Zakudya zamafuta a purrose ers-opioid ndi dopamine D2 / 3 receptor kupezeka mu ubongo wa porcine (2020)

Scientific Reports kuchuluka 9, Nambala yolemba: 16918 (2019)

Kudalirika

Kugwiritsa ntchito mankhwala osokoneza bongo mopitirira muyeso kumapangitsa munthu kuti azilakalaka kwambiri zomwe zingayambitse vuto la kunenepa kwambiri. Ma opioid ndi dopamine amalumikizana ndi zotsatira zabwino za mankhwala osokoneza bongo, komanso mphotho zachilengedwe kuchokera pazokopa monga chakudya chosavuta. Tasanthula zotsatira za sucrose pogwiritsa ntchito kulingalira kwa PET ndi [11C] carfentanil (μ-opioid receptor agonist) ndi [11C] raclopride (dopamine D2 / 3 receptor antagonist) mu ma minipigs asanu ndi awiri oletsa kubereka a Göttingen. Tidapatsanso minipigs mwayi wotsatira yankho la ola limodzi pamasiku 12 otsatizana ndipo tidaganiziranso patadutsa maola 24 atatha kulumikizana komaliza. Mu zitsanzo zochepa zazing'ono zisanu, tapanga zowonjezera [11C] carfentanil PET gawo litayamba kufotokozedwa koyamba. Tidawerengera zanzeru zomangira voxel (BPND) pogwiritsa ntchito cerebellum ngati dera lolumikiza, losasiyanitsa ndi mapu osakhala a parametric, ndikuwunika madera. Pambuyo pa masiku 12 olumikizira, BPND a tracers onse anali atachepa kwambiri mu striatum, nucleus accumbens, thalamus, amygdala, cingate cortex ndi preortalal cortex, yogwirizana ndi kayendedwe ka pansi ka ma receptor densities. Pambuyo podziyimira patokha, tapeza kuti kuchepa kwa [11C] carfentanil mu nucleus accumbens ndi cingrate cortex, wogwirizana ndi kutulutsidwa kwa opioid. Kupezeka kwapansi kwa opioid ndi dopamine receptors kungafotokozere zovuta zomwe zingayambitse chifukwa chogwiritsa ntchito sucrose.

Introduction

Asanu mwa anthu XNUMX alionse padziko lapansi ali ndi matenda onenepa kwambiri1. Monga chizindikiritso cha kagayidwe kachakudya, kunenepa kumalumikizidwa ndi matenda amtundu wa 2, matenda amtima, mavuto a kupuma, komanso chiopsezo cha kupsinjika ndi matenda a dementia2. Kuchulukitsidwa kwa zakudya zamafuta kwambiri kwachulukitsa kusiyana pakati pa njala yakunyumba yomwe imatsatila ndikusowa chakudya, ndi njala ya hedonic, kapena "kulakalaka", komwe kumachitika popanda kusowa.3,4. Popeza lamulo lanyumba lokha silingayambitse kuchuluka komwe kunenepa kwambiri, ndikofunikira kuyesa momwe ubongo umalandirira mphotho ndi chisangalalo cha zakudya zomwe zimakonda kwambiri.

Kugwiritsa ntchito mankhwala osokoneza bongo a improse kumalumikizidwa ndi kunenepa kwambiri, ndipo sucrose imayamba kuganiziridwa kuti ndi mankhwala osokoneza bongo5. Zotsatira zina zakusiyana ndi izi chifukwa chovuta kusiyanitsa zakudya zosagwiritsidwa ntchito bwino ndi mayankho a chakudya cha hedonic, komanso pakuwona zomwe zimaphatikizika muzakudya zomwe zimapangidwira, komanso njira zosiyanasiyana zomwe chakudya chimasinthira kayendedwe ka ubongo kudutsa njira zachilengedwe.6. Komabe, munthawi zina, kudya sucrose kumadzetsa mphotho ndi kulakalaka, zofananira ndi kuchuluka kwa omwe amayamba ndi mankhwala osokoneza bongo, omwe amatsogolera pakuganiza mopitilira muyeso komanso kunenepa kwambiri.6,7.

Njala imalumikizidwa ndi "kufuna" komwe kumakhudzana kwambiri ndi zotsatira za dopaminergic neurotransication munthawi zopindulitsa zambiri8, koma sizikudziwikabe kuti momwe dopamine (DA) imasinthidwira poyankha kudya mokakamiza. Kudya kwa zakudya zabwino kumalumikizidwa ndi "kukonda", komwe kumapangidwa makamaka ndi endio native opioid system, makamaka μ-opioid receptor (μOR)9,10, zomwe zitha kulimbikitsa kukhudzidwa kwa mtima kwambiri mukaletsedwa. Mu lipoti lapano, timayesa zonena kuti sucrose imatsogolera ku opioid ndi dopamine kumasulidwa komwe kumachepetsa kupezeka kwa μOR ndi DA D2 / 3 receptors. Kupezeka kwake ndi chisonyezo cha kuchuluka kwa zolandirira zomwe zilipo kuti zigwirizane ndi tracer ndipo mfundo zake sizisiyanitsa pakukhalapo kwa ligand ndi receptorensens11.

Kukhazikika kwa kudya kokakamiza kumadalira zinthu zingapo, ndipo maphunziro owerengera mwa anthu amadzutsa nkhani zoyenera. Ambiri mwa maphunziro amatero amayang'ana pakudya kwa makoswe12. Ngakhale makoswe ali ndi "mano okoma", njira zawo zothetsera kulemera, kuphatikiza, komanso kuchuluka kwa mafuta, zimasiyana mosiyana ndi anthu. Göttingen minipig ndi nyama yayikulu yodabwitsa komanso yokhala ndi ubongo wopanga bwino, womwe ungajambulidwe wokwanira. Dera lake lotanthauzira bwino komanso loyambirira13 zimapangitsa kutanthauzira kolunjika kwambiri kuntchito yaubongo. Pano, timagwiritsa ntchito positron emission tomography (PET) kuyerekezera mu vivo μOR ndi DA D2 / 3 kupezeka kwa mtundu wa minipig wa mawonekedwe a subchronic sucrose. Pachitsanzo chocheperako, tidafufuza zotsatira zoyipa za kukhalapo kwa anthu atakhala kuti tayamba kudziyesera tokha. Pomaliza, tinayesa kuyanjana pakati pa kusintha kwa kupezeka kwa receptor kwa asitikali awiriwo.

Results

Mamapu apakati oyambira a [11C] carfentanil ndi [11C] mpikisano wothamanga ungathe (BPND) akuwonetsedwa ku mkuyu. 1. Kusanthula kusintha komwe kumachitika patatha ma sucrose oyamba kutulutsa mphindi zisanu poyerekeza ndi momwe ziriri, ndipo tsiku limodzi pambuyo pa 12th kupezeka kwa ma minipigs asanu ndi awiri poyerekeza ndi momwe tidayambira kale, tidagwiritsa ntchito chiphunzitso chololera komanso chosagwirizana ndi ubongo wathunthu, njira yomwe amasankhira kukula kwa zitsanzo za kukula14.

Chithunzi 1
chithunzi1

Avereji ya anzeru yopanda voxel-osagwiritsa ntchito mosavomerezeka (BPND) mamapu opatsika pazithunzi za MRI mu sagittal view. Zambiri zimaperekedwa kwa [11C] carfentanil BPND Mwa minipigs isanu yojambulidwa pachiwonetsero, atayamba kudziyimira patatha masiku 5 atadziwika bwino (mzere wapamwamba). [11C] carfentanil BPND ya minipigs 7 yojambulidwa pachiyambipo ndipo patatha masiku 12 yodziyimira payokha iperekedwe pakati. [11C] raclopride BPND Mwa minipigs 7 yonse yojambulidwa pachiwonetsero ndipo pambuyo pa masiku 12 oyenera kulowa ikuwonetsedwa pamzere wapansi. Dziwani kuti kukula kwamtunduwu ndiwofunika kutsimikizira [11C] raclopride BPND m'madera akumidzi.

Chithunzi chachikulu kukula

Kuwonetsedwa koyambirira

Mu minipigs isanu yojambulidwa ndi [11C] carfentanil pachiyambipo ndipo atangowonekera pachiwonetsero choyamba, tidapeza chochepetsetsa kwambiri chomwe chimamangidwa mu anterior cingate cortex ndi ma nucleus anasonkhana poyankha sucrose, omwe akuwoneka mtundu wa mkuyu. 2, yosonyeza p <0.05. Tidapeza kuti 14% yachepetsa kumangirira m'malo onsewa poyerekeza ndi poyambira.

Chithunzi 2
chithunzi2

Zambiri zachepa mu [11C] carfentanil BPND pambuyo paziwonetsero zoyambira zamadzi za sucrose poyerekeza ndi zoyambira (n = 5). Ma voxel okha ndi ofunika (p <0.05) kuchepa kumawonetsedwa ngati malo amitundu akuyembekezeredwa pa T1 yolemera yolemera MRI pamlingo wa anterior cingate cortex (kumanzere) ndi nucleus accumbens (pakati) kuchokera ku stereotaxic minipig brain atlas. Dziwani kuti mulingo wofunikira kwambiri womwe ungapezeke ndi nyama zisanu ndi 5-5 ≈ 0.031 (onani bala.). Zambiri zimawonetsedwa pazigawo za ubongo wa nkhumba pamiyeso yomwe ikuwonetsedwa pa chithunzi cha sagittal (kumanja).

Chithunzi chachikulu kukula

Masiku 12 olowa

Kenako tidasanthula ma minipigs asanu ndi awiri ojambulidwa ndi [11C] carfentanil poyambira ndipo patatha masiku 12 atayimilira mosavomerezeka ndipo atapezeka atachepetsa kwambiri tracer kumanga nyama zowonekera pokhapokha poyerekeza ndi poyambira. Madera omwe amakhudzidwa kwambiri amawonetsedwa mofiira ku mkuyu. 3 (s . Kuti mupeze BPND Kuwona kusintha ndikuwonetsa kusintha kwa peresenti, tinasanthula madera ndipo tinapeza zofunika mu dera lililonse poyambira komanso tatha kugwiritsa ntchito sucrose (mkuyu. 4).

Chithunzi 3
chithunzi3

Zambiri zachepa mu [11C] carfentanil womangira angathe (BPND) pakati pamasiku oyambira pambuyo masiku 12 a kuyamwa kwa madzi a sucrose (n = 7). Ma voxels okhala ndi chofunikira (p <0.05) kuchepa kumawonetsedwa ngati madera achikuda omwe akuyembekezeredwa pa T1 zolemera za MRI kuchokera ku stereotaxic minipig brain atlas. Zambiri zimafotokozedwa pamagawo am'magawo am'magawo amiyeso pamiyeso yomwe yawonetsedwa pa sagittal chithunzi (kumanja kumanja). Dziwani kuti mulingo wofunikira kwambiri womwe ungapezeke ndi nyama 7 ndi 2-7 ≈ 0.0078 (onani bala.).

Chithunzi chachikulu kukula
Chithunzi 4
chithunzi4

Kusanthula kwa dera [11C] carfentanil womangira angathe (BPND) pakati pamasiku oyambira pambuyo masiku 12 a kuyamwa kwa madzi a sucrose (n = 7). Zambiri zimawonetsedwa ngati njira ± cholakwika chilichonse.

Chithunzi chachikulu kukula

Tidagwiritsa [11C] mpikisano wothamanga ngati tracer wa DA D2 / 3 zolandilira mu zigawo za bongo ndi zakuthambo zam'mimba mu minipigs pamunsi kenako pambuyo masiku 12 olowa nawo (mkuyu. 1). Tidapeza kuchepa kwa ma tracer omanga nyama zowonekera za sucrose, poyerekeza ndi zoyambira ndi zotsatira zazikulu (p <0.01) m'malo a preortal cortex, nucleus accumbens / ventral striatum, cingate cortex, amygdala, thalamus, mesencephalon, madera a hippocampal, ndi malo owonera (Chith. 5). Zambiri kuchokera kusanthula kwachigawo zimawonetsedwa ku mkuyu. 6.

Chithunzi 5
chithunzi5

Zambiri zachepa mu [11C] mpikisano wothamanga ungathe (BPND) pakati pamasiku oyambira pambuyo masiku 12 a kuyamwa kwa madzi a sucrose (n = 7). Ma voxels okhala ndi chofunikira (p <0.05) kuchepa kumawonetsedwa ngati madera achikuda omwe akuyembekezeredwa pa T1 zolemera za MRI kuchokera ku stereotaxic minipig brain atlas. Zambiri zimaperekedwa pamagawo azigawo zaubongo wa nkhumba pamagulu omwe akuwonetsedwa pa chithunzi cha sagittal (kumanja kumanja). Dziwani kuti mulingo wofunikira kwambiri womwe ungapezeke ndi nyama 7 ndi 2-7 ≈ 0.0078 (onani bala.).

Chithunzi chachikulu kukula
Chithunzi 6
chithunzi6

Kusanthula kwa dera [11C] mpikisano wothamanga ungathe (BPND) pakati pamasiku oyambira pambuyo masiku 12 a kuyamwa kwa madzi a sucrose (n = 7). Zambiri zimawonetsedwa ngati njira ± cholakwika chilichonse.

Chithunzi chachikulu kukula

Kuyanjana pakati [11C] raclopride ndi [11C] chidziwitso cha carfentanil

Tidayesa kulumikizana komwe kungatheke pakati [11C] raclopride ndi [11C] zoyipa za BPND madera olimba komanso osakhazikika mu minipigs pamunsi ndipo pambuyo pa masiku 12 akudya, palibe mabungwe omwe adanenedwa. Tidayesa ngati kutsika kwa ma tracer kumakhudzana, ndipo tidafananizira zosintha za BPND chifukwa [11C] mpikisano wothamanga ndi kusintha kwa BPND chifukwa [11C] carfentanil kokha mu minipigs yomwe inali ndi BP yotsikaND onse a tracers atadya sucrose (n = 6). Tapeza zosakanikirana zazowirikiza pamakonzedwe ochulukirapo (r2 = 0.91, p <0.01), koma osati kumadera ozungulira, zigawo (mkuyu. 7).

Chithunzi 7
chithunzi7

Chiyanjano pakati pa minyemba isanachitike [11C] raclopride ndi [11C] carfentanil yomanga yolumikizira (BPND) mu minipigs yotsika ya tracer yomangirira pambuyo pakulimba kwa sucrose (n = 6). Zambiri zochokera kumadera omwe akukwaniritsidwa (pamwamba) ndi striatum (pansi) zimafotokozedwa. Mgwirizano wotsimikiza (r2) ndipo ma p akuwonetsedwa pa graph iliyonse.

Chithunzi chachikulu kukula

Kukambirana

Tidazindikira zovuta zomwe zimachitika mobwerezabwereza kufikira pakubwera pa opioid ndi ma neurotransication a DA mu ubongo wam'mayi. Longitudinal mu vivo Kulingalira kwa PET kwa μOR ndi DA D2 / 3 zolandila kunawululira kuchepa kwa kupezeka kwa receptor kudutsa gawo lonse la mphotho, kuphatikiza ma bokosi a nucleus, preortalal cortex, ndi anterior cingulate cortex. Zotsatira zake zikuwonetsa kuti sucrose imakhudzanso njira zopindulira m'njira zofananira ndi mankhwala osokoneza bongo.

Kudya kwa sucrose ngati chinthu chokoma kumadziwika kuti kumasula DA ndikupangitsa kudalira makoswe15, yokhala ndi sucrose yowoneka bwino kwambiri kuposa cocaine m'makoko ena. Chifukwa chake, makoswe amagwira ntchito kwambiri kuti apatsidwe mankhwala ochepetsa mphamvu ya cocaine, ngakhale osowa chakudya5. Komabe, zotsatira za sucrose zimayendetsedwa ndi zonse homeostatic system komanso hedonic malipiro mabwalo16,17 zomwe zitha kusiyanitsa kusiyana pakati pa zopatsa thanzi ndi zovuta za thupi18. Tidasankha dongosolo la ola limodzi patsiku kuti tikulimbikitse "kupumula", monga momwe maphunziro am'mbuyomu m'makedzedwe adawululira kuchuluka kwambiri panthawi ya ola limodzi lopezeka tsiku lililonse munthawi yochepa15,19. Kafukufuku wazakudya zomwe amapeza pakudya nthawi zambiri amakumana ndi nyama zoletsa chakudya, koma mapangidwe ake sangawonetse zomwe zimapangitsa kuti kunenepa kwambiri. Nkhumba pazomwe zinali kuphunzirazi sizinali zokhazokha za chakudya ndipo zimadyetsedwa kuchuluka kwa zakudya zomwe zimakhalapo kuphatikiza kuwonjezera kuyamwa.

Ma opioid receptors (OR) akuwonetsedwa kwambiri mu ubongo, makamaka machitidwe omwe amadziwika kuti amasinthira kudya ndi njira zopindulira20. Ma OR awonetsedwa kuti ndi ofunikira pakupindulitsa ndi kubwereza komwe kumachitika chifukwa cha cocaine21,22,23,24. Kusintha komwe kumangiriza kulumikizananso ndi mayankho olimbitsa thupi pakudya ndi chisangalalo chokhudzana ndi zakudya zabwino25. Makamaka, "kukonda" chakudya kumalumikizidwa ndi endio native opioid dongosolo, makamaka μOR9,10 mu chipolopolo cha nucleus accumbens ndi ventral pallidum26. Kulowa kwa μOR agonist m'magawo osiyanasiyana amisomali ndipo kuphatikiza kwamphamvu kwa pallidum kumakulitsa machitidwe a "kukonda", kuphatikizapo kutulutsa pakamwa ndi kulumikizana, kutsatira kuchuluka kwa chakudya27,28,29. Umboni wina wopanga ma opioid pakuwongolera kayendedwe ka hedonic umachokera kwa antOR olimbana nawo omwe amathandizira kugwiritsidwa ntchito kosangalatsa kwa zonse ziwiri ad libitum- nyama ndi nyama zoletsedwa, koma ndizochepera pakudya mafuta osagwirizana ndi zakudya30,31. Mwa anthu, othandizira μOR amachepetsa kudya kwakanthawi komanso amachepetsa kusangalatsa kwa zakudya zabwino32,33,34. Kusaina kwa opioid mu ma basgateral amygdala kumathandizanso kuti chakudya chikhale "chofunikira" kudzera pakusinthana kwa kufunafuna mphotho ndi phindu la chakudya35.

Ndi [11C] carfentanil, tinapeza zithunzi za ma tracer zomangira zomwe zimakhudza kwambiri mbali zonse za andOR komanso kutulutsa kwa ubongo ma opioids amkati36,37. Tazindikira kutayika kwaposachedwa kwa kupezeka kwa inOR m'malo a nucleus accumbens ndi anterior cingrate cortex, magawo enieni a ubongo panjira yolandira mphotho, titatha kugwiritsa ntchito sucrose ndi minipigs isanu, yogwirizana ndi kumasulidwa kwa endoid opioid. Kafukufuku wam'mbuyomu wasonyeza kuti chakudya chabwino chimatha kubweretsa chisangalalo38 polimbikitsa kumasulidwa kwa opioid. Pambuyo masiku 12 olumikizana, tinawona kuchepa [11C] carfentanil binding, yomwe ili ndi kufotokozera zingapo39 kuphatikiza kumasula kwa ma endoid ndi kumangiriza kwa μOR, μOR kutulutsa mkati chifukwa chakuwonjezeka kwa opioid, ndikuwonjezera ku DA D2 / 3 receptor activation kumabweretsa heterologous desensitization of μOR40.

Pothandizira zomwe zapezeka pano, [11C] maphunziro a carfentanil a odwala omwe ali ndi bulimia41kunenepa kwambiri42,43,44, komanso vuto la kudya kwambiri45, chiwonetsero cha kuchepa kwa receptor kupezeka. Komabe, awa ndi mikhalidwe yoyipa pomwe ma minipigs amangolandila masiku 12 okha. Pakufufuza kwamikhalidwe yodyetsa kwambiri mwa abambo athanzi, kudyetsa kunapangitsa kuti pakhale kutulutsa kwambiri komanso kufalikira kwa matenda am'mimbamo, pamaso komanso kusowa kwa hedonia, ndikuti kuwamasula kwa opioid kumawonetsa metabolic komanso homeostatic, komanso hedonic, mayankho25. Phunziroli, limodzi ndi linzake lomwe likufanizira odwala ataphika chakudya chamadzimadzi chokoleti44, imagwira ntchito mwachindunji pakuphunzira kovuta kwamatupi asanu a minipigs itatha kuwonekera koyamba, koma ndi osiyana ndi kafukufuku waposachedwa wa masiku 12 pomwe kuchepetsedwa kwa kupezeka kwa receptor kumatha kuwonetsa kupitiliza ndi kugwirizananso kwa μOR.

Cortex yoyambilira ndiyofunikira popanga chisankho ndikuwonetsa kufunika kwa zinthuzo chifukwa chake cOR yomwe ili koyambirira koyambirira ikhoza kukhala ndi mlandu pakuwunika kosinthika kwa chakudya, komwe kumatha kudzetsa kuthekera kwa chakudya. Tapeza kuchepa kumangidwa mu preortal cortex, zogwirizana ndi maphunziro am'mbuyomu omwe akuwonetsa kuti kudya zamafuta ambiri kumachepetsa milingo ya μOR mRNA mu preortalal cortex46 ndikuti kulowetsedwa kwa μOR agonist mu preortalal cortex kumawonjezera kudya kosangalatsa47. Apanso, vuto limabuka ngati zakudya zamafuta kwambiri ndizovuta kwambiri zomwe zimapangitsa kuti anthu azigwiritsa ntchito zakudya zochepa, poyerekeza ndi kapangidwe kakang'ono ka chakudya, ndikuwonetsa kutulutsidwa kwa ma opioids am'mbuyo omwe amachititsa kuti anthu asamayende bwino kwambiri. , ngakhale atatha masiku 12 odziyesa okha.

DA yathandizidwapo mphotho kuchokera ku mankhwala osokoneza bongo komanso machitidwe. Kugwiritsira ntchito mankhwala osokoneza bongo a cocaine kwapezeka kuti kumaletsa ziletso za DA48. Mawonekedwe a DA D1 ndi D2 / 3 receptor amasinthidwa ndi chikonga mu ubongo wa nkhumba49, komanso m'mbuyomu omwe si anthu omwe ali ndi mbiri ya nkhanza za cocaine50, yogwirizana ndi kuzunzika kwa ma D2 / 3 zolandirira bongo51,52. Ponena za mankhwala ozunza, sucrose yawonetsedwa kuti ikweza ma receptors a DA D119 ndi kuwonjezera kutulutsidwa kwa DA53, kulimbikitsa udindo wa DA paku “kufuna” mokhudzana ndi zakudya zabwino. Kafukufuku wam'mbuyo wa PET adawonetsa kuchepa kwa kupezeka kwa striatal DA D2 / 3 receptor kupezeka kwa kunenepa kwambiri vs54,55, zofanana ndi zochulukirapo pakuchepetsa kwa omwe ali ndi mankhwala osokoneza bongo56, ndi nyama yokhala ndi zonenepa kwambiri57. M'maphunziro a makoswe, D2 / 3 receptor kugonja mu striatum kumalimbikitsa kukula kwa chakudya chokakamiza kufunafuna makoswe ndi chakudya champhamvu57.

Zowonera zathu za kupezeka kwa D2 / 3 kupezeka kwa nkhumba zitha kuwonetsa kuchuluka kwa DA poyankha kukomoka komwe kumayenderana ndi kudya kwa sucrose kuyambira pomwe DA imamasulidwa ngati gawo la kufunafuna kwa mankhwala osokoneza bongo ndi zochitika zina zosangalatsa52,58,59,60. Pamene nkhumba zidagwiritsidwa ntchito yolingalira, ndipo sizinalandire maola 24, kutsika kwa D2 / 3 BPND Nthawi zambiri zimawonetsa kuchepa kwa ma receptor chifukwa chakuwonjezeka kwa kutulutsidwa kwa DA kwa nthawi yayitali masiku 12 aliwonse. Kuchepetsa kumeneku kumatha kudzutsa mphoto zamaubongo, zomwe zimagwirizanitsidwa ndi kutsata kwa striatal DA D2 receptors. Izi zitha kufotokozera kukwera kwa mankhwala osokoneza bongo omwe adawoneka m'mbuyomu kafukufuku wamakedzana omwe amapangitsa kuti pakhale chidwi chambiri ndi cocaine, kuchepa kwa mphamvu pambuyo poti amphetamine wambiri, kuchuluka kwa kumwa mowa popewa kuyamwa, komanso kulekerera kwa zotsatira za analgesic za opiates.6.

Kafukufuku wam'mbuyomu wa kunenepa kwambiri mu Göttingen minipig adazindikira kuchepa kwa magazi m'mitsempha yamitsempha yam'madzi, malo a ventral tegmental (VTA) ndi preortal cortex, yokhala ndi Photon emission complication tomography (SPECT) yaubongo61. Potsatira zomwe tapezazi, tawona kuti a D2 / 3 amachepetsa dera la ventroforebrain lomwe lili ndi ma nucleus accumbens komanso preortalal cortex. Miyezo ya extracellular ya DA imachulukitsidwa katatu-m'mitsempha ya nucleus itatha kudya kwa makoswe omwe amayenda momasuka pakuchitika ma micodialysis62. Mu nyama zodalira sucrose, kudya mobwerezabwereza kwa sucrose kungayambitse kutulutsidwa kwa DA kuchokera ku chipolopolo cha nyukiliya63. Nyama zomwe zinkadyetsa chakudya chochepera koma sizingatheke chifukwa chokhala ndi sucrose zokhala ndi ma D2 receptor otsika mu ma nucleus64. Zakudya zololetsedwa zamafuta ochulukirapo komanso zokhala ndi sucrose zimatha kuyambitsa kupitirira kwa D1 ndi D2 receptor mRNA mu nucleus accumbens65. Kafukufuku wokhudza zotsatira za chakudya cham'kati mwake adawonetsa kuwonjezeka kwa DA mu nucleus accumbens ndi preortalal cortex pomwe chakudya chidanenedwabe kuti ndi nkhani; makoswe atangozolowera chakudya chatsopano, kutulutsa kochulukira kumakutidwa ndi maukonde, koma osati kutsogolo66. Kuthekera kosiyanako kwa malo okhala ndi momwe zinthuzo zikuchitikira m'zigawo ziwiri zitha kufotokozera kuchuluka kwakukulu komwe kumawoneka m'mbali yam'mbuyo kuposa momwe gawo lambiri la minipigs likuvumbulidwira chinthu chomwechi chomwe chidasowa masiku khumi ndi awiri. Komabe, monga sitinapangire minipigs ndi [11C] mpikisano wothamanga pambuyo pa kuyang'anira koyambirira kwa sucrose, malongosoledwe awa ndiwongoyerekeza.

Preportal cortex modulates oyang'anira ntchito, kusankha, komanso kudziletsa67. Kuchepa kwa misempha ya DA mu preortalal cortex kumapangitsa kusinthasintha kwa mphotho, kuwonetsa kuwonongeka kwa ntchito yayikulu komanso luso loti munthu azisankhira anthu okonda kunenepa.68,69. Kuphatikiza apo, kafukufuku wa PET waumunthu wophatikizidwa amachepetsa kutsogola kwa cortex kagayidwe kake ka kuchepa kwa striatal D270. Apa, tikupeza kupezeka kwa D2 / 3 receptor kupezeka kwa preortal cortex kuphatikiza ndi orbitof mbeleal cortex ya nkhumba zomwe zikuwululidwa mu mawonekedwe a sucrose.

Ma dopaminergic neurons a VTA amatumiza zowerengera ku hippocampus ndi amygdala, komwe amathandizira zizolowezi zonga zizolowezi71 ndi kusamukira ku kukhazikitsa ndi kubweretsanso mawonekedwe kwa mankhwala72,73 ndi zopatsa zakudya74,75. Kulingalira kwa ubongo waumunthu kwawonetsa kutsegulidwa kwa hippocampal poyankha kulakalaka chakudya ndi kulawa76. Zogwirizana ndi zomwe tapeza pakuchepetsedwa kwa hippocampal ndi amygdalar D2 / 3 receptor kupezeka poyankha sucrose, mapu aubongo a anthu ali ndi [18F] fallypride adawonetsa cocaine cue-adayambitsa kutulutsidwa kwa DA ku amygdala ndi hippocampus77. Mu ubongo wamakutu, kuwonetsa kwa cocaine cue kunapangitsa kuti DA amasulidwe mu amygdala78, ndikusintha kwamiyeso ya DA ya amygdala kunapangitsa mikhalidwe yofunafuna cocaine yochititsa chidwi79.

Pakufufuza kwa anthu onenepa kwambiri, kuyanjana pakati pa kupezeka kwa D2 / 3 ndi μOR, komwe kumadziwika kuti kumapezeka m'magawo otetemera, kudasokonekera mu stralatum80. Tidafanizira zofunikira za BPND Mwa atatuwo kuyesa ngati deta yatulutsanso izi. Mosiyana ndi anthuopendekera, ubongo wamakono wa nkhumba unalibe kuyanjana pakati pazofunikira za BPND Mwa zigawo ziwiri zoyambira, poyambira kapena pambuyo podziyimira. Tidayesanso ngati nyama zomwe zimatsika kwambiri pamlingo wa tracer raclentril zingakhale ndi kuchepa kwakukulu kwa tracer carfentanil, koma mmalo mwake tidapeza kulumikizana koipa m'magawo olowererapo, ndikuwonetsa kuti nyama zomwe zikusintha kwambiri pazotheka tracer raclopride anali ndi kusintha kotsika kwambiri koyerekeza kwa tracer carfentanil. Chiyanjano chophatikizana pakati pa zosinthazi chikuwonetsa kuti zotsatira za kudya kwa sucrose pazomwe zimapezeka zolandila zomwe zilipo zimayang'anidwanso mbali zina. Amadziwika kuti kumwa kwambiri zakudya zabwino, kapena mankhwala osokoneza bongo, amathamangitsidwa ndi kufuna kapena kukonda, kapena zonse ziwiri60,81. Ndizotheka kuti kukula kwa kufunafuna koyendetsedwa ndi dopamine kumanyalanyaza ukulu wa makonda woyendetsedwa ndi opioids, kapena mosinthanitsa. Umboni waposachedwa ukulozera mbali za GABAA ma receptor mu VTA ndi ma terminals a cholinergic mu striatum ndipo mwina kotekisi yomwe imakhala ngati kusintha pakati pa kudalira kodalira ndi dopamine yodziyimira payokha ya opioid82,83 zomwe zitha kufotokozera kubwezeredwa kwa dopamine ndi zotsatira za opioid mu zigawo za extcineriatal zotchulidwa pano.

Kuperewera kwa PET, komanso nyama zazikulu, ndikuchepetsa kwakumanga kwa tomography komwe kumakhudza zotsatira kuchokera kumagawo ang'onoang'ono aubongo omwe akukhudzidwa ndi machitidwe okhudzana ndi chakudya. Komabe, ngakhale zili ndi nkhawa, [11C] mpikisano wapaulendo wa maphwando omwe kale anali nawo udalembedwa mbali zonse za zigawo ndi malo akutali84,85,86,87. Kugwiritsa ntchito [11C] raclopride kuyitanitsa mtundu womwewo wa zolandila sikudzutsa nkhawa zakusagwirizana komwe kungakhudze kugwiritsidwa ntchito kwa omwe ali pachiwonetsero cha olandila omwewo m'malo osiyanasiyana. Kafukufuku waposachedwa adaphatikizanso zolemba za kumangiriza kwa11C] mpikisano wapaulendo. Alakurtti Et al. anapeza kupezekanso kwabwino kwa miyeso ya striatal raclopride womangika mu striatum, ndikwabwino kokha pakubwezeretsanso mwa kotekisi85. Pakafukufuku wina, Svensson Et al. adakambirana zinthu zingapo zomwe zikukhudza kugwiritsa ntchito [11C] mpikisano wapaulendo ngati chizindikiritso cha ext2riatal D3 / 2 zolandila poyerekeza anthu amoyo wathanzi, kuphatikiza kubereka kosakwanira mu kotekisi komanso kuchepa kwakumapeto kwa zomangira zapakhomo poyankha D3 / XNUMX yotseka88. Kuyerekeza koyeserera kunawonetsa kusiyana kwa 4-7% mu striatum ndi 13-59% m'madera ozungulira, koma nthawi yamkati mwa mayeso imafikira masiku 20, mosiyana ndi masiku ovomerezeka a 1-2 masiku ambiri. Zina mwa zinthu m'miyoyo ya maphunziro amenewo mwina zidakhala ndi nthawi yolimbikitsira zomwe zapezekazi. Zowonadi, tikuwonetsa pano kuti kuwonjezera chabe kudya kwa sucrose m'mawa kwa masiku 12 kungakhale ndi zomwe zimapangitsa kuti pakhale milungu iwiri itatha. Zina zomwe zili zodziwika monga kusewera masewera a vidiyo, kugula zinthu, kulowa muzibwenzi zatsopano ndi zochitika zogonana, kugwiritsa ntchito mankhwala osokoneza bongo kapena kusintha zakudya komanso kuchita masewera olimbitsa thupi zitha kuyambitsa milingo ya dopamine yozindikirika ndikuthekera kwakusintha kwakukulu kwamagama. Kafukufuku waposachedwa mu minipigs adayambitsa kukhazikitsidwa koyendetsedwa bwino ndipo kusiyanasiyana kumakhala kusakhalapo kapena kukhalapo kwa sucrose muzakudya. Munkhani iyi, kuchuluka kwa nyama zisanu ndi ziwiri zomwe zidali ndi mitundu yokwanira yosakwanira kumadera osiyanasiyana kuti mudziwe kuchepetsedwa kwakukulu kwa zomanga chifukwa chodziyeserera.

Zomwe zimalepheretsa kuphunzira kwaposachedwa ndi kugwiritsa ntchito mankhwala ochita kupanga ofunikira pofuna kutsimikizira kusakhazikika mkati mu vivo Kulingalira za nyama. Zotsatira za ma anesthetics enieni, komanso momwe amachitira ndi mankhwala kapena zina, zingasokoneze ma radioligands89,90. Ketamine ndi anti-glutamatergic mankhwala omwe ali ndi vuto lothana ndi vuto la mankhwala ochepetsa chidwi91,92,93, osachepetsa striatal [11C] mtundu wa anthu ochita masewera olimbitsa thupi94. Komabe, S-ketamine inapezeka kuti ikuchepetsa kupezeka kwa ma dopamine D2 / 3 receptors mu striatum of primates a anthu osazindikira omwe95. Isoflurane ndi mankhwala okongola wamba a PET. M'maphunziro am'mbuyomu, tidapeza kudziunjikira kwakukulu kwa [11C] SCH23390, radioligand ya dopamine D1 receptors kuti ikhale yokwera kwambiri mu minipigs yopanga ndi isoflurane m'malo mwa propofol, ndikuwonetsa kutuluka kwa maopaleshoni ya dopaminergic96. Pakafukufuku waposachedwa, ma minipigs onse adawonetsedwa pamanthawi onse pansi pa ketamine mankhwala osokoneza bongo komanso isoflurane anesthesia, ndikupangitsa kuyerekezera kumeneku kukhala koyenera.

Kutsiliza

Kugwiritsa ntchito chakudya chopatsa thanzi kwambiri kumatha kuyambitsa matenda, komanso kukhala zotsatira zake, kusuta kwa mankhwalawa chifukwa chokhala ndi kunenepa kwambiri. Tidayesa zonena kuti opioids ndi dopamine amalipiritsa, ofunika kuti apulumuke komanso kugwiritsa ntchito mankhwala osokoneza bongo. Minipigs yokhala ndi mwayi wambiri wogwiritsira ntchito sucrose pa masiku 12 otsatizana idawonetsa kuchepa kwa dopamine D2 / 3 ndi io − opioid receptor kupezeka kwa zigawo zobisika komanso zotalikirana, kutanthauza kuti zakudya zomwe zimakhala ndi mphamvu kwambiri pakubweza magazi mu njira zofanana ndi zomwe zimawoneka ngati mankhwala osokoneza bongo zimatha. Kuwonetsedwa koyambirira kamodzi kwa sucrose kunali kogwirizana ndi kutulutsidwa kwa opioid m'magawo aubongo omwe ali ndi mphotho. Kusintha kwa kupezeka kwa opioid ndi dopamine kumafotokozera mphamvu zomwe zingagwiritsidwe ntchito za sucrose zimagwiritsidwa ntchito mopitirira muyeso.

Zida ndi njira

Makhalidwe azinyama

Kafukufukuyu adavomerezedwa ndikuyendetsedwa ndi Danish Animal Experiments Inspectorate ndipo kuyesa konseko kunachitika molingana ndi malangizo a 2010/63 / EU a Nyumba Yamalamulo ku Europe komanso a Council on the Protection of Zinyama Zogwiritsidwa Ntchito Sayansi ndi Zitsogozo za ARRIVE. Tidagwiritsa ntchito mphindi khumi ndi zinayi za Göttingen minipigs (Ellegaard, Dalmose, Denmark). Minipigs adadyetsedwa zakudya zama pellet (6 dL, 2 times tsiku lililonse, Special Diets Services, Aarhus, Denmark) ndi madzi apampopi ad libitum. Kutentha kwachilengedwe kunali 20-22 ° C, chinyezi chapakati pa 50-55%, ndipo mpweya unkasinthidwa kasanu ndi kamodzi ola limodzi.

Kuphwanya kwa sucrose kumwa

Tidayang'ana minipiki isanu ndi iwiri ndi [11C] raclopride ndi [11C] carfentanil pamunsi, ndipo tsiku limodzi pambuyo masiku 12 otsatizana kukhudzana ndi madzi. Kuwonetsedwa kwa Sucrose kumakhala ndi ola limodzi la sucrose (sucrose, Dansukker, Copenhagen, Denmark) mwayi wamadzi (500 magalamu a sucrose mu 2 malita a madzi), tsiku lililonse masiku 12. Kuchuluka kwa kudya kwa sucrose kunalembedwa ndipo ma minipigs onse ankadya malita awiri tsiku lililonse. Tikufaniziranso asanu a minipigs omwewo ndi [11C] carfentanil, mphindi 30 pambuyo pofikira koyamba kwa sucrose, kuti aphunzire kumasulidwa kwa pachimake.

Ma minipigs adapeza pafupifupi 13.6% yolemera thupi kuchokera ku 25.4 kg (± 0.73 SEM) poyambira mpaka 28.9 kg (± 0.69 SEM) pambuyo pa kuwonekera kwa masiku a 12 a sucrose, omwe anali okwera kwambiri (kuyesa-kumodzi t-test, p < 0.001) kuposa kuwonjezeka komwe kunawonedwa mu minipigs zowongolera zomwe zimapezeka m'maphunziro am'mbuyomu, pomwe zolemera zidakwera pafupifupi 4.9% yokha, munthawi yomweyo yachitukuko.

Kuthana ndi Ubongo

Tidasala kudya nkhumba usiku wonse ndikupeza madzi kwaulere tisanalingalire. Tidakhala okonzekera komanso osagwiritsa ntchito minipigs monga tafotokozera kale97 ndikuwayika supine mu chipangizo cha PET / CT (Motorola Biograph 64 Truepoint PET). Tidachita kupanga scan yotsika ya CT asanafike pa PET iliyonse kutanthauzira kwa anatomical ndikukonzanso kwa deta ya PET. Tidatumiza ndi mtima wathunthu [11C] raclopride pamsewu woyambira (360 ± 18 MBq, zochitika zenizeni 77 ± 76 GBq / μmol, jekeseni misa 0.12 ± 0.08 μg / kg) ndipo atatha masiku 12 a sucrose (374 ± 54 MBq, zochitika zenizeni 127 ± 85 GBq / μmol, akutsitsa misa 0.06 ± 0.05 μg / kg), ndi [11C] carfentanil pa baseline (377 ± 43 MBq, zochitika zenizeni 311 ± 195 GBq / μmol, jekeseni wa 0.03 ± 0.02 μg / kg) ndipo atatha masiku 12 a sucrose (337 ± 71 MBq, zochitika zapadera 177 ± 157 GBq / μmol, jekeseni wa 0.06 ± 0.08 μg / kg) kudzera mu mtsempha wama khutu, mu 10 mL saline, pamphindi yoyamba ya scan 90 maminiti. Tinakonzanso zidziwitso za PET pogwiritsa ntchito TrueX 3D OSEM (3 iterations, 21 subsets), matrix a 256 × 256 × 109, ndi fayilo ya 2-mm Gauss, pogwiritsa ntchito mawonekedwe a 5 × 60, 3 × 300, 4 × 600 , 2 × 900 masekondi (mafelemu 14 onse, mphindi 90). Pokhazikika komanso atatha masiku 12 a sucrose, minipigs adayesedwa ndi ma tracer onse atabayidwa mphindi 100, chifukwa cha theka la moyo wa [11C] PET oyenda. Pomaliza gawo lomaliza la PET, tinalimbikitsa ma minipigs pansi pa opaleshoni yozama ya pentobarbital (100 mg / kg).

Kafukufuku wambiri ndi ziwerengero

Tidayeseza njira zowonjezera pogwiritsa ntchito PMOD 3.7 (PMOD Technologies Ltd, Zurich, Switzerland). Kutanthauzira magawo osintha kwa stereotactic kuchokera pazithunzi zomwe zimakonda nthawi ya PET, timagwiritsa ntchito ma tempel template. Tidagwiritsa ntchito matricit osinthika komanso minda yolumikizana motsatana munthawi yogwirizana ya PET. Tinapanga zithunzi zofananira za [11C] mpikisano wothamanga ungathe (BPND) pogwiritsira ntchito njira zingapo za Ichise ndi ogwira nawo ntchito98. Tidapanga chigoba chopangidwa ndi chipere cha cerebellum chomwe sichimapatula chitsimikizo kuti tipeze michere ya cerebellar minyewa nthawi yayitali m'chigawo cha D2 / 3 receptor density. Tinapanga zithunzi zofananira za [11C] carfentanil pogwiritsa ntchito kukhazikitsa mtundu wa Logan reference minofu99,100 ndi t * = 30 min. Kafukufuku wa [11C] carfentanil womanga muubongo waumunthu agwiritsa ntchito occipital cortex monga dera lotchulira36; Komabe, mu nkhumba, molingana ndi nthawi yomwe ntchito imapanikizika, kumanga kosasungika kunali kotsika mu cerebellum kuposa mu occortital cortex, zogwirizana ndi zomwe zapezeka kuchokera pa kafukufuku wa rat autoradiography101. Chifukwa chake tidasankha cerebellum ngati dera lomwe lingachitike paphunziroli.

Kusanthula kusanthula

Tidayika pamapu kuti tiwunikenso mwanzeru ndi "Statistical Non-Parametric Mapping" (SnPM v13.01, http://warwick.ac.uk/snpm) Bokosi la zida la SPM lomwe limagwiritsa ntchito chiphunzitso chosagwirizana ndi parametric kutipatsa njira yoyendetsera ziwerengero, njira yomwe ikuwonetsedwa kuti ingagwire bwino ntchito zitsanzo zazing'ono chifukwa chakuwongolera mosamalitsa positi zabodza14 ndikugwiritsa ntchito monga tafotokozera kale102. Katswiri wazophatikizira nkhumba neuroanatomy (DO) anayerekezera zithunzi zomwe zidapendekeka mpaka 5% mphamvu pamlingo wapamwamba wa Göttingen minipig atlas103,104 kutanthauzira ndi kulembera zigawo za DA D2 / 3 ndi μOR BPND kuyambira pachimake mpaka pambuyo pa sucrose. Kenako tidachita kusanthula kwa dera-la-chidwi (ROI) kuti titulutse BPND Mfundo zamadera ena zomwe zapezeka posangalatsidwa ndi kusanthula kwa SnPM, kuphatikiza ma striatum, nucleus accumbens, thalamus, amygdala, cingate cortex ndi preortal preortal. Palibe ziwerengero zowonjezereka zomwe zidachitika pa kuwunika kwa ROI, popeza zigawo izi zidapezeka kuti ndizofunikira pogwiritsa ntchito SnPM.

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Tsitsani zolemba

Zothokoza

Yunivesite ya Aarhus "AU Ideas Project Development Development" ku AML idathandizira phunziroli. Tili othokoza chifukwa cha thandizo laukadaulo kuchokera kwa ogwira ntchito ku Aarhus University Hospital PET Center ndi Aarhus University Farm chifukwa chothandizidwa ndi nyamazo. Tithokoza Profesa Morten Kringelbach, Pulofesa Jørgen Scheel-Kruger ndi Pulofesa Pofesa Arne Møller potithandiza kuyambitsa maphunziro awa.

Zambiri za wolemba

Kugwirizana

  1. Dipatimenti ya Nuclear Medicine ndi PET Center, Yunivesite ya Aarhus, Aarhus, Denmark
    • Michael Winterdahl
    • , Ove Noer
    • , Anna C. Schacht
    • , Steen Jakobsen
    • , Aage KO Alstrup
    • , Albert Gjedde
    •  & Anne M. Landau
  2. Dipatimenti ya Neurosurgery ndi CENSE, Chipatala cha Aarhus University, Aarhus, Denmark
    • Dariusz Orlowski
  3. Dipatimenti ya Nuclear Medicine, University of Southern Denmark & ​​Odense University Hospital, Odense, Denmark
    • Albert Gjedde
  4. Dipatimenti ya Neuroscience, University of Copenhagen, Copenhagen, Denmark
    • Albert Gjedde
  5. Dipatimenti ya Neurology ndi Neurosurgery, McGill University, Montreal, Canada
    • Albert Gjedde
  6. Translational Neuropsychiatry Unit, Yunivesite ya Aarhus, Aarhus, Denmark
    • Anne M. Landau

Zopereka

MW ndi AML adapanga kafukufuku ndi kusanthula; ACS ndi SJ apanga ma PET omangira; MW, AKOA ndi AML adagwira minipigs ndikuchita ma PET; MW, ON ndi AML adachita kusanthula kwa deta; DO idapereka ukadaulo wautomiki, MW, AG ndi AML kutanthauzira tsatanetsatane; MW ndi AML adalemba zolembedwa pamathandizo ndi AG; Olemba onse adavomereza mtundu womaliza wolemba pamanja.

Wolemba wofanana

Kulemba kwa Anne M. Landau.

Kulengeza zamakhalidwe

Zosangalatsa zovuta

Olembawo sanena kuti palibe mpikisano.

zina zambiri

Makalata osindikiza Chilengedwe cha Springer sichisalowerera ndale ponena za milandu yomwe ikupezeka m'mapupala osindikizidwa ndi maofesi omwe ali nawo.

Ufulu ndi zilolezo

Tsegulani Nkhaniyi ili ndi layisensi pansi pa Licore ya Creative Commons Attribution 4.0 Yadziko Lonse, yomwe imalola kugwiritsa ntchito, kugawana, kusintha, kugawa ndi kubereka mwanjira iliyonse yapakatikati kapena mtundu uliwonse, bola mutapereka mbiri yoyenera kwa wolemba woyambayo ndi gwero, ndikupatseni Lumikizani laisensi ya Creative Commons, ndikuwonetsa ngati pali zomwe zasintha. Zithunzi kapena zinthu zina zachitatu zomwe zili munkhaniyi zikuphatikizidwa mu layisensi ya Creative Commons ya nkhaniyi, pokhapokha zikuwonetsedwa mwanjira ina ya ngongole kuzinthuzo. Ngati zinthu sizikuphatikizidwa ndi layisensi ya Creative Commons ya mu kope lanu ndipo kugwiritsidwa ntchito kwanu sikuloledwa ndi malamulo kapena kupitiliza kugwiritsidwa ntchito, muyenera kupeza chilolezo mwachindunji kwa amene ali ndi ufulu. Kuti muwone chiphaso ichi, pitani http://creativecommons.org/licenses/by/4.0/.

Kusindikiza ndi Zilolezo