Zakudya zopanda thanzi zomwe zimayambitsa kunenepa kwambiri zimapangitsa D2 receptor autoinhibition mu ventral tegmental dera ndikuchepetsa kumwa mowa (2017)

PLoS One. 2017 Aug 31; 12 (8): e0183685. yani: 10.1371 / journal.pone.0183685.

Cook JB^1,2, Hendrickson LM^1,3, Garwood GM³, Toungate KM³, Nania CV¹, Morikawa H^1,3.

Kudalirika

Mofanana ndi mankhwala osokoneza bongo, ubwino wa hedonic wa chakudya ndi wovomerezeka, mbali imodzi, ndi dongosolo la mesostriatal dopamine (DA). Kudyetsa kwa nthawi yaitali chakudya chamakono choyipa kapena kugwiritsa ntchito mankhwala osokoneza bongo kumabweretsa mavuto a DA. Kafukufuku wochulukirapo wagwiritsa ntchito kusintha kwa DAergic mu striatum, koma pang'ono sadziwika za zotsatira za zakudya zamtundu wa calorie ku ventral tegmental area (VTA) DA neurons. Popeza zakudya zamakono zamakono zimapanga kusintha kwa DAergic monga zovuta, ndizotheka kuti zakudyazi zikhoza kuwonjezereka kuti zikhale zowonongeka. Komabe, zakudya zapamwamba za kalori nthawi zonse zimachepetsa vuto la psychostimulant kudya ndi malo okonda malo amtundu. Mosiyana ndi zimenezi, zakudya zamakono zowonjezera zikhoza kuonjezera kapena kuchepetsa kumwa mowa wa ethanol, koma sizikudziwika kuti zakudya zopanda zakudya zopatsa thanzi (chakudya chodyera zakudya) zimakhudza kumwa mowa. Phunziro lomwe tinali nalo, tinkadya zakudya zodyera zomwe zimakhala ndi nyama yankhumba, mapepala a mbatata, cheesecake, cookies, zakudya zachakudya zakusakaniza, zakudya zam'madzi, ndi chokoleti. Amphaka a Wistar a masabata a 3-4, omwe amapanga zovuta kwambiri. Chakudya choyambirira chisamaliro chodyetsa chimachepetsa kuchepetsa kumwa mowa wa ethanol pa masabata a 2 oyesedwa, ndipo mopepuka amachepetsa sucrose ndi chow kudya. Chofunika kwambiri, chakudya cha zakudya sizinathandize pa ethanol metabolism kapena kuchuluka kwa magazi m'magazi otsatira 2g / makilogalamu oyendetsa mafuta. InePakati pa magawo awiri, timasonyeza kuti chakudya chodyera chakudya chimapangitsa DA D2 receptor (D2R) kudziletsa ku VTA DA neurons. Zotsatira izi zikuwonetsa kuti zakudya zopanda zakudya zopanda mphamvu zomwe zimapangitsa kuti kunenepa kwambiri kumachepetsa kumwa mowa wamadzi, ndipo zimasonyeza kuti kuwonjezeka kwa D2R kudziletsa mu VTA kungapangitse kuti kuchepa kwa DAergic kuwonongeke komanso kubwezeretsa chitetezo cha chitetezo chowoneka ndi kunenepa kwambiri.

PMID: 28859110

DOI: 10.1371 / journal.pone.0183685

Zakudya zopanda thanzi zomwe zimapangitsa kuti kunenepa kunenepa kumawonjezera D2 receptor autoinhibition m'dera la ventral tegmental komanso kuchepetsa kumwa mowa.

PLoS One. 2017 Aug 31; 12 (8): e0183685. yani: 10.1371 / journal.pone.0183685. eCollection 2017.

Cook JB^1,2, Hendrickson LM^1,3, Garwood GM³, Toungate KM³, Nania CV¹, Morikawa H^1,3.

Kudalirika

Mofanana ndi mankhwala osokoneza bongo, ubwino wa hedonic wa chakudya ndi wovomerezeka, mbali imodzi, ndi dongosolo la mesostriatal dopamine (DA). Kudyetsa kwa nthawi yaitali chakudya chamakono choyipa kapena kugwiritsa ntchito mankhwala osokoneza bongo kumabweretsa mavuto a DA. Kafukufuku wochulukirapo wagwiritsa ntchito kusintha kwa DAergic mu striatum, koma pang'ono sadziwika za zotsatira za zakudya zamtundu wa calorie ku ventral tegmental area (VTA) DA neurons. Popeza zakudya zamakono zamakono zimapanga kusintha kwa DAergic monga zovuta, ndizotheka kuti zakudyazi zikhoza kuwonjezereka kuti zikhale zowonongeka. Komabe, zakudya zapamwamba za kalori nthawi zonse zimachepetsa vuto la psychostimulant kudya ndi malo okonda malo amtundu. Mosiyana ndi zimenezi, zakudya zamakono zowonjezera zikhoza kuonjezera kapena kuchepetsa kumwa mowa wa ethanol, koma sizikudziwika kuti zakudya zopanda zakudya zopatsa thanzi (chakudya chodyera zakudya) zimakhudza kumwa mowa. Phunziro lomwe tinali nalo, tinkadya zakudya zodyera zomwe zimakhala ndi nyama yankhumba, mapepala a mbatata, cheesecake, cookies, zakudya zachakudya zakusakaniza, zakudya zam'madzi, ndi chokoleti. Amphaka a Wistar a masabata a 3-4, omwe amapanga zovuta kwambiri. Chakudya choyambirira chisamaliro chodyetsa chimachepetsa kuchepetsa kumwa mowa wa ethanol pa masabata a 2 oyesedwa, ndipo mopepuka amachepetsa sucrose ndi chow kudya. Chofunika kwambiri, chakudya cha zakudya sizinathandize pa ethanol metabolism kapena kuchuluka kwa magazi m'magazi otsatira 2g / makilogalamu oyendetsa mafuta. Pakati pa magawo a midbrain, tawonetsa kuti chakudya chodyera chakudya chimapangitsa DA D2 receptor (D2R) kudziletsa ku VTA DA neurons. Zotsatira izi zikuwonetsa kuti zakudya zopanda zakudya zopanda mphamvu zomwe zimapangitsa kuti kunenepa kwambiri kumachepetsa kumwa mowa wamadzi, ndipo zimasonyeza kuti kuwonjezeka kwa D2R kudziletsa mu VTA kungapangitse kuti kuchepa kwa DAergic kuwonongeke komanso kubwezeretsa chitetezo cha chitetezo chowoneka ndi kunenepa kwambiri.

PMID: 28859110

DOI: 10.1371 / journal.pone.0183685

 

Ndemanga: Cook JB, Hendrickson LM, Garwood GM, Toungate KM, Nania CV, Morikawa H (2017) Zakudya zopanda thanzi zomwe zimapangitsa kuti kunenepa kwambiri ziwonjezere D2 receptor autoinhibition m'dera la ventral tegmental komanso kuchepetsa kumwa mowa. PLoS ONE 12 (8): e0183685. https://doi.org/10.1371/journal.pone.0183685

Editor: James Edgar McCutcheon, University of Leicester, UNITED KINGDOM

Zilandiridwa: May 24, 2017; Zavomerezedwa: August 9, 2017; Lofalitsidwa: August 31, 2017

Copyright: © 2017 Cook et al. Ichi ndi nkhani yotseguka yolumikizidwa pansi pa mawu a Chilolezo cha Creative Commons Licribution, zomwe zimaloleza ntchito, kugawidwa, ndi kubwezeretsa mwachinthu chilichonse, kupatsa wolemba woyambirira ndi chitsimikizo.

Kupezeka kwa Data: Deta zonse zoyenera zili mkati mwa pepala ndi ma fayilo Opatsirana Othandizira.

Ngongole: Ntchitoyi inathandizidwa ndi RO1 AA015521 (HM), F32AA021640 (LMH), ndi T32-AA007471 (University of Texas ku Austin, Division of Pharmacology and Toxicology, College of Pharmacy). Ndalama zimenezi zinali kapena zidalipidwa ndi National Institute on Alcohol Abuse and Alcohol. https://www.niaaa.nih.gov/. Ogulitsawo analibe gawo pa kupanga maphunzilo, kusonkhanitsa deta ndi kusanthula, chisankho chofalitsa, kapena kukonzekera malembawo.

Zofuna zokakamiza: Olembawo adanena kuti palibe zotsutsana.

Introduction

Mankhwala osokoneza bongo ndi zakudya zolimbitsa thupi ndizovomerezeka, mwa mbali, ndi masostriatal dopamine (DA) dongosolo [1]. Komanso, kuwonjezera pa mankhwala osokoneza bongo, kuphatikizapo ethanol, kapena zakudya zowonjezera zowonjezera, zimapanga mankhwala ofanana ndi DAergic. Mwachitsanzo, kutsegula kwa ethanol ndi mankhwala ena osokoneza bongo kumachepetsa D2 receptors (D2Rs) ndi mazenera a DA basal mu striatum [2-4], yomwe imasonyezanso kuti ali ndi mphamvu zowonjezera zamagetsi [5-7]. Anthu omvera amachepetsanso mawu a D2R mu striatum [8] ndi kuchepetsa kuchitapo kanthu mwamsanga poyankha chakudya chokoma [9]. Choncho, popeza matendawa amatha kutsata chakudya chokwanira kapena mankhwala osokoneza bongo ali ofanana, kuwonjezera mphamvu za zakudya zowonongeka kungapangitse kuti mankhwala osokoneza bongo amveke. N'zochititsa chidwi kuti kafukufuku wa makoswe asonyeza kuti mafuta ambiri kapena shuga amachepetsanso vuto la psychostimulant komanso malo omwe amawakonda [10-13]. Mosiyana, mafuta apamwamba kwambiri kapena shuga / kabakiteriya akhoza kuwonjezeka [14, 15] kapena kuchepa [16, 17] ethanol akumwa mu makoswe. Komabe, sizikudziwika kuti kumwa zakudya zopanda kanthu zomwe nthawi zambiri zimadya ndi anthu zimakhudza kumwa mowa.

Ku US pafupifupi 35% ya akuluakulu ndi 17% a ana ndi achinyamata ali ochepa [18]. Kukula kwa kuchuluka kwa kunenepa kwawonjezereka ndi kuwonjezeka kwopezeka kwa "zakudya zopanda kanthu" pamwamba pa mafuta, shuga, ndi zakudya zina [19], komanso kudya zakudya zimenezi n'kofunika makamaka paunyamata [20-22]. Poyesa kusonyeza mtundu wa mphamvu zowonjezera zamagetsi zomwe zimapangitsa kuti kunenepa kwambiri, ofufuzira apatsa makoswe kupeza zakudya zopanda kanthu, amatchedwa chakudya chodyera [5, 6, 23]. Chakudya chodyera zakudya zapadera chikuwonetsedwa kuti chichepetse D2Rs ndi mazenera a DA ochepa mu striatum, kuchepetsa kukhudzidwa kwa madera oyendetsa ntchito pogwiritsa ntchito mankhwala osokoneza bongo, ndi kubweretsa zakudya zolimbitsa thupi [5, 6]. Komabe, sizikudziwika ngati chakudya chodyera chakudya chimapangitsa kuti ma electrophysiological akhale a DA neurons m'dera la ventral tegmental (VTA) kapena mphamvu za kumwa mowa.

Chisamaliro cha DA chotchedwa Somatodendritic DA chimayambitsa D2Rs pa somata ndi ma dendrites a DA neurons omwe amachititsa kuti anthu asamadziwe mu vivo [24, 25] ndi mu m'galasi [26, 27] pogwiritsa ntchito njira zopangira potassium (GIRK) zotetezera mkati mwa G_{i / o} kusonyeza. Motero, kuyambitsa D2R kwa GIRK zotsatira ndi hyperpolarization ndi kuchepa neuronal excitability [28]. Mu VTA DA neurons, kulamulira mobwerezabwereza kwa ethanol kapena mankhwala oopsa a cocaine kumawonjezera D2R-mediated autoinhibition [29, 30]. Kuwonjezera apo, kutsatila mobwerezabwereza kutentha kwa ethanol mu mbewa, kuwonjezeka kwa D2R kudziletsa kumagwirizanitsa ndi kuwonjezeka kwakumwa mowa wa ethanol [29]. Ngakhale kuti ziwonekere zapamwamba za kalori zimapangitsa kuti adzidwe ngati DAergic omwe amawoneka ngati adakali, zotsatira za zakudya zamtundu wa calories pa D2R kudziletsa mu VTA DA neurons sizinadziŵike.

Phunziroli, tafufuza zotsatira za zakudya zodyera pokhapokha pokhapokha pakhomo la ethanol kapena sucrose kumwa, VTA DA neuron basal kuwombera maulendo, komanso D2R-njira yothetsera vta DA neurons. Chakudya chodyetserako zakudya m'zaka za unyamata chimapangitsa kuti munthu asamakhale ochepa kwambiri monga phenotype komanso kuchepetsa kumwa mowa mophatikizapo pogwiritsa ntchito 2 hr kumwa mowa (DID). Chofunika kwambiri, chakudya chodyetsa zakudya sizinakhudze magazi m'magazi (BECs) kapena ethanol metabolism chiwerengero cha 2 g / kg intraperitoneal (ip) jekeseni wa ethanol. Kuwonjezera pamenepo, chakudya chodyera chakudya chimapangitsa kuti D2R ikhale yophatikizapo mankhwala a VTA DA neurons.

Njira ndi zipangizo

Zolinga Zilombo za Wistar zinapezedwa ku Harlan laboratories (Indianapolis, IN) pa masabata a 3. Makoswe anali osakwatiwa omwe ankakhala m'nyumba ya Plexiglass, yomwe mbali imodzi ya khola inali ndi nsanja ya Plexiglass yokhala ndi 7 "x 4" x XUMUMX "yomwe imakhala pansi pa chakudya chodyetsera zakudya. Makoswe onse anali ndi zowunikira zoyera za ma laboratory ad libitum ndipo madzi analipo nthawi zonse kupatula pa ethanol kapena sucrose kumwa mowa. Msolo wa vivarium unasungidwa ndi 12 hr kuwala-mdima (kuwala kwa 0100 hr), kutentha kwanthawi zonse kwa 22 ± 2 ° C, ndi 65% yokhudzana ndi chinyezi. Njira zothandizira zinyama zinkatsatira zotsatira za National Institutes of Health Guidelines pansi pa University of Texas ku Austin Institutional Animal Care ndi Komiti Yogwiritsira Ntchito mavomerezedwe.

Kudyetsa zakudya zakudya

Kamodzi patsiku (1 hr mumdima) chakudya chodyera chomwe chimakhala ndi zakudya zopatsa thanzi zopatsa thanzi kuphatikiza cheesecake (Atlanta Cheesecake Company, Kennesaw, GA), nyama yankhumba (HEB, San Antonio, TX), makeke (Chips Ahoy / Oreo, Nabisco, East Hanover, NJ; chofufumitsa shuga, Vista, Zakudya za Sheare, Massillon, OH), tchipisi ta mbatata (Lays Classic / Ruffles, Frito Lay, Plano, TX) tirigu wam'mawa wambiri (CoCo Puff, General Mills, Minneapolis, MN; Froot Loops, Kellog, Battle Creek, MI), marshmallows (Kraft, Northfield, IL), kapena maswiti a chokoleti (M&M, MARS, McLean, VA) adapatsidwa gulu lodyera. Zakudya zinayi zodyerako zodyera zimayendetsedwa patsiku ndipo zakudya zosiyanasiyana zimasungidwa ndikusintha zakudya tsiku lililonse. Gulu lokhalo lokhalo limangolandira chow chow okha (LabDiet, Prolab RMH 1800, St. Louis, MO), yomwe imapezekanso pagulu lodyera la ad libitum. Zakudya za Macronutrient (kutengera ma calories operekedwa) a chow okha zakudya zimakhala ndi 14% mafuta, 65% carbohydrate, ndi 21% protein, ndipo pafupifupi chakudya chodyeracho chimakhala ndi mafuta a 42%, 52% carbohydrate, ndi 6% protein. Chakudya chodyera chidaperekedwa kwa masabata atatu kuti adye caloric ndi D3R zoyeserera zakunja (kuyambira pafupifupi masabata a 2-3) komanso masabata a 4 pazoyeserera zina zonse (kuyambira pafupifupi milungu isanu). Pazakudya zopatsa mphamvu, chakudya chodyera ndi chow chakudya chokha chimayesedwa tsiku ndi tsiku ndipo kudya kwa caloric kumayesedwa pogwiritsa ntchito chidziwitso cha macronutrient choperekedwa kuchokera kwa wopanga.

Homecage ethanol kapena sucrose kumwa

Mlungu umodzi utatha chizoloŵezi, makoswe anapatsidwa 2 hr / tsiku kuchepa kochepa kwa ethanol (10% v / v) kapena sucrose (5% w / v) yankho loyesa kumwa mowa woyambira. Pa nthawi yonse ya mowa kapena sucrose kumwa mowa madzi akugwiritsidwa ntchito ndi botolo lokhala ndi ethanol kapena solution sucrose pa 1 hr mu mdima. Potsatira msuzi wa ethanol kapena sucrose kumwa (masiku a 7), makoswe anapatsidwa chakudya chodyera kapena gulu lokha. Kenaka, makoswe anadyetsedwa zakudya zakudya kapena chowoneka kwa masabata a 4 okha. Maola makumi awiri mphambu anayi atatha kudya chakudya chomaliza, makoswe anayamba tsiku ndi tsiku ethanol kapena sucrose kumwa mowa.

Magulu a ethanol (BEC)

Pambuyo pa masabata a 4 odyera zakudya kapena zakudya zokha kudya, makoswe ankapatsidwa ethanol (2g / kg, 15% v / v mu saline, ip) 24 hr pambuyo pa chakudya chomaliza chodyera zakudya. Zida zonse za magazi (10 μL) zinasonkhanitsidwa ndi mchira mchimake pa 30, 60, ndi 120 min pamapeto mwa jekeseni wa ethanol ndipo zinawonjezeredwa ku mitsuko ya galasi ya chromatography (GC) yomwe ili ndi 90 μL ya 5M sodium chloride. Machitsanzo a ethanol anali kufufuza pa tsiku lomwelo monga kusonkhanitsa magazi ndi GC pogwiritsa ntchito Bruker 430-GC (Bruker Corporation, Fremont, CA) yokhala ndi detector yamoto yotchedwa ionization ndi Combi PAL autosampler. Mwachidule, chitsanzo chonse chinakonzedwa ndi 65 ° C kwa 3 min isanayambe chingwe cholimba (SPME; 75 μm CAR / PDMS, schisitiki; Supelco) idatulutsa mpweya wa ethanol kwa 3 min. Mitundu ya SPME inachotsamo chitsanzo mu doko la jekeseni la GC la 1 min pa 220 ° C. Helium (8.5 mL / min flow rate) amagwiritsidwa ntchito ngati galimoto yonyamulira ndi HP Innowax capillary mzere (30 mx 0.53 mm x 1 μm kufalitsa filimu; Agilent Technologies, Santa Clara, CA) amagwiritsidwa ntchito popatukana. Miyezo ya kunja ya ethanol (25, 50, 100, 200, 400, ndi 600 mg / dL) inafotokozedwa kuti iŵerengedwe mtengo wamtunduwu. Chromatograms anafufuzidwa pogwiritsira ntchito compassCDS Workstation software (Bruker Corporation, Fremont, CA), ndipo nthawi yapamwamba ya ethanol (~ 2 min yosungira nthawi) idagwiritsidwa ntchito pomanga mazira omwe amadziwika bwino.

Electrophysiology

Makoswe anali otetezedwa ndi isoflurane ndipo ubongo unachotsedwa ndipo unagawanika mu njira yozizira yomwe ili ndi (mM) 205 sucrose, 2.5 KCl, 1.25 NaH₂PO₄, 7.5 MgCl₂, 0.5 CaCl₂, 10 shuga, ndi 25 NaHCO₃, yodzaza ndi 95% O₂, ndi 5% CO₂ (~ 300mOsm / kg). Mitengo yambiri yazitali (200 μm) inagawidwa pa vibratome ndipo inaloledwa kubwezeretsa 1 hr mu kapangidwe kake (aCSF) pa 34 ° C. Zolembazo zinkachitidwa mu retal VTA 50-150 μm kuchokera kumalire apakati a chigawo chakumapeto cha tsamba lopangira opaleshoni. Panthawi yojambula, magawo amapangidwanso ndi oxygenated, kutentha (34 ° C) aCSF (mM) 126 NaCl, 2.5 KCl, 1.2 NaH₂PO₄, 1.2 MgCl₂, 2.4 CaCl₂, 11 shuga, 21.4 NaHCO₃. Zithunzi zojambulidwa ndi magulu (~ 20 MΩ seal) zinachitidwa ndi pipettes zomwe zili ndi 150mM NaCl. Zithunzi zonsezo zinkapangidwa ndi pipettes zomwe zinkakhala ndi mankhwala (mM) 115 K-methylsulfate kapena K-gluconate, 20 KCl, 1.5 MgCl₂, 10 HEPES, 0.025 EGTA, 2 Mg-ATP, 0.2 Na₂-GTP, ndi 10 Na₂-phosphocreatine (pH 7.2-7.3, ~ 285 mOsm kg^-1). Ma neuron a DA omwe amadziwika kuti ndi a Putin amadziwika ndi kuwombera kwapafupipafupi (1-5 Hz) komanso kuthekera kochita zambiri (> 1.2 ms) pakapangidwe kazipangizo, komanso lalikulu I_h (> 200 pA) poyankha gawo lama 1.5 sec yamagetsi kuchokera ku -62mV mpaka -112 mV mumayendedwe onse a cell-clamp. Zojambulitsa za Voltage-clamp zidapangidwa mosasunthika kwa -62mV, zowongoleredwa pamphambano yamadzi ya -7 mV. Zojambulidwa m'maselo onse zidatayidwa ngati kukana kwamndandanda kudakwera pamwamba pa 20 MΩ kapena kulowetsa kuyika kudatsika pansi pa 200 MΩ. Zambiri zidasefedwa pa 1-5 kHz ndikusinthidwa pamanambala pa 2-10 kHz.

Kusanthula deta

Deta imayesedwa ngati yowona ± SEM. Chiwerengero cha chiwerengero chinakhazikitsidwa ndi mayeso a Ophunzira kapena njira ziwiri za ANOVA zotsatiridwa ndi mayeso a bonferroni post hoc.

Results

Chakudya chodyera zakudya kumadya zakudya zamtundu wa caloric komanso zowonjezereka monga phenotype

Zakudya za caloric zokhala ndi zakudya zokhala ndi zakudya zokha komanso magulu okhaokha komanso magulu opangira zakudya zodyera anayesedwa pa masabata a 3. Gulu lodyera zakudya limadya kwambiri ma calories kuposa chow kokha gulu pa masabata 3 akudyetsa (kuyanjana: F_(2,62) = 22.43, p <0.0001; zakudya: F_(1,62) = 17.41, p <0.001; nthawi F_(2,62) = 254.7, p <0.0001; Chithunzi cha 1A). Gulu lodyera zakudya limadya kwambiri zakudya zopatsa thanzi kuchokera ku chakudya chodyera kusiyana ndi chow pellets m'mavhiki a 3 akudyetsa (kuyanjana: F_(2,72) = 57.22, p <0.0001; zakudya: F_(1,72) = 117.2, p <0.0001; nthawi F_(2,72) = 110.5, p <0.0001; Chifaniziro cha 1B). Ma calories opangidwa kuchokera ku mapepala a chow anali aakulu kwambiri kwa chow gulu pokha pokhapokha kuunika kwa sabata la 3 (kuyanjana: F_(2,62) = 28.80, p <0.0001; zakudya: F_(1,62) = 196.3, p <0.0001; nthawi F_(2,62) = 150.0, p <0.0001; Chithunzi cha 1C). Pamapeto pake, gulu lodyera zakudya likuwonetsa kulemera kwambiri pa masabata a 3 akudyetsa (kuyanjana: F_(2,62) = 8.188, p <0.001; zakudya: F_(1,62) = 10.62, p <0.005; nthawi F_(2,62) = 18.48, p <0.0001; Chithunzi cha 1D). Masabata anai odyera zakudya zowonjezera chakudya amachititsa kuti onenepa-monga phenotype ndi zolemera thupi kulemera kwambiri kuposa chow gulu lokha (kuyanjana: F_(27,2376) = 44.48, p <0.0001; zakudya: F_(1,2376) = 14.89, p <0.001; nthawi F_(27,2376) = 2634, p <0.0001; ZINTHU ZOTHANDIZA). Komanso, m'gulu lina la zinyama timasonyeza kuti chakudya chodyera chakudya chimadya pang'ono chow m'kati mwa masabata a 4 a chakudya chodyera zakudya poyerekeza ndi kulamulira (kuyanjana: F_(27,486) = 3.039, p <0.0001; zakudya: F_(1,486) = 601.7, p <0.0001; nthawi F_(27,486) = 8.097, p <0.0001; Chithunzi cha 1F). Zotsatira izi zikuwonetsa kuti chakudya chodyera chakudya chinayambitsa kudya zakudya zopatsa thanzi zabwino kwambiri ndipo zotsatira zake zimatayika.

Kudya kwa caloriki komanso komwe amapatsa mafuta adayesedwa pamasabata atatu. (A) Makoswe okhala ndi chakudya chamasana ndi tsiku amadya zopatsa mphamvu kwambiri m'masabata atatu akudya kuposa gulu lokha lokha (n = 3-3 / gulu). (B) Gulu lazakudya zodyeramo lidadya kwambiri ma calories kuchokera ku zakudya zodyerako kuposa zakudya za chow pellets (n = 14). (C) Gulu lokhalo lokha limadya ma calories ambiri kuchokera ku chow pellets kuposa gulu lodyera (n = 19-19 / gulu). (D) Kudya zakudya kumabweretsa kuchuluka kunenepa pamasabata atatu akudya (n = 14-19 / gulu). (E) Milungu inayi yodyera chakudya chodyera kwambiri imachulukitsa kulemera kwa thupi, poyerekeza ndi chow chokha chodyetsa (mphamvu yayikulu ya zakudya, p <3, njira ziwiri ANOVA, n = 14-19 / gulu). (F) M'masabata onse a 0.001 wopeza zakudya zodyera, gulu lodyerako zakudya limadya chow yocheperako kuposa gulu lokha lokha (zotsatira zazikulu za zakudya, p <44, njira ziwiri ANOVA, n = 46-4 / gulu). * p <0.0001, ** p <10, *** p <11, mayeso a Bonferroni post hoc.

https://doi.org/10.1371/journal.pone.0183685.g001

Chakudya choyambirira musanayambe kudyetsa chakudya chochepa chakumwa cha ethanol chosagwira ntchito pa ethanol metabolism mlingo kapena BECs

Kuti tipeze zotsatira za chakudya cham'mbuyo choyambirira chodyera pa mowa wa ethanol tinagwiritsira ntchito DID 2hr yokhala ndi malo osakwanira omwe amatha kumwa mowa (botolo limodzi, 10% v / v) omwe amamwa mowa omwe amachititsa kumwa mowa wambiri. Kugwiritsa ntchito mowa wa ethanol mowa (g / kg) patsiku la 7 isanakwane chakudya chodyera chakudya chinali chimodzimodzi pakati pa magulu (t₍₁₁₎ = 0.3295, p = 0.7480; Chithunzi cha 2A). Komabe, patatha masabata a 4 a zakudya zodyera zakudya, kumwa kwa ethanol kunachepetsedwa pa masabata a 2 a kuyesedwa (zakudya: F_(1,143) = 5.635, p <0.05; nthawi F_{(13, 143)} = 3.638, p <0.0001; Chifaniziro cha 2B). Kuchuluka kwa kuchepetsa kumwa moŵa wa ethanol kunali kwakukulu pamene chakudya cha ethanol chinakonzedweratu mu g / kg kuchokera kulemera kwa thupi kwa chakudya chodyera ndi kugula magulu okha ndi osiyana kwambiri. Ma Ethanol amadya pa masabata a 2 oyesedwa ndi 0.67 ± 0.11 g / kg pa gulu lokha ndi 0.25 ± 0.06 g / kg pa gulu la zakudya. Kusamwa kwa madzi pa masabata a 2 a mayesero sanali osiyana pakati pa magulu (zakudya: F_(1,143) = 0.1280, p = 0.7273; Chithunzi cha 2C).

(A) Kutanthauza kumwa koyambira kwa ethanol (g / kg) m'masiku 7 asanadye chakudya chodyerako kunali kofanana pakati pamagulu (p = 0.7480, Student's t-test, n = 6-7 / group). (B) Kudyetsa chakudya musanadye (masabata 4) kumachepetsa kuchuluka kwa ethanol (10%, v / v, 2hr / tsiku) omwe amadya m'masabata awiri oyesedwa (zotsatira zazikulu za zakudya, p <2, njira ziwiri ANOVA , n = 0.05-6 / gulu), (C) osakhudza kuchuluka kwa madzi (n = 7-6 / gulu). (D) Panalibe kusiyana m'malo otsetsereka a BECs (7-30 min kutsatira 120g / kg management, ip) pakati pamagulu (p = 2, regression linear, n = 0.6535-4 / group). Ma BEC anali ofanana pakati pamagulu a 5, 30, ndi 60 min post-ethanol management. BEC, ndende ya magazi ethanol; ip, mochita.

https://doi.org/10.1371/journal.pone.0183685.g002

Popeza chakudya chodyetserako chakudya chingasinthe kagwiritsidwe kachakudya, kuphatikizapo kutentha kwa ethanol, tinkagwiritsa ntchito ethanol (2g / kg, ip) ndi kuyeza BECs ku 30, 60, ndi 120 min post-injection pambuyo chakudya chakudya kapena chow kudya okha. Pogwiritsa ntchito njira zoyerekeza zoyerekeza ndi BEC otsetsereka (30-120 min post-injection) pakati pa magulu, chakudya chodyetsa zakudya sichinakhudze mphamvu ya ethanol (p = 0.6535; Chithunzi cha 2D). Kuwonjezera pamenepo, panalibe kusiyana pakati pa magulu a Edzi pakati pa magulu (chakudya: F_(1,14) = 2.056). Chifukwa chake, kusintha kwa madzi ochepetsa mphamvu ya ethanol kapena kutentha kwa ethanol m'magazi sangathe kufotokozera mowa wothira mowa wambiri pambuyo pa zakudya zopatsa thanzi.

Chakudya choyambirira musanayambe kudya zakudya zolimbitsa thupi zowononga homroge sucrose mowa ndi chakudya chow

Kuti mudziwe ngati zakudya zodyera zakudya zimasokoneza njira zowonjezeramo zomwe tinayeserapo zotsatira za chakudya choyambirira chodyera chakudya chodyera ku homroage sucrose akumwa. Pogwiritsa ntchito DID 2hr yochepa yofiira kaphatikizidwe (botolo limodzi, 5% w / v) kumwa mowa, baseline sucrose kumwa (mL / kg) zinali zofanana pakati pa magulu (t₍₂₉₎ = 0.4600, p = 0.6489; Chithunzi cha 3A). Chakudya choyambirira musanayambe kudya zakudya zochepa zimachepetsa sucrose kumwa (chakudya x nthawi yogwirizana: F_(13,377) = 2.520, p <0.005; Chifaniziro cha 3B). Ngakhale kuti kunali chakudya chofunikira x nthawi yogwirizana, kufufuza kwapositi sikunali kofunika pa nthawi iliyonse. Komabe, pogwiritsa ntchito deta (Chifaniziro cha 3B), kugwirizana pakati pa gulu ndi nthawi kungathe kufotokozedwa ndi kuchepetsa kuchepa kwa sucrose kumwa pambuyo pa chakudya chodyera zakudya. Pa sabata lachiwiri la kuyesedwa, komabe kutsitsa zakumwa kunali kofanana ndi gulu lokha. Kusamwa kwa madzi pa masabata a 2 a mayesero sanali osiyana pakati pa magulu (zakudya: F_(1,377) = 1.176, p = 0.2870; Chithunzi cha 3C). Mofanana ndi phunziro lapitalo [31], chakudya chodyera chakudya chochepa chitetezo chow chakudya (kuyanjana: F_(6,110) = 12.46, p <0.0001; zakudya: F_(1,110) = 15.46, p <0.005; nthawi F_(6,110) = 10.97, p <0.0001; Chithunzi cha 3D) masiku awiri kutsatira kudya podyera (Bonferroni posthoc test, p <2; Chithunzi cha 3D). Choncho, chakudya chodyera chakudya chimapangitsa kuchepetsa kumwa mowa mopitirira muyeso komanso kuchepetsa kuchepa kwa kumwa sucrose ndikudya chakudya.

(A) Kutanthauza koyambira kwa sucrose kumwa (mL / kg) masiku 7 asanadye chakudya chodyera anali ofanana pakati pamagulu (p = 0.6489, Student's t-test, n = 15-16 / group). (B) Kudyetsa chakudya cham'mbuyomu (masabata a 4) sucrose posachedwa (5%, w / v, 2hr / tsiku) kudya (zakudya x nthawi yolumikizana, p <0.005, ANOVA, n = 15-16 / gulu) . (C) Panalibe kusiyana pakumwa madzi pakati pamagulu (n = 15-16 / gulu). D *** p <10, mayeso a Bonferroni post hoc.

https://doi.org/10.1371/journal.pone.0183685.g003

Zakudya zodyera zakudya zimapangitsa kuti D2R iwonongeke mu VTA DA neurons

Kugwiritsa ntchito kachipangizo kameneka kanagwiritsidwa ntchito kufufuza zotsatira za chakudya chodyera pafupipafupi pafupipafupi ndi njira ya D2R yomwe imapangitsa kuti VTA DA neurons ikhale yabwino. Kudyetsa zakudya zapakudya sizinathandize kwenikweni pa basal tonic pacemaker yomwe imawombera ma VTA DA neurons (t₍₇₂₎ = 0.7294, p = 0.4681; Chizindikiro 4A ndi 4B). Kenaka, tinayesa zotsatira za zakudya zodyera pazitsulo za kunja kwa D2R pogwiritsira ntchito D2R agonist quinpirole. Chakudya chodyera zakudya kumadya kuwonjezereka kwakukulu kwa mapiritsi amtundu (100nM) omwe amaletsa mazira akunja (t₍₃₉₎ = 3.167, p <0.005; Chithunzi cha 5A) poyerekeza ndi machitidwe. Kuwonjezera apo, chakudya chodyera zakudya chinawonjezereka zotsatira zowononga za 10nM zomwe zimawombera maulendo a VTA DA neurons pa 10 min ya quinpirole administration (kuyanjana: F_(19,513) = 5.425, p <0.0001; zakudya: F_(1,513) = 16.40, p <0.0005; nthawi F_(19,513) = 39.24, p <0.0001; Chifaniziro cha 5B), komanso peresenti yoletsa kuthamanga kawirikawiri yotengedwa ndi quinpirole (t₍₂₇₎ = 3.824, p <0.001; Chithunzi cha 5C). Pazigawo zapamwamba za quinpirole (30nM) panalibe kusiyana pakati pa kulepheretsa mafupipafupi pafupipafupi pa 10 min ya quinpirole administration (chakudya: F_(1,304) = 0.1049, p = 0.7502; Chithunzi cha 5D) kapena peresenti yoletsa kuwombera pakati pa magulu (t₍₁₆₎ = 0.05265, p = 0.9587; ZINTHU ZOTHANDIZA). Choncho, chakudya chodyera chakudya chinapangitsa kuti phokoso likhale lopangidwa ndi quinpirole (100nM) kunja ndikuwonjezereka mphamvu yowonongeka pamtundu wa quinpirole.

(A) Basal tonic kuwombera mafupipafupi a VTA DA neurons anali ofanana pakati pa magulu (p = 0.4681, T test test, n = 36-38 / gulu). (B) Misonkho ya VTA DA yothamanga pamapeto a masabata a 4 a chow (buluu) kapena chakudya chofiira (chofiira). DA, dopamine; VTA; malo amtunda.

(A) Zakudya zodyera zakudya zapamwamba zowonjezera chiwerengero cha mapiritsi amtundu wa 100 nM). Kusamba kwa quinpirole kunkaperekedwa kwa 10 min ndi sulpiride (1 μM) mofulumira kunasinthira pakalipano ya quinpirole. Zitsanzo za mazira akunja ozungulira (V_h = -62 mV) ya chow kokha (buluu) kapena chakudya chodyeramo chakudya chamakoswe ofiira (ofiira) (n = 16-25 / gulu). (B) Kudyetsa zakudya kumawonjezera kuletsa kwa 10 nM quinpirole pa VTA DA neuron kuwombera pafupipafupi pa 10 min ya quinpirole bath application (zotsatira zazikulu za zakudya, p <0.0005, njira ziwiri ANOVA, n = 13-16 / gulu) ndi (C) quinpirole-mediated peresenti yoletsa kuwombera pafupipafupi (p <0.001, Student's t-test). Oimira mayendedwe a DA neuron kuwombera pafupipafupi poyambira kapena 10 nM quinpirole kutsatira kutsatira chow kokha (buluu) kapena chakudya chodyeramo (chofiira). (DE) Kuletsa kuwombera kwa DA neuron pafupipafupi ndi 30 nM quinpirole kunali kofanana pakati pamagulu (n = 9 / gulu). Kutsatira 10 min ya 30 nM quinpirole bath application, sulpiride (1 μM) idayikidwa kusamba kuti isinthe mwachangu quinpirole-Mediated choletsa pafupipafupi kuwombera. Oimira mayendedwe a DA neuron kuwombera pafupipafupi poyambira kapena 30 nM quinpirole kutsatira kutsatira chow kokha (buluu) kapena chakudya chodyeramo (chofiira). *** p <0.001, mayeso a ophunzira. DA, dopamine; D2R, dopamine D2 cholandilira; GIRK, G-protein-gated mkati mkati yothetsera potaziyamu njira; VTA; malo am'magazi amkati.

https://doi.org/10.1371/journal.pone.0183685.g005

Kukambirana

Cholinga cha kafukufuku wamakono chinali kufufuza zotsatira za chakudya chodyera zakudya zakumwa za mowa komanso VTA DA neuron physiology. Chakudya choyambirira chisanafike kudyetsa chakudya kunachepetsera kumwa mowa mopitirira masabata a 2 a kuyesedwa, koma sikunathandize pa ethanol metabolism kapena BECs potsatira 2g / kg (ip) ethanol administration. Zatsimikiziridwa bwino kuti zakudya zamakono komanso zakudya zopatsa thanzi zimapangitsa kuti DAergic iwonongeke mu striatum, yomwe yatumizidwa kuti ipepetse mphoto [32-34]. Komabe, zotsatira za zakudya zomwe zimapangitsa kuti kunenepa kwambiri ku midzi ya DA neurons zisadziŵike. Pano, tikuwonetsa kuti chakudya chokwanira chodyera chakudya chimapangitsa D2R kudziletsa ku VTA DA neurons, popanda zotsatira pa basal tonic pacemaker kuthamanga kawirikawiri mu kagawo. Sizowonongeka ngati kuchulukitsidwa kwa D2R kupititsa patsogolo chakudya cha zakudya kumachepetsa kuchepetsa mowa wa mowa, komabe kuwonjezeka kwa DA neuron autoinhibition kungapereke mphotho ya hypofunction yomwe ikuwonetsedwa ndi kunenepa kwambiri.

Zotsatira za zakudya zakudya zodyerako pa zakumwa za ethanol

Kudya chakudya choyambirira musanayambe kudyetsa kunachititsa kuchepa kwa nthawi yaitali kumalo osokoneza bongo kumwa mowa. Mavotolo onse a ethanol omwe amawonongedwa adachepetsedwa kwa masabata a 2 pambuyo pakudya chakudya. Kuwonjezera apo, chakudya chodyetsa zakudya sichinakhudze mabungwe a BEC kapena mphamvu ya ethanol yomwe imatsatira 2g / makilogalamu oyendetsa mafuta. Choncho, kuchepetsa kumwa mowa wa ethanol sizingathe kufotokozedwa ndi zakudya kapena kulemera kwa thupi kumene kumapangitsa kuti kusintha kwa madzi amadzimadzi kapena kuchepa kwa ethanol mu magazi. Mosiyana ndi kumwa mowa wambiri, sucrose mowa ndi chakudya chaching'ono zinachepetsedwa mochepa. Potsirizira pake, chakudya choyambirira chodyera chakudya chinapangitsa kuti kuchepa kwautomoni kukhale kosatha, poyerekeza ndi madyerero achilengedwe.

Sitikudziwa bwinobwino momwe zakudya zimakhudzira kumwa mowa mu makoswe. Choncho, mu phunziro la tsopano, makoswe anadyetsedwa zakudya zomwe zili ndi zakudya zopanda zakudya zomwe nthawi zambiri zimadya ndi anthu. Zotsatira zamakono zimagwirizana ndi kafukufuku waposachedwapa omwe amasonyeza kuti kudya kwamtundu wa mafuta olemera kwambiri kapena zakudya zamtundu wa mafuta wambiri-kudyetsa mphulupulu zomwe sizinenepa kwambiri zimachepetsa kukonda mafakitale [16]. Komanso, zakudya zapuloteni zotsika kwambiri zapakhungu zimasonyeza kuti kuchepetsa kumwa mowa pamatope [17], komabe, kudya kwa ethanol kunayesedwa panthawi ya zakudya. Choncho, kumwa moŵa wa ethanol kungakhale kuchepetsedwa malinga ndi kufunika kwa caloric m'malo mochepetsera mphamvu zothandizira ethanol. Mosiyana ndi zimenezi, masiku oyambirira (succinis) masiku ochepa (masiku a 21) kapena zakudya zapamwamba (masiku a 7) asonyezedwa kuti aziwonjezera kumwa mowa wa mowa [14, 15]. Maphunziro awiriwa anagwiritsa ntchito 12 hr kufotokoza kwa 4-5 kuwonjezeka kwa mafuta a ethanol (1,2,4,7, kapena 9%) kwa masiku 4 aliyense, omwe ndi osiyana kwambiri ndi 2 kufika kwa 10% mafuta omwe amagwiritsidwa ntchito phunziroli. Kusiyanitsa kwa zotsatira za zakudya zamtundu wa calorie pa mowa wa mowa ukhoza kukhala chifukwa cha kusiyana kwa zakudya zowonjezera zakudya, nthawi ndi nthawi ya zakudya zomwe zimadya, kumwa mowa wothira paradigm ntchito, kapena mavuto / mitundu yowonongeka.

Zotsatira za zakudya zodyera pa D2R autoinhibition

Kudyetsa zakudya zamakono kumawonjezera D2R autoinhibition, yomwe imamvekanso potsatira mobwerezabwereza mafuta owonjezera. Labu lathu lawonetsa kale kuti kukonza mobwerezabwereza kwa ethanol mu mbewa kumapangitsa mphamvu ya D2R kupitilira kunja kwa ma VTA, ndipo imachepetsa Ca²⁺ kudalira kwachidziwitso cha madziwa [29]. Phunzirolo, kutulutsa mowa mobwerezabwereza kunabweretsa zotsatira zolepheretsa kugwiritsidwa ntchito pafupipafupi pa 10 nM ndi 30 nM. Komabe, chakudya chodyera zakudya chinapangitsa kuti chiopsezo chowombera pafupipafupi chikhalepo pa 10 nM concentration (Chizindikiro cha 5B ndi 5C). Ngakhale kuti sitinadziwe ngati chakudya chamagetsi chinasinthidwa ndi chakudya chodyetserako zakudya, zotsatirazi zimasonyeza kuti chakudya chodyera zakudya chinapangitsa chidwi cha quinpirole kuti chilepheretse kuwombera kwa DA. Mauthenga oopsa a cocaine (20 mg / kg) amasonyezanso kuti akuwonjezera mazira a kunja kwa D2R pambali ya nigra pars compacta ya mbewa [30]. Mosiyana ndi zimenezi, methamphetamine kudziwonetsera kwawonetsedwe kwawonetseredwa kuti kuchepetseni ma D2R-mpweya wamakono mu VTA, yomwe inalinso Ca²⁺ wodalira [35]. Choncho, mosiyana ndi njira zopangira mankhwala osokoneza bongo kapena zakudya zamtundu wa kalori zambiri zimachepetsa kufotokoza kwa D2R, kugwiritsa ntchito mankhwala osokoneza bongo ndi zotsatira zosiyana pa ma D2R / GIRK-mediated currents. Kuyenera kudziŵika kuti kuchepetsa chakudya kumaphatikizapo kudya mankhwala osokoneza bongo [36], kuphatikizapo ethanol [37], ndipo amachepetsa D2R autoinhibition [38]. Popeza kuti chakudya chodyera chakudya chimapangitsa kuti D2R isamangidwe komanso kuchepetsa kudya kwa ethanol, zidzakhala zofunikira kudziwa mgwirizano pakati pa kudya, kusintha kwa D2R kudziletsa, ndi kumwa mowa wa ethanol. Kudziwa kwathu, pali phunziro limodzi lokha lomwe linayang'ana zotsatira za kudya-kunenepa kunenepa kwa D2R autoinhibition. Phunziro limenelo, kudya kwakukulu kwa mafuta kunenepa kwambiri sikudasinthire zotsatira zoletsedwa za quinpirole (3-100 nM) pa VTA DA neuron kuwombera pamitengo [39]. Komabe, kugwiritsidwa ntchito moyenera kwa quinpirole (3, 10, 30, ndi 100 nM) kunachititsa kuchepetsa zotsatira zoletsedwa za kuwombera, motsogolera olemba kunena kuti mbewa zowonongeka zowonongeka kwambiri za D2R poyerekeza poyerekeza ndi ziwalo zowonongeka. Sizodziwikiratu zomwe zikugwirizana ndi izi zotsutsana ndi zotsatira za zakudya zodyera m'makoswe pogwiritsa ntchito zakudya zamtundu wapamwamba pa mbewa pa D2R autoinhibition. Maphunziro ena akuyenera kudziwa zotsatira za zakudya zowonjezera mphamvu ndi zakudya zowonongeka pa VTA DA neurons ndi D2R.

Sindikudziwa ngati kuchepa kwa mowa wa ethanol kapena zotsatira za electrophysiological zakhudzidwa ndi kuwonjezeka kwa thupi mu phunziro la tsopano. Komabe, zakudya zamtundu wa calorie zingathe kuchepetsa dongosolo la DA [13] komanso kuchepetsa kumwa mowa [16] popanda kusowa kunenepa. Kuwonjezeka kwakukulu kumagwirizana ndi kusintha kwa leptin, insulini, ndi ghrelin, zonse zomwe zingathe kupanga ntchito ya DA [40-42]. Choncho, sitingathe kuwonetsa kuti kusintha kwa njira zotsegula kunyumbaostase kungakhudze zotsatira. Sitikutha kuwonetsa kuti chakudya chodyera zakudya chikhoza kusintha kusintha kwa khalidwe labwino chifukwa chomwa mowa ndi sucrose kumwa kumangoyesedwa pa nthawi ya 2.

Phunziro la tsopano likusiyana ndi maphunziro apitalo [5, 6] omwe awona zotsatira za chakudya chodyera ku DA dongosolo mwa kupereka chakudya chodyetsa pa nthawi ya unyamata m'malo mokalamba. Kuphatikizidwa pamodzi, deta ikuwonetsa kuti chakudya cha achinyamata komanso akuluakulu akudyetsa chakudya chimapangitsa kuti pakhale njira zothandizira DA komanso zimapereka mphotho yachisokonezo. Ngakhale kuti sizikudziwika kuti kudya zakudya zodyera pakadali kumakhudza bwanji kudziletsa kwa D2R, kuyendetsa mankhwala osokoneza bongo kungapangitse D2R kudziletsa poyendetsa nthawi yaunyamata [29] kapena akadzakula [30].

Kuwonjezeka kwa kuwonjezereka kwa D2R kudzipatula ndi dziko la hypodopaminergic pambuyo pa chakudya chakumwa zakudya pa kumwa mowa wa m'thanol ndi khalidwe lopweteka

Mu vivo, kuwonjezeka kwa D2R kudziletsa kungachepetse chiwerengero cha DA neuron kuthamanga kawirikawiri, motero, kuchepetsanso dongosolo la DA ndi kupereka gawo la hypodopaminergic. Mu phunziro laposachedwapa ndi phunziro lapitalo kuchokera ku lab lathu [29], sitinapeze kuti mawu a basal DAergic mu kagawo kake monga sulpiride satha kusintha mavoti a DA neuron. Komabe, mu vivo ntchito ya DA neurons imapitiriridwabe ndi maiko a DA komanso D2R. Choncho, kuchulukitsidwa kwa D2R kupititsa patsogolo chakudya kumapangitsa kuti kuchepetsedwa kwa chiwerengero cha DA neurons mu nyama yosakanikirana, komanso kumapangitsa kuti dziko la hypodopaminergic liziyendetsa zakudya zambiri [19]. Mofananamo, umboni wochuluka wochokera kuzinthu zowonongeka ndi zaumunthu wapangitsa kuganiza kuti dziko la hypodopaminergic limapangitsa kuti munthu asamangokhalira kumwa mowa wambiri ndi kubwerera m'mbuyo [43, 44]. Zotsatira zamakono zikuwonjezera ku mabuku omwe akukula omwe amasonyeza kuti zakudya zopatsa thanzi zimapangitsa kuti Daergic azisinthasintha mofanana ndi dziko la hypodopaminergic [5, 6]. Ngakhale kuti dziko la hypodopaminergic lakhala likugwiritsidwa ntchito mobwerezabwereza kuti ligwiritse ntchito moŵa wochuluka wa ethanol, zakudya zopatsa thanzi zomwe zimapangitsa kuti pakhale hypodopaminergia sizikuwonjezera kumwa mowa wambiri. Ntchito yapitayi mu labata yathu inasonyeza kuti kachitidwe ka ethanol kawiri kawiri kanali kowonjezera D2R autoinhibition, yomwe inkagwirizana ndi kuwonjezeka kwakumwa kwa ethanol kumwa mu mbewa [29]. Phunzirolo, tinatsimikiza kuti kuchuluka kwa D2R kudzipangitsa kutengera mowa mobwerezabwereza wothandizira mafuta kunapangitsa kuti pulogalamu ya hypodopaminergic ikhale yotchuka kwambiri. Kuphatikizidwa pamodzi, zikuwoneka kuti ndizomveka kuti mawu a hypodopaminergic omwe amapangidwa ndi mphamvu zopanda mphamvu zowonjezera zakudya zopatsa thanzi amatsogolera ku khalidwe lokwanira / lopangidwira lokhazikika lomwe limalimbikitsa kwambiri. Inde, kuwonjezera mphamvu za zakudya zowononga sizikutanthauzira mowa mopitirira muyeso kugwiritsa ntchito mankhwala osokoneza bongo, koma mmalo mwake, kawirikawiri zimachepetsa kudya kwa mankhwala. Umboni wammbuyo ndi zotsatira zamakono zimathandizira izi popeza chiyanjano chowonjezera cha zakudya zodyerako chimapanga chakudya chokakamiza cha chakudya chokoma [6], koma amachepetsa ethanol ndi sucrose zakumwa monga tikuwonetsera pano. Kuwonjezera apo, chakudya chowombera chinachepetsanso mochepa potsatira chakudya chodyetsa zakudya. Komanso, zakudya zamtundu wa mafuta kapena shuga zakhala zikuwonetsedwa kuchepetsa vuto la psychostimulant kudya ndi kukonda malo okhala ndi makoswe [10-13]. Kafukufuku wochuluka wodwala matenda a matenda akuwonetseranso kuti kulemera kwa umunthu sikugwirizana kwambiri ndi vuto la mowa kapena mankhwala osokoneza bongo [45-48]. Mosiyana, pali maphunziro ochepa omwe amapereka umboni wakuti kale chakudya chambiri cha mafuta kapena sucrose administration chimapangitsa kumwa mowa mopitirira muzakoswe [14, 15] kapena kuti kunenepa kwambiri kumayenderana ndi vuto logwiritsa ntchito mowa mwa anthu [49]. Mavuto osakaniza a ethanol angapangitsenso mphamvu zowonjezera pa mankhwala osokoneza bongo. Mwachitsanzo, kutentha kwapadera kwa ethanol kumawonjezera mafuta a ethanol [50], koma alibe mphamvu pa cocaine self-administration [51], ngakhale kuyang'anira kosatha kwa ethanol kapena cocaine zonse zimapanga kusintha komweko mu dongosolo la DA. Kuwonjezera apo, malinga ndi momwe dziko la hypodopaminergic limakhudzira kumwa mowa wa ethanol ndi kubwerera m'mbuyo, kafukufuku waposachedwapa anafufuza kusintha kwa dongosolo la DA panthawi yonse ya chizoloŵezi choyambitsana ndi makoswe ndi anthu, ndipo anasonyeza kuti kudziletsa kumakhala ndi matenda oyambirira a hypodopaminergia ndiyeno hyperdopaminergia ikatha msinkhu, zomwe zingabweretse chiopsezo [52]. Choncho, zopotoka za DAergic zimagwiritsidwa ntchito ndi mowa wa mowa komanso kusokoneza mowa, koma kugwirizana pakati pa DA ndi kumwa mowa mopitirira muyeso sikudali bwino.

Kuwonjezeka kwa kuwonjezeka kwa D2R kudziletsa mu zakudya zowonongeka

Kuwonjezeka kwa D2R kudziletsa kungapangitse kuti kuchepa kwa DNA kuwonongeke komanso kupereka mphulupulu yomwe imapangidwanso ndi kudya kwambiri. Kunenepa kwambiri kumakhudzana ndi kuchepa kwa mphotho komanso kukhumudwa kwa maganizo ndi kukhumudwa komwe kumagwiritsidwa ntchito pang'onopang'ono kuti kuchepetsedwa kwa DA kuwonetseke [32, 33, 53]. Kudyetsa zakudya zakudya zapakudya kwawonetseredwa kuti kuchepetsa mazinga a DA komanso madera a DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) ndi homovanillic acid (HVA) mu NAc [5]. Komanso, kafukufuku wina adawonetsa kuti makoswe amadziwika kwambiri omwe amawonetseratu 50% ochepa DA omwe ali mu NAC poyerekeza ndi machitidwe [54]. Maphunziro awiriwa amatsimikizira kuti chakudya chodyetsa chakudya ndi kunenepa kwambiri ndi makoswe omwe ali ndi vuto lachilendo ku DA pogwiritsa ntchito kukonza kagawo ka NAC. Mwachitsanzo, makoswe otsika kwambiri amakhala ndi kuchepa kwa dothi la DA biosynthetic enzyme tyrosine hydroxylase ndi vesicular monoamine transporter 2 (VMAT2) yomwe ingachepetse chiwerengero cha DA ndi kutulutsa [54]. Komabe, chinthu chosayiwalika m'munda ndikutengapo mbali kwa thupi la VTA kumene ma CD ambiri amachokera. Zotsatira zamakono zikusonyeza kuti kuwonjezeka kwa D2R kudziletsa kungayambitse kuwonongeka kwa DAergic ndi kuperewera kwa zakudya. Choncho, kufufuza zochitika za presynaptic mesolimbic mu NAC ndi VTA zingapereke chidziwitso ku njira zogwiritsira ntchito njira zopangitsa kuti thupi likhale wochuluka kwambiri.

Mawuwo

Kuchulukitsidwa kwa DA mu njira ya anthu olemera kwambiri ndi makoswe alembedwa bwino [6, 8, 19]. Kafukufuku wamakono akusonyeza kuti kuwonjezeka kwa D2R kudzichepetsa mu VTA kungathandizenso kudya zakudya zophatikizapo za DA kuphatikizapo kupatsa mphulupulu zomwe zimachitika ndi kunenepa kwambiri. Ngakhale zakudya zamtundu wa kalori komanso mankhwala osokoneza bongo amachititsa kusintha komweku mu njira ya DAlimbic DA, timasonyeza kuti chakudya chodyetsa chakudya chimachepetsa mpweya wa mowa m'khola. Zonsezi zikuwoneka kuti zakudya zopatsa thanzi zomwe zimapangitsa kuti zakudya zowonongeka mu DA zikhoza kutsogolera zakudya zodyera [6], pamene kuchoka ku zakudya zodyera kumawonjezera kuledzera kwa nthawi yaitali kwa mowa wa ethanol ndipo kumapititsa patsogolo kuwononga madalitso achilengedwe (ie, sucrose ndi chow pellets). Zotsatirazi zikuwonjezera ku mabuku omwe akukula omwe amachititsa kuti kudyetsa kunenepa ndi kusokoneza bongo kumabweretsa zofanana zowonjezereka m'madera oyendetsera mphoto. Kafukufuku wopitilira m'magulu a DAergic omwe amatha kusintha chifukwa chodya zakudya zowonjezera kwambiri kapena kumwa mankhwala osokoneza bongo angapangitse kudziŵa bwino njira zomwe zimayambitsa mavuto aakulu a thanzi la anthu.

Kusamalitsa mfundo

 

 

S1 Data.xlsx

 

  

	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24	25	26	27	28	29	30	31	32	33	34	35	36	37	38	39	40	41	42	43	44	45	46	47	48
1
2
3		Chithunzi 1A. Malori pa Sabata
4		Chow kokha (ID)	1	2	3	4	5	6	7	8	9	10	11	12	13	14
5		Sabata 1	464	484	504	456	492	176	276	284	376.4445	463.5555	438.6667	392	283.1111	301.7778
6		Sabata 2	712	700	788	680	728	452	492	452	660.8	705.6	733.6	672	621.6	571.2
7		Sabata 3	662.6667	653.3333	802.6667	634.6667	630	512	484	488	700	728	777	452.6667	616	576.3333
8
9		Zakudya Zakudya Zakudya Zakudya	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19
10		Sabata 1	810.11	783.9116	813.6035	857.5615	705.5117	780.7995	354.83	414.8343	354.5233	515.7778	386.4445	393.1111	466.1111	489.3333	337.5555	466.4445	398.8889	440.5555	320.2222
11		Sabata 2	971.8041	1003.042	946.6136	1012.289	946.2327	926.5184	569.1601	530.6304	546.8109	788.8925	740.2822	916.6797	680.6889	857.7944	756.5599	805.8618	796.4995	834.9358	687.0909
12		Sabata 3	1258.863	1219.169	1219.993	1210.393	1121.678	1124.869	631.8867	656.8687	587.3893	897.3823	882.5435	936.5898	860.3552	1045.424	864.0526	990.0101	867.4072	941.0391	893.0363
13
14
15		Chithunzi 1B. Gwero la Calories (Gulu la zakudya zodyera zakudya)
16		Chow pellets	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19
17		Sabata 1	144	128	112	60	156	64	132	104	189.7778	96.44444	59.11111	199.1111	233.3333	15.55556	208.4444	80.88889	71.55556	34.22222	116
18		Sabata 2	320	268	292	224	284	148	76	188	243.6	207.2	243.6	201.6	366.8	221.2	324.8	212.8	182	201.6	312
19		Sabata 3	182	182	149.3333	102.6667	196	184	68	204	207.6667	144.6667	238	156.3333	284.6667	163.3333	245	221.6667	228.6667	142.3333	261.3333
20
21		Zakudya zakudya	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19
22		Sabata 1	694.11	639.9116	685.6035	745.5615	645.5117	624.7995	290.83	282.8343	250.5233	326	290	334	267	256	322	258	318	369	286
23		Sabata 2	659.8041	683.0422	678.6136	720.2889	722.2327	642.5184	421.1601	454.6304	358.8108	545.2925	533.0823	673.0798	479.0889	490.9944	535.3599	481.0618	583.6995	652.9358	485.4909
24		Sabata 3	997.5293	1037.169	1037.993	1061.059	1019.012	928.8688	447.8867	588.8687	383.3893	689.7157	737.8768	698.5898	704.0219	760.7576	700.7192	745.0101	645.7406	712.3724	750.7029
25
26		Chithunzi 1C. Ma calories ochokera ku Chow
27		Chow kokha (ID)	1	2	3	4	5	6	7	8	9	10	11	12	13	14
28		Sabata 1	464	484	504	456	492	176	276	284	376.4445	463.5555	438.6667	392	283.1111	301.7778
29		Sabata 2	712	700	788	680	728	452	492	452	660.8	705.6	733.6	672	621.6	571.2
30		Sabata 3	662.6667	653.3333	802.6667	634.6667	630	512	484	488	700	728	777	452.6667	616	576.3333
31
32		Zakudya Zakudya Zakudya Zakudya	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19
33		Sabata 1	144	128	112	60	156	64	132	104	189.7778	96.44444	59.11111	199.1111	233.3333	15.55556	208.4444	80.88889	71.55556	34.22222	116
34		Sabata 2	320	268	292	224	284	148	76	188	243.6	207.2	243.6	201.6	366.8	221.2	324.8	212.8	182	201.6	312
35		Sabata 3	182	182	149.3333	102.6667	196	184	68	204	207.6667	144.6667	238	156.3333	284.6667	163.3333	245	221.6667	228.6667	142.3333	261.3333
36
37		Chithunzi 1D. Kulemera Kwambiri pa Sabata (g)
38		Chow kokha (ID)	1	2	3	4	5	6	7	8	9	10	11	12	13	14
39		Sabata 1	55	57	61	50	52	35	39	36	45.5	49.7	52.5	46.9	40.6	39.2
40		Sabata 2	64	58	63	52	67	52	51	48	48.5	51.3	54.25	51.35	44.9	42.3
41		Sabata 3	43	51	57	49	39	32	43	40	50.75	52.5	55.5625	54.6875	48.125	44.625
42
43		Zakudya Zakudya Zakudya Zakudya	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19
44		Sabata 1	61	63	62	70	60	58	33	37	37	51.8	42	53.2	42.7	55.3	49.7	47.6	48.3	49.7	46.2
45		Sabata 2	67	72	70	69	59	59	52	58	59	58.95	50	59.55	50.05	66.7	57.3	56.15	58.2	52.55	55.8
46		Sabata 3	68	63	66	66	61	59	43	54	47	64.3125	56	64.3125	55.5625	75.25	63	62.5625	65.625	54.6875	63
47
48		Chithunzi 1E. Kulemera kwa thupi (g)
49		Chow kokha (ID)	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24	25	26	27	28	29	30	31	32	33	34	35	36	37	38	39	40	41	42	43	44	45	46
50	tsiku	1	180	183	190	217	226	193	181	203	197	223	211	134	207	195	206	208	182	148	147	183	167	174	199	159	184	157	174	178	185	145	186	228	222	208	224	222	211	216	150	169	150	147	159	163	172	165

 

 

 

 

 

 

 

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

chithgawo

 

 

 

 

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Deta zazikulu za Fini 1.

(XLSX)

S1 Data. Deta yaikulu Chithunzi cha 1.

https://doi.org/10.1371/journal.pone.0183685.s001

(XLSX)

S2 Data. Deta yaikulu Chithunzi cha 2.

https://doi.org/10.1371/journal.pone.0183685.s002

(XLSX)

S3 Data. Deta yaikulu Chithunzi cha 3.

https://doi.org/10.1371/journal.pone.0183685.s003

(XLSX)

S4 Data. Deta yaikulu Chithunzi cha 4.

https://doi.org/10.1371/journal.pone.0183685.s004

(XLSX)

S5 Data. Deta yaikulu Chithunzi cha 5.

https://doi.org/10.1371/journal.pone.0183685.s005

(XLSX)

Kuvomereza

Tikufuna kuvomereza Jorge Tovar Diaz, Regina Mangieri, Nhi Le, Jeremiah Ling, ndi Trevor Hadley kuti awathandize. Tikufunanso kuthokoza Michela Marinelli pa zokambirana za sayansi zamtengo wapatali ndi Christopher Mazzone kuti athandizidwe kukonza zolembedwazo.

Zothandizira

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Onani Nkhani

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