Reducitur ad insulin vitro Narratur apud D2 dopaminérgico Minus Angiospermae / 3 Receptors in ventralis subplana Striatum de Healthy Nonobese Pugnatisne secum dum homines (2015)

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

Caravaggio F1, C Borlido1, M Hahn1, Feng Z1, G Fervaha1, P Gerretsen1, S Nakajima1, E Plitman1, adversissimas haud XXIII Chung1, ego Iwata1, A Wilson1, Rem G1, A Francisco Guerrero-Graff2.

Abstract

Background:

Cibum PROCLIVITAS est a topic in neuroscience contentione actum. Testimonium enim insinuat diabete ad reducere levels dopamine in in nucleus basali accumbens, similis homines ad medicamento PROCLIVITAS. Est ignotum si sensitivum ad insulin campester in endogenous dopamine ventrali striatum ab hominibus. Id quod iam ante per agonist dopamine in D2/3 receptor Radiotracer [11C] - (+) - PHNO dopamine et subtiliter fiebat deperditio provocatione. Separatim sano specimen Personarum si interrogari possent mutari dopamine deperditionem insulina suavitate.

DE MODIS:

Insulin sensus fuerit æstimatum ut inter se de re ieiunio PLASMA GLYCOSA et insulin in usus Homeostasis Model aestimatione II. Et undecim sanus nonobese nondiabetic homines (3 feminam) provisum est a baseline [11C] - (+) - PHNO scan, 9 qui praebebat dopamine scan per deperditionem, permittens opiniones endogenous dopamine in D dopamine2/3 receptor. Dopamine in effectum per deperditionem yl alfa-para-tyrosine (64mg / kg, P.). In sanis hominibus 25 (9 femina) ieiuniis et plasma glucose acquisita Ante dopamine demit.

effectus:

Endogenous dopamine in D dopamine ventrali striatum2/3 insulin receptor quod prorsus neglegunt connectuntur (r(7) =. 84, .005 = P), negatiue connectuntur cum insulin campester (r (7) = -. 85, .004 = P). GLYCOSA campester erant non connectuntur cum endogenous dopamine in D dopamine ventrali striatum2/3 receptor (R (7) = -. 49, .18 = P). Congruenter acutis dopamine in sanus fiebat deperditio homines signanter minuatur sensum insulin (T (24) = 2.82, .01 = P) insulin campester auctus (T (24) = - 2.62, .01 = P) et mutare non GLYCOSA campester (T (24) = - 0.93, .36 = P).

Conclusio:

In sanis hominibus ad sensitivum insulin minuatur dopamine in B minor endogena dopamine2/3 receptor in ventrali striatum. Sed et anguli dopamine deperditionem reduces insulin sensus imminuerentur. Hi Inventiones, ut habeat momenti implicationes neuropsychiatric populi metabolicae abnormitates.

© Apud 2015. Oxford University Press Author pro CINP.

Keywords:

D2; diabete; dopamine; GLYCOSA, insulin

Introduction

Quod continuum augmentum in invaluisset ADIPS et diabete in North America, quod cogitavi ut overconsumption coniunctum est summus adipem / summus saccharo cibis, opposuit sibi onus grave publica salutem (Mokdad et al., 2001; Seaquist, 2014). Et a conceptu cibum PROCLIVITAS, altum edules cibos interponat quo videtur quod lucra ut medicinae ex abusu (Park et al., 2007), Magna quaestio manet in topic (Ziauddeen et al., 2012; Volkow et al., 2013a). In vivo in cerebrum imaginatio studia alere homines hoc conceptu praebuere documentumque cerebri similes mutationes inter obesus homines et apud homines medicamento PROCLIVITAS (Volkow et al., 2013a, 2013b). Specialius est, uti demonstratum est alta emissionem tomography (DELICTUS) obesus homines, ut et homines habeant cum medicamento PROCLIVITAS minus D dopamine2/3 (Felis D2/3R) available in striatum (Wang et al., 2001), An PROCLIVITAS sicut neural-size: smaller; quod etiam dicitur in talpas overconsume edules cibos (Johnstonii et Kenny 2010).

Striatal dopamine praesertim ventralem striatum (VS) sit amet turpis mercedis modulator cibi sumptionem (Palmiter, 2007). Diabete insulin sensus reducta suadere quod plures lineas et (IS) ut ad minorem endogena dopamine in VS. Reducitur dopaminergicae areae cerebrum actio huius observatam refert Diabetic et vespertiliones intima postmortem, cum summa indicavit dopamine ab imminutos rates (Crandall et Fernstrom, 1983; Et Trulson Himmel, 1983; Saller, 1984; Bitar et al., 1986; Bradberry et al., 1989; Takada et Kono, 1994) Et metabolismus (Saller, 1984; Kwok et al., 1985; Bitar et al., 1986; Et Juorio Kwok: 1986; Lackovic et al., 1990; Et Yang Chen, 1991; Lim et al., 1994). Talpas facta demonstrant streptozotocin hypoinsulinemic per gradus rediguntur dopamine in in nucleus basali accumbens (Murzi et al., 1996; O'Dell et al., 2014) Tum ferrum rettuderim flammamque release dopamine in responsione ad amphetamine (Murzi et al., 1996; O'Dell et al., 2014). Notabiliter, insulin modulatur ipsa cellula superficies sunt (cf.Garcia et al., 2005; Et dabunt al., 2011) Et munus (Divo et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011) Transporter de dopamine (dat.) Praeterea, insulin receptores non expressit in medulla nervi accumbens et dopaminergicae areae neurons (Werther et al., 1987; Figlewicz et al., 2003), Ubi sunt, liquido neuronal accendi, industria homeostasis, sicut et modus rebus respondeo ut reddas cibum cocaini et amphetamine (Galici et al., 2003; Konner et al., 2011; Schoffelmeer et al., 2011; Mebel et al., 2012; Labouebe et al., 2013). Simul, haec notitia suadeant quod potest ad minuatur Ad inferioribus dopamine in endogenous VS.

Ad date, 2 DELICTUS studiis inquisiverunt de necessitudine inter D striatal dopamine2/3R availability Add magis ieiunium fregerit et fossata neuroendocrine hormones (Dunn et al., 2012; Guo et al., 2014). Using Radiotracer parem [18F] -fallypride, Dunn et collegae (2012) D, ut demonstratum dopamine2/3R prout superius dictum connectuntur cum Not available in in sample nonobese et obesus mulieribus. Cum sensitivo Radiotracer sit obstrictio ad dopamine in endogenous basi collocantur (Laruelle et al., 1997; Attems et al., 2001), Maxime autem homines ad haec, quod inventum est minus sit reducta cum endogenous dopamine D occupantem2/3Igitur R est in VS eritque vinculum est ad Radiotracer baseline. Est etiam demonstratum est, quod DELICTUS hominum minus habent PROCLIVITAS COCAINUM cum endogenous dopamine in D2/3R, in Us (Not et al., 2009). Quae cum altius hominum testimonium habere et insulin resistentiam in D minus endogenous dopamine2/3R, in Us sustentaret modulatory munus in insulin signalling dopaminergicae areae circulis cerebrum praemium (Et dabunt al., 2011), Cibus quaerimus et se gerendi rationibus (Pal et al., 2002). Autem, non studiis probavi quid directum in vivo opiniones endogenous dopamine in D levels2/3R et est in hominibus, in Us referunt aestimationes.

Ad Pet uti cum maxime D radioligands2/3R fieri potest directum ad consequi opiniones endogenous dopamine D occupantem2/3R in vivo in homines. Hoc potest fieri per mutationem comparet percent in binding potentiale (BPND) Inter baseline DELICTUS scan anguli dopamine et scan per deperditionem (Laruelle et al., 1997; Attems et al., 2001). Ex ad negotium exemplar, quod est D Radiotracer binding2/3R fuisse propensam ad levels dopamine in basi collocantur: in BP mutatND post deperditio dopamine in mentem venerit quantum dopamine in occupantem receptores, in basi collocantur (Laruelle et al., 1997; Attems et al., 2001). Acuti dopamine detractio fieri potest effectum apud homines a Inhibito dopamine in via synthetica para-tyrosine, tyrosine hydroxylase yl alpha precursor (AMPT). Hoc paradigma libere uti iam illustrare differences in endogenous dopamine levels D occupantem2/3R per striatum hominum et neuropsychiatric de morbo (Not et al., 2009).

Has developed coetus noster [11C] - (+) - PHNO, Radiotracer ad D primus agonist DELICIUM2/3R (Wilson et al., 2005; Guerrero-inserere et al., 2008; Caravaggio et al., 2014). Usus est agonist Radiotracer, quae debet, pressius in endogenous ligand binding imitantur atque exprimunt, potest offerre magis sensitivo officiatorie significant estimate et dopamine in endogenous ab hominibus. Praeterea, convalidatur, si nuper in usu [11C] - (+) - PHNO endogenous estimate et dopamine in D levels2/3R AMPT provocatione usus est (Caravaggio et al., 2014). Simul, in vivo homine designa tractus notitia suadeant quod est esse sensitivo et variationes in endogenous dopamine levels radiotracers ut parem [11C] -raclopride (Shotbolt et al., 2012; Caravaggio et al., 2014) Et ita melius est ut in enucleando differences in endogenous dopamine in D levels2/3R apud homines. uti [11C] - (+) - PHNO corpus massa index (BMI) nonobese range inter inventa sunt positive connectuntur cum BPND VS sed non in dorso striatum (Caravaggio et al., 2015). Explicandum est potentiale ad hoc inventum est, quod apud homines maiorem habent BMI minus endogenous dopamine D occupantem2/3R in VS. Et hoc inventum ultra priorem necessitudinem inter subsidia rei cum endogenous dopamine est, et nominatim de VS ut metiri [11C] - (+) - PHNO.

uti [11C] - (+) - PHNO dopamine et acuta quasi exempli prae fiebat deperditio, ut primum quaerebant examine vel opiniones endogenous dopamine in D2/3R in nobis sanus, qui ad humans nonobese sit. Hypothesized nos homines, qui non habent minus sit reducta cum endogenous dopamine D occupantem2/3R basi collocantur in diebus nos in expensis. Sanus participantium providere sunt aestimanda: 1) per probationem conceptu ad necessitudinem inter cerebrum est, et dopamine mutationes quae possunt fieri absque coram confusione morbo in civitatibus et 2) quia futurum est velit fermentum orci comparationes in nationibus. Et quaesivit utrum hoc determinare reducing dopamine in endogenous AMPT posset ducunt ad mutationes in in sanis hominibus capta est. Dumque explicamus ad necessitudinem inter levels dopamine in cerebro est, et in vivo in homines repraesentet magni momenti primus gradus actionis inter ea quae ad salutem metabolicae, industria homeostasis, et in circulos praemium sani cerebri atque morbo (Volkow et al., 2013a, 2013b).

Modi et Materials

participantium

Data est enim 9 participantium qui contribuere in partem aestimationis studio dopamine in endogenous CARUS, cum antea relatum (Caravaggio et al., 2014). Omnia recte participantium utebatur, de quis major medical, aut psychiatricis inordinationem et liber ad arbitrium colloquium orci in Neuropsychiatric Mini Internationalis Colloquium, basic officinarum probat et Electrocardiography. Participantium et nonsmokers et negans habere requiritur in screen urinam medicamentis ex abusu et / aut inter se DELICTUS scan ante et graviditate ad inclusion. Per studium et probatus est Research Center enim ADJECTIO et in VII Ethicorum Board of Aliquam, Toronto, et consensu omnium participantium provisum litteris certiorem fecit.

Metyrosine / AMPT Administration

Ordo AMPT, adductus est deperditio dopamine alibi editis (Attems et al., 2001; Caravaggio et al., 2014). Breviter dopamine deperditionem inductus per kilogram corporis pondus oralis administratione 64mg metyrosine XXV horas. Lorem pondere et non particeps fuit POTIONATUS> 25mg. Metyrosine esset administratum, in VI pari portione medicatur in hoc tempore: 4500:6 sum, 9:00 pm (post 12 horas), 30:3.5 pm (post VIII horas), and 5:00 pm (post XII horas) a die I et 8:9 am (XXI horis post) et 00:12 (horis post XXV) 1. quod post AMPT in die DELICTUS scan est scheduled ad meridiem XII, metyrosine XXVIII horas post primum dose. Suosque ab in directum AMPT observationis in administratione investigationis et dormivit pernoctare in hospitium designatum-stratoria et facilitate AMPT dosing ad monitor et schedule pro potential latus effectus. Praeterea res eruditi erant bibere saltem durante fluidis 6L II die admissionis, ne formatio gemmae chrystallinae AMPT urinæ cedere: et fluidi intake est monitored ad invigilandum obsequio. Praeterea, ad alkalinize urina, quae augetur AMPT solubility, sodium bicarbonate (00g), ante diem datum viva 21:10 post meridiem ad vesperam in I et I die ad 00:25 sum de administratione.

Data ieiunio PLASMA

Praesent nisi peterentur abstinuisse bibere aqua fluida 10 collectis in sanguinem antequam 12 horis opus 9 colliguntur: 00 am. Nam quae participantium provisum DELICTUS scans (n ​​= 11), ieiunium sanguine opus factum colligitur DELICTUS scan die basi collocantur. Viginti quinque sanus participantium (9 feminas pertinent, ut sit senectute ± = 31 11, BMI: 22, 28) ieiunium sanguine opus provisum (9: 00 sum) in basi collocantur et post accipiens 5 AMPT bibitur. Nam istis 13 Poterat 24 horis opus colligere sine sanguine. Reliquis rebus ita 4 6 sanguine opus ad dies 7 seorsum 4 10 dum dies est 14 seorsum 2 36 dum dies est 43 mi. Conlatum in sanguine GLYCOSA mensura continens tubum stoppered cinereo-mL 4 et potassium sodium fluoride tamquam servatore oxylatis anticoagulant ut. PLASMA GLYCOSA enim esset tentare si ex EX 200 Analyser (Siemens) per accommodationem contingit esse GLYCOSA, 6 hexokinase-modum-phosphas Gen. Conlatum in mensura insulina sanguine rubro-mL 6 stoppered fistulam piedevas nulla. Quod serum erat resolvitur in Access 2 Analyser (Beckman Coulter) paramagnetico usus earum pars quantitatis terminum chemiluminescent inmunoenzimático ad insulin campester humanae in serum. Index digesta est GLYCOSA pro arbitrio et per se subiecto fuerit æstimatum propter famem super plasma GLYCOSA et insulin per Homeostasis Model aestimatione II (HOMA2) computata per University of Oxford HOMA2 calculator (v2.2.2; http://www.dtu.ox.ac.uk/homacalculator/) (Wallace et al., 2004). Opiniones effectum per se connectuntur cum ea vir HOMA2 ad effectum, cum hyperinsulinemic euglycemic Vertebrata (Antonius Matthaeus et al., 1985; Et separabis et al., 1998).

DELICIAE Imaging

Participantium 2 exegit [11C] - (+) - DELICTUS scans PHNO, unus ad alterum sub basi collocantur et conditionibus sequentibus horis 25 AMPT adductus, dopamine deperditionem. Quod autem radiosynthesis [11C] - (+) - DELICTUS PHNO et acquisitionem vitae imagines sunt, in sequentibus singillatim alibi (Wilson et al., 2000, 2005; Guerrero-inserere et al., 2010). Breviter, acquiritur per imagines sunt magno senatus, caput camera, dicata ratio CARUS (CPS, HRRT: Siemens M. Imaging) radioactivity mensuræ in cerebrum 207 in crassitudine crustae cum 1.2mm se. In planum est, quod senatus in medium-width, maximum ~ 2.8mm plena. Medio acquiritur usus sunt lustrat 137C (T1/2 30.2 = y, Apoc 662 = E) unius photon-punctum fonte ADTENUATIO providere disciplina, et qui egreditur semen eorum notitia in album modus acquiritur. In reconstructione a rudis notitia sunt percolantur tergo-proiectio. Pro basi collocantur [11C] - (+) - PHNO lustrat (n = 11), quod sit radioactivity consectetuer erat 9 (± 1.5) MCI, cum propria operatio est 1087 (± 341) MCI / μmol et infusum Massa 2.2 (± 0.4) μg. Nam cum transitionibus, dopamine lustrat (n = 9), intelliguntur in pondere et radioactivity 9 (± 1.6) MCI, cum ex propria operatio 1044 (± 310) MCI / μmol et Massa infusum 2.1 (± 0.4) μg. Interim pondere radioactivity nulla differentia (t(8) = 0.98, P= .36), propria operatio (t(8) = 1.09, P= .31), massa vel infusum (t(8) = - 0.61, P= .56) deperditionem inter basi collocantur et dopamine lustrat (n = 9). [11C] - (+) - PHNO intuens data sunt acquiritur per 90 postinjection minutes. Intuens statim completum fuit in tabulis data sunt redefined in 30 (1 15-of-minute 1 16-minute tempus et duratione et 30, 5).

Analysis Image

In regione rem (ROI) analysis, quia -based [11C] - (+) - PHNO alibi passim actum est in detail (Guerrero-inserere et al., 2008; Tziortzi et al., 2011). Ut paucis dicamus, tempus operatio curvarum (TACs) ex nescis sunt in patria adeptus a dynamic imagines CARUS cum ad spatium inter subiectum est scriptor co-registered MRI imago. A MRI est scriptor co-adnotatione de re inter se spatii DELICTUS iis artibus uti normalized mutua notitia algorithm (Studholme et al., 1997), Ut implemented in SPM2 (SPM2, Wellcome Department of Cognitive Neurology, London: http://www.fil.ion.ucl.ac.uk/spm). Quod per TACs sunt resolvitur in DNA facilius Reference Ratio (Et Lammertsma Cicero, 1996) In cerebello per regionem ut referat ad a quantitatis trahunt ex binding estimate: binding potentiale ad nondisplaceable cellula (BPND), Quod certis adiunctis communis nomenclaturae in imagine reversibly binding radioligands vivo (Innis et al., 2007). Et ex exsecutionem facilius Reference textus munus Ratio (Lens et al., 1997) Quod applicantur ad dynamic imagines DELICIAE et generate modularem Voxel sapientes, BPND per PMOD maps (v2.7, PMOD Technologies, Zurich, Helvetia). In range ex quibus erant munera generatae (K2et min - K2et max) Erat autem 0.006 0.6. Et in locis imagines normalised MNI magnitudinis cerebri Voxel fixum cum interpolatione spatium proximus 2 × × 2 2mm3 per SPM2. Regional BPND tunc essent opiniones definiri nescis ex spatio MNI. Est dorso striatum VS eritque (dorsale insula, olim insula putamen, dorsalium, in sequentibus constabit putamen) et secundum eorum defined Mawlawi et al. (2001).

Aestimans Endogenous gradus dopaminérgico

Computationes et gradus endogenous dopamine in D2/3R et sunt secundum exemplar quod negotium of binding radiotracers sicut [11C] - (+) - ad D PHNO2/3R dopamine in sensitivo est aequa (Laruelle et al., 1997; Attems et al., 2001; Cumming et al., 2002). Verisimile est autem hoc exemplar: 1) D basi collocantur2/3R BPND confusus est dopamine endogenous, hoc est, propter unionem dopamine in superiore et inferiore ad valorem ipsius D2/3R BPND; 2) D2/3R BPND accuratius infra detractio Status vero numero refert D.2/3R: et 3) in D fractorum incremento2/3R BPND post deperditio dopamine [id est: * 100 (Impar deperditionem BPND - gre BaselineND) / Baseline BPND = ΔBP%ND] Linearly est proportionalem esse baseline dopamine in D concentration2/3R, provisum est a processus, non mutare numerum deperditionem dopamine et affinitates D2/3R. Sic et ΔBP%ND, Oportet sub Isto posito, habetur tamquam indicem semiquantitative in endogenous dopamine in D levels2/3R (Attems et al., 2001). Ex antecedentibus digeruntur, in substantia nigra dopamine endogena potuimus pretium neque certo possumus aestimare endogena hypothalamus dopamine in omnibus rebus et pallidum ventrali (Caravaggio et al., 2014). Ideo haec non Kings hodiernam analysis, quaestionem.

Statistical analysis

In priori casu nostro utrum sit inter endogena dopamine in VS. Conducted exploratory digeruntur inter nos est, et dopamine in endogenous reliquum striatum: caudata, putamen et Globus pallidus.

Basi collocantur relationes inter BPND illi explorati, et in omnibus reperta per ROI modo magis explicito, dopamine in endogenous levels (si). Statistical analyses sunt conducted per SPSS (v.12.0: SPSS Chicago, IL) et GraphPad (v.5.0: GraphPad Software, La Jolla, CA). Normalitatem iam constituta est in variables usus est Augustinus, De Nabu test. Omnes testes gradu constitútus significationem P<05 (Pygmy-II).

Results

Undecim sana, et nonobese nondiabetic hominum (3 feminam) participatur in DELICIAE de his studiis; restant adhuc de illis data sunt super antea relatum (mensam 1) (Caravaggio et al., 2014). Intus autem plena specimen subjecta (n = 11), in examen correlationes inter variabilibus particeps metabolicae positive connectuntur, quod, cum esset aetate lumbos circumferentiam (r(9) =. 76, P= .007), et waist circumferentiam positive connectuntur cum ieiunio insulin campester (r(9) =. 80, P= .003) (mensam 2).

1 mensam. 

particeps Mauris diam

 Baseline participes DELICIUM 

(N = 11)

DELICIAE AMPT, 

participantium

(N = 9)

Aetate (annorum)29 (8)29 (9)
range:20 43,20 43,
Ieiunium Glucosum, (g / L)5 (0.3)5 (0.3)
range:4.3 5.3,4.3 5.3,
Ieiunio insulin (pmol / L)31 (25)34 (26)
range:15 101,15 101,
Insulin sensus (S%)211 (70)197 (70)
range:53 276,53 276,
Corpus Missam Index (kg / m2)25 (2.4)25 (2.4)
range:22 28,22 28,
Lumbos circumferentiam (cm)35 (6)36 (7)
range:27 52,27 52,

  • Values ​​minime indicant cum vexillum digredior parenthesi notatis.

    Abbreviations: AMPT alfa-para-tyrosine yl; CARUS, alta emissionem tomography.

2 mensam. 

Kessinger Publishing Correlations inter metabolicae VARIABILIUM

 AgeBMIlumbos circumferentiamIeiunium strictumieiunio insulin
sensum insulin-0.179 (P= .599)-0.571 (P = .067)-0.602† (P = .050)-0.517 (P = .103)-0.926*** (P = .0001)
ieiunio insulin0.422 (P = .196)0.529 (P = .095)0.795** (P = .003)0.598† (P = .052) 
Ieiunium GLYCOSA0.420 (P = .199)0.063 (P = .855)0.516 (P = .104)  
lumbos circumferentiam0.756** (P = .007)0.466 (P = .149)   
Corpus Missam Index0.050 (P = .883)    

  • †Aequa relatio tunc instituitur ad trend of campester nuntiandi obstrictum: 0.05 (2 haliaeetus).

  • **Aequa relatio tunc instituitur ad 0.01 significant gradu (2 haliaeetus).

  • ***Aequa relatio tunc instituitur ad 0.001 significant gradu (2 haliaeetus).

Et DELICTUS scan baseline 11 de novem subiectis provisum etiam ut scan sub-acuto AMPT adductus dopamine fiebat deperditio, hoc provisum opiniones endogenous dopamine D occupantem2/3R in diebus nos in expensis basi collocantur (id est, per mutationem percent [11C] - (+) - gre PHNOND ante et post deperditio dopamine). Aestimari basi collocantur dopamine D possessionem2/3R digesta est in VS esset positive connectuntur cum (r(7) =. 84, P= .005) (figure 1), a Quod cum peraeque ratione manere per se est moderantum aetate (r(6) =. 86, P= .007) BMI (r(6) =. 72, P= .04), lumbos circumferentiam (r (6) =. 75, P= .03) et PLASMA campester of AMPT (r(6) =. 84, P= .009). Concurrently aestimatum basi collocantur dopamine D possessionem2/3R prout superius dictum connectuntur cum ieiunio insulin campester in Us (r(7) = -. 85, P= .004) sed ne de GLYCOSA gradus in ieiuniis se connectuntur (r(7) = -. 49, P= .18). Dopamine in possessionem VS non connectuntur cum BMI (r(7) =. 09, P= .80) aut lumbos circumferentiam (r(7) = -. 30, P= .41).

1 figure. 

Necessitudo inter insulin sensus taxata (animo) in D dopamine et endogenous2/3 receptores (D2/3R) in ventrali striatum (VS) de 9 homines sanus.

Notabiliter, in correlationibus suis ex supra aestimationem basi collocantur dopamine D possessionem2/3R agebantur mediante negotium dopamine sinistram non recto VS VS. In specie agitur de possessionibus dopamine in sinistra VS non connectuntur cum EST (r(7) =. 41, P= .28) ieiunio insulin campester (r(7) = -. 46, P.22 =) vel Glucosum, (r(7) = -. 33, P= .39), cum recta vs dopamine in possessionem fuisse digesta est positive connectuntur cum (r(7) =. 75, P= .01), prout se connectuntur cum ieiunio insulin campester (r(7) = -. 73, P= .02), et non connectuntur cum GLYCOSA campester (r(7) = - 39., P= .31).

Intus autem plena specimen subjecta (n = 11), basi collocantur [11C] - (+) - gre PHNOND VS iure existimatum esse in negationem apud se connectuntur (r(9) = -. 65, P= .02) (figure 2). Et sic, cum in ultimis participantium dopamine in endogenous D occupantem2/3R summa erat greND a basi collocantur, ordinare binding designa tractus pro competition cum reducitur in endogenous ibant et dopamine in Thom. Concurrently ieiunio insulin campester sunt positive connectuntur cum [11C] - (+) - gre PHNOND in dextro VS (r(9) =. 77, P= .006), dum nihil nisi conuenienter sumus ieiunio GLYCOSA campester (r(9) =. 27, P= .43). Notabiliter [11C] - (+) - gre PHNOND VS ad sinistram non connectuntur cum EST (r(9) = -. 35, P= .29) et ieiunio insulin campester (r(9) =. 53, P= .09) et Glucosum, (r(9) =. 08, P= .81).

2 figure. 

Necessitudo inter D basi collocantur dopamine2/3 (Felis D2/3R) availability - [11C] - (+) - gre PHNOND - et aestimant sensum insulin (animo) in 11 homines sanus.

Exploradora digeruntur digesta est aestimari revelatum est quia non connectuntur cum endogenous opiniones dopamine in D2/3In insula R (r(7) =. 47, P= .20) putamen (r(7) =. 52, P.15 =) vel Globus pallidus (r(7) =. 33, P= .40). Et non correlationes inter opiniones fuerunt in his regionibus cupiditatem autem habens negotium dopamine et ieiunio insulin campester GLYCOSA, tum BMI et waist circumferentiam (Omnes P> 05: non data ostensum est).

Reducing examine ad quam pertinet endogenous dopamine ET 25 sanus regit (aevum sit = ± 31 11: femina 9) providit etiam ieiunando PLASMA GLYCOSA campester of insulin et ante et post AMPT dopamine deperditionem. AMPT significantly magis ieiunium insulin campester augeri plasma (t(24) = - 2.62, P= .01) significantly dum non est ille Palladius de ieiunio PLASMA GLYCOSA campester (t(24) = - 0.93, P= .36). De nota, est aestimari AMPT signanter minuatur (t(24) = 2.82, P= .01) (figure 3). Removere subditos plus quam octo, 2 collectione sanguinis discrimen inter prefatas eventus mutare opus non significantly (Indicium non est ostensum est).

3 figure. 

Dopamine deperditionem per modum anguli yl alfa-para-tyrosine (AMPT) in insulin sensus taxata (IS), jejunium plasma GLYCOSA et insulin campester in 25 sanus homines (represent errorem inducent vectes D). 8 ad subditos suos contra deperditionem vergit bona est: permansit 6 2 augetur.

Discussion

Using the agonist Radiotracer [11C] - (+) - PHNO dopamine et acuta quasi exempli prae fiebat deperditio, et demonstrabo ad primum id est positive connectuntur cum endogenous dopamine in D levels2/3R in VS. Vel in absentia dolore magna aliqua aperta dysregulation GLYCOSA, dopamine in gradibus inferioribus endogenous VS consociata sunt, cum sit reducta. Unde nova ingressus inventum est in linea cum basi collocantur D scrutandis previous studiis in vivo DELICIUM2/3R Not available in obesus homines (Dunn et al., 2012) Et sustinet homo postmortem inventa prior (Lackovic et al., 1990) Tum est in animalibus reperta Preclinical (Murzi et al., 1996; O'Dell et al., 2014). In DELICIAE et linea Inventiones: sentiuntur reducing endogenous dopamine in specimen sanus homines esse consociata est cum imminutos.

Testimonium cerebri insinuat et insulin resistentiam co-deveniretur cum periphericis insulin resistentia, reducere insulin-repugnant hominum GLYCOSA metabolismi in probans prefrontal cortex in responsione ad periphericis insulin VS eritque (Anthony et al., 2006). Interestingly, D centralis2/3R agonism GLYCOSA concentratione in peripheriam in rodents non crescat, non solum in cerebri (Arneric et al., 1984; Et Saller Kreamer, 1991). In hoc prospectu, id suadeat bromocriptine comment quod est, non specificae receptor agonist, est enim indicavit curatio de diabete (Grunberger, 2013; Saint et al., 2013). Sicut centro recedis dopamine / insulin receptor muneris in nobis, ut homines habeat orci effectus in curatio de metabolicae. Sciendum est autem, cum mutatur a dopamine in accumbens mutationes in sanguine GLYCOSA responsio ad hyperinsulinemia, hoc potest esse universa necessitudinem cum leo (VS acuti inveterata) et dose (physiologica nobis supraphysiological) adventum effectus, tum esse momenti (Et Hajnal bello, 2006).

Limitations in nostra sampling non includit current studio hominum et GLYCOSA dysregulation; Ita neque propria sunt effectus orci Cardiometabolic de morbis animi aversi et aperta sunt difficile est explanare. Suggesserant, quod futurum est quid examine studiis GLYCOSA gradus dysmetabolism (eg, insulin resistentia, prediabetes, diabete) sunt ad endogenous dopamine in campestribus quoque et dopamine release VS ab hominibus. Praeterea considerandum est, an haec sit futurum studiis values ​​alter in faciem treatment pro metabolic deficits. Magni aliunde momenti est ut magna placerat in examine per dysregulation GLYCOSA concentratione et dopamine in hominibus quam in VS ad muneris modus agendi causas cuiusque praemium processus. Denique nostri, in current studio parva sample. Dum nos non expressis verbis control pro multiple comparationes Aliquam sit amet est quod ad necessitudinem inter observatus est, et dopamine in endogenous aestimatur ut VS ad correptionem superesse Bonferroni (corrigendos P valorem limina nuntiandi obstrictum: P= .01 (0.05 / 4 Kings). Studiorum examinans futurum AMPT dopamine in cerebro est inter endogena sample moles maior adhibenda conarentur. Propter nostra parva magnitudine exempli, ut diutius a baseline exploring relationes inter [11C] - (+) - gre PHNOND estque aliud rois VS. Praesertim futuro [11C] - (+) - PHNO studiis uti sample moles maior in examine necessitudinem inter quid est, et baseline BPND in substantia nigra et hypothalamus: regionum 100% de qua [11C] - (+) - gre PHNOND signum quod ex D3R D vs.2R (Searle et al., 2010; Tziortzi et al., 2011). Ad nostram scientiam, studia hactenus nondum spectaverimus si quae erit differentialis necessitudinem inter media D3R D vs.2R expressio cum periphericis insulin resistentiam in hominibus et animalibus. Id suadeat, haec inquisitio, quia D3R potest ludere a munus in insulin secretio in peripheria (Et Ustione Piston, 2012), Et D3R knockout habebat mures aureos et dolore magna aliqua sunt propria, quasi habens-prone sexualium phaenotypo (McQuade et al., 2004).

Insulina quod inter mutationes in concentratione dopamine cibique vicissitudine Mutatis mutari videntur insulina operationem mesolimbic dopamine ratio circa esum ciborum praemium (Figlewicz et al., 2006; Labouebe et al., 2013). Hoc est, ut suggesserant insulin potest inhibere dopamine neurons in areae tegmentalis ventralis (VTA) et sic minuere release dopamine in accumbens (Palmiter, 2007). Notabiliter, insulin injections acutus, ut ostensum est prohibere cibi redundantia et Mopsopio dulcia sunt in VTA summus pinguibus, in satiamini talpas ordines manipulique pascere esurientem (Mebel et al., 2012). Praeterea, talpas hypoinsulinemic demonstrant auctus ad pascendas mutatam peragitur functio munerum, quae medulla accumbens (Pal et al., 2002). In talpas sano data suadeant quod auget periphericis insulin injections potest release dopamine in in nucleus accumbens (Potter et al., 1999), Per se potest retribuens et insulin (Et Jouhaneau Le Magnen, 1980; Et Castonguay Dubuc, 1989). Sic opus diei in acutis vel chronica quae a machinationibus insulin receptor activation afficit systematis mesolimbic dopamine et dopamine in levels non omnino patet. Praeterea, incertum est quomodo possunt haec systems mutata in nobis sanus metabolicae civitatibus his, qui infirmabantur.

Plures studiis probavi quod afficiat insulina DAT medicamentis partum praemium actis illius actus conviciis DAT qualis Amfetamina amet (Et dabunt al., 2011). Eg hypoinsulinemic talpas minus auto-gerere amphetamine (Galici et al., 2003), Augendae cum auget accumbens in insulin-adductus impulsivity cocaini minimi (Schoffelmeer et al., 2011). Attamen hypothetica insulina meatus qua exprimit muneris nota mutare DAT mixta servandis eventus studiorum curam ultra longis acutis vel ad tractanda insulina striatum (Galici et al., 2003; Divo et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011; Divo et al., 2012; O'Dell et al., 2014) Et VTA (Figlewicz et al., 1996, 2003; Mebel et al., 2012). Multi ex illis explorati differentially non studia modo afficiunt insulin DAT quae in dorso sunt striatum nobis VS, accumbens core nobis vel dicitur. Et hoc potest esse potentiale fons discrepant, cum expressio, moderationis, atque in diversis diversum esse, ut munus de DAT striatal subregions (Nirenberg et al., 1997; Siciliano et al., 2014). Ad nostrae cognitionis non est in hominibus vivo in cerebrum imaginatio studio quaesierit de necessitudine inter insulin resistentia et striatal DAT dispositis. Inventiones de necessitudine inter disponibilitatem in BMI et striatal DAT misceri homines sunt (Chen et al., 2008; Galectin et al., 2013; van Leipzig et al., 2013), Quamquam haec non facta de studiis VS. Interestingly, amphetamine et manducans CORPULENTIA pueritia users referre excelsum incidentiae de Sermonis Castrensis Reliquiae (Ricca et al., 2009), Et adhuc momenti Illuminationes excitare cibum et disordines morum et neurochemical overlaps inter medicamento praemium (Volkow et al., 2013b).

Quod inventum est: minus enim est vena dopamine in consociata cum imminutos effectus VS potuit habere ad artes et cibum medicamento PROCLIVITAS. Hoc est, ut suggesserant auctus BMI et morum sunt, ad cibi redundantia presináptico dopamine reducta facultatem ad summam complectitur de sano homines striatum (Wilcox et al., 2010; Wallace et al., 2014). Data ex Wang et consortes (2014) suadeant ut obesus ostensionem hominum dopamine release attenuatus est in VS In responsione calorie consummatio nonobese homines comparari. Sed et per SPECT, ut suggesserant, qui sunt obesus mulieres reducere demonstrant striatal release dopamine in responsione ad amphetamine (van Leipzig et al., 2014). Hæc obtundi potest etiam imitari VS dopamine release videtur in diabetic cum medicamento PROCLIVITAS et vespertiliones in homines, in responsum ad psychostimulants (Volkow et al., 2009). Hoc magni momenti esse si homines evolvere diabete et missis et ostendis striatal dopamine in responsione ad cibum release, cues cibus, et / vel psychostimulants. Simul, in vivo in cerebrum imagine studiis suadeant quod homines forsitan insulin resistentia, et sunt dolore magna aliqua consociata cum imminutos dopamine synthesin release, et in sono endogenous VS.

Dum necessitudine aliqua est, et nos non invenire gradus endogenous dopamine in dorso sunt striatum, Aliquam sit amet animalis studiis, in lumine multa mihi retulit quod, mutasse quaedam in dorso striatal dopamine et ipsam vitam neurons in substantia nigra in relatione ad insulin resistentia (Horatius et al., 2011). Confecta, maxime vero homines, in responsum ad cibum release dopamine in dorso sunt striatum inventa in connectuntur cum prandium ratings de amoeno, (Parvus et al., 2003). Forsitan, rei digesta est primo motum VS muneris dopamine et mutationes in dorso striatal dopamine muneris maiorem evidentiam in insulin resistentiam. Est possibile quod in praesenti est underpowered studio et / aut non sample a angustus range de deprehendere quod effectum est quae in dorso sunt striatum.

Haec data sunt illis neuropsychiatric perturbationes momenti effectus insulin resistentiam in quam ut cooperatores tune morbidas aut concurrant. Eg suadeant quod nexus inter aliquot lineas of development of insulin resistentia et Parkinson scriptor morbus (Santiago, et Potashkin), Alzheimer scriptor morbus (Willette et al., 2014), Et tristitia (Pan etiam et al., 2010). Hypothesi, ut convenienter bono universali sociaberis, ut insulin resistentia minuatur striatal dopamine, quod minus est non posse conferre possent ad temptor Deus enim intemptator in tutela effectus PSYCHOSIS in homines et SCHIZOPHRENIA. Ut cursus prima res, personas schizophrenia medicatis numquam maior certa indicia saevitiae reducta connectuntur cum insulin resistentia (Chen et al., 2013). Cum satis constet schizophrenia personis, necnon moveri propinquis (Fernandez-egea et al., 2008), Plus verisimile habere metabolicae abnormitates sunt; Haec inventa sunt ante et post usum antipsychotic lifestyle habitum est moderantum (A Cella Patricii et al., 2012). Item possunt esse propriae differentiae subgroups de variationes communiter GLYCOSA tolerantia apud homines designari per aliam viam tenuimus ab SCHIZOPHRENIA experiri symptom severitatem (A Cella Patricii et al., 2009). In contextu horum Inventiones, combined historical observationis cum ea meliorare possunt comas adductus insulin-psychotici salubria (Occidens et al., 1955), Ad appellandum statutum est media virgis peculiaribus insulin potest ludere a partes significantes in dopamine neurons in curatio de morbis et SCHIZOPHRENIA (Lovestone et al., 2007). DELICIAE et studia dum in futurum Sermonis Castrensis Reliquiae actionem mutuam in insulin resistentiam appareat centralis dopamine levels certe dignam existimarit.

De cetero fratres per deperditionem provocatione dopamine DELICIAE et acuto, ut supra ostensum est, quod primum aestimat quae digesta est a D ad gradus in endogenous dopamine2/3R homines in nobis sanus. Sed dapibus endogena argute personarum mutare valentibus dopamine existimatum. Simul sumpta, sunt reperta ut in enucleando praemissa represent magni momenti sit status interface cum metabolicae morbis psychicis talis ut Maior SCHIZOPHRENIA.

Interest DE PECCATO

Dr. Nakajima tradit autem acceptis a Iaponia ad Promotio Society of Science Research hospitalis et Inokashira Fund scriptor speaker et honoraria a GlaxoSmith Catullus: Pharmaceutical Janssen, Pfizer, et Yoshitomiyakuhin 3 in praeteritum annis. Dr. Guerrerro currently Graff, accipit auxilium research in his externum funding agencies: Canadian Research Institutionum salutem et US National Institute of Health et y Ciencia Mexico Instituto de Bacteria para en la Capital del Conocimiento Distrito Foederatum (ICyTDF). Et accepi etiam professio Cicero de officiis ultricies Laboratories: tentoriis Turnebus Plc Ingressusque est Gedeon, et tectae; Janssen stipendium dent; speaker et Eli Lilly ultricies a. Dr. Rem quem accepimus investigationis auxilium sibi consulens feodis, vel loquentis fees a Canadian diabete Consociationis, in Canadian Institutionum salutem Research, Cornelius-La Rupe Laboratorios Farmacéuticos Rovi, Medicure, Neurocrine Biosciences, Novartis Canada, Research hospitalis Fund, Canada Foundation quia Innovation et SCHIZOPHRENIA Societas vestibulum. Et auctores alios non indicaverunt competing ad utilitates.

Acknowledgments

Hoc fuit studium funded per Canadian Institutionum salutem Research (PENICULUS, 114989) et US National Institute of Health (RO1MH084886, 01A2). Gratias ago auctoribus DELICIAE Center Center enim ADJECTIO et in ualetudinem virgam ad auxilium, in technica notitia collectio. Et quoque sincere agere Yukiko Mihash, Mar Gloria: Thushanthi Balakumar et Danielle Uy pro auxilium.

Hic articulus est PAXS Demo distribui per verba de Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), Cujus beneficio et liberam reuse, distribution: et generativa in aliquo medium, provisum est originale opus est bene citatis.

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