Indima ye-Orexin-1 Iindlela zokufumana i-Compulsive Food Consomption kwiModeli yokuTywala kwiiRats zamaKhosi (2012)

I-Neuropsychopharmacology. I-2012 Aug; I-37 (9): 1999-2011.

Ipapashwe kwi-intanethi ye-2012 ngoMeyi 9. doi: 10.1038 / npp.2012.48

PMCID: PMC3398727

ULaura Piccoli,^1,^4,^5,⁶ UMaria Vittoria Micioni Di Bonaventura,^2,^4,^* UCarlo Cifani,^2,⁴ I-Vivian JA Costantini,^1,^5,⁶ UMario Massagrande,^1,^5,⁶ UDino Montanari,^1,^5,⁶ UPrisca Martinelli,^1,^5,⁶ UMarinella Antolini,^1,^5,⁶ URoberto Ciccocioppo,² UMaurizio Massi,² U-Emilio Merlo-Pich,³ URomano Di Fabio,^1,^5,⁶ kwaye UMauro Corsi^1,^5,⁶

Ulwazi loMbhali ► Iinqununu zeSihloko ► Ulwazi lobunikazi kunye neelayisensi ►

Eli nqaku liye khankanywe ngu amanye amanqaku kwi-PMC.

Abstract

Ii-Orexins (i-OX) kunye nee-receptors zazo (OXR) zilinganisa ukondla, ukuvusa, uxinzelelo kunye nokusebenzisa iziyobisi. Iinkqubo ze-Neural ezikhuthaza kunye nokomeleza ukusetyenziswa gwenxa kweziyobisi zinokunyanzelisa ukufuna nokutya. Ke ngoko, iziphumo ze-GSK1059865 (5-bromo-N-[(2S,5S) -1- (3-fluoro-2-methoxybenzoyl) -5-methylpiperidin-2-yl] methyl-pyridin-2-amine), OX ekhethiweyo₁I-antagonist, JNJ-10397049 (N- (2,4-dibromophenyl) -N′ - [(4S,5S) -2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl] urea), OX ekhethiweyo₂I-antagonist, kunye ne-SB-649868 (N-[((2.)S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX₁/ OX₂I-antagonist yavavanywa kwimodeli yokutya okuzinkonkxiweyo (BE) kwimodeli yamabhinqa. I-BE yokutya okunomdla kakhulu (HPF) kukhutshwe imijikelezo emithathu yokuthintelwa kokutya kulandelwa ngoxinzelelo, ukuphakanyiswa ngokuveza iigundane kwi-HPF, kodwa ukubathintela ekubeni bangakwazi ukufikelela kuyo kwi-15 min. Uvavanyo lwe-Pharmacokinetic yazo zonke iikhompawundi zafunyanwa phantsi kweemeko ezifanayo zokuvavanya ezisetyenziselwa kuvavanyo lokuziphatha. I-Topiramate yayisetyenziswa njengendawo ekubhekiswa kuyo njengoko ikhetha iibhloko KUKHO kwiirati nabantu. Umkhombandlela onxulumene nedosi kwimiphumela yokulala-yokuphembelela yokuchasana ne-OXR wathelekiswa kusetyenziswa iprysomnography kwiimvavanyo zeparallel. I-SB-649868 kunye ne-GSK1059865, kodwa hayi i-JNJ-10397049, yancitshiswa ngokukhethekileyo i-BE ye-HPF ngaphandle kokuchaphazela ukutya okuqhelekileyo kwepellet, kumadosi angakhange alale. Ezi ziphumo zibonakalisa, okokuqala, indima ephambili ye-OX₁Iindlela ze-BE, ziphakamisa ukuba ukukhetha kuchasene ne-OX₁R unokumela inoveli yonyango olungenasiphumo sonyango lwe-BE kunye nezinye iingxaki zokutya ezinento enyanzelekileyo.

Internet: I-orexin-1 i-receptor antagonist, i-orexin-2 i-receptor antagonist, ukutya okuzinkcinkca, iigundane zabasetyhini, ukusetyenziswa kokutya okunyanzelekileyo

INTSHAYELELO

Iziqwengana zokutya okuzinkozo (BE) ebantwini zibonakaliswa kukusetyenziswa okunyanzelekileyo, okungekho sekhaya kokusetyenziswa okungaqhelekanga kokutya okuthandekayo (HPF) ngexesha elifutshane. Nangona bengalambanga, izihloko zidla ngokukhawuleza kunesiqhelo kude kube ngokuziva zingonwabanga ngokupheleleyo. Njengoko kuchaziwe yi-DMS-IV-TR (Umbutho we-Psychiatric Association, i-2000), ezi ziqendu zihamba kunye nemvo yokulahleka kokulawula kokutya, kwaye zinxulunyaniswa nemvakalelo yoxinzelelo, ucekisekiso, uxinzelelo, unetyala ngokutya ngokugqithisileyo, kunye nokutya wedwa ngenxa yeentloni.

BE imele inqaku eliphambili le-bulimia amanosa, apho iziqendu ze-BE zilandelwa kukuziphatha okujolise ekuphepheni ukuzuza ubunzima, njengokuzihlanza ngokwakho. Iziqendu ezikhulukazi nezingapheliyo ze-BE zibonisa iziganeko eziqhelekileyo ezenzeka nakwizifundo ezinesifo sokutya kakhulu okutya kakhulu (BED) (UWalsh kunye noDevlin, 1998). I-BED ibonakaliswa ngeziqendu eziphindaphindiweyo ze-BE kwimeko yokungaziphathi kakuhle yokuziphatha ukuphepha ukuzuza ubunzima. Inkqubo yokuqonda ye-BED kwi-DSM-IV-TR ibonisa ukuba iziqendu ze-BE kufuneka zenzeke okungenani iintsuku ze-2 ngeveki kwiinyanga ze-6. I-BED inxulunyaniswa nonyango lwe-morbidity yonyango kunye neengqondo.KwiJavaras okqhubekayo, 2008; IGrucza okqhubekayo, 2007; UFassino okqhubekayo, 2003). Kuqikelelwa ukuba I-BE ibandezeleka malunga ne-5% yabantu abadala base-US ngexesha ebomini babo (I-Foulds Mathes okqhubekayo, 2009) kwaye inegalelo ekwandiseni ukutyeba kakhulu kunye ne-pathologies enxulumene nazo (Hudson okqhubekayo, 2007; Heath, 1998; I-Devlin okqhubekayo, 2000; Yanovski, 2003).

Amayeza akhoyo, njenge topiramate (McElroy okqhubekayo, 2007; McElroy okqhubekayo, 2009) okanye sibutramine (I-Appolinario okqhubekayo, 2000; UWilfley okqhubekayo, 2008), kuye kwaxelwa ukuba ukunciphisa i-BE kwizifundo zekliniki. Nangona kunjalo, ulawulo lwabo lunxulumene neziphumo ezibi ezahlukeneyo, ezibonisa iingxaki ezinzima ngexesha lonyango olungapheliyo (McElroy okqhubekayo, 2009; Carter okqhubekayo, 2003; I-Yager, i-2008). Ngokukodwa, i-sibutramine isarhoxisiwe kutshanje kwintengiso yaseYurophu, ngelixa i-topiramate iyaziwa ngokungahambi kakuhle kwezinto zayo. Unyango olwenziweyo lwe-bulimia amanosa kunye ne-BED ngaphandle kwemiphumo emibi kakhulu ifuneka ngamandla.

Kwi-1998, amaqela amabini azimeleyo achonga iklasi entsha ye-neuropeptides evela kwi-hypothalamic nuclei (Sakurai okqhubekayo, 1998; de Lecea okqhubekayo, 1998). Ezi peptides, zibizwa ngokuba yi-orexin-A (OXA) kunye ne-orexin-B (OXB) (ekwabizwa ngokuba yi-hypocretin 1 kunye ne-hypocretin 2), ziveliswa ngokuveliswa kweproteyypyl ye-peptide ye-pre-OX kwaye zibophelela kwi-GPCRs ezimbini, ezizezi-OX- I-1 kunye nee-OX-2 receptors (OX₁R kunye ne-OX₂R) (ikwabizwa ngokuba yiHcrtR1 kunye neHcrtR2). I-OX₁I-R idityaniswa ne-Gq / 11, ngelixa izifundo zisebenzisa iiseli ze-neuronal zibonisa ukuba i-OX₂I-R idityaniswe kwi-Gq, Gs, kunye neeproteni zeGi. Kwinkqubo ye-nervous central, OX₁R kunye ne-OX₂R bonisa ukwahlula ngaphezulu, kodwa ubukhulu becala bahluke kwaye bahambelana, iipatheni zokuhambisa (Sakurai, 2007). Iindawo zobuchopho ezifana ne-infralimbic cortex, hippocampus, kunye ne-locus coeruleus zibonisa ukubonakalisa okuphezulu kwe-OX₁R, kanti i-OX₂I-R kuphela ye-receptor eboniswe kwi-nucleus ye-arcuate, i-tuberomammillary nucleus, kunye ne-dorsomedial and lateral hypothalamus (LH). Zombini ii-receptors zikhoyo kwi-cortex yangaphambili, i-amygdala, ibhedi yendawo yokulala ye-stria terminalis, i-duventricular thalamic nucleus, i-dorsal raphe, indawo ye-ventral tegmental (VTA), kunye ne-laterodorsal tegmental nucleus-peduncolo pontine nucleus (Lu okqhubekayo, 2000; Marcus okqhubekayo, 2001; I-Trivesi okqhubekayo, 1998). Ezi ziphumo zibonisa ukuba ii-OXs kunye nee-receptors zazo zinokudlala indima ebanzi kulawulo kwinkqubo yovalo ephakathi.

I-physiology yesimo sokuvuka / sokulala yenye yamacandelo apho indima ye-OX ifundwe kakhulu. Ewe, ukuphazamiseka kwe-OX signing in Prero-OX Knice knockout kuvelise indlela yokuphawuleka eneempawu eziphantse zifane nezo zabaguli abane-narcolepsy, isifo esingalawulekiyo esidla ngokulala kakhulu esinokuthi sihambisane nokugula kakhulu, ukukhubazeka kweengqondo, kunye nokuqaqanjelwa sisisu. (IChemelli okqhubekayo, 1999). Ukulala kakhulu kubonakalisa ukubonakalisa ukungakwazi ukugcina ukuvuka okwandisiweyo.

Ukongeza, inkcaso efanayo yokuzibandakanya zombini ze-OX₁R kunye ne-OX₂R okanye ukuthintelwa okukhethiweyo kwe-OX₂Iziphumo zokungeniswa kwefuthe elinamandla le-hypnotic (IBrisbare-Roch okqhubekayo, 2007; Dugovic okqhubekayo, 2009; UDi Fabio okqhubekayo, 2011).

Idatha kuluncwadi ikwaxhasa indima yendlu ye-OX kwinkqubo yokutya, kulawulo lokutya kwasekhaya kunye nokufumana umvuzo. Ukongeza ekuboniseni i-narcolepsy phenotype, iigundane ze-OX zokunkqonkqoza zikwimeko ethelekisayo xa kuthelekiswa nobunzima kunye nelitha elilingana nobudala, ebonisa indima ye-OXs ekumodleni ukondla kunye nemetabolism yamandla (Willie okqhubekayo, 2001). Ukufakwa kwe-OXA kwi-lateral ventricle yeats, ngexesha lesigaba sokuqala sokukhanya, kubangele ukunyuka okuhambelana nokutya kokutya kwiigundane (Sakurai okqhubekayo, 1998), eyayivalwe ngonyango lwangaphambi kwexesha kunye ne-OX₁I-antagonist SB-334867 (Haynes okqhubekayo, 2000; Rodgers okqhubekayo, 2001). Indima yee-OXs ekutyeni ukutya okusekwe kumvuzo ibhalwe liphepha lakutsha nje le UPerello okqhubekayo (2010), ukubonisa ukuba ukunyuka kwexabiso elinomvuzo lokutya okunamafutha aphezulu abangelwa yi-ghrelin kuxhomekeke kwi-OX; Ngaphaya koko, i-SB-334867 iye yanikelwa ekuthinteleni ukutya okunamafutha aphezulu (UNair okqhubekayo, 2008). Ukwenza kusebenze i-OX₁Icandelo licandelo eliyimfuneko lokuphendula okuqiniswe kukutya, ukukhuthaza, okanye zombini (Isalf okqhubekayo, 2010). Ukongeza, ii-neuron ze-LH OX zenziwa zasebenza ezihambelana nemivuzo encinci njengokutya (Harris okqhubekayo, 2005), ukucebisa ngendima enokubakho yenkqubo ye-OX ekuphenduleni imeko yangaphandle yendalo enxulunyaniswe nemiba yengqondo yokondla.

Iingxelo zamva nje ziyayixhasa indima yokubonakaliswa kwe-OX kwimpembelelo ekhuthazayo nakwimpembelelo yeziyobisi zokuxhatshazwa (Harris okqhubekayo, 2005; Borgland okqhubekayo, 2006; Jupp okqhubekayo, 2011; uphononongo, yabona I-Bonci kunye ne-Borgland, i-2009; UMartin-Fardon okqhubekayo, 2010). Ke, ukuvalwa kwe-OX₁R kunciphisa ethanol (Lawrence okqhubekayo, 2006) kunye nicotine ukuzilawulaHollander okqhubekayo, 2008), Inhibits-cue-invuselelo yokuvuselelwa kwe-ethanol- (Lawrence okqhubekayo, 2006), icocaine- (Smith okqhubekayo, 2010), kunye nokufuna-morphine (Harris okqhubekayo, 2005), kwaye iphinda ibeke uxinzelelo-olubangelwa kukuvuselelwa kwecocaine- (Iboutrel okqhubekayo, 2005-Ukufuna-ethanolIzityebi okqhubekayo, 2008). Ngapha koko, ubungqina bamva nje budibanise ne-OX₂Iindlela zokukhetha-kumvuzo wokufumana utywala kunye nokuziphathaShblock okqhubekayo, 2011).

Ubungqina buqokelela ukuba ukutyeba okuthe kratya kokutya okuthile phantsi kweemeko ezithile kuvelisa isimilo kunye notshintsho kwingqondo olufana nelizwe elinomlutha (igolide okqhubekayo, 2003; UKenny, 2011; IPelchat okqhubekayo, 2004; Oats okqhubekayo, 2008; Ifland okqhubekayo, 2009; IGearhardt okqhubekayo, 2011a). Iinkqubo ze-Neural ezikhuthaza kunye nokomeleza ukusetyenziswa gwenxa kweziyobisi ziye zacetyiswa kwiindlela zokuziphatha ezinxulunyaniswa nokufuna ukutya kunye nokutya ukutya (UJohnson noKenny, i-2010; I-Hoebel, 1985; IVolkow kunye neWise, 2005; UCorwin okqhubekayo, 2011; IGearhardt okqhubekayo, 2011b; wang okqhubekayo, 2011). Ezi ziphumo ziphakamise umbuzo wokuba ngaba inkqubo ye-OX inokuba nayo nendima yokuphazamiseka kwindlela yokutya ebonakaliswa yiziqendu ezinyanzelekileyo zokuxinana, ezinjenge-bulimia amanosa kunye neBED.

Ke ngoko, olu phononongo lwalunenjongo yokuphanda iziphumo ze-OX ezimbini₁/ OX₂I-antagonist SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (UDi Fabio okqhubekayo, 2011), i-OX ekhethiweyo₁I-antagonist GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi okqhubekayo, 2011), kunye ne-OX ekhethiweyo₂I-antagonist JNJ-10397049 (N- (2,4-dibromophenyl) -N′ - [(4S,5S) -2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl] urea) (McAtee okqhubekayo, 2004; Dugovic okqhubekayo, 2009) kwimodeli ye-BE echazwe ngu Cifani okqhubekayo (2009), apho iziqendu ze-HPF ze-HPF zikhutshelwa kwiigundane zabasetyhini ngemijikelezo yothintelo lokutya / ukutya kwakhona kunye noxinzelelo olukhulu. Abachasi abathathu bavavanywa kuqala in vitro kwi-rat ephindaphindayo ye-OX₁R kunye ne-OX₂Ukumisela ubungakanani bazo kunye nokuqinisekisa ukukhetha kwabo kwezi zinto zimbini zangaphantsi ezilandelelanayo. Iichemacokinetics (PKs) zazo ziye zavavanywa kwaye iidosi zakwazi ukukhupha iimpembelelo ze-hypnotic zamiselwa kwimodeli yokulinganisa ukulala. Ekugqibeleni, iikhompawundi zavavanywa kwiidosi ezichaziweyo kwimodeli ye-BE.

IMPAHLA NENKQUBO

izilwanyana

Lonke uphando olubandakanya izilwanyana lwenziwa ngokungqinelana nomyalelo wase-Europe u-86/609 / EEC olawula intlalontle yezilwanyana kunye nokukhuselwa, nto leyo eyavunywa nguMthetho wase-Itali waseMelika. 116, 27 Januwari 1992, nangokophononongo lwangaphakathi olwenziwe yiGlaxoSmithKline Committee of Animal Research & Ethics (CARE) nakwinkampani yeNkqubo malunga noKhathalelo kunye nokuSetyenziswa kwezilwanyana zaselebhu.

Imithi

I-SB-649868 (UDi Fabio okqhubekayo, 2011), GSK1059865 (Gozzi okqhubekayo, 2011), kunye neJNJ-10397049 (McAtee okqhubekayo, 2004) zenziwe kwiiLabhoratri ze-GSK. I-OXA yanikezelwa yiCalifornia Peptides Research (ikati. 471-99, CA). Myo- [1,2-3H(N)] i-inositol (NET-906, imisebenzi ethile: 51 Ci / mol) kunye ne-yttrium silrate RNA binding beads (RPNQ0013) ithengwe kuPerkin-Elmer (Italy). I-Topiramate (iTopamax; iJanssen-Cilag) ithengwe eJanssen-Cilag. Yayifumaneka kumacwecwe, ancitshiswa aba ngumgubo ngaphambi kolawulo.

Uvavanyo lwe-1: Inkuthazo ye-SB-649868, JNJ-10397049, kunye ne-GSK1059865 kwi-Rat OX₁I-Rat OX₂R

Inkcubeko yeseli

Iiseli ze-basophil leukemia zihanjiswa ngokuzinzileyo nge-rat OX₁R (rOX₁I-R) okanye i-rat OX₂R (rOX₂I-R) yafunyanwa kwi-α-MEM (i-Invitrogen / GIBCO) eyongezwe nge-10% ye-fetal bovine serum (FBS, PAA), 100 U / ml penicillin G, 100 U / ml streptomycin (Ipena / Strep; i-Invitrogen / GIBCO), kunye ne-400 I-μg / ml geneticin (i-Invitrogen / GIBCO), kwi-37 ° C nge-5% CO₂ Kwindawo enomswakama.

Ukuqokelelwa kwe [³H] inositol phosphates (i-IPs)

Ukuqokelelwa kwe [³H] inositol phosphates (IPs) yalinganiswa njengoko kuchaziwe ngaphambili (Ndityisiwe okqhubekayo, 2003) ngezihlengahlengiso ezilandelayo. Imigca yeseli iveza rOX ngokuqinisekileyo₁R okanye i-rOX₂I-R yayihlwayelwe kwiiplate ze-96-kakuhle zethayile kwi-3 × 10⁴ iiseli kakuhle kunye ne-1.5 × 10⁴ iiseli kakuhle, ngokulandelanayo, kwi-α-MEM eyongezwe nge-10% FBS kunye nePeni / Strep ngaphandle kofuzo. Emva kwe-24 h, inkcubeko ephakathi yayifunwa kwaye i-100 μl ye-medium medium eyongezwe i-10 μCi / ml NET-906 (Perkin-Elmer) yongezwa kwiseli; ke, i-1 μCi ye-radiolabeled inositol yasetyenziswa equleni ngalinye. Emva kwe-16 h ye-incubation, iiseli zahlanjwa kabini nge-assay buffer (1 × HBSS, 20 mM HEPES (pH 7.4), kunye ne-0.1% ye-bovine serum albhamuin kunye ne-10 mM LiCl), ngaphambi kokongezwa kwe-agonists okanye abachasi. I-antagonists yafakwa kwi-30 min kwi-37 ° C ngaphambi kokuvuselelwa kwe-agonist. Iingqokelela zokuphendula (CRCs) ze-OXA ukusukela kwi0.0001 ukuya kwi10 μM zenziwa. Emva kwe-1 h yokufakwa ngaphakathi kwi-37 ° C, i-buffer ye-assay yafunwa, i-80 μl ngequla ngalinye le-0.1 M ye-ice-ebandayo yongezwa, kwaye iiseli zashiyelwa i-30 min incubation kubushushu begumbi. Umlinganiso we-20 μl yokukhutshwa kweseli yongezwa kwi-80 μl ye-yttrium silicate beads (YSi SPA; Perkin-Elmer; 12.5 mg / ml), ishukunyiselwe i-1 h kubushushu begumbi, kwaye ishiywe kwi-4 ° C kwi-2 h ngaphambili ukubala kwiPackard ephezulu-ye-NXT Microplate Scintillation Counter.

Idatha ibonakaliswe njenge-% eyona mpendulo ye-agonist ibalwe ngolu hlobo lulandelayo:% eyona mpendulo ye-agonist = (cpm_umchasiNgentsimbi yesibini_isiseko) / cpm_{iimpendulo eziphezulu}Ngentsimbi yesibini_isiseko) × 100.

I-In vitro uhlalutyo kwedatha

Ii-CRC zazilungiselelwe ngohlalutyo lwe-sigmoidal nonlinear regression esebenzisa iGraphPad Prism 5.0 isoftware (Isoftware yeGraphPad, iSan Diego, CA) ukufumana i-agonist EC₅₀ (uxinzelelo lwe-agonist olufunekayo ukufumana i-50% yempendulo enkulu).

Ubuninzi (K_B= ukuchasana okungagungqiyo ngokungagungqiyo) zabachasi abangaguqukiyo zachazwa ngokusetyenziswa kwemodeli yokulinganisa yokusebenza yokungafikeleliyo kukhuphiswano (Kenakin okqhubekayo, 2006). I K_B Ixabiso lezinto ezichasayo zabalwa ngohlalutyo lukaSchild (I-Arunlakshana kunye neSchild, 1959). Kwi-SB-649868 kuphela komchasi we-IC₅₀ ibaliwe. Sicebe impendulo eveliswe yi-1 μM OXA ngokungabikho kunye nobukho bokugxila okungafaniyo komntu ochasayo. NDIYABONA₅₀ ichazwa njengolu xinzelelo lwembambano efunekayo ukuthintela i-50% impendulo eveliswe yi-agonist. Iziphumo zibonakalisiwe njenge-PEC₅₀ (−log₁₀ EC₅₀), ipheK_B (−log₁₀ K_B), okanye i-pIC₅₀ (−log₁₀ IC₅₀), kwaye ziboniswa njengezingenantsingiselo ± I-SEM okanye intsingiselo ye-95% yemida yokuqiniseka (95% CL) ubuncinci beemvavanyo ezintathu ezizimeleyo. Zonke izidakamizwa ezivavanyiweyo zachithwa kwi-dimethyl sulfoxide (DMSO) kwaye zaphinda zaxutywa kwi-buffer ye-assay yokunika uxinzelelo lokugqibela lwe-DMSO olungadluli kwi-0.5%.

Ukuzama i-2: Ukuqulunqwa kwePK kwiigundane zaBesilisa nabasetyhini

Ukuvavanya ukuboniswa kwegazi kwe-PK ukulala kunye nezifundo ze-BE, iiprofayili zePK zemixube ziye zahlalutywa kwiirhasi zowesilisa nabasetyhini kwiimeko ezifanayo zokuvavanya ukulala kunye novavanyo lwe-BE. Iiprofayili zePK ziphandwe emva kolawulo nge-gavage ye-3 mg / kg SB-649868 kwimigundwane yabasetyhini nabesilisa, ulawulo lwe-10 mg / kg kwibhinqa kunye ne-5 mg / kg kwimigundane yamadoda ye-JNJ-10397049 Iigundane zabasetyhini kunye nolawulo olunomdla kumagazi angamadoda e-10 mg / kg ye-GSK1059865. Iisampulu zegazi zaqokelelwa ngethambo lobufazi ngamathuna ukuya kuthi ga kwi-4 h emva kolawulo. Iisampulu ze-Brain zaqokelelwa ekupheleni kovavanyo. Uxinzelelo lwe-SB-649868, JNJ-10397049, kunye ne-GSK1059865 egazini kunye neesampuli zengqondo kumiselwe ngokusebenzisa indlela esekwe kukuchaneka kweprotein kulandele uhlalutyo lwe-HPLC-MS / MS. Iiparameter ezingezizo iicandelo zePK zaye zafunyanwa kwiinkonzo zegazi − ixesha lokuphatha kusetyenziswa iphakheji yeWinNonlin v.4.0 (Pharsight, Mountain View, CA). Iiparamitha ze-PK zibonakalisiwe njengezingenantsingiselo ± SD (Funda kunye neBraggio, 2010).

Uvavanyo lwe-3: Isiphumo se-SB-649868, JNJ-10397049, kunye neGSK1059865 kwimodeli yokulala yeRat

izilwanyana

I-Male Sprague-Dawley rats (275-300 g; Charles River, Calco, Como, Italy) zigcinwe zodwa kwindawo yomjikelo we-12-h ukukhanya-komnyama (kukhanya kwi-0300 h) i-1 kwiveki ngaphambi kotyando. Ukufikelela kukutya namanzi kwakuvunyelwe ad adum. Ukuqokelela imiqondiso ye-biopotential, i-miniature multichannel telemetric transmitter (TL10M3-F40-EET; Idatha yezeNzululwazi Int.) Yayifakelwe ngaphakathi izilwanyana. Ii-electrod ezimbini zaye zalungiswa ngokusisigxina ngamazinyo kwisamente ukurekhoda i-cortical electroencephalogram (EEG). Babenxibelelana ngokuthe ngqo ne dura mater ngemingxunya emibini egrunjwe ngommandla we-Fronto-parietal. Ezinye i-elektrode ezimbini zazilungisiwe kwimisipha emathanjeni, yokurekhoda i-electromyograph (EMG) okanye kwingingqi ye-periorbital yeso ukurekhoda i-electrooculogram (EOG).

Ukurekhoda

Emva kokuphola emva koqhaqho, izilwanyana zigcinwe kwindawo yazo esekhayeni kwindawo elawulwa ngamaqondo obushushu (21 ± 1 ° C) ngokufumana ukutya namanzi ad adum. Izilwanyana ezifakwayo zibonakalise ukuziziphatha ngendlela eqhelekileyo emva nje kokuphola kuqhaqho. Nangona kunjalo, ukuvumela iipateni zokulala eziqhelekileyo ukuba ziphinde zenziwe, izilwanyana zasetyenziswa emva kwexesha leveki ye-3. Iimeko zokusingqongileyo ezichazwe apha ngasentla bezigcinwe kwizifundo zonke zokulala. Ngexesha lokuvavanywa, izilwanyana ezihamba ngokukhululekileyo zahlala kwizindlu zazo zamakhaya kwizifumene. Iimpawu ze-EEG kunye ne-EMG okanye ze-EOG zazirekhodwa ngokuqhubekayo kusetyenziswa i-DSI yedatha yokubuza idatha I-EEG yomkhondo, eyahlulahlulwe yangama-10-s epochs, yatshintshwa ngokwedijithali (inguqu ye-FFT) ukubonelela ngombane wamandla δ, θ, α, yaye β iibhendi ukwahlula iipatheni ezintathu ezahlukeneyo zomsebenzi kwi-rat (vuka, ukulala kweNREM, kunye nokulala kweREM). Amakishi anikwe inkqubo yokufaka amanqaku ngokuzenzekelayo (Inqanaba lokulala, i-DSI) yahanjiswa kumqondiso wedijithali we-EEG kwaye emva koko yaqinisekiswa ngovavanyo lokujonga lwe-EEG kunye ne-EMG / EOG yokulandelwa ngabaqhubi abaqeqeshiweyo, abangaboniyo kunyango lweziyobisi. Uhlalutyo lweeparamitha zokulala zibandakanyiwe: i-latency ukuya kwi-NREM yokulala (ixesha lokuphumla ukuya kwii-epochs zokuqala ezilandelelanayo ze-NREM emva kwenaliti)) ixesha lokulala.

Unyango lweziyobisi

Unyango lwamachiza lwenziwa ngokwendlela ehleliweyo yengubo ye-crossover apho, kwiiseshoni zovavanyo ezahlukeneyo, isilwanyana ngasinye safumana isithuthi okanye unyango ngeziyobisi. Iigundane zaziphathwa ngentsimbi yovavanyo okanye imoto ehamba nayo, kumthamo we-2 ml / kg, i-6 h emva kokucima isibane (sexesha le-Circadian (CT) 18). Ushicilelo lwenzelwa ixesha elilandelayo lovavanyo lwe3-h. I-SB-649868 yachithwa kwi-0.5% HPMC (hydroxy-propyl-methyl-cellulose) (w / v) kumanzi afakwe emanzini kwaye yalawulwa yi-gavage kwi-doses ye-3 kunye ne-10 mg / kg. I-JNJ-10397049 yachithwa kwi-mygliol 812N, yaze yalawulwa ngokukuko kwiidosi ze-5 kunye ne-25 mg / kg. I-GSK1059865 yachithwa kwi-0.5% HPMC (w / v) kumanzi afakelweyo kwaye ilawulwa ngokuchanekileyo kwimithamo ye-5 kunye ne-25 mg / kg.

Uhlalutyo lwedatha

Yonke idatha ibonakalisiwe njengentsingiselo ye-SEM. Iziphumo zahlalutywa kusetyenziswa uhlalutyo lwendlela enye yokwahluka (ANOVA). Post-hoc uthelekiso lwenziwa novavanyo lukaDunnett. Ubalo lweenkcukacha manani lwacwangciswa P

Uvavanyo lwe-4: Ukutya kakhulu

izilwanyana

Iigundane zabasetyhini-i-Sprague-Dawley (Charles River) zasetyenziswa. Ubunzima bomzimba wabo yayingu-225-250 g ekuqaleni kovavanyo. Iigundane ziye zanxityaniswa kwizikhewu eziphakathi komjikelo we12-h / umjikelo wobumnyama (ukukhanya kwi-0800 h) nge ad adum chow kunye namanzi kwiiveki ze-2 ngaphambi kweemvavanyo. Zigcinwe kwigumbi elinobushushu obungaguqukiyo (20-22 ° C) kunye nomswakama (45-55%). Iigundane zigcinwe kwizindlu ezixhonywe ngodonga olunye; umgangatho nodonga lwangaphambili lwalwenziwe ngegridi yentsimbi. Ubungakanani bomgangatho wekholeji babungama-30 cm x 30 cm; i-cage yayiyi-30 cm ukuphakama. Umnyango wangaphambili (30 cm x 20 cm) edityaniswa ngegridi yentsimbi wawukhona kudonga olungaphandle lwe-cage ukuvumela ukufikelela ngaphakathi kwecala. Inxalenye eseleyo yedonga langaphambili yayixhotywe nge-Burette yokusela.

idayethi

Izilwanyana zanikwa iipellets zokutya ezisemgangathweni, i-4RF18 (Meduola; Settimo Milanese, Milano, Italy; 2.6 kcal / g). I-HPF yayilicwecwe elilungiselelwe ngokuxuba uNutella (Ferrero, Alba, Torino, Italy) ukhilimu wetshokholethi (5.33 kcal / g; 56%, 31%, kunye ne-7% evela kwi-carbohydrate, amanqatha, kunye neeproteni, ngokulandelanayo), iipellets zokutya okusekwe emhlabeni ( I-4RF18; Meduola; Settimo Milanese), kunye namanzi kwinqanaba elilandelayo / i-boima pesenti: 52% Nutella, 33% pellets yokutya, kunye ne-15% yamanzi. Ukutya kwe-HPF yayinomxholo we-caloric we-3.63 kcal / g. Iipellets ezisemgangathweni zazinikezelwa ngaphakathi kwisikhongozelo sentsimbi egreyidi leyo yayixhonywa kudonga lwangaphandle lwekhoji; isuswe kwikheji yokulinganisa ubunzima bayo ukumisela ukutya i-pellet yokutya. I-HPF yanikezelwa kwikomityi yekofu; Ukuphathwa kwekomityi kufakwe kwigreyidi yentsimbi engaphandle kweleji kwaye yaxhonywa eludongeni.

Inkqubo yoxinzelelo

Kwimizuzu ye-15, ikomityi yekofu yase-China ene-HPF ibekwe ngaphakathi kwisikhongozeli sensimbi egxunyekwe eludongeni olungaphandle lwe-cage. Kule meko, isilwanyana sakwazi ukubona ikomityi apho yafumana i-HPF ngeentsuku 5, 6, 13, kunye ne-14 yomjikelo wokuqala wokuqala, yakwazi ukuyibona ngokwayo i-HPF, kwanokuhoya ivumba layo. Ngeli xesha le-15-min, i-rat ebandakanyeka kwiintshukumo eziphindaphindiweyo zangaphambili, intloko, kunye netrunk, ijolise ekufumaneni i-HPF, kodwa ayikwazanga ukufikelela kuyo.

Oku kuvelise imeko yoxinzelelo ngobumnene ebangela ukwanda okukhulu kumanqanaba e-serum corticosterone (Cifani okqhubekayo, 2009). Emva kwe-15 min, ikomityi ibekwe ngaphakathi kwe-gage yamagundane amaqela oxinzelelo, ukuze i-HPF ifikeleleke kuwo.

Unyango lweziyobisi

Ngomhla we-25, iikhompawundi okanye imoto eyahlukeneyo yanikwa ngaphambi kokufikelela kwi-HPF. I-SB-649868 yachithwa kwi-0.5% HPMC (w / v) kumanzi afakelweyo kwaye ilawulwa yi-gavage kwi-doses ye-1 kunye ne-3 mg / kg. I-Topiramate yachithwa kwi-0.5% HPMC (w / v) kumanzi afakwe emanzini kwaye yalawulwa yi-gavage kwi-dosi ye-60 mg / kg. I-JNJ-10397049 yachithwa kwi-0.5% HPMC (w / v) kumanzi afakwe emanzini kwaye yalawulwa ngokukuko kumathamo e-1 kunye ne-3 mg / kg. I-GSK1059865 yachithwa kwi-0.5% HPMC (w / v) kumanzi afakelweyo kwaye ilawulwa yi-gavage kwi-doses ye-10 kunye ne-30 mg / kg. Zonke iziyobisi okanye imoto yazo yayiqhutywa nge-1 h ngaphambi kokufikelela kwi-HPF.

Uvavanyo lwe-4A: Iziphumo zeSB-649868 kunye neTopiramate

Ukuvavanya indima yabachasene ne-OXR kwi-BE, umchasi we-OXR engakhethiyo, i-SB-649868, yavavanywa kwimodeli yethu ye-BE.

Izilwanyana zahlulwa zaba ngamaqela amane ezilwanyana ze-27 isilwanyana ngasinye, esihambelana nomzimba kunye nokutya ukutya kwemihla ngemihla: (1) engathintelwanga kwaye ingachazwanga kuxinzelelo (NR + NS) iqela; (2) isithintelo kwaye singaboniswanga kwixinzelelo (R + NS) iqela; (3) engathintelwanga kwaye iveze uxinzelelo (NR + S) iqela; kunye (4) isithintelo kwaye siveze uxinzelelo (R + S) kwiqela. Nje ukuba yabelwe kwelinye lala maqela, iigundane zahlala kwiqela lonke kwisifundo. Iigundane ezivezwe kuxinzelelo zazikhutshelwa kwigumbi elahlukileyo kunelo lamaqela angakhanyiswanga kuxinzelelo. Iigundane zazivezwa kwimijikelezo yemini emithathu ye-8-elandelwa ngovavanyo lokugqibela ngosuku lwe-25 (1 Table):

Ishedyuli eyamkelweyo ukuba ivise ukuTya ngokuBambisa

Iqela le-NR + NS laline-chow ad adum Ngeentsuku ze-4, ngeentsuku 5 kunye ne-6 bafumana i-chow + HPF ye-2 h; ngeentsuku 7 kunye ne8 babenazo i-chow ad adum; kwaye ngemini 25 babengakhange baboniswe uxinzelelo;
Iqela lesibini laline-chow kunye ne-HPF njenge-NR + NS, kodwa ngosuku lovavanyo (usuku lwe-25) bavezwa koxinzelelo (NR + S);
Iqela lesithathu (i-R + NS) lalithintele i-66% yexesha eliqhelekileyo leentsuku ze-4, banikwa i-chow kunye ne-HPF (2 h) ngeentsuku ze-5 kunye ne-6 kunye ne-chow kuphela ngeentsuku ze-7 kunye ne-8; ngemini 25 khange babonakale kuxinzelelo.
Iqela le-R + S lalithintele kwi-66% yeyona nto yesiqhelo yeentsuku ze-4, banikwa i-chow kunye ne-HPF (2 h) ngeentsuku ze-5 kunye ne-6 kunye ne-chow kuphela ngeentsuku ze-7 kunye ne-8; kwaye ngemini ye-25 bavezwa uxinzelelo.

Umjikelo weentsuku ze-8 waphindwa kathathu, kodwa kumjikelo wesithathu izilwanyana zazingenako ukufikelela kukutya kwe-HPF.

Ngomhla i-25, iqela ngalinye leerenti ze-27 zahlulahlulwa zaba ngamaqela amancinci amathathu kwaye zaphathwa, ngokulandelanayo, ngesithuthi, i-SB-649868, 1 okanye i-3 mg / kg, enikezwe yi-gavage 1 h ngaphambi kokufikelela kwi-HPF.

Ukuthathwa kwe-HPF kubonakaliswe njengokukhula kcal / kg ngokufakwa ± SEM; Ukufunwa kwe-HPF kulinganiswe kwi-15, 30, 60, kunye ne-120 min emva kokuqala kokufikelela. Ukutya kwe-pellet yokutya kwakulinganiswa kuphela kwi-120 min, kuba iziphumo zophando lwangaphambili zibonisa ukuba ukutya i-pellet yokutya yayincinci kakhulu, kunye nokuphepha ukuphazamiseka kwizilwanyana ngexesha lovavanyo.

I-Topiramate, esetyenziswe njengesixhobo sokuchaza le paradigm yovavanyo (Cifani okqhubekayo, 2009), kuvavanywe kwiigundane ezifanayo, iintsuku ze-10 emva kokuphela kovavanyo lwe-SB-649868. Kwezi zilwanyana ze-108, i-72 yahlulwa yangamaqela amane (izilwanyana ze-18 kwiqela ngalinye) ezichazwe ngaphambili. Emva kosuku olunye ekuphumeni kovavanyo lokuqala, la maqela eerhasi afumane umjikelo weentsuku ze-8 ezongeziweyo: amaqela e-NR + NS kunye ne-NR + S ayeneentsuku ze-8 ze-chow ad adum, ngelixa i-R + NS kunye ne-R + S amaqela eneentsuku ze-4 zos zithintelwe kwi-66% yokufumana okuqhelekileyo kulandelwa ziintsuku ze-4 ad adum. Kulomjikelo ongezelelweyo, onke amaqela ebengenako ukufikelela kwi-HPF. Ngemini elandelayo, amaqela e-NR + S kunye ne-R + S atyhilwa ngoxinzelelo, ngelixa amaqela e-NR + NS kunye ne-R + engekho. Ngolu suku, i-topiramate (60 mg / kg) okanye imoto yayo yayiqhutywa nge-gavage 1 h ngaphambi kokufikelela kwi-HPF.

Uvavanyo lwe-4B: Iziphumo zeJNJ-10397049 kunye neGSK1059865

Ukuphanda i-OXR ebandakanyekayo ekunciphiseni iziqendu ze-BE, i-OX ekhethiweyo₂I-antagonist, JNJ-10397049, kunye ne-OX ekhethiweyo₁I-antagonist, i-GSK1059865, yavavanywa kwimodeli yethu ye-BE.

Iirhasi zowesifazane ezongezelelweyo ze-54, ezahlulahlulwe zangamaqela amabini (i-NR + NS kunye ne-R + S) yamagundane e-27, zangeniswa kwinkqubo efanayo yovavanyo njengakwilingo le-4A. Kuphela ngamaqela amabini eagundane asetyenzisiweyo koluvavanyo njengoko zombini i-NR + S kunye nee-R + NS ziye zangabonisi ukuba yi-BE. Ngosuku lovavanyo (ngemini ye-25), i-1 h ngaphambi kokufikelela kwi-HPF, iigundane zaphathwa nge-JNJ-10397049 (1 kunye ne-3 mg / kg) okanye isithuthi sayo.

Emva kosuku olunye ekuphumeni kovavanyo lweJNJ-10397049, iqela elifanayo lamagundane lafumana umjikelo weentsuku ze-8 ezalandelwa ngosuku 10 (njengoko kuchaziwe kulingo lwangaphambili) ngonyango lwe-GSK1059865. I-GSK1059865 (10 kunye ne-30 mg / kg) okanye imoto yayo yayiqhutywa nge-gavage 1 h ngaphambi kokufikelela kwi-HPF.

Uhlalutyo lwedatha

Yonke idatha ibonakalisiwe njengeentsingiselo ± I-SEM kwaye ixabiso ngalinye libonisa intsingiselo yenani lezilwanyana kwiqela ngalinye njengoko kuchaziwe kwiintsomi. Idatha yahlalutywa ngeendlela ezimbini i-ANOVA ngokuthelekisa phakathi kwesifundo sokuhlola amaqela okanye unyango ngamachiza, kunye nokuthelekisa okungaphakathi kwesihloko ixesha lokujonga. Post-hoc uthelekiso lwenziwa ngovavanyo lweBonferroni. Ukubaluleka kobalo kubekiwe P

IINKCUKACHA

Uvavanyo lwe-1: Inkuthazo ye-SB-649868, JNJ-10397049, kunye ne-GSK1059865 kwi-ROX₁I-R kunye ne-ROX₂R

I-OXA (0.1 nM-10 μM) yonyuse i- [³H] Ukuqokelelwa kwe-IP ngendlela yokuxhomekeka koxinzelelo kunye ne-pEC₅₀ Ixabiso le-7.79 ± 0.04 (n= 16) kunye 7.68 ± 0.04 (n= 16) kwi-ROX₁I-R kunye ne-ROX₂R, ngokulandelelana. Kwi-ROX₁I-R, JNJ-10397049 (1 μM-33 μM; Umzobo 1a) kunye ne-GSK1059865 (0.3 nM-10 nM; Umzobo 2a) Uvelise ubuchasi obungenakuchithwa kunye nokutshintsha okuxhomekeke ekunene kwe-OXA EC₅₀ kunye nokwehla okubonakalayo kwempendulo enkulu ye-agonist. Kubalwe pK_B amaxabiso yayiyi-5.73 ± 0.16 (n= 3) kunye 8.77 ± 0.12 (n= 3) yeJNJ-10397049 kunye neGSK1059865, ngokwahlukeneyo. I-SB-649868 (0.1, 0.3, 0.6, kunye ne-1 nM) (Umzobo 3a) Uvelise ukunciphisa okukhulu kwe-OXA impendulo enkulu, ngaphandle kokutshintsha kwe-agonist EC₅₀. I-pIC eqikelelweyo₅₀ Ixabiso yayingu-9.46 ± 0.02 (n= 3). Kwi-ROX₂I-J JNJ-10397049 (10 nM-0.3 μM) (Umzobo 1b) kunye ne-GSK1059865 (0.1-3.3 μM) (Umzobo 2b) uvelise iprofayili yodidi olungumlinganiso kunye nokutshintsha okufanayo kwe-OXA EC₅₀ ngaphandle koxinzelelo lwempendulo enkulu ye-agonist. Imithambeka efunyenwe kuhlalutyo lokubuyela umva kukaSchild yayiyi-1.17 (95% CL 0.92-1.42) kunye ne-0.86 (95% CL 0.71-1.00) yeJNJ-10397049 kunye ne-GSK1059865, ngokwahlukeneyo, kwaye zazingahlukanga ngokwamanani (P> 0.05). Ukuthintela amathambeka ukuya kwelinye, ipheK_B amaxabiso yayiyi-8.49 (95% CL 8.34-8.63; n= 3) kunye ne-6.90 (95% CL 6.80-6.99; n= 3) yeJNJ-10397049 kunye neGSK1059865, ngokwahlukeneyo. I-SB-649868 (0.1-3.3 nM) (Umzobo 3b) uvelise iddi-ekunene ethembekileyo yokutshintsha kwe-OXA EC₅₀, ehamba kunye nokwehliswa kwempendulo enkulu ye-agonist. Ngokusebenzisa imodeli yokusebenza yohlalutyo lobuhlanga olungenakho ukhuphiswano, njengoko kuchaziwe kwizixhobo kunye neeNdlela, apK_B Ixabiso le-9.35 ± 0.15 (n= 3) ibaliwe.

Umzobo 1

[³I-H] inositol phosphates (IPs) ingqokelela yamanani aqokelelweyo (yi-CRC) ye-orexin-A (OXA) (•) kwiiseli ze-basophil leukemia (RBL) iiseli ezibonisa: i-OX₁R (rOX₁R) (a) phambi kwe-1 (Δ), 3.3 (▾), 10 ...

Umzobo 2

[³I-H] inositol phosphates (IPs) ingqokelela yamanani aqokelelweyo (yi-CRC) ye-orexin-A (OXA) (•) kwiiseli ze-basophil leukemia (RBL) iiseli ezibonisa: i-rOX₁R (a) phambi kwe0.3 (▴), 1 (▾), 3.3 (♦) ...

Umzobo 3

[³I-H] inositol phosphates (IPs) ingqokelela yamanani aqokelelweyo (yi-CRC) ye-orexin-A (OXA) (•) kwiiseli ze-basophil leukemia (RBL) kwiiseli ezibonisa: iROX₁R (rOX₁R) (a) phambi kwe0.1 (□), 0.3 (Δ), ...

Ukuzama i-2: Ukuqulunqwa kwePK kwiigundane zaBesilisa nabasetyhini

Ukuchongwa kwe-PK kwiirhasi zamadoda kuphandiwe kwiimeko ezifanayo zokuvavanya njenge-Test 3, kwaye zibonisiwe kwi 2 Table.

IParacokinetic Parameters ze-SB-649868, JNJ-10397049, kunye ne-GSK1059865 kwi-Male Sprague-Dawley Rats

C_max ye-SB-649868 kwi-3 mg / kg yayiyi-333 ± 52 ng / ml kunye ne-AUC 1260 ± 262 ng^*h / ml.

C_max ye-JNJ-10397049 kwi-5 mg / kg yayiyi-14.2 ± 1.0 ng / ml kunye ne-AUC 64 ± 4.3 ng^*h / ml.

C_max ye-GSK1059865 kwi-10 mg / kg yayiyi-366 ± 70 ng / ml kunye ne-AUC 1290 ± 320 ng^*h / ml.

Ukuchongwa kwe-PK kwiirhasi zabasetyhini kuphandwe kwiimeko ezifanayo zokuvavanya njenge-Test 4, kwaye zibonisiwe kwi 3 Table.

IParacokinetic Parameters ze-SB-649868, JNJ-10397049, kunye ne-GSK1059865 kwi-Female Sprague-Dawley Rats

C_max ye-SB-649868 kwi-3 mg / kg yayiyi-572 ± 115 ng / ml kunye ne-AUC 1708 ± 331 ng^*h / ml.

C_max ye-JNJ-10397049 kwi-10 mg / kg yayiyi-369 ± 97 ng / ml kunye ne-AUC 457 ± 224 ng^*h / ml.

C_max ye-GSK1059865 kwi-10 mg / kg yayiyi-268 ± 29 ng / ml kunye ne-AUC 768 ± 46 ng^*h / ml.

Uvavanyo lwe-3: Isiphumo se-SB-649868, JNJ-10397049, kunye neGSK1059865 kwimodeli yokulala yeRat

Iprofayili ye-hypnotic ye-OXR antagonists yavavanywa ngaphezulu kwexesha le-3-h kwisigaba esisebenzayo somgangatho, iqala isigaba sokurekhoda kwi-CT 18 (izibane zicinywe kwi-CT 12) yomjikelezo wokukhanya komnyama. I-CT 18 ikhethwe ngokukhethekileyo ukuba ivumele iwindow enkulu yokuvavanya iimpembelelo ze-hypnotic of compounds.

Kule meko yokuvavanywa, i-OX kabini₁/ OX₂I-antagonist i-SB-649868 (3 kunye ne-10 mg / kg, nge-gavage) yabangela ukwehla okuqinileyo kokuvuka (F (2, 21) = 22.9; P<0.01), kunye nokwehla kokulala (F (2, 21) = 9.11; P<0.01) xa kuthelekiswa neqela lolawulo. Uvavanyo lukaDunnett emva kwe-ANOVA lubonise isiphumo esibalulekileyo kwi-3 kunye ne-10 mg / kg (P<0.01) kuzo zombini iiparameter zokulala. Uhlalutyo lweepateni zokulala lubonisa ukwanda kuzo zombini i-NREM kunye nokulala kwe-REM kuzo zombini iidosi (Itheyibhile 4a).

Iziphumo ze-SB-649868 (nguGavage) kwiParamitha zokulala kwiiRats

I-OX ekhethiweyo₂I-antagonist JNJ-10397049 (5 kunye ne-25 mg / kg, ngokungabinamali) ibonise isiphumo se-hypnotic, njengoko kutyhilwe kukuhla kwe-wakeness (F (2, 14) = 18.8; P<0.01) kunye nokulala emva kwexesha (F (2, 14) = 4.8; P<0.05). Uvavanyo lukaDunnett olulandela i-ANOVA lubonise ukuba ukwehla kwakubalulekile ngokwezibalo kuzo zombini i-5 kunye ne-25 mg / kg (P<0.01 yokuvuka kunye P<0.05 yokulala kade). Ukonyuka kokulala kwe-NREM kwaqwalaselwa kuzo zombini iidosi (P<0.01), kodwa akukho siphumo saqwalaselwa kukulala kwe-REM (Itheyibhile 4b).

Iziphumo zeJNJ-10397049 (ip) kwiiParamitha zokulala kwiiRats

I-OX ekhethiweyo₁R i-antagonist GSK1059865 (5 kunye ne-25 mg / kg, ngokungabinamali) ivelise umkhuba wokunciphisa ukuphaphama (F (2, 14) = 3.27; P<0.05) kunye nokulala emva kwexesha (F (2, 20) = 1.73; P> 0.05). Uhlalutyo lweepateni zokulala lubonakalise ukwanda kuphela ekulaleni kwe-NREM, ngokwezibalo kubungakanani bedosi ephezulu yovavanyo (P<Uvavanyo lukaDunnett lulandela i-ANOVA); akukho siphumo saqwalaselwa kukulala kweREM (Itheyibhile 4c).

Iziphumo ze-GSK1059865 (ip) kwiiparamitha zokulala kwiiRats

Uvavanyo lwe-4A. IYA: Isiphumo se-SB-649868 kunye neTopiramate

I-ANOVA ityhile umehluko obonakalayo ekusetyenzisweni kwe-2-h HPF kula maqela mane ngamagundwane alandela ukuphathwa kwezithuthi (F (3, 32) = 13.81; P<0.01). Njengoko kubonisiwe kwi Umzobo 4, emva kolawulo lweenqwelo-mafutha ukuthatha inxaxheba kwe-HPF kwiqela le-R + yayinophawu oluphezulu kunolo lweqela lolawulo (i-NR + NS). Ukuthathwa kwe-HPF kweerandi ze-R + S kwakubhengezwa kakhulu kumzuzu wokuqala we-15 yokungena kuwo; Ukufunwa kwe-HPF kweqela le-NR + S kwakungekhohlukileyo kunelo lolawulo (NR + NS), nto leyo ebonisa ukuba uxinzelelo alwanelanga ukuba lube. Ngaphaya koko, ukuthathwa kwe-HPF kweqela le-R + NS kwakwehlukile kakhulu kulawulo (i-NR + NS), kubonakalisa ukuba imijikelezo yokuthintelwa kokutya akwanelanga ukubangela i-BE. Ke ngoko, i-BE inokubangelwa kukudibana okungafaniyo phakathi kokutya kunye noxinzelelo.

Umzobo 4

Iziphumo zokungena kwe-SB-649868 (1 kunye ne-3 mg / kg, nge-gavage) okanye imoto yayo kukutya okuthandekayo (HPF). Amaxabiso abonakaliswa njengento enesidima ± I-SEM yeempuku ezilithoba. ^**P<0.01, umahluko kwiigundane eziphathwe ngezithuthi; apho kungaboniswanga, ...

Ukuthathwa kweepellets zokutya ezisemgangathweni bekukuncinci kakhulu (malunga ne-3-4% ye-calories yonke yokutya kwi-2 h test), kwaye ayichaphazelekanga kukuthintelwa kokutya, uxinzelelo, okanye ukudityaniswa kokubini.

Njengoko kuboniswe kuyo Umzobo 4, I-SB-649868 inciphise kakhulu ukuthathwa kwe-HPF kwiqela le-R + S (F (2, 24) = 18.63; P<0.01), kodwa hayi kwamanye amaqela: NR + NS (F (2, 24) = 0.91; P> 0.05); R + NS (F (2, 24) = 0.16; P> 0.05); I-NR + S (F (2, 24) = 1.1; P> 0.05). Post-hoc ukuthelekisa kutyhila ukuba isiphumo se-SB-649868 kwiqela le-R + s sibaluleke kakhulu kulo lonke ixesha amanqaku aphendula impendulo ephezulu ye-3 mg / kg. Idosi ye-1 mg / kg kwiqela le-R + S ibonise imeko yokuncitshiswa engabalulekanga ngokwezibalo.

Uvavanyo lwe-topiramate lubonakalise umahluko obonakalayo ekusetyenzisweni kwe-2-h HPF (F (3, 32) = 3.93; P<0.01) yamaqela ahlukeneyo alandela ulawulo lwezithuthi. I-Topiramate elawulwa kwi-60 mg / kg yokukhetha kunciphise ukungena kwe-HPF (F (1, 16) = 6.57; P<0.01) kwiqela R + S (Umzobo 5), kodwa hayi kwi-NR + NS, NR + S, kunye neqela le-R + NS. Idatha ye-NR + S kunye namaqela e-R + yeNS ayiboniswanga.

Umzobo 5

Iziphumo zomphezulu we-topiramate (60 mg / kg, nge-gavage) okanye imoto yayo kukutya okuthandekayo (HPF). Amaxabiso abonakaliswa njengento enesidima ± I-SEM yeempuku ezilithoba. ^*P<0.05, umahluko kwiigundane eziphathwe ngezithuthi; apho kungaboniswanga, umahluko ...

Uvavanyo lwe-4B. IYA: Isiphumo seJNJ-10397049 kunye neGSK1059865

Ngokuya kuvavanyo lwangaphambili, i-ANOVA iqinisekisile ukuba iqela le-R + S libonakalise ukunyuka okukhulu kwe-HPF ye-ula (F (1, 16) = 16.17; P<0.01). I-JNJ-10397049 ayichaphazelekanga ukondla nokuba kukwiqela le-NR + NS (F (2, 26) = 0.23; P> 0.05) okanye kwiqela R + S (F (2, 24) = 0.49; P> 0.05) (Umzobo 6a).

Umzobo 6

Iziphumo zokungena kwe-JNJ-10397049 (1 kunye ne-3 mg / kg, intraperitoneally) (a) okanye i-GSK1059865 (10 kunye ne-30 mg / kg, nge-gavage) (b) kukutya kakhulu okufumaneka ngokutya (HPF). Amaxabiso abonakaliswa njengento enesidima ± I-SEM yeempuku ezilithoba. ^*P<0.05, umahluko ...

Iziphumo ezifunyenweyo zibonisa ukuba i-OX₂I-antagonism ayikhange ichaphazele indlela yokondla. Ngenxa yoko, isiphumo esibonwe ngaphambili nge-SB-649868 sasinokuconjululwa ngendlela eyi-OX₁Iindlela Ukuqinisekisa oku kufunyanwa, iOX ekhethiweyo₁I-R antagonist GSK1059865 (10 kunye ne-30 mg / kg) yavavanywa. I-ANOVA ibonakalise umahluko obonakalayo phakathi kwamaqela ngokuphendula kunyango lwezithuthi (F (1, 16) = 17.1; P<0.01), eqinisekisa isiphumo se-BE kwiqela le-R + S. I-GSK1059865 (kumthamo we-10 kunye ne-30 mg / kg) ayichaphazelekanga ukondla kwiqela le-NR + NS (F (2, 24) = 0.10; P> 0.05). Kwiqela le-R + S, i-ANOVA ibonise isiphumo esibalulekileyo (F (2, 23) = 4.20, P<0.05) (Umzobo 6b). Post-hoc ukuthelekisa kutyhila ukuba isiphumo se-GSK1059865 kwiqela le-R + kwi-doses ye-10 kunye ne-30 mg / kg yayinokubaluleka kwamanani kwi-15, 30, kunye ne-60 min emva kokufikelela simahla kwi-HPF.

UKUQALA

Ubungqina obuninzi bubonisa ukuba ukutya, uxinzelelo kunye neendlela ezimbi zichaphazela izizathu ze-BE kwizigulana ezine-BED okanye i-bulimia amanosa (Zolile okqhubekayo, 2000; UFreeman noGil, 2004). Ewe, amaxesha okutya atyholwayo axhaphakile kwimbali yabantu abatyebileyo, nangona indlala ngokwayo ingabonakali ngathi yanele ukuba ibekho kwi-BE yokungabikho koxinzelelo kunye nemeko yokuziphatha engentle (Iipolivy okqhubekayo, 1994; Amanzi okqhubekayo, 2001). Ubungqina obuqwalaselwayo bucebisa ukuba i-BE inokubangelwa kukudibana okungafaniyo phakathi kokutya kunye noxinzelelo; ke ngoko, uxinzelelo lwendalo kunye nembali yokuthintelwa kokutya okujikelezayo kunokuba noxanduva lokufika kwayo kunye nokugcina (Isitya okqhubekayo, 2001; Crowther okqhubekayo, 2001; Wolff okqhubekayo, 2000). Ngokuhambelana, izithintelo zokuphindaphindiweyo zokutya zihlala zinamandla okuxela ngokutya ngokuphendula uxinzelelo (Zolile okqhubekayo, 2000).

Ukudityaniswa kokutya kunye noxinzelelo nako kudlala indima ebalulekileyo kuphuhliso lwe-BE kwimodeli yethu yangaphambili. Kumzekelo ophuhliswe ngu Cifani okqhubekayo (2009), BE uphakanyiswa ngu-yo-yo kukutya kunye nokuveza uxinzelelo ku-HPF. Kule modeli, iigundane zabasetyhini zivezwa kwimijikelezo ephindaphindiweyo yezithintelo kunye nenkqubo yoxinzelelo ebonakaliswa kukuvezwa kwezilwanyana kwi-HPF ngaphandle kokufumana ukufikelela kuyo.

Njengoko kuchaziwe kwintshayelelo, iindlela ze-OX ziye zabethelelwa kulawulo lwasekhaya kunye nokondla okusekwe kumvuzo, nakwisishukumisi sesiyobisi sokuxhatshazwa (I-Bonci kunye ne-Borgland, i-2009). Ukuhambisana nombono wokuba iinkqubo ze-neural ezikhuthaza kunye nokomeleza ukusetyenziswa kweziyobisi gwenxa zinokuziphatha okukhoyo okuhambelana nokufuna ukutya kunye nokutya (IGearhardt okqhubekayo, 2011b), Olu phando luphande ngokubanakho kwe-OXR antagonist yokuthintela ii-episode ze-BE kunye nokuvavanya ukubandakanyeka kwe-OX₁ kunye ne-OX₂ iindlela kulawulo lweziqendu ze-BE.

Ngesi sizathu, amakhompiyutha amathathu axele kuncwadi ukuba anokukhetha okwahlukileyo vs OX₁ kunye ne-OX₂ Ii-receptors zabantu zavavanywa: i-OX ezimbini₁/ OX₂I-antagonist (SB-649868), i-OX ekhethiweyo₂I-antagonist (JNJ-10397049), kunye ne-OX ekhethiweyo₁I-antagonist (GSK1059865). Sebenzisa iidosi ezichasene neekhemikhali, abathathu abachasene ne-OXR bavavanywa kuqala in vitro kwi-rat ephindaphindayo ye-OX₁R kunye ne-OX₂Ukumisela i-potency kunye nokuqinisekisa ukukhetha kwabo koluhlobo lwezilwanyana. OX eyahlukileyo₁/ OX₂Ukukhethwa kwe-R kwaqinisekiswa kwiigundane kusetyenziswa [³H] inositol assay.

Ukuvavanya ukubonakaliswa kwegazi le-PK ukuxhasa ukulala kunye nezifundo ze-BE, iiprofayili zePK zemixube ziye zahlalutywa kwiirhasi zowesilisa nabasetyhini, kuba ezi yayizezokwabelana ngesondo ekulaleni kunye kuvavanyo lwe-BE, ngokulandelanayo.

Emva koko, iidosi ezinokukwazi ukuhambisa iziphumo ze-hypnotic zazigqunywe kwimodeli yokulala yokulala. Ekugqibeleni, iikhompawundi zavavanywa kwiidosi ezichaziweyo kwimodeli ye-BE.

OX₁R kunye ne-OX₂R abachasi baxelwa kuncwadi ukuba babandakanyeke kulawulo lokulala, ngakumbi ukubangela iimpembelelo ze-hypnotic (UDi Fabio okqhubekayo, 2011; Gozzi okqhubekayo, 2011; Dugovic okqhubekayo, 2009). Kwimodeli yokulala eyi-hyppecic yokulala kwi-rats zamadoda, iziphumo ezifunyenweyo zibonise ukuba i-OX kabini₁/ OX₂I-antagonist, i-SB-649868, ifaka ifuthe le-hypnotic, kokubini kwisakhono sokuqhuba kunye nokugcina ubuthongo, ukufikelela kwisiphumo esibalulekileyo kwi-3 mg / kg. Ifana ne-SB-649868, i-OX₂I-antagonist JNJ-10397049 ibonise isiphumo esihle se-hypnotic kunye nokuncipha okukhulu kwexesha elichithwe kwi-5 mg / kg. Ngokuchasene noko, i-OX₁I-GSK1059865 ye-antagonist ibonise ukungahambi kakuhle kwe-hypnotic ukubamba kunye nokugcina ukulala. Oku kufunyanisiweyo kuhambelana nezinye iingxelo ezibonisa ukuba i-OX₂R inokubaluleka ngakumbi kune-OX₁R ekulamleni isiphumo se-OX sokulala (Sakurai, 2007; IBrisbare-Roch okqhubekayo, 2007; Malherbe okqhubekayo, 2009; Dugovic okqhubekayo, 2009; UDi Fabio okqhubekayo, 2011).

I-SB-649868, yavavanywa kwiimeko ezine ezahlukeneyo zoxinzelelo kunye nokuthintelwa kokutya (i-NR + NS, R + NS, NR + S, R + S), yakwazi ukunciphisa i-HPF kuphela kwiqela le-R + S. Kwi-3 mg / kg, i-SB-649868 yayineziphumo ezifanayo nezo zibonwa nge-topiramate. Njengakwi-topiramate, i-SB-649868 ayikhange iguqule ukungena kwe-HPF kwezinye iimeko zokuthintela ukutya kunye noxinzelelo.

I-OX₂I-antagonist, i-JNJ-10397049, kuvavanywa kwiimeko ezifanayo ayibonisanga nasiphi na isiphumo sokuthathwa kwe-HPF kuzo zonke ezi meko zovavanyo.

Ezi ziphumo zibonakalisa ngokucacileyo ukuba i-OX₁I-R ibandakanyeka kulawulo lwezehlo ze-BE kwaye yacebisa indima enokuthathwa yi-OX₁Iqela elichasene nomva ukuze libuyise umba we-Episode obangelwa luxinzelelo kunye nokutya okunesithintelo. Ukuqinisekisa le hypothesis, i-OX ekhethiweyo₁I-GSK1059865 ye-antagonist yavavanywa kwizilwanyana ezinqunyelwe kunye ezixinzelelweyo. Iziphumo ezifunyenweyo ziqinisekisile ukuba i-OX₁Abachasene ne-R bathintele ukunyuka kokutya kwe-HPF kwiigundane ze-R + S, ngaphandle kokuchaphazela ukusetyenziswa kokutya kulawulo (NR + NS).

Ukungabikho kwesiphumo seJNJ-10397049 akunakubonwa ekubonakalisweni okungafunekiyo komatshini kwizilwanyana ezingeniswe kwimodeli ye-BE. Ukuvavanywa kwe-PK kweJNJ-10397049 kubonise umahluko wesini, kwaye abantu basetyhini bavezwa ngakumbi kunegundane lamadoda kwidosi efanayo ye-JNJ-10397049 (10 mg / kg). Ixabiso eliqikelelweyo le-AUC yayiyi-64 ng^*h / ml kwiirhasi zowesilisa vs 457 ng^*h / ml kwiigundane zabasetyhini (phantse amaxesha asixhenxe aphezulu). Ke ngoko, kugqitywe kwelokuba ukufunyanwa kwesilwanyana kwimodeli ye-BE kwi-1 kunye ne-3 mg / kg JNJ-10397049 kwakungaphezulu koku kufezekisiweyo kufundo lokulala kwi-5 kunye ne-25 mg / kg. Ngakolunye uhlangothi, akukho mehluko wesini okwaqwalaselwa kwi-PK ye-SB-649868 kunye ne-GSK1059865, kwaye ukubhencwa kwezi komdibaniso zombini bekugcwele kwimigca yamadoda neyabafazi.

Njengoko kuchaziwe kwintshayelelo, uxinzelelo sisiseko esiphambili se-BE. Iiseti zedatha ezininzi ziye zaveliswa kwishumi leminyaka elixhasayo kwindima edlalwa yi-OX peptides kwimimandla enobushushu obuphezulu, kubandakanya noxinzelelo, le yokugqibela inxulunyaniswa namaxabiso aphezulu e-OXergic neurotransmission. Ii-neurons ze-OX ezikwi-pervelopical-dorsomedial hypothalamus ziye zacetywa ukuba zenze ukuba kusebenze uxinzelelo loxinzelelo (UHarris no-Aston-Jones, i-2006, uphononongo, yabona I-Koob, i-2008). Mhlawumbi, i-OXA evela kule ndawo ye-hypothalamic isebenzisa ii-neurons ezibonisa i-CRF kwi-nucleus ye-hypotalamus ye-hypothalamus nakwindawo ephakathi ye-amygdala (Sakamoto okqhubekayo, 2004). Ngokuhambelana, OX₁Iqela elichasayo linqanda ukubuyiselwa kwe-ethanol kunye nokufuna ukuzimela okubangelwa ngumxinzelelo wehemicology yohimbine (Izityebi okqhubekayo, 2008) kunye ne-OXA iphinda ibuyele kwindlela yokuziphatha efuna i-cocaine (Iboutrel okqhubekayo, 2005). Kungekudala, I-Kubaki (2011) yafumanisa ukuba inkqubo ye-OX yenye yeemodyuli ezifanelekileyo kwimijikelezo ye-neural elawula imisebenzi ye-autonomic kunye nokuziphatha ngokweemvakalelo. Iziphumo ezifunyenwe ngaphambili Johnson okqhubekayo (2010) ibonise ukuba i-OX ekhethiweyo₁I-SB334867 ye-antagonist ibonakalise indlela yokuziphatha efana nexhala, kwaye yathintela ukunyuka kwe-locomotion, ukubetha kwentliziyo, kunye neempendulo zoxinzelelo lwegazi olubangelwa ngumngeni we-sodium lactate kumgangatho.

Izifundo ezininzi zibonisa ukuba umgaqo oluguquliweyo we-striatal dopamine (DA) unokubakho kwizigulana ezine-bulimia amanosa ne-BED (Bello kunye Hajnal, 2010; Broft okqhubekayo, 2011; wang okqhubekayo, 2011). Izifundo zikaHoebel kunye nabasebenza kunye (ukuphononongwa kwakhona, yabona IAvena kunye neBocarsly, 2011) baveze utshintsho kutshintsho lwe-striatal ye-DA kunye ne-receptor binding, efanayo naleyo ebonwe ekuphenduleni kwiziyobisi zokuphathwa gadalala. I-Neopopeptides eveliswe kwi-LH inokulinganisa umsebenzi we-VTA-DA kunye ne-striatal neurons. Iprojekthi ye-neuron equlathe ii-neurons esuka kwi-LH iye kwi-VTA, apho i-OX₁Iindima eziyidlalayo ebalulekileyo kulawulo lokuhanjiswa kwe-mesolimbic ye-DA kunye neepropati ezinomvuzo zeziyobisi ezahlukeneyo zokuxhatshazwa kunye nokutya (Ithuba okqhubekayo, 2010; Uramura okqhubekayo, 2001; UZheng okqhubekayo, 2007). Ngaphezulu, iziqendu ze-BE zinokulawulwa ngefuthe elithile kumvuzo nakwiinkqubo zokuqiniswa kwe-HPF. Kule meko, kunomdla ukuqaphela ukuba i-OX neurons kwi-LH icetyelwe ukulamla ukusebenza kwembuyekezo (uphononongo, bona I-Koob, i-2008). Yiyo loo nto kucetyiswa ukuba ii-neurons ze-OX kwi-LH zenziwa zasebenza ngokunxulumana nemivuzo, njengokutya okanye iziyobisi, kunye nokukhuthaza ii-neurons ze-OX kwi-LH zibuyisela iziyobisi ezifuna iigundane (Harris okqhubekayo, 2005).

Iqela lethu lisandula ukubonakalisa ngendlela ye-MX yangaphambili₁R endaweni ye-OX₂Rula uguqule imeko yengqondo ye-mesolimbic kunye nenxalenye ye-insula, iindawo ezixhonywe ekusebenzeni okunomvuzo (Gozzi okqhubekayo, 2011). Ezi datha ziqinisekisa kwaye zandisa iziphumo zangaphambili ze-OX₁Inendima edlala indima ekuqhubekisweni kwemivuzo kunye nokuthotyelwa kwemikhwa yokufuna iziyobisi (Iboutrel okqhubekayo, 2005; Umthetho okqhubekayo, 2006; Hollander okqhubekayo, 2008; Smith okqhubekayo, 2010). Ke ngoko, kuya kuqhubeka umsebenzi wokuvavanya ukuba ingaba isiphumo sokucaphukisa kwi-OX sikhutshiwe₁Iqela elichasayo linxulumene nefuthe lazo kuxinzelelo okanye kwiindlela zokuvuza, okanye kuzo zombini.

Ukuqukumbela, iziphumo ezifunyenwe kolu phononongo kusetyenziswa abachasi abathathu be-OXR ngokukhetha okungafaniyo kwe-OX₁R vs OX₂R ubonakalise ngokucacileyo indima eyahlukeneyo ye-OXR kulawulo lweziqendu ze-BE nakwimodyuli yokulala. Idatha yethu iqinisekise indima ephambili ye-OX₂Iindlela zokulawula ukulala. Ukongeza, babonisa okokuqala ukuba i-OX₁Iindlela ze-R zidlala indima ephambili kulawulo lweziqendu ze-BE. Ezi ziphumo zibonisa ukuba ujoliso lwe-OX₁R unokumela indlela enomdla yenekhemikhali kunyango lweziphazamiso ezinxulumene ne-BE.

Imibulelo

Sibulela uGqr Charles Pickens ngokulungiswa kwesitayile.

amaNqaku

I-EM-P ngumsebenzi osisigxina we-GSK.

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