Thibelo ea Ventral e tlamang dopamine D2 / 3 receptor agonist empa ha e hanyetsane e bolela esale pele sehlabelo se tloaelehileng sa 'mele (2015)

Biol Psychiatry. 2015 Jan 15; 77 (2): 196-202. Doi: 10.1016 / j.biopsych.2013.02.017. Epub 2013 Mar 27.

Caravaggio F1, Raitsin S1, Gerretsen P2, Nakajima S3, Wilson A2, Graff-Guerrero A4.

inahaneloang

LITLHAHISO:

Lipatlisiso tsa Positron emission tomography li bontšitse hore ho fumaneha ha dopamine D2 / 3 (D2 / 3R) ho tsamaellana hampe le index ea 'mele ea mmele ka BMI empa e se lithutong tse phetseng hantle.. Leha ho le joalo, lithuto tsa peitron emission tomography tse fetileng ha lia ka tsa sheba ka ho khetheha ho ventral striatum (VS), e phethang karolo ea bohlokoa ho susumetseng le ho fepa. Ntle le moo, lithuto tsena li sebelisitse li-radiotracers tsa antagonist feela. Likhoto tse tloaelehileng tse nang le boima bo fuoang monyetla oa ho ja lijo tse nang le mafura a mangata li bonts'a maikutlo a boits'oaro ho li-agonist tsa D2 / 3R empa eseng ho bahanyetsi. Sensitization e amahanngoa le kamano e eketsehileng ea D2 / 3R, e amang ho tlama ha agonists empa eseng bahanyetsi.

LITLHAHISO:

Re ile ra hlahloba kamano pakeng tsa BMI ka har'a mefuta ea nonobese (18.6-27.8) le ho fumaneha ha D2 / 3R ho VS ka ts'ebeliso ea "agonist radiotracer [(11) C] - (+) - PHNO (n = 26) le mohanyetsi [(11) C] -raclopride (n = 35) ho batho ba phetseng hantle.

LIKOTSO:

Ho VS, re fumane khokahano e nepahetseng pakeng tsa BMI le [(11) C] - (+) - PHNO e tlamang empa ha e na kamano le [(11) C] -raclopride e tlamang. Tlhahlobo ea bobeli e senotsoe hore ha ho kamano pakeng tsa BMI le ho itlama ka mokokotlong oa dorsal striatum ka radiotracer.

CONCLUSIONS:

Re fana ka maikutlo a hore ho batho bao e seng baBobese, BMI e phahameng e ka amahanngoa le ho eketseha ha tumellano ea D2R ho VS. Ts'ebetso ena e atamelaneng e kanna ea baka tšusumetso ea menyetla ea lijo mme ea loants'ana le litlamorao tsa ho satiety, ka ho etsa joalo fepa.

Copyright © 2015 Mokhatlo oa Biology Psychiatry. E phatlalalitsoe ke Elsevier Inc. Litokelo tsohle li sirelelitsoe.

LINKOTSO:

Lenane la boima ba 'mele; Dopamine D (2) receptor; Tlatsetso ea lijo; Ho Nona Haholo; PET; Ventral striatum

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Keywords: Lenane la boima ba 'mele, dopamine D2 receptor, ho lemalla lijo, botenya, PET, ventral striatum

Ho nona ke e 'ngoe ea lisosa tse ka sehloohong tsa lefu le thibeloang, ho fihla maemong a seoa United States mme ho ama 35.7% ea batho ba baholo le 17% ea bacha (1). Pono e ntseng e hola e tiisa hore ho ja ho tlola ke tlatsetso ea lijo. Bopaki bo fana ka maikutlo a hore dopamine ea morao-rao, e kenyelletsang moputsong, tšusumetso le tšebeliso ea lijo, e fetotsoe ho botenya (2). Ho lemalla ho tšoana le dopaminergic dysfunction, haholo-holo e fokotsitsoeng striatal dopamine D2/3 amohela (D2/3R) phumaneho, e bonoe mefuteng ea litekanyetso ea botena (3,4) le ho batho ba batenya ho vivo (5-8).

Positron emission tomography (PET) thuto ka radiotracer ea antagonist [11C] -raclopride e fumane hore striatal D e tlase2/3Ho fumaneha ha R ho boletsoe esale pele ka index e phahameng ea 'mele (BMI) ho batho ba batenya haholo empa eseng lithutong tse se nang' mele (5). Tea hae e khahlanong le se fumanoeng litotong tse sa fuoeng tse fuoang monyetla oa ho fumana mahala mahala, moo tlase [11C] -raclopride e tlamang kahare ea ventral striatum (VS) e boletse esale pele boima ba 'mele bo boholo le ho rata cocaine (9).

VS, ho kenyelletsoa le li-bokono tsa li-nucleus, e bapala karolo ea bohlokoa ho sebetsanang le meputso e khahlisang le boitšoaro bo khothalletsang ho batla meputso e joalo ka lijo tse fumanehang habonolo (2). Kahoo, liphetoho ho D2/3Ho fumaneha ha VS ho ka fetola thepa le tšebeliso ea lijo, tse amang boima ba 'mele. Ts'ebetso ea Lefts'e la Lefats'e ka lehlakoreng le leng ha motho a sebetsana le lijo tsa mofuta oa lijo o bolela esale pele hore batho ba tla phela hantle (10) 'me e lumellana le tokollo ea dopamine ho arabela khalemelo ea litefiso (11). Lithuto tsena li fana ka maikutlo a hore ts'ebetso ea VS le D2/3Ho fumaneha ha R ho ka bontša liphetoho tse amanang le BMI e tloaelehileng.

Boithuto bo fetileng ba PET ba BMI ha bo so ka bo hlahloba D2/3Ho fumaneha ka har'a VS; ho fapana le moo, sebaka sa thahasello (ROI) se sekaseka striatum eohle (5), le caudate le putamen (6,7), kapa tumello e thehiloeng ho voxelh (7) li ne li sebelisoa. Ho feta moo, lithuto tsa PET tsa pejana li sebelisitse D feela2/3R mohanyetsi oa radio-tracer [11C] -raclopride. Likhoto tse tloaelehileng tse nang le boima bo fuoang phihlello ea mahala lijong tse phahameng tsa mafura li bonts'a maikutlo a boits'oaro ho tsamaisa le ho sa tsamaee D2/3R agonists empa eseng antagonists (12). Boikutlo bona bo boetse bo bonoa mehlaleng ea litheko tsa lithethefatsi (13) hape e amahanngoa le ho eketseha ha D2R itlammey (14-16).

Sena se fana ka maikutlo a hore, joalo ka koae le amphetamine, ho pepesetsoa lijo tse nang le mafura a mangata ho ka eketsa ho ananeloa ha dopamine ho D.2Rits. E hlokometsoe ho vitro hore li-radiotracers tsa agonist li amehile haholo ka liphetoho ho D2R amanang ho feta bahanyetsi ba radio radio. Eketsehile D2Rustity, e pakiloeng ke radonist radiotracer e tlamang, e fumanoe e ka ba teng ntle le phetoho ebile e bile e fokotsehile ka kakaretso ea D2Litsi tse tlamang li fanoa ka sensorization ea amphet-amine (14). Ka lebaka leo, liphapang tsa BMI ka har'a maemo a tloaelehileng li ka amana le phapang ea VS ea dopamine agonists empa eseng bahanyetsi.

Phuputso ena e fupere likamano lipakeng tsa BMI e phetseng hantle le D2/3Ho fumaneha ha VS bathong, ka ts'ebeliso ea radiotracer ka bobeli ba agonist [11C] - (+) - PHNO le mohanyetsi [11C] -raclopride. Ho utloisisa litlhaloso tsa dopaminergic ea BMI e tloaelehileng ho tla thusa ho hlakisa bofokoli bo bonoang ho botenya mme ho ka tsebisa mehlala ea hona joale ea lithethefatsi tsa lijo le nts'etsopele ea maano a thibelo ea lipale le merero ea kalafo.

Mekhoa le Lisebelisoa

Lihlooho

Barupeluoa bohle ba ne ba le letsoho le letona mme ba se na bothata bofe kapa bofe bo ka sehloohong ba bongaka kapa ba kelello joalo ka ha ho laetsoe ke tlhahlobo ea bongaka ea bongaka, Puisano ea Mini-International Neuropsychiatric, liteko tsa mantlha tsa laboratori le electrocardiography. Le ha botenya e ne e se mekhoa ea ho qheleloa ka thoko, ka lebaka la ho qheleloa ka thoko ho maemo a mantlha a bongaka (joalo ka lefu la tsoekere kapa lefu la pelo), re ile ra etsa sampole feela batho ba maemong a tloaelehileng a BMI (<30). Barupeluoa ba ile ba hlokoa hore ba be le skrini se fosahetseng sa moroto bakeng sa lithethefatsi tsa tlhekefetso le / kapa bokhachane ha li kenyelelitsoe le pele ho scan ninemanga ea PET. Barupeluoa le bona ba kopiloe hore ba tlohele joala kapa caffeine matsatsi a 3 pele PET e hlahloba. Ke lintlha tse bokelletsoeng ho tsoa ho bankakarolo ba sa tsubeng tse ileng tsa hlahlojoa bakeng sa thuto ena. Mohlala o ileng oa hlahlojoa bakeng sa boithuto ba hajoale o ile oa bokelloa ke laboratori ea rona ho tsoa liphuputsong tse fapaneng tsa PET tse ileng tsa amoheloa ke Boto ea Boitšoaro ea Patlisiso ea Setsi sa Lithethefatsi le Bophelo ba Kelello, Toronto. Barupeluoa bohle ba fane ka tumello e ngotsoeng e nang le tsebo.

PET Ho etsisa

Radiosynthesis ea [11C] - (+) - PHNO le [11C] -raclopride le ho fumaneha ha litšoantšo tsa PET ho hlalositsoe ka botlalo libakeng tse ling (17-19). Ka bokhutšoanyane, litšoantšo li ile tsa fumaneha ka ts'ebeliso ea sistimi ea khamera ea PET e phahameng, e inehetseng hloohong. Qeto ea sefofaneng e ne e le bophara ba "207 mm" ka bophara ba halofo. Likarolo tsa phetisetso li fumanoe ka ts'ebeliso ea 137Cs (T1/2 = Lilemo tse 30.2, matla = 662 KeV) mohloli o le mong oa setšoantšo bakeng sa ho fana ka khalemelo, 'me tlhaiso-leseling e fumanoe ka lethathamo la lenane. Lintlha tse qaqileng li ile tsa qaptjoa bocha ka liforamo tsa morao-rao. Tekanyo ea radioacaction e bolelang [11C] - (+) - PHNO (n = 26) e ne e le 8.96 (± 1.68) mCi, e nang le ts'ebetso e ikhethang ea 1009.44 (± 289.35) mCi / μmoL. Tekanyo ea radioacaction e bolelang [11C] -raclopride (n = 35) e ne e le 9.22 (± 2.49) mCi, e nang le ts'ebetso e itseng ea 1133.39 (± 433) mCi / μmoL. [11C] - (+) - Tlhahlobo ea skena ea PHNO e fumanoe bakeng sa metsotso e 90 kamora ho entoa. Hang ha tlhahlobo e felile, datha li ile tsa hlalosoa bocha liforeimi tse 30 (1 - 15 nako ea 1-min le 16-30 ea bolelele ba 5-min). [11C] -raclopride ya data e fumanoe metsotso e 60 mme e nchafalitsoe liforeimi tse 28 (1 - 5 ea nako ea 1-min, 6-25 ea nako ea metsotso e 2, le 26-28 ea bolelele ba 5-min).

Tlhahlobo ea litšoantšo

Tlhahlobo e thehiloeng ROI bakeng sa [11C] - (+) - PHNO le [11C] -raclopride e hlalositsoe ka mokhoa o qaqileng libakeng tse ling (20). Ka bokhutšoanyane, li-curve tsa ts'ebetso tsa nako (TACs) ho tsoa ho li-ROI li fumanoe litšoantšong tse matla tsa PET tse sebakeng sa khale ho buuoang ka setšoantšo se seng le se seng sa mantlha sa matla a matla a sefahleho (MRI). Ngoliso ea mantlha ea thuto ka 'ngoe ea MRI ho ea sebakeng sa PET e entsoe ka ts'ebeliso ea algorithm e tloaelehileng ea tlhaiso-leseling (21) jwaloka ha e kenngwa tshebetsong ho SPM2 (SPM2, Lefapha la Wellcome la Cognitive Neurology, London; http://www.fil.ion.ucl.ac.uk/spm). Li-TAC li ile tsa hlahlojoa ka mokhoa oa Simplified Reference Tissue Way (SRTM) (22), ka "cerebellum" e sebelisoang joalo ka sebaka sa ts'upiso, ho fumana tekanyo ea ho tlama: ho tlama ho ka 'nang hoa khoneha (BP)ND). Ts'ebetso ea ts'ebetso ea motheo ea SRTM (23) e sebelisitsoe litšoantšong tse matla tsa PET ho hlahisa parametric voxelwise BPND limmapa ka PMOD (v2.7; PMOD Technologies, Zurich, Switzerland). Litšoantšo tsena li ile tsa fetoloa ka lehare sebakeng sa boko sa Montreal Neurological Institute (MNI) ka ho fetoleloa ha moahelani ea haufi ka boholo ba voxel e behiloeng ka 2 × 2 × 2 mm.3 ka SPM2. BP ea tikolohoND likhakanyo li ne li nkiloe ho ROI tse hlalositsoeng sebakeng sa MNI. Li-ventral striatum le dorsal striatum (dorsal caudate, kamorao ho mona ke caudate; dorsal putamen, kamora putamen) li hlalositsoe ho latela Mawlawi et al a. (24). Tlhaloso e entsoe ka mengolo ea motho ea nkang karolo ea MRI e shebaneng le sefofane sa coronal. VS (tlase), caudate, le putamen (ka mokhoa o phahameng) li hlalositsoe ke mohala o kopanyang karohano pakeng tsa moeli o kantle oa setamen o nang le mola o otlolohileng o fetela ntlheng e kholo ka ho fetisisa ea morao le ea sekoaelo sa kahare le setsi sa karolo of anterior commissure (AC). Mohala ona o ne o atolosoa ntlheng ea kahare ea caudate. Meeli e meng ea VS e ne e bonoa ka ponyo ea lets'oao le bosootho bo botenya mme e ne e khetholoha habonolo ho meaho e haufi. VS e ne e nkuoa mohlala ho tloha moeling oa ka ntle oa striatum ho ea fihla sefofaneng sa AC coronal. Caudate le eona e ne e le sampole ho tloha moeling oa eona o ka ntle ho ea sefofaneng sa AC coronal. Kahoo, bakeng sa VS, sebaka se kopaneng se kenyelletsa karolo e kahare le e kahare ea striatum, ha ho buuoa ka AC e nang le boko bo otlolohileng moleng oa AC-PC. Bakeng sa caudate, sebaka se nang le sampole se ne se kenyelletsa karolo e ka tlaase ea hlooho ea caudate le karolo ea boraro ea 'mele ea caudate. Putamen e ne e nkuoa sampole ho tloha kamoreng ea eona ea ka ntle ho ea ho meeli e ka morao ka ho slices ka morao ho sefofane sa AC. Bakeng sa [11C] -raclopride scans, BPND hoantianti nigra ROI e ne e sa fumanehe hobane ho tlama sebaka sena ho oela ka har'a mekhahlelo ea lerata (20).

Tlhahlobo ea Litekanyetso

Litlhahlobo tsa lipalopalo li ile tsa etsoa ka tšebeliso ea SPSS (v.12.0; SPSS, Chicago, Illinois) le GraphPad (v.5.0; GraphPad Software, La Jolla California). Li-coefficients tsa sehlahisoa tsa pearson li ile tsa baloa ho hlahloba kamano pakeng tsa BMI le BPND ho ROI. Tloaelo ea maemo a fetohileng e ile ea khethoa ka tlhahlobo ea D'Agostino-Pearson. Moithuti t teko le tlhahlobo e tobileng ea Fisher e sebelisitsoe moo ho loketseng. Boemo ba bohlokoa ba liteko tsohle bo behiloe ho p <.05 (mehatla e 'meli).

Results

Boitsebiso bo tsoang ho baithaopi ba 46 ba phetseng hantle ba ile ba hlahlojoa, bao ba bang ba bona ba tlalehiloeng pele (20,25,26). Ho ile ha hlahlojoa lithuto tse mashome a mabeli a metso e tšeletseng le [11C] - (+) - PHNO le lithuto tse 35 li tlalehiloe le [11C] -raclopride. Sekhahla sa lithuto tsena (n = 15) e entsoe ka radiootracers ka tatellano e hanyetsanang, bonyane lihora tse 3 ka karohano. BMI e ne e baloa joalo ka kg / m2 (Lethathamo 1). Ho ne ho se na phapang nakong ea letsatsi leo ka lona [11C] - (+) - PHNO le [11C] -raclopride scans ha lia ka tsa fumanoa, leha e le bakeng sa disampole tse felletseng (t59 = .16, p = .87) leha e le hore lipampiri tse fumanehang li fumanehiloe ka li-tracer ka bobeli (t28 = .97, p = .34). Ka har'a sampole e felletseng ea batho ba fekiloeng [11C] - (+) - PHNO, BMI e ne e sa amane le lilemo (r = .27, p = .18) ebile ha e fapana ka thobalano (t24 = .42, p = .66). Ka har'a sampole e felletseng ea batho ba fekiloeng [11C] -raclopride, BMI e ne e sa amane le lilemo (r = .21, p = .23) ebile ha e fapana ka thobalano (t33 = .21, p = .84).

Lethathamo 1  

Morupeli oa Lipuisano

BPND ea [11C] - (+) - PHNO ho VS e ne e hokahane haholo le BMI (r = .51, p = .008) mohlaleng o felletseng (n = 26) (Setšoantšo sa 1). Sena se tsamaisana le boholo bo boholo ba phello (27), ka phapang e arolelanoeng ea 26% (r2 = .26). Ha ho lilemor = .14, p = .50) kapa thobalano (r = .02, p = .92) e ne e amana le BPND ho VS. Ho fanoe ka phapang e ka bang teng pakeng tsa hemisphere (10,11), re ile ra leka liteko tsa hemisphere. Athe BMI e ne e hokahane le BPND ka ho le letšehali (r = 40, p = .04) le ho le letona (r = .58, p = .002) li-hemispheres, likhokahano tse itšetlehileng ka tsona t Teko e senotse hore khokahano e ne e le matla ho hemisphere e nepahetseng (t23 = -2.01, p <.05) (Setšoantšo sa 2). Boithuto ba bobeli bo senotse hore BMI e ne e sa tsamaellane le BPND ka boitsebiso (r = .21, p = .31), putamen (r = .30, p = .14), globus pallidus (r = −.06, p = .79), kapa substantia nigra (r = .31, p = .13). Le ha VS e ne e le ROI ea rona ea mantlha, hoa bohlokoa hore kamano e pakeng tsa BMI le BPND ho VS e ile ea pholoha khalemelo bakeng sa lipapiso tse ngata. Ho na le li-ROI tse hlano ka kakaretso: li-ventral striatum, caudate, putamen, globus pallidus, le substantia nigra. Kahoo, mokhoa oa bohlokoa oa tokiso ea Bonferroni-11C] - (+) - Litlhahiso tsa PHNO-BMI li ne li tla ba teng p = .01 (.05 / 5 = .01). Ho laola lilemo kapa bong ha hoa ka ha fetola liphetho tsa rona haholo [11C] - (+) - PHNO (ya data ha e bontšoe).

Setšoantšo sa 1  

Kopano lipakeng tsa index ea boima ba 'mele (BMI) le [11C] - (+) - PHNO e tlamang e ka khonehang e sa khoneheng (BP)ND) ho "ventral striatum" ea sampole e felletseng ea lithuto (n = 26).
Setšoantšo sa 2  

Karolelano ea [11C] - (+) - PHNO e tlamang e ka khonehang e sa khoneheng (BP)ND) limmapa tsa boko bakeng sa batho ba ka har'a setšoantšo sa pele sa index ea 'mele (BMI) (n = 7) le tse ka har'a sebaka sa bone sa BMI (n = 7). Karolo ea BMI bakeng sa likhoele e tjena: ...

Le [11C] - (+) - PHNO, litla-morao tse kang ho nyekeloa ke pelo li 'nile tsa bonoa ka boima bo entsoeng> 3 μg (28). Leha lithuto tsohle tsa rona li ile tsa hlahlojoa ka boima bo entiloeng <3 μg (2.26 ± .36), re ne re batla ho felisa monyetla oa hore liphetho tsa rona li bakiloe ke lethal dose. Ho ne ho se na kamano lipakeng tsa boima bo entsoeng (μg) le BPND ho VS (r = .14, p = .51; hemisphere e nepahetseng: r = .12, p = .58; hemisphere: r = .15, p = .48) kapa ka BMI (r = .01, p = .96). Ha ho ts'ebetso e khethehileng (mCi / μmol) kapa palo e kentsoeng (mCi) ea [11C] - (+) - PHNO e ne e amana le BPND ho VS (r = −.11, p = .58 le r = −.14, p = .50, ka ho latellana) kapa BMI (r = −.06, p = .77 le r = −.13, p = .53, ka ho latellana). Kahoo, mokhatlo o hlokometsoeng pakeng tsa [11C] - (+) - PHNO BPND mme BMI ha e hlahisoe ke phello e ferekanyang ea tekanyo ea tracer kapa boima.

BPND ea [11C] -raclopride ho VS e ne e sa tsamaellane le BMI (r = −.09, p = .61) mohlaleng o felletseng (n = 35) (Setšoantšo sa 3). Ha ho na khokahano ho eng kapa eng ea hemisphere (ka ho le letšehali: r = −.22, p = .28; ka ho le letona: r = .28, p = .87). Ha ho lilemor = −.23, p = .19) kapa thobalano (r = −.14, p = .44) e ne e amana le BPND ho VS. Boithuto ba bobeli bo senotse hore ha ho kamano le BMI ho caudate (r = −.04, p = .82), putamen (p = −.06, p = .75), kapa globus pallidus (r = −.06, p = .75). Ho laola lilemo kapa bong ha hoa ka ha fetola liphetho tsa rona haholo [11C] -raclopride (ya data ha e bontšoe).

Setšoantšo sa 3  

Kopano lipakeng tsa index ea boima ba 'mele (BMI) le [11C] -raclo-ikhohomosang e tlamang e sa khoneheng (BP)ND) ho "ventral striatum" ea sampole e felletseng ea lithuto (n = 35).

Ho fanoa ka kamano pakeng tsa BMI le BPND ho VS ka li-radiotracers tse peli, re ile ra hlahloba sehlopha sa barupeluoa (n = 15) ba ileng ba hlahlojoa ka bobeli. Sena se ne se etsoa ho laola ka mokhoa o hlakileng liphapang tsa motho ka mong tse ka bang teng lipakeng tsa disampole tse felletseng. Hape, re bone khokahano e ntle pakeng tsa BMI le BPND ka VS le [11C] - (+) - PHNO (r = .55, p = .03) empa ha ho khokahano le [11C] -raclopride (r = −.16, p = .56). Litumellano-tse amanang t Teko e senotse hore khokahano lipakeng tsa BMI le [11C] - (+) - PHNO BPND e ne e le matla haholo ho feta khokahano pakeng tsa BMI le [11C] -raclopride BPND (t12 = 2.95, p <.05). Sena se tšehetse liphetho tsa rona ka mehlala e felletseng (Setšoantšo sa 4).

Setšoantšo sa 4  

Kamano lipakeng tsa index ea mmele (BMI) le matla a tlamang a ke keng a khoneha (BPND) ho "ventral striatum" sehlopheng sa lihlooho (n = 15) e ngotsoe ka bobeli (A) [11C] - (+) - PHNO le (B) [11C] -raclopride.

Puisano

Thutong ea PET ea hona joale, re fuputse hore na ho fapana ho BMI e tloaelehileng ho amana joang le D2/3Ho fumaneha ha VS bathong, ka ts'ebeliso ea radiotracer ea agonist le antagonist, [11C] - (+) - PHNO le [11C] -raclopride, ka ho latellana. Ho ts'ehetsa liphumano tse fetileng (5,6), BMI kahare ho maemo a tloaelehileng e ne e sa tsamaellane le [11C] -raclopride e tlamang ho VS. Empa, BMI e tloaelehileng e ne e amana hantle le [11C] - (+) - PHNO e tlama ho VS. Liphetho tsena tse arohaneng li netefalitsoe tlhahlobo ea lithuto tse hlophisitsoeng ka bobeli ba li-radiotracers, ho laola tšusumetso ea karohano ea karolo.

Phapang pakeng tsa radioligand e tlamang ho vivo hangata e hlalosoa ka liphetoho bonyane ho tse tharo tsa paramente: palo ea li-receptor tse fumanehang (Bmax), litekanyetso tsa dopamine tsa endo native (tlholisano e tlamang), kapa tumellano ea li-receptor bakeng sa ligand (Kd). Ka ts'ebeliso ea D3R antagonist GSK598809, ho hakanngoa hore ~ ​​74% ea [11C] - (+) - Pontšo ea PHNO ho VS ea motho e amahanngoa le tlama ho D2R, athe ~ 26% e hlahisitsoe ke D3R (29). Ka mokhoa o ts'oanang, ho hakanngoe lithutong tse seng tsa motho tse ~ 19% ea [11C] -raclopride letšoao ho VS e ka lula ho D3R-khethileng lihanyetsi BP897 (30). Haeba liphetho tsa rona li bakiloe ke liphetoho ho D2Polelo, ho ka se be bonolo hore [11C] - (+) - PHNO e ne e tla bona phetoho empa [11C] -raclopride e hana, haholo hobane [11C] -raclopride e ngola lipalo tse kholo tsa D2Rs in vitro (31). Hape ha ho na monyetla hore liphetho tsa rona ka [11C] - (+) - PHNO e emetse polelo e fetotsoeng ea D3Rs hobane monehelo oa D3Lits'oaetso tsa VS bakeng sa mahlaseli a mahlaseli ka bobeli li nyane, leha monyetla ona o ke ke oa hlakoloa ka botlalo. Ntle le moo, ha re bone kamano e teng lipakeng tsa BMI le BPND ho li-ROI tseo boholo ba [11C] - (+) - Pontšo ea PHNO e hlahisoa ke D3Ho tlama: the sub-stantia nigra (100%) le globus pallidus (65%) (29). Leha D3Ho fanoe ka tšebetso ea R ho ama monyetla oa ho natefeloa ke botena ho litoeba (30), bopaki bo tsoakiloe (32). Ho latela seo re se fumaneng, bopaki ba morao-rao ho batho ba nonneng haholo le ba batenya haholo bo fana ka maikutlo a hore D3Li-Rs ha li arabele likarabo tsa boko ho litekanyetso tsa lijo (33).

Monyetla o mong ke hore lintho tseo re li fumaneng ka [11C] - (+) - PHNO e ka hlalosoa ka ho fokotseha hoa litekanyetso tsa dopamine tsa endo native tse nang le BMI e phahameng. Ka bobeli [11C] - (+) - PHNO le [11C] -raclopride e amehile ka liphetoho maemong a dopamine ea endo native (34,35). Ka tšebeliso ea phephetso ea amphetamine lithutong tse phetseng hantle, ho hakantsoe hore [11C] - (+) - PhNO e na le linako tse 1.65 e le hlokolosi haholo ka liphetoho dopamine ea morao-rao ho VS ha e bapisoa le [11C] -raclopride (36). Ho nka karohano ena molemong oa kutloisiso, haeba lintho tseo re li fumaneng ka [11C] - (+) - PHNO e ne e tsamaisoa feela ka ho fokotseha hoa dopamine ea endo native, re ne re ka lebella hore tšebelisano-kholo e lumellanang pakeng tsa BMI le [11C] -raclopride BPND ho VS ho ba .30. Cheffility ea bonono e bonoang e ne e le -.089. Ho feta moo, liperesente li eketseha ka karolelano [11C] - (+) - PHNO BPND ho tloha ho batho ba bobebe ho fetisisa ho ba sampole ea rona (bao ba halofo ea pele le ea bone, ka tatellano) e ne e le 17.87%. Haeba phetoho ena e ne e le feela ka lebaka la dopamine ea endo native, re ka be re lebelletse keketseho ea 10.83% ho [11C] -raclopride BPND ho tloha ho oa pele ho isa ho oa bone oa ntoa. Sebakeng seo, re bone phetoho ea percent9.38%. Kahoo, re fana ka maikutlo a hore haeba kamano e pakeng tsa BMI le [11C] - (+) - PHNO BPND e ne e tsamaisoa feela ke liphetoho ho dopamine ea morao-rao, ho ka be ho bile le tšekamelo ea ho hokahana ho nepahetseng le [11C] -raclopride. Fuoa hore D3Rs e na le kamano e phahameng ea makhetlo a 20 ea dopamine ho feta D2Rs in vitro (15,16), phokotso efe kapa efe maemong a dopamine ea endo native e ka ama [11C] - (+) - PHNO BPND ho D2Rs pele ho D3Rs (36). Ka hona, ha ho na monyetla hore sephetho se bonoang le [11C] - (+) - PHNO e hlahisoa ke phapang e teng bokhoni ba eona ba ho bona liphetoho dopamine ea morao-rao ho D3Rs bapisoa le D2Rs ha ho bapisoa le [11C] -raclopride.

Re tiisa hore liphumano tsa rona li kanna tsa hlalosoa ke liphetoho ho D2R amanang ho [11C] - (+) - PHNO ho VS. Ho bontšitsoe ka vitro hore agonist le antagonist radioligands li bitsa palo e fapaneng ea D2Rits. Ka ho khetheha, D2R agonists empa eseng bahanyetsi ba amehile ka liphetoho ho palo ea "linaha tse sebetsang" kapa "tšehetso e phahameng" ea "receptor" (ke hore, e kopantsoeng le liprotheine tsa G-protein) (14). Le ha ketsahalo ena e ntse e lokela ho lekoa ho vivo, kamano e ntle pakeng tsa [11C] - (+) - PhNO e tlamang le BMI ka har'a mofuta oa nonobese e kanna ea e-ba teng ka lebaka la kamano e atamelaneng bakeng sa dopamine ho D.2Rs ho VS e nang le BMI e kholo. Sena se eketsehile D2Ratana e ka amana le tšusumetso e eketsehileng ea ho ja lijo tse fumanehang habonolo (37,38). Sena se ts'ehetsoa ke phuputso ea morao-rao litoebung tse fumane hore palo ea ho ja ka mokhoa oa sucrose nakong ea karolo e lefifi e amana hantle le D.2Boikutlo ba kutlo ea li-nucleus bo bokellanang, joalo ka ha D2R ea litoeba tse jang sucrose e na le kutloisiso e kholo ho ts'ebetsong le ho etsoa ke dopamine (39).

Ka har'a mofuta o tloaelehileng, BMI e phahameng e ka tsamaisoa ke keketseho ea thepa ea lijo. Likhoto tsa lijo li lokolla dopamine ho VS ea litoeba (40) hape e ka tsosa ho fepa ka likhoto tse matlafatsang (41) le batho (42). Ntle le moo, ts'ebetso ea VS ho araba mekhoa e metle ea lijo e rereloa ho ba le boima ba 'mele ho basali ba phetseng hantle (10) hape e amana hantle le tokollo ea dopamine nakong ea litebello tsa moputso (11). Kephetse D2Ho tloaelana le R ho VS ho kanna ha baka litlamorao tse susumetsang tsa litekanyetso tsa lijo, ka ho etsa joalo eketsa palo ea lijo. Ka lehlakoreng le leng, leptin le insulin, lihormone tse bonts'ang matla a mangata, li fokotsa ho supa dopamine ka har'a li-nucleus tse bokellanang le ho hatella ho fepa (43). Thus, eketseha D2Rato la rona le ka sebetsana le ho hlasimoloha ho tšoaetsoang ke litekanyetso tsa dopamine tse fokotsang, ka ho etsa joalo ho ka ba le “ho se tsebe nako ea ho emisa” ho ja.

Seo re se fumaneng hammoho le lipatlisiso tsa nakong e fetileng li fana ka maikutlo a kamano e sa lumellaneng pakeng tsa D2Ts'ebetso ea R le BMI ho botenya ho fapana le bophelo bo botle. Boima bo phahameng kahare ho maemo a tloaelehileng bo ka tsamaisoa ke ho eketseha ha D2Ratlelano (tšusumetso ea maikutlo), ha boima bo boholo ho botenya bo ka tsamaisoa ke phokotso ea D2Polelo (khaello ea moputso). Ho nona ho amana le phokotso ea kakaretso ea D2Polelo3,5), e beha seipone se fokotsoang D2Polelo e bonoang ke ho lemalla lithethefatsi44). Sena se fana ka maikutlo a hore, leha boitšoaro ba ho fepa bo ka ba teng ka nako e telele, boemo ba botena, joalo ka bokhoba ba lithethefatsi, bo ka fapana ka mokhoa o fapaneng.. Sena se tšehetsoa ke taba ea hore tlase [11C] -raclopride e tlamang ho striatum e kopantsoe le BMI e kholo ho batho ba batenya empa eseng lithutong tsa taolo e phetseng hantle (5). Kamehla, batho ba batenya ho feta tekano ba ka khona ho jara Taq1 al1 of a D2Mofuta oa mofuta (45), e amanang le D e fokotsehile2Polelo le [11C] -raclopride e tlamang46). Sena se tsoela pele se tšehetsa se fokotsang [11C] -raclopride e tlamang ka botenya e bonts'a ho fokotseha ha D2Polelo, e lebisang ho "phello ea khaello ea moputso," eo ka eona batho ba batenya ho feta tekano ba lokelang ho lefa tefo ea ts'ebetso ea li-circuits tsa meputso (5). Patlisiso ea nako e tlang e ea hlokahala ho hlahloba karolo ea D2R tumellanong le botenya.

Hobane sena e ne e le thuto e nahannoeng hape, re ne re se na tekanyo e tobileng ea tefo ea moputso lithutong tsa rona. Leha ho le joalo, tlhaloso ea rona e lumellana le liphumano tsa morao-rao tsa kamano e seng molaong pakeng tsa maikutlo a ho putsa (SR) le BMI (31), e kileng ea phetoa baneng (33). Lithuto tsena li bonts'a hore kahare ho BMob ea nonobese, ho na le kamano e ntle lipakeng tsa SR tse itlalehang le BMI, hoo BMI e phahameng e amanang le SR e eketsehang. Kahoo, ka har'a mofuta o tloaelehileng, BMI e phahameng e ka amahanngoa le ho eketseha ha takatso ea lijo bakeng sa meputso e joalo ka lijo. Re fana ka maikutlo a hore keketseho ea D2Reme e ka ba mochine o kenyang letsoho molemong oa moea. Lithuto tsena li boetse li hlokometse hore ho na le kamano e mpe lipakeng tsa BMI le SR, hoo hore BMI e phahameng e ne e amahanngoa le SR e fokotsehileng. Sena se tsamaisana le ho nona haholo ho amahanngoa le khaello ea moputso e lebisang ho ho nona ho feta tekano, le D e fokotsehileng2Polelo ea ho fana ka karolo e tlatselletsang ea likokoana-hloko.

Sehlopha sa rona, hammoho le ba bang, ha sea ka sa fumana boima bo tloaelehileng ho amanang le D2Ts'ebetso ho dorsal striatum. Ts'ebetso e sa tloaelehang ea dorsal striatum e ka amana ka ho khetheha le botenya le / kapa bokhoba ba lijo. Fokotsa D2Polelo e bonoa mokhoeng oa batho ba batenya haholo.6) le mehlaleng ea liphoofolo tse batenya haholo (3). Bacha ba kotsing ea ho ba le botenya ba ts'ebetso e kholo ho caudate e nepahetseng ha ba fumana lijo tse fumanehang hantle le moputso oa chelete.47). Ka mokhoa o ts'oanang, batho ba batenya haholo ba bonts'a ts'oaetso ea tsoekere ea glucose le ts'ebetso e arabang methapo ea lijo ka har'a caudate e nepahetseng nakong ea euglycemic hyperinsulinemia (e khothalletsang satiety) (48). Ho khahlisang, re fumane hore kamano pakeng tsa BMI e tloaelehileng le [11C] - (+) - PNO e tlamang e ne e le matla ho VS e nepahetseng. Patlisiso ea nako e tlang e lokela ho hlakisa karolo ea dorsal le ventral striatum le hemisphere e ngoe le e ngoe ho BMI.

Hona le likhaello tse 'maloa thutong ea hona joale. Taba ea pele, thuto ena e ile ea khutla. Taba ea bobeli, ha re ka ra lekanya ka kotloloho boits'oaro ba ho ja kapa ho ratoa ke litho tsa sehlopha. Taba ea boraro, leha bongata ba [11C] - (+) - Pontšo ea PHNO ho VS e bakoa ke D2Ha re tlama, re ne re sitoa ho bonahatsa monehelo oa D3Rs; ka hona, liphetoho ho D3Polelo ha e khone ho hlalosoa ka botlalo. Qetellong, ha rea ​​ka ra hlahloba maemo a dopamine a endo native; ka hona, monehelo oa eona o ke ke oa hlalosoa ka botlalo. Boithuto bona bo rala motheo oa ho hlahloba karolo ea D2Sebaka sa marang-rang sa agonist se tlamang ho etiology, kalafo le thibelo ea botena.

lumela hore baa fokola

Bangoli ba leboha basebeletsi ba Setsi sa PET setsing sa Tlatsetso ea Bokhoba le Phekolo ea kelello, ho kenyeletsoa Alvina Ng le Laura Nguyen, ka thuso ea botekgeniki ea ho bokella data. Ba boetse ba leboha Wanna Mar, Carol Borlido, le Kathryn Kalahani-Bargis ka thuso ea ho kenya letsoho mosebetsing.

Boithuto bona bo ne bo tšehelitsoe ka karolo e itseng ke Canadian Institutes of Health Research (MOP-114989) le US National Institute of Health (RO1MH084886-01A2).

Mongolo o botlaaseng ba leqephe

 

Ngaka Nakajima o tlaleha hore o amohetse lithuso ho Mokhatlo oa Japane oa Phuputso ea Mahlale le Inokashira le tlotla ea sebui ho tsoa GlaxoSmith Kline, Janssen Pharmaceutical, Pfizer, le Yoshitomiyakuhin nakong ea lilemo tse 3 tse fetileng. Ngaka Graff-Guerrerro hajoale o fumana tšehetso ea lipatlisiso ho tsoa ho li-agency tse latelang tsa lichelete tsa Canada: Litsi tsa Canada tsa Patlo ea Bophelo, Setheo sa Naha sa Bophelo sa US, le Instituto de Ciencia y Tecnología para la Capital del Conocimiento en el Distrito Federal (ICyTDF). Hape o amohetse matšeliso a lits'ebeletso tsa profeshenale ho tsoa ho Abbott Laboratories, Gedeon-Richter Plc, le Lundbeck; fana ka tšehetso e tsoang ho Janssen; le matšeliso a sebui a tsoang ho Eli Lilly. Mong. Caravaggio, Mme Raitsin, Dr. Gerretsen, le Dr. Wilson ha baa tlaleha lithahasello tsa lichelete kapa likhohlano tse ka bang teng.

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