LINKA HO ETSA TLHOTSO TSE FELENG
inahaneloang
Ho sebelisoa tsoekere e ngata ho bontšitsoe ho kenya letsoho ka kotlolloho ho boima ba mmele, ka hona ho tlatsetsa seoa sa lefatše la ho ba le botenya lefatšeng ka bophara. Ho khahlisang, tšebeliso e eketsehileng ea tsoekere e bontšitsoe ho phahamisa maemo a dopamine ka makhetlo a mangata ka har'a nucleus accumbens (NAc), tseleng ea moputso oa mesolimbic e tšoanang le lithethefatsi tse ngata tsa tlhekefetso. Re tlaleha hore varenicline, FDA e amoheloang ke nicotinic acetylcholine receptor (nAChR) e arolang dopamine tseleng ea moputso oa mesolimbic, e fokotsa haholo ts'ebeliso ea sucrose, haholo-holo ho paradigm ea tšebeliso ea nako e telele. Liphetho tse tšoanang li ile tsa bonoa le lithethefatsi tse ling tsa NAChR, e leng mecamylamine le cytisine. Ho feta moo, re bonts'a hore tšebeliso ea nako e telele ea sucrose e eketsa α4 *2 * mme e fokotse α6β2 * nAChRs bokong ba li-nucleus, karolo ea bohlokoa ea boko e amanang le moputso. Ha re kopantsoe hammoho, liphetho tsa rona li supa hore lithethefatsi tsa nachR joalo ka varenicline li ka emela leano la kalafo la noha la ho fokotsa tšebeliso ea tsoekere.
Tlhaloso: Shariff M, Quik M, Holgate J, Morgan M, Patkar OL, Tam V, et al. (2016) Neuronal Nicotinic Acetylcholine Receptor Modulators Phokotsa Ho Reka Tsoekere. PLoS ONE 11 (3): e0150270. Doi: 10.1371 / journal.pone.0150270
mohlophisi: James Edgar McCutcheon, Univesithing ea Leicester, UNITED KINGDOM
Re amohetse: September 30, 2015; E amohetse: February 11, 2016; E phatlalalitsoe: March 30, 2016
Copyright: © 2016 Shariff et al. Ena ke sengolo se bulehileng sa phihlello se tsamaisitsoeng tlasa maemo a License ea Boikarabelo ba Creative Commons, e lumellang hore ho sebelisoe, ho abeloa, le ho beleha ho sa sebelisetsoe, ho fana ka moqapi le mohloli oa pele.
Ho fumaneha ha Data: Lintlha li fumaneha ho tsoa pokellong ea data ea inthanete www.jalle-tr.com le mosebeletsi DOI: 10.6084 / m9.figshare.2068161.
Lithuso: Lithuto tsena li tšehelitsoe ka chelete ke ba latelang: www.arc.gov.au; 2. Lekhotla la Naha la Patlisiso le Bophelo le Bongaka - fana ka ID 1049427 (ho SEB), www.nhmrc.gov.au; le 3. Setsi sa Naha sa Bophelo - fana ka ID ID59910 (ho MQ) www.nih.gov.
Lithahasello tse tsitsitseng: Bangoli ba boletse hore ho na le lithahasello tsa tlhōlisano tse teng.
1. Selelekela
Ho sebelisa tsoekere e ngata ho kenella e le e 'ngoe ea likarolo tsa bohlokoa le tse ka tlase tsa seoa sa ho ba le botenya hona joale, eo hona joale e leng ntho e etsahalang lefatšeng ka bophara [1, 2]. Ka sebele, ho itlopa joala ka mokhoa oa ho itlopa joala ho bontšitsoe ho phahamisa maemo a dopamine ka makhetlo a mangata ka mokokotlong oa kinus (NAc) [3-6], karolo ea bohlokoa ea lithethefatsi tsa tlhekefetso [7-14]. Ho feta moo, tšebeliso ea tsoekere e sa foleng ea tsoekere e baka keketseho ea polelo ea li-receptor tsa dopamine D1 ho NAc, ho fokotseha ha polelo ea D2 receptors ho NAc le striatum [15-17] hape le keketseho ea dopamine D3 receptor mRNA ho NAc le caudate-putamen. Liphetoho tse tšoanang li bonoa ha motho a arabela cocaine le morphine [18-24].
Ho feta moo, ho fokotseha ha maemo a enkephalin mRNA ho NAc [25e bonoe ka mor'a tšebeliso e ngata ea tsoekere [17], ka ho elelloa ka mokhoa o tšoanang ho ts'oaroa ka liente tsa khafetsa tsa morphine [22, 23] kapa lithutong tsa batho tse itšetlehileng ka koae [cocaine]26]. Khabareng, nakong ea ha motho a khaotsa ho pepeseha sucrose, likhoto li bontša ho se lekane ho dopamine le acetylcholine, ke hore, dopamine e ntse e fokotseha ha maemo a acetylcholine a ntse a eketseha [27], e tšoanang le liphetoho tse bonoang ka lithethefatsi tse 'maloa tsa tlhekefetso, ho kenyelletsa morphine, nikotine le joala [28-30]. Sena se eketsa tšusumetso ho fuputsa tsamaiso ea limbic joalo ka sepheo sa kalafo se ka fokotsang tšebeliso ea tsoekere.
Sisteme ea limbic ke pokello e hokahaneng ea likarolo tsa boko ho kenyelletsa le sebaka sa NAc le sebaka sa "VTA" se kenyeletsang maemo a maikutlo joalo ka tebello ea moputso le khothatso [31]. Mabapi le ts'ebeliso ea tsoekere, sisteme ea mesolimbic e bonts'itsoe ho bonts'a karabelo e fetelletseng ea ts'usumetso ea ts'usumetso ho lits'oants'o tsa sucrose [32-34]. Ho joalo, lithuto tsa liphoofolo li bontšitse hore tšebeliso ea nako e telele ea lijo tse matlafatsoang e ka baka phetoho tseleng ea moputso oa kelello, e bonts'a ho se leka-lekane mosebetsing o tloaelehileng oa moputso homeostasis [35, 36].
Boemong ba limolek'hule, Acetylcholine (ACh) e tsoang ho li-interinurons tsa cholinergic tsa NAc e tlama ho li-receptor tsa neuronal nicotinic acetylcholine receptors (nAChR), mme e hlophisa tokollo ea dopamine (DA) le boits'oaro bo matlafalitsoeng [37]. Ho khahlisang, ho bontšitsoe ka sucrose, leha e le ka mokhoa o sa reroang, ho ama tokollo ea DA ho NAc ka li-nAChR [38], ho fana ka maikutlo a hore li-nAChR ke sepheo se tšepisang bakeng sa pharmacotherapy.
Le ha ho tsejoa li-subtypes tse ngata tsa NAChR tsamaisong ea methapo, ho kenyelletsa le NAc, ho tsebahatsoa ha li-subtype (N) tsa NAChR tse amehang ho buisaneng le ho boloka tšebeliso ea sucrose ha li tsejoe. Varenicline, agonist e sa lekanyetsoang ho α4β2 *, α6β2 *, le α3β2 * -nAChRs (* e bontša ho ba teng ha li-subunits tse ling ho rarahaneng ea receptor) le agonist e felletseng ho α7 le α3α4 * subtypes [39, 40] e fokotsa litakatso tsa nicotine le matšoao a ho ikhula [41] hammoho le ho fokotsa tšebeliso ea joala [42]. Varenicline e bonts'a katleho ea ho tlohela ho tsuba ka mokhoa oa pele, e ntlafatsa ka mokhoa o hlakileng tokollo ea DA ho NAc 'me ea bobeli, e fumana tokollo ea DA e bakang nicotine ka tlholisano e thibela saete e tlamang ea NAChR [43, 44]. Ka lebaka la ho kenya letsoho ha acetylcholine ho takatso ea lijo, ho tla ba monate ho leka ts'ebetso ea varenicline ho fokotsa ts'ebeliso ea sucrose Ntle le moo, ho hlahlojoa ha lithethefatsi tse ling tsa NAChR ho ka thusa ho tseba hore na ho ka ba le li-subunits tsa nachR tse boletsoeng.
2. Lisebelisoa le mekhoa
2.1 Lithethefatsi
5% (w / v) sucrose le 0.2% (w / v) litharollo tsa saccharin (Sigma, ST. Louis, USA) li ne li lokisitsoe ka metsing a RO-tap. Varenicline (6,7,8,9-tetrahydro-6,10-methano-6H pyrazino [2,3-h] [3] benzazepine tartrate), mecamylamine (N, 2,3,3-Tetramethylbicyclo [2.2.1] heptan-2-amine hydrochloride), le (-) - cytisine ((1)R,5S) -1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido [1,2-a] [1,5] diazocin-8-e mong li ile tsa rekoa ho Tocris (Bristol, UK).
2.2 Liphoofolo le matlo
Liroto tsa banna tsa Wistar tse libeke tse hlano (183g ± 14g) (ARC, WA, Australia), li ne li bolokiloe ka bonngoe mokotleng o mong oa moea o mong le o mong oa Plexiglas. Likhoto li ne li hokahantsoe le maemo a bolulo a motho ka mong, ho sebetsana le potoloho e khutlisetsang letsatsi matsatsi a 5 pele ho liteko. Likhoto tsohle li ne li behiloe ka kamoreng e laoloang ke maemo a leholimo ea 12-h e khutlisetsang leseli / lefifi (mabone a tima 9 hoseng) kamore e nang le phihlello ea lijo (litekanyetso tse tloaelehileng tsa rat) le metsi. Ts'ebetso ea liteko e ile ea latela litataiso tsa ARRIVE mme ea amoheloa ke Komiti ea Boitšoaro ea Komiti ea Boitšoaro ea Liphoofolo ea Queensland le Komiti ea Boitšoaro ea Liphoofolo ea Univesithi ea Queensland, ho latela molao oa Europe (European Communities Council Directive ea la 24 Pulungoana 1986, 86 / 609 / EEC).
2.3 Ho kenella hare ho libotlolo tse peli tsa botlolo ka libotlolo
Phallo ea nakoana ea 5% ea sucrose ea libotlolo tse peli e fetotsoe ho tsoa ho [45]. Metsi ohle a hlahisoa ka libotlolo tsa polasetiki tse nang le li-300-ml tse nang le likhaba tse noeloang tse sa kenngoeng ka tšepe tse kentsoeng ka li-grommets tse peli ka pele ho kharetene kamora ho qala ha potoloho ea leseli le lefifi. Ho ile ha hlahisoa libotlolo tse peli ka nako e le ngoe: botlolo e le 'ngoe e nang le metsi; botlolo ea bobeli e nang le sucrose ea 5% (w / v). Sebopeho sa botlolo ea sucrose ea 5% (w / v) e ile ea fetoloa ka mokhoa o mong le o mong ho hlahisa monyetla oa ho rata litheko. Mabotlolo a ile a beoa boima ba 30 min, 2 h, le 24 h kamora hore ho hlahisoe maro, 'me litekanyo li isoe ho 0.1gram e haufinyane. Boima ba 'mela o mong le o mong bo ne bo boetse bo lekanyetsoa ho lekanya ligrama tsa moroalo oa sucrose ka kilogramu ea boima ba' mele. Ka Mantaha kamora pheletso ea nako ea matlo a ntlafalitsoeng, likhoto (183 ± 14 g, n = 10–12) li ile tsa fuoa monyetla oa ho kena ka botlolong e le 'ngoe ea 5% (w / v) le botlolo e le' ngoe ea metsi. Kamora 24 h, botlolo ea sucrose e ile ea nkeloa sebaka ke botlolo ea bobeli ea metsi e neng e fumaneha bakeng sa 24 h. Mokhoa ona o ile oa phetoa ka Laboraro le Labohlano; Matsatsing a mang kaofela, likhoto li ne li fumana metsi a sa lekanyetsoang. Tsamaiso ea lithethefatsi e qalile kamora hore likhoto li bolokile maemo a noo a tsitsitseng a 20 ± 5 g / kg) ea tharollo ea 5% (w / v) bakeng sa (a) ho pepeseha ha nakoana [~ libeke tse 4 (likarolo tse 13 tsa ho nooa); le, (b) ho pepesetsoa nako e telele [~ libeke tse 12 (likarolo tse 37 tsa ho noa)]. Boima ba 'mele bo bohlokoa qalong ea liteko tsa lithethefatsi e ne e le 373 ± 26g bakeng sa nako e khuts'oane, le 550 ± 48 g bakeng sa nako e telele. Bo-ramahlale ba nachR, bahanyetsi le koloi ba ile ba tsamaisoa joalo ka ha ho hlalositsoe.
Bakeng sa ho bapisa tšebeliso ea sesole ea boithaopo ea boithatelo liphoofolong tse sebelisang protocol ea ho kenella ea nako e telele le protocol e tsoelang pele ea phihlello, sehlopha se arohaneng (n = 10) sa litoeba tsa libeke tse 5 tsa wistar se ile sa bolokoa protocol ea sucrose e tsoelang pele ea 5% libeke. Likhoto tsena li ne li fuoa botlolo e le 'ngoe ea 4% sucrose le botlolo e le' ngoe ea metsi ka lihora tse 5 ka letsatsi, matsatsi a supileng ka beke bakeng sa nako ea tlhahlobo. Mabokose a 'mankhonthe le a metsi a ne a belisoa letsatsi le leng le le leng (libeke tse 24 tse nang le libotlolo) ho lekanya ho ja le ho rata. Boima ba liphoofolo le bona bo ne bo tlalehiloe matsatsing ana. Ho beoa ha botlolo ea sucrose ho ile ha fetoloa letsatsi le leng le le leng ho laola likhetho tsa lehlakore.
Ho feta moo, ho fumana phello ea varenicline ts'ebelisong ea sesebelisoa se seng se nang le khalori, saccharin 0.2% (w / v), e hlahisitsoe ho sehlopha se arohaneng sa likhoto (n = 10) joalo ka protocol ea nako le nako ea ho fihlella e hlalositsoeng mona. Libeke tse 4 ho tloha qalong ea tšebeliso ea saccharin, likhoto li ile tsa tsamaisoa ka varenicline li sebelisa sekwere sa latin ka tekong joalokaha ho hlalositsoe. Kamora nako, sehlopha se ikemetseng sa litoeba sethaleng sa phihlello ea phihlello e neng e etselitsoe mokhoa oa ho ikatisa se ile sa bolaoa ka boqhekanyetsi mme mehopolo e tlositsoe kapele, e le leqhoaqane ka isopentane leqhoeng le omileng mme e bolokiloe ka -80 ° C. Bokong bo ile ba beoa karolo ea (8 μm) maemong a striatum ba sebelisa kristostat (Leica Microsystems Inc., Deerfield, IL) e behiloeng ka -15 ho isa ho 20 ° C. Likarolo li ne li kenngoa ka har'a li-slide tse koahetsoeng ka poly-L-lysine, li omisitsoe le ho bolokoa ka -80 ° C ho fihlela li sebelisoa bakeng sa autoradiography. Likhoto tse jang metsi (ke hore, ha ho na sucrose) li ile tsa sebelisoa e le taolo.
2.4 Mananeo a kalafo
Likhoto tsa Wistar li ile tsa aroloa ka lihlopha tsa 10-12. Bakeng sa likhoto ka ho nooa ha nakoana le ho nooa ha nako e telele, Varenicline (koloi, 0.3, 1 le 2 mg / kg) e ile ea fuoa phoofolo e 'ngoe le e' ngoe e sebelisa moralo oa sekwere sa Latin. Ntle le moo, sehlopheng sa likhoto (n = 8), ts'ebeliso ea lijo kamora ts'ebetso ea varenicline e tlalehiloe ho gram e haufi ea 0.1 ka linako tsohle. Kamora moo, kamora hore a khutlele ho noeng ea mantlha, mecamylamine (koloi, 0.5, 1 le 2 mg / kg), e ile ea tsamaisoa joaloka pele. Ka sehlopha se arohaneng sa likhoto, (-) - cytisine (koloi, 2 le 4 mg / kg) e ne e tsamaisoa ho sebelisoa moralo oa sekwere sa Latin. Qetellong, sehlopha se ikhethileng sa likhoto se noang nakoana e khutšoane se ile sa fuoa varenicline joaloka pele. Ho latela moralo oa sekwere sa Latin, rat e ngoe le e ngoe e ne e sebetsa e le taolo ea eona. Methapo e sebelisitsoeng thutong ena e bontša tse sebelisitsoeng ho lingoliloeng tse fumanehang [46-51].
Lithethefatsi tsohle li qheletsoe ka letsoai le ho sebelisoa e le ente ea subcutaneous (sc), ka bongata ba 1 ml / kg, metsotso e 30 pele ho hlahisoa libotlolo tsa sucrose le tsa metsi. Litharollo tsohle tsa lithethefatsi li ne li lokisoa kapele pele ho ente e ngoe le e ngoe.
2.5 125I-Epibatidine Boitsebiso bo ikemetseng
Tlamahano ea 125I-epibatidine (2200 Ci / mmol; Perkin Elmer Life Science, Boston, MA, USA) e entsoe joalokaha ho tlalehiloe pejana [52]. Li-Slide li kentsoe pele ho 22 ° C bakeng sa metsotso e 15 ho buffer e nang le 50 mM Tris, pH 7.5, 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl2, le 1.0 mM MgCl2. Ba ne ba cheketsoa metsotso e 40 ka 0.015 nM 125I-epibatidine boteng kapa ho ba sieo ha α-conotoxin MII (α-CtxMII) (100 nM). Ka mor'a moo ba ne ba hlatsuoa, ba omisoa, 'me ba pepesoa le Kodak MR Filimi ka 125Litekanyetso tsa I-microscale (GE Healthcare, Chalfont St. Giles, Buckinghamshire, UK) matsatsi a 5-7. Nonspecific binding e ile ea hlahlojoa boteng ba nicotine ea 100 μM mme e ne e ts'oana le filimi e se nang letho.
2.6 Dopamine transporter autoradiography
Ho tlama ho transporter ea dopamine (DAT) e ne e lekantsoe e sebelisoa 125I-RTI-121 (2200 Ci / mmol; Perkin Elmer Life Science, Boston, MA, USA), joalo ka ha ho hlalositsoe pele [53]. Likarolo tse bonoa li ile tsa kenngoa habeli bakeng sa metsotso e 15 ho isa ho e le ngoe ho 22 ° C ho 50 mM Tris-HCl, pH 7.4, 120 mM NaCl, le 5 mM KCl, ea ntan'o kenngoa 2 h ho buffer ka 0.025% bovine serum albin, 1 μM fluoxetine, le 50 pM 125I-RTI-121. Fluoxetine e ne e sebelisetsoa ho thibela thepa e neng e tlameletsoe ho batsamaisi ba serotonin Likarolo tsa metsi li ne li hlatsuoa ka 0 ° C bakeng sa 4 x 15 min e le ngoe ka buffer le hang ka metsing a batang a moea, omisitsoeng moea, 'me a pepesetsoa filimi ea Kodak MR ka matsatsi a mabeli 125Litekanyetso tsa I-microscale (GE Healthcare). Nomifensine (100 μM) e ne e sebelisetsoa ho hlalosa tlama e seng e khethehileng.
Tlhahlobo ea data
Lenaneo la ImageQuant le tsoang GE Healthcare le ne le sebelisetsoa ho lekola boleng ba methapo ea kutlo ho tsoa lifiliming tsa autoradiographic. Melemo ea lithane tse ka morao e ne e tlositsoe ho tishu e tlamang ho lekola tlamo ea radioligands ka ho khetheha. Melao e ikhethileng e tlamang e ile ea fetoloa ho fetoha li-fmol / mg tis ho sebelisa li-curves tse tloaelehileng tse khethiloeng ho tloha 125Ke litekanyetso. Tlhokomelo e ile ea nkuoa ho netefatsa hore balimo ea methapo ea methapo e fumanehang ka har'a methati.
Lipalopalo tsohle le li-fittle tsa li-curve li entsoe ka GraphPad Prism 6 (Graph Pad Software Co, San Diego, CA, USA). Lipapiso tsa lipalopalo li ne li etsoa ho sebelisoa tlhahlobo ea t-test e sa lefelloeng, tlhahlobo ea tsela e le 'ngoe (ANOVA) e lateloang ke Newman — Keuls ea lipapiso tse ngata tsa papiso kapa mekhoa e' meli ea ANOVA e lateloang ke tlhahlobo ea Bonferroni post hoc. Boleng ba p ≤0.05 bo ne bo nkuoa bo le bohlokoa. Likeletso tsohle li hlahisoa e le moelelo mean SEM ea palo e bonts'itsoeng ea liphoofolo, le boleng ba tokollo bakeng sa phoofolo e 'ngoe le e' ngoe e emelang kakaretso ea matšoao a 6 - 15 ho tsoa ho sekala sa 1-2.
3. Liphetho
3.1 Varenicline e fokotsa tšebeliso ea sucrose u sebelisa paradigm ea mekhahlelo e 'meli
Ho hlahloba litlamorao tsa varenicline likhutlong tse khutšoane (beke tse 4) le nako e telele (beke tse 12), re sebelisitse mokhoa oa ho khetha libotlolo tse peli tsa botlolo [54]. Sub-cutaneous (sc) tsamaiso ea varenicline ho likhoto tse jang nako e khutšoane (Setšoantšo sa 1A) ho fokotse tšebeliso ea sucrose [F (3, 33) = 3.8, P <0.05]. Tlhahlobo ea Post hoc e senotse hore ke 2 mg / kg feela e fokotsitseng ts'ebeliso ea sucrose haholo. Ka lehlakoreng le leng, ka likhoto tsa nako e telele tsa sucroseSetšoantšo sa 1B), ha varenicline e fokotse tšebeliso ea sucrose [F (3, 24) = 15.24, P <0.0001], post hoc analysis e senotse ka bobeli 1 le 2 mg / kg e fokotsehile haholo ts'ebeliso ea sucrose ka mokhoa o itšetlehileng ka tekanyetso ha e bapisoa le koloi. Hape, systemic varenicline ha ea ka ea ama ts'ebeliso ea chow ka nako efe kapa efe e lekiloeng le litekanyetso tsohle tse sebetsang, tsa nako e khuts'oane le e telele. Ho khahlisang ke hore tsamaiso ea sc ea varenicline ho likhoto tse jang saccharin nakoana (libeke tse 4) (Setšoantšo sa 1C) fokotsa lijo tse nang le "saccharin"F (3, 24) = 5.67, P <0.05]. Tlhahlobo ea Post hoc e senotse hore ke 2 mg / kg feela e fokotsitseng ts'ebeliso ea saccharin. Maemong 'ohle a kaholimo, bohlokoa bo ile ba bonoa nakong ea metsotso e 30, ho se bohlokoa ho 2hr le 24hr timpoint
Varenicline (2 mg / kg) e fokotsehile haholo ts'ebeliso ea sucrose (feiga 1A) kamora ho qeta nako e khuts'oane (libeke tse 4) ho pepesehela sucrose. Athe, ka bobeli (1 le 2 mg / kg ea varenicline li fokotsehile haholo ts'ebeliso ea sucrose (feiga 1B) ho latela ho pepesoa ha nako e telele (libeke tse 12). Varenicline (2 mg / kg) e fokotsehile haholo ts'ebeliso ea saccharin (feiga 1C) kamora ho pepeseha nako e khuts'oane (libeke tse 4) ho pepesoa ke saccharin. Melao e hlahisoa e le mokhoa oa ho ja ka mokhoa oa "sucrose" (g / kg) EM SEM (mehato ea ANOVA e lateloang ke Newman-Keuls post hoc test). *, P <0.05; **, P <0.01 ha e bapisoa le koloi, n = 10-12.
Ntle le moo, ho fapana le phello ea varenicline mabapi le tšebeliso ea sucrose le saccharin ka nako e khuts'oane (libeke tse 4) liphoofolo tse jang tse ling ho protocol ea nako e khuts'oane, varenicline ha e fokotse tšebeliso ea sucrose ho liphoofolo ka tsoelo-pele ea phihlello ea nako ea nakoana. (Libeke tse 4) (Boitsebiso bo sa bontšoa). Ho ke ho hlokomeloe hore likhoto tse mabapi le phihlello ea nako le nako li sebelisa ts'ebetso e kholo ho feta 30 mins ea tlhahiso ea botlolo ho feta likhoto mabapi le phihlello e tsoelang pele joalo ka khetho ea tlhahlobo ea t-tiles e sa laeloang ea bobeli (t = 4.025, df = 13, P <0.01). Kahoo, liteko tsohle tse ling thutong ena li sebelisitse protocol ea phihlello ea nakoana. Maemong ohle, ts'ebeliso ea metsi ha ea ameha.
3.2 Mecamylamine, mohanyetsi ea se nang moea oa tlholisano, ea seng khahlanong le nachR o fokotsa tšebeliso ea likhakanyo ka tšebeliso ea "paradigm" ea libotlolo tse peli.
Ka mor'a moo re ile ra hlahloba litlamorao tsa mecamylamine, mohanyetsi ea se nang tlholisano, ea sa khetholleng nAChR, tšebeliso ea sucrose ka mokhoa o ts'oanang oa phihlello ea libotlolo tse peli joalo ka ha ho boletsoe kaholimo. Mecamylamine e fokotse tšebeliso ea sucrose ka nako e khuts'oanyane [F (3, 33) = 5.9, P <0.01 30min; F (3, 33) = 10.91, P <0.001 2hr] le likhoto tse jang nako e telele tsa sucrose [F (3, 21) = 4.6, P <0.05 30 mets; F (3, 21) = 10.42, P <0.001 2hr]. Tlhahlobo ea Post hoc e senotse hore lethal dose la 2 mg / kg le fokotsehile haholo ts'ebeliso ea sucrose nakong ea 30 min nakong e khuts'oane (Setšoantšo sa 2A) le likhoto tse telele tse jang maliSetšoantšo sa 2B), le nakong ea 2hr timepoint. Hape, 1 mg / kg e ne e le nako e khuts'oane ea nakoana ho 2hr timepoint. Ts'ebeliso ea Sucrose ha ea ka ea ameha ho 24hr timepoint bakeng sa litekanyetso li lekantsoeng. Ts'ebeliso ea metsi ha ea ka ea angoa ke nako le litekanyetso li kae.
Mecamylamine (2 mg / kg) e fokotsehile haholo ts'ebeliso ea sucrose ka nako e khuts'oanyane (libeke tse 4) le nako e telele (libeke tse 12) litekanyetso tsa ho pepesoa ha li-sucrose (feiga 2A le 2B). Lits'ebetso li hlahisoa joalo ka mokhoa o sebelisoang ka mokhoa oa "suEM" o sebelisitsoeng (g / kg) ± SEM (mehato ea ANOVA e phetoang e lateloa ke Newman — Keuls post hoc test). *, P <0.05; **, P <0.01; ***, P <0.001 ha e bapisoa le koloi, n = 12.
3.3 Cytisine e fokotsa tšebeliso ea sucrose u sebelisa paradigm ea nako e telele ea libotlolo
Sehlopha sa bobeli sa likhoto se ile sa lekoa le (-) - cytisine, ngaka ea on2-ea khethiloeng ea NAChR. Cytisine e fokotsehile haholo ts'ebeliso ea sucrose ka nako e khuts'oanyane [F (2, 22) = 7.18, P <0.01 30min; F (2, 22) = 6.82, P <0.01 2hr] le likhoto tse jang nako e telele tsa sucrose [F (2,20) = 19.43, P <0.0001 30min; F (2,20) = 12.94, P <0.001 2hr). Tlhahlobo ea Post hoc e senotse hore lethal dose ea 4 mg / kg e fokotsehile haholo ts'ebeliso ea sucrose nakong ea 30 min nakong e khuts'oane (Setšoantšo sa 3A) le likhoto tse telele tse jang maliSetšoantšo sa 3B), le nakong ea 2hr timepoint. Ts'ebeliso ea Sucrose ha ea ka ea ameha ho 24hr timepoint bakeng sa litekanyetso li lekantsoeng. Hape, tšebeliso ea metsi ha ea ka ea angoa ke nako le nako.
Cytisine (4 mg / kg) e fokotsehile haholo ts'ebeliso ea sucrose (feiga 3A le 3B) kamora ho qalella ho nooa ka nako e khuts'oanyane (libeke tse 4) le nako e telele (libeke tse 12) ea litekanyetso tsa nako e telele. Lits'ebetso li hlahisoa joalo ka mokhoa o sebelisoang ka mokhoa oa "suEM" o sebelisitsoeng (g / kg) ± SEM (mehato ea ANOVA e phetoang e lateloa ke Newman — Keuls post hoc test). *, P <0.05; **, P <0.01; ***, P <0.001 ha e bapisoa le koloi, n = 12.
3.4 Ho pepesetsoa tšebeliso ea nako e khuts'oanyane ea nako e khutšoane (beke tse 4) le nako e telele (beke tse 12) ho eketsa α4β2 * 'me ho fokotse ho tlama ha cy6β2 * nAChR
Striatum e na le lipalo tse peli tse kholo tsa nachRs, e leng α4β2 * le α6β2 * subtypes [55]. Ho tseba hore na kalafo ea sucrose e fetotsoeng halelele hakae cy4β2 * le α6β2 * polelo e fetotsoeng subtype bokong, re lekantse 125I-epibatidine e tlamang ho ba sieo le ho ba teng ha α-CtxMII, e thibelang α6β2 * nAChRs (Setšoantšo sa 4A le 4B). Ho tlama ho hlophisitsoeng boteng ba α-CtxMII ho emela tse etsahalang ho α4β2 * nAChRs, ha phapang lipakeng tsa kakaretso le α4β2 * nAChR e tlamang e hlalosoa e le tlamo ea α6β2 * nAChR. α4 (non α6) β2 * nAChRs li eketsehile haholo ho NAc ea liphoofolo tse tšoaroang ka nako e khuts'oane le tsa nako e telele (T-teko e sa sebetseng; p = 0.024 le <0.0001, ka ho latellana). Ka lehlakoreng le leng, α6β2 * nAChRs (Fig 4C le 4D) li fokotsehile haholo ka nako e khutšoane (tlhahlobo ea t-liteko; p = 0.028) hammoho le tlhahlobo ea nako e telele (t-test e sa lefelloeng; p = 0.0035) ka kalafo ea sucrose. Qetellong, re boetse re bapisa ho tlama ha dopamine transporter (DAT) ka 125I-RTI-121 e tlamang ho lekola modulation ea dopamine shuttling ho litšoelesa tse tšoeroeng ke sucrose. Ha ho na phetoho e kholo e boneng nako e khuts'oanyane (beke ea 4) le nako e telele (beke ea 12) (tlhahlobo ea T e sa lefelloeng; p = 0.290 le 0.263, ka ho latellana).
Bohlokoa tlhahlobo ea α4 (noncy6) non2 * nAChR e sebelisang 125E-Epibatidine e tlamang ho se be teng le ho ba teng ha α-CtxMII e bonts'a keketseho e kholo ea α4 (noncy6) β2 * nAChRs (A le B) ka ho fokotseha ha α6β2 * nAChRs (C le D) kamora nako e khuts'oanyane (beke ea 4) ) le ho qeta nako e telele (libeke tse 12) a pepesa pepesane ea khetho ea libotlolo tse peli. Dopamine transporter (DAT) joalo ka ha ho boletsoe ke 125Ho tlama I-RTI-121 ha ho bontše phetoho e kholo ea nako e khuts'oane (beke tse 4) le nako e telele (beke tse 12) (E le F ka ho latellana). Boleng bo bong le bo bong bo emela se bolelang _ SEM ea liphoofolo tse 'ne ka sehlopha. Bohlokoa ba phapang ho likhoto tse tšoaroang ke koloi, **** p <0.0001, ** p <0.01, * p <0.05.
4. Puisano
Phuputso e teng e bonts'a hore tsamaiso ea varenicline e hlophisitsoeng e hlahisitse phokotso e thehiloeng ho litekanyetso ea tšebeliso ea sucrose e sebelisang paradigm ea likhetho tse peli., haholo-holo ka mor'a ho sebelisa nako e telele ea sucrose. Hoa tsebahala hore varenicline, agonist ea nakoana ho neuronal α4 neur2 *, α6β2 *, le α3β2 * -nAChRs le agonist e felletseng ho α7 le α3β4 * nAChR subtypes [39, 40], e fokotsa litakatso tsa nicotine le matšoao a ho ikhula [41], hammoho le tšebeliso ea tšebeliso ea ethanol lithutong tsa liphoofolo [42]. Ntle le moo, varenicline e bonts'itsoe ho nka lehlakore lipakeng tsa NAc [56], karolo ea bohlokoa tseleng ea moputso oa maoto le bokong. E kile ea bontšoa hore ho fepa ho satiety ho eketsa ACh ho li-accumbens [57], haholo maemong a tšebeliso ea sucrose [58]. Ika ho khahlisang, ke khatello ea maikutlo lipakeng tsa dopamine (DA) le acetylcholine (ACh) tsamaisong ea limbic, haholo-holo ho NAc e fumanoeng e khanna le ho boloka boits'oaro bo khothalletsang bokhoba ba lintho tsa tlhekefetso. [59, 60]. Ho khahlisang, varenicline ha e a ka ea ama tšebeliso ea sucrose ho paradigm ea nako e khuts'oane ea likhetho tse peli tse fanang ka maikutlo a hore ho fihlella ha sucrose ho ka kenya letsoho phetohong ea methapo eo varenicline e sebetsang ho eona. Leha ho le joalo, lithuto tsa nako e tlang li tla hlokahala ho netefatsa sena. Ho feta moo, ho hlile ho monate hore varenicline ha ea fella feela ho sucrose empa hape le tšebeliso ea saccharin ntle le ho ama ho kenella ha metsi, ho fana ka maikutlo a ho fumaneha hoa lijo tse monate joalo ka ha ho le bohlokoa, haholo-holo mabapi le ho kenya letsoho ha tsamaiso ea limbic. Ho feta moo, kamora ho qeta nako e telele (libeke tse 12) a pepesetsoa ho sucrose, lethalinyana le tlase la varenicline le ne le sebetsa hantle ho fokotsa tšebeliso ea sucrose joalo ka lethal dose e phahameng. Karabelo ena e khethollang e ka hlahisoa ke liphetoho tse bonoeng ha ho tlangoa α4β2 e nang le li-subunits tsa NacR joalokaha ho bontšitsoe thutong ena.
Hape re hlokometse hore mecamylamine, mohanyetsi ea se nang boikhethelo ea seng molemong oa tlholisano ea nAChR o theotse tšebeliso ea sucrose. Ho fumana ha rona ho ts'ehetsoa ke phuputso ea morao-rao e fumanoeng hore mecamylamine e fokotse tšusumetso ea pavlovian ea sugar [61le ts'ebetso ea boitaolo, leha e le ka tekanyetso e phahameng haholo [62]. Ho feta moo, a a vitro Ts'ebeliso ea mecamylamine ho NAc, e fokotsehile ghrelin-Mediated accumbal DA tokollo [63]. Cytisine, setsebi sa ts'ebetso sa AC2 se khethiloeng sa NAChR, se rekisitsoeng e le thuso ea ho tlohela ho tsuba Tabex linaheng tsa Europe tse bochabela, le sona se fokotsa ts'ebeliso ea sucrose. Tlaleho ea pejana, leha ho le joalo, e neng e etsa lipatlisiso ka litlamorao tsa ts'ebeliso ea cytisine ts'ebelisong ea ethanol e fihletse qeto ea hore cytisine (3 mg / kg, sc) ha e ea fokotsa ho ja ka mokhoa oa boithaopo [64]. Ntle le phapang ea mefuta e teng e teng [65], ho bile le phapang e ngata lipakeng tsa liteko tsa rona le tse tlalehiloeng ke Sajja le Rahman (2011). Haholo-holo, Sajja le Rahman (2011) ba sebelisitse lethal e phahameng ka ho fetisisa (3 mg / kg) le 4 mg / kg thutong ea rona. Leha ho le joalo, haeba lintlha tsena li ka bakoa ke phapang e hlokometsoeng ha e hlake hona joale.
Ntle le moo, ho tla hlokomeloa hore phello ea mecamylamine le cytisine mabapi le ho fokotsa ts'ebeliso ea sucrose nako e telele ho feta thutong ea rona (2hr vs 30min), mohlomong ka lebaka la bongata bo pharalletseng ba likhatiso tsa NAChR tse lebisitsoeng ke mecamylamine le cytisine ha li bapisoa le tseo. e lebisitsoe ho varenicline [66, 67]. Ntle le moo, li-pharmacokinetics tse fapaneng tsa mecamylamine le cytisine ha li bapisoa le varenicline, le tsona li ka kenya letsoho ts'ebetsong ena e bonoang. Monyetla ona leha ho le joalo o oa inahanela ebile o tla hloka ho hlahlojoa lithutong tsa kamoso. Hape, ho nyekeloa hoa pelo kapa litla-morao ho ka ahloloa hobane litekanyetso tse sebelisitsoeng thutong ea rona ea varenicline (0.3-2 mg / kg), mecamylamine (0.5-2 mg / kg) le cytisine (2-4 mg / kg) li ts'oana le Litaba tse sebelisitsoeng lithutong tse fetileng, e leng varenicline (0.3-3 mg / kg), mecamylamine (0.5- mg mg / kg) le cytisine (4-0.3 mg / kg) [46-51, 68-70].
Tlhokomeliso ea hore ha se li-agreists tsa nakoana feela tse sebetsanang le "cytisine", empa le mecamylamine ea ho hanyetsa, tšebeliso e mpe ea sucrose e ka fana ka temohisiso mochine oa molek'hule moo lithethefatsi tsa β2 * nAChR li hlahisang phello ea tsona. Tlhaloso e le 'ngoe ke hore e kenyelletsa takatso ea nachR. Le ha ho thehiloe ka nepo hore li-acetylcholine le li-agonists tsa NAChR li lebisa ts'ebetsong ea nAChR, sena se lateloa ka potlako ke liphetoho tsa limolek'hule tse lebisang ho koaloa ha seteraeke le block receptor kapa desensitization [71-73]. Ho 'nile ha fanoa ka maikutlo a hore lithethefatsi tsa nicotine le nicotinic receptor li fana ka litlamorao tsa boits'oaro ka ho lakatsa li-receptor tsa nicotinic ho khothalelitsoe ho etsa ts'ebetso ea bona ea ts'ebetso, bonyane ka karolo, ho analgesia, khatello ea maikutlo, ho khaotsa ho tsuba le ba bang [74-76]. Haeba li-agonists tsa NAChR li sebelisa litholoana tsa tsona tse ntle ka ho li-receptor blockade, bahanyetsi ba hao ba ka ba molemo ho feta pono ea bongaka. Ntle le moo, li-agonists tsa nakoana tsa nachR, tse kang varenicline, li ka atleha haholoanyane kalafong.
Phuputsong ea morao-rao, re fumane hape hore ho pepesetsoa ha nako e telele ea sucrose ho felletse ka keketseho ea α4β2 * le ho fokotseha ha li-receptor tsa α6β2 * nAChR ho NAc. Ho khahlisang, tsamaiso ea nicotine e baka phetoho e ts'oanang maemong a α4β2 * le α6β2 * nAChR, le boholo bo ts'oanang le bo fumanoeng thutong ea morao tjena le sucrose [77-79]. Leha mekhoa e ikarabellang bakeng sa sena e ntse e sa utloisisoe ka botlalo, ho fanoe ka tlhahiso ea hore liphetoho ho α4β2 * le α6β2 * nAChR li kenya letsoho ho ts'ebetsong ha nicotine le ho itaola. [80-84]. Ka papiso, liphetoho tse bonojoang ke li-nAChR tse nang le tšebeliso ea sucrose li ka tlatsetsa tlatsetso ea litlamorao tsa sucrose. Re lokela ho hlokomela hore hajoale ha ho hlakehe hore na liphetoho tse bonoang maemong a li-α4β2 * le α6α2 * nAChR li bakoa ke ho tsebahala ha sucrose kapa ka lebaka la tšebeliso ea caloric e eketsehileng. Le ha varenicline e bile le litlamorao tse tšoanang ho tšebeliso ea saccharin le ho sebelisa scrose thutong ea rona, ho fana ka maikutlo a ho tsebahala ka mokhoa o khahlisang, lithuto tsa nako e tlang li reretsoe ho se kenye keketseho ea caloric e eketsehang joalo ka lebaka la liphetoho tse bonoang maemong a polelo a nachR. Sena se tla thusa ho hlakisa mochini o tlisang liphetoho tse amohelang thuto ea rona. Mabapi le ts'ebeliso ea tsoekere 'me, haholo, tšebeliso ea lijo, khopolo-taba e sala e le mabapi le menyetla ea lijo tsena. Ehlile, tlhahlobo ea moraorao ke Hebebrand le basebetsi mmoho [85] e lemoha phapang e pakati lipakeng tsa bokhoba ba lijo le mokhoa o itseng o ratehang oa ho lemalla joala. Leha ho na le likhopolo-taba tsena, mekhoa ea tlhaho ea tlhaho le ea tlhaho e amanang le tšebeliso ea tsoekere, e beha tseleng ea mesolimbic e le sepheo se khahlisang sa ho kena lipakeng kalafong ea meriana.
Qetellong, ho kena-kenana le meriana le li-nAChR ho ama tšebeliso ea sucrose. Ntle le moo, ho ipapisitse le li-agonists le lihanyetsi tse fapaneng tsa li-nachR tse lekiloeng, re fihlela qeto ea hore li-β2 * nAChR li kentse letsoho phetisong ea litlamorao tsa litheko ho latela tšebeliso ea sucrose. Re bontša hore sucrose e buisana le keketseho ea li-α4β2 * le ho fokotseha ha li-α6β2 * nAChRs ho NAc, ho fana ka maikutlo a sebaka sena e le mokhethoa ea hlakileng oa ho fetola tšebeliso ea sucrose. Lithuto tse ling li hlophiselitsoe ho netefatsa karolo e bohlasoa ea NAc ho feto-fetoheng mokhoa oa ho jella boits'oaro e le ts'ebetso ea li-NAChR. Qetellong, boithuto ba rona bo fana ka maikutlo a mokhoa o hlakileng oa ho thusa ho fokotsa tsoekere.
Ho tšehetsa Boitsebiso
doi: 10.1371 / journal.pone.0150270.s001
(DOCX)
lumela hore baa fokola
Bangoli ba ka thabela ho leboha Carla Campus ka thuso e ntle ea botekgeniki lithutong tsena.
Menehelo ea Mongoli
O ile a amohela le ho hlophisa liteko: MS SEB JH MM MQ. O entse liteko: MS MQ JH MM OLP VT AB. Ho hlahlobisisa data: MS MQ VT AB OLP. Li-reagents tse kentsoeng / lisebelisoa / lisebelisoa tsa tlhahlobo: MS MQ SEB AB JH MM OLP. Ngola pampiri: MS MQ SEB MM AB JH OLP.
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