa. Ma ANOVA a njira ziwiri ndi njira ya Holm-Sidak zinagwiritsidwa ntchito poyerekeza magulu onse mu kuyesa kwa DR antagonist. Mayeso awiri a t osaphatikizidwa adagwiritsidwa ntchito poyerekeza magulu a Naive-Sal ndi Naive Amph ndi vuto lililonse la chithandizo cha ma virus vector (GFP kapena ΔJunD), chifukwa deta inali yosiyana kwambiri m'magulu a ΔJunD kuti ilole kusanthula kwa ANOVA. Magawo onse ofunika adakhazikitsidwa pa p < 0.05.

Zowonongeka za virale.

Makoswe aamuna adapatsidwa mankhwala oletsa ululu ndi ketamine (87 mg/ml/kg; ip) ndi xylazine (13 mg/ml/kg ip), adayikidwa mu chipangizo cha stereotaxic (Kopf Instruments), ndipo adalandira majekeseni ang'onoang'ono a ma vectors a recombinant adeno-associated viral omwe amalemba GFP yokha (protein green fluorescent), kapena ΔJunD (dominant-negative binding partner wa ΔFosB) ndi GFP, mu NAc (coordinates: AP +1.5, ML ±1.2 kuchokera ku bregma; DV −7.6 kuchokera ku chigaza), mu voliyumu ya 1.5 μl/hemisphere kwa mphindi 7 pogwiritsa ntchito syringe ya Hamilton (Harvard Apparatus). ΔJunD imachepetsa ΔFosB-mediated transcription mwa kupikisana ndi ΔFosB motero kuletsa kumangirira kwa ΔFosB ku dera la AP-1 mkati mwa madera olimbikitsira majini omwe ali pachiwopsezo ( Winstanley et al., 2007 ; Pitchers et al., 2010b ). Ngakhale kuti ΔJunD imagwirizana kwambiri ndi ΔFosB, n'zotheka kuti zotsatira zina zomwe zawonedwa za ΔJunD zitha kuyambitsidwa ndi kutsutsa mapuloteni ena a AP-1. Komabe, zikuwoneka kuti ΔFosB ndiye puloteni yayikulu ya AP-1 yomwe imawonetsedwa pansi pa mikhalidwe yoyesedwa ( Pitchers et al., 2010b ). Pakati pa milungu itatu ndi inayi pambuyo pake, nyama zidakumana ndi zogonana nthawi zinayi motsatizana kapena zidapitilizabe kukhala zopanda nzeru kuti zipange magulu anayi: GFP yopanda nzeru yogonana, GFP yodziwa zogonana, ΔJunD yopanda nzeru yogonana, komanso ΔJunD yodziwa zogonana. Zokumana nazo zogonana zidapangidwa ndi magawo anayi otsatizana otsatizana a tsiku ndi tsiku. Nyama zidayesedwa CPP ndi diOlistics. Kutsimikizira malo obayira kunachitika monga tafotokozera kale ( Pitchers et al., 2010b ). Zigawo za NAc (coronal; 100 μm) zidathandizidwa ndi chitetezo cha mthupi cha GFP (1:20,000; antibody ya kalulu yotsutsana ndi GFP; Invitrogen). Kufalikira kwa kachilomboka kunali kokha ku gawo la chipolopolo cha NAc, ndi kufalikira kwina mpaka pakati.

Otsutsa a D1R / D2R.

Makoswe aamuna anapatsidwa jekeseni ya mkati mwa peritoneal (0.1 ml/kg) ya ketamine (87 mg/ml) ndi xylazine (13 mg/ml), ndipo anaikidwa mu chipangizo choyezera kutentha (Kopf Instruments). Ma cannula otsogolera a bilateral 21-gauge (Plastics One) anatsitsidwa kupita ku NAc pa AP +1.7, ML ±1.2 kuchokera ku bregma; −6.4 DV kuchokera ku chigaza ndipo anamangidwa ndi dental acrylic, atamangiriridwa ku zomangira zitatu zomwe zinayikidwa mu chigaza. Zinyama zinkasamalidwa tsiku lililonse kuti zizolowere njira zolowetsera mkati mwa milungu iwiri yochira. Mphindi khumi ndi zisanu asanayambe nthawi iliyonse ya mating tsiku lililonse mwa kuyambitsa yaikazi yolandira, makoswe aamuna adalandira ma microinjections awiriawiri a D1R antagonist R(+)SCH-23390 hydrochloride (Sigma-Aldrich), D2 receptor (D2R) antagonist S-(-)eticlopride hydrochloride (Sigma-Aldrich) adasungunuka mu sterile saline (0.9%; iliyonse pa 10 μg mu 1 μl pa hemisphere; idasungunuka mu 0.9% saline), kapena saline (1.0 μl pa hemisphere), pa flow rate ya 1.0 μl/min pa mphindi imodzi yotsatiridwa ndi mphindi imodzi ndi jakisoni wa cannula wosiyidwa m'malo mwake kuti mankhwala afalikire. Kuchuluka kwa jakisoniyu kudzalowetsa core ndi shell, chifukwa ma infusions a 0.5 μl amangopezeka ku shell kapena core subdivisions ( Laviolette et al., 2008 ). Mlingo wa mankhwalawa unachokera ku kafukufuku wakale wosonyeza kuti mlingo uwu kapena wocheperako unakhudza khalidwe la mankhwala kapena mphotho zachilengedwe ( Laviolette et al., 2008 ; Roberts et al., 2012 ). Amuna olamulira anakhalabe osadziwa kugonana koma adalandira saline ya intra-NAc asanayikidwe mu khola lopanda kanthu, panthawi ya magawo anayi ogwirira ntchito tsiku ndi tsiku. Sabata imodzi pambuyo pa gawo lomaliza la kugonana kapena kugwira ntchito, amuna adayesedwa kuti apeze Amph CPP, ndi kusanthula kwa msana ndi ΔFosB. Kugwiritsa ntchito magawo anayi, m'malo mwa magawo asanu monga momwe zinalili mu zoyeserera zina, kunasankhidwa kuti kuthetse kuwonongeka kwakukulu kwa NAc komwe kumachitika chifukwa cha kulowetsedwa mobwerezabwereza motero kulola kusanthula kwa msana ndi ΔFosB. Zoonadi, kuwonongeka sikunawonekere, ndipo kusanthula kwa msana ndi ΔFosB mu NAc kwa nyama zomwe zinalowetsedwa ndi saline kunawonetsa deta yofanana ndi magulu omwe sanalowetsedwa mu zoyeserera zam'mbuyomu. Njira ya ANOVA ndi Holm-Sidak yokhala ndi tanthauzo lokhazikika pa p < 0.05 idagwiritsidwa ntchito kudziwa momwe khalidwe logonana limathandizira pakugonana.

Results

Kugonana kwa ΔFosB komwe kumachitika chifukwa cha kugonana kumakhala kosatha

Choyamba, mgwirizano wa nthawi pakati pa kusintha kwa kugonana komwe kumachitika chifukwa cha ΔFosB, dendritic spines mu NAc, ndi Amph-CPP unadziwika, makamaka pambuyo pa nthawi yochepa komanso yayitali yodziletsa kulandira mphotho yogonana (7 kapena 28 d). Kale, zidawonetsedwa kuti zochitika zogonana za magawo 5 ogonana tsiku lililonse zidayambitsa kusonkhanitsa kwa ΔFosB mu dongosolo lonse la mesolimbic, makamaka mu NAc ( Wallace et al., 2008 ; Pitchers et al., 2010b ). Mu maphunziro am'mbuyomu awa, milingo ya ΔFosB idayesedwa mkati mwa tsiku limodzi pambuyo pa khalidwe la kugonana, ndipo sizinadziwike ngati kusonkhanitsa kwa ΔFosB kudapitilira pambuyo pa nthawi yayitali yodziletsa kulandira mphotho. Amuna odziwa kugonana adasinthidwa tsiku limodzi, 7, kapena 28 d pambuyo pa nthawi yomaliza ya magawo 5 ogonana tsiku lililonse, pomwe amuna adagonana mpaka nthawi imodzi. Kulamulira kopanda nzeru pogonana kudasinthidwa nthawi yomweyo pambuyo pa magawo 5 ogwirira ntchito tsiku lililonse. Chiwerengero cha maselo a ΔFosB-IR mu chipolopolo cha NAc ndi pakati chinali chachikulu kwambiri kuposa zowongolera zachiwerewere nthawi zonse ( Chithunzi 1 A , chipolopolo; 1 d, p = 0.022; 7 d, p = 0.015; Chithunzi 1 B : pakati; 1 d, p = 0.024; 7 d, p < 0.001; 28 d, p < 0.001), kupatula mu chipolopolo cha NAc pambuyo pa kudziletsa kwa masiku 28 ( p = 0.280). Chifukwa chake, kukwera kwa ΔFosB kumapitirirabe panthawi yodziletsa pambuyo pa zokumana nazo zogonana kwa nthawi yosachepera masiku 28.

Chithunzi 1.     

Chithunzi 1.     

Zochitika zogonana zinayambitsa kuwonjezeka kwachangu komanso kosalekeza kwa chiwerengero cha maselo a ΔFosB-IR. Kusintha kwa kuchuluka kwa maselo a ΔFosB-IR mu chipolopolo cha NAc ( A ) ndi pakati ( B ) mwa nyama zogonana (zakuda) poyerekeza ndi zolamulira zogonana (zoyera) ( n = 4 gulu lililonse). Deta ndi yapakati pa gulu ± SEM. * p < 0.05, kusiyana kwakukulu poyerekeza ndi zolamulira zopanda nzeru. Woyimira zithunzi za Naive 1 d ( C ), Exp 1 d ( D ), Exp 7 d ( E ), ndi Exp 28 d ( F ). ac, Anterior commissure. Scale bar, 100 μm.

Kugonana kwapangidwe kowonongeka kwa dendritic spines ndikumalizira

Pitchers et al. (2010a) adanena kale pogwiritsa ntchito njira zoberekera za Golgi kuti zomwe zimachitika pogonana pambuyo pa masiku 7, koma osati tsiku limodzi, zoletsa mphotho zinayambitsa kuwonjezeka kwakukulu kwa nthambi za dendritic ndi kuchuluka kwa minga ya dendritic pa chipolopolo cha NAc ndi ma neurons apakati ( Pitchers et al., 2010a ). Pano, spinogenesis mwa amuna osadziwa bwino za kugonana komanso odziwa zambiri idawunikidwa masiku 7 kapena masiku 28 pambuyo pa gawo lomaliza la kugonana. Zomwe zapezeka pano pogwiritsa ntchito njira yolembera ma diOlistics zatsimikizira kuti zomwe zimachitika pogonana pambuyo pa nthawi yoletsa kugonana kwa masiku 7 zidawonjezera kuchuluka kwa minga ya dendritic ( F (1,8) = 9.616, p = 0.015; Chithunzi 2 A–C ). Makamaka, kuchuluka kwa minga ya dendritic kudawonjezeka kwambiri mu chipolopolo cha NAc ndi pakati ( Chithunzi 2 A : chipolopolo, p = 0.011; pakati, p = 0.044). Komabe, kuchuluka kwa msana kumeneku kunali kwakanthawi kochepa ndipo sikunapezekenso pambuyo pa nthawi yayitali yodziletsa kugonana ya masiku 28 m'chigawo chilichonse cha NAc ( Chithunzi 2 B ).

Chithunzi 2.     

Chithunzi 2.    

Chidziwitso cha kugonana chinachulukitsa kuchuluka kwa mitsempha ya dendritic mu NAC ndipo amathandizira Amph kupereka. A, B, Chiwerengero cha misomali ya dellritic mu chipolopolo cha NAc ndi phokoso la 7 d (A) kapena 28 d (DB ya nyama zakuda [zoyera] ndi zodziwa; n = 4 kapena 5). Deta ndi gulu lotanthauza ± SEM. #p <0.05, kusiyana kwakukulu poyerekeza ndi kuwongolera zopanda nzeru. C, Zigawo zoimira dendritic kuchokera ku Naive 7 d ndi Exp 7 a magulu omwe amagwiritsidwa ntchito poyeza msinkhu. Mzere wamtengo, 3 μm. D, Nthawi imene amatha kupitilira (amph kapena saline) panthawi yoyezetsa magazi kupatulapo chiwerengero cha pretest (CPP) kwa ziwalo zogonana (zoyera) kapena zodziwa (nyama zakuda) zomwe zimayesedwa ngati 7 d kapena 28 d mutatha kukwanitsa komaliza kapena Gawoli: Naive-Sal (7 d pambuyo pakugwira ntchito; n = 8), Amph Naive (7 d pambuyo pakugwira ntchito; n = 9), Exp-sal (gulu limodzi la zinyama zayesedwa ngati 7 d kapena 28 d pambuyo pa kukwatira; n = 7), 7 d Exp Amph (7 d pambuyo kukwanitsa; n = 9), ndi 28 d Exp Amph (28 d pambuyo pa kukwanitsa; n = 11). Magulu a Sal alandire Sal akuphatikizana ndi zipinda zonse ziwiri. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zogonana.

Kugonana komwe kumakhudzidwa kwambiri ndi Amph kulipira kumakhala kwamuyaya

Poyamba tidawonetsa kuti zomwe zidachitika pogonana pambuyo pa masiku 7-10 a kudziletsa zidapangitsa kuti Amph ilandire mphotho yowonjezera ( Pitchers et al., 2010a ). Makamaka, nyama zomwe zidakumana ndi zogonana zidapanga malo ofunikira kwambiri (CPP) pamlingo wocheperako wa Amph (0.5 kapena 1.0 mg/kg) zomwe sizinapangitse CPP kukhala yoletsa kugonana. Kafukufuku wapano adatsimikizira ndikuwonjezera zotsatira zam'mbuyomu powonetsa mphotho yowonjezera ya Amph mwa nyama zomwe zidakumana ndi zogonana pambuyo pa masiku 7 komanso nthawi yodziletsa kugonana ya masiku 28 ( Chithunzi 2 D ; F (2,24) = 4.971, p = 0.016). Makamaka, nyama zomwe zinali ndi nthawi yogonana ndi anthu omwe anali ndi nthawi yodziletsa kugonana kwa masiku 7 kapena 28 zinakhala nthawi yayitali kwambiri mu chipinda chokhala ndi Amph panthawi yoyesedwa pambuyo poyesedwa poyerekeza ndi zoletsa zoyipa zomwe zinali ndi nthawi yogonana zomwe zinalandira saline m'zipinda zonse ziwiri ( Chithunzi 2 D : Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Kutsimikizira zomwe zapezeka kale, nyama zomwe zinali ndi nthawi yogonana sizinakhale nthawi yayitali mu chipinda chokhala ndi Amph panthawi yoyesedwa pambuyo poyesedwa ndipo sizinasiyane ndi gulu lolamulira la saline losagonana ndi anthu ( Chithunzi 2 D ) ( Pitchers et al., 2010a ).

Ntchito yaFosB ndi yofunika kwambiri pa zochitika za kugonana zomwe zimapangitsa kuti Amph apindule

Zotsatira zake zikuwonetsa kuti zomwe zimachitika pogonana zimayambitsa kusonkhanitsa kwa ΔFosB kwa nthawi yayitali mu ma neuron a NAc komwe kumalumikizidwa ndi mphotho yowonjezera ya Amph . Kuti adziwe ngati kuchuluka kwa ntchito ya ΔFosB ndikofunikira kwambiri pa mphotho yowonjezera ya Amph, ΔJunD, mnzake wolumikizana ndi ΔFosB yemwe amaletsa kulembedwa kwa ΔFosB ( Winstanley et al., 2007 ), adawonetsedwa mopitirira muyeso kudzera mu kusamutsa majini komwe kumachitika ndi ma gene mu NAc ( Chithunzi 3 A , B ). Zotsatira za mayeso a Amph CPP zidawonetsa kuti kuchepetsa ntchito ya ΔFosB powonetsa ΔJunD mu NAc kunaletsa zotsatira za zomwe zimachitika pogonana komanso kudziletsa kulandira mphotho ya kugonana kwa masiku 7 pa mphotho yowonjezera ya Amph. Zinyama za ΔJunD zogonana sizinapange CPP yofunika kwambiri ya Amph ndipo sizinasiyane ndi nyama za ΔJunD zogonana ( Chithunzi 3 B ). Mosiyana ndi izi, nyama zolamulira za GFP zogonana zidapanga CPP ya Amph monga momwe zasonyezedwera ndi chiwerengero chachikulu cha CPP poyerekeza ndi zolamulira za GFP zogonana ( Chithunzi 3 B , p = 0.018).

Chithunzi 3.    

Chithunzi 3.    

Kuchepetsa ntchito ya ΔFosB mu NAc kunaletsa mphotho ya AMPH yodziwika bwino komanso kuwonjezeka kwa kuchuluka kwa minga ya NAc mwa nyama zomwe zimagonana ndi anthu ena . A , Zithunzi zoyimira za kufotokozera kwa GFP mwa nyama zitatu zomwe zimalandira jakisoni wa recombinant adeno-associated viral-ΔJunD yolunjika ku nucleus accumbens, kuwonetsa malo ang'onoang'ono (kumanzere), apakati (pakati), ndi akulu (kumanja). ac, Anterior commissure; LV, lateral ventricle. Scale bar, 250 μm. B , Chithunzi cha Schematic cha malo odziwika bwino komanso machitidwe a kufalikira kwa kachilombo. Mu nyama zonse, GFP idapezeka mu chipolopolo, koma kufalikira mpaka pakati kunali kosiyanasiyana. C , Kuchuluka kwa nthawi yomwe imagwiritsidwa ntchito mu chipinda cholumikizidwa ndi Amph panthawi yoyeserera pambuyo poyesa kupatula pretest (CPP score) ya nyama zopanda ubwenzi (zoyera) komanso zodziwa bwino (zakuda) zomwe zidalandira jakisoni wa GFP control vector (Naive, n = 9; Exp, n = 10) kapena ΔJunD vector (Naive, n = 9; Exp, n = 9). D , Zithunzi zoyimira magawo a dendritic ochokera ku GFP yodziwa zachiwerewere ndi ΔJunD zomwe zimagwiritsidwa ntchito poyesa kuchuluka kwa msana. Scale bar, 3 μm. E , Chiwerengero cha misana ya dendritic mu NAc ya nyama zopanda ukazi (zoyera) ndi zodziwa (zakuda) zomwe zidalandira jakisoni wa GFP control vector kapena ΔJunD vector. Deta ndi yapakati pa gulu ± SEM. * p < 0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zopanda ukazi. # p < 0.05, kusiyana kwakukulu kuchokera ku zowongolera zodziwa za GFP.

Zotsatira zochepetsera kuchuluka kwa ΔJunD sizinali chifukwa cha kusokonezeka kwa khalidwe la kugonana panthawi yogonana. Kuwonetsedwa kwa ΔJunD mu NAc kwawonetsedwa kale kuti kumalepheretsa kuchita bwino kwa khalidwe la kugonana pambuyo pa kugonana ( Pitchers et al., 2010b ). Zoonadi, izi zatsimikiziridwa mu kuyesa kwamakono. Zinyama zolamulira GFP zinawonetsa kuchedwa kochepa pakukwera, kulowa m'mimba, ndi kutuluka kwa umuna, komanso kukwera pang'ono ndi kutuluka m'mimba patsiku lachinayi lotsatizana la mayeso okwatira, poyerekeza ndi tsiku loyamba la kugonana ( Table 1 ). Mosiyana ndi zimenezi, nyama zomwe zinabayidwa ndi ΔJunD sizinawonetse kuchedwa kochepa kwambiri pakukwera kapena kulowa m'mimba kapena kuchuluka kochepa kwa zikwakwa patsiku lachinayi la kugonana poyerekeza ndi loyamba. Chifukwa chake, kulowetsedwa kwa ΔJunD mu NAc kunachepetsa zotsatira za kugonana. Komabe, panalibe kusiyana kwakukulu pakati pa magulu ogwirizana pakati pa GFP control ndi magulu ophatikizidwa ndi ΔJunD panthawi ya mayeso aliwonse ogwirizana, zomwe zikusonyeza kuti zotsatira za ΔJunD infusions pa kukhudzidwa kwa Amph CPP chifukwa cha kugonana sizimachokera ku kusiyana kwa zomwe zimachitika pogonana ( Table 1 ).

Onani gome ili:     

Gulu 1.    

Magawo a khalidwe la kugonana panthawi yopeza chidziwitso chogonana m'magulu omwe adalandira NAc infusions ya ma virus a GFP- kapena ΔJunD-expressing a

ΔFosB ndi yofunikira kwambiri kuwonjezeka kwa chiwerewere kuwonjezeka kwa NAc dendritic spines

Ntchito yaFosB inkafunikanso kuwonjezeka kwa msinkhu wa msana wa NAC neurons pambuyo pa chiwerewere ndi kugonana kwa 7 d kugonana (Chith. 3C,D). Pofufuza msana mu NAC ya nyama zomwe zafotokozedwa pamwambapa kwa CPP, njira ziwiri za ANOVA zinasonyeza zotsatira zazikulu zokhudzana ndi kugonana (F(1,34) = 31.768, p <0.001) ndi mankhwala a vector vector (F(1,34) = 14.969, p = 0.001), komanso kugwirizana (F(1,34) = 10.651, p = 0.005). Mwachidziwitso, nyama zogonana za GFP zokhudzana ndi kugonana zinali ndi ziphuphu zambiri za NAC poyerekeza ndi maulamuliro a GFP okhudzana ndi kugonana (Chith. 3D: p <0.001), kutsimikizira zomwe tidapeza m'mbuyomu (Pitchers et al., 2010a). Mosiyana ndi izi, nyama zogonana zogonana sizinali zosiyana kwambiri ndi magulu a anthu osagonana ndi magulu ankhanza, ndipo anali ochepa kwambiri poyerekeza ndi nyama zogonana za GFP zogonana (Chith. 3D: p <0.001). Chifukwa chake, MAFotokozedwe a NAc mu NAc adatseka zovuta zakugonana ndikupereka mphotho yodziletsa pa NAc spinogenesis.

Wotsutsa wa D1R amalepheretsa chizoloŵezi cha kugonana-chinapangitsa kuti ΔFosB zisamangidwe

Kuti mudziwe ngati D1R kapena D2R ikugwira ntchito mu NAc panthawi yogonana ikufunika kuti ΔFosB ikule bwino komanso kuti Amph CPP ikhale yolimbikitsidwa, nyama zinalandira mankhwala a D1R kapena D2R antagonist (kapena saline) mu NAc mphindi 15 musanayambe nthawi iliyonse yogonana. Chofunika kwambiri, D1R kapena D2R antagonist infusions mu NAc sizinakhudze kuyamba kapena kuwonetsa khalidwe la kugonana panthawi iliyonse yogonana ( Chithunzi 4 D–F ). Momwemonso, kusagwirizana kwa D1R kapena D2R sikunalepheretse zotsatira zolimbikitsa za kugonana pa kugonana, chifukwa magulu onse adawonetsa kuthandizira khalidwe la kugonana , zomwe zikuwonetsedwa ndi kuchepa kwa nthawi yogonana pa tsiku lachinayi poyerekeza ndi tsiku loyamba ( Chithunzi 4 F ) ( F (1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Chithunzi 4.    

Chithunzi 4.    

Otsutsa dopamine receptor omwe adalowetsedwa mu NAc sanakhudze khalidwe la kugonana. Zigawo za Coronal NAc ( A , +2.2; B , +1.7; C , +1.2 kuchokera ku bregma) zomwe zikusonyeza malo obayira mkati mwa NAc a nyama zonse. Ma Cannula anali a mbali ziwiri koma amaimiridwa mbali imodzi kuti nyama zonse ziwoneke mosavuta (Naive-Sal, yoyera, n = 7; Exp-Saline; imvi yakuda, n = 9; Exp D1R Ant, imvi yopepuka, n = 9; Exp D2R Ant, wakuda, n = 8). ac, Anterior commissure; LV, lateral ventricle; CPu, caudate-putamen. Mount latency ( D ), intromission latency ( E ), ndi ejaculation latency ( F ) kwa magulu onse ogonana (Saline, yoyera; D1R Ant, imvi; D2R Ant, yakuda). Deta ikuyimira amatanthauza ± SEM. * p < 0.05, kusiyana kwakukulu pakati pa tsiku 1 ndi tsiku 4 mkati mwa chithandizo.

Kufufuza kwa chiwerengero cha ΔFosB-IR maselo mu NAC 7 d pambuyo pa kutaya kwa NAc kotsiriza ndi kukambirana mmagulu kapena kuwonetserana bwino kunawonetsa kusiyana kwakukulu pakati pa magulu onse a NAc shell (F(3,29) = 18.070, p <0.001) ndi pachimake (F(3,29) = 10.017, p <0.001). Choyamba, chidziwitso cha kugonana mu saline-infused controls chinachititsa kuti ΔFosB iwonongeke poyerekeza ndi machitidwe achiwerewere (Chith. 5A, chipolopolo p <0.001; Chith. 5B: core, p <0.001), kutsimikizira zotsatira pamwambapa. Kutsutsana kwa D1R, koma osati D2R, kulepheretsa kapena kuchepetsa kusokonekera kwa ΔFosB. Mu chipolopolo cha NAc, wotsutsana ndi D1R yemwe amathandizira amuna ogonana sanasonyeze kuwonjezeka kwa ma cell a osBFosB-IR poyerekeza ndi kuwongolera zachiwerewere (Chith. 5A: p = 0.110), ndipo kufotokoza kwaFosB kunali kochepa kwambiri poyerekeza ndi amuna amchere amchere (Chith. 5A: p = 0.002). M'katikati mwa NAC, kutsutsana kwa D1R kunali ndi zotsatira zochepa: ΔFosB yowonjezereka kwambiri mu amuna omwe amachitira nkhanza D1R poyerekeza ndi machitidwe amchere amchere (Chith. 5B: p = 0.031), koma kuphulika kumeneku kunali kochepa kwambiri poyerekeza ndi amuna ochizira amchere (Chith. 5B: p = 0.012). Mankhwala otsutsana ndi D2R sanakhudze ΔFosB kudulidwa monga amuna omwe anali ndi chiwerewere omwe analandira mdani wa D2R anali ndi chiwerengero chachikulu cha maselo a FosB-IR poyerekeza ndi machitidwe a saline amchere (Chith. 5A: chipolopolo, p <0.001; Chith. 5B: core, p <0.001) ndi amuna omwe amathandizidwa ndi D1R ()Chith. 5A: chipolopolo, p <0.001; Chith. 5B: core, p = 0.013), ndipo sanali kusiyana ndi amuna amchere odziwa zachiwerewere.

Chithunzi 5.     

Chithunzi 5.     

Kuletsa D1R mu NAc kumachepetsa kuchuluka kwa maselo a ΔFosB-IR mu NAc ya nyama zogonana. Kusintha kwa kuchuluka kwa maselo a ΔFosB-IR mu chipolopolo cha NAc ( A ) ndi pakati ( B ) mwa nyama zogonana (zakuda) poyerekeza ndi zolamulira zogonana (zoyera) (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Deta ndi yapakati pa gulu ± SEM. * p < 0.05, kusiyana kwakukulu poyerekeza ndi zolamulira zopanda nzeru. # p < 0.05, kusiyana kwakukulu poyerekeza ndi nyama zogonana za saline ndi D2R Ant. Woimira zithunzi za Naive Sal ( C ), Exp Sal ​​( D ), Exp D1R Ant ( E ), ndi Exp D2R Ant ( F ). ac, Anterior commissure. Scale bar, 100 μm.

Pofuna kuwongolera kufalikira kwa otsutsa a D1R kapena D2R mu dorsal striatum, ΔFosB expression idasanthulidwa m'dera lomwe lili pafupi ndi NAc komanso pafupi ndi lateral ventricle, chifukwa kulowetsedwa kwa ΔFosB mu dorsal striatum ndi psychostimulants ndi opiates kumadalira ntchito ya D1R ( Zhang et al., 2002 ; Muller ndi Unterwald, 2005 ). Chidziwitso chogonana chinawonjezera kuchuluka kwa maselo a ΔFosB-ir mu dorsal striatum mwa amuna omwe amalandira saline (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p < 0.001), kutsimikizira lipoti lathu lapitalo ( Pitchers et al., 2010b ). Komanso, D1R kapena D2R antagonist infusions mu NAc zomwe zakhudza kugonana zomwe zayambitsa ΔFosB mu dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir cells; Exp-D2R: 83.9 ± 4.4 ir cells; p < 0.001 poyerekeza ndi zowongolera za Naive-Sal). Zomwe zapezekazi zikusonyeza kuti kufalikira kwa antagonist infusions kunali kokha ku NAc.

Wotsutsa D1R ku NAc amalepheretsa Amph kupereka mphotho

D1R ikusungidwa mu NAc panthawi yomwe ikugonjetseranso kugonana komwe kunachititsa kuti Amph athandizidwe, athandizidwe, atayesedwa 7 d pambuyo pa kutaya kwa NAC kotsiriza ndi kuyesedwa kwa mating (F(3,29) = 2.956, p = 0.049). Zinyama zokhudzana ndi kugonana zomwe zinalandira saline ku NAc panthawi ya kukambirana zimathera nthawi yochuluka kwambiri mu chipinda cha Amph-paired poyerekeza ndi amuna achiwerewere (Chith. 6A, p = 0.025), kutsimikizira zotsatira pamwambapa. Mosiyana ndi izi, nyama zokhudzana ndi kugonana zomwe zinkalandira mdani wa intra-NAc D1R pa nthawi ya kukwatira sizinapange CPP kwa Amph. Iwo sanali osiyana ndi maulamuliro okhudzana ndi chiwerewere, ndipo anakhala nthawi yochepa mu chipinda cha Amph-paired poyerekeza ndi saline (Chith. 6A: p = 0.049) kapena wotsutsa D2R (Chith. 6A: p = 0.038) amachititsa amuna omwe amadziwika ndi kugonana. D2R otsutsana ndi matendawa sanagwirizane ndi Amph omwe amathandizidwa kuti adzalandire mphoto monga zinyama zogonana ndi NAC D2R omwe amatsutsana ndi matendawa.Chith. 6A: p = 0.040) ndi D1R amene amatsutsa zinyama (Chith. 6A: p = 0.038), ndipo sanali kusiyana ndi amuna amchere odziwa zachiwerewere.

Chithunzi 6.     

Chithunzi 6.     

Kuletsa ma D1 receptors ku NAc kumathetsa mphamvu za Amph kupindula ndikuwonjezereka mankhwala opatsirana pogwiritsa ntchito ziweto zogonana. A, Nthawi yochuluka mu chipinda chotchedwa Amph-paired Room pamapeto pa mayesero kupatula chiwerengero cha pretest (CPP, masekondi) kwa anthu opatsirana pogonana (oyera, n = 6) ndi nyama zodziwa (zakuda) zomwe zinalandira saline (n = 7), wotsutsa D1R (n = 9), kapena wotsutsa D2R (n = 8). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zamchere. #p <0.05, kusiyana kwakukulu kuchokera ku nyama zodziwika bwino za D1R Ant. B, Chiwerengero cha mankhwala osokoneza bongo (pa 10 μm) kwa anthu opatsirana pogonana (oyera, n = 7) ndi nyama zodziwa (zakuda) zomwe zinalandira saline (n = 8), wotsutsa D1R (n = 8), kapena wotsutsa D2R (n = 8). Deta ndi gulu lotanthauza ± SEM. *p <0.05, kusiyana kwakukulu poyerekeza ndi zowongolera zamchere zamchere. #p <0.05, kusiyana kwakukulu ndi kuwongolera mchere wambiri.

Mankhwala otsutsana a D1R amachititsa kuti kugonana kugwire ntchito - kunapangitsa NAc spinogenesis

Kufufuza kwa msinkhu wa msana m'kati mwa NAc ya nyama zomwezo zimasonyeza kuti D1R kulumikiza panthawi yomwe imatetezera anafunika kuwonjezera kuchulukitsa kwa msana wa NAc pambuyo pa zochitika zogonana ndi 7 d za kugonana kwapadera (Chith. 6B; F(3,26) = 41.558, p <0.001). Makamaka, zowongolera zamchere zamchere komanso nyama zotsutsana ndi D2R zinali ndi mitsempha yochulukirapo poyerekeza ndi zowononga zamchere zamchere (Chith. 6B: p <0.001) kutsimikizira zomwe tidapeza m'mbuyomu (Pitchers et al., 2010a) ndi zomwe zili ndi GFP zowononga tizilombo toyambitsa matenda tafotokozedwa pamwambapa. Mosiyana ndi zimenezi, D1R wotsutsana ndi chiwerewere-ankalowetsa nyama zomwe zinali zosiyana ndi saline yachisembwere (kugonana)Chith. 6B). Panali ndi zotsatira zochepa za kulowetsedwa kwa D2R kutsutsana monga D2R inalowetsa zinyama zikuwonetsa kuchepa kwa msana kuposa momwe zimakhalira ndi mchere (Chith. 6B: p = 0.02), koma nambala yochulukirapo ya spines poyerekeza ndi machitidwe olimbitsa thupi amchere ndi azimayi omwe amadziwika ndi D1R (p <0.001; Chith. 6B). Choncho, D1R yoletsedwa ku NAC nthawi yolepheretsa zotsatira zokhudzana ndi kugonana komanso kuletsa kudziletsa pa NAc spinogenesis.

Kukambirana

Mu kafukufuku waposachedwa, tawonetsa kuyanjana pakati pa mphotho yachilengedwe ndi ya mankhwala osokoneza bongo, pomwe mphotho yachilengedwe imatsatiridwa ndi nthawi yodziletsa. Makamaka, tawonetsa kuti zomwe takumana nazo ndi khalidwe logonana, kutsatiridwa ndi masiku 7 kapena 28 a kudziletsa, zimayambitsa mphotho yowonjezera ya Amph . Zomwe zapezekazi zikufanana ndi gawo lofunikira la nthawi yodziletsa kugwiritsa ntchito mankhwala osokoneza bongo pakukulitsa chilakolako cha mankhwala osokoneza bongo ( Lu et al., 2005 ; Thomas et al., 2008 ; Wolf, 2010b , 2012 ; Xue et al., 2012 ). Kuphatikiza apo, ΔFosB yochokera ku mphotho yachilengedwe mu NAc ndiyofunikira kwambiri pa zotsatira zodziletsa zachilengedwe pa mphotho ya psychostimulant, mwina kudzera mu spinogenesis mu NAc panthawi yodziletsa mphotho. Tawonetsa kuti kudzikundikira kwa ΔFosB mu NAc pambuyo pa zochitika zogonana kumakhala kokhalitsa ndipo kumadalira ntchito ya NAc D1R panthawi yogonana. Komanso, kukwezedwa kwa ΔFosB komwe kumachitika chifukwa cha D1R mu NAc kwawonetsedwa kuti ndikofunikira kwambiri pakupeza mphotho yowonjezera ya Amph komanso kuchuluka kwa msana mu NAc, ngakhale kuti zotsatira izi za kugonana zimadalira nthawi yodziletsa kulandira mphotho yogonana ( Pitchers et al., 2010a ). Pomaliza, tawonetsa kuti NAc spinogenesis ikhoza kuthandizira pakukula koyamba kwa kuwonetsa kwakanthawi kochepa kwa mphotho yolimbikitsidwa ya Amph koma sikofunikira kwambiri kuti mphotho yowonjezereka ya mankhwala ipitirire, chifukwa kuchuluka kwa msana mu NAc kunali kwakanthawi ndipo kumawonekera pambuyo pa masiku 7, koma osati masiku 28, nthawi yodziletsa.

Kwakhala kudziwika kwa nthawi yayitali kuti dopamine imatulutsidwa mu NAc panthawi ya khalidwe lachilengedwe la mphotho, kuphatikizapo khalidwe la kugonana. Mkazi akalandira dopamine, dopamine yakunja mu NAc imawonjezeka ndipo imakhalabe yokwera panthawi ya kugonana ( Fiorino et al., 1997 ). Kafukufuku wapano wasonyeza kuti kulowetsa dopamine receptor antagonists mu NAc panthawi ya kugonana sikunakhudze kuyambitsa kapena kuchita khalidwe la kugonana, zomwe zikugwirizana ndi lingaliro lakuti dopamine siili ndi gawo pa kuwonetsa khalidwe la mphotho, koma m'malo mwake imawonetsa mphamvu ya chilimbikitso cha zizindikiro zokhudzana ndi kugonana ( Berridge ndi Robinson, 1998 ). Zoonadi, zizindikiro zolosera mphotho ya kugonana zimayambitsa kuyambitsa ma neurons mkati mwa dongosolo la mphotho ya dopamine ya mesolimbic, kuphatikizapo maselo a dopaminergic m'dera la ventral tegmental ndi cholinga chawo, NAc ( Balfour et al., 2004 ). Khalidwe lobwerezabwereza la kugonana limayambitsa ΔFosB mu NAc, yomwe imalimbikitsa kulimbitsa khalidwe la kugonana komwe kumabwera chifukwa cha zomwe zachitika ( Pitchers et al., 2010b ). Zotsatira zaposachedwa zikusonyeza kuti kukwera kwa ΔFosB komwe kumachitika chifukwa cha kukwera kwa thupi kumadalira kwambiri kuyambika kwa D1R mu NAc panthawi yokwera. Kupeza kumeneku kukugwirizana ndi kafukufuku wakale wosonyeza kuti kuperekedwa mobwerezabwereza kwa psychostimulant kunachulukitsa ΔFosB mu NAc medium spiny neurons yomwe imatulutsa D1R ( Lee et al., 2006 ; Kim et al., 2009 ) ndipo kuti kukwera kwa ΔFosB kotereku kumadalira kuyambika kwa D1R ( Zhang et al., 2002 ). Kuphatikiza apo, mayankho a mankhwala okhudzidwa, omwe nthawi zambiri amawonedwa mwa nyama yodziwa bwino mankhwala, amatha kupangidwa popanda kuwonetsedwa kwa mankhwala kale chifukwa cha kuchuluka kwa ΔFosB mu D1R yomwe imatulutsa ma neuron mu striatum ( Kelz et al., 1999 ). Chifukwa chake, mphotho zachilengedwe komanso zamankhwala zimawonjezera ΔFosB mu NAc kudzera mu njira yodalira D1R kuti ilimbikitse machitidwe a mphotho.

Komanso, zomwe zapezeka pano zikusonyeza kuti ΔFosB ndi mkhalapakati wofunikira kwambiri pakati pa chidziwitso cha mphotho zachilengedwe ndi mphotho ya psychostimulant. Monga taonera, ntchito ya ΔFosB mu NAc yakhala ikukhudzidwa kale ndi mayankho a mankhwala osokoneza bongo, chifukwa ΔFosB yochulukirapo mu NAc imachititsa kuti cocaine iyambe kugwira ntchito pambuyo popatsidwa mankhwala obwerezabwereza ( Kelz et al., 1999 ), imawonjezera chidwi cha cocaine ndi morphine CPP ( Kelz et al., 1999 ; Zachariou et al., 2006 ), ndipo imayambitsa kudzipatsa cocaine wochepa ( Colby et al., 2003 ). Kafukufuku wapano akuwonetsa kuti kuletsa ntchito ya D1R kapena ΔFosB mu NAc panthawi yogonana kunathetsa chidziwitso cha Amph chomwe chimayambitsa kugonana.

Kafukufuku waposachedwa wasonyeza kuti nthawi yodziletsa kulandira mphotho yogonana ikufunika kuti munthu azindikire Amph reward ndi NAc spinogenesis. Tikuganiza kuti ΔFosB panthawiyi yodziletsa imakhudza ntchito ya mitsempha mwa kusintha mawonekedwe a majini kuti ayambitse spinogenesis ndikusintha mphamvu ya synaptic . Zoonadi, kuletsa kulowetsedwa kwa ΔFosB mu NAc panthawi yogonana kunaletsa kuchuluka kwa msana mu NAc komwe kunapezeka pambuyo poti munthu wasiya kulandira mphotho. Komanso, kulowetsedwa kwa D1R antagonist mu NAc musanayambe nthawi iliyonse yogonana kunaletsa kuwonjezeka kwa ΔFosB komwe kunayambitsidwa ndi zochitika zogonana komanso kuchuluka kwa msana komwe kunatsatira.

ΔFosB ndi chinthu cholembera kuti chikhale ngati choyimitsa cholembera kapena chopondereza kuti chikhudze mafotokozedwe a zowonongeka za majeremusi zomwe zingasokoneze mphamvu ndi mphamvu ya synaptic mu NAC (Nestler, 2008). Makamaka, ΔFosB imayambitsa cyclic-dependent kinase-5 (Bibb et al., 2001; Kumar et al., 2005), chinthu cha nyukiliya κ B (NF-κB) (Russo et al., 2009b), ndi GluA2 subunit ya glutamate AMPA receptor (Vialou et al., 2010) ndi rimafotokoza zolembera za jekeseni wam'mbuyo oyambirira (Pitchers et al., 2010b) ndi histone methyltreferase G9 (Maze et al., 2010). Cxc-dependent kinase-5 imayambitsa mapuloteni a cytoskeletal ndi kutuluka kwa neurite (Taylor ndi al., 2007). Kuwonjezera apo, kuyambitsa NF-κB kumawonjezera chiwerengero cha mitsempha ya dendritic mu NAC, pamene kukanizidwa kwa NF-κB kunachepetsanso mitsempha ya dendritic yowonjezera ndipo imapangitsa kuwonjezeka kwa cocaine kuwonjezeka pamphepete (Russo et al., 2009b). Chifukwa chake, mphotho ya kugonana imachulukitsa ΔFosB mu NAC, yomwe ingasinthe Nc kuperewera kwazambiri mwachitsanzo (ie, cyclic-dependent kinase-5, NF-κB) ndi kuti zotsatira zake zonse ndi mphotho ya mankhwala, monga momwe Russo et al. (2009a) chifukwa cha zochita za mobwerezabwereza cocaine.

Kafukufuku wosadziwika bwino mu kafukufukuyu anali wakuti kuchuluka kwa msana mu NAc kunali kosakhalitsa, ndipo sikunapezekenso patatha masiku 28 kuchokera pamene munthu wagonana. Chifukwa chake, kuchuluka kwa msana kunagwirizana ndi kuyamba kwa mphotho yowonjezera ya Amph ndipo kungathandize pakukula koyamba kapena kuwonetsa kwakanthawi kochepa kwa mayankho a Amph okhudzidwa. Komabe, kuchuluka kwa msana sikunali kofunikira kuti mphotho yowonjezera ya Amph ipitirire pambuyo pa nthawi yayitali yodziletsa. Tawonetsa kale kuti zomwe zimachitika pogonana zimayambitsa kuwonjezeka kwa kanthawi kochepa (7, koma osati masiku 28, pambuyo pa kukwatirana komaliza) kwa NMDA receptor subunit NR-1 mu NAc, komwe kunabwerera ku magawo oyambira pambuyo pa nthawi yayitali yodziletsa mphotho ( Pitchers et al., 2012 ). Kuwonjezeka kumeneku kwa NMDA receptor kunaganiziridwa kuti kukuwonetsa ma synapses chete omwe amayambitsidwa ndi kugonana ( Huang et al., 2009 ; Brown et al., 2011 ; Pitchers et al., 2012 ), ndipo kukuwonetsa kuthekera kwakuti kukula kwa msana komwe kumayambitsidwa ndi zochitika zogonana kumadalira ntchito yowonjezera ya NMDA receptor ( Hamilton et al., 2012 ).

Pomalizira, kafukufuku wamakono akuwonetseratu kuwonetsetsa kwapakati pa mphotho ya mankhwala chifukwa cha mphotho (kugonana) ndi kudalira kwake pa nthawi yopuma. Komanso, mapulasitikiwa amatsutsana ndi ΔFosB pogwiritsa ntchito D1R kukhazikitsa ku NAC. Choncho, deta imasonyeza kuti kutaya kwa mphotho zapadera pambuyo pothandizira mphotho kungapangitse anthu kukhala osatetezeka ku chitukuko cha mankhwala osokoneza bongo komanso kuti mkhalapakati mmodzi wa chiopsezo ichi ndi ΔFosB ndi zolembera zake zolembera pansi.

Mawu a M'munsi

  • Adalandira October 16, 2012.
  • Kukonzanso kunalandira December 12, 2012.
  • Adalandira December 23, 2012.

  • Ntchitoyi inathandizidwa ndi Institute of Health Research (LMC) ku Canada, National Institute of Mental Health (EJN), ndi Natural Sciences ndi Engineering Research Council of Canada (KKP ndi LMC). Tikuthokoza Dr. Catherine Woolley (University of Northwestern University) kuti athandizidwe ndi njira zolemba ma dilisti.

  • Olembawo salengeza kuti palibe mpikisano wa ndalama.

  • Mndandanda wa zolembera uyenera kuuzidwa kwa Dr. Lique M. Coolen, Dipatimenti ya Physiology ndi Biophysics, Medical Center ya University of Mississippi, 2500 North State Street, Jackson, MS 39216. [imelo ndiotetezedwa]

Zothandizira

  1. ↵
    1. Sungani ME,
    2. Yu L,
    3. Coolen LM

    (2004) Kugonana ndi kugonana komwe kumagwirizanitsa kugonana kumayambitsa masolimbic dongosolo mu makoswe amphongo. Neuropsychopharmacology 29: 718-730.

  2. ↵
    1. Berridge KC,
    2. Robinson TE

    (1998) Kodi ntchito ya dopamine ndi mphoto yotani: zotsatira za hedonic, kuphunzira mphoto, kapena kulimbitsa mtima? Rev Brain Res Brain Rev Rev 28: 309-369.

  3. ↵
    1. Bibb JA,
    2. Chen J,
    3. Taylor JR,
    4. Svenningsson P,
    5. Nishi A,
    6. Snyder GL,
    7. Yan Z,
    8. Sagawa ZK,
    9. Ouimet CC,
    10. Nairn AC,
    11. Nestler EJ,
    12. Greengard P

    (2001) Zotsatira za cocaine nthawi zonse zimayang'aniridwa ndi neuronal mapuloteni Cdk5. Nature 410: 376-380.

  4. ↵
    1. Bradley KC,
    2. Meisel RL

    (2001) Kugonana kwapadera kwa c-Fos mu nucleus accumbens ndi ntchito ya amphetamine yolimbikitsana ikulimbikitsidwa ndi chizolowezi chogonana cham'mbuyo mwa amayi a ku Syria. J Neurosci 21: 2123-2130.

  5. ↵
    1. Brown TE,
    2. Lee BR,
    3. Mu P,
    4. Ferguson D,
    5. Dietz D,
    6. Ohnishi YN,
    7. Lin Y,
    8. Suska A,
    9. Ishikawa M,
    10. Huang YH,
    11. Shen H,
    12. Kalivas PW,
    13. Sorg BA,
    14. Zukin RS,
    15. Nestler EJ,
    16. Dong Y,
    17. Schlüter OM

    (2011) Njira yokhazikika yophatikizapo mawu osokoneza bongo chifukwa cha kulimbikitsa okonda kupanga cocaine. J Neurosci 31: 8163-8174.

  6. ↵
    1. Cameron CM,
    2. Carelli RM

    (2012) Kudziletsa kwa Cocaine kumapangitsa kuti phokoso likhale lopanda mphamvu pazifukwa zotsatiridwa ndi cocaine ndi sucrose. Eur J Neurosci 35: 940-951.

  7. ↵
    1. Chen BT,
    2. Chiyembekezo FW,
    3. Bonci A

    (2010) Mapuloteni othandizira kuti asamangogwiritsira ntchito mankhwala osokoneza bongo. Ann NY Acad 1187: 129-139.

  8. ↵
    1. Colby CR,
    2. Whisler K,
    3. Steffen C,
    4. Nestler EJ,
    5. Kudzikonda DW

    (2003) Mchitidwe wodabwitsa wa maselo opatsirana wa ΔFosB umalimbikitsa cocaine. J Neurosci 23: 2488-2493.

  9. ↵
    1. Fiorino DF,
    2. Coury A,
    3. Phillips AG

    (1997) Kusintha kwa mphamvu mu nucleus accumbens dopamine efflux pa Coolidge zotsatira mu makoswe. J Neurosci 17: 4849-4855.

  10. ↵
    1. Forlano PM,
    2. Woolley CS

    (2010) Kuwerengera koyambirira kwa kugonana koyambirira ndi kumbuyo kwapakati pachisokonezo cha kugonana mu nucleus accumbens. J Comp Neurol 518: 1330-1348.

  11. ↵
    1. Frohmader KS,
    2. Pitchers KK,
    3. Sungani ME,
    4. Coolen LM

    (2010a) Kusakaniza zosangalatsa: kubwereza zotsatira za mankhwala okhudza kugonana kwa anthu ndi zinyama. Horm Behav 58: 149-162.

  12. ↵
    1. Frohmader KS,
    2. Wiskerke J,
    3. RA wanzeru,
    4. Lehman MN,
    5. Coolen LM

    (2010b) Methamphetamine amagwiritsa ntchito njira zochepa zogonana zogonana ndi makoswe. Neuroscience 166: 771-784.

  13. ↵
    1. Hamilton AM,
    2. O WC,
    3. Vega-Ramirez H,
    4. Stein IS,
    5. Hell JW,
    6. Patrick GN,
    7. Zito K

    (2012) Kuwonjezeka kwa ntchito zokhudzana ndi kukula kwa madontho atsopano a dendritic kumayendetsedwa ndi proteasome. Neuron 74: 1023-1030.

  14. ↵
    1. Hedges VL,
    2. Chakravarty S,
    3. Nestler EJ,
    4. Meisel RL

    (2009) Δ FosB kufotokoza momveka bwino pakati pa nucleus accumbens kumapatsa mphoto ya kugonana kwa amayi achi Syria. Chiberekero cha Chiberekero Behav 8: 442-449.

  15. ↵
    1. Huang YH,
    2. Lin Y,
    3. Mu P,
    4. Lee BR,
    5. Brown TE,
    6. Wayman G,
    7. Marie H,
    8. Liu W,
    9. Yan Z,
    10. Sorg BA,
    11. Schlüter OM,
    12. Zukin RS,
    13. Dong Y

    (2009) Chidziwitso cha cocaine mu vivo chimapanga timagulu tambirimbiri. Neuron 63: 40-47.

  16. ↵
    1. Hyman SE,
    2. Malenka RC,
    3. Nestler EJ

    (2006) Njira zowonongeka zowonongeka: gawo la maphunziro okhudzana ndi mphoto ndi kukumbukira. Annu Rev Neurosci 29: 565-598.

  17. ↵
    1. Kalivas PW

    (2009) Ma glutamate homeostasis akuganiza kuti ndizovuta. Nat Rev Neurosci 10: 561-572.

  18. ↵
    1. Kauer JA,
    2. Malenka RC

    (2007) Mapuloteni oyambirira ndi oledzera. Nat Rev Neurosci 8: 844-858.

  19. ↵
    1. Kelley AE

    (2004) Kukumbukila ndi kuledzera: gawo logawana neural ndi njira zamagulu. Neuron 44: 161-179.

  20. ↵
    1. Kelz MB,
    2. Chen J,
    3. Carlezon WA Jr.,
    4. Whisler K,
    5. Gilden L,
    6. Beckmann AM,
    7. Steffen C,
    8. Zhang YJ,
    9. Marotti L,
    10. Kudzikonda DW,
    11. Tkatch T,
    12. Baranauskas G,
    13. Surmeier DJ,
    14. Neve RL,
    15. Duman RS,
    16. Picciotto MR,
    17. Nestler EJ

    (1999) Chiwonetsero cha chinthu cholembera ΔFosB mu ubongo amalamulira mphamvu zokhudzana ndi cocaine. Nature 401: 272-276.

  21. ↵
    1. Kim Y,
    2. Teylan MA,
    3. Baron M,
    4. Sands A,
    5. Nairn AC,
    6. Greengard P

    (2009) Methylphenidate-inachititsa kuti dendritic apange mapangidwe ndi mafotokozedwe a FosB mu nucleus accumbens. Proc Natl Acad Sci USA 106: 2915-2920.

  22. ↵
    1. Koob GF,
    2. Volkow ND

    (2010) Mankhwala osokoneza bongo. Neuropsychopharmacology 35: 217-238.

  23. ↵
    1. Kumar A,
    2. Choi KH,
    3. Renthal W,
    4. Tsankova NM,
    5. Theobald DE,
    6. Truong HT,
    7. Russo SJ,
    8. Kulepheretsa Q,
    9. Sasaki TS,
    10. Whistler KN,
    11. Neve RL,
    12. Kudzikonda DW,
    13. Nestler EJ

    (2005) Chromatin kukonzedwanso ndi njira yofunika kwambiri yomwe imayambira kuphulika kwa poizoni ya cocaine mu striatum. Neuron 48: 303-314.

  24. ↵
    1. Laviolette SR,
    2. Lauzon NM,
    3. Bishopu SF,
    4. Sun N,
    5. Tan H

    (2008) Dopamine chizindikiro kudzera mwa D1 -fanana ndi D2-like receptors mu nucleus accumbens pakati ndi chipolopolo mosiyana zimapangitsa chikonga mphoto mphamvu. J Neurosci 28: 8025-8033.

  25. ↵
    1. Lee KW,
    2. Kim Y,
    3. Kim AM,
    4. Helmin K,
    5. Nairn AC,
    6. Greengard P

    (2006) Kupangidwa kwa Cocaine komwe kunapangidwira msana m'kati mwa D1 ndi D2 dopamine receptor yomwe imakhala ndi timadzi timene timene timakhala timene timayambira. Proc Natl Acad Sci USA 103: 3399-3404.

  26. ↵
    1. Lennette DA

    (1978) Chinthu cholumikizira bwino chokhala ndi microscopy ya immunofluorescence. Am J Clin Pathol 69: 647-648.

  27. ↵
    1. Lu L,
    2. Hope BT,
    3. Dempsey J,
    4. Liu SY,
    5. Bossert JM,
    6. Shaham Y

    (2005) Njira yayikulu yowonetsera kayendedwe ka ERK ndi yofunika kwambiri kuti munthu azikhala ndi chikhumbo cha cocaine. Nat Neurosci 8: 212-219.

  28. ↵
    1. Mameli M,
    2. Lüscher C

    (2011) Mapuloteni osakanikirana ndi mankhwala osokoneza bongo: njira zophunzirira zatha. Neuropharmacology 61: 1052-1059.

  29. ↵
    1. Maze I,
    2. Covington HE 3rd.,
    3. Dietz DM,
    4. Kuyika Q,
    5. Renthal W,
    6. Russo SJ,
    7. Mankhwala M,
    8. Mouzon E,
    9. Neve RL,
    10. Haggarty SJ,
    11. Ren Y,
    12. Sampath SC,
    13. Pewani YL,
    14. Greengard P,
    15. Tarakhovsky A,
    16. Schaefer A,
    17. Nestler EJ

    (2010) Udindo wofunikira wa histone womwe umatulutsa tizilombo toyambitsa matenda G9a mu pulasitiki yopangidwa ndi cocaine. Science 327: 213-216.

    1. McCutcheon YO,
    2. Wang X,
    3. Tseng KY,
    4. Wolf ME,
    5. Marinelli M

    (2011) Mapepala a AMPA omwe amapezeka pamtundu wa calcium amapezeka pamtunduwu pambuyo pochoka kwa cocaine podziteteza koma osati cocaine. J Neurosci 31: 5737-5743.

  31. ↵
    1. Meisel RL,
    2. Mullins AJ

    (2006) Chidziwitso chogonana pa makoswe aakazi: njira zamagulu ndi zotsatira zogwira ntchito. Resin ya ubongo 1126: 56-65.

  32. ↵
    1. Muller DL,
    2. Unterwald EM

    (2005) D1 dopamine receptors amachititsa ΔFosB kulowetsa phokoso striatum patatha kayendedwe ka morphine. J Pharmacol Exp Ther 314: 148-154.

  33. ↵
    1. Nestler EJ

    (2008) Njira zolembera zolaula: udindo wa ΔFosB. Philos Trans R Soc Lond B Biol Sci 363: 3245-3255.

  34. ↵
    1. Nestler EJ,
    2. Barrot M,
    3. Kudzikonda DW

    (2001) ΔFosB: kusinthana kwa maselo osakaniza. Proc Natl Acad Sci USA 98: 11042-11046.

  35. ↵
    1. Olausson P,
    2. Jentsch JD,
    3. Tronson N,
    4. Neve RL,
    5. Nestler EJ,
    6. Taylor JR

    (2006) ΔFosB mkati mwa nucleus accumbens imayendetsa khalidwe lothandizira chakudya ndi cholinga. J Neurosci 26: 9196-9204.

  36. ↵
    1. CM yosungidwa

    (2011) Mphoto zachilengedwe, kutsekemera kwa magazi, komanso mankhwala osokoneza bongo. Neuropharmacology 61: 1109-1122.

  37. ↵
    1. Perrotti LI,
    2. Hadeishi Y,
    3. Ulery PG,
    4. Barrot M,
    5. Monteggia L,
    6. Duman RS,
    7. Nestler EJ

    (2004) Kuchokera kwa ΔFosB muzochitika za ubongo zokhudzana ndi mphoto pambuyo povutika maganizo. J Neurosci 24: 10594-10602.

  38. ↵
    1. Perrotti LI,
    2. Weaver RR,
    3. Robison B,
    4. Renthal W,
    5. Maze I,
    6. Yazdani S,
    7. Elmore RG,
    8. Knapp DJ,
    9. Selley DE,
    10. Martin BR,
    11. Sim-Selley L,
    12. Bachtell RK,
    13. Kudzikonda DW,
    14. Nestler EJ

    (2008) Kusiyanitsa kwa DFF kudulidwa mu ubongo ndi mankhwala osokoneza bongo. Synapse 62: 358-369.

  39. ↵
    1. Pitchers KK,
    2. Sungani ME,
    3. Lehman MN,
    4. Richtand NM,
    5. Yu L,
    6. Coolen LM

    (2010a) Kutsegula m'mimba mu njira ya masolimbic yomwe imapangidwanso ndi mphotho ya chilengedwe komanso zotsatirapo zodziletsa. Biol Psychiatry 67: 872-879.

  40. ↵
    1. Pitchers KK,
    2. Frohmader KS,
    3. Vialou V,
    4. Mouzon E,
    5. Nestler EJ,
    6. Lehman MN,
    7. Coolen LM

    (2010b) ΔFosB mkatikati mwa nucleus accumbens ndi yofunika kwambiri kuti ikulimbikitseni zotsatira za kugonana. Chiberekero cha Chiberekero Behav 9: 831-840.

  41. ↵
    1. Pitchers KK,
    2. Schmid S,
    3. Di Sebastiano AR,
    4. Wang X,
    5. Laviolette SR,
    6. Lehman MN,
    7. Coolen LM

    (2012) Chidziwitso cha mphotho zachilengedwe chimasintha kupezeka kwa AMPA ndi NMDA kupezeka kwa ntchito ndi ntchito mu nucleus accumbens. PLoS One 7: e34700.

  42. ↵
    1. Roberts MD,
    2. Gilpin L,
    3. Parker KE,
    4. Kuphunzitsa ana,
    5. Will MJ,
    6. Booth FW

    (2012) Dopamine D1 receptor modulation mu nucleus accumbens amachepetsa voluntary gudumu yothamanga mu makoswe othamangira kuyenda kutali. Physiol Behav 105: 661-668.

  43. ↵
    1. Russo SJ,
    2. Mazei-Robison MS,
    3. Ables JL,
    4. Nestler EJ

    (2009a) Zomwe zimachititsa kuti thupi likhale lopweteka komanso mapulasitiki amatha kukhala oledzeretsa. Neuropharmacology 56 (Suppl 1): 73-82.

  44. ↵
    1. Russo SJ,
    2. Wilkinson MB,
    3. Mazei-Robison MS,
    4. Dietz DM,
    5. Maze I,
    6. Krishnan V,
    7. Renthal W,
    8. Graham A,
    9. Birnbaum SG,
    10. Green TA,
    11. Robison B,
    12. Lesselyong A,
    13. Perrotti LI,
    14. Bolaños CA,
    15. Kumar A,
    16. Clark MS,
    17. Neumaier JF,
    18. Neve RL,
    19. Bhakar AL,
    20. Barker PA,
    21. et al.

    (2009b) Chinthu cha nyukiliya κB chizindikiro cha malamulo othandizira kuti azikhala ndi mphotho ndi cocaine mphotho. J Neurosci 29: 3529-3537.

  45. ↵
    1. Taylor JR,
    2. Lynch WJ,
    3. Sanchez H,
    4. Olausson P,
    5. Nestler EJ,
    6. Bibb JA

    (2007) Kuletsedwa kwa Cdk5 mu nucleus accumbens kumapangitsa kuti anthu azikhala ndi mphamvu zolimbikitsa komanso zokakamiza za cocaine. Proc Natl Acad Sci USA 104: 4147-4152.

  46. ↵
    1. Tenk CM,
    2. Wilson H,
    3. Zhang Q,
    4. Pitchers KK,
    5. Coolen LM

    (2009) Mphoto yokhudza kugonana mu makoswe aamuna: zotsatira za kugonana pogonana pamalo okondeka omwe akugwirizana ndi kuthamangitsidwa ndi kutuluka. Horm Behav 55: 93-97.

  47. ↵
    1. Thomas MJ,
    2. Kalivas PW,
    3. Shaham Y

    (2008) Kutsegula m'mimba mu disolimbic dopamine dongosolo ndi mowa wa cocaine. Br J Pharmacol 154: 327-342.

  48. ↵
    1. Vialou V,
    2. Robison AJ,
    3. Laplant QC,
    4. Covington HE 3rd.,
    5. Dietz DM,
    6. Ohnishi YN,
    7. Mouzon E,
    8. Kuthamanga AJ 3rd.,
    9. Watts EL,
    10. Wallace DL,
    11. Iñiguez SD,
    12. Ohnishi YH,
    13. Steiner MA,
    14. Warren BL,
    15. Krishnan V,
    16. Bolaños CA,
    17. Neve RL,
    18. Ghose S,
    19. Berton O,
    20. CA Tamminga,
    21. et al.

    (2010) ΔFosB m'madera ozungulira mphotho amaphatikizapo kuthandizira kupsinjika maganizo ndi mayankho ogonjetsa. Nat Neurosci 13: 745-752.

  49. ↵
    1. Wallace DL,
    2. Vialou V,
    3. Rios L,
    4. Carle-Florence TL,
    5. Chakravarty S,
    6. Kumar A,
    7. Graham DL,
    8. Green TA,
    9. Kirk A,
    10. Iñiguez SD,
    11. Perrotti LI,
    12. Barrot M,
    13. DiLeone RJ,
    14. Nestler EJ,
    15. Bolaños-Guzmán CA

    (2008) Mphamvu ya ΔFosB yomwe imakhalapo pamtundu wa chikhalidwe chogwirizana ndi mphotho. J Neurosci 28: 10272-10277.

  50. ↵
    1. Werme M,
    2. Messer C,
    3. Olson L,
    4. Gilden L,
    5. Thorén P,
    6. Nestler EJ,
    7. Brené S

    (2002) Δ FosB imayendetsa magudumu akuthamanga. J Neurosci 22: 8133-8138.

  51. ↵
    1. Winstanley CA,
    2. Kuyika Q,
    3. Theobald DE,
    4. Green TA,
    5. Bachtell RK,
    6. Perrotti LI,
    7. DiLeone RJ,
    8. Russo SJ,
    9. Garth WJ,
    10. Kudzikonda DW,
    11. Nestler EJ

    (2007) ΔFosB induction in orbitofrontal cortex imaphatikizapo kulekerera kusokonezeka maganizo kwa cocaine. J Neurosci 27: 10497-10507.

  52. ↵
    1. Wolf ME

    (2010a) Triangle ya Bermuda ya cocaine-yomwe inachititsa kuti munthu asagwiritsidwe ntchito. Miyambo ya Neurosci 33: 391-398.

  53. ↵
    1. Wolf ME

    (2010b) Kulamulidwa kwa malonda a AMPA pamtengowo womwe umapezeka ndi dopamine ndi cocaine. Neurotox Res 18: 393-409.

  54. ↵
    1. Wolf ME

    (2012) Katswiri wa sayansi: zotsatira za khalidwe la cocaine zinasinthidwa. Nature 481: 36-37.

  55. ↵
    1. Xue YX,
    2. Luo YX,
    3. Wu P,
    4. Shi HS,
    5. Xue LF,
    6. Chen C,
    7. Zhu WL,
    8. Ding ZB,
    9. Bao YP,
    10. Shi J,
    11. Epstein DH,
    12. Shaham Y,
    13. Lu L

    (2012) Ndondomeko yowonongeka kwa kukumbukira kusokoneza chilakolako cha mankhwala ndi kubwereranso. Science 336: 241-245.

  56. ↵
    1. Zachariou V,
    2. Bolanos CA,
    3. Selley DE,
    4. Theobald D,
    5. Cassidy MP,
    6. Kelz MB,
    7. Shaw-Lutchman T,
    8. Berton O,
    9. Sim-Selley LJ,
    10. Dileone RJ,
    11. Kumar A,
    12. Nestler EJ

    (2006) Chofunika kwambiri kuti ΔFosB ikhale pamtundu wa morphine. Nat Neurosci 9: 205-211.

  57. ↵
    1. Zhang D,
    2. Zhang L,
    3. Lou DW,
    4. Nakabeppu Y,
    5. Zhang J,
    6. Xu M

    (2002) Dopamine D1 receptor ndi mkhalapakati wofunikira wa kayendedwe ka mtundu wa cocaine. J Neurochem 82: 1453-1464.

Nkhani zomwe zikufotokoza izi

  • Kupereka kotheka kwa mtundu wa synaptic plasticity mu Aplysia kuti apereke mphotho, kukumbukira, ndi zovuta zawo mu ubongo wa mammalian Kuphunzira & Kukumbukira, 18 Seputembara 2013, 20 (10): 580-591

KUPHUNZIRA KONSE - Gawo Lokambirana:

Phunziroli, tawonetsa kuponderezana pakati pa malipiro a chilengedwe ndi mankhwala, pamene malipiro a chilengedwe amatsatidwa ndi nthawi yodziletsa. Mwachindunji, ife tawonetsa chidziwitso cha khalidwe la chiwerewere, titatsatiridwa ndi 7 kapena 28 d kudziletsa, zimayambitsa Amph kupititsa patsogolo.

Zomwe zapezekazi zikufanana ndi gawo lofunika kwambiri la nthawi yodziletsa kugwiritsa ntchito mankhwala osokoneza bongo poyambitsa chilakolako cha mankhwala osokoneza bongo (Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Kuphatikiza apo, FosB yachilengedwe yochokera ku mphotho mu NAc ndiyofunikira kwambiri pa zotsatira zodziwitsa anthu za kudziletsa kwachilengedwe pa mphotho ya psychostimulant, mwina kudzera mu spinogenesis mu NAc panthawi yodziletsa kulandira mphotho.

Tawonetsa kuti kuchuluka kwa FosB mu NAc pambuyo pa zochitika zogonana kumakhala kokhalitsa ndipo kumadalira ntchito ya NAc D1R panthawi yogonana . Kuphatikiza apo, kukwera kwa FosB komwe kumayendetsedwa ndi D1R mu NAc kwawonetsedwa kuti ndikofunikira kwambiri pakupeza mphotho yowonjezera ya Amph komanso kuchuluka kwa msana mu NAc, ngakhale kuti zotsatira izi za zochitika zogonana zimadalira nthawi yodziletsa kulandira mphotho yogonana (Pitchers et al., 2010a). Pomaliza, tawonetsa kuti NAc spinogenesis ingathandize pakukula koyamba kwa kuwonetsa kwakanthawi kochepa kwa mphotho yolimbikitsidwa ya Amph koma sikofunikira kwambiri kuti mphotho yowonjezereka ya mankhwala ipitirire, chifukwa kuchuluka kwa msana mu NAc kunali kwakanthawi ndipo kumawonekera pambuyo pa masiku 7, koma osati masiku 28, nthawi yodziletsa.

Kwakhala kudziwika kwa nthawi yayitali kuti dopamine imatulutsidwa mu NAc panthawi ya machitidwe achilengedwe a mphotho, kuphatikizapo khalidwe la kugonana . Mkazi akalandira dopamine, extracellular dopamine mu NAc imawonjezeka ndipo imakhalabe yokwera panthawi ya kukwatira (Fiorino et al., 1997). Kafukufuku wapano wasonyeza kuti kulowetsa dopamine receptor antagonists mu NAc panthawi ya kukwatira sikunakhudze kuyambitsa kapena kuchita khalidwe la kugonana, zomwe zikugwirizana ndi lingaliro lakuti dopamine siili ndi gawo pakuwonetsa khalidwe la mphotho, koma m'malo mwake imawonetsa mphamvu ya chilimbikitso cha zizindikiro zokhudzana ndi kugonana (Berridge ndi Robinson, 1998). Inde, zizindikiro zolosera za mphotho ya kugonana zimayambitsa kuyambitsa ma neurons mkati mwa dongosolo la mphotho ya dopamine ya mesolimbic, kuphatikiza maselo a dopaminergic m'dera la ventral tegmental ndi cholinga chawo, NAc (Balfour et al., 2004).

Khalidwe logonana mobwerezabwereza limayambitsa FosB mu NAc, yomwe imayambitsa kulimbitsa khalidwe la kugonana komwe kumabwera chifukwa cha zomwe zachitika (Pitchers et al., 2010b). Zotsatira zaposachedwa zikuwonetsa kuti kukwera kwa FosB komwe kumabwera chifukwa cha kukwera kwa mating kumadalira kwambiri kuyambika kwa D1R mu NAc panthawi yokwera. Kupeza kumeneku kukugwirizana ndi kafukufuku wakale wosonyeza kuti kuperekedwa mobwerezabwereza kwa psychostimulant kunawonjezera FosB mu NAc medium spiny neurons yomwe imatulutsa D1R (Lee et al., 2006; Kim et al., 2009) ndipo kuti kukwera kwa FosB kotereku kumadalira kuyambika kwa D1R (Zhang et al., 2002). Kuphatikiza apo, mayankho a mankhwala okhudzidwa, omwe nthawi zambiri amawonedwa mwa nyama yodziwa bwino mankhwala, amatha kupangidwa popanda kuwonetsedwa kwa mankhwala kale chifukwa cha kuchuluka kwa FosB mu D1R yomwe imatulutsa ma neuron mu striatum (Kelz et al., 1999). Chifukwa chake, mphotho zachilengedwe komanso zamankhwala zimawonjezera FosB mu NAc kudzera mu njira yodalira D1R kuti ilimbikitse machitidwe a mphotho.

Komanso, zomwe zapezeka pano zikusonyeza kuti FosB ndi mkhalapakati wofunikira kwambiri pakati pa chidziwitso cha mphotho zachilengedwe ndi mphotho ya psychostimulant. Monga taonera, ntchito ya FosB mu NAc yakhala ikukhudzidwa kale ndi mayankho a mankhwala osokoneza bongo, chifukwa FosB yochulukirapo mu NAc imachititsa kuti cocaine iyambe kugwira ntchito pambuyo popatsidwa mankhwala obwerezabwereza (Kelz et al., 1999), imawonjezera chidwi cha cocaine ndi morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), ndipo imayambitsa kudzipatsa cocaine wochepa (Colby et al., 2003). Kafukufuku wapano akuwonetsa kuti kuletsa ntchito ya D1R kapena FosB mu NAc panthawi yogonana kunathetsa chidziwitso cha kugonana chomwe chinapangitsa kuti Amph alandire mphotho . Chifukwa chake, mphotho zachilengedwe ndi mankhwala sizimangogwirizana panjira imodzi ya mitsempha, zimalumikizana pa ma molekyulu omwewo (Nestler et al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), ndipo mwina mu ma neuron omwewo mu NAc (Frohmader et al., 2010b), kuti akhudze mphamvu yolimbikitsira ndi "kufuna" kwa mitundu yonse iwiri ya mphotho (Berridge ndi Robinson, 1998).

Kafukufuku waposachedwa wasonyeza kuti nthawi yodziletsa kulandira mphotho yogonana ikufunika kuti Amph reward ndi NAc spinogenesis zidziwike. Tikuganiza kuti FosB panthawiyi yodziletsa imakhudza ntchito ya mitsempha mwa kusintha momwe majini amagwirira ntchito kuti ayambitse spinogenesis ndikusintha mphamvu ya synaptic. Zoonadi, kuletsa kulowetsedwa kwa FosB mu NAc panthawi yogonana kunaletsa kuchuluka kwa msana mu NAc komwe kunapezeka pambuyo poti mphotho yachotsedwa. Komanso, kulowetsedwa kwa D1R antagonist mu NAc musanayambe nthawi iliyonse yogonana kunaletsa kuwonjezeka kwa FosB komwe kunayambitsidwa ndi zomwe zimachitika pogonana komanso kuchuluka kwa msana komwe kunatsatira . FosB ndi chinthu cholembera chomwe chimagwira ntchito ngati choyambitsa kapena choletsa kulembera kuti chikhudze kuwonetsedwa kwa majini ambiri omwe angakhudze kuchuluka kwa msana ndi mphamvu ya synaptic mu NAc (Nestler, 2008). Mwachindunji, FosB imayambitsa cyclic-dependent kinase-5 (Bibb et al., 2001; Kumar et al., 2005), nuclear factor B (NF-B) (Russo et al., 2009b), ndi GluA2 subunit ya glutamate AMPA receptor (Vialou et al., 2010) ndikuletsa kulembedwa kwa jini yoyamba ya c-fos (Pitchers et al., 2010b) ndi histone methyltransferase G9 (Maze et al., 2010). Cyclicdependent kinase-5 imayang'anira mapuloteni a cytoskeletal ndi kukula kwa neurite (Taylor et al., 2007). Kuphatikiza apo, kuyambitsa NF-B kumawonjezera kuchuluka kwa dendritic spines mu NAc, pomwe kuletsa NF-B kumachepetsa basal dendritic spines ndikuletsa kuwonjezeka kwa cocaine mu spines (Russo et al., 2009b). Chifukwa chake, mphotho yogonana imawonjezera FosB mu NAc, yomwe ingasinthe kuchuluka kwa msana wa NAc kudzera mu zolinga zingapo (monga, cyclic-dependent kinase-5, NF-B) ndipo zotsatira zake zonse ndi mphotho ya mankhwala osokoneza bongo , monga momwe Russo et al. (2009a) adanenera za zochita za cocaine wobwerezabwereza.

Kafukufuku wosadziwika bwino mu kafukufukuyu anali wakuti kuchuluka kwa msana mu NAc kunali kosakhalitsa, ndipo sikunapezekenso patatha masiku 28 mutagonana. Chifukwa chake, kuchuluka kwa msana kunagwirizana ndi kuyamba kwa mphotho yowonjezera ya Amph ndipo kungathandize pakukula koyamba kapena kuwonetsa kwakanthawi kochepa kwa mayankho a Amph okhudzidwa. Komabe, kuchuluka kwa msana sikunali kofunikira kuti mphotho yowonjezera ya Amph ipitirire pambuyo pa nthawi yayitali yodziletsa. Tawonetsa kale kuti zokumana nazo zogonana zimayambitsa kuwonjezeka kwa kanthawi kochepa (7, koma osati masiku 28, pambuyo pa kugonana komaliza) kwa NMDA receptor subunit NR-1 mu NAc, yomwe idabwerera kumlingo woyambira pambuyo pa nthawi yayitali yodziletsa mphotho (Pitchers et al., 2012). Kuwonjezeka kwa kuchuluka kwa NMDA receptor kunaganiziridwa kuti ndi chizindikiro cha ma synapses osalankhula omwe amayambitsidwa ndi kugonana (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), ndipo zikusonyeza kuti kukula kwa msana komwe kumayambitsidwa ndi kugonana kumadalira ntchito yowonjezera ya NMDA receptor (Hamilton et al., 2012).

Pomalizira, kafukufuku wamakono akuwonetseratu kupititsa patsogolo kwa mankhwala a mankhwala chifukwa cha mphotho (kugonana) ndi kudalira kwake pa nthawi yobwerera. Komanso, mapulasitikiwa amatsitsimutsana ndi FosB kudzera ku activation D1R ku NAc. Choncho, deta imasonyeza kuti kuwonongeka kwa mphotho pambuyo pa zotsatira za mphotho kungapangitse anthu kukhala osatetezeka ku chitukuko cha mankhwala osokoneza bongo ndi kuti mkhalapakati mmodzi wa chiopsezo ichi ndi FosB ndi zolembera zolembera pansi.