LINK POU KONPLÈ ETID
Abstrè
Konsomasyon sik depase yo montre kontribye dirèkteman nan pran pwa, kidonk kontribye nan epidemi obezite k ap grandi atravè lemond. Enteresan, ogmante konsomasyon sik yo te montre repete ogmante nivo dopamine nan nwayo accumbens (NAc), nan chemen rekonpans mesolimbik nan sèvo a menm jan ak anpil dwòg abi.. Nou rapòte ke varenicline, yon agonist pasyèl reseptè nikotinik asetilkolin (nAChR) apwouve nan FDA ki modil dopamine nan chemen rekonpans mesolimbik nan sèvo a, siyifikativman diminye konsomasyon sikwoz, espesyalman nan yon paradigm konsomasyon alontèm. Rezilta menm jan an te obsève ak lòt dwòg nAChR, sètadi mecamylamine ak cytisine. Anplis de sa, nou montre ke konsomasyon sikwoz alontèm ogmante α4β2 * ak diminye α6β2 * nAChRs nan nwayo accumbens la, yon rejyon kle nan sèvo ki asosye ak rekonpans. Ansanm, rezilta nou yo sijere ke dwòg nAChR tankou varenicline ka reprezante yon nouvo estrateji tretman pou diminye konsomasyon sik.
Sitasyon: Shariff M, Quik M, Holgate J, Morgan M, Patkar OL, Tam V, et al. (2016) Modilatè reseptè asetilkolin nikotinik newonal diminye konsomasyon sik. PLoS YON 11(3): e0150270. doi:10.1371/journal.pone.0150270
Editè: James Edgar McCutcheon, Inivèsite Leicester, Wayòm Ini
resevwa: Septanm NAN, NAN; Aksepte: Fevriye NAN, NAN; Published: 30ye mas 2016
Copyright: © 2016 Shariff et al. Sa a se yon atik aksè louvri ki distribye dapre kondisyon ki nan Creative Commons Wikimedia, ki pèmèt san restriksyon, distribisyon, ak repwodiksyon nan nenpòt mwayen, bay otè orijinal la ak sous yo kredite.
Done Disponibilite: Done yo disponib nan depo done sou entènèt www.figshare.com ak asistan DOI: 10.6084/m9.figshare.2068161.
Finansman: Etid sa yo te finanse pa bagay sa yo: 1. Konsèy Rechèch Ostralyen - sibvansyon ID FT1110884 (pou SEB), www.arc.gov.au; 2. National Health & Medical Research Council – sibvansyon ID 1049427 (pou SEB), www.nhmrc.gov.au; ak 3. Enstiti Nasyonal Sante – sibvansyon ID NS59910 (pou MQ), www.nih.gov.
Konpetisyon enterè: Otè yo te deklare ke pa gen okenn enterè konpetisyon egziste.
1. Entwodiksyon
Konsomasyon sik twòp enplike kòm youn nan eleman esansyèl ak kache nan epidemi aktyèl la obezite, ki kounye a se yon fenomèn atravè lemond.1, 2]. Indeed, binge sucrose drinking has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc) [3-6], yon karakteristik kle nan dwòg abi [7-14]. Moreover, chronic intermittent sugar intake causes an increase in the expression of dopamine D1 receptors in the NAc, decrease in the expression of D2 receptors in the NAc and striatum [15-17] ak tou yon ogmantasyon nan dopamine D3 reseptè mRNA nan NAc a ak caudate-putamen la. Chanjman ki sanble yo te note an repons a kokayin ak morfin [18-24].
Furthermore, a decrease in enkephalin mRNA levels in the NAc[25] te obsève apre konsomasyon sik tanzantan [17], ak obsèvasyon menm jan an repons a piki repete nan morfin [22, 23] oswa nan moun ki depann de kokayin [26]. Finalman, pandan retrè nan ekspoze sikwoz kwonik, rat yo montre yon move balans nan dopamine ak asetilkolin, sa vle di nivo dopamine diminye pandan nivo asetilkolin ogmante.27], menm jan ak chanjman yo obsève ak plizyè dwòg abi, tankou morfin, nikotin ak alkòl [28-30]. Sa a ajoute UN pou mennen ankèt sou sistèm lenbik la kòm yon sib posib terapetik pou redwi konsomasyon sik.
Sistèm limbik la se yon koleksyon estrikti nan sèvo ki konekte ansanm, ki gen ladan NAc ak zòn tegmental ventral (VTA) ki kode eta emosyonèl tankou antisipasyon rekonpans ak motivasyon.31]. An relasyon ak konsomasyon sik, yo te montre sistèm mesolimbik la montre yon repons egzajere ankourajman ankourajman nan siyal pou sikwoz.32-34]. Vreman vre, etid sou bèt yo te montre ke konsomasyon alontèm nan manje gou ka lakòz chanjman nan chemen rekonpans sèvo yo, ki montre yon move balans nan omeyostazi pwosesis rekonpans nòmal la. [35, 36].
Nan nivo molekilè, Acetylcholine (ACh) ki soti nan interneuron kolinerjik NAc la mare ak reseptè asetilkolin nikotinik newòn yo (nAChR), epi li modil liberasyon dopamine (DA) ak konpòtman ranfòse.37]. Enteresan, yo te montre sikwoz, byenke endirèkteman, afekte liberasyon DA nan NAc la atravè nAChRs.38], sijere ke nAChR yo se yon sib pwomèt pou farmakoterapi.
While numerous nAChR subtypes have been identified in the limbic system, including the NAc, identification of the nAChR subtype(s) involved in mediating and maintaining sucrose consumption is not known. Varenicline, a partial agonist at α4β2*, α6β2*, and α3β2*-nAChRs (*denotes the presence of other possible subunits in the receptor complex) and a full agonist at α7 and α3β4* subtypes [39, 40] diminye anvi nikotin ak sentòm retrè [41] osi byen ke nan diminye konsomasyon alkòl [42]. Varenicline montre efikasite pou sispann fimen pa premyèman, modere amelyore lage DA nan NAc la epi dezyèmman, atenue lage DA ki pwovoke nikotin pa konpetitif bloke sit obligatwa nAChR la.43, 44]. Etandone patisipasyon asetilkolin nan apeti, li pral enteresan pou teste efikasite varenicline nan diminye konsomasyon sikwoz Anplis de sa, tès lòt dwòg nAChR ka ede yo idantifye potansyèl subunite nAChR yo vize.
2. Materyèl ak metòd
NAN Dwòg
Yo te prepare 5% (w/v) sikwoz ak 0.2% (w/v) solisyon sakarin (Sigma, ST. Louis, USA) nan dlo RO-tiyo. Vareniklin (6,7,8,9-tetrahydro-6,10-methano-6H pirazino [2,3-h][3] tartrat benzazepin), mecamylamine (N,2,3,3-Tetramethylbicyclo [2.2.1] heptan-2-amine hydrochloride), ak (-)-sitisin ((1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pirido[1,2-a][1,5]diazocin-8-one) yo te achte nan men Tocris (Bristol, UK).
2.2 Bèt ak Lojman
Rat Wistar gason senk semèn (183g ± 14g) (ARC, WA, Ostrali), yo te loje endividyèlman nan kaj ayere plèksiglas doub nivo. Rat yo te aklimate ak kondisyon lojman endividyèl yo, manyen, ak sik limyè ranvèse 5 jou anvan kòmansman eksperyans yo. Tout rat yo te loje nan yon 12-h ranvèse sik limyè/fè nwa ki kontwole klima (limyè koupe a 9 am) chanm ak aksè san limit nan manje (chow estanda rat) ak dlo. Pwosedi eksperimantal yo te suiv direktiv ARRIVE yo epi yo te apwouve pa Komite Etik Queensland University of Technology Animal Ethics Committee ak University of Queensland Animal Ethics Committee, an akò ak lejislasyon Ewopeyen an (Ewopeyen Kominote Konsèy Directive nan 24 Novanm 1986, 86/). 609/EEC).
2.3 Intermittent-access two-bottle choice drinking paradigm
Aksè tanzantan 5% sikwoz de boutèy chwa bwè paradigm te adapte de [45]. Tout likid yo te prezante nan boutèy plastik gradye 300-ml ak ti gout pou bwè asye pur antre nan de grommets nan devan kalòj la apre kòmansman sik limyè nwa a. Yo te prezante de boutèy ansanm: yon boutèy ki gen dlo; dezyèm boutèy la ki gen 5% (w/v) sikwoz. Plasman nan boutèy sikwoz 5% (w/v) te altène ak chak ekspoze nan kontwòl pou preferans bò. Boutèy yo te peze 30 min, 2 èdtan, ak 24 èdtan apre yo fin prezante likid yo, epi yo te pran mezi yo nan 0.1gram ki pi pre a. Yo te mezire pwa chak rat tou pou kalkile gram konsomasyon sikwoz pou chak kilogram pwa kò. Nan Lendi apre fen peryòd aklimatizasyon lojman an, rat (183 ± 14 g, n = 10-12) te bay aksè a yon boutèy sikwoz 5% (w/v) ak yon boutèy dlo. Apre 24 èdtan, yo te ranplase boutèy sikwoz la ak yon dezyèm boutèy dlo ki te disponib pou pwochen 24 èdtan yo. Modèl sa a te repete nan Mèkredi ak Vandredi; Tout lòt jou rat yo te gen aksè san limit nan dlo. Administrasyon dwòg la te kòmanse apre rat yo te kenbe nivo bwè debaz ki estab (20 ± 5 g/kg) nan 5% (w/v) solisyon sikwoz pou (a) ekspoze kout tèm [~4 semèn (13 sesyon bwè)]; epi, (b) ekspoze alontèm [~12 semèn (37 sesyon bwè)]. Pwa kò an mwayèn nan kòmansman tès dwòg la te 373 ± 26 g pou kout tèm, ak 550 ± 48 g pou alontèm. Agonis nAChR, antagonis, ak machin yo te administre jan sa dekri.
Yo nan lòd yo konpare konsomasyon sikwoz debaz volontè nan bèt lè l sèvi avèk pwotokòl aksè tanzantan an kont pwotokòl aksè kontinyèl la, yo te kenbe yon gwoup separe (n = 10) rat wistar ki gen 5 semèn sou yon pwotokòl sikwoz 5% aksè kontinyèl pou 4. semèn. Rat sa yo te bay aksè a yon boutèy sikwoz 5% ak yon boutèy dlo 24 èdtan pa jou, sèt jou pa semèn pou dire eksperyans la. Yo te peze sikwoz ak boutèy dlo chak jou (total 56 sesyon ak boutèy yo peze) pou kalkile konsomasyon sikwoz ak preferans. Pwa bèt yo te anrejistre tou nan jou sa yo. Plasman boutèy sikwoz la te chanje chak jou pou kontwole preferans bò yo.
Anplis de sa, pou detèmine efè varenicline sou konsomasyon yon edulkoran ki pa kalorik, sakarin 0.2% (w/v), yo te prezante bay yon gwoup separe rat (n = 10) dapre pwotokòl aksè tanzantan ki dekri isit la. 4 semèn nan kòmansman konsomasyon sakarin, yo te bay rat vareniklin lè l sèvi avèk yon kare latin nan dòz jan sa dekri. Anfen, yon gwoup separe rat sou pwotokòl sikwoz tanzantan-aksè ki te deziyen pou otoradiografi yo te touye pa dekapitasyon ak sèvo yo byen vit retire, jele nan izopentane sou glas sèk epi estoke nan -80 ° C. Lè sa a, sèvo yo te seksyon (8 μm) nan nivo striatum a lè l sèvi avèk yon kriostat (Leica Microsystems Inc., Deerfield, IL) mete nan -15 a -20 ° C. Seksyon yo te dekonjle monte sou glisad poly-L-lysine kouvwi, seche epi estoke nan -80 ° C jiskaske yo itilize pou otoradografi. Rat konsome dlo (sa vle di pa gen sikwoz) yo te itilize kòm kontwòl.
2.4 Orè tretman yo
Rat Wistar yo te divize an gwoup 10-12. Pou rat sou bwè alontèm epi tou pou bwè alontèm, yo te administre Varenicline (veyikil, 0.3, 1 ak 2 mg / kg) nan chak bèt lè l sèvi avèk yon konsepsyon kare Latin. Anplis de sa, nan yon gwoup rat (n = 8), konsomasyon manje apre administrasyon varenicline te anrejistre nan 0.1 gram ki pi pre a nan tout pwen tan. Imedyatman, apre yo fin retounen nan bwè debaz, mecamylamine (veyikil, 0.5, 1 ak 2 mg / kg), yo te administre menm jan anvan. Nan yon gwoup rat separe, (-)-sitizin (machin, 2 ak 4 mg/kg) yo te administre lè l sèvi avèk konsepsyon kare Latin nan. Anfen, yo te administre varenicline yon gwoup separe rat ki te bwè sakarin pou yon ti tan. Dapre konsepsyon kare Latin, chak rat te sèvi kòm pwòp kontwòl li yo. Dòz yo itilize nan etid sa a reflete sa yo itilize nan literati ki egziste deja [46-51].
Tout dwòg yo te fonn nan saline epi yo te administre kòm yon piki lar (sc), nan yon volim 1 ml / kg, 30 minit anvan sikwoz ak boutèy dlo yo te prezante. Tout solisyon dwòg yo te prepare imedyatman anvan chak piki.
2.5 125I-Epibatidine otoradiografi
Binding of 125Yo te fè I-epibatidin (2200 Ci/mmol; Perkin Elmer Life Sciences, Boston, MA, USA) jan yo te rapòte anvan [XNUMX].52]. Slides were pre-incubated at 22°C for 15 min in buffer containing 50 mM Tris, pH 7.5, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, ak 1.0 MM MgCl2. Yo te enkube pou 40 minit ak 0.015 nM 125I-epibatidine in the presence or absence of α-conotoxin MII (α-CtxMII) (100 nM). They were then washed, dried, and exposed to Kodak MR Film with 125Estanda I-microscale (GE Healthcare, Chalfont St. Giles, Buckinghamshire, UK) pou 5–7 jou. Nonspecific obligatwa te evalye nan prezans 100 μM nikotin e li te menm jan ak vid fim nan.
2.6 Otoradiografi transpòtè dopamine
Binding to the dopamine transporter (DAT) was measured using 125I-RTI-121 (2200 Ci/mmol; Perkin Elmer Life Sciences, Boston, MA, USA), jan sa te dekri deja [53]. Thawed sections were pre-incubated twice for 15 min each at 22°C in 50 mM Tris-HCl, pH 7.4, 120 mM NaCl, and 5 mM KCl, and then incubated for 2 h in buffer with 0.025% bovine serum albumin, 1 μM fluoxetine, and 50 pM 125I-RTI-121. Fluoxetine te itilize pou bloke lyezon sib ak transpòtè serotonin yo. Seksyon yo te lave nan 0 ° C pou 4 × 15 min chak nan tanpon ak yon fwa nan dlo glas-frèt, lè sèk, epi ekspoze pou 2 jou nan fim Kodak MR ak 125Estanda I-microscale (GE Healthcare). Nomifensine (100 μM) te itilize pou defini ki pa espesifik obligatwa.
2.7 Analiz done
Yo te itilize pwogram ImageQuant de GE Healthcare pou detèmine valè dansite optik nan fim otoradyografik yo. Valè tisi background yo te soustraksyon nan total tisi obligatwa pou evalye espesifik obligatwa nan radyoligand yo. Lè sa a, valè obligatwa espesifik yo te konvèti nan tisi fmol / mg lè l sèvi avèk koub estanda detèmine nan 125I standards. Care was taken to ensure that sample optical density readings were within the linear range.
Tout estatistik ak ekipman koub yo te fèt lè l sèvi avèk GraphPad Prism 6 (Graph Pad Software Co., San Diego, CA, USA). Konparezon estatistik yo te fèt lè l sèvi avèk analiz t-tès ki pa pè, analiz yon sèl-fason nan divèjans (ANOVA) ki te swiv pa yon Newman-Keuls tès konparezon miltip oswa de-fason ANOVA ki te swiv pa Bonferroni post hoc tès. Yon valè p ≤0.05 te konsidere kòm enpòtan. Tout valè yo eksprime kòm mwayèn ± SEM nan kantite bèt ki endike yo, ak valè lage pou chak bèt ki reprezante mwayèn 6-15 siyal ki soti nan 1-2 tranch.
3. Rezilta yo
3.1 Varenicline diminye konsomasyon sikwoz lè l sèvi avèk paradigm chwa de boutèy ak aksè tanzantan.
Pou egzamine efè vareniklin nan kout tèm (4 semèn) ak alontèm (12 semèn) rat ki konsome sikwoz, nou te itilize paradigm pou bwè chwa de boutèy ak aksè tanzantan.54]. Administrasyon anba-kutane (sc) varenicline nan rat konsome sikwoz pou yon ti tan (Fig 1A) diminye konsomasyon sikwoz [F (3, 33) = 3.8, P <0.05]. Analiz post hoc revele ke sèlman 2 mg / kg siyifikativman diminye konsomasyon sikwoz. Kontrèman, nan rat bwè sikwoz alontèm (Fig 1B), pandan ke varenicline diminye konsomasyon sikwoz [F (3, 24) = 15.24, P < 0.0001], analiz post hoc revele tou de 1 ak 2 mg / kg siyifikativman diminye konsomasyon sikwoz nan yon fason ki depann de dòz konpare ak machin. Epitou, vareniklin sistemik pa te afekte konsomasyon chow nan nenpòt nan pwen tan yo teste ak tout dòz efikas, tou de kout tèm ak alontèm. Enteresan, administrasyon sc de varenicline nan rat konsome sakarin kout tèm (4 semèn) (Fig 1C) decreased saccharin intake [F (3, 24) = 5.67, P <0.05]. Analiz post hoc revele ke sèlman 2 mg / kg siyifikativman diminye konsomasyon sakarin. Nan tout ka ki anwo yo, yo te obsève siyifikasyon nan pwen tan 30 min, ki pa gen okenn siyifikasyon nan pwen tan 2hr ak 24hr.
Vareniklin (2 mg / kg) siyifikativman diminye konsomasyon sikwoz (figi 1A) apre ekspoze kout tèm (4 semèn) nan sikwoz. Lè nou konsidere ke, tou de (1 ak 2 mg / kg vareniklin siyifikativman diminye konsomasyon sikwoz (figi 1).B) apre ekspoze alontèm (12 semèn) sikwoz. Vareniklin (2 mg/kg) siyifikativman diminye konsomasyon sakarin (figi 1C) apre ekspoze kout tèm (4 semèn) nan sakarin. Valè yo eksprime kòm mwayèn konsomasyon sikwoz (g/kg) ± SEM (repete-mezi ANOVA ki te swiv pa Newman-Keuls apre tès hoc). *, P <0.05; **, P <0.01 konpare ak machin, n = 10–12.
Anplis de sa, kontrèman ak efè vareniklin sou konsomasyon sikwoz ak sakarin nan bèt ki konsome sikwoz a kout tèm (4 semèn) sou pwotokòl aksè tanzantan an, vareniklin pa t diminye konsomasyon sikwoz nan bèt sou aksè kontinyèl nan sikwoz kout tèm. (4 semèn) (Done yo pa montre). Li dwe remake ke rat sou aksè tanzantan konsome siyifikativman plis sikwoz nan premye 30 minit yo nan prezantasyon boutèy pase rat sou aksè kontinyèl jan yo detèmine pa yon tès t ki pa pè de ke (t = 4.025, df = 13, P <0.01). Pakonsekan, tout plis eksperyans nan etid sa a itilize pwotokòl aksè tanzantan an. Nan tout ka yo, konsomasyon dlo pa te afekte.
3.2 Mecamylamine, yon antagonist nAChR ki pa konpetitif, ki pa selektif, diminye konsomasyon sikwoz lè l sèvi avèk paradigm chwa de boutèy ak aksè tanzantan.
Apre sa, nou te egzamine efè mecamylamine, yon antagonist nAChR ki pa konpetitif, ki pa selektif, sou konsomasyon sikwoz nan menm paradigm chwa de boutèy tanzantan-aksè a jan sa di pi wo a. Mecamylamine diminye konsomasyon sikwoz nan kout tèm.F (3, 33) = 5.9, P < 0.01 30min; F (3, 33) = 10.91, P <0.001 2hr] ak rat ki konsome sikwoz alontèm [F (3, 21) = 4.6, P < 0.05 30 min; F (3, 21) = 10.42, P <0.001 2hr]. Post hoc analysis revealed that the dose of 2 mg/kg significantly decreased sucrose consumption at the 30 min timepoint in short-term (Fig 2A) and long-term sucrose-consuming rats (Fig 2B), ak nan tan an 2hr tou. Epitou, 1 mg / kg te siyifikatif a kout tèm nan tan an 2hr. Konsomasyon sikwoz pa te afekte nan tan 24hr pou dòz yo teste. Konsomasyon dlo pa te afekte nan nenpòt ki pwen tan ak dòz.
Mecamylamine (2 mg / kg) siyifikativman diminye konsomasyon sikwoz nan kout tèm (4 semèn) ak alontèm (12 semèn) rat ekspoze sikwoz (figi 2A ak 2B). Valè yo eksprime kòm sikwoz mwayèn konsome (g / kg) ± SEM (repete-mezi ANOVA ki te swiv pa Newman-Keuls apre tès hoc). *, P <0.05; **, P <0.01; ***, P <0.001 konpare ak machin, n = 12.
3.3 Cytisine diminye konsomasyon sikwoz lè l sèvi avèk paradigm chwa de boutèy aksè tanzantan.
Yon dezyèm gwoup rat yo te teste ak (-)-sitizin, yon agonist nAChR β2-selektif. Cytisine siyifikativman diminye konsomasyon sikwoz nan kout tèm.F (2, 22) = 7.18, P < 0.01 30min; F (2, 22) = 6.82, P <0.01 2hr] ak rat ki konsome sikwoz alontèm [F (2,20) = 19.43, P < 0.0001 30min; F (2,20) = 12.94, P < 0.001 2hr). Post hoc analysis revealed that the dose of 4 mg/kg significantly decreased sucrose consumption at the 30 min timepoint in short-term (Fig 3A) and long-term sucrose-consuming rats (Fig 3B), and at the 2hr timepoint as well. Sucrose consumption was not affected at the 24hr timepoint for the doses tested. Also, water consumption was not affected at any timepoint and dose.
Cytisine (4 mg / kg) siyifikativman diminye konsomasyon sikwoz (figi 3A ak 3B) apre aparisyon nan bwè nan kout tèm (4 semèn) ak alontèm (12 semèn) rat ekspoze sikwoz. Valè yo eksprime kòm sikwoz mwayèn konsome (g / kg) ± SEM (repete-mezi ANOVA ki te swiv pa Newman-Keuls apre tès hoc). *, P <0.05; **, P <0.01; ***, P <0.001 konpare ak machin, n = 12.
3.4 Ekspozisyon a tou de kout tèm (4 semèn) ak alontèm (12 semèn) konsomasyon sikwoz ogmante α4β2 * ak diminye α6β2 * nAChR subtip obligatwa nan nwayo accumbens la.
Striatum a gen de gwo popilasyon nAChRs, α4β2* ak α6β2* subtip [55]. Pou detèmine kijan tretman sikwoz alontèm modifye ekspresyon subtip α4β2* ak α6β2* nan sèvo a, nou mezire. 125I-epibatidin obligatwa nan absans ak prezans α-CtxMII, ki bloke α6β2 * nAChRs (Fig 4A ak 4B). Binding determined in the presence of α-CtxMII represents that occurring at α4β2* nAChRs, while the difference between total and α4β2* nAChR binding is defined as α6β2* nAChR binding. α4(non α6)β2* nAChRs were significantly increased in the NAc of both short-term and long-term sucrose-treated animals (unpaired T-test; p = 0.024 and <0.0001, respectively). By contrast, α6β2* nAChRs (Fig 4C and 4D) were significantly decreased short-term (unpaired t-test; p = 0.028) as well as long-term (unpaired t-test; p = 0.0035) with sucrose treatment. Lastly, we also compared the binding of the dopamine transporter (DAT) by 125I-RTI-121 binding to assess the modulation of dopamine shuttling in sucrose treated rats. There was no significant change observed short-term (4 week) and long-term (12 week) (unpaired T-test; p = 0.290 and 0.263, respectively).
Kantite analiz de α4 (nonα6) β2 * nAChR obligatwa lè l sèvi avèk 125I-Epibatidine binding in the absence and presence of α-CtxMII show show a significant increase in α4(nonα6)β2* nAChRs (A and B) with a decrease in α6β2* nAChRs (C and D) after short-term (4 week) and long-term (12 week) sucrose exposure in the intermittent-access two-bottle choice paradigm. Dopamine transporter (DAT) as determined by 125I-RTI-121 obligatwa pa montre okenn chanjman enpòtan a kout tèm (4 semèn) ak alontèm (12 semèn) (E ak F respektivman). Chak valè reprezante mwayèn _ SEM nan kat bèt pou chak gwoup. Siyifikasyon diferans nan rat machin-trete, ****p<0.0001, **p <0.01, *p <0.05.
4. Diskisyon
The present study shows that systemic administration of varenicline produced a dose-dependent reduction of sucrose consumption using the intermittent-access two-bottle choice paradigm, espesyalman apre konsomasyon sikwoz alontèm. Li konnen varenicline, yon agonist pasyèl nan newòn α4β2*, α6β2*, ak α3β2*-nAChRs ak yon agonist konplè nan subtip nAChR α7 ak α3β4*.39, 40], diminye anvi nikotin ak sentòm retrè [41], osi byen ke diminye konsomasyon etanòl nan etid sou bèt [42]. Furthermore, varenicline has been shown to mediate its effect at the level of the NAc [56], yon rejyon kle nan chemen rekonpans limbik nan sèvo a. Li te deja montre ke manje nan sasyete ogmante ACh nan accumbens la.57], espesyalman nan yon kontèks konsomasyon sikwoz [58]. MwenEnteresan, li se dysregulation nan balans ant dopamine (DA) ak asetilkolin (ACh) nan sistèm nan limbic, espesyalman nan NAc a ki te jwenn kondwi epi kenbe konpòtman ki perpétuer dejwe sibstans ki sou abi. [59, 60]. Enteresan, varenicline pa t 'afekte konsomasyon sikwoz nan paradigm chwa a kout tèm aksè kontinyèl de-boutèy sijere ke aksè tanzantan nan sikwoz ka kontribye nan chanjman newolojik pou ki varenicline efikas. Syans nan lavni, sepandan, yo pral nesesè yo rann kont sa a. Anplis de sa, li se patikilyèman enteresan sa varenicline diminye non sèlman sikwoz, men tou konsomasyon sakarin san yo pa afekte konsomasyon dlo, suggesting palatability to sweet foods as important, especially in terms of the possible involvement of the limbic system. Furthermore, following longer (12 weeks) exposure to sucrose, a lower dose of varenicline was as effective in reducing sucrose consumption as the higher dose. This differential response could be attributed to the changes observed in binding for the α4β2 containing nAChR subunits as demonstrated in this study.
Nou menm tou nou te obsève ke mecamylamine, yon antagonist nAChR ki pa selektif ki pa konpetitif redwi konsomasyon sikwoz. Konklizyon nou an sipòte pa yon etid resan ki te jwenn ke mecamylamine diminye motivasyon ankourajman pavlovyen pou suga.r [61] ak administrasyon pwòp tèt ou, byenke nan dòz ki pi wo anpil [62]. Pli lwen, yon vitro aplikasyon mecamylamine nan NAc a, diminye ghrelin-medyatè accumbal DA liberasyon [63]. Cytisine, a β2 selective nAChR agonist, marketed as a smoking cessation aid Tabex in eastern European countries, also reduced sucrose consumption. An earlier report, however, investigating the effects of cytisine on ethanol consumption concluded that cytisine (3 mg/kg, s.c) did not reduce voluntary sucrose intake [64]. Anplis diferans potansyèl espès yo [65], te gen anpil diferans pwosedi ant eksperyans nou yo ak sa yo rapòte pa Sajja and Rahman (2011). Pi miyò, Sajja ak Rahman (2011) te itilize yon dòz ki pi ba ki pi wo (3 mg / kg) kont 4 mg / kg nan etid nou an. Sepandan, si faktè sa yo ka atribiye a diferans yo obsève se pa klè kounye a.
Anplis de sa, li dwe remake ke efè mecamylamine ak cytisine sou diminye konsomasyon sikwoz pou yon peryòd tan ki pi long nan etid nou an (2hr vs 30min), petèt akòz seri a pi laj nan subinit nAChR vize pa mecamylamine ak cytisine konpare ak sa yo. vize pa vareniklin [66, 67]. Anplis de sa, pharmacokinetics diferans nan mecamylamine ak cytisine kòm konpare ak varenicline, ka tou kontribye nan efè sa a obsève. Sepandan, posiblite sa yo se spéculatif epi yo pral bezwen envestige nan etid nan lavni. Epitou, kè plen oswa efè lokomotè yo ka eskli paske dòz yo itilize nan etid nou an pou vareniklin (0.3-2 mg/kg), mecamylamine (0.5-2 mg/kg) ak cytisine (2-4 mg/kg) yo sanble ak dòz yo te itilize nan etid anvan yo, sètadi varenicline (0.3-3 mg / kg), mecamylamine (0.5-4 mg / kg) ak cytisine (0.3-5 mg / kg) [46-51, 68-70].
Obsèvasyon an ke se pa sèlman agonist yo pasyèl varenicline ak cytisine, men tou, mecamylamine nan antagonis, redwi konsomasyon sikwoz ka bay insight nan mekanis nan molekilè kote dwòg β2 * nAChR pwovoke efè yo. Yon entèpretasyon posib se ke li enplike desensibilisation nAChR. Malgre ke li byen etabli ke asetilkolin ak agonist nAChR okòmansman mennen nan deklanchman nAChR, sa a se byen vit swiv pa modifikasyon molekilè ki mennen nan fèmen kanal ak yon blòk reseptè oswa desensibilizasyon.71-73]. Li te sijere ke nikotin ak nikotinik reseptè dwòg egzèse efè jeneral konpòtman yo atravè desensibilisation nan reseptè nikotinik yo te sijere pou kache mekanis yo nan aksyon, omwen an pati, sou analgesia, depresyon, sispann fimen ak lòt moun.74-76]. Si agonis nAChR fè efè benefisye yo atravè yon blokaj reseptè, antagonis yo ka pi itil nan yon pwendvi klinik. Altènativman, agonist pasyèl nAChR, tankou varenicline, ka pi efikas nan terapetik.
Nan etid aktyèl la, nou te jwenn tou ke ekspoze sikwoz alontèm te lakòz yon ogmantasyon nan α4β2 * ak yon diminisyon nan α6β2 * reseptè nAChR nan NAc la. Enteresan, administrasyon nikotin rezilta nan chanjman ki sanble nan nivo yo α4β2 * ak α6β2 * nAChRs, ak nan yon grandè menm jan ak sa yo jwenn nan etid la prezan ak sikwoz. [77-79]. Malgre ke mekanis ki responsab pou sa a toujou pa fin konprann, li te sijere ke chanjman nan α4β2 * ak α6β2 * nAChRs kontribye nan ranfòsman nikotin ak oto-administrasyon. [80-84]. By analogy, the observed changes in nAChRs with sucrose intake may underlie the addictive properties of sucrose. Li ta dwe remake ke kounye a li pa klè si chanjman yo obsève nan nivo yo nan α4β2 * ak α6β2 * nAChRs yo akòz palatabilite nan sikwoz oswa akòz ogmante konsomasyon kalorik. Pandan ke varenicline te gen efè menm jan an sou konsomasyon sakarin ak sikwoz nan etid nou an, sijere ke palatabilite kòm yon pwopozisyon atire, etid nan lavni yo jistifye yo eskli ogmante konsomasyon kalorik kòm yon faktè kozatif pou chanjman yo obsève nan nivo ekspresyon nAChR. Sa a pral ede tou klarifye mekanis ki kache chanjman reseptè yo prezante nan etid nou an. An tèm de konsomasyon sik ak, pi jeneralman, konsomasyon manje, espekilasyon rete konsènan pwopriyete yo depandans nan manje sa yo. Vreman vre, yon revizyon resan pa Hebebrand ak kòlèg [85] disène diferans ki genyen nuans ant dejwe manje ak nomenklatur ki pi pito nan manje dejwe. Malgre sa yo espekilasyon, konpòtman an ak neral korelasyon an relasyon ak konsomasyon sik, poze chemen mesolimbik la kòm yon sib atire pou entèvansyon farmakoterapi.
In conclusion, pharmacological interference with nAChRs affects sucrose consumption. Furthermore, based on the various nAChRs agonists and antagonists tested, we conclude that β2* nAChRs are involved in mediating pharmacological effects on sucrose consumption. We demonstrate that sucrose mediates an increase in α4β2* and decrease in α6β2* nAChRs in the NAc, suggesting this region as a highly plausible candidate in modulating sucrose consumption. Further studies are warranted to validate the putative role of the NAc in modulating sucrose consuming behaviour as a function of the nAChRs. Lastly, our study suggests a completely novel putative treatment strategy for reducing sugar consumption.
Sipòte enfòmasyon
doi: 10.1371 / journal.pone.0150270.s001
(DOCX)
Remèsiman
The authors would like to thank Carla Campus for excellent technical assistance in these studies.
Otè Kontribisyon
Vin ansent ak fèt eksperyans yo: MS SEB JH MM MQ. Fè eksperyans yo: MS MQ JH MM OLP VT AB. Analize done yo: MS MQ VT AB OLP. Kontribye reyaktif/materyèl/zouti analiz: MS MQ SEB AB JH MM OLP. Ekri papye a: MS MQ SEB MM AB JH OLP.
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