Saameyntii ΔFosB-dul-marin-xumada ku aaddan daaweynta opioid iyo cannabinoid-dhexdhexaadinta ee calaamadaha nucleus (2011)

Neuropharmacology. 2011 Dec;61(8):1470-6. doi: 10.1016/j.neuropharm.2011.08.046.

Sim-Selley LJ, Xildhibaan Cassidy, Sparta A, Zachariou V, Nestler EJ, Selley DE.

source

Department of Pharmacology iyo Toxicology iyo Machadka Daroogada iyo Daroogada Alcohol, Virginia Commonwealth University of Medicine, Richmond, VA 23298, USA.

aan la taaban karin

Qodobka xasaasiga ah ee xasaasiga ah ee ΔFosB waxaa lagu soo rogaa nucleus accumens (NAc) oo soo noqnoqda oo soo noqnoqota oo soo noqnoqota oo la xidhiidha isticmaalka daroogooyinka xad-dhaafka ah, iyo ficil-celinta is-beddelka ee ΔFosB ee qallalka ayaa kor u qaadaya sifooyinka wanaagsan ee morphine iyo cocaine. Si kastaba ha noqotee, saldhigga farsamaynta ee indha-indhayntu waa mid si buuxda loo fahmay. Waxaan adeegsanay habka muraayada maskaxda ah oo leh qaabka loo yaqaan 'ΔFosB' dopamine D (1) reseptor / dynorphin-ku jirta neur-mareenka qanjidhada dhalmada si loo ogaado saameynta ΔFosB ee salfiga opioid iyo cannabinoid ee NAc. Natiijooyinka waxay muujiyeen in firfircoonida G-protein dhexdhexaad ah iyo joojinta adenylyl cyclase lagu horumariyey NAc ee jiirarka oo muujiyay ΔFosB. Sidoo kale, kappa opioid inhibir ah adenylyl cyclase waxaa lagu horumariyey ΔFosB oo muujinaya jiirarka. Taa bedelkeeda, calaamadaha cannabinoid-dhexdhexaadiyaha ah ee dhexdhexaadintu ma kala duwan yihiin jadeecada oo ay u badan tahay in badan oo ΔFosB iyo jiirarka. TNatiijooyinka xasaasiyadu waxay soo jeedinayaan in astaamaha daaweynta opioid iyo cannabinoid ay si kala duwan u bedeleen ereyada ΔFosB, waxayna tilmaamayaan in ereyada ΔFosB ay soo saari karto qaar ka mid ah saameynteeda iyada oo la adeegsanayo soo-saarka xasaasiga ah ee mu iyo kappa opioid ee NAc.

Keywords: G protein, adenylyl cyclase, striatum

1. Hordhac

Cudurka Opioid iyo Cannabinoid CB₁ duubayaasha (CB₁R) waa bartilmaameedyada neurobiological ee loogu talagalay laba nooc oo daroogo ah oo loo isticmaalo daroogada kuwaas oo ay ka mid yihiin morphine, herooin iyo opioids oo rijeetooyin ah, iyo marijuana (Δ⁹-tetrahydrocannabinol (THC), siday u kala horreeyaan. Dhibaatooyinka ba'an ee opioids iyo cannabinoids ayaa dhexdhexaadinaya G-borotiinka-ku duubnaanta xayeysiiska ah ee dhaqdhaqaaqa G_{i / o} borotiinada oo soo saaraan jawaabaha hoose ee waxtarka leh sida xayiraadda cyclase adenylyl (Carruurta, 1991, Carruurta, et al., 1992, Howlett, et al., 2002). Mashiinka, xasuusta xasuusta iyo saameynta nafsiga ah ee Δ⁹-THC waxaa soo saaray CB₁R (Huestis, et al., 2001, Zimmer, et al., 1999), kuwaas oo si ballaaran loogu qaybiyey maskaxda, oo leh heerar sare ee ganglia basal, hippocampus iyo cerebellum (Herkenham, et al., 1991). Dhibaatooyinka kufsiga iyo saameynta wanaagsan ee daawooyinka daaweyneed ee la xariira iyo kuwa loo isticmaalo daawooyinka opioid ayaa badanaa dhexdhexaadinaya astaamaha Mio opioid (MOR) (Matthes, et al., 1996), kuwaas oo ku kordhay nidaamka limbic iyo maskaxda (Mansour, iyo al., 1994). Nidaamka mesolimbic, oo ka kooban qiyaasaha dopaminergic-ka ee ka imanaya qaybta xudunta (VTA) ee nucleus accumens (NAc), ayaa kaalin muhiim ah ka qaadata saameynta wanaagsan ee opioids iyo cannabinoids (Bozarth iyo Wise, 1984, Vaccarino, et al., 1985, Zangen, iyo al., 2006), iyo sidoo kale daroogooyinka kale ee xadgudubka ah (Koobka iyo Volkow, 2010). Waxaa intaa dheer, nidaamyada halista ah ee opioid iyo cannabinoid waxay ku lug leeyihiin saamaynta waxqabadka leh ee daroogooyinka kala duwan ee daawooyinka nafsiga ah (Maldonado, iyo al., 2006, Trigo, iyo al., 2010). Sidaa daraadeed, waxaa muhiim ah in la xakameeyo hababka loo adeegsado opioid iyo CB₁R signaling waxaa lagu xakumay NAc.

Su'aal dhexe oo ku saabsan maan-dooriyaha daroogada ayaa ahaa in la aqoonsado borotiinka oo dhexdhexaadinaya ka-gudubka ka soo noqnoqoshada ilaa saameynta muddada fog ee daawooyinka nafsiga ah. Waxyaabaha loo yaqaan 'AP-1' ee isweydaarsiga ΔFOSB ayaa si gaar ah u xiiso leh maxaa yeelay waa badeeco kala duwan oo kala duwan fosb hiddo-wadaha oo ku urursan soo noqnoqashada soo noq-noqoshada daroogooyinka xadgudubka ama abaalmarinta dabiiciga ah (McClung, iyo al., 2004, Nestler, 2008, Nestler, et al., 1999). Waxaan ogaanay in ΔFosB ay ku dhacdo maskaxda ka dib soo noqnoqoshada soo noqnoqda ee morphine, Δ⁹-THC, kookaha ama ethanol, oo leh daroogo kasta oo soo saaraya qaab shisheeye oo khaas ah oo ka mid ah ereyada ΔFosB (Perrotti, iyo al., 2008). Daraasaad joogta ah oo laga helay daawooyinka ayaa ahaa in ΔFosB ay aad u soo jiidatay qiiqa, halkaas oo dhammaan afarta daroogo ay ku dhufteen ΔFosB xuddunta NAc iyo dhamaantood marka laga reebo Δ⁹-THC waxay si aad ah u sababtay bandhigida NAc qolof iyo caudate-putamen.

Daraasadaha Pharmacological-ka waxay muujiyeen in Iskuduwaha Dopamin D₁ Aqbalaha (D₁R) antagonist SCH 23390 ayaa xannibay ΔFosB induction ee NAc iyo caudate-putamen ka dib markii la isku daro maamulka kookeynta ama morphine, oo muujinaya muhiimadda D₁R-muujinta qanjirrada (Muller iyo Unterwald, 2005, Nye, et al., 1995). Saameynta ΔFosB ee joojinta dabeecadaha daroogada dhexdhexaadiya ayaa la baaray iyada oo la isticmaalayo jiirka jimicsiga oo qeexaya ΔFosB dadweynaha qanjirada gaarka ah ee NAc iyo qiyaasta caanka ah (Chen, iyo al., 1998). Mice oo muujiya ΔFosB ee dynorphin / D₁R Nirada maskaxda ee NAc iyo qaamuuska caanka ah (line 11A) waxay muujinayaan jawaabaha isbedelka ee daroogada xadgudubka, gaar ahaan kor u qaadista xasaasiga ah saamaynta waxqabad ee kookeynta ama morphine (Colby, et al., 2003, Kelz, et al., 1999, Zachariou, et al., 2006). Isbeddelladani waxay ka dhaceen maqnaansho isbedel ah heerarka MOR ama subagaha kala duwan ee G protein. Si kastaba ha ahaatee, heerarka mRNA ee dynorphin ayaa la yareeyay NAc ee ΔFosB muujinaya jiirka (Zachariou, et al., 2006), oo tilmaamaya in hal bartilmaameed oo ah ΔFosB uu yahay hiddaha oo ku xakameynaya fayraska opioid peptide endogenous. Horumarinta ΔFosB ayaa sidoo kale soo saari kara isbeddel habdhismeed iyada oo la xakameynayo calaamadaha soo celinta ee NAc, laakiin suurtagalnimada suurtagal ma ahan in la baaro. Sidaa daraadeed, daraasaddan hadda waxay isticmaashay naqshadda mashiinka dhirta ah si loo go'aamiyo in kororka sare ee ΔFosB ee dynorphin / D₁R oo ay ku jirto neuronka qoorta ee jirka ayaa wax ka beddelaya dhaqdhaqaaqa G-protein dhexdhexaad ah iyo MOR- iyo KOR-dhexdhexaadinta xayiraadda adenylyl cyclase in NAc. Saamaynta ΔFosB ee CB₁Hawlgallada G-protein dhexdhexaad ah ayaa sidoo kale la qiimeeyey sababtoo ah Δ⁹-CSC waxay ku dhacdaa ΔFosB ee NAc (Perrotti, iyo al., 2008) iyo habka endocannabinoid waxaa loo yaqaanaa si loo xakameeyo wareegyada abaalmarinta maskaxda (Gardner, 2005, Maldonado, iyo al., 2006), laakiin saameynta ΔFosB ee nidaamka endocannabinoid ayaan la baarin.

2. Qalabka iyo Hababka

2.1. Reagents

[³⁵S] GTPNS (1250 Ci / mmol), [α-³²P] ATP (800 Ci / mmol) iyo [³H] cAMP (26.4 Ci / mmol) ayaa laga soo iibsaday PerkinElmer (Shelton, CT). ATP, GTP, GDP, cAMP, serum albumin, bustin serum albumin, creatine phosphokinase, papaverine, imidazole iyo WIN-55212-2, waxaa laga iibsaday Sigma Aldrich (St. Louis, MO). GTPNS waxaa laga iibsaday shirkadda Roche Diagnostic Corporation (Chicago, IL). DAMGO waxaa bixiyay Barnaamijka Daryeelka Bulshada ee Machadka Qaran ee Xad-gudubka Daroogada (Rockville, MD). Diyaargarowga Econo-1 scintillation waxaa laga helay Fisher Scientific (Norcross, GA). Daawada Ecolite scintillation waxaa laga helay ICN (Costa Mesa, CA). Dhammaan kiimikooyinka kale waxaa laga helay Sigma Aldrich ama Fisher Scientific.

2.2. Mice

Jiirka jinsiga ah ee laga soo gooyey NSE-tTA (line A) × TetOp-ΔFosB (line 11) ayaa la sameeyay sida lagu sharaxay Kelz et al. (Kelz, et al., 1999). Jadeecada Bitransgenic ayaa uuraysatay oo ku sara maray doxycycline (100 μg ee cabbitaanka biyaha) si loo xakameeyo muujinta transgene. Isbuucyada 8 da'da, doxycycline waxaa laga saaray biyaha si loogu badiyo jeebka si loo oggolaado muujinta transgene, halka jiirarka haray lagu hayay doxycycline si loo xakameeyo transgene. Mindhicirada ayaa la soo ururiyay toddobaadyo ka dib, waqtigaas oo saameyn ku yeeshay saamiga isgaadhsiinta ee ΔFOSB ugu badnaan (McClung iyo Nestler, 2003). Xabbad labaad oo loo yaqaan "transgenic mouse" ayaa loo adeegsaday taas oo loo yaqaan "Δc-Jun", "antagonist" ee c-Jun, oo lagu muujiyay D₁R / dynorphin iyo D₂R / enkephalin unugyada qanjidhada, hippocampus iyo kortex (Peakman, et al., 2003). C-Jun iyo jeegareynta qoysaska Jun ee la xidhiidha qoyaanka Fos ee qoysaska iyo isku xirnaanta goobta AP-1 ee gen ee bartilmaameedka si loo xakameeyo waraaqda. Si kastaba ha ahaatee, qaybta N-terminus of c-Jun (Δc-Jun) wuxuu kakoobi karaa kakooban oo aan si firfircoon u shaqeyn karin oo awood u leh inuu diidi karo DNA-ga xiritaanka xarumaha firfircoon ee AP-1. Jiirka jinsiga ah ee laga soo gooyey NSE-TTA (line A) × TetOp-FLAG-Δc-Jun (line E) ayaa lagu sameeyay sida lagu qeexay Peakman et al. (Peakman, et al., 2003). Jadeecada Bitransgenic ayaa uuraysatay oo ku sara maray doxycycline (100 μg ee cabbitaanka biyaha) si loo xakameeyo muujinta transgene. Pups ayaa laga raray toddobaadyada 3, oo loo kala qaybiyey, oo loo kala qaybiyay kooxo, iyadoo kala badhna lagu hayo biyo iyo biyo kala duwan oo biyo ah oo la cabbo si loo soosaaro sheegitaanka FLAG-Δc-Jun. Mindhicirada waxaa la soo ururiyay toddobaadyo ka dib, waqtigaas oo heerarka ugu sarreeya ee FLAG-Δc-Jun lagu cabbiray (Peakman, et al., 2003). Dhamaan hababka xayawaanka waxaa loo sameeyey si waafaqsan Hay'adaha Qaranka ee Hagaha Caafimaadka ee Daryeelka iyo Isticmaalka Xayawaanada Layli.

2.3. Diyaarinta Xasilaadda

Maskaxda waxaa lagu keydiyay -80 ° C ilaa maalinta baaritaanka. Ka hor inta aan la tijaabin, maskax kasta ayaa la dhalaalay, waxaana NAc laga saaray barafka. Shay kasta waxaa lagu dhexdhigay 50 mM Tris-HCl, 3 MM MgCl₂, 1 MM EGTA, pH 7.4 (buunxumo xardhan) oo leh 20 oo ka timid mashiinka dhalada ee xNUMX ° C. Homogenate waxaa laga dhigay xarun xNUMX × g at 4 ° C loogu talagalay 10 min, dib loo cusbooneysiiyey xargaha xargaha, mar labaad xarfaha xNUMX × g at 4 ° C ee 10 min oo dib loo furay 50 mM Tris-HCl, 3 MM MgCl₂, 0.2 MM EGTA, 100 MM NaCl, pH 7.4 (baaritaan ku samee). Heerarka qudaarta waxaa lagu go'aamiyey qaabka Bradford (Bradford, 1976) iyadoo la adeegsanayo heerarka 'serum albumin' (BSA) ee loo yaqaan 'BSA'.

2.4. Agonist-Digniin [³⁵S] GTP SS

Xasuuso ayaa horay loo xakameeyay daqiiqado 10 at 30 ° C adenosine deaminase (3 mU / ml) oo lagu baaray. Xubnayaasha (5-10 μg protein) ayaa lagu kululeyn jiray 2 hr at 30 ° C ee baaritaanka isku-darka ah oo ay ku jiraan 0.1% (w / v) BSA, 0.1 nM [³⁵S] GTPNS, 30 μM GDP iyo adenosine deaminase (3 mU / ml) oo leh weji la'aan iyo diidmo ku habboon ee DAMGO ama WIN55,212-2. Xakameyn aan loo baahneyn ayaa lagu qiyaasey 20 μM GTPNS. Qaboojinta ayaa la joojiyay iyada oo loo marayo shaandhada GF / B muraayadaha faleebada, oo ay ku xigto 3 oo la socota 3 MY iceX mX Tris-HCI, pH 50. Raajo-xoqidda waxaa lagu go'aamiyey sawir-qaade dheecaan ah oo la isku qurxiyo ka dib markii laga soo saaray habka fayradaha ee dheecaanka xajmiga Econo-7.4.

2.5. Adenylyl Cyclase Assay

Xanuunada (5-25 μg protein) ayaa horey loogu sii daray adenosine deaminase sida kor lagu sharaxay, ka dibna lagu daro 15 min minus 30 ° C iyadoo joogta ama maqnaansho 1MM forskolin, iyadoo leh ama aan lahayn DAMGO, U50,488H ama WIN55,212-2, 50 μM ATP, [α-³²PNG XMUMX mM DTT, 1.5 mM DTT, 0.2 mM DTT, 0.1% (w / v) BSA, 50 AMM cyclic AMP, 50 μM GTP, 0.2 mM papaverine, 5 mM phosphocreatine, unug 20 / ml abuurka fosfokinase iyo adenosine deaminase (3 m / ml) mugga kama dambaysta ah ee 100 ul Xaaladahan oo kale, wadarta [α-³²P] CAMP-ka soo kabashada wuxuu guud ahaan ka yaraa 1% wadarta wadarta guud ee [α-³²P] ATP kasta oo tijaabooyin ah. Dareen-celinta ayaa joojisay karkarinta 3 min iyo [³²P] Cyclic AMP waxaa loo gooyey qaybta labka ah (Dowex iyo alumina) ee Salomon (Salomon, 1979). [³H] cAMP (10,000 dpm) waxaa lagu darey tuubo kasta kahor intaan saldhigga foosha lagu darin waa heer gudaha ah. Raaxo-qabashada waxaa lagu go'aamiyay qaab-daaweyn sawir-qaade (45% efficiency) ³H) ka dib markii 4.5 ML la yareeyay xNUMX ml ee dareeraha 'Ecolite scintillation'.

2.6. Falanqaynta xogta

Haddii aan si kale loo sheegin, xogta waxaa loo soo sheegayaa qiimaha macnaha erayga 4-8 oo tijaabo ah oo kala duwan, mid kasta oo lagu sameeyay sadexleey. Net-kiciyay [³⁵S] Qalabka GTPNS waxaa loo xisaabiyaa sida agonist-kicin lagu xaddidayo basal khafiif ah. Waxqabadka loo yaqaan 'forskolin-stimulated activity cyclase' waxaa lagu qeexay asxolin-kicinta dhaqdhaqaaqa - dhaqdhaqaaqa asalka ah (pmol / mg / min). Qiyaasta xakameynta firfircoonida loo yaqaan 'forskolin-stimulated activity cyclase' ayaa lagu qeexay sida (hawlaha loo yaqaan 'forskolin-stimulured activity' la'aantiis maqnaanshaha agonist - net forskolin-stimulating activity iyadoo jiritaanka agonist / net forksolin-stimululated activity marka maqnaanshaha agonist) x XUM. Dhammaan falanqaynta farsamooyinka iyo falanqeynta tirakoobka waxaa lagu sameeyay iyadoo la adeegsanayo Prism 100c (GraphPad Software, Inc., San Diego, CA). Curriculum-ku-oolka saameynta waxaa lagu falanqeeyay nidaam aan caadi ahayn oo qummanaan ah si loo helo EC₅₀ iyo E_max qiimaha. Muhiimadda tirakoobka ee xogta saameynta ku-leh saamaynta waxaa lagu go'aamiyey falanqaynta laba-dhinac ee isbeddelka (ANOVA), iyadoo la adeegsanayo qiyaasta agonistaha iyo indha-indheysiga (on or off) sida arrimaha ugu muhiimsan. Muhiimadda tirakoobka qiimaha gogol-xajinta (E_max ama EC₅₀) waxaa go'aamiyay laba-dabo ee labo-cagaarsho Ardayga ee t-imtixaanka, iyadoo la adeegsanayo saxitaanka Welch ama beddelka xididka laba geesoodka ah ee xogta halka ay lagama maarmaanka u tahay in lagu saxo kala duwanaanshaha aan sinnayn (oo lagu ogaanayo F-test) EC₅₀ qiimaha.

3. Natiijooyinka

3.1. Saameynta ereyada ΔFosB ee opioid iyo cannabinoid-ku-dhex-dhexaadin ah ee firfircoonaanta G-protein

Si loo go'aamiyo haddii MOR- ama CB₁R-dhexdhexaadinta isugeynta G-protein ayaa lagu beddelay muujinta isdhexgalka ee ΔFosB ee NAc, agonist-stimulated [³⁵S] GTPRS waxay ku xiran tahay xargo gooni ah oo laga diyaariyey gobolkaan ee jiirarka xajmiga ah ee xaalada deg dega ah (ΔFosB on) ama aan sheegin (ΔFosB off) ΔFosB transgene. DAMGO-da analog-ka ah ee "MOR-selective" ayaa loo isticmaalay in la dhaqaajiyo MOR iyo cannabinoid aminoalkylindole WIN55,212-2 ayaa loo isticmaalay in lagu dhaqaajiyo CB₁R. Tilmaamayaashan hore ayaa loo soo bandhigay inay yihiin agonistayaal buuxa oo ku yaal MOR iyo CB₁R, siday u kala horreeyaan (Breivogel, et al., 1998, Selley, et al., 1997). Uma suurta-galin in la baaro dhaqdhaqaaqa G-protein dhexdhexaad ah maxaa yeelay signalku aad ayuu u hooseeyaa maskaxda jiirka (Carruurta, et al., 1998). Natiijooyinka waxay muujiyeen dhiirigelinta ku-tiirsanaan-ku-tiirsan ee firfircoonaanta G-protein by DAMGO iyo WIN55,122-2 ee NAc oo ka yimid ΔFosB iyo ΔFOSB ee jiirarka (Jaantuska 1). Dhaqdhaqaaqa DAMGO-kiciyey (Jaantus 1A), laba-geesood ah ANOVA ee xogta uruurinta saamaynta ayaa muujisay saamaynta ugu weyn ee xaaladda ΔFosB (p <0.0001, F = 22.12, df = 1) iyo uruurinta DAMGO (p <0.0001, F = 29.65, df = 5) oo aan lahayn isdhexgalka weyn (p = 0.857, F = 0.387, df = 5). Falanqaynta aan tooska ahayn ee dib-u-eegista cilladaha foojignaanta waxay muujisay DAMGO E aad u weyn_max qiimaha ku jira ΔFosB jiirarka (E_max = 73 ± 5.2% xayeysiin) marka loo eego jiirka jimicsiga ΔFosB (E_max = 56 ± 4.1% kicinta; p <0.05 oo ka duwan ΔFosB jiirka jiirka ardayda 't-test'). DAMGO EC₅₀ qiimaha ma uusan kala duwanayn ΔFosB iyo jiirarka ΔFosB (302 ± 72 nM ujeeda 212 ± 56 nM, siday u kala horreeyaan, p = 0.346).

Saameynta ereyada ΔFosB ee dulucda ujeeda [³⁵S] GTPNS ee ku xiran NAc. Xubnaha ka yimid ΔFosB-muujinta (ΔFosB on) ama xakamaynta (ΔFosB off) jiir ayaa lagu tijaabiyey sida lagu sharxay Hababka isticmaalka maaddooyinka kala duwan ...

Marka laga soo tago natiijooyinka la helay DAMGO-da MON agonist, ma jirin kala duwanaansho ku xirnaanta xaaladaha ΔFosB ee ku-meel-gaadhka ah ee fir-fircoonida G-protein ayaa lagu arkay adonabinoid agonist WIN55,212-2 (Jaantus 1B). Labada dhinac ee ANOVA ee xogta uruurinta saamaynta ee WIN55,212-2 ayaa muujisay saameyn weyn oo weyn oo ku saabsan uruurinta WIN55,212-2 (p <0.0001, F = 112.4, df = 7), laakiin ma ahan heerka ΔFosB (p = 0.172 , F = 1.90, df = 1) mana jirin wax isdhexgal ah (p = 0.930, F = 0.346, df = 7). Sidoo kale, wax saameyn ah kuma yeelan xaaladda ΔFosB xaaladda WIN55,212-2 E_max qiimaha (103 ± 6% oo ka soo horjeeda 108 ± 8% xayeysiinta ee ΔFosB jiirarka iyo saarista jiirka, siday u kala horreeyaan, p = 0.813 ee imtixaanka t-ardayga) ama EC₅₀ qiimaha (103 ± 20 nM) 170 ± 23 nM ee ΔFosB jiirarka saaran iyo ka saarista, siday u kala horreeyaan, p = 0.123).

Iyadoo lagu saleynayo qaabka cursida iyo xaqiiqda ah in daraasadaheena hore ay muujiyeen curyaaminta isdhaafsiga WIN55,212-2 ee maskaxda (Breivogel, et al., 1999, Breivogel, et al., 1998), Xubnaha WIN55,212-2 ayaa sidoo kale lagu falanqeeyay iyadoo la isticmaalayo qaab-laba-goob. Falanqaynta xogta celceliska ah waxay muujisay waxoogaa horumarin ah oo ku wanaagsan wanaagga iyadoo la adeegsanayo habka laba-goobood (R² = 0.933 iyo 0.914, isku darka isku dhufashada = 3644 iyo 5463 ee ΔFosB jiirarka iyo saarista jiirka, siday u kala horreeyaan) marka la barbardhigo halbeegga keliya² = 0.891 iyo 0.879, wadarta isku dhufashada = 6561 iyo 6628 ee ΔFosB oo ku yaal jiirarka iyo jiirka, siday u kala horreeyaan). Si kastaba ha ahaatee, ma jirin faraqyo muhiim ah oo u dhaxeeya ΔFosB oo ku yaal jiirarka iyo jiirka ee E_max ama EC₅₀ qiimaha sare ee xoogaga ama hooseeya (Jaantuska dhammeystiran 1), inkastoo ay jireen isbeddel dhinaca EC ah₅₀ qiimaha sare ee jaangooyaha ee jiirarka leh ee ΔFosB (EC₅₀sare = 28.0 ± 10.6 nM) marka la barbardhigo kuwa leh ΔFOSB (EC₅₀sare = 71.5 ± 20.2 nM; p = 0.094). Waxaa intaa dheer, ma jirin wax saameyn ah oo ku saabsan xaaladda ΔFOSB ee basal [³⁵S] GTPSS ee ku xiran xuubyada NAc (253 ± 14 oo ka soo horjeeda 226 ± 14 fmol / mg ee ΔFosB oo ku yaal jiirarka iyo jiirka, siday u kala horreeyaan, p = 0.188). Xogtaasi waxay muujinaysaa in muujinta isdhexgalka ee ΔFosB ee NAc ee jadeeca kordhiyay firfircoonaanta G-protein dhexdhexaadin ah iyada oo aan si weyn u saameyn CB₁Waxqabadka G-dhexdhexaad ama G-protein oo dhexdhexaad ah.

3.2. Saameyntii ΔFosB ee daawada opioid iyo cannabinoid-dhexdhexaadin ah ee xakamaynta adenylyl cyclase

Si loo qiimeeyo saamaynta isdhexgalka isweydaarsiga ah ee ΔFosB ku saabsan habeynta waxqabadka hoose ee waxqabadka hoosta MOR iyo CB₁R, xakamaynta 1 μM forskolin-stimulated waxqabadka isbeddelidda adenylyl waxaa lagu baaray xuubabka NAc. Marka lagu daro MOR- iyo CB₁R-dhexdhexaadinta xakameynta dhaqdhaqaaqa adenylyl ee dhaqdhaqaaqa, saamaynta hawlaha KOR ayaa sidoo kale la baaray iyada oo la adeegsanayo agabka U50,488 ee KOR-xulasho buuxda (Zhu, et al., 1997), sababtoo ah natiijooyinkii hore waxay muujiyeen in mRNA dynorphin uu ahaa bartilmaameedka ΔFosB ee modelka xajmiga ah (Zachariou, et al., 2006). Natiijooyinka waxay muujinayaan in DAMGO, U50,488 iyo WIN55,212-2 ay soo saareen mid kasta oo ku salaysan xakamaynta isbeddelka dhaqdhaqaaqa adenylyl ee labada ΔFosB labadaba iyo ΔFOSB ee jiirarka (Jaantuska 2). Labada dhinac ee ANOVA ee xogta saameynta xoogga leh ee DAMGO (Jaantus 2A) ayaa shaaca ka qaaday saameynaha muhiimka ah ee ΔFosB status (p = 0.0012, F = 11.34, df = 1) iyo uruurinta DAMGO (p <0.0001, F = 29.61, df = 6), laakiin majiro isdhexgal muhiim ah (p = 0.441, F = 0.986 , df = 6). Falanqaynta aan tooska ahayn ee dib-u-eegista DAMGO goos goosyada saameynta waxay muujisay hoos u dhac aad u hooseeya DAMGO EC₅₀ qiimaha ΔFosB ee jiirka (101 ± 11 nM) marka la barbar dhigo ΔFosB jiirarka ka baxsan (510 ± 182 nM, p <0.05 ardayga t-imtixaankiisa). Si kastaba ha noqotee, ma jirin farqi weyn oo u dhexeeya DAMGO E_max qiimaha (20.9 ± 1.26% illaa 19.8 ± 1.27% xannibaadda ΔFosB ee jiirka iyo jiirka, siday u kala horreeyaan, p = 0.534).

Saameynta ereyada ΔFosB ku saabsan joojinta dhaqdhaqaaqa adenylyl ee dhaqdhaqaaqa NAc. Xubno ka yimid ΔFosB-muujinta (ΔFosB on) ama xakamaynta (ΔFosB off) jiir ayaa lagu tijaabiyey sida lagu sharxay Hababka iyadoo ay joogaan 1 μM ...

Korno-kicinta adenylyl cyclase xakameyntu waxay sidoo kale u kala duwan tahay sida farsamooyinka isdhexgalka ee ΔFosB (Jaantus 2B). Labada dhinac ee ANOVA ee U50,488 xogta saamaynta ku leh saamaynta ayaa muujisay saamaynta ugu weyn ee xaaladda ΔFosB (p = 0.0006, F = 14.53, df = 1) iyo U50,488 fiirsashada (p <0.0001, F = 26.48, df = 3) , oo aan lahayn isdhexgal weyn (p = 0.833, F = 0.289, df = 3). Falanqaynta aan tooska ahayn ee dib-u-eegista cilladaha foojignaanta ayaa muujiyay U50,488 E weyn_max qiimaha 'osFosB' ee jiirka (18.3 ± 1.14% xakameyn) marka la barbardhigo ΔFosB jiirarka (12.5 ± 2.03% xannibaadda; p <0.05 oo ka duwan ΔFosB oo ay ku socoto t-test ardayga), oo aan lahayn farqi weyn U50,488 EC₅₀ qiimaha (310 ± 172 nM) 225 ± 48 nM ee ΔFosB jiirarka saaran iyo ka saarista, siday u kala horreeyaan, p = 0.324).

Iyadoo liddi ku ah saameynta lagu arkay MOR iyo KOR, ma jirin saameyn muhiim ah oo muujinaysa ereyga ΔFosB ee layskaga celin karo ee lagu xakameynayo cyclase adenylyl by agonist cannabinoid WIN55212-2 (Jaantus 2C). Labada dhinac ee ANOVA ee WIN55,212-2 xogta saameyn ku yeelashada saameynta waxay muujisay saameyn weyn oo ku saabsan uruurinta daroogada (p <0.0001, F = 23.6, df = 2), laakiin maaha heerka osFosB (p = 0.735, F = 0.118, df = 1) sidoo kale ma jirin isdhexgal muhiim ah (p = 0.714, F = 0.343, df = 2). Intaa waxaa sii dheer, wax saameyn ah kuma yeelan xaaladda ΔFosB xaaladda basal ama forskolin-kicinta waxqabadka adenylyl cyclase maqnaanshaha agonist kasta. Waxqabadka Basal adenylyl cyclase wuxuu ahaa 491 ± 35 pmol / mg / min gudaha osFosB jiirarka marka loo barbar dhigo 546 ± 44 ee jiirka 'osFosB' (p = 0.346 ardayga t-test). Sidoo kale, waxqabadka adenylyl cyclase ee joogitaanka 1 forsM forskolin wuxuu ahaa 2244 ± 163 pmol / mg / min gudaha osFosB jiirka iyo 2372 ± 138 pmol / mg / min gudaha ΔFosB jiirka (p = 0.555).

3.3. Saameyntii ΔcJun ee daawada opioid iyo cannabinoid-dhexdhexaad ah ee xakamaynta adenylyl cyclase

Sababtoo ah muujinta isdhexgalka ee ΔFosB ee kor u qaadista signal-celinta ee MOR iyo KOR ilaa adenylyl cyclase ee NAc, waxay daneyneysay in la go'aamiyo in gabi ahaanba diidmada diidmada 'ΔFosB-dhexdhexaadinta' transcription-ka wax ka beddeli karto soo-qabsashada opioid-ka soo horjeeda. Si wax looga qabto su'aashan, xakameynta dhaqdhaqaaqa loo yaqaan 'DasGO' iyo 'U50,488' ee loo yaqaan 'forskolin-stimulated activity pathetic adenylyl' waxaa lagu baaray xargaha laga soo diyaariyay NAc ee jiirarka bitransgenic ee xaalad ahaan ugu hadlaya ΔcJun. Natiijooyinka waxay muujin waayeen saameyn weyn oo muujinaysa ereyada ΔcJun ee ku saabsan xakamaynta dhaqdhaqaaqa adenylyl ee dhaqdhaqaaqa by MOR ama KOR (Jaantuska 3). Labada dhinac ee ANOVA ee isku xirnaanta saameynta DAMGO waxay muujiyeen saameyn weyn oo muhiim ah oo ku saabsan uruurinta DAMGO (p <0.0001, F = 20.26, df = 6), laakiin maaha heerka ΔcJun (p = 0.840, F = 0.041, df = 1) mana jirin is dhexgal muhiim ah (p = 0.982, F = 0.176, df = 6). Sidoo kale, ma jirin farqi weyn oo u dhexeeya E_max ama EC₅₀ qiimaha u dhexeeya jiirarka oo leh ΔcJun on (E_max = 23.6 ± 2.6%; EC₅₀ = 304 ± 43 nM) ama ΔcJun off (E_max = 26.1 ± 2.5%, p = 0.508; EC₅₀ = 611 ± 176 nM, p = 0.129). Natiijooyin isku mid ah ayaa lagu arkay U50,488, sida in labada dhinac ee ANOVA ee gooladaha fiirsashada saamaynta muujisay saameyn weyn oo urursanaan (p <0.0001, F = 11.94, df = 6), laakiin aan ahayn heerka ΔcJun (p = 0.127 , F = 2.391, df = 1) mana jirin is dhexgal muhiim ah (p = 0.978, F = 0.190, df = 6). Sidoo kale, ma jirin farqi weyn oo u dhexeeya E_max ama EC₅₀ qiimaha u dhexeeya jiirarka oo leh ΔcJun on (E_max = 14.8 ± 2.9%; EC₅₀ = 211 ± 81 nM) ama off (E_max = 16.7 ± 1.8%, p = 0.597; EC₅₀ = 360 ± 151 nM, p = 0.411).

Saamaynta ΔcJun ee muujinaysa xakameynta dhaqdhaqaaqa adenylyl ee dhaqdhaqaaqa NAc. Xubnaha ka yimid ΔcJun-expressing (ΔcJun on) ama xakamaynta (Jirsi) jiir ayaa lagu kululaaday joogitaanka DAMGO (A), U50,488H (B) ama WIN55,212-2 ...

Muujinta ΔcJun sidoo kale saameyn weyn kuma yeelanin ka hortagga adenylyl cyclase ee NAc ee Canoninoid agonist. Labada dhinac ee ANOVA ee WIN55,212-2 gooladaha wax ku oolka ah waxay muujiyeen saameyn weyn oo muhiim ah oo ku saabsan uruurinta WIN55,212-2 (p <0.0001, F = 15.53, df = 6), laakiin aan aheyn nooca genotype (p = 0.066, F = 3.472, df = 1) mana jirin is dhexgal muhiim ah (p = 0.973, F = 0.208, df = 6). Sidoo kale, ma jirin farqi weyn oo u dhexeeya WIN55,212-2 E_max qiimaha (13.0 ± 2.3% iyo 13.6 ± 0.9% in la xakameeyo ΔcJun oo ka soo horjeeda jiirarka, siday u kala horreeyaan, p = 0.821) ama EC₅₀ qiimaha (208 ± 120 nM iyo 417 ± 130 nM ee ΔcJun marka laga reebo jiirarka, siday u kala horreeyaan, p = 0.270). Sidaa darteed, inkasta oo ay jirto isbedel yar oo ku yimid hoos udhaca awoodda WIN55,212-2 ee jiirarka oo muujinaya ΔcJun, transgene si aad ah uma beddelin cannabinoid xakamaynta adenylyl cyclase. Waxaa intaa dheer, wax saameyn ah ma lahayn saamiga ΔcJun ee basal ama forskolin-kicin kara dhaqdhaqaaqa adenylyl. Hawlgabka basal adenylyl wuxuu ahaa 1095 ± 71 pmol / mg / min iyo 1007 ± 77 pmol / mg / min (p = 0.403) ee jiirarka oo leh jimicsi ama ΔcJun gooni ahaan. Xilliga Raadinta Adenylyl oo ay dhiirigelisay 1 μM forskolin wuxuu ahaa 4185 ± 293 pmol / mg / min illaa 4032 ± 273 pmol / mg / min (p = 0.706) ee jiirarka oo leh jimicsi ama ΔcJun.

3.4. Wadahadal

Natiijooyinka daraasaddan ayaa muujisay in kor u kaca firfircoonaanta G-protein ee MOR-dhexdhexaadinta iyo kicinta adenylyl cyclase ee NAc ee jiirarka leh muujinta muuqaalka transgenic ee ΔFosB ee dynorphin / D₁R oo ku jira neurons. KOR-dhexdhexaadinta xakameynta dhaqdhaqaaqa adenylyl ee dhaqdhaqaaqa ayaa sidoo kale la xoojiyay NAc ee ΔFosB oo muujinaya jiirarka, taas oo soo jeedinaysa in ΔFosB ay nidaamiso nidaamka dhammaystiran ee opioid ee NAc. DAMGO E_max qiimaha wuxuu ahaa mid weyn oo loogu talagalay [³⁵S] GTPSS oo ku xiran, iyo EC₅₀ qiimaha wuxuu ku yaryahay adenylyl cyclase inhibitor, ee ΔFosB jeexjeexay jiirarka marka loo eego jiirarka. Natiijooyinkaasi waxay soo jeedinayaan suurtagalnimada qoondaynta cirfiidka ee wax-qabadka wax-qabadka laakiin maaha hawlgalka G-protein marka la eego xaaladaha tijaabada. Xaqiiqada ah in xaddiga ugu badan ee xakameynta adenylyl cyclase by KOR agonist uu saameeyey ΔFosB ayaa muujinaya qadar yar oo soo dhaweeynaya jawaabta KOR-dhexdhexaad ah, iyada oo la socota heerka hoose ee xarumaha KOR ee maskaxda niyaddaUnterwald, et al., 1991). Taa bedelkeeda, CB₁Waxqabadka G-protein dhexdhexaad ah iyo xakamaynta wareegga adenylyl ayaa aan ku dhicin ereyga ΔFosB, waxay soo jeedinayaan in nidaamka opioid iyo cannabinoid ay ku kala duwan yihiin jawaabtooda ΔFosB ee NAc neurons.

Saameynta ΔFosB ee ku saabsan calaamadaha loo yaqaan opioid-medieptor-mediated interacting waxay ku xiran tahay warbixintayagii hore ee ΔFosB ee muujinaysa saamaynta ba'an ee joogtada ah ee morphine (Zachariou, et al., 2006). Mid ka mid ah helitaanka daraasaddaani waxay ahayd in jiirarka ay la socdaan muujinta transgenik ee ΔFosB ee dynorphin / D₁R xanuunka qanjirka 'striatal' wuxuu ahaa mid aad u xasaasi u ah morphine xaaladdiisa daaweynta marka loo eego kontoroolka. Intaas waxaa sii dheer, saameyntani waxaa loo adeegsadey ficil-celin fara badan oo loo yaqaan "ΔFosB" iyada oo la adeegsanaayo NAc. Indho-indhayntu waxay la socotaa natiijooyinka iminka socda ee muujinaya inay kor u qaadeen MOR-ta NAc.

Waxaan horey u aqoonsanay hingka codka dynorphin sida bartilmaameedka ΔFosB, oo soo jeediyay in dinorphin la yareeyay ay ku haboon tahay sifooyinka wanaagsan ee mira-dhalinta ee morphine ee ΔFosB jadeecada (Zachariou, et al., 2006). Natiijooyinka xaadirka ah waxay muujinayaan in KOR-dhexdhexaadinta xakameynta adenylyl cyclase ee NAc lagu horumariyo ΔFosB oo muujinaya jiirarka, taas oo laga yaabo inay ka tarjumto kororka korriinka KOR ka dib marka loo eego dynorphin. Daraasado hore ayaa muujiyay in KOR loo hagaajiyay gobollada maskaxda qaarkood ee jiirka jilicsan ee prodynorphin, oo ay ku jiraan NAc (Clarke, et al., 2003).

Marka loo eego ΔFosB, muujinta isdhex-galka ah ee ΔcJun, iskudhufka diidmada ah ee khatarta ah ee ka dhexjirta ΔFosB lamaane cJun, ma baddalin adenylyl cyclase inhibitor by MOR ama KOR agonists. Natiijooyinkani waxay soo jeedinayaan in heerarka aasaasiga ah ee ΔFosB ee hoos udhaca, oo aan hoos u dhicin, ma ciyaarin kaalin muhiim ah ee lagu hayo daaweeynta gardarrada opioid ee heerkan isbeddelka signalka ee NAc. Xaqiiqda ah saameynta wanaagsan ee mira dhalinta ee morphine waxaa hoos u dhacay ereyga ΔcJun ee daraasadihii hore (Zachariou, et al., 2006) waxay soo jeedineysaa in xitaa ficil-celinta morphine ee ΔFOSB inta lagu gudajiro nidaamka qaboojinta ay muhiim u tahay hagaajinta jawaabaha habdhaqanka ee daroogada ama saameynta transcriptional ee ΔFosB ee aan ahayn kuwa saameeya calaamadda proximal ee soo dhaweeyayaashu waxay u saameyn karaan abaalmarinta opioid. Xaalad kasta, natiijooyinka daraasaddan ayaa muujinaysa, marka faahfaahinta ΔFosB ay sare u kacday heerarka asaliga ah ee durbaanka dynorphin / D₁R-muujinta qanjidhada, waxaa jira koror xoog leh ee isku xirka MOR iyo KOR si loo xakameeyo cyclase adenylyl ee NAc.

Farsamooyinka ay Morr-iyo KOR-dhexdhexaadintu muujinayaan ΔFosB qadarin la'aantu ma cadda, laakiin waxaan hore u muujinnay in heerka MOR, oo ay qiimeeyeen [³H] naloxone, ma aha mid ka duwan NAc ee ΔFosB on jiidka off (Zachariou, et al., 2006). Daraasaddan ayaa lagu ogaaday in Gra_iHeerarka borotiinka 1 iyo 2 saamayn kuma yeelan gobolkan iyada oo la adeegsanayo ereyo ΔFosB. Si kastaba ha ahaatee, falanqaynta hiddaha hiddaha ee hore ayaa muujisay in Gα_o mRNA waxaa lagu hagaajiyay NAc ee ΔFosB ee jiirarka (McClung iyo Nestler, 2003). Waxay noqon doontaa mid xiiso u leh daraasadaha mustaqbalka si loo eego saameynta isdhaafka ΔFosB ee ku saleysnaanta sub-G-protein ee heerarka borotiinka iyo sidoo kale muujinta borotiinno kala duwan oo G protein ah.

Waxaa xiiso leh in ereyada ΔFosB aysan kor u qaadin CB₁R-dhexdhexaadinta dhexdhexaadinta ee NAc. Waxaa macquul ah in wax laga badalo CB₁Tilmaameyntu waxay ku dhacdaa dad aan kala go 'lahayn oo ah nuuroono oo lagu qotomiyey dhammaan diyaarinta NAc. Tusaale ahaan, maamulka Δ⁹- THC si weyn ayey u keentay ΔFosB xudunta, laakiin maaha qolof, ee NAc (Perrotti, iyo al., 2008). Anigandeed, waxaa la muujiyay in caqabadda la leh Δ⁹-THC ka dib markii la soo celiyo maamulka Δ⁹-THC sii kordhiyay dopamine ee NAc core, laakiin hoos u sii daayay qolofka (Cadoni, iyo al., 2008). Waxaa sidoo kale muhiim ah in la ogaado in line-ka 11A ee jiirarka bitransgenic muujiyaan ΔFosB oo kaliya in dynorphin / D₁R dhexdhexaad ah oo dhexdhexaad ah oo nuucyaal ah, laakiin CB₁R waxaa lagu muujiyey labadaba dynorphin / D₁R iyo enkephalin / D₂R Rabshadaha qanjidhada dhalmada (positive neurons)Hohmann iyo Herkenham, 2000), iyo sidoo kale on terminals of kortikal afferents (Robbe, et al., 2001). Muujinta xakameyn aan caadi aheyn oo ka mid ah waraaqaha ΔFosB ee dhexdhexaadinta ah, ΔcJun, sidoo kale wax saameyn ah kuma laheyn calaamadaynta cannabinoid, laakiin inkasta oo ΔcJun si macquul ah loo muujiyo labadaba D₁ iyo D₂-shabaabinta dadweynaha qanjidhada dhexdhexaadka ah ee jilicsan (Peakman, et al., 2003). Waxaa suurtogal ah, si kastaba ha noqotee, in ereyada ΔFosB asalkiisu hooseeyo uu hoos u dhaco in ΔcJun uusan saameyn doonin calaamadaha soo celinta, sida lagu soo jeediyay natiijooyinka MOR iyo KOR. Waxa kale oo suurtagal ah in CB₁R signaling waxaa si fudud u kordhay ereyada ΔFosB basal, sida in dheeraad ah sii kordhinta ΔFosB ama xannibay tallaabooyinka ay ΔcJun lahaa saameyn yar oo aan gaarin heerka ah ee muhiimadda tirakoob. Taageerada aan tooska ahayn ee turjumaankan waxaa lagu arki karaa marka la barbardhigo WIN55,212-2 EC₅₀ qiimaha u dhexeeya jiirada muujinaya ΔcJun ka soo horjeeda ΔFosB. Saamaynta WIN55,212-2 EC₅₀ qiimaha adenylyl cyclase xakamaynta ee jiirarka oo muujinaya muujinta ΔcJun ee EC₅₀ qiimaha G-protein-ku-samaynta jiirarka ee jiirarka oo muujinaya muujinta ΔFosB wuxuu ahaa 4.0, halka iskudhufka isku midka ah ee jiirarka aan lahayn induction of transgene ahaa 1.2.

Teeda kale, cannabinoids waxay dhalin kartaa ereyada ΔFosB iyada oo aan wax saameyn toos ah ku yeelan CB₁R signaling. Xaaladdan, cannabinoids waxay u beddeli kartaa jawaab celinta saamaynta nafsiyadeed ee daroogooyinka kale iyada oo loo marayo nidaamka isweydaarsiga ΔFosB. Anigaxaqiiqda, maamulka ee Δ⁹-THC waxay soo saartaa dareen-celinta iskudhexyaada iyo amphetamine (Cadoni, iyo al., 2001, Lamarque, et al., 2001), waafaqsan qiyaasahan. Waxaa intaa dheer, maamulka soo noqnoqda ee cannabinoid agonist CP55,940 ayaa lagu soo warramey in uu kordhinayo firfircoonaanta G-protein dhexdhexaad ah ee NAc, taasoo la mid ah jiirarka si xushmad leh u muujinaya ΔFosB daraasaddan (Vigano, et al., 2005). Saameynta ΔFosB ee ku saabsan Δ⁹Habdhaqanka dhexdhexaadinta ah ee dhexdhexaadinta ah ee aan dhexdhexaadin ee DHC-ta ah looma qiimeynin, laakiin natiijooyinka imika ma xallinayaan isdhexgalka. Natiijooyinka tan iyo daraasaddeena hore (Zachariou, et al., 2006) waxay muujiyaan isbeddellada ΔFosB ee MOR iyo KOR / dynorphin oo ku yaal qanjirada. Saameynta wanaagsan ee Δ⁹-THC, sida lagu qiyaaso mudnaanta booska, waxaa lagu tirtiraa jiirka jeexjeexa ee MOR, halkaasoo laga saaro KOR⁹-Ururka UDUB iyo muujiyay Δ⁹-Dhibaatada booskaTHC (Ghozland, et al., 2002). Sidoo kale, siideynta xaalad degdeg ah ee Δ⁹-THC wuxuu ka maqan yahay qulqulatada pro-dynorphin marka la barbar dhigo jiirka jilicsan (Zimmer, et al., 2001). Xogtaasi waxay soo jeedineysaa in Δ⁹-THC waxaa laga yaabaa in ay ku fiicnaado ka dib markii ay soo baxday ΔFosB iyo soo-saarista MOR signaling hoos u dhigista muujinta dynorphin.

Soo koobidy, natiijooyinka daraasaddan waxay muujisay in muujinta ΔFosB ee D₁R / dynorphin nuujiyeyaasha qunyar-socodka ah ayaa waxay kor u qaadeen muujinta MOR- iyo KOR-dhexdhexaad ah heerarka G-protein dhexdhexaad ah ee ka hortagga firfircoonida adenylyl ee dhaqdhaqaaqa NAc. Natiijadan waxay la socotaa daraasad muujisay doorka habka loo yaqaan 'opioid system' ee abaalmarinta (abaalmarinta)Trigo, iyo al., 2010), oo ku siiyaan farsamooyin karti leh oo saameynaya dhibaatooyinka ΔFOSB-dhexdhexaadinta abaalmarinta. Taa bedelkeeda, CB₁Calaamadaha R-dhexdhexaadinta ee NAc si aad ah uma saameeynin ereyada ΔFosB ee shuruudaha lagu baaray shuruudaha la baaray, in kasta oo daraasado dheeraad ah loo ogolyahay in la ogaado saameynta ΔFosB induction on nidaamka endocannabinoid.

Cilmi-baarisyo muhiim ah

Calaamadaha MOR waxaa lagu hormariyaa xajmiga nucleus ee jiirarka oo muujiya ΔFosB
KOR isdilidda adenylyl cyclase ayaa sidoo kale lagu hormariyaa jiirarka muujinaya ΔFosB
Faafinta ΔFosB ma baddalayso CB₁R signaling in xajmiga nucleus

Qalabka Dheeraadka ah

01

Riix halkan si aad u aragto.^{(45K, pdf)}

Mahadnaq

Qorayaashu waxay u mahadceliyeen Hengjun He, Jordan Cox iyo Aaron Tomarchio si ay u caawiyaan farsamo [³⁵S] GTP-ga baaritaanno ku xiran. Daraasadani waxaa taageeray USPHS Deeqaha DA014277 (LJS), DA10770 (DES) iyo P01 DA08227 (EJN).

Qoraalada

Diidmada Daabacaha: Tani waa faylka PDF ee qoraallada aan la saadaalin Karin ee la aqbalay daabacaadda. Adeeg ahaan macaamiisheena waxaan siineynaa qoraalkan hore ee qoraal gacmeedka. Qoraalku wuxuu qaadan doonaa nuqulka, qeexidda, iyo dib-u-eegista caddaynta la soo gudbiyey ka hor inta aan lagu daabicin foomka ugu dambeeya ee la heli karo. Fadlan xusuuso in inta lagu jiro qaladaad habka wax soo saarka laga yaabo in la ogaado taas oo saameyn karta mawduuca, iyo dhammaan sharciyeynta sharciga ah ee khuseeya qoraalka.

tixraacyada

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