Zotsatira za ΔFosB zowonongeka pamagulu a opioid ndi cannabinoid omwe amatha kufotokozera mwachangu mu nucleus accumbens (2011)

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

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

gwero

Dipatimenti ya Pharmacology ndi Toxicology ndi Institute for Drug and Alcohol Studies, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.

Kudalirika

Chinthu cholembera chosakaniza ΔFosB chimapangidwira mkati mwa nucleus accumbens (NAc) mwa kupezeka kwa mankhwala osokoneza bongo angapo, ndipo kufotokozera kwapadera kwa ΔFosB mu striatum kumapangitsa kuti phindu la morphine ndi cocaine. Komabe, maziko a kayendedwe ka zochitika izi ndi osamvetsetseka bwino. Tinagwiritsa ntchito chitsanzo cha bitransgenic phokoso ndi mawu ofooketsa a ΔFosB mkati dopamine D (1) receptor / dynorphin-containing inferred neurons kuti adziwe zotsatira za ΔFosB kufotokozera pa chizindikiro cha opioid ndi cannabinoid receptor mu NAc. Zotsatira zinawonetsa kuti muchitetezo cha G-mapuloteni a opioid ndi kulepheretsedwa kwa adenylyl cyclase kunalimbikitsidwa mu NAc ya mbewa zomwe zinalongosola FFB. Mofananamo, kappa opioid inhibition ya adenylyl cyclase inalimbikitsidwa mu ΔFosB kufotokoza mbewa. Mosiyana ndi zimenezi, kusankhanso kwapopopopotopang'ono kosavomerezeka sikukanasiyana pakati pa ntchentche zowonongeka ΔFosB ndi mbewa zoyendetsa. TZotsatira zake zikusonyeza kuti chizindikiro cha opioid ndi cannabinoid receptor zimasiyanasiyana mosiyana ndi kufotokozera ΔFosB, ndipo zimasonyeza kuti ΔFosB imatulutsa zotsatira zake kudzera mu chizindikiro cha mu kapu ndi kappa opioid receptor mu NAC.

Keywords: G-mapuloteni, adenylyl cyclase, striatum
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1. Introduction

Opioid receptors ndi CB Cannabinoid1 receptors (CB1R) ndizomwe zimagwiritsidwa ntchito pa njira za mankhwala zomwe zimagwiritsidwa ntchito kwambiri kuphatikizapo morphine, heroin ndi mankhwala opioid, ndi marijuana (Δ9-tetrahydrocannabinol (THC)), motero. Zotsatira zoopsa za opioid ndi mankhwala osokoneza bongo zimayanjanitsidwa ndi mapuloteni a G-mapuloteni omwe amachititsa makamaka Gi / o mapuloteni ndi kutulutsa mayankho otsika m'munsimu monga kuletsa adenylyl cyclase (Amayi, 1991, Childers, et al., 1992, Howlett, et al., 2002). Zovuta, kukumbukira kukumbukira ndi zotsatira za psychoactive za Δ9-TC zimapangidwa ndi CB1R (Huestis, et al., 2001, Zimmer, et al., 1999), zomwe zimagawidwa kwambiri mu ubongo, ndipo zimakhala zovuta kwambiri m'magulu a basal, hippocampus ndi cerebellum (Herkenham, et al., 1991). Zotsatira zowonongeka ndi zopindulitsa za mankhwala ambiri okhudzana ndi opioid ogwiritsidwa ntchito komanso ogwiritsidwa ntchito molakwika amatsutsana kwambiri ndi opioid receptors (MOR) (Matthes, et al., 1996), zomwe zimapangidwira mu limbic system ndi ubongo (Mansour, et al., 1994). Masolimbic, omwe amapangidwa ndi dopaminergic kuchokera ku ventral tegmental area (VTA) mpaka nucleus accumbens (NAc), amathandiza kwambiri pampindulitsa ya opioid ndi mankhwala ophera tizilombo (Bozarth ndi Wanzeru, 1984, Vaccarino, et al., 1985, Zangen, et al., 2006), komanso mankhwala ena osokoneza bongo (Koob ndi Volkow, 2010). Kuwonjezera pamenepo, machitidwe oopsa a opioid ndi cannabinoid amaphatikizapo zotsatira zabwino za magulu angapo a mankhwala osokoneza bongo (Maldonado, et al., 2006, Trigo, et al., 2010). Choncho, ndikofunikira kufotokozera njira zomwe opioid ndi CB1Zisonyezero zimayikidwa mu NAC.

Funso lofunika kwambiri m'munda wogwiritsira ntchito mankhwala osokoneza bongo ndilokutulukira mapuloteni omwe amachititsa kuti pakhale kusintha kwa mankhwala osokoneza bongo. Chinthu cha AP-1 cholembera ΔFosB chiri chochititsa chidwi makamaka chifukwa ndizosiyana kwambiri ndi zinthu zina zomwe zimapangidwa ndi foswe jini lomwe limaphatikizapo pobwereza mobwerezabwereza ku mankhwala osokoneza bongo kapena madalitso achilengedwe (McClung, et al., 2004, Nestler, 2008, Nestler, et al., 1999). Tapeza kuti ΔFosB imapangidwira mu ubongo akutsata mobwerezabwereza ku morphine, Δ9-CC, cocaine kapena ethanol, ndi mankhwala aliwonse omwe amapanga gawo lapadera la DFFB (Perrotti, et al., 2008). Kupeza mankhwala mosagwirizana kunali kuti ΔFosB inkapangidwira kwambiri mu striatum, kumene mankhwala onse anayi adayambitsa ΔFosB mu core NAC ndi onse kupatula Δ9-TC inachititsa chidwi kwambiri ku NAC shell ndi caudate-putamen.

Maphunziro a zachipatala anasonyeza kuti co-administration ya dopamine D1 receptor (D1R) Wotsutsa SCH 23390 analetsa ΔFosB kulowetsa mu NAC ndi caudate-putamen pambuyo pa cocaine kapena administration morphine, posonyeza kufunika kwa D1R-kufotokoza neurons (Muller ndi Unterwald, 2005, Nye, et al., 1995). Zotsatira za ΔFosB zokhudzana ndi khalidwe la mankhwala osokoneza bongo zafufuzidwa pogwiritsa ntchito mbewa za bitransgenic zomwe zimalongosola FFB m'madera enaake a nec ndi dorsal striatum (Chen, et al., 1998). Nkhumba zomwe zimafotokoza DFBB mu dynorphin / D1R positive neurons mu NAc ndi dorsal striatum (mzere 11A) amasonyeza mayankho omwe asinthidwa ku mankhwala osokoneza bongo, makamaka kuwonjezereka kwa mphamvu za cocaine kapena morphine (Colby, et al., 2003, Kelz, et al., 1999, Zachariou, et al., 2006). Kusintha kumeneku kunachitika pokhapokha kusintha kwa magawo a MOR kapena magulu ang'onoang'ono a mapuloteni a G. Komabe, miyendo ya dynorphin mRNA inachepetsedwa mu NAC ya ΔFosB yosonyeza mbewa (Zachariou, et al., 2006), kuwonetsa kuti chilolezo chimodzi cha ΔFosB ndi jini yomwe ikukumana ndi peptide yodalirika ya opioid. DFBB induction ingapangitsenso kusintha kwa khalidwe pakulamulira chizindikiro cha receptor mu NAC, koma izi sizinayambe kufufuzidwa. Choncho, kafukufukuyu akugwiritsa ntchito chitsanzo cha bitransgenic mouse kuti adziwe ngati kudandaula kwakukulu kwa ΔFosB mu dynorphin / D1R yomwe ili ndi ntchentche zowonongeka zimasintha zochita za G-mediated G-mapuloteni ndi kuyankhulana kwa EC-KOR ndi adorlyl cyclase mu NAC. Zotsatira za ΔFosB pa CB1Ntchito yowonjezeredwa ya G-R inayesedwanso chifukwa Δ9-TC maofesi amachititsa kuti ΔFosB mu NAc (Perrotti, et al., 2008) ndipo dongosolo la endocannabinoid limadziwika kuti lizilamulira ma circuits a mphotho za ubongo (Gardner, 2005, Maldonado, et al., 2006), koma zotsatira za ΔFosB pa dongosolo la endocannabinoid sizinafufuzidwe.

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2. Zida ndi njira

2.1. Reagents

[35S] GTPγS (1250 Ci / mmol), [α-32P] ATP (800 Ci / mmol) ndi [3H ]AMP (26.4 Ci / mmol) anagulidwa ku PerkinElmer (Shelton, CT). ATP, GTP, GDP, CAMP, serum albumin, creatine phosphokinase, papaverine, imidazole ndi WIN-55212-2, anagulidwa ku Sigma Aldrich (St. Louis, MO). GTPγS idagulidwa kuchokera ku Roche Diagnostic Corporation (Chicago, IL). DAMGO inaperekedwa ndi Drug Supply Program ya National Institute on Drug Abuse (Rockville, MD). Econo-1 scintillation madzi amapezeka kuchokera ku Fisher Scientific (Norcross, GA). Ecolite scintillation fluid inapezedwa ku ICN (Costa Mesa, CA). Mankhwala ena onse anapezeka ku Sigma Aldrich kapena Fisher Scientific.

2.2. Mphungu

Manyowa a bitransgenic omwe amachokera ku NSE-tTA (mzere A) × TetOp-ΔFosB (mzere 11) anapangidwa monga momwe anafotokozera ku Kelz et al. (Kelz, et al., 1999). Nthata za Bitransgenic zinalengedwa ndipo zinakulira pa doxycycline (100 μg m'madzi akumwa) kuti zisawononge machitidwe olakwika. Pa masabata a 8, doxycycline imasiyidwa m'madzi kwa theka la mbewa kuti alolere kulankhula, pamene mbewa zotsalira zinasungidwa pa doxycycline kuti zisawonongeke. Masabata anasonkhanitsidwa masabata a 8 pambuyo pake, nthawi yomwe zotsatira zapasitomu za ΔFosB zimakhala zazikulu (McClung ndi Nestler, 2003). Mzere wachiwiri wamagulu wathanzi unagwiritsidwa ntchito momwe Dc-Juni, wotsutsa wamkulu wa c-Jun, akufotokozedwa mu D1R / dynorphin ndi D2R / enkephalin maselo a striatum, hippocampus ndi parietal cortex (Peakman, et al., 2003). C-Jun ndi mapuloteni ena a banja la Jun amachepetsa mapuloteni amtundu wa Fos ndipo amamanga malo a AP-1 omwe amawunikira kuti asinthe. Komabe, truncation ya N-terminus ya c-Jun (Δc-Jun) imachititsa kuti zovutazo zisamayende bwino ndipo zimatha kulepheretsa DNA kumangiriza maofesi akhama AP-1. Manyowa a bitransgenic omwe amachokera ku NSE-tTA (mzere A) × TetOp-FLAG-Δc-Jun (mzere E) anapangidwa monga momwe tafotokozera ku Peakman et al. (Peakman, et al., 2003). Nthata za Bitransgenic zinalengedwa ndipo zinakulira pa doxycycline (100 μg m'madzi akumwa) kuti zisawononge machitidwe olakwika. Mafupa adayamwa kuyamwa kwa masabata a 3, ophatikizana, ndi ogawidwa m'magulu, ndi theka kusungidwa pa madzi otchedwa doxycycline ndi theka pa madzi osamwa nthawi zonse kuti apangitse mawu a FLAG-Δc-Jun. Maubongo amasonkhanitsidwa masabata a 6 pambuyo pake, nthawi yomwe miyeso yambiri ya FLAG-Δc-Jun yayesedwa (Peakman, et al., 2003). Njira zonse zinyama zinkachitidwa motsatira ndondomeko ya National Health Institute for Care and Use of Animals Animals.

2.3. Kukonzekera kwa Membrane

Ubongo unasungidwa pa -80 ° C mpaka tsiku la yesero. Asanayese, ubongo uliwonse unasungunuka, ndipo NAc inagawidwa pa ayezi. Chitsanzo chilichonse chinali chofanana ndi 50 mM Tris-HCl, 3 mM MgCl2, 1 mM EGTA, pH 7.4 (membrane buffer) ndi zilonda za 20 kuchokera ku homogenizer ya galasi pa 4 ° C. The homogenate anali centrifuged ku 48,000 × g pa 4 ° C kwa 10 min, yatsitsidwanso mu membrane buffer, centrifuged kachiwiri pa 48,000 × g pa 4 ° C kwa 10 min ndipo adatsitsidwanso mu 50 mM Tris-HCl, 3 mM MgCl2, 0.2 mM EGTA, 100 mM NaCl, pH 7.4 (kugwiritsira ntchito mankhwala). Mapuloteni amadziwika ndi njira ya Bradford (Bradford, 1976) pogwiritsira ntchito serum albumin (BSA) monga muyezo.

2.4. Zovuta35S] GTPγS Kubweza

Zilondazi zinayambitsidwa kutsogolo kwa 10 Mphindi pa 30 ° C ndi adenosine deaminase (3 mU / ml) muzitsulo zowonongeka. Nkhumba (5-10 μg mapuloteni) zinakonzedwa chifukwa cha 2 hr pa 30 ° C mu chikhomo chokhala ndi 0.1% (w / v) BSA, 0.1 nM [35S] GTPγS, 30 μM GDP ndi adenosine deaminase (3 mU / ml) ndi popanda zoyenera za DAMGO kapena WIN55,212-2. Kumanga kosayenera kunayesedwa ndi 20 μM GTPγS. Mafakitalewa anachotsedwa ndi kusungunuka kudzera mu fereji ya galasi ya GF / B, kenako kutsuka kwa 3 ndi 3 ml ozizira 50 mM Tris-HCl, pH 7.4. Kusweka kwa radioactivity kunatsimikiziridwa ndi scintillation spectrophotometry yamadzimadzi pambuyo panthawi yonse yazitsulo mu Econo-1 scintillation madzi.

2.5. Adenylyl Cyclase Assay

Nkhumba (5-25 μg mapuloteni) zidakonzedweratu ndi adenosine deaminase monga tafotokozera pamwambapa, ndipo zimayambitsidwa ndi 15 min pa 30 ° C pamaso kapena kupezeka kwa 1μM forskolin, popanda DAMGO, U50,488H kapena WIN55,212-2, 50 μM ATP, [α-32P] ATP (1.5 μCi), 0.2 mM DTT, 0.1% (w / v) BSA, 50 μM AMP, 50 μM GTP, 0.2 mM papaverine, 5 mM phosphocreatine, 20 magawo / ml creat phosphokinase ndi adenosine deaminase (3 mU / ml) pamapeto omaliza a 100 μl. Pansi pa zinthu izi, chiwerengero cha [α-32P] cAMP yowonongeka kawirikawiri inali yochepa kuposa 1% ya chiwerengero chawonjezeka [α-32P] ATP mu chitsanzo chilichonse. Zotsatirazo zinathetsedwa potentha kwa 3 min ndi [32P] Chipangizo cha AMP chinasankhidwa ndi njira ya Salomo (Dowex ndi alumina)Salomon, 1979). [3H] cAMP (10,000 dpm) inawonjezeredwa ku chubu lililonse pasanayambe chithunzi cha chromatographie monga choyendera chamkati. Mauthengawa anali otsimikiziridwa ndi scrollation spectrophotometry (45% yogwira ntchito 3H) Pambuyo pa 4.5 ml ya mcherewu inasungunuka mu 14.5 ml wa Ecolite scintillation fluid.

2.6. Kusanthula deta

Pokhapokha ngati tawonetsedwa kwina, deta imatchulidwa kuti ndiyeso yamtengo wapatali ± SE ya 4-8 yoyezetsa zosiyana, iliyonse yomwe inkachitidwa katatu. Zosokonezedwa ndi Net [35S] GTPγs kumanga amawerengedwa monga agonist-stimulated kumangiriza osus basal kumanga. Ntchito ya forskolin yomwe imalimbikitsa ntchito ya adenylyl cyclase imatanthauzidwa ngati ntchito ya forskolin - ntchito yosambira (pmol / mg / min). Kuletsa kwa peresenti ya ntchito ya forskolin yomwe imalimbikitsa ntchito ya adenylyl cyclase imatanthawuza kuti (ntchito yosakanikirana ndi forskolin yopanda ntchito ya agonist - net forskolin yomwe inachititsa chidwi poyang'ana ntchito ya agonist / net forskolin yomwe inachititsa chidwi ngati palibe agonist) × 100. Kufufuza konse koyenera ndi zowerengetsera kunkachitika pogwiritsa ntchito Prism 4.0c (GraphPad Software, Inc., San Diego, CA). Zokakamiza zowonongeka zinkasanthuledwa ndi kusintha kwachinthu chosagwirizana ndi malamulo kuti apeze EC50 ndi EMax mfundo. Chiwerengero cha chiwerengero cha deta-yosokoneza deta chinatsimikiziridwa ndi kusintha kwa njira ziwiri (ANOVA), pogwiritsira ntchito mlingo wa agonist ndi majekeseni (kapena kuchoka) monga zinthu zazikulu. Chiwerengero cha chiwerengero cha miyezo yoyenera kupindika (EMax kapena EC50) idatsimikiziridwa ndi mayeso a Wophunzira awiri-tailed awiri, pogwiritsa ntchito kuwongolera kwa Welch kapena kusintha kwa mizere yayikulu pomwe kuli kofunikira kukonza kusiyanasiyana (kopezeka ndi F-mayeso) ku EC50 Miyezo.

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3. Zotsatira

3.1. Zotsatira za ΔFosB kutchulidwa pa ntchito yowonjezeretsa G-mapuloteni opioid ndi cannabinoid

Kuti mudziwe ngati MOR- kapena CB1Kukonzekera kwa mapuloteni a G-R kunasinthidwa ndi kufotokozera mwachidule maonekedwe a ΔFosB mu NAC, okonzedwa ndi agonist [35S] GTPγs yokakamiza inayesedwa m'magulu ang'onoang'ono okonzedwa kuchokera kudera lino la mbewa za bitransgenic zomwe zikufotokozera (ΔFosB pa) kapena kusonyeza (ΔFosB kuchoka) dala la ΔFosB. The MOR-selective enkephalin analog DAMGO idagwiritsidwa ntchito popangitsa MOR ndi aminoalkylindole WIN55,212-2 inagwiritsidwa ntchito poyambitsa CB1R. Izi zimagwiritsidwa ntchito kale kuti zikhale zodzaza ndi agonist ku MOR ndi CB1R, mofanana (Breivogel, et al., 1998, Selley, et al., 1997). Sizinali zotheka kukayezetsa ntchito ya mapuloteni a G-mediation chifukwa cha chizindikiro cha ubongo kwambiri.Childers, et al., 1998). Zotsatira zimasonyeza kukondweretsa kwambiri kwa G-mapuloteni ntchito ndi DAMGO ndi WIN55,122-2 ku NAc kuchokera kuFFBB ndi ΔFosB pa mbewa (Chithunzi 1). Ntchito yothandizira DAMGO (Chithunzi 1A), njira ziwiri za ANOVA za zomwe zimachitika chifukwa cha ndende zimawulula zazikuluzikulu za ΔFosB (p <0.0001, F = 22.12, df = 1) ndi ndende ya DAMGO (p <0.0001, F = 29.65, df = 5) yopanda kulumikizana kwakukulu (p = 0.857, F = 0.387, df = 5). Kusanthula kosasunthika kwamakina azomwe zinawonetsa kuti DAMGO E ndi wamkuluMax gwiritsani ntchito ΔFosB pa mbewa (EMax = 73 ± 5.2% kukakamiza) poyerekezera ndiFFobu kuchotsa mbewa (EMax = 56 ± 4.1% kukondoweza; p <0.05 yosiyana ndi osBFosB pa mbewa ndi mayeso a Ophunzira). DAMGO EC50 Makhalidwe sanali osiyana pakati pa ΔFosB ndi ΔFosB kusiya mbewa (302 ± 72 nM kutsutsana ndi 212 ± 56 nM, motero, p = 0.346).

Chithunzi 1 

Zotsatira za kufotokoza kwaFosB pa agonist-kunalimbikitsa [35S] GTPγs imangiriza mu NAC. Nsonga kuchokera ku DFFB-kufotokoza (ΔFosB pa) kapena kulamulira (ΔFosB kuchoka) mbewa zinayesedwa monga momwe zifotokozedwera mu Njira pogwiritsa ntchito malo osiyanasiyana ...

Mosiyana ndi zotsatira zomwe zimapezeka ndi MOR agonist DAMGO, palibe kusiyana kwa DFF komwe kunkapezeka pa G-mapuloteni owonetserako anawonedwa ndi agnist WonxNUMX-55,212 (Chithunzi 1B). ANOVA wa njira ziwiri za data ya WIN55,212-2 yokhudzidwa ndi ziwonetsero zinawunikira chidwi chachikulu cha ndende ya WIN55,212-2 (p <0.0001, F = 112.4, df = 7), koma osati ya osBFosB (p = 0.172 , F = 1.90, df = 1) ndipo panalibe kulumikizana (p = 0.930, F = 0.346, df = 7). Mofananamo, panalibe zotsatira za osBFosB pa WIN55,212-2 EMax Malingaliro (103 ± 6% motsutsana ndi 108 ± 8% kusonkhezeredwa mu DFB ndi kuchotsa mbewa, motsatira, p = 0.813 ndi mayeso a Ophunzira) kapena EC50 Zokwanira (103 ± 20 nM motsutsana XUMUM ± 170 nM mu DFB ndi kuchotsa mbewa, motsatira, p = 23).

Malingana ndi mawonekedwe a ma curves ndi kuti maphunziro athu akale asonyeza biphasic WIN55,212-2--making'onoting'ono amakutu mu ubongo (Breivogel, et al., 1999, Breivogel, et al., 1998), ma curve a WIN55,212-2 adagwiritsidwanso ntchito pogwiritsa ntchito malo awiri. Kufufuza kwa chiwerengero chowonetseratu chinawonetsa kusintha pang'ono kwa ubwino woyenera pogwiritsa ntchito njira ziwiri (R2 = 0.933 ndi 0.914, malo ambiri = 3644 ndi 5463 mu ΔFosB pang'onopang'ono ndi makoswe, motsatira) poyerekezera ndi malo amodzi (R2 = 0.891 ndi 0.879, malo ambiri = 6561 ndi 6628 mu ΔFosB pang'onopang'ono ndi makoswe, motsatira). Komabe, palibe kusiyana kwakukulu komwe kunapezeka pakati pa ΔFosB ndi kuchotsa mbewa mu EMax kapena EC50 Zotsatira za malo otsika kapena otsika (potency sites)Table Supplementary 1), ngakhale kuti panali chikhalidwe chakumsika kwa EC50 Gwiritsani ntchito malo okwezeka a potency mu makoswe ndi ΔFosB pa (EC50mkulu = 28.0 ± 10.6 nM) poyerekeza ndi omwe ali ndi FosB (EC50mkulu = 71.5 ± 20.2 nM; p = 0.094). Komanso, panalibe zotsatira za deta yaFFBB pa basal [35S] GTPγs imamangiriza mu ziwalo za NAc (XUMUM ± 253 poyerekeza ndi XUMUM ± 14 fmol / mg mu ΔFosB pambali ndi pamphuno, potsatira, p = 226). Deta imeneyi ikuwonetsa kuti mawu osokoneza bongo a FFBB mu NAC ya mbewa adachulukitsanso ntchito ya G-mapuloteni osakaniza popanda kusintha CB1Ntchito yothandizidwa ndi G-mediated kapena yochepa.

3.2. Zotsatira za ΔFosB pa katemera wa opioid ndi cannabinoid ovomerezedwa ndi adeclyse cyclase

Kufufuza zotsatira za kutanthauzira kwachidziwitso cha DFF pa zochitika za m'munsi zochitika ndi MOR ndi CB1R, kulephera kwa 1 μM forskolin-yolimbikitsidwa ntchito ya adenylyl cyclase inayesedwa mu chipinda cha NAc. Kuwonjezera pa MOR- ndi CB1Kuwonetseratu njira yothandizira ntchito ya adenylyl cyclase, zotsatira za ntchito ya KOR zinayambanso kuwonedwa pogwiritsira ntchito KON-agonist full U50,488 (Zhu, et al., 1997), chifukwa zotsatira zammbuyo zasonyeza kuti dynorphin mRNA inali cholinga cha ΔFosB muchitsanzo cha bitransgenic (Zachariou, et al., 2006). Zotsatira zinawonetsa kuti DAMGO, U50,488 ndi WIN55,212-2 zimapanga ndondomeko yotetezeka ya ntchito ya adenylyl cyclase onse ΔFosB ndi ΔFosB pa mbewa (Chithunzi 2). Njira ziwiri za ANOVA za damgo-effect data effect (Chithunzi 2A) adawulula zotsatira zazikulu za ΔFosB (p = 0.0012, F = 11.34, df = 1) ndi ndende ya DAMGO (p <0.0001, F = 29.61, df = 6), koma palibe kulumikizana kwakukulu (p = 0.441, F = 0.986 , df = 6). Kusanthula kosasintha kwa ma DAMGO ma curve-effect curves kuwulula kutsika kwambiri kwa DAMGO EC50 mtengo mu osBFosB pa mbewa (101 ± 11 nM) poyerekeza ndi ΔFosB mbewa (510 ± 182 nM, p <0.05 ndi mayeso a ophunzira). Komabe, panalibe kusiyana kwakukulu mu DAMGO EMax Malingaliro (20.9 ± 1.26% poyerekeza ndi 19.8 ± 1.27% kulepheretsa mu DFB ndi kuchotsa mbewa, motsatira, p = 0.534).

Chithunzi 2 

Zotsatira za ΔFosB kuwonetsera katetezedwe ka ntchito ya adenylyl cyclase ku NAc. Zilonda za DFBB-kufotokoza (ΔFosB pa) kapena kulamulira (ΔFosB kuchoka) mbewa zinayesedwa monga momwe zifotokozedwera mu Njira pamaso pa 1 μM ...

KOR-mediated adenylyl cyclase inhibition imasiyananso monga ntchito ya inducible kufotokozera mwachidule ya ΔFosB (Chithunzi 2B). ANOVA ya njira ziwiri za U50,488 yokhudzidwa ndi ziwonetsero zidawonetsa zotsatira zazikulu za ΔFosB (p = 0.0006, F = 14.53, df = 1) ndi ndende ya U50,488 (p <0.0001, F = 26.48, df = 3) , popanda kulumikizana kwakukulu (p = 0.833, F = 0.289, df = 3). Kusanthula kosasunthika kwamakina azomwe zimachitika pamavumbula U50,488 EMax kufunika kwa osBFosB pa mbewa (18.3 ± 1.14% choletsa) poyerekeza ndi ΔFosB mbewa (12.5 ± 2.03% choletsa; p <0.05 yosiyana ndi osBFosB yoyesedwa ndi Student's t-test), popanda kusiyana kwakukulu mu U50,488 EC50 Zokwanira (310 ± 172 nM motsutsana XUMUM ± 225 nM mu DFB ndi kuchotsa mbewa, motsatira, p = 48).

Mosiyana ndi zotsatira zomwe zinapangidwa ndi MOR ndi KOR, panalibe zotsatira zochititsa chidwi za kutanthauzira mawu a DFFB pofuna kulepheretsa adenylyl cyclase ndi agnist antioxidant WIN55212-2 (Chithunzi 2C). ANOVA ya njira ziwiri za WIN55,212-2 zomwe zimapangitsa kuti anthu azigwiritsa ntchito mankhwala osokoneza bongo (p <0.0001, F = 23.6, df = 2), koma osati ΔFosB (p = 0.735, F = 0.118, df = 1) ndipo panalibe kulumikizana kwakukulu (p = 0.714, F = 0.343, df = 2). Komanso, panalibe zotsatira za ΔFosB pa basal kapena forskolin-stimulated adenylyl cyclase ntchito popanda agonist aliyense. Zochita za adenylyl cyclase zinali 491 ± 35 pmol / mg / min mu ΔFosB pa mbewa poyerekeza ndi 546 ± 44 mu ΔFosB mbewa (p = 0.346 ndi Student's t-test). Momwemonso, ntchito ya adenylyl cyclase pamaso pa 1 µM forskolin inali 2244 ± 163 pmol / mg / min mu ΔFosB pa mbewa motsutsana ndi 2372 ± 138 pmol / mg / min mu osBFosB kuchokera mbewa (p = 0.555).

3.3. Zotsatira za ΔcJun pazitsulo za opioid ndi cannabinoid zothandizira odwala adenylyl cyclase

Chifukwa chakuti inducible mawu osagwiritsidwa ntchito a ΔFosB opititsa patsogolo kutsegulidwa kwa chizindikiro kuchokera ku MOR ndi KOR kupita ku adenylyl cyclase ku NAc, zinali zosangalatsa kudziwa ngati chodetsa chosokoneza choipa cha ΔFosB-mediated transcription chingayese chizindikiro cha opioid receptor m'njira yosiyana. Kuti athetse funsoli, kulepheretsa ntchito ya forskolin yomwe inachititsa kuti adenylyl cyclase ntchito ndi DAMGO ndi U50,488 ifufuzidwe m'magulu opangidwa kuchokera ku NAC a bitransgenic mbewa posonyeza kuti ΔcJun. Zotsatirazo sizinapangitse zotsatira zapadera za mawu a DJun pa kulepheretsa ntchito ya adenylyl cyclase ndi MOR kapena KOR (Chithunzi 3). ANOVA wa njira ziwiri za DAMGO zokhotakhota-zowoneka bwino zidawonetsa kukhudzidwa kwakukulu kwa ndende ya DAMGO (p <0.0001, F = 20.26, df = 6), koma osati ya JcJun udindo (p = 0.840, F = 0.041, df = 1) ndipo panalibe kulumikizana kwakukulu (p = 0.982, F = 0.176, df = 6). Mofananamo, panalibe kusiyana kwakukulu mu EMax kapena EC50 Miyeso pakati pa mbewa ndi ΔcJun pa (EMax = 23.6 ± 2.6%; EC50 = 304 ± 43 nM) kapena ΔcJun off (EMax = 26.1 ± 2.5%, p = 0.508; EC50 = 611 ± 176 nM, p = 0.129). Zotsatira zofananira zidawonedwa ndi U50,488, kotero kuti ANOVA wa njira ziwiri zama curve-effect curves adawonetsa chidwi chachikulu (p <0.0001, F = 11.94, df = 6), koma osati ΔcJun status (p = 0.127 , F = 2.391, df = 1) ndipo panalibe kulumikizana kwakukulu (p = 0.978, F = 0.190, df = 6). Momwemonso, panalibe kusiyana kwakukulu mu EMax kapena EC50 Miyeso pakati pa mbewa ndi ΔcJun pa (EMax = 14.8 ± 2.9%; EC50 = 211 ± 81 nM) kapena kuchoka (EMax = 16.7 ± 1.8%, p = 0.597; EC50 = 360 ± 151 nM, p = 0.411).

Chithunzi 3 

Zotsatira za ΔcJun kuwonetsetsa ntchito ya adenylyl cyclase ku NAc. Nkhumba za DC (zizindikiro za DC) zowonongeka (ΔcJun pa) zitsamba zinayambidwa pamaso pa DAMGO (A), U50,488H (B) kapena WIN55,212-2 ...

Kufotokozera kwa JcJun sikunakhudzenso kwambiri kuletsa kwa adenylyl cyclase mu NAc ndi cannabinoid agonist. ANOVA wa njira ziwiri za WIN55,212-2 curveffect curves adawonetsa chidwi chachikulu cha ndende ya WIN55,212-2 (p <0.0001, F = 15.53, df = 6), koma osati ya genotype (p = 0.066, F = 3.472, df = 1) ndipo panalibe kulumikizana kwakukulu (p = 0.973, F = 0.208, df = 6). Momwemonso, panalibe kusiyana kwakukulu mu WIN55,212-2 EMax Zokwanira (13.0 ± 2.3% ndi 13.6 ± 0.9% zowonongeka muZomwe zikugwirizana ndi mbewa, motsatira, p = 0.821) kapena EC50 Malingaliro (208 ± 120 nM ndi 417 ± 130 nM m'Chipangizo chogwirizana ndi mbewa, potsatira, p = 0.270). Choncho, ngakhale kuti panalibe njira yochepa yochepetsera mphamvu ya WIN55,212-2 m'magulu akufotokoza ΔcJun, kulakwitsa kumeneku sikunasinthe kwambiri njira yothetsera adenylyl cyclase. Komanso, panalibe zotsatira za udindo wa Δcun pa ntchito ya basal kapena ya forskolin yomwe inachititsa kuti adenylyl cyclase ntchito. Ntchito yamagulu ya adenylyl cyclase inali 1095 ± 71 pmol / mg / min ndi 1007 ± 77 pmol / mg / min (p = 0.403) m'magulu okhala ndi DJun kapena pamtunda. Ntchito ya Adenylyl cyclase yomwe inachititsa kuti 1 μM forskolin ikhale 4185 ± 293 pmol / mg / min ndi 4032 ± 273 pmol / mg / min (p = 0.706) m'magulu omwe ali ndi DCun kapena pamtunda.

3.4. Kukambirana

Zotsatira za kafukufukuyu zinavumbulutsira kupititsa patsogolo kwa mapuloteni a MOR-mediated G-protein ndi kulepheretsa adenylyl cyclase mu NAc ya mbewa zomwe zimatulutsa mawu osasuliridwa a ΔFosB mu dynorphin / D1R yomwe ili ndi neurons. Chinthu choletsedwa cha KOR cha ntchito ya adenylyl cyclase chinathandizidwanso mu NAC ya ΔFosB yosonyeza mbewa, zomwe zikusonyeza kuti ΔFosB imayendetsa dongosolo la opioid yodalirika mu NAC. DAMGO EMax Mtengo unali waukulu kwa MOR-wowonjezera [35S] GTPγs imamanga, ndi EC yake50 Mtengo unali wotsikira kwa adenylyl cyclase inhibition, mu ΔFosB pamwamba-kufotokoza mbewa poyerekeza ndi makoswe olamulira. Zofukufukuzi zikusonyeza kuti mungathe kupeza malo osungiramo mapulogalamu kuti musamawononge mavitamini koma osati G-mapuloteni owonetsetsa pansi pa zovuta zomwe zimayesedwa. Kafukufuku amene anapeza kuti KOR agonist inachititsa kuti KOR agonist iwonongeke kwambiri chifukwa cha mafotokozedwe a ΔFosB.Unterwald, et al., 1991). Mosiyana, CB1Ntchito yowonjezeretsa ya G-R komanso kulepheretsa adenylyl cyclase kusakhudzidwa ndi kufotokoza kwaFosB, kutanthauza kuti ma opioid ndi maynabinoid machitidwe amasiyana poyankhidwa ndi ΔFosB mu NAC neurons.

Zotsatira za ΔFosB pa chizindikiro cha opioid receptor-mediated zikugwirizana ndi lipoti lathu lapitalo kuti ΔFosB mawu mu statum anasinthidwa kwambiri ndi zotsatira zopweteka za morphine (Zachariou, et al., 2006). Chimodzi mwa zomwe anapeza pa phunziroli chinali mbewa zomwe zimagwiritsa ntchito ΔFosB mu dynorphin / D1Mitsempha yowonongeka inali yowopsya kwambiri ku morphine m'malo mwa chikhalidwe kusiyana ndi kulamulira. Komanso, zotsatirazi zinayesedwa ndi mafotokozedwe apadera a ΔFosB ndi jekeseni yeniyeni mu NAC. Zomwe zikuwonetseratu zikugwirizana ndi zotsatira zomwe zikuwonetseratu kupititsa patsogolo kwa MOR ku NAC.

Tinazindikiranso kale kuti jini limasintha Dynorphin ngati cholinga cha ΔFosB, ndipo akuganiza kuti kuchepa kwa dynorphin kungakhale kofanana ndi zomwe zimapindula kwambiri ndi morphine mu ΔFosB bitransgenic mbewa (Zachariou, et al., 2006). Zotsatira zamakono zikuwonetsa kuti kulephera kwa KOR kwa adenylyl cyclase mu NAc kumapangidwira mu ΔFosB kufotokoza mbewa, zomwe zingasonyeze kuwonjezereka kwapomveka kwa KOR mphamvu zowonongeka dynorphin. Kafukufuku wakale asonyeza kuti KOR inalembedwa m'madera ena a ubongo a prodynorphin kugwedeza mbewa, kuphatikizapo NAc (Clarke, et al., 2003).

Mosiyana ndi ΔFosB, kutchulidwa kosavuta kwa mawu a ΔcJun, mutant osasunthika pamtundu wa ΔFosB womanga bwenzi cJun, sanasinthe adenylyl cyclase kulepheretsedwa ndi MOR kapena KOR agonists. Zotsatira izi zimasonyeza kuti ma basal of expression ΔFosB, omwe ali otsika kwambiri, samathandiza kwambiri kusunga chizindikiro cha opioid receptor pa mlingo uwu wa kusinthidwa kwa chizindikiro mu NAc. Chowona kuti zotsatira zabwino zopindulitsa za morphine zinachepetsedwa ndi kufotokoza kwaAcJun mu phunziro lathu lapitalo (Zachariou, et al., 2006) zimasonyeza kuti morphine inductions ya ΔFosB panthawi yomwe imakhala yofunika kwambiri pakuyendetsa mayankho a khalidwe kwa mankhwala kapena kuti kusintha kwa mankhwala a ΔFosB kupatulapo omwe amachititsa kuti opioid receptors aziwonetsa mopitirira malire angapangitse mphoto ya opioid. Mulimonsemo, zotsatira za phunziroli zikuwonetseratu kuti, pamene kufotokoza kwaFFB kukukweza pamwamba pa msinkhu wa dalorphin / D1R-kufotokoza neurons, kuwonjezeka kwakukulu mu kulumikizana kwa MOR ndi KOR kuti chiwonetsero cha adenylyl cyclase mu NAc.

Njira zomwe MOR- ndi KOR-zisonyezeranako zowonjezera zimakonzedwa ndi kufotokoza kwaFosB mosadziwika bwino, koma takhala tikuwonetsa kuti mazinga a MOR, akuyesedwa ndi [3H] naloxone kumangiriza, si yosiyana ndi NAc ya ΔFosB potsutsana ndi mbewa (Zachariou, et al., 2006). Phunziro lomwelo linapeza kuti GαiZida za 1 ndi 2 sizidakhudzidwe kudera lino ndi kufotokoza kwaFosB. Komabe, kafukufuku wam'mbuyomu wakale anasonyeza kuti Gαo MRNA inalembedwa mu NAC ya ΔFosB pa mbewa (McClung ndi Nestler, 2003). Zidzakhala zosangalatsa m'zochitika zamtsogolo kuti ziwone bwinobwino zotsatira za mafotokozedwe a DFFB omwe amapezeka pa G-protein subunit expression pa mapuloteni komanso momwe mavitamini ambiri amathandizira mapuloteni.

N'zochititsa chidwi kuti kufotokoza kwaFFB sikunapangitse CB1Kuwonetseratu pakati pa R ndi NAc. N'zotheka kuti kusintha kwa CB1Kuwonekera kumachitika m'madera osiyanasiyana a neurons omwe amavomereza mu NAC yonse yokonzekera. Mwachitsanzo, kuyang'anira Δ9- THC inachititsa kwambiri ΔFosB pachimake, koma osati chipolopolo, cha NAc (Perrotti, et al., 2008). IneNdakhala ndikukumana ndi mavuto, ndipo ndawonetsa kuti vutoli ndi D9-TC ikutsatiridwa mobwerezabwereza Δ9-CC yowonjezera dopamine kumasulidwa mu NAC core, koma inachepa kumasulidwa mu chipolopolo (Cadoni, et al., 2008). Ndikofunika kudziwa kuti mzere wa 11A wa mbewa za bitransgenic umaonetsa DFFB basi mu dynorphin / D1R zabwino zowonongeka zamatenda a striatum, koma CB1R amasonyezedwa mu zonse dynorphin / D1R ndi enkephalin / D2R nthenda zopweteka (Hohmann ndi Herkenham, 2000), komanso kumapeto kwa magulu a cortical (Robbe, et al., 2001). Kufotokozera kwasintha kwapadera kwa ΔFosB-kulembedwa kwapakati, ΔcJun, sikudakhalanso ndi zotsatira zowonetsera chizindikiro chodziwika bwino, ngakhale kuti ΔcJun inducibly inafotokozedwa mwa onse awiri D1 ndi D2-kukhala ndi anthu a zinyontho zamphongo zofiira m'magulu awa (Peakman, et al., 2003). N'zotheka, komabe, kuti mawu ochepa a ΔFosB ali okwanira kwambiri kuti ΔcJun sangawononge chizindikiro cha receptor, monga momwe zanenedwa ndi zotsatira ndi MOR ndi KOR. N'zotheka kuti CB1Kuzindikiritsa kumakhala kosavuta ndi mawu ochepa a ΔFosB, omwe akuwonjezeka kwambiri ΔFosB kutanthauzira kapena kutseka zochita zake ndi ΔcJun anali ndi zotsatira zochepa chabe zomwe sizinafikire chiwerengero cha chiwerengero. Thandizo losavomerezeka la kutanthauzira uku likhoza kuwonetsedwa poyerekeza WIN55,212-2 EC50 Makhalidwe abwino pakati pa mbewa zosonyeza DNA ndi DFF. Chiŵerengero cha WIN55,212-2 EC50 Kufunika kwa adenylyl cyclase kutayika mu mbewa zomwe zimawonetseratu ΔcJun kwa EC50 kufunika kwa G-mapuloteni kuyambitsidwa mu mbewa ndi kufotokoza kwa ΔFosB anali 4.0, pamene chiŵerengero chomwecho mu mbewa popanda kukopetsedwa kwa transgene anali 1.2.

Mwinanso, zovuta zowonjezera zingapangitse kufotokozera ΔFosB popanda kuthandizira mwachindunji CB1R akuwonetsa. Pa zochitikazi, zida zowonongeka zimatha kuyanjanitsa ndi zotsatira zogwiritsira ntchito mankhwala ozunguza bongo kudzera pa malamulo a FosB-mediated transcriptional. Inen ndithu, kulamulira kwa Δ9-THC imapangitsa kuti thupi likhale lodziwitsira kwa opioid ndi amphetamine (Cadoni, et al., 2001, Lamarque, et al., 2001), mogwirizana ndi mfundo imeneyi. Komanso, kuyendetsa mobwerezabwereza kwa agonist agonist CP55,940 kunanenedwa kuti kuwonjezeketsa kukonza mapuloteni a G-MOR mu NAC, mofananamo ndi ndondomeko zofotokozera ΔFosB mu phunziro lino (Vigano, et al., 2005). Zotsatira za kufotokozera ΔFosB pa Δ9-Makhalidwe a-TC-mediated sanayesekezedwe, koma zotsatira zomwe zilipo sizilepheretsa kuyanjana. Zotsatira za izi ndi phunziro lathu lapitalo (Zachariou, et al., 2006) asonyeze kusintha kwaFosB-komwe kunachititsa kusintha mu MOR ndi KOR / dynorphin mu striatum. Zotsatira zopindulitsa za D9-TC, ngati imayeretsedwa ndi malo okonda, imathetsedwa mu mbewa zosasunthika za MOR, pamene kuchotsedwa kwa KOR kuchepetsedwa Δ9-TC malo osokoneza ndi kuwululira D9-TC malo okonda (Ghozland, et al., 2002). Mofananamo, malo ovomerezeka amakhala osokonezeka kwa Δ9-TC sichikupezeka pogogoda p-dynorphin poyerekeza ndi mbewa zakutchire (Zimmer, et al., 2001). Deta iyi imasonyeza kuti Δ9-THC ikhoza kukhala yopindulitsa kwambiri pambuyo pa ΔFosB kutulutsidwa ndi kupititsa patsogolo kwa kuwonetsa MOR ndi kuchepetsa mawu a dynorphin.

Mwachiduley, zotsatira za phunziro lino zasonyeza kuti mawu a DFF mu D1R / dynorphin zowonongeka bwino zimapangitsa kuti MOR- ndi KOR asamveke bwino pamtundu wa G-mapuloteni omwe amachititsa kuti ntchito ya adenylyl cyclase ikhale yotetezedwa ku NAC. Izi zikugwirizana ndi maphunziro omwe atsimikizira kuti gawo la opioid limapatsa mphotho (Trigo, et al., 2010), ndi kupereka njira yothetsera ΔFosB-zotsatira zake pamphoto. Mosiyana, CB1Kuwonetseratu kwapakati pa NAC sikunakhudzidwe kwambiri ndi kufotokozera ΔFosB kumeneku, ngakhale kuti maphunziro owonjezereka ndi oyenerera kudziwa momwe zotsatira za APF zolembedwera panthawi yopuma.

Mfundo Zofufuzidwa

  • Kuwonetsa MOR kumapangidwira mu nkhono yomwe imakhala ndi mbewa zomwe zimalongosola FFB
  • KOR kulephera kwa adenylyl cyclase imathandizidwanso m'magulu akufotokoza ΔFosB
  • Kufotokozera kwaFFB sikusintha CB1R kuwonetsera mu nucleus accumbens
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Zowonjezera Zowonjezera

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Zothokoza

Olembawo ayamika Hengjun He, Jordan Cox ndi Aaron Tomarchio kuti athandizidwe ndi [35S] GTPγS imamangiriza mayesero. Phunziroli linalimbikitsidwa ndi Zothandizira za USPHS DA014277 (LJS), DA10770 (DES) ndi P01 DA08227 (EJN).

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Mawu a M'munsi

Chodzikanira cha Wosindikiza: Imeneyi ndi fayilo ya PDF ya zolembedwa zosavomerezeka zomwe zavomerezedwa kuti zifalitsidwe. Monga ntchito kwa makasitomala athu ife tikupereka malemba oyambirira a zolembedwazo. Mipukutuyi idzayambanso kujambula, kufotokozera, ndi kubwereza umboni umene umapezekapo musanatulutsidwe mawonekedwe ake omalizira. Chonde dziwani kuti panthawi yopanga zolakwika zingapezeke zomwe zingakhudze zomwe zili, komanso zotsutsana ndi malamulo zomwe zimagwiritsidwa ntchito pa magaziniyo.

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Zothandizira

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