Kev Cai thiab Tshuaj Kev Noj Qab Haus Huv Tsawg ntawm Txoj Cai Nraum Feem Ntau Ntawm Cov Neeg Ua Haujlwm nrog ΔFosB ua Tus Nruab Nrab Tus Nruab Nrab (2013)

Txoj kev kawm no tau kuaj xyuas qhov tshwm sim ntawm kev sib deev ntawm DeltaFosB thiab cuam tshuam ntawm DeltaFosB ntawm tus cwj pwm kev sib deev thiab nqi zog. Cov qauv kev hloov pauv molecular paub uas tshwm sim nrog kev quav tshuaj yeeb tshuaj tau pom tib yam nkaus li tshwm sim nrog kev sib deev. Hauv lwm lo lus, DeltaFosB hloov zuj zus rau kev nyiam sib deev, tseem siv tshuaj yaj yeeb hijack no tib yam mechanism. Qhov no xaus kev sib cav txog hais tias kev quav yeeb quav tshuaj muaj qhov txawv ntawm kev coj tus cwj pwm li cas, thiab kev coj cwj pwm li cas tsuas yog kev quab yuam (txawm hais tias txhais tau li cas). Kev ua haujlwm zoo ib yam, kev siv tshuab ib qho, tib qho kev hloov ntawm tes, kev coj tus cwj pwm cuam tshuam – nrog qhov sib txawv me me.

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

TXHEEJ TXHEEM

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

Tau qhov twg los

Department of Anatomy & Cell Biology, Schulich Lub Tsev Kawm Ntawv ntawm Tshuaj thiab Kev Kho Hniav, 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 thiab Friedman Lub Hlwb Lub Hlwb, Mount Sinai Lub Tsev Kawm Ntawv ntawm Tshuaj, New York, New York 10029, thiab Chaw Haujlwm ntawm Neurobiology thiab Anatomical Sciences thiab Physiology thiab Biophysics, Tsev Kawm Ntawv ntawm Mississippi Medical Center, Jackson, Mississippi 39216.

Abstract

Tshuaj ntawm kev tsim txom induce neuroplasticity hauv qhov nqi zog ntawm ntuj, qhov nucleus accumbens (NAc), yog li ua rau kev loj hlob thiab kev qhia ntawm kev coj tus cwj pwm. Cov pov thawj tsis ntev los no qhia tias cov txiaj ntsim ntawm ntuj yuav ua rau kev hloov pauv hauv NAc, qhia txog tias cov tshuaj yuav qhib cov tswv yim ntawm cov khoom zoo sib luag nrog kev zoo siab, thiab cia kom muaj kev sib tshuam sib txawv nruab nrab ntawm lub ntuj thiab yeeb tshuaj.

Nyob rau hauv txoj kev tshawb no, peb pom tias kev sib deev hauv cov txiv neej nas thaum ua raws li luv luv los ntev heev ntawm kev sib deev ntawm kev sib deev ua rau amphetamine nqi zog, qhia los ntawm qhov xav tau qhov zoo tshaj rau qhov qis dua (0.5 mg / kg) amphetamine. Ntxiv mus, qhov pib, tab sis tsis yog qhov qhia ntev dua, ntawm kev ua zoo tshaj hauv amphetamine yog correlated nrog ib qho kev nce nyob rau hauv dendritic spines hauv lub NAc. Tom ntej no, lub luag haujlwm tseem ceeb rau kev sib hloov ntawm ΔFosB nyob rau hauv kev sib deev kev ua kom zoo dua amphetamine thiab nqi nce ntxiv hauv dendritic spines rau NAc neurons raug tsim los siv viral vector gen hloov ntawm tus neeg tseem ceeb tsis sib thooj sib nrauj ΔJunD. Tsis tas li ntawd, nws tau qhia tias kev sib deev kev txhawb nqa kev sib deev, ΔFosB, thiab spinogenesis yog nyob ntawm kev sib deev dopamine D1 receptor activation nyob rau hauv NAc. Pharmacological blockade ntawm D1 reseptor, tiam sis tsis D2 tus neeg mob, nyob hauv lub NAc thaum muaj tus cwj pwm kev sib deev attenuated ΔFosB induction thiab tiv thaiv tau nce ntxiv spinogenesis thiab nqi zog amphetamine.

TTxawm li cas los xij, cov kev tshawb pom no qhia tau tias cov tshuaj ntawm kev tsim txom thiab kev coj tus cwj pwm coj ncaj ncees ua raws li cov qauv ntawm lub cev thiab lub cev ntawm cov yas uas tiv thaiv kev quav yeeb quav tshuaj, thiab qhov teeb meem no tau nce ntxiv los ntawm ΔFosB thiab nws cov hom phiaj rau kev hloov qis.

Introduction

Kev coj tus cwj pwm coj zoo thiab cov nqi tshuaj muaj nqi los ntawm cov kab mob neural, qhov chaw ua haujlwm mesolimbic dopamine (DA), uas cov nucleus accumbens (NAc) plays lub luag haujlwm (Kelley, 2004). Tshuaj ntawm kev tsim txom induce neuroplasticity nyob rau hauv lub tshuab mesolimbic, uas yog plays lub luag hauj lwm zoo nyob rau hauv kev hloov los ntawm kev siv yeeb tshuaj rau kev quav tshuaj yeeb (Hyman li al, 2006; Kauer thiab Malenka, 2007; Kalivas, 2009; Chen et al., 2010; Koob thiab Volkow, 2010; Hma, 2010a; Mameli thiab Luscher, 2011). Nws tau raug hypothesized tias cov tshuaj thiab kev ntshaw nyiaj tsis ua rau tib lub paj hlwb nyob hauv lub cev mesolimbic, thiab li ntawd cov tshuaj uniquely qhib thiab hloov no Circuit Court (Cameron thiab Carelli, 2012). Txawm li cas los xij, nws tau paub meej tias ntuj thiab tshuaj yeeb muaj txiaj ntsig cuam tshuam rau lub cev mesolimbic hauv ob qho tib si thiab ntau txoj kev uas tso cai rau ib qho kev sib tshuam nruab nrab ntawm kev qhuas ntawm ntuj, hais tias kev sib deev nqi zog, thiab cov txiaj ntsim ntawm kev siv yeeb tshuaj (Frohmader li al., 2010a; Pitchers li al., 2010a; Olsen, 2011).

Kev coj tus cwj pwm sib deev yog qhov txiaj ntsim zoo siab (Tenk et al., 2009),

Cov kev tshawb pom no hais tias kev ua neej thiab kev sib tw tshuaj muaj txiaj ntsim zoo sib xws ntawm cov kev cai ntawm neural yas, uas tshwm sim tuaj yeem cuam tshuam txog kev quav yeeb tshuaj.

Lub hom phiaj ntawm qhov kev tshawb fawb tam sim no yog los txiav txim siab txog kev kho kev lag luam ntawm tes kho kev sib deev nrog kev sib raug zoo, uas yog ua rau cov nqi kho mob zoo dua. Tshwj xeeb, lub luag hauj lwm ntawm qhov kev sib hloov ntawm ΔFosB yog tshawb xyuas vim nws tau koom tes nrog cov teeb meem ntawm ob qho tib si ntawm ntuj thiab tshuaj yeeb (Nestler li al., 2001; Werme thiab lwm tus, 2002; Olausson li al., 2006; Wallace li al., 2008; Cov Nyiaj Txiag thiab lwm tus, 2009; Pitchers li al., 2010b). Ntxiv rau, lub luag haujlwm ntawm dopamine D1 receptors (D1R) rau kev sib daj sib deev vim yog kev sib daj sib deev raug soj ntsuam vim tias NAc ΔFosB induction thiab muaj zog qeeb qeeb tom qab kev tswj hwm kev noj qab haus huv hauv D1R-muaj neurons (Lee et al., 2006; Kim et al., 2009) thiab nyob ntawm D1R ua kom (Zhang li al., 2002).

Ntawm no, peb siv viral vector-mediated kev qhia ntawm tus tseem ceeb-tsis thwj rau tus khub rau ΔFosB, dioclism labeling, thiab cov tshuaj noj tshuaj los ntsuas qhov kev xav tias kev cuam tshuam txog kev sib deev ntawm qhov kev sib deev tom qab los ntawm kev hwm abstinence ntawm Amph tus nqi zog yog kho los ntawm D1R-nyob induction ntawm ΔFosB hauv NAc thiab kev nce ntxiv ntawm NAc qaum kev sib npaug. Ua ke, cov kev tshawb pom tau muab pov thawj tias cov khoom siv yeeb tshuaj thiab kev quav tshuaj sib koom muaj ntau cov tswv yim ntawm neural plasticity, nrog ΔFosB ua tus tseem ceeb tshaj plaws.

Ntaub ntawv thiab kev

Tsiaj txhu.

Cov pojniam (225-250 g) cov poj niam (210-220 g) Sprague Dawley nas (Charles River Laboratories) muaj nyob hauv Plexiglas cages hauv tib lub txiv neej pw ua ke thoob plaws hauv kev sim, nyob rau hauv qhov kub thiab txias thiab cov av qaub thiab ntawm 12 / 12 h teeb / tsaus voj voog nrog zaub mov thiab dej dawb. Cov pojniam koom nrog rau cov mating zaug tau ovariectomized thiab tau txais cov kab mob subcutaneous uas muaj 5% estradiol benzoate (Sigma-Aldrich) thiab los ntawm 500 μg progesterone (hauv 0.1 ml ntawm sesame roj; Sigma-Aldrich) 4 h ua ntej kuaj. Tag nrho cov txheej txheem tau pom zoo los ntawm Tsiaj Ceg Tsam thiab Siv Cov Pawg Saib Xyuas Tsev Kawm Ntawv ntawm University of Western Ontario thiab University of Michigan thiab ua raws li Canadian Council ntawm Tsiaj Saib Xyuas Kev Noj Qab Haus Huv thiab Lub Tebchaws Hauv Huv Kev Noj Qab Haus Huv cov txheej txheem uas muaj feem xyuam nrog vertebrate tsiaj hauv kev tshawb nrhiav.

Kev coj cwj pwm sib deev.

Mating zaug tshwm sim thaum lub sijhawm tsaus ntuj (ntawm 2 thiab 6 h tom qab pib ntawm qhov tsaus ntuj nti) nyob rau hauv dim dim illumination, nyob rau hauv huv kev xeem cuaj (60 × 45 × 50 cm). Txiv neej nas mated rau ejaculation thaum 4 los 5 txhua hnub mating zaug. Tsib kev xaiv tsib raug xaiv vim peb tau pom yav dhau los hais tias qhov teebmeem no ua rau kom muaj kev ywj pheej ntawm kev sib deev ntev (ntev)Pitchers li al., 2010b), cross-sensitization rau Amph locomotor kev ua si (Pitchers li al., 2010a), thiab nqi zog (Pitchers li al., 2010a). Ejaculation raug xaiv los ntawm qhov kawg ntawm txhua qhov kev sib hais mating vim peb yav tas los pom tias nws yog qhov tseem ceeb rau kev sib deev kev ntawm Amph locomotor sensitization (Pitchers li al., 2010a), uas tsis tshwm sim thaum tsiaj tau pub rau phooj ywg nrog cov maum tsis pom ntawm ejaculation. Cov cwj pwm kev sib deev tsis sib xws (piv txwv li, latency rau thawj mount, intromission thiab ejaculation, thiab cov mounts thiab intromissions) raug kaw raws li tau piav yav tas los (Pitchers li al., 2010b). Rau tag nrho cov kev sim, cov kev ua plees ua yi muaj kev sib raug zoo rau kev coj tus cwj pwm (tag nrho cov ejaculations thiab latency rau ejaculation thaum txhua tus mating kev sib ntsib). Tom qab qhov kev sib tw zaum thib tsib, txiv neej tseem nyob nrog cov neeg sib deev tib yam nkaus thiab tsis pub niam txiv sib yuav thaum sib deev ntev txog 1, 7, lossis 28 d. Cov tsiaj txhu uas ua poj niam txiv neej tau sib deev tau sib kho thiab nyob hauv tib chav hauv cov tub ntxhais hluas kev sib deev. Tsis tas li ntawd, naive tus cwj pwm tau muab tso rau hauv cov kev xeem huv cuaj rau ib teev thaum 5 hnub sib law liag, tsis muaj kev nkag tau rau ib tug poj niam kws txais tos.

ΔFosB qhia.

Cov tsiaj txhu tau tso tshuaj loog (sodium pentobarbital; 390 mg / kg; ip) thiab ua tau zoo hlwv nrog 50 ml ntawm 0.9% saline, ua raws li 500 ml ntawm 4% paraformaldehyde (Sigma-Aldrich) hauv 0.1 m phosphate buffer (PB) rau lub sij hawm point thiab DR antagonist thwmsim. Lub hlwb raug muab tshem tawm thiab xa rov qab rau 1 h tom chav tsev sov li qub hauv tib lub sijhawm kho, tom qab 4 ° C hauv 20% sucrose thiab 0.01% sodium azide hauv 0.1 m PB. Rau cov DR thag kev sim, lub hlwb tau raug tshem tawm thiab hla raws txoj kab ntawm sagittal. Ib nrab yog muab tso rau hauv PB thiab siv rau DiOlistics, thiab lwm tus tau ua tiav rau ΔFosB. Coronal sections (35 μm) tau txiav nrog lub microtome free (Microm H400R), muab sau rau plaub cov lus qhia hauv koog quas (cryoprotectant) (30% sucrose thiab 30% ethylene glycol hauv 0.1 m PB) thiab muab cia rau hauv-20 ° C. Dawb-ntu tshooj raug ntxuav heev nrog 0.1 m PBS, pH XUM, nruab nrab ntawm incubations, thiab tag nrho cov kauj ruam nyob hauv chav sov. Seem tau raug 7.35% H2O2 (10 min) thiab tsim kom muaj kabmob (1 h; PBS muaj 0.1% BSA, Fisher; thiab 0.4% Triton X-100, Sigma-Aldrich). Tshaj ntawd tau muab cov kabmob yav tsaus ntuj tso rau hauv lub yias-FosB kabmob polyclonal antibody (1: 5K; sc-48 Santa Cruz Biotechnology), yav tas los (Perrotti li al., 2004, 2008; Pitchers li al., 2010b)). Lub yias-FosB antibody tau tsa tawm tsam ib cheeb tsam sab hauv sib koom los ntawm FosB thiab ΔFosB, thiab tau raug pom yav dhau los ua rau pom tseeb ΔFosB hlwb thaum lub sijhawm cov ntsiab lus siv hauv qhov kev tshawb fawb no (> 1 d tom qab kev txhawb nqa) (Perrotti li al., 2004, 2008; Pitchers li al., 2010b). Tom ntej no, cov khej tau raug muab siv ua ke rau hauv biotin-conjugated tshis anti-luav IgG (1 h; 1: 500 hauv PBS +; Laboratoryies), avidin-biotin-horseradish peroxidase (1 h; ABC elite; 1: 1000 hauv PBS; Vector Laboratories) , thiab 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) nrog 0.02% nickel sulfate nyob 0.1 m PB nrog hydrogen peroxide (0.015%). Cov ntawv tau nce mus rau Superfrost thiab iav slides (Fisher) thiab coverlipped nrog dibutyl phthalate xylene.

Cov zauv ntawm ΔFosB-Huab hlwb tau suav hauv NAc plhaub thiab cov tub ntxhais kawm nyob hauv cov cheeb tsam ntawm kev ntsuas (400 × 600 μm) raws li yav tas los tau piav (Pitchers li al., 2010b). Ob tshooj tau suav rau NAc subregion, kwv yees ib tus tsiaj. Nyob rau lub sij hawm kev sim, cov zauv ntawm ΔFosB-IR hlwb tau hais txog kev hloov ntawm pawg neeg tswj hwm ntawm lub sij hawm tsim nyog thiab muab piv rau cov pawg neeg paub thiab cov sib txeeb rau txhua pawg neeg ntawm lub sij hawm taw tes uas siv tsis tau t cov kev xeem nrog qhov tseem ceeb ntawm p <0.05. Hauv txoj kev sim ΔJunD-AAV thiab DR kev thaiv kev ua haujlwm, ob txoj kev lossis ib-txoj kev ANOVA, raws li, thiab txoj kev siv Holm – Sidak tau siv. Tsis tas li ntawd, cellsFosB-IR hlwb tau suav rau hauv dorsal striatum (thaj chaw ntawm kev txheeb xyuas: 200 × 600 μm), tam sim ntawd dorsal rau NAc thiab nyob ib sab mus rau sab nraud ventricle, hauv txhua tus tsiaj hauv DR antagonist sim. Ib-txoj kev ANOVA thiab t kev xeem raug siv los sib piv ntawm pawg.

DiOlistics.

Rau lub sij hawm taw tes thiab ΔJunD viral experiment, nas tsuag tau muab ntxim rau intracardially nrog 50 ml saline (0.9%), raws li 500 ml ntawm 2% paraformaldehyde hauv 0.1 m PB. Lub hlwb raug sab laug (100 μm coronal) siv lub vibratome (Microm) thiab cov ntawv khaws cia hauv 0.1 m PB nrog 0.01% sodium azide ntawm 4 ° C. Txheej ntawm tungsten particles (1.3 μm inch, Bio-Rad) nrog lub lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate; Invitrogen) tau ua raws li yav tas los (Forlano thiab Woolley, 2010). DI-coated tungsten particles tau xa mus rau hauv cov ntaub so ntswg ntawm 160-180 psi siv Helios Gene Gun system (Bio-Rad) los ntawm lub lim nrog 3.0 μm pore loj (BD Biosciences) thiab tso cai rau diffuse los ntawm lub paj hlwb hauv 0.1 m PB rau 24 h thaum uas tiv thaiv teeb meem ntawm 4 ° C. Tom qab ntawd, lub kaum hli tom qab 4% paraformaldehyde hauv PB rau 3 h nyob rau hauv chav sov, ntxuav hauv PB, thiab muab ntim rau hauv cov txheej txheem kaw (Bio-Rad) nrog cov gelvatol uas muaj cov tshuaj tiv thaiv kev 1,4-diazabicyclo (2,2) octane ( 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

DiI-labeled neurons raug imaged siv Zeiss LSM 510 m confocal tsom xam (Carl Zeiss) thiab helium / neon 543 nm laser. Rau txhua tus tsiaj, 2-5 neurons hauv txhua NAc subcorder, los yog hauv lub plhaub (raws li qhov chaw nyob rau hauv cov teeb meem, nrog rau kev xav ntawm sab nrauv thiab sab nrauv) nyob rau hauv ΔJunD-AAV thiab DR antagonist experiments, tau siv los nrhiav lub cheeb tsam ntawm kev txaus siab rau qhov kev txiav txim thib ob rau kev txiav txim siab qaum. Rau txhua qhov neuron, 2-4 dendrites tau soj ntsuam kom muaj nuj nqis tag nrho cov dendritic ntev ntawm 40-100 μm. Dendritic segments tau siv 40 × dej-immersion lub hom phiaj ntawm 0.25 μm intervals raws li z-axis, thiab 3D duab yog rov kho dua tshiab (Zeiss) thiab underwent deconvolution (Autoquant X, Media Cybernetics) siv kev siv (qhov muag tsis pom) thiab theoretical PSF qhov raws li kev pom zoo los ntawm tus software. Spin density tau quantified siv cov Filament module ntawm Imaris software pob (version 7.0, Bitplane). Cov zauv ntawm dendritic spines tau hais txog 10 μm, kwv yees rau txhua lub neuron thiab tom qab ntawd rau txhua tus tsiaj. Cov kev sib txawv sib txawv raug txiav txim siab siv ob txoj kev ANOVAs thaum lub sij hawm series sim ntawm kev sib daj sib deev thiab cov tsiaj paub txhua lub sij hawm taw tes (yam: kev sib deev thiab NAc subregion) thiab hauv txoj kev sim neej ΔJunD (yam: kev sib deev thiab kev vector vector), thiab -nov ANOVA nyob rau hauv qhov DR antagonist experiment. Pawg kev sib piv tau ua nrog Holm-Sidak txoj kev nrog ib qhov tseem ceeb ntawm p <0.05.

Txaus siab nyiam qhov chaw.

CPP kev sim tsim tau zoo tib yam li yav tas los tau piav (Pitchers li al., 2010a), siv qhov kev sib tw peb qhov chaw nruab nrab (Med Associates), thiab kev tsim txoj hauv kev kawm, nrog tib leeg kev sib tw ntawm d-Amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc ntawm cov hauv paus dawb) nyob rau hauv qhov chaw sib tw thiab lub saline hauv lub chamber unpaired thaum lub sijhawm lwm hnub, thiab tau ua thaum thawj ib nrab ntawm lub teeb theem. Tswj tsiaj tau saline hauv ob qho chaw.

CPP cov qhab nia raug muab xam rau txhua tus tsiaj raws li lub sij hawm siv (hauv vib nas this) nyob rau hauv qhov kev sib tw ua ke thaum lub sij hawm qhov kev ntsuam xyuas rho tawm qhov pretest. One-way ANOVAs thiab Holm-Sidak txoj kev raug siv los sib piv cov pawg hauv lub sij hawm kev sim. Unpaired t sim nrog qhov tseem ceeb ntawm p <0.05 tau siv los sib piv Naive-Sal thiab Naive Amph nyob rau txhua lub sijhawm taw tes rau hauv lub sij hawm sim kev sim, thiab nyob rau hauv txhua qhov kev kho mob viav vias hauv kev sim ΔJunD sim. Hauv lub sijhawm sim, ib-txoj kev ANOVAs thiab txoj kev Holm-Sidak tau siv los piv cov pab pawg sib deev (Exp-Sal, 7 d Exp Amph thiab 28 d Exp Amph), thiab tsis tau t kev xeem raug siv los piv cov 2 pawg neeg sib tw. Ob txoj kev ANOVA thiab Holm-Sidak txoj kev raug siv los piv rau txhua pawg hauv DR DR antagonist. Ob unpaired t kev ntsuam xyuas raug siv los piv Naive-Sal thiab Naive Amph pawg nrog txhua yam kab mob viral kho mob (GFP los yog ΔJunD), raws li cov ntaub ntawv sib txawv dhau los hauv pawg ΔJunD kom pom zoo ANOVA. Tag nrho cov qib tseem ceeb tau teeb tsa p <0.05.

Viral vector thwmsim.

Txiv neej cov nas muaj tshuaj loog (KNSH) (87 mg / ml / kg; ip) thiab xylazine (13 mg / ml / kg ip), muab tso rau hauv ib lub tshuab stereotaxic (Kopf Instruments), thiab tau txais ob leeg microinjections ntawm recombinant adeno kab mob vectors encoding GFP nkaus xwb (ntsuab fluorescent protein), los yog ΔJunD (tseem ceeb tsis zoo sib xws ntawm ΔFosB) thiab GFP, rau hauv NAc (coordinates: AP + 1.5, ML ± 1.2 ntawm bregma DV-7.6 ntawm pob txha), hauv ib ntim ntawm 1.5 μl / hemisphere dhau 7 min siv lub Hamilton syringe (Harvard Apparatus). ΔJunD txo ΔFosB-mediated transcription los ntawm competitively heterodimerizing nrog ΔFosB thiab li no tiv thaiv txog kev txuam ntawm ΔFosB rau thaj av AP-1 hauv thaj tsam ntawm cov neeg tawm tsam (Winstanley li al., 2007; Pitchers li al., 2010b). Txawm hais tias ΔJunD khi nrog cov affinity siab rau ΔFosB, nws muaj peev xwm hais tias qee qhov kev pom zoo ntawm ΔJunD tej zaum yuav raug kho los ntawm kev tiv thaiv lwm cov protein AP-1. Txawm li cas los xij, nws pom tau tias ΔFosB yog tus protein ntau AP-1 uas tau muab teev rau hauv cov kev sim (Pitchers li al., 2010b). Hnub tom qab ntawm 3 thiab 4, cov tsiaj tau txais kev sib deev thaum 4 sib law liag los sis tseem pheej yig los tsim cov 4 pawg: kev sib deev nrog GFP, kev sib deev nrog GFP, kev sib daj sib deev poj niam, thiab kev sib deev uas muaj kev sib raug zoo nrog ΔJunD. Kev sib deev kev ua yog ntawm 4 sib law liag txhua hnub sib kho. Cov tsiaj txhu tau sim rau CPP thiab diOlistics. Kev txheeb xyuas qhov tseeb ntawm qhov chaw txhaj tshuaj tau ua tiav raws li tau piav qhia yav tas los (Pitchers li al., 2010b). NAc seem (coronal; 100 μm) raug tiv thaiv kab mob GFP (1: 20,000; luav anti-GFP antibody; Invitrogen). Kis tau tus kab mob no feem ntau txwv rau lub plhaub plhaub ntawm NAc, nrog rau kev sib kis mus rau qhov tseem ceeb.

D1R / D2R antagonists.

Txiv neej cov nas muaj tshuaj loog nrog anesthetized nrog rau kev txhaj tshuaj intraperitoneal (0.1 ml / kg) ntawm ketamine (87 mg / ml) thiab xylazine (13 mg / ml), thiab muab tso rau hauv ib lub twj siv lub tshuab stereotaxic (Kopf Instruments). Ob sab 21-gauge guide cannulas (Plastics One) tau qis mus rau NAc ntawm AP + 1.7, ML ± 1.2 los ntawm bregma; -6.4 DV los ntawm pob txha taub hau thiab ruaj khov kho nrog acrylic kho hniav, adhered rau peb screws teem rau hauv pob txha taub hau. Tsiaj txhu tau saib xyuas txhua hnub rau kev noj qab haus huv rau cov txheej txheem infusion thaum lub sij hawm 2 lub caij rov qab rov qab. Fifteen feeb ua ntej pib ntawm 4 txhua txhua hnub mating zaug los ntawm kev nthuav qhia cov poj niam receptive, cov txiv neej nas tau txais bilateral microinjections ntawm D1R antagonist R (+) SCH-23390 hydrochloride (Sigma-Aldrich), D2 receptor (D2R) antagonist S- ( -) eticlopride hydrochloride (Sigma-Aldrich) tau muab pov tseg hauv kev ntsev kom muaj ntsev (0.9%; txhua qhov ntawm 10 μg hauv 1 μl per hemisphere; μl / min dhau ib 0.9 min interval raws 1.0 min nrog rau cov tshuaj txhaj pliag sab laug tso rau hauv qhov chaw rau kev siv tshuaj yaj yeeb. Qhov ntim ntawm qhov kev txhaj tshuaj no yuav kis tau rau ob qho tseem ceeb hauv lub plhaub thiab plhaub, xws li kev xa tawm ntawm 1.0 μl yog txwv rau plhaub los yog cov tseem ceeb ntawm cov tub ntxhais kawm (Laviolette li al., 2008). Cov tshuaj noj tau raws li cov kev tshawb fawb yav dhau los uas qhia tias cov tshuaj noj los yog qis dua los cuam tshuam kev siv yeeb tshuaj lossis kev coj tus cwj pwm ntawm tus kheej (Laviolette li al., 2008; Roberts li al., 2012). Tswj cov txiv neej pw ua ke nrog kev sib deev tab sis tau txais kev pabcuam ntawm NAc saline ua ntej muab tso rau hauv qhov kev xeem ntawv khoob, thaum 4 txhua hnub kev sib tham. Ib lub lis piam tom qab kawg mating los yog kev sib kho, sib yuav tau kuaj rau Amph CPP, thiab txha nqaj thiab soj ntsuam ΔFosB. Kev siv ntawm plaub zaug, tsis yog tsib zaug xws li hauv lwm cov kev sim, raug xaiv los tshem tawm ntau qhov kev puas tsuaj rau NAc tshwm sim los ntawm cov rov qab infusions thiab yog li cia rau tus txha nqaj thiab ΔFosB tsom xam. Xwb, kev puas tsuaj tsis pom, thiab kev soj ntsuam ntawm qaum thiab ΔFosB hauv NAc ntawm cov tsiaj cov kis tau tus kab mob tau pom cov ntaub ntawv zoo li cov pab pawg uas tsis yog siv hauv cov kev sim ua dhau los. Ob txoj kev ANOVA thiab Holm-Sidak txoj kev nrog qhov tseem ceeb ntawm p <0.05 tau siv los txiav txim siab txog kev sib daj sib deev los ntawm kev yooj yim ntawm kev sib deev.

tau

Kev sib deev kev xav ntawm kev sib deev ΔFosB yog qhov ntev tshaj plaws

Ua ntej, qhov kev sib txuas ntawm lub cev ntawm kev sib txawv ntawm kev sib deev nyob rau hauv cov lus qhia ΔFosB, qhov dendritic spines hauv NAc, thiab Amph-CPP tau txiav txim siab, tshwj xeeb tom qab luv luv thiab ntev ntev ntawm kev tsis txaus siab ntawm kev sib deev (7 lossis 28 d). Yav dhau los, nws tau pom hais tias kev sib deev ntawm 5 txhua hnub mating zaug tau los ntawm kev txuam ntawm ΔFosB thoob plaws hauv lub cev mesolimbic, hauv lub NAc (Wallace li al., 2008; Pitchers li al., 2010b). Hauv cov kev tshawb xyuas yav dhau los, theem ΔFOSB raug ntsuas tawm hauv 1 d tom qab tus cwj pwm kev ua plees ua yi, thiab nws tsis paub hais tias seb puas yog ΔFosB tsom zuj zus mus ntev tom qab lub sij hawm ntev tshaj ntawm cov nqi zog abstinence. Cov tub ntxhais hluas muaj kev sib deev muaj perfected 1, 7, lossis 28 d tom qab kawg ntawm 5 txhua hnub cov mating zaug, thaum lub caug txiv neej mus rau ib qho ejaculation. Kev tswj kev sib deev ntawm kev sib deev tau ua tiav nrog tib lub sij hawm taw tes tom qab kawg ntawm 5 txhua hnub kev sib tham. Cov zauv ntawm ΔFosB-O hlwb nyob rau hauv NAc plhaub thiab tub ntxhais muaj yig tshaj kev tswj poj niam txiv neej txhua lub sijhawm (Daim duab. 1A, plhaub; 1 d, p = 0.022; 7 d, p = 0.015; Daim duab. 1B: tub ntxhais; 1 d, p = 0.024; 7 d, p <0.001; 28 d, p <0.001), tshwj tsis yog NAc lub plhaub tom qab 28 d tsis ua (p = 0.280). Yog li, ΔFosB upregulation tsawv ntev thaum lub caij nyoog tsis txaus siab txog kev sib deev rau ib lub caij nyoog tsawg kawg 28 d.

Daim duab 1.     

Kev sib daj sib deev tshwm sim los ntawm kev sib txuam tam sim thiab tsis tuaj yeem ua rau cov zauv ntawm ΔFosB-IR hlwb. Hloov cov naj npawb ntawm ΔFosB-O hlwb nyob hauv NAc plhaub (pauv).A) thiab tub ntxhais (B) hauv kev ua plees ua yi (cov tsiaj) cov tsiaj txhu piv nrog kev sib deev nrog pojniam (dawb) (n = 4 txhua pab pawg). Cov ntaub ntawv yog pawg neeg SEM. *p <0.05, tseem ceeb sib txawv piv nrog naive tus tswj. Tus sawv cev ntawm cov duab ntawm Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), thiab Exp 28 d (F). ac, Anterior commissure. Nplai bar, 100 μm.

Kev sib deev ntawm kev paub ntau dua tuaj hauv dendritic spines yog qhov ntev

Pitchers li al. (2010a) yav tas los tshaj tawm siv Golgi impregnation cov tswv yim hais tias kev sib deev ua raws 7 d, tiam sis tsis 1 d, kev muab nqi zog ntawm kev sib tw ua rau nws loj hlob tuaj dendritic branching thiab naj npawb ntawm dendritic spines ntawm NAc plhaub thiab tub ntxhais neurons (Pitchers li al., 2010a). Ntawm no, spinogenesis nyob rau hauv kev sib deev naïve thiab cov txiv neej muaj kev raug tshuaj xyuas yog 7 d los 28 d tom qab kawg mating sib kho. Cov kev tshawb nrhiav tam sim no uas siv ib qho kev tawm tswv yim txog kev lag luam tau paub tseeb tias kev sib deev kev ua neej raws 7 d ncua kev sib daj sib deev ntau ntxiv cov kab zauv ntawm dendritic spines (F(1,8) = 9.616, p = 0.015; Daim duab. 2A-C). Tshwj xeeb, cov dendritic spines tau nce ntau hauv NAc plhaub thiab tub ntxhais (Daim duab. 2A: plhaub, p = 0.011; ntxhais, p = 0.044). Txawm li cas los xij, qhov no nce mus rau qhov qis qis qis dua thiab tsis ntev tom qab lub sij hawm ntev ntawm kev sib deev ntawm 28 d hauv NAc subclion (Daim duab. 2B).

Daim duab 2.    

Kev sib daj sib deev tshwm sim los ntawm kev nce hauv cov dendritic spines nyob hauv lub NAc thiab qhov khoom plig Amphe Amplitude. A, B, Tus naj npawb ntawm dendritic spines hauv NAc plhaub thiab tub ntxhais ntawm 7 d (A) los yog 28 d (DB ntawm kev sib daj sib deev [dawb] thiab cov tsiaj [paub] [dub]; n = 4 lossis 5). Cov ntaub ntawv yog pawg neeg SEM. #p <0.05, tseem ceeb sib txawv piv nrog naive tus tswj. C, Tus neeg sawv cev dendritic ntu ntawm Naive 7 d thiab Exp 7 d pawg uas siv los ntaus nqi qaum ntu. Nplai bar, 3 μm. D, Cov sij hawm siv nyob rau hauv lub khawm ob leeg (Amph los yog saline) thaum kuaj tom qab rho tawm qhov ua ntej (CPP score) rau kev sib daj sib deev (dawb) lossis kev paub txog (cov tsiaj) cov tsiaj tau sim 7 d lossis 28 d tom qab kawg mating los tuav sib kho: Naive-Sal (7 d tom qab tuav; n = 8), Naive Amph (7 d tom qab tuav; n = 9), Exp-Sal (ua ke pawg ntawm cov tsiaj kuaj 7 d lossis 28 d tom qab mating; n = 7), 7 d Exp Amph (7 d tom qab mating; n = 9), thiab 28 d Exp Amph (28 d tom qab mating; n = 11). Sal pawg neeg tau txais Sal paired nrog ob leeg. *p <0.05, qhov sib txawv tseem ceeb piv nrog kev sib daj sib deev hauv lub cev.

Kev sib deev kev xav ntawm Amph yog qhov ntev-ntev

Peb yav tas los qhia tias kev sib deev nrog 7-10 d ntawm abstinence ua rau Amph txhawb zog (Pitchers li al., 2010a). Tshwj xeeb tshaj plaws, kev ua plees ua yi tsim kev mob siab (CPP) rau kev txo qis Amph (0.5 los yog 1.0 mg / kg) uas tsis ua rau CPP hauv kev tswj kev sib deev. Kev tshawb xyuas tam sim no paub tseeb thiab txuas ntxiv los ntawm cov txiaj ntsim tau los ntawm Amph tus nqi zog tshaj hauv kev sib deev nrog cov tsiaj tom qab 7 d thiab 28 d lub caij nyoog sib deev tsis tuaj yeem (Daim duab. 2D; F(2,24) = 4.971, p = 0.016). Tshwj xeeb, cov tsiaj txhu muaj kev sib deev nrog 7 lossis 28 d abstinence lub sijhawm siv sijhawm ntau dua nyob rau hauv Amph Ob Chav chav tsev thaum kuaj tom qab sib piv nrog kev sib deev tsis zoo txog kev tswj xyuas uas tau txais cov khoom saline hauv ob qho chaw (Daim duab. 2D: Exp-Sal vs 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). Kev pom zoo txog cov kev tshawb nrhiav yav dhau los, cov tsiaj nyhuv ntawm kev sib deev tsis siv sijhawm ntau dua nyob hauv Amph Ob Chav chav nyob rau lub sijhawm kuaj tom qab thiab tsis txawv hauv cov neeg nyiam kev sib daj sib deev (Daim duab. 2D) (Pitchers li al., 2010a).

ΔFosB kev ua ub no yog qhov tseem ceeb rau kev sib deev kev tsim los ntawm Amph tus nqi zog

Qhov tshwm sim ua kom pom tseeb hais tias kev sib deev ua rau mob ntev ntev ntawm ΔFosB nyob rau hauv NAc neurons correlated nrog enhanced Amph nqi zog. Los txiav txim siab seb puas muaj cov kev ua ntau dua ΔFosB yog qhov tseem ceeb rau Amph nqi zog, ΔJunD, uas yog ib tus neeg tseem ceeb ntawm kev sib koom tes ntawm ΔFosB uas ua rau luam cov ntawv ΔFosB kho kom haum (Winstanley li al., 2007), yog overexpressed ntawm kis vector-mediated noob hloov nyob rau hauv lub NAc (Daim duab. 3A,B). Cov qhab-nees ntawm Amph CPP cov kev kuaj pom tau tias qhov kev ua tau ntawm kev ua haujlwm ΔFosB los ntawm kev qhia ΔJunD hauv NAc tiv thaiv qhov teebmeem ntawm kev sib deev thiab 7 d kev sibtw kev sib deev tsis txaus ntseeg ntawm Amph nqi zog. Kev sib deev nrog kev sib deev tsis yog tus twg ua tsis tau tus CPP rau Amph thiab tsis txawv ntawm poj niam txiv neej poj niam (ΔJunD tsiaj txhu)Daim duab. 3B). Hauv kev sib piv, kev sib deev ua neej nrog GFP tswj cov tsiaj ua rau CPP rau Amph raws li tau pom los ntawm CPP qhov qhab nia loj dua piv nrog kev tswj ntawm kev sib daj sib deev GFP (Daim duab. 3B, p = 0.018).

Daim duab 3.    

Txaus siab rau ΔFosB kev ua ub no hauv NAc blocked AMPH nqi zog thiab nce hauv ntau tus NAc spines hauv kev ua plees ua yi tus tsiaj. A, Cov duab sawv cev ntawm GFP qhia hauv peb hom tsiaj uas tau txais kev txhaj tshuaj ntawm recombinant adeno-kis Viral-ΔJunD qhia ntawm cov keeb kwm nucleus, cov duab me me (sab laug), nruab nrab (nruab nrab), thiab loj (txoj cai) txhaj tshuaj. ac, Anterior commissure; LV, ib sab pos hniav. Nplai bar, 250 μm. B, Schematic kev qhia ntawm ntau qhov chaw thiab cov qauv sib kis ntawm tus kab mob. Hauv txhua tus tsiaj, GFP tau kuaj pom hauv lub plhaub, tab sis kis mus rau qhov tseem ceeb yog txawv. C, Cov sij hawm siv nyob hauv Amph-paired Chamber thaum lub sij hawm kev soj ntsuam tom qab rho tawm qhov pretest (CPP qhab nia) rau kev sib deev naiv (dawb) thiab kev paub (cov tsiaj) cov tsiaj uas tau txais txhaj koob tshuaj GFP tswj vector (Naive, n = 9; Tshaj, n = 10) los yog ΔJunD vector (Naive, n = 9; Tshaj, n = 9). D, Cov sawv cev ntawm cov neeg sawv cev ntawm kev sib tw ntawm kev sib daj sib deev los ntawm kev sib daj sib deev GFP thiab ΔJunD siv los ntsuas qhov paj hlwb. Nplai bar, 3 μm. E, Dendritic spines nyob rau hauv lub NAc ntawm kev sib daj sib deev (dawb) thiab kev paub txog (dub) tsiaj txhu uas tau txais kev txhaj tshuaj GFP tswj vector los yog ΔJunD vector. Cov ntaub ntawv yog pawg neeg SEM. *p <0.05, tseem ceeb sib txawv piv nrog naive tus tswj. #p <0.05, qhov sib txawv tseem ceeb ntawm GFP kev paub tswj hwm.

Cov teebmeem ntawm ΔJunD tsis pom kev zoo yog tsis tshwm sim ntawm kev cuam tshuam ntawm kev coj tus cwj pwm thaum muaj kev sib deev ntawm kev sib deev. Daim ntawv qhia ntawm ΔJunD hauv NAc tau pom hais tias kom tsis txhob muaj kev ywj pheej ntawm kev sib deev tom qab kev sib deev (Pitchers li al., 2010b). Tseeb, qhov no tau txais kev pom zoo ntawm qhov kev xyaum ua tam sim no. GFP tswj cov tsiaj tuaj yeem pom latencies mus rau qhov chaw, ntu, thiab ejaculation, thiab tsawg dua nce thiab nkag mus rau lub sijhawm plaub hnub sib law liag, piv nrog thawj hnub ntawm mating (rooj 1). Hauv kev sib piv, cov tsiaj uas tau txhaj cov tsiaj ΔJunD tsis tau pom cov latencies loj dua los nce los yog nkag mus lossis tsawg dua ntawm cov khoom nce thaum hnub plaub ntawm mating piv nrog thawj. Yog li, ΔJunD infusions rau hauv NAc ua rau kom muaj kev sib deev ntawm kev sib deev. Txawm li cas los xij, tsis muaj qhov sib txawv ntawm qhov tsis sib haum ntawm GFP kev tswj thiab cov pab pawg neeg ΔJunD thaum lub sij hawm xeem cov mating, qhia tau hais tias cov teebmeem ntawm txoj kev sib deev ntawm kev sib deev ntawm kev sib daj sib deev ntawm Amph CPP tsis yog qhov tshwm sim ntawm qhov txawv ntawm mating kev per se (rooj 1).

Saib cov lus qhia:     

Cov lus 1.    

Cov kev hloov ntawm kev sib deev thaum muaj kev sib deev hauv cov pab pawg uas tau txais NAc infusions ntawm GFP- lossis ΔJunD-tshaj tawm viral vectorsa

ΔFosB yog qhov tseem ceeb rau kev sib deev kev tsim ua rau nce hauv NAc dendritic spines

ΔFosB kev ua si kuj tau ntxiv rau qhov nce ntxiv qis ntawm NAc neurons tom qab sib deev thiab 7 d kev sib deev nqi zog abstinence (Daim duab. 3C,D). Rau kev txheeb xyuas kev lag luam hauv NAc ntawm cov tsiaj txheeb raws li piav saum toj no rau CPP, ob txoj kev ANOVA pom qhov teeb meem tseem ceeb ntawm ob qho kev sib deev (F(1,34) = 31.768, p <0.001) thiab kev kho tus mob viral vector (F(1,34) = 14.969, p = 0.001), nrog rau kev sib raug zoo (F(1,34) = 10.651, p = 0.005). Tshwj xeeb, kev sib deev nrog GFP kev tswj tsiaj muaj ntau tus NAc spines piv nrog kev tswj ntawm kev sib deev GFP (Daim duab. 3D: p <0.001), lav tias peb tau tshawb pom yav dhau los (Pitchers li al., 2010a). Hauv kev sib txawv, kev sib deev kev paub txog cov tsiaj ΔJunD tsiaj tsis zoo sib txawv ntawm cov poj niam txiv neej poj niam (ΔJunD), thiab tau qis tshaj piv nrog kev sib deev GFP cov tsiaj txhu (Daim duab. 3D: p <0.001). Yog li, expressionJunD qhia hauv NAc thaiv qhov cuam tshuam ntawm kev sib deev kev sib deev thiab muab nqi zog tsis sib deev ntawm NAc spinogenesis.

D1R antagonist blocks kev sib deev uas yog vim ΔFosB upregulation

Los txiav txim siab seb qhov D1R los yog D2R ua rau hauv NAc thaum lub sij hawm mating yuav tsum tau rau kev sib deev kev sib txeeb ΔFosB upregulation thiab sensitized Amph CPP, tsiaj tau txais qhov chaw infusions ntawm D1R los yog D2R antagonist (los yog saline) rau hauv NAc 15 min ua ntej txhua 4 txhua hnub sib law liag. Tseem ceeb heev, tsis yog D1R los yog D2R antagonist infusions rau hauv NAc cuam tshuam los yog kev qhia ntawm kev coj tus cwj pwm thaum lub sij hawm ib qho ntawm cov mating zaug (Daim duab. 4D-F). Zoo li no, D1R los yog D2R kev tiv thaiv tsis tiv thaiv yooj yim ntawm kev sib deev ntawm kev sib deev, raws li tag nrho cov pab pawg pom tau hais tias kev coj cwj pwm sib deev, evidenced ntawm luv ejaculation latencies rau hnub 4 piv rau hnub 1 (Daim duab. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ntsaum, p = 0.007; D2R Ntsaum, p <0.001).

Daim duab 4.    

Dopamine receptor antagonists kis mus rau hauv NAc tsis cuam tshuam rau kev sib deev tus cwj pwm. Coronal NAc cov ntawv (A, + 2.2; B, + 1.7; C, + 1.2 los ntawm bregma) qhia tias intra-NAc txhaj tshuaj rau tag nrho cov tsiaj. Cannulas tau ob sab tab sis cov sawv cev tuaj yeem rau kev yooj yim ntawm kev nthuav qhia ntawm txhua tus tsiaj (Naive-Sal, dawb, n = 7; Exp-Saline; tsaus zeej, n = 9; Exp D1R Ntsaum, lub teeb txho, n = 9; Exp D2R Ntsaum, dub, n = 8). ac, Anterior commissure; LV, ib sab plhu; CPU, caudate-putamen. Mount latency (D), qhov latency intraumission (E), thiab ejaculation latency (F) rau tag nrho cov neeg tau ntsib kev sib deev (Saline, dawb; D1R Ant, grey; D2R Ant, dub). Cov ntaub ntawv sawv cev tam sis ◆ SEM. *p <0.05, qhov sib txawv tseem ceeb ntawm hnub 1 thiab hnub 4 hauv kev kho.

Kev soj ntsuam ntawm cov naj npawb ntawm ΔFosB-IR nyob rau hauv NAc 7 d tom qab kawg NAc infusion thiab mating los yog kev sib kho sib qhia qhia qhov sib txawv ntawm cov pawg hauv NAc plhaub (F(3,29) = 18.070, p <0.001) thiab tub ntxhais (F(3,29) = 10.017, p <0.001). Ua ntej, kev paub txog kev sib deev hauv kev tswj kav dej muaj ntsev ua rau muaj kev txhim kho tseem ceeb ntawm ΔFosB piv nrog kev tswj kev sib deev (Daim duab. 5A, plhaub p <0.001; Daim duab. 5B: tub ntxhais, p <0.001), lav cov txiaj ntsig saum toj no. Antagonism ntawm D1R, tab sis tsis yog D2R, tiv thaiv lossis attenuated qhov kev txhim kho ntawm ΔFosB. Hauv NAc lub plhaub, D1R cov thaiv kev ua haujlwm los tiv thaiv kev sib deev ntawm cov txiv neej pom tias tsis muaj qhov nce hauv cellsFosB-IR cov hlwb piv nrog kev tswj kev sib deev (Daim duab. 5A: p = 0.110), thiab qhia ΔFosB tau qis dua piv rau kev sib deev nrog kev sib deev (Daim duab. 5A: p = 0.002). Hauv cov tub ntxhais kawm hauv NAc, D1R antagonism tau muaj cov nyhuv ib nrab: ΔFosB tau nce hauv D1R antagonists-caug piv nrog cov poj niam tswj xyuas kev nyab xeeb (Daim duab. 5B: p = 0.031), tab sis qhov kev kho kom zoo no tau qis dua piv nrog kev sib deev nrog kev kho mob nkeeg (Daim duab. 5B: p = 0.012). D2R antagonist kho tsis zoo rau ΔFosB induction li kev sib deev tej cwj pwm uas tau txais D2R antagonist tau muaj ntau dua ntawm ΔFosB-IR hlwb piv nrog cov kev tswj xyuas cov poj niam (Daim duab. 5A: plhaub, p <0.001; Daim duab. 5B: tub ntxhais, p <0.001) thiab D1R tiv thaiv kab mob kev tsis taus poj niam (Daim duab. 5A: plhaub, p <0.001; Daim duab. 5B: tub ntxhais, p = 0.013), thiab tsis txawv ntawm kev sib deev kev paub txog tus txiv neej.

Daim duab 5.     

Kev thaiv D1R hauv lub NAc attenuates qhov nce ntawm ntau npaum li ΔFosB-IR hlwb nyob hauv lub NAc ntawm kev ua plees ua yi. Hloov cov naj npawb ntawm ΔFosB-O hlwb nyob hauv NAc plhaub (pauv).A) thiab tub ntxhais (B) hauv kev ua plees ua yi (cov tsiaj) cov tsiaj txhu piv nrog kev sib deev nrog pojniam (dawb) (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ntsaum, n = 9; Exp D2R Ntsaum, n = 8). Cov ntaub ntawv yog pawg neeg SEM. *p <0.05, tseem ceeb sib txawv piv nrog naive tus tswj. #p <0.05, qhov sib txawv tseem ceeb piv nrog ntsev thiab D2R Ant ntsib cov tsiaj. Sawv cev ntawm cov duab ntawm Naive Sal (C), Tso Tuaj (D), Exp D1R Ant (E), thiab Exp D2R Ant (F). ac, Anterior commissure. Nplai bar, 100 μm.

Los tswj kom muaj kev sib kis ntawm D1R los yog D2R antagonists rau hauv dorsal striatum, kev qhia ΔFosB tau soj ntsuam nyob hauv thaj tsam tam sim ntawd dorsal rau NAc thiab nyob ib sab rau lub plhaw sab nraud, raws li induction ntawm ΔFosB nyob rau hauv cov nyom dorsal striatum los ntawm psychostimulants thiab opiates yog nyob ntawm D1R kev ua si (Zhang li al., 2002; Muller thiab Unterwald, 2005). Kev sib daj sib deev tau nce tus zauv ntawm cov koob tshuaj ΔFosB-mob hauv dorsal striatum hauv cov neeg raug kho (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), lav paub peb daim ntawv qhia dhau los (Pitchers li al., 2010b). Tsis tas li ntawd, tsis yog D1R los yog D2R antagonist infusions rau hauv NAc cuam tshuam nrog kev sib daj sib deev uas yog vim ΔFosB nyob rau ntawm qhov kev mob qog (DxNUMXR: 1 ± 82.75 IR hlwb; p <0.001 piv nrog Naive-Sal kev tswj). Qhov kev tshawb pom pom tau hais tias kev kis tus kabmob ntawm cov neeg kis kabmob feem ntau nyob rau NAc.

D1R antagonist nyob rau hauv NAc blocks sensitized amph nqi zog

D1R blockade nyob rau hauv NAc thaum lub sij hawm mating kuj blocked kev sib deev kev mob vim yog Amph tus nqi zog, kuaj 7 d tom qab zaum kawg NAJ infusion thiab kev kuaj mating (F(3,29) = 2.956, p = 0.049). Cov tsiaj txhu muaj kev sib deev uas tau txais saline hauv NAc thaum lub caij sib dhos tau siv ntau lub sij hawm hauv Amph Ob Chav chav sib piv nrog cov txiv neej poj niam txiv neej (Daim duab. 6A, p = 0.025), kev lees paub txog cov ntsiab lus saum toj no. Hauv kev sib piv, kev sib deev tej tsiaj txhu uas tau txais intra-NAc D1R antagonist thaum mating tsis ua ib tug CPP rau Amph. Lawv tsis txawv ntawm kev tswj poj niam txiv neej, thiab siv ho sijhawm tsawg dua hauv Amph-paired Chamber piv nrog saline (Daim duab. 6A: p = 0.049) los yog D2R antagonist (Daim duab. 6A: p = 0.038) kis tau ntawm kev sib deev nrog txiv neej. D2R antagonist infusions tsis cuam tshuam Ampl nqi zog zoo li kev sib deev tej tsiaj nrog NAc D2R antagonist infusions ua ib qho tseem ceeb ntawm Amph CPP piv nrog cov kev tswj xyuas cov poj niam (Daim duab. 6A: p = 0.040) thiab D1R antagonist ntsib tej tsiaj (Daim duab. 6A: p = 0.038), thiab tsis txawv ntawm kev sib deev kev paub txog tus txiv neej.

Daim duab 6.     

Blocking D1 receptors nyob rau hauv NAc abolishes Amph nqi zog thiab nce dendritic spines nyob rau kev sib deev tej tsiaj. A, Cov sij hawm siv nyob hauv Amph Ob Chav Chamber thaum lub sijhawm xeem dhau qhov kev xeem ntawv (Predest (CPP score, vib nas this) rau kev sib daj sib deev (dawb, n = 6) thiab kev paub txog (dub) cov tsiaj uas tau txais saline (n = 7), D1R antagonist (n = 9), los yog D2R antagonist (n = 8). Cov ntaub ntawv yog pawg neeg SEM. *p <0.05, qhov sib txawv tseem ceeb piv nrog naive kua ntsev tswj. #p <0.05, qhov sib txawv ntawm D1R Ant ntsib cov tsiaj. B, Tus naj npawb ntawm dendritic spines (ib 10 μm) rau kev sib deev naïve (dawb, n = 7) thiab kev paub txog (dub) cov tsiaj uas tau txais saline (n = 8), D1R antagonist (n = 8), los yog D2R antagonist (n = 8). Cov ntaub ntawv yog pawg neeg SEM. *p <0.05, qhov sib txawv tseem ceeb piv nrog naive kua ntsev tswj. #p <0.05, qhov sib txawv tseem ceeb los ntawm kev tswj tuav dej muaj ntsev.

D1R antagonist kho vaj tse txog kev sib daj sib deev vim yog NAc spinogenesis

Kev txheeb ntawm qhov nqaj qaum nyob rau hauv NAc ntawm cov tsiaj tib yam pom tau hais tias D1R ua rau lub sij hawm mating raug tseev kom nce NAc txha nruj dua tom qab kev sib deev thiab 7 d ntawm kev sib deev nqi zog abstinence (Daim duab. 6B; F(3,26) = 41.558, p <0.001). Tshwj xeeb, kev tiv thaiv kev tiv thaiv kev muaj mob muaj ntsev muaj txiaj ntsig thiab D2R cov tsiaj thaiv kev ua txhaum tau muaj tus lej siab ntau dua piv nrog kev tswj cov kua qaub ua kom sib deev (Daim duab. 6B: p <0.001) qhia tias peb tau tshawb pom yav dhau los (Pitchers li al., 2010a) thiab kev tshawb nrhiav nrog GFP tswj viral vectors piav qhia saum toj no. Hauv kev sib piv, kev sib deev kev paub txog D1R antagonist-infused tsiaj tsis txawv ntawm kev sib daj sib deev thiab roj ntsha los ntawm kev tswj hwm (Daim duab. 6B). Muaj ib cov nyhuv ntawm D2R antagonist infusion li D2R infused tsiaj pom tau qis qis qis qis dua kev sib deev ntawm cov kev tswj xyuas ntsev (Daim duab. 6B: p = 0.02), tab sis ho muaj ntau tus naj npawb ntawm spines piv rau cov kev tswj hwm kev sib deev ntawm cov kev sib deev thiab D1R kho tej txiv neej (p <0.001; Daim duab. 6B). Li no, D1R blockade nyob rau hauv lub NAc thaum mating blocked cov teebmeem kev sib deev thiab kev pabcuam abstinence ntawm NAc spinogenesis.

kev sib tham

Nyob rau hauv txoj kev tshawb nrhiav tam sim no, peb pom tau tias kev sib tw ntawm kev sib sib zog nqus pa thiab yeeb tshuaj, thaum lub ntuj tsim nuj rov qab los ntawm ib lub sij hawm txwv. Tshwj xeeb, peb tau pom tias qhov kev paub nrog kev sib deev, kev ua raws li 7 los yog 28 ntawm kev tsis txaus siab, ua rau muaj kev txhawb siab Amph. Cov kev tshawb pom no muaj qhov zoo sib xws nrog lub luag haujlwm tseem ceeb ntawm lub sij hawm ntev me ntsis los ntawm kev siv yeeb tshuaj ntawm kev tsim txom hauv kev tsim kom muaj cov tshuaj yeeb yaj yeeb (Lu thiab al., 2005; Thomas et al., 2008; Hma, 2010b, 2012; Xue li al., 2012). Tsis tas li ntawd, ntuj nqi zog vim yog ΔFosB hauv lub NAc yog qhov tseem ceeb rau kev cuam tshuam ntawm kev cuam tshuam dab tsi ntawm kev qhuas tus nqi ntawm kev xav ntawm psychostimulant, uas muaj feem ntawm spinogenesis hauv NAc thaum lub sij hawm ib qho kev zam ntawm kev tsim txiaj. Peb pom tau hais tias kev txuam nrog ΔFosB hauv NAc tom qab kev sib deev yog qhov ntev thiab nyob ntawm NAc D1R kev ua si thaum lub sij hawm sib dhos. Nyuam qhuav, qhov DxNUMXR sib kho ntawm ΔFosB upregulation nyob rau hauv NAc tau qhia tias tseem ceeb heev rau kev txhawb zog Amph thiab nce tus nqus qis hauv NAc, txawm tias cov txiaj ntsig ntawm kev sib deev yog nyob ntawm ib lub caij nyoog ntawm kev yuam deev (Pitchers li al., 2010a). Thaum kawg, peb pom tau hais tias NAc spinogenesis yuav ua rau lub sijhawm pib ntawm kev qhia txog Amph nqi zog tiam sis tsis tseem ceeb rau kev qhia ntxiv txog kev txhawb nqa kev noj tshuaj, raws li nce tus nqaj qaum nyob rau hauv NAc tau ntev thiab pom tom qab 7 d, tab sis tsis 28 d, lub sij hawm tsis txaus siab.

Nws tau ntev tau paub tias dopamine raug tso tawm hauv NAc thaum muaj kev coj tus cwj pwm coj zoo, nrog rau kev coj tus cwj pwm. Raws li kev taw qhia ntawm ib tug poj niam receptive, extracellular dopamine nyob rau hauv lub NAc yog nce thiab tseem nce siab thaum lub sij hawm mating (Fiorino li al., 1997). Txoj kev tshawb xyuas tam sim no pom tias infusing dopamine receptor antagonists mus rau hauv NAc thaum mating tsis tau muaj kev ntxim rau cov kev pib lossis kev ua haujlwm ntawm kev coj tus cwj pwm, uas zoo ib yam nrog cov kev xav hais tias dopamine tsis koom nrog kev qhia ntawm kev coj tus cwj pwm kev ua se, rau kev saib xyuas ntawm kev siab ntsws ntawm kev sib deev nrog kev sib deev (Berridge thiab Robinson, 1998). Xwb, cues predictive ntawm cov nqi zog ntawm kev sib deev ua rau kev ua rau cov neurons hauv lub paj hlwb mesolimbic dopamine zog, nrog rau cov dopaminergic hlwb hauv cheeb tsam ventral tegmental thiab lawv lub hom phiaj, lub NAc (Balfour li al., 2004). Cov cwj pwm ua plees ua yi rov qab ua rau ΔFosB nyob hauv NAc, uas tig los kho cov kev tsim kho kev sib daj sib deev (Pitchers li al., 2010b). Cov kev tshwm sim tam sim no qhia tau hais tias mating vim yog ΔFosB upregulation yog, qhov tseeb, nyob ntawm D1R ua rau hauv lub NAc thaum lub sij hawm mating. Qhov kev tshawb pom no yog raws li cov kev tshawb fawb dhau los uas qhia tau hais tias kev pheej yig ntawm kev kho mob hlwb nce qib ntau dua ΔFosB hauv NAc nrab kab zauv neurons tawm D1R (Lee et al., 2006; Kim et al., 2009) thiab hais tias xws li ΔFosB upregulation yog nyob ntawm D1R activition (Zhang li al., 2002). Tsis tas li ntawd, cov lus teb rau cov tshuaj yeeb dej caw, feem ntau pom nyob rau hauv cov tshuaj tua tsiaj, tuaj yeem ua rau tsis muaj cov tshuaj yeeb yaj kiab ua ntej los ntawm kev sib txuam ntawm ΔFosB hauv D1R qhia txog cov neurons hauv cov paj hlwb (Kelz li al., 1999). TTxawm li cas los xij, ob qho tib si ntawm ntuj thiab tshuaj yeeb yog nce siab rau ΔFosB nyob rau hauv NAc ntawm D1R-nyob rau qhov cuab yeej cuab tam kom ua rau tus cwj pwm coj zoo dua.

Ntxiv mus, cov kev tshawb pom tam sim no qhia tau tias ΔFosB yog tus tseem ceeb ntawm kev sib tw ntawm qhov kev sib tw ntawm qhov khoom plig thiab nqi zog ntawm kev puas siab ntsws. Raws li tau hais, cov kev ua ntawm ΔFosB hauv NAc tau ua yav dhau los hauv cov lus teb rau cov tshuaj yeeb dej caw, xws li ΔFosB overexpression hauv NAc ua rau cov neeg ua hauj lwm pib ua kom muaj yeeb yaj kiab tom qab ua ntej los yog rov ua dua tshiab (Kelz li al., 1999), tsub kom muaj zog rau cov yeeb tshuaj thiab yeeb tshuaj morphine (CPP)Kelz li al., 1999; Zachariou li al., 2006), thiab ua rau yus tswj hwm kev qis tshaj ntawm cov tshuaj yeeb dawb (Colby li al., 2003). Txoj kev tshawb xyuas tam sim no qhia tau hais tias qhov blockade ntawm D1R los yog ΔFosB cov kev ua hauv NAc thaum lub sij hawm sib sau cov kev sib deev uas tau ua rau kev xav ntawm Amph.

Txoj kev tshawb xyuas tam sim no pom tau hais tias lub sijhawm tsis pub dhau ntawm qhov khoom plig ntawm kev sib deev yuav tsum tau ua rau lub siab ntawm Amph thiab NAc spinogenesis. Peb txheeb xyuas tau tias ΔFosB thaum lub sij hawm sib cav tsis zoo no cuam tshuam txog kev ua kom lub cev tsis ua hauj lwm los ntawm kev hloov cov kev nqes noob qaum los qhia pib spinogenesis thiab hloov kho zog. Xwb, thaiv qhov induction ntawm ΔFosB hauv lub NAc thaum mating tiv thaiv tau nce tus nqaj qaum ntom hauv lub NAc kuaj tom qab muab txiaj ntsig abstinence. Ntxiv mus, kis ntawm D1R antagonist mus rau hauv NAc ua ntej txhua qhov kev sib koom ua mating tiv thaiv qhov kev sib deev kev tsim kho nce hauv ΔFosB thiab tom qab ntxiv nce tus nqaj qaum ceev.

ΔFosB yog ib qho tseem ceeb tshaj plaws uas ua tau los ua ib tus neeg ua hauj lwm los sis repressor los cuam tshuam cov lus ntawm ib lub noob ntawm lub hom phiaj uas tuaj yeem cuam tshuam kev sib zog thiab kev sib zog ua zog hauv lub NAc (Nestler, 2008). Hais dua, ΔFosB activates cyclic-dependent kinase-5 (Bibb li al., 2001; Kumar li al., 2005), nuclear tau ntses κ B (NF-QB) (Russo li al., 2009b), thiab GluA2 subunit ntawm AMP receptor glutamate (Vialou li al., 2010) thiab represses transcription ntawm tus poj niam tam sim ntawd thaum ntxov (Pitchers li al., 2010b) thiab histone methyltransferase G9 (Maze li al., 2010). Cyclic-dependent kinase-5 tswj xyuas cov kabmob cytoskeletal thiab neurite outgrowth (Taylor li al., 2007). Ntxiv mus, activating NF-QB nce tus naj npawb ntawm dendritic spines nyob rau hauv NAc, whereas inhibition of NF-KOB poob basal dendritic spines thiab nplov cov cocaine induced nce hauv spines (Russo li al., 2009b). Yog li, kev sib deev nqi zog nce rau ΔFosB hauv NAc, uas yuav hloov NAc spine density los ntawm ntau lub hom phiaj (piv txwv li, kinemat-dependent kinase-5, NF-κB) thiab tias tag nrho qhov kev txiav txim siab yog cov nqi tshuaj yeeb tshuaj, xws li hypothesized los ntawm Russo li al. (2009a) rau cov yeeb yam ntawm cov neeg ua haujlwm dua.

Kev soj ntsuam ntawm qhov kev tshawb nrhiav tam sim no yog tias qhov nce ntawm qhov kev sib ntxiv ntawm qhov nAc yog qhov ntev, thiab tsis pom ntawm 28 d tom qab kev sib deev. Yog li, kev txha nqaj qaum zog yog sib raug zoo nrog qhov pib ntawm Amph tus nqi zog thiab yuav pab txhawb rau thawj kev loj hlob los yog kev qhia luv cov lus Amph responses. Txawm li cas los xij, kev nce tus qaum kev lag luam tsis yog qhov yuav tsum tau ua rau cov kev xav ntawm Amph Amplification tom qab lub sij hawm ntev ntev. Peb tau pom hais tias qhov kev sib deev ua rau lub sijhawm luv (7, tiam sis tsis 28, hnub tom qab mating kawg) nce ntxiv ntawm NMDA tus neeg tau txais kev pabcuam NR-1 nyob rau hauv NAc, uas tau hloov mus rau qib theem pib tom qab lub sijhawm ntev tshaj ntawm kev muab nqi zog abstinence (Pitchers li al., 2012). Qhov no nce NMDA receptor qhia tau hais tias yog qhov tseeb ntawm kev sib deev kev sib deev uas ua rau kev sib tw ua ke (Huang li al., 2009; Brown thiab al., 2011; Pitchers li al., 2012), thiab qhia txog tias qhov kev sib deev ntawm qhov kev sib deev txha nqaj qaum kev loj hlob yog nyob ntawm NMDA tus neeg tau txais kev pab (Hamilton li al., 2012).

Thaum xaus, txoj kev tshawb nrhiav tam sim no tseem ceeb tshaj qhov kev sib tw ntawm kev siv tshuaj yaj yeeb ntawm ib qho khoom plig (kev sib daj sib deev) thiab nws qhov kev vam khom rau ntawm lub sij hawm tsis muaj nqi. Ntxiv mus, qhov kev coj cwj pwm no yog kho los ntawm ΔFosB ntawm D1R ua rau hauv NAc. Yog li ntawd, cov ntaub ntawv qhia tias tsis tau txais txiaj ntsig ntawm ntuj tom qab cov nqi zog yuav ua rau cov neeg muaj cuabkav rau txoj kev tiv thaiv kev quav tshuaj yeeb thiab tias ib tus neeg tuaj kho ntawm no muaj kev tiv thaiv ntau yog ΔFosB thiab nws cov hom phiaj qis tshaj plaws.

Tshooj ntawv

  • Tau txais lub kaum hli 16, 2012.
  • Kho nqi lus tau txais lub Kaum Ib Hlis 12, 2012.
  • Lub Xya hli ntuj 23, 2012.

  • Cov hauj lwm no tau txhawb los ntawm Canadian Institutes of Health Research (LMC), Lub Koom Haum Lub Tebchaws ntawm Kev Xiam Hlwb (EJN), thiab Natural Sciences thiab Engineering Research Council hauv Canada (KKP thiab LMC). Peb ua tsaug rau Dr. Catherine Woolley (Northwestern University) kom tau txais kev pabcuam nrog kev tawm tswv yim ntawm dioctism.

  • Cov sau phau ntawv tshaj tawm tsis muaj kev sib tw nyiaj txiag.

  • Kev xa ntawv yuav tsum xa moog rua Dr. Lique M. Coolen, Department of Physiology hab Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. [email tiv thaiv]

References

  1. Teb zoo!
    1. Balfour Kuv,
    2. Yu L,
    3. Coolen LM

    (2004) Tus cwj pwm ntawm kev sib deev thiab kev sib deev kev sib raug zoo cs qhib cov txheej txheem mesolimbic hauv cov txiv neej nas. Neuropsychopharmacology 29: 718-730.

  2. Teb zoo!
    1. Berridge KC,
    2. Robinson TE

    (1998) Lub luag haujlwm ntawm dopamine hauv nqi zog: txiaj ntsim zoo li cas, kev txhawb nqa kev kawm, lossis kev txhawb siab? Hlwb Hlwb Lub Hlwb 28: 309-369.

  3. Teb zoo!
    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) Teebmeem ntawm tus kabmob ntev raug rau cov yeeb-yaj-kiab yog tswj los ntawm tus kabmob paj hlwb Neuronal Cdk5. xwm 410: 376-380.

  4. Teb zoo!
    1. Bradley KC,
    2. Meisel RL

    (2001) Kev sib deev cwj pwm ntawm kev sib deev ntawm tus cwj pwm ntawm cov nucleus thiab kev ua haujlwm hauv amphetamine-stimulated locomotor yog ua los ntawm kev sib deev kev sib deev hauv cov poj niam Syrian Hamsters. J Neurosci 21: 2123-2130.

  5. Teb zoo!
    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) Ib qho kev sib tw hauv lub suab seev raws li kev lag luam uas muaj yeeb yaj kiab. J Neurosci 31: 8163-8174.

  6. Teb zoo!
    1. Cameron CM,
    2. Carelli RM

    (2012) Cocaine abstinence alters nucleus accumulates firing dynamics thaum lub hom phiaj ntawm kev coj ua rau kev ua yeeb yam rau cocaine thiab sucrose. Eur J Neurosci 35: 940-951.

  7. Teb zoo!
    1. Chen BT,
    2. Hopf FW,
    3. Bonci A

    (2010) Synaptic plasticity nyob rau hauv lub cev mesolimbic: kev siv tshuaj rau kev quav yeeb tshuaj. Ann NY Acad Sci 1187: 129-139.

  8. Teb zoo!
    1. Colby CR,
    2. Whisler K,
    3. Steffen C,
    4. Nestler EJ,
    5. Tus kheej DW

    (2003) Striatal cell type-specific overexpression ntawm ΔFosB ua kom muaj kev txhawb siab rau cov yeeb tshuaj. J Neurosci 23: 2488-2493.

  9. Teb zoo!
    1. Fiorino DF,
    2. Lub Tsev Laus A,
    3. Phillips AG

    (1997) Cov kev hloov hauv cov pos hniav tau tsim cov dopamine efflux thaum lub caij Coolidge nyob rau hauv cov txiv neej nas. J Neurosci 17: 4849-4855.

  10. Teb zoo!
    1. Forlano PM,
    2. Woolley CS

    (2010) Quantitative analysis of pre-and postsynaptic poj niam txiv neej sib txawv ntawm cov nucleus accumbens. J Comp Neurol 518: 1330-1348.

  11. Teb zoo!
    1. Frohmader KS,
    2. Pitchers KK,
    3. Balfour Kuv,
    4. Coolen LM

    (2010a) Ua kom lom zem: xyuas cov txiaj ntsig ntawm cov yeeb tshuaj ntawm kev sib deev tus cwj pwm ntawm tib neeg thiab tsiaj qauv. Horm Behav 58: 149-162.

  12. Teb zoo!
    1. Frohmader KS,
    2. Wiskerke J,
    3. RIAJ txawj ntse,
    4. Lehman MN,
    5. Coolen LM

    (2010b) Methamphetamine ua rau subpopulations ntawm neurons txoj cai tswj kev sib deev hauv cov txiv neej nas. neuroscience 166: 771-784.

  13. Teb zoo!
    1. Hamilton AM,
    2. Huag WC,
    3. Vega-Ramirez H,
    4. Stein YOG,
    5. Ntuj raug txim JW,
    6. Patrick GN,
    7. Zito K

    (2012) Kev ua haujlwm ntawm kev loj hlob ntawm cov kab mob dendritic tshiab yog tswj los ntawm cov proteasome. Neuron 74: 1023-1030.

  14. Teb zoo!
    1. Cov nqi VL,
    2. Chakravarty S,
    3. Nestler EJ,
    4. Meisel RL

    (2009) Δ FosB overexpression nyob rau hauv cov keeb kwm nucleus pabcuam kev sib deev hauv cov pojniam Samsters. Cov Nroj Hlwb 8: 442-449.

  15. Teb zoo!
    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) Nyob rau hauv vivo neeg ua hauj lwm kev tsim cov cim suab ntsiag to. Neuron 63: 40-47.

  16. Teb zoo!
    1. Hyman SE,
    2. Malenka RC,
    3. Nestler EJ

    (2006) Neural mechanisms ntawm kev quav tshuaj: lub luag haujlwm ntawm txoj kev kawm thiab kev nco. Annu Rev Neurosci 29: 565-598.

  17. Teb zoo!
    1. Kalivas PW

    (2009) Lub glutamate homeostasis hypothesis ntawm kev quav tshuaj. Nat Kaw Neurosci 10: 561-572.

  18. Teb zoo!
    1. Kauer JA,
    2. Malenka RC

    (2007) Synaptic plasticity thiab tiv thaiv. Nat Kaw Neurosci 8: 844-858.

  19. Teb zoo!
    1. Kelley AE

    (2004) Nco thiab quav: sib koom ua neural circuitry thiab molecular mechanisms. Neuron 44: 161-179.

  20. Teb zoo!
    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. Tus kheej DW,
    11. Tkatch T,
    12. Baranauskas G,
    13. Surmeier DJ,
    14. Neve RL,
    15. Duman RS,
    16. Picciotto MR,
    17. Nestler EJ

    (1999) Cov kev qhia ntawm qhov sib txuam ntawm ΔFosB nyob rau hauv lub hlwb tswj kev ua kom muaj tus cocaine. xwm 401: 272-276.

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

    (2009) Methylphenidate induced dendritic spine tsim thiab ΔFosB qhia hauv nucleus accumbens. Proc Natl Acad Sci USA 106: 2915-2920.

  22. Teb zoo!
    1. Koob GF,
    2. Volkow ND

    (2010) Neurocircuitry ntawm kev quav tshuaj. Neuropsychopharmacology 35: 217-238.

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

    (2005) Chromatin remodeling yog ib qho tseem ceeb ntawm txoj kev pib coj cocaine vim raug mob hauv kev mob plab. Neuron 48: 303-314.

  24. Teb zoo!
    1. Laviolette SR,
    2. Lauzon NM,
    3. Npis sov SF,
    4. Hnub N,
    5. T H

    (2008) Dopamine signaling los ntawm D1 zoo li tiv thaiv D2 zoo li receptors nyob rau hauv nucleus accumbens ntxhais tiv thaiv plhaub txawv modulates nicotine nqi zog rhiab heev. J Neurosci 28: 8025-8033.

  25. Teb zoo!
    1. Lee KW,
    2. Kim Y,
    3. Kim kuv,
    4. Helmin K,
    5. Nairn AC,
    6. Greengard P

    (2006) Cocaine induced dendritic spine tsim hauv D1 thiab D2 dopamine reseptor-muaj cov kab mob nruab nrab cov kabmob neurons hauv nucleus accumbens. Proc Natl Acad Sci USA 103: 3399-3404.

  26. Teb zoo!
    1. Lennette DA

    (1978) Ib qho kev txhim kho nruab nrab ntawm cov kab mob hauv immunofluorescence microscopy. Am J Clin Pathol 69: 647-648.

  27. Teb zoo!
    1. Lu L,
    2. Kev cia siab BT,
    3. Dempsey J,
    4. Liu SY,
    5. Bossert JM,
    6. Shaham Y

    (2005) Central amygdala ERK signaling txoj kab yog qhov tseem ceeb rau kev tsim kom muaj kev sib tw ntawm cov yeeb yaj kiab. Nat Neurosci 8: 212-219.

  28. Teb zoo!
    1. Mameli M,
    2. Lüscher C

    (2011) Synaptic plasticity thiab tiv: kawm mechanisms ploj mus awry. Neuropharmacology 61: 1052-1059.

  29. Teb zoo!
    1. Tshawb Nrhiav Kuv,
    2. Covington Nws 3rd.,
    3. Dietz DM,
    4. LaPlant Q,
    5. Renthal W,
    6. Russo SJ,
    7. Mechanic M,
    8. Mouzon E,
    9. Neve RL,
    10. Haggarty SJ,
    11. Losyog Y,
    12. Sampath SC,
    13. Hurd YL,
    14. Greengard P,
    15. Tarakhovsky A,
    16. Schaefer A,
    17. Nestler EJ

    (2010) Lub luag hauj lwm tseem ceeb ntawm cov keeb kwm methyltransferase G9a nyob rau hauv yeeb yaj kiab plhuav. Science 327: 213-216.

    1. McCutcheon JE,
    2. Wang X,
    3. Tseng KY,
    4. Hma Me,
    5. Marinelli M

    (2011) Calcium-permeable AMPA receptors muaj nyob rau hauv nucleus accumbens synapses tom qab ntev tshem tawm ntawm kev tswj yus tus kheej tab sis tsis experimenter-cocaine administered. J Neurosci 31: 5737-5743.

  31. Teb zoo!
    1. Meisel RL,
    2. Mullins AJ

    (2006) Kev sib deev kev ua niam txiv hauv cov poj niam: tus qauv ntawm tes thiab kev ua haujlwm zoo. Lub hlwb mis 1126: 56-65.

  32. Teb zoo!
    1. Muller DL,
    2. Unterwald EM

    (2005) D1 dopamine receptors modulate ΔFosB induction rau hauv daj striatum tom qab kev siv tshuaj morphine. J Pharmacol Exp Ther 314: 148-154.

  33. Teb zoo!
    1. Nestler EJ

    (2008) Cov txheej txheem ntawm kev quav tshuaj: txoj haujlwm ntawm ΔFosB. Sawv Cev Rau Lub Tsev Kawm Sawv Daws Los Angeles B B Sci 363: 3245-3255.

  34. Teb zoo!
    1. Nestler EJ,
    2. Barrot M,
    3. Tus kheej DW

    (2001) ΔFosB: ib qho kev nkag siab ntawm kev quav kev quav tshuaj. Proc Natl Acad Sci USA 98: 11042-11046.

  35. Teb zoo!
    1. Olausson P,
    2. Jentsch JD,
    3. Tronson N,
    4. Neve RL,
    5. Nestler EJ,
    6. TAYLOR JR

    (2006) ΔFosB nyob rau hauv nucleus accumbens tswj cov khoom noj khoom haus muaj zog thiab kev txhawb zog. J Neurosci 26: 9196-9204.

  36. Teb zoo!
    1. Olsen CM

    (2011) Cov txiaj ntsim qub, kev pleev xim rau lub cev, thiab kev quav yeeb quav tshuaj. Neuropharmacology 61: 1109-1122.

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

    (2004) Induction ntawm ΔFosB nyob rau hauv cov nqi zog ntawm lub paj hlwb tom qab mob nyhav. J Neurosci 24: 10594-10602.

  38. Teb zoo!
    1. Perrotti LI,
    2. Weaver RR,
    3. Robison B,
    4. Renthal W,
    5. Tshawb Nrhiav Kuv,
    6. Yazdani S,
    7. Elmore RG,
    8. Knapp DJ,
    9. Selley DE,
    10. Martin BR,
    11. Sim-Selley L,
    12. Bachtell RK,
    13. Tus kheej DW,
    14. Nestler EJ

    (2008) Cov qauv txawv ntawm ΔFosB pib nyob rau hauv lub hlwb los ntawm kev siv yeeb tshuaj. synapse 62: 358-369.

  39. Teb zoo!
    1. Pitchers KK,
    2. Balfour Kuv,
    3. Lehman MN,
    4. Richtand NM,
    5. Yu L,
    6. Coolen LM

    (2010a) Neuroplasticity nyob rau hauv lub mesolimbic system induced los ntawm ntuj plig thiab nqi zog tom qab abstinence. Biol Psychiatry 67: 872-879.

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

    (2010b) ΔFosB nyob rau hauv cov keeb kwm nucleus yog qhov tseem ceeb rau kev txhawb nqa cov teeb meem ntawm kev sib deev. Cov Nroj Hlwb 9: 831-840.

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

    (2012) Kev Tshaj Tshaaj ntawm Kev Tshaj Tawm Kev Tshaj Tawm ntawm AMPA thiab NMDA tus neeg ua hauj lwm faib tawm thiab kev ua haujlwm hauv cov keeb kwm keeb kwm. PLOS Ib 7: e34700.

  42. Teb zoo!
    1. Roberts MD,
    2. Gilpin L,
    3. Parker KE,
    4. Tus Me Nyuam Kawm Ntawv TE,
    5. Yuav MJ,
    6. Lub rooj zaum FW

    (2012) Dopamine D1 reseptor modulation hauv nucleus accumbens lowers yeem log khiav hauv cov nas bred khiav siab. Physiol Behav 105: 661-668.

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

    (2009a) Neurotrophic thiab yam ntxwv ntawm cov quav tshuaj. Neuropharmacology 56 (Khoom 1): 73-82.

  44. Teb zoo!
    1. Russo SJ,
    2. Wilkinson MB,
    3. Mazei-Robison MS,
    4. Dietz DM,
    5. Tshawb Nrhiav Kuv,
    6. Krishnan V,
    7. Renthal W,
    8. Graham A,
    9. Birnbaum SG,
    10. Ntsuab TA,
    11. Robison B,
    12. Tshaj 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) Nuclear factor κB signaling regulates neuronal morphology thiab yeeb-tshuaj nqi zog. J Neurosci 29: 3529-3537.

  45. Teb zoo!
    1. TAYLOR JR,
    2. Lynch WJ,
    3. Sanchez H,
    4. Olausson P,
    5. Nestler EJ,
    6. Bibb JA

    (2007) Kev Cuam Tshuam ntawm Cdk5 nyob rau hauv cov keeb kwm keeb kwm keeb kwm muaj peev xwm ua rau cov teeb meem ntawm locomotor-activating thiab incentive-motivational ntawm cocaine. Proc Natl Acad Sci USA 104: 4147-4152.

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

    (2009) Kev sib deev nqi zog hauv cov txiv neej nas: cov teebmeem kev sib deev ntawm kev nyiam qhov chaw nyiam nrog ejaculation thiab intromissions. Horm Behav 55: 93-97.

  47. Teb zoo!
    1. Thomas MJ,
    2. Kalivas PW,
    3. Shaham Y

    (2008) Neuroplasticity nyob rau hauv lub mesolimbic dopamine system thiab yeeb dawb. Br J. Pharmacol 154: 327-342.

  48. Teb zoo!
    1. Vialou V,
    2. Robison AJ,
    3. Laplant QC,
    4. Covington Nws 3rd.,
    5. Dietz DM,
    6. Ohnishi YN,
    7. Mouzon E,
    8. Rush 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. Tamminga CA,
    21. et al.

    (2010) ΔFosB nyob rau hauv lub paj hlwb cov nqi zog nruab nrab ntawm cov teeb meem kev nyuab siab thiab cov lus teb antidepressant. Nat Neurosci 13: 745-752.

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

    (2008) Cov khoom ntawm ΔFosB nyob rau hauv lub nucleus cog rau ntawm kev coj tus cwj pwm kev txi. J Neurosci 28: 10272-10277.

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

    (2002) Δ FosB tswj lub log khiav. J Neurosci 22: 8133-8138.

  51. Teb zoo!
    1. Winstanley CA,
    2. LaPlant Q,
    3. Theobald DE,
    4. Ntsuab TA,
    5. Bachtell RK,
    6. Perrotti LI,
    7. DiLeone RJ,
    8. Russo SJ,
    9. Garth WJ,
    10. Tus kheej DW,
    11. Nestler EJ

    (2007) ΔFosB induction nyob rau hauv orbitofrontal cortex mediates siab rau kev lag luam uas muaj kev sib raug zoo. J Neurosci 27: 10497-10507.

  52. Teb zoo!
    1. Hma ME

    (2010a) Lub Roob Ceg Ceg Ib Daim duab peb sab ntawm cov yeeb yaj kiab. Hloov Neurosci 33: 391-398.

  53. Teb zoo!
    1. Hma ME

    (2010b) Kev cai ntawm AMPA tus neeg muag khoom txav hauv kev sib deev accumbens los ntawm dopamine thiab cocaine. Neurotox Res 18: 393-409.

  54. Teb zoo!
    1. Hma ME

    (2012) Neuroscience: kev coj cwj pwm ntawm cov yeeb yaj kiab hloov. xwm 481: 36-37.

  55. Teb zoo!
    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) Ib txoj kev nco-ntxias cov txheej txheem los tiv thaiv kev siv yeeb tshuaj thiab kev rov qab. Science 336: 241-245.

  56. Teb zoo!
    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) Lub luag haujlwm tseem ceeb rau ΔFosB nyob rau hauv lub nucleus accumbens nyob rau hauv kev txiav txim morphine. Nat Neurosci 9: 205-211.

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

    (2002) Tus dopamine D1 tus neeg pleev kiab tuaj yog ib qho tseem ceeb rau tus cwj pwm coj los ntawm tus yeeb yaj kiab. J Neurochem 82: 1453-1464.

Cov khoom sau tsab ntawv no

KEV KAWM TXHUA TUS NEEG - KEV SAIB XYUAS DUA:

Nyob rau hauv txoj kev tshawb nrhiav tam sim no, peb pom tau tias kev sib tw ntawm kev sib sib zog nqus pa thiab yeeb tshuaj, thaum lub ntuj tsim nuj rov qab los ntawm ib lub sij hawm txwv. Tshwj xeeb, peb tau pom tias qhov kev paub txog tus cwj pwm ntawm kev sib deev, raws li 7 los yog 28 d ntawm abstinence, ua rau Amph nqi zog.

Cov kev tshawb pom no muaj qhov zoo sib xws nrog lub luag haujlwm tseem ceeb ntawm lub caij nyoog tsis pub dhau los ntawm kev siv yeeb siv tshuaj los ntawm kev tsim kom muaj kev siv tshuaj yeeb (Lu, al., 2005; Thomas et al., 2008; Hma, 2010b, 2012; Xue thiab al., 2012). Tsis tas li ntawd, qhov nqi zog-vim yog qhov FosB nyob rau hauv NAc yog qhov tseem ceeb rau kev cuam tshuam ntawm kev cuam tshuam dab tsi ntawm qhov khoom plig ntawm kev xav ntawm kev xav ntawm psychostimulant, uas muaj feem ntawm spinogenesis nyob rau hauv NAc thaum lub sij hawm ib qho kev zam ntawm kev tsim txiaj.

Peb pom tau tias? FosB txuam rau hauv NAc tom qab kev sib deev yog qhov ntev thiab ntev rau NAc D1R kev ua si thaum lub sij hawm sib tw. Ua ntej, qhov D1R-kho kom haum hauv FosB upregulation hauv lub NAc tau qhia tias tseem ceeb heev rau kev txhawb zog siab rau Amph thiab nce qaum kev sib tw hauv lub NAc, txawm tias cov txiaj ntsim tau los ntawm kev sib deev yog nyob ntawm ib lub caij nyoog ntawm kev sib deev ntawm kev sib deev (Pitchers thiab al., 2010a). Thaum kawg, peb pom tau hais tias NAc spinogenesis yuav ua rau lub sijhawm pib ntawm kev qhia txog Amph nqi zog tiam sis tsis tseem ceeb rau kev qhia ntxiv txog kev txhawb nqa kev noj tshuaj, raws li nce tus nqaj qaum nyob rau hauv NAc tau ntev thiab pom tom qab 7 d, tab sis tsis 28 d, lub sij hawm tsis txaus siab.

Nws tau ntev tau paub tias dopamine raug tso tawm hauv NAc thaum muaj kev coj tus cwj pwm coj zoo, nrog rau kev coj tus cwj pwm. Thaum qhia txog poj niam receptive, tus kab mob dacas hauv cov NAc ntau dua thiab tseem raug siab thaum lub sij hawm sib tw (Fiorino li al., 1997). Txoj kev tshawb xyuas tam sim no pom tias infusing dopamine receptor antagonists mus rau hauv NAc thaum mating tsis tau muaj kev ntxim rau cov kev pib lossis kev ua haujlwm ntawm kev coj tus cwj pwm, uas zoo ib yam nrog cov kev xav hais tias dopamine tsis koom nrog kev qhia ntawm kev coj tus cwj pwm kev ua se, rau kev saib xyuas ntawm kev siab ntsws ntawm kev sib deev nrog kev sib deev (Berridge thiab Robinson, 1998). Xwb, cues predictive ntawm cov nqi zog ntawm kev sib deev ua rau kev ua rau cov neurons hauv lub paj hlwb mesolimbic dopamine, nrog rau cov kab mob dopaminergic hauv cheeb tsam ventral tegmental thiab lawv lub hom phiaj, NAc (Balfour li al., 2004).

Cov kev ua plees ua yi rov qab ua ke dua tuaj? FosB nyob rau hauv NAc, uas tig los kho cov kev tsim kho ntawm kev coj tus cwj pwm (Pitchers li al., 2010b). Qhov tshwm sim tam sim no qhia tias mating-vim? FosB upregulation yog, qhov tseeb, nyob ntawm D1R ua rau hauv lub NAc thaum lub sij hawm mating. Qhov kev tshawb pom no zoo ib yam li cov kev tshawb fawb dhau los uas qhia tias kev rov ua hauj lwm ntxiv kev mob hlwb nce siab ntxiv? FosB nyob rau hauv NAc nrab kab zauv neurons tawm D1R (Lee et al., 2006; Kim et al., 2009) thiab hais tias? FosB upregulation yog nyob ntawm D1R activition (Zhang thiab al., 2002). Tsis tas li ntawd, cov lus teb ua rau cov tshuaj tsis haum, feem ntau pom nyob hauv ib qho tshuaj yeeb tshuaj, yuav raug ua thaum tsis muaj cov tshuaj yeeb los ntawm kev sib kis los ntawm FosB nyob D1R tawm ntawm cov neurons hauv cov paj hlwb (Kelz thiab al., 1999). Yog li, ob lub ntuj thiab tshuaj yeeb muaj txiaj ntsim loj tuaj? FosB nyob rau hauv NAc ntawm D1R-nyob ntawm cov cuab yeej ua rau kev coj tus cwj pwm coj zoo.

Ntxiv mus, cov kev tshawb nrhiav tam sim no qhia tau tias FosB yog tus tseem ceeb ntawm kev sib tw ntawm qhov kev sib tw ntawm qhov khoom plig thiab kev pab cuam ntawm kev puas siab ntsws. FosB overexpression nyob rau hauv NAc ua rau tus neeg ua haujlwm rau cov neeg ua haujlwm rau cov neeg ua haujlwm tom qab ua ntej los yog rov ua dua tshiab (Kelz thiab al., 1999), tsub kom muaj zog rau cov tshuaj yeeb dej cawv thiab Morphine CPP (Kelz li al., 1999; Zachariou et al., 2006), thiab ua rau yus tswj hwm kev txo qis ntawm cocaine (Colby li al., 2003). Kev kawm tam sim no qhia tau hais tias blockade ntawm D1R los yog? FosB yam nyob rau hauv lub NAc thaum mating abolished deev kev ua rau sensitization ntawm Amph nqi zog. Thus, ntuj thiab tshuaj yeeb tsuaj tsis yog nyob ntawm tib txoj hlab ntsha ntawm neural, lawv ntws los ntawm tib lub cev tshuaj tua (Nestler li al., 2001; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b), thiab yuav ua rau tib lub neurons hauv lub NAc (Frohmader li al., 2010b), los txhawb txoj kev siab ntsws thiab kev xav "ntawm ob hom kev ntshaw (Berridge thiab Robinson, 1998).

Txoj kev tshawb xyuas tam sim no pom tau hais tias lub sijhawm tsis pub dhau ntawm qhov khoom plig ntawm kev sib deev yuav tsum tau ua rau lub siab ntawm Amph thiab NAc spinogenesis. Peb pom tau tias? FosB thaum lub caij nyoog no yuav cuam tshuam dab tsi ua rau lub cev tsis ua hauj lwm los ntawm kev hloov cov kev nqes noob qaum mus rau kev pib spinogenesis thiab hloov ua kom muaj zog. Xwb, blocking induction ntawm? FosB nyob rau hauv lub NAc thaum mating tiv thaiv tau nce tus txha nraub qaum nyob hauv lub NAc kuaj tom qab muab txiaj ntsig abstinence. Ntxiv mus, kuvnfusion ntawm ib tug D1R antagonist rau hauv NAc ua ntej txhua mating sib kho tiv thaiv kev sib deev kev tsim vim li cas nce hauv FosB thiab cov ntxiv mus ntxiv tus kab txha nqaj. FosB yog ib qho tseem ceeb tshaj plaws uas ua tau los ua ib tus kws kho mob los sis cov neeg ua hauj lwm los cuam tshuam rau cov kev qhia ntawm ib lub hauv paus ntawm cov noob caj noob ceg uas yuav tig los ua tus cwj pwm qis thiab ua kom muaj zog hauv lub NAc (Nest, 2008). Ntau tshaj plaws,? FosB qhib qhov kev cuam tshuam txog kev hloov kinase-5 (Bibb li al., 2001; Kumar li al., 2005), qhov zoo tshaj? B (NF-? B) (Russo thiab lwm tus, 2009b), thiab GluA2 subunit ntawm glutamate AMPA reseptor (Vialou et al., 2010) thiab cov kab lus tshaj tawm ntawm tus poj niam thaum nyuam qhuav pib dua (Phooj Ywg, 2010b) thiab histone methyltransferase G9 (Maze li al., 2010). Cyclicdependent kinase-5 tswj cov roj ntsha proteins thiab cov paj hlwb (Taylor et al., 2007). Ntxiv mus, activating NF-? B nce tus naj npawb ntawm dendritic spines nyob rau hauv NAc, whereas inhibition ntawm NF-? B poob basal dendritic spines thiab blocks cov yeeb-koog nce nyob rau hauv spines (Russo li al., 2009b). Yog li, kev sib deev nqi zog nce? FosB hauv NAc, uas yuav hloov NAc spine density los ntawm ntau lub hom phiaj (piv txwv, cyclic-dependent kinase-5, NF-? B) and hais tias tag nrho qhov tsim nyog tau txais txiaj ntsim tshuaj yeeb tsuaj, raws li tau hypothesized los Russo li al. (2009a) rau cov yeeb yam ntawm cov neeg ua hauj lwm cocaine

Kev soj ntsuam ntawm qhov kev tshawb nrhiav tam sim no yog tias qhov nce ntawm qhov kev sib ntxiv ntawm qhov nAc yog qhov ntev, thiab tsis pom ntawm 28 d tom qab kev sib deev. Yog li, kev txha nqaj qaum zog yog sib raug zoo nrog qhov pib ntawm Amph tus nqi zog thiab yuav pab txhawb rau thawj kev loj hlob los yog kev qhia luv cov lus Amph responses. Txawm li cas los, kuvtsis yog qhov yuav tsum tau ua rau qhov tsis txaus siab ntawm Ampl nqi zog tom qab lub sij hawm ntev ntev lawm. Peb tau pom hais tias qhov kev sib deev ua rau lub sijhawm luv (7, tiam sis tsis 28, hnub tom qab mating kawg) nce ntxiv ntawm NMDA tus neeg tau txais kev pabcuam NR-1 nyob rau hauv NAc, uas tau hloov mus rau qib theem pib tom qab lub sijhawm ntev tshaj ntawm kev muab nqi zog abstinence (Pitchers li al., 2012). Qhov no nce NMDA tus neeg ua haujlwm tau txais kev pom zoo yog qhov pom tau tias yog vim kev sib deev nrog kev sib deev uas muaj kev sib deev (Huang et al., 2009; Brown thiab al., 2011; Pitchers et al., 2012), thiab qhia txog qhov kev sib deev kev tsim Tus txha nqaj qaum kev loj hlob yog nyob ntawm kev ua kom muaj zog NMDA chaw ua haujlwm (Hamilton li al., 2012).

Thaum kawg, txoj kev tshawb nrhiav tam sim no tseem ceeb tshaj qhov kev sib tw tshuaj ntawm kev siv tshuaj yaj yeeb ntawm ib qho khoom plig (kev sib deev) thiab nws qhov kev vam khom rau ntawm lub sij hawm uas tsis tau them nqi. Ntxiv thiab, qhov kev coj cwj pwm no yog kho kom haum los ntawm FosB ntawm D1R ua rau hauv NAc. Yog li ntawd, cov ntaub ntawv qhia tias tsis tau txais txiaj ntsig ntawm ntuj tom qab tau txais txiaj ntsig ntawm kev ua lag luam yuav ua rau cov neeg muaj kev yoojyim rau txoj kev tiv thaiv kev quav yeeb tshuaj thiab tias ib tus neeg tuaj kho ntawm qhov kev puas tsuaj ntxiv no yog FosB thiab nws cov hom phiaj ntawm kev hloov qis dua.