Kutloisiso ea 'mele ea insulin e fokotsehile e amana le Dopamine e fokolang e fokolang ho bafani ba D2 / 3 ba Ventral Striatum ea Batho ba phelang hantle ba sa sebete (2015)

Int J Neuropsychopharmacol. 2015 Feb 25. pii: pyv014. doi: 10.1093 / ijnp / pyv014.

Caravaggio F1, Borlido C1, Hahn M1, Feng Z1, Fervaha G1, Gerretsen P1, Nakajima S1, Plitman E1, Chung JK1, Iwata Y1, Wilson A1, Remington G1, Graff-Guerrero A2.

inahaneloang

LITLHAHISO:

Bokhoba ba lijo ke taba eo ho phehisanoang ka eona mabapi le neuroscience. Bopaki bo fana ka maikutlo a hore lefu la tsoekere le amana le litekanyetso tse fokotsitsoeng tsa basop dopamine ka har'a li-nucleus tse bokellaneng, tse tšoanang le batho ba lemaletseng lithethefatsi.. Ha ho tsejoe hore na maikutlo a insulin a amana le maemo a dopamine a endo native ho "ventral striatum" ea batho. Re ile ra hlahloba sena re sebelisa agonist dopamine D2/3 receptor radiotracer [11C] - (+) - PHNO le phephetso e matla ea ho fokola ha dopamine. Mohlala o mong o fapaneng oa batho ba phetseng hantle, re ile ra hlahloba hore na ho theoha ha dopamine ho ka fetola kutloisiso ea insulin.

LITLHAHISO:

Boikutlo ba insulin bo ne bo lekantsoe bakeng sa thuto e 'ngoe le e' ngoe ho tsoa ho glucose e potlakileng ea plasma le insulin e sebelisang Tlhatlhobo ea Model II ea Homeostasis. Batho ba leshome le motso o mong ba phetseng hantle ba se nang bophelo bo botle le ba nondiabetesic (3 femme) ba fana ka motheo [11C] - (+) - ScNO ea PHNO, 9 e neng e fane ka scan ninete e tlisoang ke dopamine depletion, e lumellang likhakanyo tsa dopamine ea endo native ho dopamine D2/3 receptor. Dopamine depletion e fumanoe ka alpha-methyl-para-tyrosine (64mg / kg, PO). Ho batho ba phetseng hantle ba 25 (9 femme), plasma e potlakileng le tsoekere e fumanoe pele le ka mor'a dopamine depletion.

LIKOTSO:

Dopamine ea tlhaho e fumanehang ka har'a methapo ea methapo2/3 receptor e ne e amana hantle le sensulin ea insulin (r(7) =. 84, P = .005) mme e tsamaellane hampe le maemo a insulin (r (7) = -. 85, P = .004). Mefuta ea glucose e ne e sa tsamaellane le dopamine ea endo native ho "ventral striatum dopamine D"2/3 mokamoli (r (7) = -. 49, P = .18). Nako le nako, ho fokola ha dopamine ho batho ba phetseng hantle ho fokolitse kutloisiso ea insulin (t (24) = 2.82, P = .01), ho eketseha ha insulin (t (24) = - 2.62, P = .01), mme ha a ka a fetola maemo a glucose (t (24) = - 0.93, P = .36).

QETELLO:

Ho batho ba phetseng hantle, ho fokotseha ha kutloisiso ea insulin ho amana le dopamine e nyane ea semmuso ho dopamine D2/3 receptor ka har'a ventral striatum. Ho feta moo, ho fokola ha dopamine ho fokotsa khatello ea kelello ea insulin. Liphumano tsena li ka ba le litlamorao tsa bohlokoa bakeng sa lipolao tsa neuropsychiatric tse nang le khaello ea metabolic.

© Sengoli 2015. E phatlalalitsoe ke Oxford University Press lebitsong la CINP.

LINKOTSO:

D2; lefu la tsoekere; dopamine; tsoekere; insulin

Selelekela

Keketseho e sa khaotseng ea ho ata ha botenya le lefu la tsoekere Amerika Leboea, eo ho nahanoang hore e amana le ho nona ha lijo tse nang le mafura a mangata / tsoekere e ngata, ho baka moroalo o moholo oa bophelo bo botle ba sechaba (Mokdad et al., 2001; Leoatle la leoatle, 2014). Taba ea bokhoba ba lijo, moo lijo tse fumanehang habonolo li bonoa e le monate oa lithethefatsi tsa tlhekefetso (Lenoir et al., 2007), e lula e le sehlooho se tsekoang haholo (Ziauddeen et al., 2012; Volkow et al., 2013a). Lithutong tsa monahano oa bongo oa vivo ho batho ba tšehelitse mohopolo ona, ho bonahatsa liphetoho tse tšoanang lipakeng tsa batho ba batenya le batho ba lemaletseng lithethefatsi (Volkow et al., 2013a, 2013b). Haholo-holo ho bontšitsoe ka ho sebelisa positron emission tomography (PET) hore batho ba batenya le batho ba lemaletseng lithethefatsi ba na le dopamine e fokolang.2/3 amohela (D2/3R) ho fumaneha ha striatum (Wang et al., 2001), letshwao le ts'oanang le bokhoba ba ho lemalla le tsona li hlokometse litoebeng tse fetisang lijo tse matlafatsoang (Johnson le Kenny, 2010).

Striatal dopamine, haholo-holo ho ventral striatum (VS), ke module ea bohlokoa ea moputso oa lijo le lithethefatsi le ts'ebeliso (Palmiter, 2007). Ho na le lintlha tse 'maloa tse fanang ka bopaki ba hore lefu la tsoekere le ho fokotseha ha insulin sensitivity (IS) ho ka amana le ho fokotseha ha nako ea setho sa dopamine ho VS. Ts'ebetso ea dopaminergic e fokotsehileng ea ts'ebetso e hlokometse litoeba tsa lefu la tsoekere le methapo ea batho ea postmortem, joalo ka ha ho bonts'itsoe ke litekanyetso tsa dopamine synthesis (Crandall le Fernstrom, 1983; Trulson le Himmel, 1983; E khuts'oanyane, 1984; Bitar et al., 1986; Bradberry et al., 1989; Kono le Takada, 1994) le metabolism (E khuts'oanyane, 1984; Kwok et al., 1985; Bitar et al., 1986; Kwok le Juorio, 1986; Lackovic et al., 1990; Chen le Yang, 1991; Lim et al., 1994). Liroto li entse hypoinsulinemic ka streptozotocin ho bonts'a litheko tse tlase tsa dopamine ho li-nucleus accumbens (Murzi et al., 1996; O'Dell et al., 2014) hammoho le ho lokolloa ha dopamine ka mokhoa o phollatsi ho arabela amphetamine (Murzi et al., 1996; O'Dell et al., 2014). Haholo-holo, insulin e fetola polelo ea seleng (Garcia et al., 2005; Daws et al., 2011) le tšebetso (Owens et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011) ea transporter ea dopamine (DAT). Ho feta moo, li-receptor tsa insulin li hlahisoa ka har'a li-nucleus bokellane le li-neuron tsa midbrain dopaminergic neurons (Werther et al., 1987; Figlewicz et al., 2003), moo ba ka fetolang ho thunya ha neuronal, homeostasis ea matla, le likarabo tsa boitšoaro ho khothatsong e khotsofatsang joalo ka lijo, cocaine le amphetamine (Galici et al., 2003; Konner et al., 2011; Schoffelmeer et al., 2011; Mebel et al., 2012; Labouebe et al., 2013). Ka kopanelo, lintlha tsena li fana ka maikutlo a hore ho fokotseha ha IS ho ka amana le maemo a tlase a dopamine ea endo native ho VS.

Ho fihla joale, lithuto tsa 2 PET li fuputse kamano lipakeng tsa striatal dopamine D2/3Ho fumaneha le maemo a ho itima lijo a lihomone tsa neuroendocrine (Dunn et al., 2012; Guo et al., 2014). U sebelisa radiotracer ea antagon [18F] Dunn le basebetsi-'moho (2012) o bontšitse hore dopamine D2/3Ho fumaneha ha VS ho ne ho hokahanngoa hampe le IS mohlaleng oa basali ba batenya le ba sa bueng. Kaha radiotracer e tlamang e ameha ka dopamine ea endo native motheong oa motheo (Laruelle et al., 1997; Verhoeff et al., 2001), Tlhaloso e le 'ngoe e ka fumanoang bakeng sa ho fumana sena ke hore batho ba fokotsehileng ba na le dopamine e nyane ea tlhaho ea D2/3R ho VS mme ka hona ho tlangoa haholoanyane ha radiotracer motheong oa motheo. Ho boetse ho bontšitsoe le PET hore batho ba lemaletseng koae ba na le dopamine e fokolang ea tlhaho ho D2/3R ho VS (Martinez et al., 2009). Bopaki ba hore batho ba nang le insulin e phahameng le bona ba na le dopamine e nyane haholo ho D2/3R ho VS e ne e tla ts'ehetsa karolo ea modulatory ea ho fana ka insulin ho li-circuits tsa moputso oa boko dopaminergic (Daws et al., 2011) le boits'oaro bo batlang lijo (Pal et al., 2002). Leha ho le joalo, ha ho na lithuto tsa vivo tse ileng tsa hlahloba hore na likhakanyo tse tobileng tsa litekanyetso tsa dopamine ea endo native ho D li kae2/3R ho VS li amana le likhakanyo tsa IS ho batho.

Ho sebelisa PET ka li-radioligands tsa D2/3R, hoa khonahala ho fihlela likhakanyo tse tobileng tsa dopamine ea nako e telele ea D2/3R bathong ka vivo. Sena se ka etsoa ka ho bapisa phetoho ea liperesente ho bokhoni bo tlamang (BP)ND) lipakeng tsa sekheo sa PET ea scan ninete le skena tlas'a komello e matla ea dopamine (Laruelle et al., 1997; Verhoeff et al., 2001). E ipapisitse le mofuta oa ho lula teng, kaha radiotracer e tlamang ho D2/3R e nahanela maemo a dopamine motheong oa motheo, liphetoho ho BPND kamora ho theoha ha dopamine ho bonts'a hore na dopamine e ne e lutse ho hakae li-receptors (Laruelle et al., 1997; Verhoeff et al., 2001). Acute dopamine depletion e ka fihlella ho batho ka ho thibela synthetic dopamine ka tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Paradigm ena e sebelisitsoe ho hlakisa liphapang maemong a dopamine a endo native dopamine a leng ka har'a D2/3R ho striatum ea batho ba nang le lefu la neuropsychiatric (Martinez et al., 2009).

Sehlopha sa rona se tsoetse pele [11C] - (+) - PHNO, radiotracer ea pele ea agonist ea P2/3R (Wilson et al., 2005; Graff-Guerrero et al., 2008; Caravaggio et al., 2014). Ts'ebeliso ea "radiotracer" ea agonist, e lokelang ho etsisa haufi-ufi matla a amanang le lesapo la mokokotlo, e ka fana ka khakanyo e matla le e sebetsang ea tekanyo ea dopamine ea endo native ho batho. Ho feta moo, haufinyane re netefalitse tšebeliso ea [11C] - (+) - PHNO ho hakanyetsa litekanyetso tsa dopamine tsa endo native ho D2/3R sebelisa phephetso ea AMPT (Caravaggio et al., 2014). Ka kopanelo, ho vivo data ea motho e bonts'a hore tracer ena e tsotella haholo phapang ea litekanyetso tsa dopamine tsa nako e telele ho feta li-radiotracers tsa antagonist tse kang [11C] -raclopride (Shotbolt et al., 2012; Caravaggio et al., 2014) ka hona ho ka ba molemo ho hlakisa liphapang maemong a maqhubu a dopamine ho D2/3R bathong. E sebelisa [11C] - (+) - PHNO index ea boima ba 'mele (BMI) ka har'a mofuta o sa fumaneheng e fumanoe e lumellana hantle le BPND ho VS empa eseng dorsal striatum (Caravaggio et al., 2015). Tlhaloso e 'ngoe e ka fumanoang bakeng sa phumano ena ke hore batho ba nang le BMI e kholo ha ba na dopamine e fokolang ea sebakeng sa D2/3R ho VS. Phumano ena ea pejana e ts'ehetsa ho fuputsa kamano e pakeng tsa IS le dopamine ea endo native ka kotloloho ho VS joalo ka ha e lekantsoe le [11C] - (+) - PHNO.

E sebelisa [11C] - (+) - PHNO le parate ea dopamine e fokotsang matla haholo, re batlile ho hlahloba ka lekhetlo la pele hore na likhakanyo tsa "dopamine" tsa mehleng li teng ho D2/3R ho VS ea batho ba phetseng hantle, bao e seng batho ba amanang ba amanang le IS. Re kholoa hore batho ba fokotsehileng ba na le dopamine e nyane e tsoang D2/3R ho VS motheong oa motheo. Barupeluoa ba phetseng hantle ba ile ba hlahlojoa hore ba fane ka: 1) bopaki ba mohopolo oa kamano pakeng tsa IS le dopamine ea boko ntle le ho ba le liphetoho tse ferekanyang tse ka hlahang libakeng tsa mafu; le 2) tekanyetso ea papiso e tlang lipapaling tsa bakuli. Re boetse re batla ho tseba hore na ho fokotsa dopamine ea morao-rao ka AMOP ho ka lebisa ho liphetoho ho IS ho batho ba phetseng hantle. Ho hlakisa likamano lipakeng tsa IS le maemo a dopamine bokong ba batho ho vivo e ne e tla ba mohato oa bohlokoa oa pele oa ho utloisisa sebopeho lipakeng tsa bophelo bo botle ba metabolic, homeostasis ea matla, le li-circuits tsa moputso oa boko ho tsa bophelo le bokuli (Volkow et al., 2013a, 2013b).

Mekhoa le Lisebelisoa

barupeluoa ba

Lintlha tsa 9 tsa bankakarolo, tse kenyang karolo ea thuto e lekanyang dopamine ea morao-rao le PET, li kile tsa tlaleheloa (Caravaggio et al., 2014). Barupeluoa bohle ba ne ba le letsoho le letona 'me ba se na bothata bofe kapa bofe ba bongaka kapa mafu a kelello joalo ka ha ho laetsoe ke tlhahlobo ea bongaka, Mini International Neuropsychiatric Puisano, liteko tsa motheo tsa laboratori, le elektroniki. Barupeluoa e ne e se ba sa tsubeng 'me ba ne ba lebelletsoe ho ba le lesira la moroto le sa lokang bakeng sa lithethefatsi tsa tlhekefetso le / kapa boimana ha ho kenyelletsoa le pele ho scan e mong le e mong oa PET. Boithuto bona bo amohetsoe ke Boto ea Boitšoaro ea Lipatlisiso ea Setsi sa Tlatsetso le Bophelo ba Kelello, Toronto, mme bohle ba nkileng karolo ba ile ba fana ka tumello e ngotsoeng.

Tsamaiso ea Metyrosine / AMPT

Ts'ebetso ea ho fokola ha dopamine ea dopamine e phatlalalitsoe libakeng tse ling (Verhoeff et al., 2001; Caravaggio et al., 2014). Ka bokhutšoanyane, ho felloa ke matla ha dopamine ho bakiloe ke tsamaiso ea molomo ea 64mg metyrosine ka kilogram ea boima ba 'mele bakeng sa lihora tsa 25. Ho ikemetse ka boima ba 'mele, ha ho morupeluoa ea ileng a fuoa> 4500mg. Metyrosine e ne e sebelisoa ka litekanyetso tse 6 tse lekanang ka linako tse latelang: 9:00 hoseng, 12:30 thapama (lihora tse 3.5), 5:00 thapama (lihora tse 8 tsa poso), le 9:00 thapama (poso lihora tse 12) ka letsatsi la 1 , le 6:00 am (poso lihora tsa 21) le 10:00 am (poso lihora tsa 25) ka letsatsi la 2. The post AMPT PET scan e ne e lokiselitsoe 12 pm, lihora tsa 28 kamora lethal dose ea pele ea metyrosine. Lihlooho li ne li shebiloe ka kotloloho nakong ea tsamaiso ea AMPT mme li robala bosiu bo le bong libetheng tsa lipatlisiso tse khethiloeng ke sepetlele ho tsamaisa lenane la litekanyetso tsa AMPT le ho lekola litlamorao tse ka bang teng. Ntle le moo, lithuto li ile tsa laeloa ho noa bonyane 4L ea maro nakong ea kamohelo ea matsatsi a 2 ho thibela ho theoa ha likristale tsa AMPT ka morong, mme ho kenella ka mokelikeli ho ne ho lekiloe ho netefatsa ho latela. Ntle le moo, ho alkalinise moroto, o eketsang ho qhibiliha ha AMPT, sodium bicarbonate (1.25g) e ile ea fuoa molomo ka 10:00 bosiu mantsiboea a pele ho letsatsi la 1 le ka 7:00 hoseng ka letsatsi la 1 la tsamaiso.

Tlhahisoleseling ea Plasma e potlakileng

Barupeluoa ba ile ba kopuoa ho hana ho ja le ho noa lino tse metsi ntle le metsi a 10 ho lihora tsa 12 pele ho pokello ea mosebetsi oa mali, e bokelitsoeng ho 9: 00 am. Bakeng sa barupeluoa ba faneng ka li-scans tsa PET (n = 11), mosebetsi oa mali o potlakileng o ile oa bokelloa ka letsatsi la sekepe sa PET scan. Barupeluoa ba mashome a mabeli a metso e mehlano ba nang le phepo e nepahetseng (basali ba 9, ba bolela lilemo = 31 ± 11, BMI: 22-28) ba fane ka ts'ebetso ea mali e potlakileng (9: 00 am) basement le ka mor'a ho amohela tekanyetso ea 5 ea AMPT. Bakeng sa 13 ea lithuto tsena, ho ne ho khonahala ho bokella mosebetsi oa mali 24 lihora tse le 'ngoe. Bakeng sa lithuto tse setseng, 4 e fane ka mosebetsi oa mali 6 ho matsatsi a 7 ka thoko, 4 e fane ka 10 matsatsing a 14 ka thoko, 2 e fane ka 36 matsatsing a 43 ka thoko. Mali bakeng sa tekanyo ea tsoekere a ile a bokelloa ka mothong oa 4-mL grey stoppered tube e nang le sodium fluoride e le motsoako o thibellang le potasiamo e le anticoagulant. Plasma e ile ea ts'oaroa ha glucose ho EXL 200 Analyzer (Motorola) e sebelisa mokhoa o ikhethileng oa mokhoa oa hexokinase-glucose-6-phosphate dehydrogenase. Mali bakeng sa tekanyo ea insulin a ile a bokelloa ka mothong o omisitsoeng oa 6-mL red stoppered o se nang li-additi. Serum e ile ea hlahlojoa ho Access 2 Analyzer (Beckman Coulter) e sebelisa karoloana ea paramagnetic, chemiluminescent immunoassay bakeng sa boikemisetso bo bongata ba maemo a insulin serum ea motho. Lenane la IS la ho lahla glucose le ne le hakanngoa bakeng sa thuto e 'ngoe le e' ngoe ho tloha glucose e potlakileng le insulin e sebelisang Homeostasis Model Assessment II (HOMA2), e lekantsoeng le Calculator ea Univesithi ea Oxford HOMA2 (v2.2.2; http://www.dtu.ox.ac.uk/homacalculator/) (Wallace et al., 2004). Likhakanyo tsa IS tse fumanoang li sebelisa HOMA2 li hokahane haholo le tse fumanoeng ka mokhoa oa khatello ea methapo ea hyperinsulinulin-euglycemic (Matthews le al., 1985; Levy et al., 1998).

PET Ho etsisa

Barupeluoa ba ile ba feta tlasa 2 [11C] - (+) - PhNO PET e hlahloba, e le 'ngoe tlasa maemo a motheo' me e 'ngoe ka lihora tsa 25 ka mor'a ho theoha ha dopamine ea AMPT. Radiosynthesis ea [11C] - (+) - PHNO le ho fumaneha ha litšoantšo tsa PET ho hlalositsoe ka botlalo libakeng tse ling (Wilson et al., 2000, 2005; Graff-Guerrero et al., 2010). Ka bokhutšoanyane, litšoantšo li ne li fumanoe ho sebelisoa qeto e phahameng, sistimi ea kh'amera e ikemiselitseng PET (CPS-HRRT; Motorola Molecular Imaging) e lekanyang radioactivity ho li-XlicNXX tsa boloi ka boholo ba 207mm ka 'ngoe. Qeto ea sefofane e ne e le ~ 1.2mm ka botlalo ka halofo e kholo. Likarolo tsa phetiso li fumanoe ho sebelisoa a 137Cs (T1/2 = 30.2 yr, E = 662 KeV) mohloli o le mong oa lifoto ho fana ka khalemelo, 'me tlhaiso-leseling e fumanoe ka lethathamo la lenane. Lintlha tse qaqileng li ile tsa qaptjoa bocha ka mokhoa o hlakileng oa ho fepa. Bakeng sa motheo [11C] - (+) - PHNO scans (n ​​= 11), lethathamo la radioacuction e ne e le 9 (± 1.5) mCi, ka ts'ebetso e itseng ea 1087 (± 341) mCi / µmol le bongata bo kenelletseng ba 2.2 (± 0.4) .g. Bakeng sa scopamine-depleted scans (n ​​= 9), lethal dose ea radioacuction e ne e le 9 (± 1.6) mCi, e nang le ts'ebetso e itseng ea 1044 (± 310) mCi / µmol le bongata bo kenelletseng ba 2.1 (± 0.4) µg. Ho ne ho se na phapano ea hore u ka sebelisa lethathamo la radioacaction (t(8) = 0.98, P= .36), ketsahalo e ikhethileng (t(8) = 1.09, P= .31), kapa letheba le boima (t(8) = - 0.61, P= .56) lipakeng tsa motheo le dopamine depletion scans (n ​​= 9). [11C] - (+) - Tlhahlobo ea skena ea PHNO e fumanoe XinUMX ea metsotsoana ea postinjection. Ha ho hlahlojoa ho se ho phethiloe, datha li hlalositsoe liforeimeng tsa 90 (30-1 ea 15-dimin-time and 1-16 of 30 -iminite time.

Tlhahlobo ea litšoantšo

Tikoloho ea thahasello (ROI) - tlhahlobo-leseling e thehiloeng ho [11C] - (+) - PHNO e hlalositsoe ka mokhoa o qaqileng libakeng tse ling (Graff-Guerrero et al., 2008; Tziortzi et al., 2011). Ka bokhutšoanyane, li-curve tsa li-time task (TACs) ho tsoa ho li-ROI li ile tsa fumanoa litšoantšong tse matla tsa PET tse sebakeng sa khale ho buuoang ka setšoantšo se seng le se seng se ngolisitsoeng ka molao sa MRI. Ngoliso e kopanetsoeng ea MRI ea thuto e ngoe le e ngoe ho sebaka sa PET e fihletsoe ka ts'ebeliso ea "algorithm" e tloaelehileng ea litabaStudholme et al., 1997), joalo ka ha e kenngoa tšebetsong ho SPM2 (SPM2, Lefapha la Wellcome la Cognitive Neurology, London; http://www.fil.ion.ucl.ac.uk/spm). Li-TAC li ile tsa hlahlojoa ho sebelisoa mokhoa oa Simplified Reference Tissue Way (Lammertsma le Hume, 1996) Ho sebelisa "cerebellum" joalo ka sebaka sa litšupiso, ho fumana likhakanyo tsa ho tlama: ho tlama motho ea ka bang teng mokokotlong (BP)ND), joalo ka ha ho hlalosoa ke tumellano ea tumellano ea "vivo imaging" ea radioligands e tlamang hape (Innis et al., 2007). Ts'ebetso ea ts'ebetso ea motheo ea Mokhoa o Ngotsoeng oa Reference Tissue (Gunn et al., 1997) e sebelisitsoe litšoantšong tse matla tsa PET ho hlahisa parametric voxel-bohlale BPND limmapa tse sebelisang PMOD (v2.7, PMOD Technologies, Zurich, Switzerland). Mefuta eo mesebetsi ea motheo e hlahisitsoeng ka eona (K2motsotso - K2max) e ne e le 0.006 ho 0.6. Litšoantšo tsena li ile tsa fetoloa ka lehare sebakeng sa boko sa MNI ka ho kenella ka Neighbor Neighbor ka boholo ba voxel bo kentsoeng ho 2 x 2 × 2mm3 sebelisa SPM2. BP ea tikolohoND likhakanyo li ne li nkiloe ho ROI tse hlalositsoeng sebakeng sa MNI. The VS and dorsal striatum (dorsal caudate, kamora mona ho ne ho hlalosoa ka mokhoa o hlakileng le oa morao-rao) ho latela Mawlawi et al. (2001).

Ho hakanya Maemo a Dopamine a Kantle

Khakanyo ea litekanyetso tsa dopamine ea endo native ho D2/3R e ne e ipapisitse le mohlala oa ho lula moo ho kopantseng radiotracers joalo ka [11C] - (+) - PHNO ea D2/3R e nahanela maemo a dopamine (Laruelle et al., 1997; Verhoeff et al., 2001; Cumming et al., 2002). Ho nahanoa ka mofuta ona hore: 1) basement D2/3R BPND e ferekantsoe ke dopamine ea morao-rao, ke hore, ha e le holimo moo ho nang le dopamine, e fokotsang boleng ba D2/3R BPND; 2) D2/3R BPND tlasa depletion e bonahatsa ka nepo boemo ba 'nete ba D2/3R; le 3) keketseho e makatsang ea D2/3R BPND kamora ho theoha ha dopamine [ke hore, 100 * (Depletion BP)ND - Motheo oa BPND) / Baseline BPND = % ΔBPND] e tsamaellana hantle le mantlha a tšebetso ea dopamine ea mantlha ho D2/3R, ha feela ts'ebetso ea dopamine depletion ha e fetole palo le tumellano ea D2/3R. Kahoo,% ΔBPND, tlasa monahano o nepahetseng, e nkuoa e le index ea semiquantitative ea maemo a dopamine a endo native ho D2/3R (Verhoeff et al., 2001). Ho latela lipatlisiso tsa rona tsa pejana, re ne re sa khone ho hakanyetsa dopamine ea endo native ho "nigraanti", ebile ha rea ​​ka ra khona ho hakanya dopamine ea endo native ho hypothalamus le ventral pallidum bakeng sa lithuto tsohle (Caravaggio et al., 2014). Ka hona, li-ROI tsena ha lia ka tsa fuputsoa tlhahlobisong ea hajoale.

Tlhahlobo ea Litekanyetso

Polelo ea rona ea mantlha e ne e le ho hlahloba kamano lipakeng tsa IS le dopamine ea endo native ho VS. Re entse tlhahlobo ea lipatlisiso lipakeng tsa IS le dopamine ea morao-rao lithutong tse ling kaofela: caudate, putamen le globus pallidus.

Kamano lipakeng tsa mantlha BPND mme li Fuputsoe ka ROI ho hlakisa liphetho tsa mofuta ofe kapa ofe tsa dopamine (haeba li teng). Litlhahlobo tsa lipalopalo li ile tsa etsoa ho sebelisoa SPSS (v.12.0; SPSS, Chicago, IL) le GraphPad (v.5.0; GraphPad Software, La Jolla, CA). Tloaelo ea maemo a fetohileng e ile ea khethoa ho sebelisoa tlhahlobo ea D'Agostino-Pearson. Boemo ba bohlokoa ba liteko tsohle bo behiloe ho P<.05 (2-mohatla).

Results

Batho ba leshome le motso o mong ba phetseng hantle, ba se nang 'mele le batho ba nondiabetesic (3 basali) ba nkile karolo karolong ea PET ea thuto; sephutheloana sa lintlha tsena se tlalehiloe pele ho (Lethathamo 1) (Caravaggio et al., 2014). Ka har'a sampole e felletseng ea lithuto (n = 11), tlhahlobo ea likhakanyo lipakeng tsa sethala se nkang karolo ea metabolism e bontšitse hore lilemo li ne li lumellana hantle le sekhahla sa letheka (r(9) =. 76, P= .007), le ho potoloha ha letheka ho ne ho amana hantle le maemo a ho itima lijo a insulin (r(9) =. 80, P= .003) (Lethathamo 2).

Tafole 1. 

Morupeli oa Lipuisano

 Barupeluoa ba PET ba Phelang 

(n = 11)

AMPT-PET 

barupeluoa ba

(n = 9)

Lilemo (lilemo)29 (8)29 (9)
mefuta:20-4320-43
Tsoekere e potlakisang (mmol / L)5 (0.3)5 (0.3)
mefuta:4.3-5.34.3-5.3
Ho itima lijo insulin (pmol / L)31 (25)34 (26)
mefuta:15-10115-101
Insulin sensitivity (% S)211 (70)197 (70)
mefuta:53-27653-276
Index ea Mass Mass (kg / m2)25 (2.4)25 (2.4)
mefuta:22-2822-28
Lebelo (cm)35 (6)36 (7)
mefuta:27-5227-52
  • Lits'ebetso li bonts'a mokhoa ka ho kheloha ho tloaelehileng ho li-parentheses.

    Maelefatso: AMPT, alpha-methyl-para-tyrosine; PET, positron emission tomography.

Tafole 2. 

Pearson Correlations lipakeng tsa Metabolic Variables

 AgeBMIWaist CircumferenceGlucose e potlakilengHo itima lijo insulin
Sensibisiso ea insulin-0.179 (P= .599)-0.571 (P = .067)-0.602 (P = .050)-0.517 (P = .103)-0.926*** (P = .0001)
Ho potlakisa insulin0.422 (P = .196)0.529 (P = .095)0.795** (P = .003)0.598 (P = .052) 
Ho pepela glucose e potlakileng0.420 (P = .199)0.063 (P = .855)0.516 (P = .104)  
Sekhechana sa mokokotlo0.756** (P = .007)0.466 (P = .149)   
'Mele' Misa Index0.050 (P = .883)    
  • Correlation e maemong a bohlokoa: 0.05 (2-tailed).

  • **Correlation e bohlokoa ho boemo ba 0.01 (2-tailed).

  • ***Correlation e bohlokoa ho boemo ba 0.001 (2-tailed).

Lithuto tse robong tsa 11 li fane ka scan ninete ea PET ea bobeli hammoho le skena tlasa khatello ea matla ea dopamine ea AMPT; Sena se fane ka likhakanyo tsa "dopamine" tsa mehleng ea khale2/3R ho VS motheong oa motheo (ke hore, liperesente lia fetoha ho [11C] - (+) - PHNO BPND pele le ka mora dopamine depletion). Khakanyo ea mantlha ea dopamine ea ho lula ha D2/3R ho VS e ne e tsamaisana hantle le IS (r(7) =. 84, P= .005) (Setšoantšo sa 1), a tlhabollo e ileng ea sala kamora ho laola lipalo-palo ka boits'oaro bakeng sa lilemo (r(6) =. 86, P= .007), BMI (r(6) =. 72, P= .04), waist circumference (r (6) =. 75, P= .03), le maemo a plasma a AMPT (r(6) =. 84, P= .009). Ka nako e ts'oanang, kholo ea kholo ea mantlha ea dopamine e lula ho D2/3R ho VS e ne e tsamaellana hampe le maemo a insulin a ho itima lijo (r(7) = -. 85, P= .004) empa e ne e sa tsamaellane le litekanyetso tsa ho itima lijo tsa tsoekere (r(7) = -. 49, P= .18). Ho lula ha Dopamine ho VS ha hoa ka ha kopanngoa le BMI (r(7) =. 09, P= .80) kapa sekhahla sa letheka (r(7) = -. 30, P= .41).

Setšoantšo sa 1. 

Kamano pakeng tsa sensopivityity ea insulin (IS) le dopamine ea endo native ho D2/3 li-receptors (D2/3R) ho ventral striatum (VS) ea batho ba phetseng hantle ba 9.

Haholo, likhokahano tse kaholimo le khakanyo ea litheko tsa dopamine ea mantlha ea D2/3R e ne e khannoa haholo ke ho lula ha dopamine ho VS e nepahetseng empa eseng VS e tlohetsoeng. Ka ho khetheha, ho lula ha dopamine ho VS e ka letsohong le letšehali ho ne ho sa kopantsoe le IS (r(7) =. 41, P= .28), maemo a itima lijo a insulin (r(7) = -. 46, P= .22), kapa glucose (r(7) = -. 33, P= .39), athe ho lula ha dopamine ho VS e nepahetseng ho ne ho hokahane le IS (r(7) =. 75, P= .01), e amanang hantle le maemo a ho itima lijo a insulin (r(7) = -. 73, P= .02), mme e sa tsamaellane le maemo a tsoekere (r(7) = - 39., P= .31).

Ka har'a sampole e felletseng ea lithuto (n = 11), basement [11C] - (+) - PHNO BPND ka ho le letona VS e ne e amana hantle le khakanyo e hakanyetsoang ea IS (r(9) = -. 65, P= .02) (Setšoantšo sa 2). Kahoo, barupeluoa ba nang le litekanyetso tse tlase haholo tsa dopamine ea nako e telele ea D2/3R e ne e na le BP e phahameng ka ho fetisisaND motheong oa motheo, o lumellanang le tlholisano e fokotsehileng ea ho ts'oaroa ha tracer ea tlamiso ka dopamine ea endo native ka IS e fokotsehileng. Ka nako e ts'oanang, maemo a insulin a ho itima lijo a ne a amana hantle le [11C] - (+) - PHNO BPND ho VS e nepahetseng (r(9) =. 77, P= .006), ha ho ne ho sena khokahano le litekanyo tsa tsoekere e potlakileng (r(9) =. 27, P= .43). Haholo, [11C] - (+) - PHNO BPND ka ho le letšehali VS e ne e sa tsamaellane le IS (r(9) = -. 35, P= .29) kapa maemo a itima lijo a insulin (r(9) =. 53, P= .09) le tsoekere (r(9) =. 08, P= .81).

Setšoantšo sa 2. 

Kamano lipakeng tsa basel dopamine D2/3 amohela (D2/3R) phumaneho - [11C] - (+) - PHNO BPND - le kutloisiso ea "insulin sensitivity" (IS) ho batho ba phetseng hantle ba 11.

Litlhahlobo tse hlalositsoeng li senotse hore khakanyo ea IS e ne e sa amane le litekanyetso tsa dopamine ea endo native ho D2/3R ho caudate (r(7) =. 47, P= .20), putamen (r(7) =. 52, P= .15), kapa globus pallidus (r(7) =. 33, P= .40). Ho ne ho boetse ho se na khokahano lipakeng tsa likhakanyo tsa ho lula ha dopamine libakeng tsena le litekanyo tsa ho itima lijo tsa insulin kapa tsoekere, hammoho le BMI le sekhahla sa letheka (tsohle P> .05; data e sa bontšoang).

Ho hlahloba hore na ho fokotsa dopamine ea endogenous ho ama IS joang, taolo e phetseng hantle ea 25 (e bolela lilemo = 31 ± 11; 9 femme) e boetse e fana ka litekanyetso tsa "insulin" tsa "" "" "insulin" le "glucose" pele le kamora ho fokola ha dopamine. AMPT e ile ea eketsa ka bongata boemo ba plasma ba ho itima lijo (t(24) = - 2.62, P= .01) ha e sa fetole haholo phapang ea plasma ea tsoekere e potlakileng (t(24) = - 0.93, P= .36). Bonneteng, AMPT e fokotsehile haholo hakanyetso e hakantsoeng ea IS (t(24) = 2.82, P= .01) (Setšoantšo sa 3). Ho tlosa lithuto tseo tse nang le nako e fetang ea beke ea 2 pakeng tsa ho bokella mosebetsi oa mali ha hoa ka ha fetola haholo litholoana tse boletsoeng ka holimo (data e sa bontsitsoeng).

Setšoantšo sa 3. 

Tšusumetso ea ho fokola ha dopamine depletion ka alpha-methyl-para-tyrosine (AMPT) mabapi le insulin sensitivity (IS), le litekanyetso tsa plasma tse potlakileng tsa insulin le glucose, ho batho ba phetseng hantle ba 25 (liphoso tsa liphallelo li emela SD). Bakeng sa lithuto tsa 8, litekanyetso tsa bona tsa depletion tsa IS li hanyetsane le tloaelo e akaretsang: 6 e eketsehile mme 2 e ile ea lula e ts'oana.

Puisano

U sebelisa radiotracer ea agonist [11C] - (+) - PHNO le parate ea dopamine e fokotsang matla haholo, re bonts'a ka lekhetlo la pele hore IS e lumellana hantle le litekanyetso tsa dopamine tsa endopale ho D.2/3R ho VS. Ha ho na le botenya kapa khatello e phahameng ea khatello ea tsoekere maling, litekanyetso tsa "dopamine" tse tlase tse tsoang ho VS li amana le IS. Taba ena e fumaneha e tsamaellana le lithuto tsa PET tsa Vivo PET tse ntseng li hlahloba2/3Ho fumaneha ka VS ea batho ba batenya haholo (Dunn et al., 2012) mme e ts'ehetsa liphetho tsa batho ba postmortem ba nakong e fetileng (Lackovic et al., 1990) le liphetho tsa pele ho liphoofoloMurzi et al., 1996; O'Dell et al., 2014). Tumellanong le liphetho tsa PET, ho fokotsa dopamine ea morao-rao ka sampole ea batho ba phetseng hantle ho ne ho amana le IS.

Bopaki bo fana ka maikutlo a hore ho hanyetsa insulin ho sebetsa le ho ts'oaroa ha insulin, batho ba hanyetsang insulin ba bonts'ang metabolism ea glucose ho VS le cortex ea pele ho karabelo ho insulin.Anthony le al., 2006). Ho khahlisang, bohareng ba D2/3R agonism ka litoeba e ka eketsa likhahla tsa "glucose" sebakeng sa potoloho, eseng feela bokong (Arneric et al., 1984; E Senyane le Kreamer, 1991). Tlas'a moelelo ona, e tiisa hore bromocriptine, e leng nonspecific dopamine receptor agonist, e bontšoa kalafo ea lefu la tsoekere (Grunberger, 2013; Kumar et al., 2013). Kahoo, ho fetoha ha dopamine / insulin receptor ea bohareng ba VS ea batho ho ka ba le litlamorao tsa kalafo kalafong ea mathata a metabolic. Re lokela ho hlokomela hore le ha dopamine ka har'a li-accumbens e fetoloa ke liphetoho tsoekere ea mali ho arabela hyperinsulinemia, kamano ena e ka ba e rarahaneng, ka nako ea nako (acute vs aakulu) le litekanyetso (physiological vs supraphysiological) ka bobeli li bonahala li le bohlokoa (Bello le Hajnal, 2006).

Meeli ea thuto ea rona ea morao-rao e kenyelletsa ho se nkele sampole batho ba sa sebetseng tsoekere; ka hona, ho thata ho bua ka maikutlo a bongaka a amanang le ho phahama ha pelo. Ho khothalletsoa hore lithuto tsa nako e tlang li hlahlobe hore na li-degree tsa glucose dysmetabolism (mohlala, ho hanyetsa insulin, prediabetes, lefu la tsoekere) li amana joang le litekanyetso tsa dopamine tsa endo native le tlhahiso ea dopamine ho VS ea batho. Ntle le moo, lithuto tsa nakong e tlang li lokela ho hlahloba hore na litekanyetso tsena lia fetoha ha li shebane le kalafo bakeng sa khaello ea metabolic. Ntle le moo, ho bohlokoa ho hlahloba tšebeliso ea methapo ea tsoekere ho batho hore na dopamine e tsepame le ho sebetsa ho VS e amana joang le maikutlo, tšusumetso le ts'ebetso ea moputso. Qetellong, mohlala oa rona thutong ea hona joale o nyane. Le ha re sa ka ra laola ka ho hlaka lipapiso tse ngata, ho bohlokoa ho hlokomela hore kamano e bonoang pakeng tsa IS le dopamine e hakanyetsoang ea dopamine ho VS e tla pholoha tokiso ea Bonferroni (e lokisitsoe P boleng molemong oa bohlokoa: P= .01 (0.05 / 4 ROIs). Boithuto ba nako e tlang ba AMPT bo hlahloba kamano pakeng tsa dopamine ea morao-rao bokong le IS e lokela ho leka ho hira mehlala e meholo ea sampole. Ka lebaka la boholo ba rona ba mohlala ba mohlala, re hanne ho hlahloba likamano lipakeng tsa mantlha [11C] - (+) - PHNO BPND mme e ho ROIs ntle le VS. Ka ho khetheha, bokamoso [11C] - (+) - Lithuto tsa PHNO tse sebelisang mehlala e meholo ea sampole li lokela ho hlahloba kamano pakeng tsa IS le baster BPND ka haraantiantia nigra le hypothalamus: libaka tseo 100% ea [11C] - (+) - PHNO BPND letšoao le hlahisoa ke D3R vs D2R (Searle et al., 2010; Tziortzi et al., 2011). Ho tsebo ea rona, lithuto ha li so hlahlobe hore na ho na le kamano e fapaneng pakeng tsa D3R vs D2Polelo ka ho hanyetsa ka insulin ho kenella ho liphoofolo kapa ho batho. Patlisiso ena e tiisa hore D3R a ka bapala karolo ea "seculin" ea "insulin"Ustione le Piston, 2012), le D3Litoeba tsa Routout li tšoauoa ka hore li na le tšekamelo ea ho ba botenyaMcQuade et al., 2004).

Kamano ke efe lipakeng tsa insulin, liphetoho lipuisanong tsa dopamine, le moputso oa lijo? Liphetoho ho insulin li bonahala li ntlafatsa ts'ebetso ea sistamine ea mesolimbic dopamine, e amang phepelo le moputso oa lijo (Figlewicz et al., 2006; Labouebe et al., 2013). Ho 'nile ha fanoa ka tlhahiso ea hore insulin e ka thibela li-dopamine neurons sebakeng sa "ventral tegmental tegmental" (VTA) mme ka hona ea fokotsa ho lokolloa ha dopamine ka har'a li-accumbens (Palmiter, 2007). Haholo-holo, liente tsa insulin tse matla ho VTA li bontšitsoe ho thibela ho nona lijo tse matla tse nang le mafura a mangata mekokotlong ntle le ho fetola lijo tse matlafatsang.Mebel et al., 2012). Ho feta moo, litoeba tsa hypoinsulinemic li bonts'a phepelo e eketsehang e amanang le ts'ebetso e fetotsoeng ea li-nucleus accumbens (Pal et al., 2002). Boitsebiso bo ka har'a litoeba tse phetseng hantle bo fana ka maikutlo a hore ente tsa insulin tsa "peripheral insulin" li ka eketsa tlhahiso ea dopamine ho li-nucleus accumbens (Potter et al., 1999), mme insulin ka se e ka u tsoela molemo (Jouhaneau le Le Magnen, 1980; Castonguay le Dubuc, 1989). Kahoo, mekhoa le ts'ebetso e sebetsang ea insulin receptor e sebetsang kapa e sa foleng e ama tsamaiso ea mesolimbic dopamine le maemo a dopamine ho eona ha a hlake hantle. Ntle le moo, ha ho tsejoe hantle hore na lits'ebetso tsena li ka fetoha joang maemong a phetseng hantle a metabolic le a nang le mafu.

Boithuto bo 'maloa bo ithutile hore na insulin e ama joang boits'oaro ba DAT le boits'oaro bo amanang le moputso ho lithethefatsi tsa tlhekefetso tse sebetsang ho DAT, joalo ka cocaine le amphetamine (Daws et al., 2011). Mohlala, hypoinsulinemic rodices e ithaopela ho sebetsa ka tlase amphetamine (Galici et al., 2003), ha insulin e ntse e eketseha ka har'a li-accumbens e ntlafatsa matla a khothalletsoang ke koae (cocaine)Schoffelmeer et al., 2011). Leha ho le joalo, le ha lits'ebetso tsa limolek'hule tseo insulin e ka fetolang tšebetso ea DAT le polelo li tsejoa, liphetho tse tsoakaneng li 'nile tsa bonoa ho latela lithuto tse sebelisang mananeo a ho kula haholo kapa a sa foleng a insulin bakeng sa striatum (Galici et al., 2003; Owens et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011; Owens et al., 2012; O'Dell et al., 2014) le VTA (Figlewicz et al., 1996, 2003; Mebel et al., 2012). Bongata ba lithuto tsena ha li so hlahlobe ka nepo hore na insulin e ama joang ka har'a DAT ho dorsal striatum vs VS, kapa le bokello ba maqhubu a maiketsetso. Sena e kanna ea ba sesosa sa pherekano, hobane polelo, molawana, le ts'ebetso ea DAT li kanna tsa fapana meahong e fapaneng ea litheko (Nirenberg et al., 1997; Siciliano et al., 2014). Ho tsebo ea rona, ha ho tlhahlobo ea vivo ea bongo ea motho ea vivo e ileng ea etsa lipatlisiso mabapi le kamano ea pakeng tsa insulin le ho fumaneha ha li-striatal DAT. Liphumano tse mabapi le kamano pakeng tsa BMI le striatal DAT fumaneha ho batho li kopantsoe (Chen le al., 2008; Thomsen et al., 2013; van de Giessen et al., 2013), leha lithuto tsena li sa ka tsa hlahloba VS. Ho khahlisang, basebelisi ba amphetamine ba tlaleha liketsahalo tse ngata tsa botenya ba bongoana le ho ja psychopathology (Ricca et al., 2009), e totobatsa ho feta boitšoaro le bohlokoa ba maikutlo lipakeng tsa moputso oa lijo le lithethefatsi (Volkow et al., 2013b).

Ho fumana hore haufinyane IS e amana le dopamine e fokolitsoeng ho VS ho ka ba le litlamorao bakeng sa likhopolo tsa lijo le bokhoba ba lithethefatsi. Ho 'nile ha fanoa ka maikutlo a hore boits'oaro bo bongata ba BMI le boikoetliso bo amanang le ho fokotsa bokhoni ba mantlha ba dopamine ho striatum ea batho ba phetseng hantle (Wilcox et al., 2010; Wallace et al., 2014). Lintlha tse tsoang Bang le basebetsi-mmoho (2014) fana ka maikutlo a hore batho ba batenya haholo ba bonts'a ho lokolloa ha dopamine ka VS ho arabela ts'ebeliso ea khalori ha e bapisoa le batho ba sa tsubeng. Ho feta moo, ka ho sebelisa SPECT, ho khothalelitsoe hore basali ba batso ba batenya haholo ba bonts'itse tokollo ea dopamine e theotsoeng ho arabela amphetamine (van de Giessen et al., 2014). Sena se kanna sa bonts'a ho lokolloa ha dopamine ea VS e sa bonahaleng litšoantšong tsa lefu la tsoekere le ho batho ba lemaletseng lithethefatsi ka lebaka la li-psychostimulants (Volkow et al., 2009). Ho tla ba bohlokoa ho hlakisa hore na batho ba nang le lefu la tsoekere le bona ba bonts'a phokotso ea tlhahiso ea dopamine e tsoang karabong ea lijo, lithahasello tsa lijo le / kapa psychostimulants. Ka kopanelo, lithutong tsa ho nahana ka bokong ba vivo ho batho li fana ka maikutlo a hore botenya le mohlomong insulin e hokahana le tlhahiso ea dopamine e lokolotsoeng, tokollo le molumo oa endo native ho VS.

Le ha re sa fumana kamano efe kapa efe lipakeng tsa IS le maemo a endo native dopamine ka har'a dorsal striatum, ho bohlokoa ho totobatsa hore lithuto tse 'maloa tsa liphoofolo li tlalehile liphetoho ka dorsal striatal dopamine le ts'ebetso ea li-neurons ka har'a insigia e kholo mabapi le insulin ho hanyetsa.Morris et al., 2011). Haholo-holo, ho batho tokollo ea dopamine ka lebaka la lijo tse tsoang dorsal striatum e fumanoe e kopantsoe le litekanyetso tsa monate oa lijo (Tse nyenyane le al., 2003). Mohlomong, ho fokotseha ha IS ho ama dopamine ea VS e sebetsa pele, ka liphetoho dorsal driamine dopamine e bonahala feela ka ho hanyetsa insulin haholo. Ho ka etsahala hore thuto ea morao-rao e ile ea matlafatsoa mme / kapa ea se ke ea mohlala sampole e lekaneng ea IS ho bona phello ho dorsal striatum.

Lintlha tsena li na le moelelo oa bohlokoa bakeng sa mathata ao a amanang le neuropsychiatric ao ho wona insulin e ka bang co-morbid kapa a ts'oanang. Mohlala, lintlha tse 'maloa tsa bopaki li fana ka khokahano lipakeng tsa khanyetso ea insulin le nts'etsopele ea lefu la Parkinson (Santiago le Potashkin), lefu la Alzheimer's (Willette et al., 2014), le khatello ea maikutlo (Pan et al., 2010). Tumellanong le ts'oaetso ea hore insulin ho hanyetsa e ka amahanngoa le dopamine e fokotsehileng, ho ho lekanya ho hakanya hore IS e ka tlase e ka fana ka litlamorao ho ts'ireletso ea kelello ho batho ba nang le lefu la kelello. Mohlala, ketsahalong ea pele ea Chaena, batho ba sa bueng ka letho ba nang le lefu la kelello, ho hanyetsa insulin ho hoholo ho ile ha kopanngoa le ho fokola ha matšoao a nepahetseng (Chen le al., 2013). Ho thehiloe hantle hore batho ba nang le schizophrenia, hammoho le beng ka bona ba sa tšoaroang (Fernandez-Egea et al., 2008), ba na le monyetla oa ho ba le mathata a mangata a metabolism; sena se fumanoe pele ho tšebeliso ea antipsychotic le kamora ho laola mekhoa ea bophelo (Kirkpatrick et al., 2012). Ho feta moo, phapang ea mamello ea tsoekere e ka khetholla lihlopha tsa batho ba nang le lefu la kelello le tšoauoang ke lithuto tse fapaneng tsa matšoao a fapaneng (Kirkpatrick et al., 2009). Maemong a liphumano tsena, ho kopantsoe le lipono tsa nalane tsa hore li-comas tse kentsoeng insulin li ka ntlafatsa matšoao a psychotic (West et al., 1955), hoa khahla ho hakanya hore insulin e bohareng e bolelang li-dopamine neurons e ka bapala karolo ea methapo le kalafo ea lefu la kelello (schizophrenia).Lovestone et al., 2007). Lithuto tsa PET tsa nakong e tlang tse ntseng li hlahloba tšebelisano lipakeng tsa psychopathology le ho hanyetsa insulin maemong a dopamine a bohareng ka sebele li bonahala li le mabaka.

Qetellong, ka ho sebelisa PET le phephetso e matla ea ho fokola ha dopamine, re bontšitse ka lekhetlo la pele likhakanyo tsa IS li amanang le maemo a dopamine ea endo native ho D2/3R ho VS ea batho ba phetseng hantle. Ntle le moo, ho fokotsa dopamine ea morao-rao ho batho ba phetseng hantle ho ka fetola tekanyetso ea IS. Ha li kopantsoe hammoho, liphumano tsena li bontša mohato oa bohlokoa oa pele oa ho hlakisa hore na boemo ba metabolic bo ka ikamahanya le maloetse a maholo a kelello a kang schizophrenia.

Tlhaloso ea Thahasello

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 fetileng tsa 3. 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, Setsi sa Bophelo sa Naha sa US, le Instituto de Ciencia y Tecnologıa para la Capital del Conocimiento en el Distrito Federal (ICyTDF). Hape o amohetse matšeliso a lits'ebeletso tsa botsebi 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. Ngaka Remington o fumane tšehetso ea lipatlisiso, litefiso tsa ho buisana le litefiso tsa sebui se tsoang Mokhatlong oa Lefu la Tsoekere oa Canada, Lekhotla la Canada la Patlisiso ea Bophelo, Hoffman-La Roche, Laboratorios Farmacéuticos Rovi, Kalafo, Neurocrine Bioscience, Novartis Canada, Lipatlisiso tsa Letlole la Lipetlele-Canada bakeng sa Innovation, le Mokhatlo oa Schizophrenia oa Ontario. Bangoli ba bang ha ba na thahasello ea tlholisano ea ho hlahisa.

lumela hore baa fokola

Boithuto bona bo tšehelitsoe ke Canadian Institutes of Health Research (MOP-114989) le US National Institute of Health (RO1MH084886-01A2). Bangoli ba leboha basebeletsi ba Setsi sa PET setsing sa Tlatsetso ea Tlatsetso le Bophelo bo Botle ba kelello bakeng sa thuso ea botekgeniki pokellong ea data. Ba boetse ba leboha ka tieo Yukiko Mihash, Wanna Mar, Thushanthi Balakumar, le Danielle Uy ka thuso ea bona.

Ena ke sengoloa sa Open Access se tsamaisitsoeng tlasa maemo a laesense ea Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/), e lumellang tšebeliso e sa thijoeng, phetiso le phetiso ea mofuta o fe kapa o fe, ha feela mosebetsi oa pele o boletsoe ka nepo.

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