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Abstract
Excess sugar contribuere ostensum est consummatio directe ad pondus lucrum, ita worldwide operam ad crescente obesity epidemiam. Interestingly, ut ostensum est consummatio auctus sugar campester in in nucleus saepe attollunt dopamine accumbens (NAC), mesolimbic praemium in via cerebri similes multis medicamentis ex abusu. Nos referre quod varenicline, nicotinic probatus per FDA-receptor (Nachr) agonist parte modulatur id praemium mesolimbic dopamine in via cerebri, significantly reducere saccharo consummatio, maxime in longa-terminus consummatio exemplar. Similia praecessi observatae fuerunt Nachr alia pharmaca, nimirum mecamylamine et cytisine. Ceterum volumus ostendere, quod diu-term saccharo consummatio crescit, et decrescit α4β2 α6β2 * * nAChRs in in nucleus accumbens, regionem cerebri consociata cum clavis praemium. Simul sumpta, nos suadeant quod Nachr eventus medicamento curatio ut varenicline duorum regum felicissimam strenuitatem se novi belli ad reducere saccharo consummatio.
citation: Shariff M, Quik M, J Holgate, M Morgan, Patkar Domine, Tam V, et al. (2016) Neuronal Nicotinic receptor Modulators Reducere attractio. 11 PLoS ONE (3) e0150270. doi: 10.1371 / journal.pone.0150270
Editor: Thomas James Bacon, University of Leicester, USA
accepistis: September 30, 2015; accepit: February 11, 2016; published: March 30, 2016
Copyright: © 2016 Shariff et al. Utrum aditum patentem haec verba distributa Creative Commons Attribution License, Cujus usus ad tempus non, distribution: et generativa in aliquo medium, provisum est fons et auctor non originali credi unde petitur.
Data Availability: Praesto sint online notitia ex notitia repositio www.figshare.com cum puero DOI: 10.6084 / m9.figshare.2068161.
funding: Funded a studiis haec sunt quae sequuntur: 1. Consilium Research Australia -, da id FT1110884 (ut Cicero Rede für) www.arc.gov.au; 2. Salutem & National Medical ipsum Concilium -, da id (MXLIX)CDXXVII (ut Cicero Rede für) www.nhmrc.gov.au; 3. et National Institute of Health - det id NS59910 (ad MQ) www.nih.gov.
Competing utilitates; Et auctores declaravit habent utilitates, quod neque competing est.
1. Introduction
Excess sugar consummatio sit devinxit ut essentialis components in current underlying et dolore magna morbi, qui modo est a worldwide phaenomenon [1, 2]. Immo saccharo binge bibens est ostensum est saepe ut elevet in nucleus dopamine in levels accumbens (NAC) [3-6], A key pluma de abusu Stupefactivorum medicamentorum [7-14]. Praeterea, longos intermittendi attractio in augmento expressio dopamine in NAC D1 receptores, decrescunt in D2 expressio receptores, in NAC et striatum [15-17] Et augmentum et dopamine D3 mRNA in NAC caudato-putamen. Similes mutationes notatur in responsione ad MORPHINUM amet [18-24].
Ceterum decrementum enkephalin cDNA levels in NAC [25] Quod animadversum post consummatio sugar spatia intermissa [17], Et similes saepius observationes In responsio ad MORPHINUM injectiones [22, 23]-Dependens aut COCAINUM rebus humanis [26]. Denique per recessum ab inveterata patefacio sucrose, ostende mures inclusi essent et dopamine in iniquitate acetylcholine, id est dopamine levels acetylcholine campester, dum pauci proventus [27], Similis mutationes casleu cum abusu pluribus medicamina possunt, inter MORPHINUM, Vocatus et consectetuer [28-30]. Limbic ratio investigare potest impetum addit curationis scopum reducere saccharo consummatio est.
Limbic structuras cerebrum systema est coniuncti including de collectione et areae tegmentalis ventralis NAC (VTA) encode motus, qui in huiusmodi exspectatione civitatibus praemium et motum [31]. In relatione ad sugar consummatio in mesolimbic ratio est, ut ostensum est qui extollit effrenatam display incitatur ad responsum salience cues ut sucrose [32-34]. Immo animalis studiis ostenditur quod diu terminus sumptionem cibi edules potest facere mutationes in cerebrum praemium vias suggerentes in iniquitate normalis praemium processus homeostasis [35, 36].
Ad hypothetica campester, Acetilcolina (Th) ad a cholinergic interneurons nicotinic acetylcholine receptoribus neuronal caecis NAC (Nachr), and release of modulatur ipsa? Dopamine (DA) pepigerunt et postea partum [37]. Interestingly, sucrose ostensum est, quamvis oblique, et afficit, et quidem ex DA release in via NAC nAChRs [38], Quod nempe in bonis et nAChRs Pharmacotherapy ad scopum.
Dum numerosis Nachr cuique limbic system have been identified in, inter quas NAC, idem est subtype Nachr (s) involved in mediare et maintaining consummatio saccharo non sciatur. Varenicline, ex parte contigit in agonist α4β2 *: * α6β2 et α3β2 -nAChRs * (* 'enim est praesentia Domini in aliis possibile subunits receptor) et ad plenum agonist α7 cuique * et α3β4 [39, 40] Reduces nicotine recessus symptoms et iussis [41] Tum ad fidem reducendo Vocatus consummatio [42]. Varenicline ostendit efficaciam dui a primo mediocriter, deinde NAC in enhancing da release eximentes, attenuantes consectetuer adductus DA-release certatim cursitant per claudebant Nachr binding site [43, 44]. Datum apud involvement acetylcholine appetitus, erit probare interesting saccharo consummatio, reducendo efficaciam varenicline in Praeterea, tentatio est aliter, ut adiuvet identify a potential medicamento Nachr Nachr subunits quod targeted.
2. Materiae et methoda
Medicamenta 2.1
5% (w / v), et saccharo 0.2% (w / v) saccharin solutions (Sigma, st., USA) parata sunt in RO-ICTUS aqua. Varenicline (6,7,8,9, tetrahydro, 6,10, 6 methano,H pyrazino [2,3-h] [3] benzazepine tartrate kalium), mecamylamine (N, 2,3,3, Tetramethylbicyclo [2.2.1] heptan-amine 2-dose), et (-) - cytisine ((1R,5S), -1,2,3,4,5,6 hexahydro, 1,5, 8 methano,H-pyrido [1,2-a] [1,5] diazocin, 8-one) hii empti sunt ex Tocris (Bristol, UK).
2.2 animalium et habitationi
Quinque-septem-senem masculum mures inclusi essent Wistar (± 183g 14g) (ARC, WA, Australia), proque domo longis singulos campester Plexiglas uentilandam duo caveis praeferebantur. A mures inclusi essent petitur, parum familiariter habitationi conditionibus singula, tractantem ac levi retro-5 exolvuntur diebus ante initium experimenta. A mures inclusi essent omnia sunt proque domo longis lucem caeli, continentem 12 reversed-h / tenebris cycle (off in lumine 9 sum), cubiculum cum plena accessum ad cibum (vexillum Chow rat) et aqua. Et experimentalem ratio secuta est pervenire guidelines et probatus in VII Ethicorum operum compositio Suspendisse in Sydney University uoluit animal Ethic Committee and the University of Queensland animal Ethic Committee, iuxta iuris Europae leges (Europae communitatibus Concilium Notationes directivae de 24 November 1986, 86 / 609 / BEC).
Intermittendi 2.3, aditus duos utrem bibens exemplar electionis
Et intermittendi bibens accessum 5% saccharo duo arbitrium-utrem exemplar fuit accommodata a [45]. G-300 sistebantur in omnibus fluidis, ferrum Aliquam bibendum lectus plastic utres cum duabus fistulis insertis grommets caveam hoc principium in fronte tenebris lux redit. Fuerunt simul duos utres alterum vas aqua; secundo lagenam quibus 5% (w / v) saccharo. Et de collocatione 5% (w / v), alternasse cum saccharo fuit utrem preferences parte unaquaque enim control nuditate. Utres gravati 30 min 2 H h 24 sistebantur in fluidis, quos proxime 0.1gram dimensiones. Mus etiam utriusque mensurae pondus P. saccharo attractio per kilogram computare pondus. Lunae In fine autem post tempus habitationi acclimatization, mures inclusi essent (± 183 14 g, 10, 12 = n) unus aditus ad lagenam data sunt 5% (w / v), et saccharo unam lagenam aquae. Post h 24, in saccharo substitutum est cum utrem aqua utrem secundum quod est available pro tunc 24 h. Hanc admonitionem quarta et sexta; Aditum aquatoribus ex infinito iam tempore soricibus cetera. Medicamento administratione coepisse post mures inclusi essent habebant firmum basi collocantur bibens levels (20 ± 5 g / kg) de 5% (w / v) saccharo solutio (a) brevis terminus nuditate [~ 4 hebdomades (13 bibens sessiones)]; et (b) diu terminus nuditate [~ 12 hebdomades (37 bibens sessiones)]. Et quod probatio intelliguntur corpus pondus ad initium medicamento 373 ± 26g pro brevis-term et 550 ± 48 g per longum-term. Et Nachr agonists, antagonistis suscipiunt, et vehiculum administratum sunt sicut descripsit.
In quo conferenda voluntariis basi collocantur saccharo consummatio, in animalibus per intermittendi, obvius protocol versus in continua accessum protocol, separatum coetus (n = 10) de 5-week vetus Wistar mures inclusi essent inconvulsa maneret in continua-accessum 5% saccharo protocol ad 4 hebdomades. Hi sunt mures inclusi essent data est aditus ad unam lagenam 5% saccharo et utrem aquae 24 unius horae dies, septem diebus a septimana in experimentum durante. Utribus aquam quotidie patior saccharo (ad summam coetus novos 56 gravati) attractio saccharo ratio praetulerunt. In diebus illis et etiam ponderationes animalis memoriae. Alternasse cum saccharo ipsum cotidie collocatione parte freno mauris.
Ceterum determinare ad effectum de varenicline in consummatio de non-caloric sweetener, saccharin 0.2% (w / v), was presented sunt separatum coetus ab mures inclusi essent (n = 10) quod per intermittendi, obvius protocol describitur labefactentur. 4 hebdomades saccharin consummatio ab initio, quod paulatim ad quadratum mures inclusi essent administratum varenicline usus Latina descripsit. Denique separatum ab mures inclusi essent in in saccharo coetus aditum intermissos spiritus, ut protocol Pisces praescripti sunt in cerebro brevi remota sunt a ceruicum messis, et rediit in isopentane in gelu siccum in manipulos redactæ -80 ° F. In cerebro sunt ergo sectioned (8 μm) de gradu in usus cryostat striatum (Leica Microsystems Inc. Deerfield, II) posuit in -15 ad -20 ° F. In CALEFACTO sectiones erant mounted onto poly-L-coated labitur lysine, dum arida seposita ad -80 propter Pisces ° F. Carborundum perussi aqua (id est sine saccharo) usi velut potestate.
Curatio 2.4 cedulas
A mures inclusi essent Wistar sunt divisa in coetus, 10 12. A mures inclusi essent pro brevis-term longa-terminus bibens et bibens, Varenicline (Vehiculum 0.3, et 1 2 mg / kg) animalis esset administratum est inter quadratum latine usus consilio. Ceterum ab mures inclusi essent in coetus (n = 8), cum cibum consummatio administrandae varenicline memoriae fuit, cum in proxima Samiae 0.1 gram puncta in omni tempore. Deinde post reditus basi collocantur et bibens, mecamylamine (Vehiculum 0.5, et 1 2 mg / kg), antequam esset administratum est. Et separatum ab mures inclusi essent coetus (-) - cytisine (Vehiculum 2 et 4 mg / kg) administratum esset usura quadratum Latinam consilio. Denique ad coetus separatum ab mures inclusi essent esset administratum bibit saccharin brevis-term varenicline ut prius. Per quadratum consilio ut Latine, ut suum quisque rat servivit potestate. Quod bibitur in quo qui usi sunt in studiis reflectunt litterae extant [46-51].
Telae eorum quasi venenum ius omne soluta SAL (SC) infusum in volumine 1 ml / kg saccharo aqua utres 30 min ante fuerunt. Mauris ante omnia parata singulis iniectio solutiones.
2.5 125Pisces ego Epibatidine
of binding 125Ego epibatidine (2200 Ci / g, Vita item Perkini, Elmer Sciences, Boston, MA, USA) factum est, ut ante relatum [52]. Labitur ad eorum pre-incubated 22 ° C min 15 quiddam continet in 50 Tris mM, pH 7.5: mM 120 Sodium, 5 KCl mM: mM 2.5 CaCl2Et 1.0 mM MgCl2. Nm 40 incubatis per se min 0.015 125Ego praesentia vel absentia epibatidine in α-Conotoxin MII (α-CtxMII) (nm 100). Tunc lota siccata et praeberent Kodaly MR Book 125Ego microscale signis (curis GE, Chalfont Sancti Egidii, Buk 'UK) ad 5, 7 diebus. Specificae ligandi censeri coram 100 μM blank amet consectetuer et similes.
Pisces 2.6 dopaminérgico transporter
Ligans ad dopamine transporter (DAT) ad mensuram gomor per 125Ego RTI, 121 (2200 Ci / g, Vita item Perkini, Elmer Sciences, Boston, MA, USA), ut supradictum [53]. Dilapsa diffunderet sectiones erant pre-incubated bis in 15 min se ad 22 ° C in 50 mM Tris, HCl, pH 7.4, 120 mM Sodium et 5 mM KCl et tunc incubatis pro 2 h In quiddam est 0.025% bovine serum albumin, 1 μM fluoxetine et 50 pM 125Ego RTI, 121. Off-binding ad scopum esse angustos Fluoxetine ad serotonin transporters Sections sunt ad laverunt 0 4 x ° C min 15 in se quiddam in glaciem-frigida aqua, et semel, exaruit caeli et patere pro film cum recta MR 2 hodie Kodak 125Ego microscale signis (GE Pharma). Nomifensine (100 μM) define est ad non-specifica fides.
Data 2.7 Analyses
ImageQuant est a progressio ad determinare opticos, in GE curis density values ex autoradiographic films. Summa virium subtrahere TEXTUS binding background TEXTUS values sunt ad aestimandas certis in radioligands binding. Imprimis igitur et convertimini ad fmol values Paperback / mg TEXTUS usura a vexillum curva determinari 125Et signis. Legebantur enim densitatem specimen bene cura inter linearia accumsan rhoncus.
Conducted per Prisma inspicerem GraphPad sunt omnes caerimonias et sinum mutant 6 (Software metus lacinia purus Co., San Diego, CA, USA). Statistical comparatis factae sunt per T-test analysis coniugij expers, inter collegas discrepare, ita analysis (ANOVA) Newman, secuta est per plures rationes Keuls test aut duos-via ANOVA Bonferroni sequitur hoc post test. ≤0.05 considerandum est de p valorem A significant. Interea omnes valores ± SEM expressa indicat de numero animalium in requiem ipsius, pro quolibet animali 6 mediocris persona, 15 1 2 significationibus a purus.
3. results
3.1 Varenicline reduces saccharo consummatio per intermissos spiritus, accessum ad duo arbitrium-exemplar utrem
Ut brevi-terminus in examine effectis varenicline (4 sabbati) et longa-term (12 sabbati), perussi mures inclusi essent saccharo, non-usum intermittendi bibens exemplar electionis utrem aditus duos [54]. Sub-cutaneus (c) ex administratione varenicline mures inclusi essent in brevi-terminus perussi saccharo (Vide Fig 1A) Saccharo attractio minuatur [F (3, 33) = 3.8, P <0.05]. Post hoc manifesti sint quoniam non analysis II mg / kg saccharo consummatio signanter minuatur. Contra vero in longa-term bibendi mures inclusi essent saccharo (Vide Fig 1B), Dum varenicline ibant et saccharo consummatio [F (3, 24) = 15.24, P <0.0001], et post hoc revelatum est analysis I et II mg / kg saccharo consummatio signanter minuatur in pondere-dependens modo comparari cum vehiculo portatur. Item, systemica varenicline Chow consummatio autem non ponitur in aliquo effective et bibitur de timepoints probata, utrumque brevis et longa-term-term. Interestingly, scilicet administrationem varenicline ab mures inclusi essent in brevi-terminus perussi saccharin (IV weeks) (Vide Fig 1C) Attractio minuatur saccharin [F (3, 24) = 5.67, P <0.05]. Post hoc manifesti sint quoniam non analysis II mg / kg signanter minuatur saccharin consummatio. In omnibus casibus superius, significat quod celebrabatur ad XXX min timepoint et non pertinentibus ad 2hr timepoint et 30hr.
Varenicline (2 mg / kg) signanter minuatur saccharo consummatio (Fig 1A) cum brevis-term (4 hebdomades) exposita saccharo. Cum ambo (1 et 2 mg / kg saccharo consummatio in signanter minuatur varenicline (Fig 1B) Post longum-term (12 hebdomades) exposita saccharo. Varenicline (2 mg / kg) signanter minuatur saccharin consummatio (Fig 1C) cum brevis-term (4 hebdomades) saccharin nuditate. Quae illis sunt contraria medium est expressit saccharo attractio (g / kg) ± SEM (repetita mensura et mensura ANOVA, sequitur hoc post Keuls test-Newman). *; P <0.05; **, P <0.01 comparari vehiculo, n = 10, 12.
Ceterum, praeter effectum ex varenicline de sucrose et saccharin consummatio in brevi-term (4 hebdomades) saccharo-perussi animalia per intermissos spiritus, obvius protocol, varenicline non pauci numero saccharo consummatio per animalia in continua-aditum saccharo brevis-term (4 hebdomades) (Indicium non est ostensum est). Est autem attendendum quod non sit intercisa, accessum ad consummationem mures inclusi essent in significantly magis saccharo quam primum 30 min ab mures inclusi essent in continua utrem visum est, aditum ad arbitrium duo haliaeetus T-test: pauloque supra (T = 4.025, DF vocetur 13, P <0.01). Unde: experimentorum omnia adhuc in hoc studio, intermittendi usus ad obvius protocol. In omnibus casibus aqua non consummatio affectus.
3.2 Mecamylamine, a non-competitive, non-electionem selectivam Nachr parem reduces saccharo consummatio per intermissos spiritus, accessum ad duo arbitrium-exemplar utrem
Deinde nos examinasti mecamylamine effectus est, a non-competitive, non-electionem selectivam Nachr parem in in saccharo consummatio, non continuo idem aditus duos utrem exemplar electionis, ut supra dictum est. Mecamylamine ibant et saccharo consummatio in brevi-term [F (3, 33) = 5.9, P <0.01 30min; F (3, 33) = 10.91, P <0.001hr 2] et longa-terminus perussi-saccharo mures inclusi essent [F (3, 21) = 4.6, P <0.05 min XXX; F (3, 21) = 10.42, P <0.001hr 2]. Post hoc manifesti sint quoniam analysis est et rubore laudabunt II mg / kg saccharo consummatio in signanter minuatur per XXX min timepoint brevis-term (Vide Fig 2A) Et mures inclusi essent longa-terminus perussi-saccharo (Vide Fig 2B), Et quoque in 2hr timepoint. Item, 1 mg / kg significant erat brevis-term ad 2hr timepoint. Consummatio saccharo non affectus ad 24hr timepoint pro portione medicatur temptavit. Aqua non consummatio ullus affectus ad timepoint Et dedit.
Mecamylamine (2 mg / kg) saccharo consummatio in signanter minuatur brevis-term (4 hebdomades) et longa-term (12 hebdomades) exposita saccharo mures inclusi essent (Fig 2A et 2B). Determinatis hoc pacto valoribus expressit sunt, consumentur velut medium saccharo (g / kg) ± SEM (repetita mensura et mensura ANOVA, sequitur hoc post Keuls test-Newman). *; P <0.05; **, P <0.01; ***, P <0.001 comparari vehiculo, n = 12.
3.3 Cytisine reduces saccharo consummatio per intermissos spiritus, accessum ad duo arbitrium-exemplar utrem
A mures inclusi sunt temptavit A secundo coetus est (-) - cytisine a electionem selectivam, β2 Nachr agonist. Signanter minuatur Cytisine saccharo consummatio in brevis terminus [F (2, 22) = 7.18, P <0.01 30min; F (2, 22) = 6.82, P <0.01hr 2] et longa-terminus perussi-saccharo mures inclusi essent [F (2,20) = 19.43, P <0.0001 30min; F (2,20) = 12.94, P <0.001hr 2). Post hoc manifesti sint quoniam analysis est et rubore laudabunt IV mg / kg saccharo consummatio in signanter minuatur per XXX min timepoint brevis-term (Vide Fig 3A) Et mures inclusi essent longa-terminus perussi-saccharo (Vide Fig 3B), Et quoque in 2hr timepoint. Consummatio saccharo non affectus ad 24hr timepoint pro portione medicatur temptavit. Item, aqua non consummatio ullus affectus ad timepoint Et dedit.
Cytisine (4 mg / kg) signanter minuatur saccharo consummatio (Fig 3A et 3B) post dies ingruentis bibens brevi-term (4 hebdomades) et longa-term (12 hebdomades) exposita saccharo mures inclusi essent. Determinatis hoc pacto valoribus expressit sunt, consumentur velut medium saccharo (g / kg) ± SEM (repetita mensura et mensura ANOVA, sequitur hoc post Keuls test-Newman). *; P <0.05; **, P <0.01; ***, P <0.001 comparari vehiculo, n = 12.
Patefacio ut 3.4 tam brevis-term (4 sabbati) et longa-term (12 sabbati) saccharo consummatio crescit, et decrescit α4β2 α6β2 * * Nachr subtype binding in in nucleus accumbens
Et continet duas major striatum nAChRs populi, et α4β2 α6β2 * * cuique [55]. Ad determinare quam diu-term treatment saccharo mutatio α4β2 * * α6β2 et flectitur ad cerebrum subtype expressio nos metiri 125Non-binding epibatidine in absentia et praesentia, ex α CtxMII, et cuneos α6β2 * nAChRs (Vide Fig 4A et 4B). Α determinari coram-binding CtxMII repraesentet α4β2 * nAChRs geruntur, differentia inter totalis et α4β2 * * Nachr binding primum ergo dicendum quod α6β2 Nachr binding. α4 (non α6) auctus in NAC β2 * nAChRs sunt significantly ex utraque brevis-term longa-term sucrose, tractata ac bestiae (coniugij expertem T-test, et p = 0.024 <0.0001 respective?) partem. Sed α6β2 * nAChRs (Vide Fig 4C et 4D) Sunt significantly diminuitur brevis-term (coniugij expertem T-test: p = 0.028) quod etiam diu-term (coniugij expertem T-test: p = 0.0035) cum saccharo curatio. Postremo etiam comparari ad binding transporter de dopamine (DAT) a 125Non-binding 121 RTI, Rubellius Blandus similitudinem modulatis dopamine shuttling in saccharo tractata mures inclusi essent. Erat ibi non significant mutatio ista servata est brevis-term (4 sabbati) et longa-term (12 sabbati) (coniugij expertem T-test, et p = 0.290 0.263, respective).
Digeruntur quantitatis α4 (nonα6) β2 * Nachr per binding 125Ego Epibatidine binding in absentia et in praesentia in α-CtxMII spectaculum ostendit a significant augmentum in α4 (nonα6) β2 * nAChRs (A et B), cum minor α6β2 * nAChRs (C et D) cum brevis-term (4 sabbati ) et longa-term (12 sabbati) exposita saccharo-RARUS accessum ad duo arbitrium-utrem exemplar. Dopaminérgico transporter (DAT) determinatae 125CXXI-binding RTI ego ostendam non significant mutatio aliqua brevis-term (IV sabbati) et longa-term (XII week) (E et F respective). Quisque valorem repraesentat medium _ SEM de quattuor animalibus per coetus. A mures inclusi essent vehiculum refert, De significatione tractata, p **** <121: ** p <4, p * <12.
4. disputationem
Studium ostendit quod in praesenti est systemica administratio dependens varenicline produci qui iamiam terminantur, Reductio onerum saccharo consummatio per intermissos spiritus, accessum ad duo arbitrium-exemplar utrem, maxime post diu-terminus consummatio saccharo. Varenicline ut notum est, ex parte contigit in agonist neuronal * α4β2, α6β2 * et * α3β2 -nAChRs et ad plenum agonist α7 Nachr cuique * et α3β4 [39, 40], Et reduces autem desideria fuge nicotine recessus symptoms [41], Tum de dupla sesquitertia, in ethanol praeservatum consummatio animalis studiis [42]. Ceterum varenicline ostensum est effectus medios et a gradu in NAC [56], Limbic praemium regione a key via ad cerebrum. Quod est ante ostensum est, quod non ad satietatem sumentes augetur multorum pascentium in ach accumbens [57], Saccharo consummatio de specie in context [58]. egonterestingly, est ex statera inter dysregulation dopamine (DA) et acetylcholine (Th) ad limbic system, quae praecipue in fuerat NAC invenerunt expellam ad partum, qui perpetuare, et ponere substantias abusu ad PROCLIVITAS [59, 60]. Interestingly, hoc varenicline consummatio saccharo non ponitur in brevi-terminus continui, aditus duos utrem nihil ad arbitrium imago non continuo est contribuere potest obvius ut sucrose neurological mutationes in quo sit effective varenicline. Futurum studia tamen hoc scire oportebit. Praeterea maxime interesting sed consummatio saccharo non remittuntur sine afficiens varenicline saccharin aqua attractio palatability alimentaque mitia consilium est momenti est, praesertim in terms of potest ad efficiendum attinet, limbic system. Ceterum hoc iam (12 hebdomades) exposita saccharo, minus est efficax in reducendo, ut erat pondere varenicline saccharo consummatio, ut in superiore dedit. Hocque responsum posset attribuitur ad α4β2 binding mutationes apparent in quibus demonstratum est Nachr subunits hoc studium.
Nos mecamylamine observatum etiam est, a non-competitive Nachr parem non-electionem selectivam reducere saccharo consummatio. Recens studium a quo nostrum inventum facit deprehendi mecamylamine ibant et decrescebant pavlovian excitat enim momento sugar [61], Et administrationis se operant, sed altius bibitur quantum ad [62]. Praeterea, in in vitro, per applicationem ex mecamylamine NAC minuitur ghrelin mediata accumbal DA-release [63]. Cytisine a electionem selectivam β2 Nachr agonist, venales Tabex in auxilium ut dui Europae regionibus orientem, et reducere saccharo consummatio. Et antea fama vero, consummatio in perspiciendis effectis cytisine in ethanol praeservatum concludi cytisine (3 mg / kg, sC) voluntariis saccharo attractio minuere non [64]. Praeterea potentiale et differentia speciei [65]: Experimentorum multi processualibus, quae inter nos et nuntiavit in Sajja et Rahman (2011). Notissimus, et Sajja Rahman (2011) inferiore utendum est summa dose (3 mg / kg) versus 4 mg / kg in studio. Autem, si uni attribuenda sit illa res observata differences nunc incertum est.
Ceterum hoc quoque videndum est, ut effectus ex mecamylamine et cytisine ad reducere saccharo consummatio per longius temporis spatium in studio (2hr nobis 30min), maybe debitum ad recipiendum multa Nachr subunits targeted per mecamylamine et cytisine quod comparari eorum targeted per varenicline [66, 67]. Porro de Farmacocinética mecamylamine et differentiale respectu cytisine varenicline potest conferre observatum est. Haec vero est speculativa, et non opus est hanc methodum investigandi possibilities studia in futuro. Item, nauseam aut locomotor effectus potest esse et quod bibitur in nostro studio pro varenicline (0.3, 2 mg / kg), mecamylamine (0.5, 2 mg / kg) et cytisine (2, 4 mg / kg) similes bibitur de studiis usus est prior, nimirum varenicline (0.3, 3 mg / kg), mecamylamine (0.5, 4 mg / kg) et cytisine (0.3, 5 mg / kg) [46-51, 68-70].
Et hoc non solum ex parte agonists varenicline et cytisine observationis, sed etiam parem mecamylamine, rei praebere saccharo consummatio sive perceptio verorum quibus hypothetica mechanism β2 * Nachr effectus pharmaca inducere. Ita unum fieri potest, ut involves est interpretatio Nachr desensitization. Quamquam satis constabat primum ad agonists acetylcholine Nachr Nachr activation et hoc cito per conclusionem et hypothetica immutationes ad aggrediendum desensitization receptor vel [71-73]. Hoc est, ut suggesserant nicotinic receptor ac mauris consectetuer via vulgus edendis vires suas altiore effectus desensitization et morum receptorum nicotinic est suggesserant subesse in mechanism de actio, saltem partim, in AAS, exanimationes incidamus, dui et alii [74-76]. Si Nachr agonists via vulgus edendis vires suas commodum effectus a receptor obsidione premere posset, antagonistis suscipiunt magis utile sit ex parte orci. Vel, in parte Nachr agonists, ut varenicline sit therapeutically efficaciora.
In current studio nos et saccharo exposita inveni quod diu terminus augmentum in praecessi in decrementa α4β2 * * Nachr α6β2 per receptores in NAC. Interestingly, commutationes administrandae consectetuer similes eventus in in α4β2 * * nAChRs α6β2 et in campestribus quoque et in magnitudine similis est adeptus, ut in praesens studium cum saccharo [77-79]. Cum tamen hoc plane non comprehenditur in machinationibus sunt responsible nam, ut dictum, ut suggesserant, et mutationes in α4β2 * * α6β2 nAChRs contribuere consectetuer egestas, et rursus se administratione, [80-84]. Similiter observatorum mutationes in nAChRs cum saccharo attractio saccharo sit sub proprietatibus addictive. Est autem attendendum est, quod nunc incertum est, si observatorum mutationes in campestribus quoque et in α4β2 * * α6β2 nAChRs sunt ex palatability de sucrose et ex auctus caloric attractio. Dum varenicline quod similis effectus et saccharo consummatio in saccharin in nostrum studium, suggerente quod sane animum rapit, palatability propositionis, quae futura studiis dignam existimarit excludere auctus est quod caloric attractio putativam causales elementum spectantibus ad mutationes in Nachr expressio levels. Etiam hoc clarificatus ad mechanism underlying receptor mutationes presented in studio. Verbis consummatio saccharo et universaliter cibi sumptionem, addictive speculatio circa passiones cibi permanet. Immo est per recens recensionem Hebebrand et domini [85] Nuanced differentias inter aliqua discernit, in cibum PROCLIVITAS, et multo malle sensualium pictus comedere PROCLIVITAS. Quamvis haec speculationes humanae et neural correlates in relatione ad saccharo consummatio, est ponere quod sane animum rapit mesolimbic devium ducit ad scopum Pharmacotherapy interveniret.
Denique pharmacological uelut tabes nAChRs saccharo afficit. Ceterum, probata antagonistis suscipiunt et fundatur in varii nAChRs agonists quod nichil * β2 pharmacological effectus nAChRs infandae cupiditatis involvunt per media in saccharo consummatio. Nos demonstrabo, quod medians saccharo augmentum et diminutio α4β2 α6β2 * * nAChRs in NAC, omnes dum hortatur ut hanc regionem admodum veri simile candidatus in modulating saccharo consummatio. Praeterea studiis sunt, selige warrantizavit praesumptum partes NAC de sucrose in modulating mores consumens munus est a nAChRs. Denique, nostro studio putative, quasi novi curatio omnino belli ad reducere saccharo consummatio.
Concilium Information
doi: 10.1371 / journal.pone.0150270.s001
(DOCX)
Acknowledgments
De auctoribus similis esset, Carl campo gratias ago pro subsidium in his studiis technica optimum.
Flora auctor
Concipiuntur, et experimenta per disposito, Sumptibus MM MS Cicero Rede für MQ sollicitatur. Experimenta facere: Sumptibus MM OLP, vt AB secet MS. Lunaris examinetur in notitia, vt quae secet AB OLP, MS. Reagentia operam / materiae / analysis paginae MS quae secet AB Cicero Rede für OLP, Sumptibus MM. Scripsit actis diurnis proscribat: Cicero Rede für MS quae secet AB Sumptibus MM OLP.
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