I-Profound Increases in Dopamine Ukukhululwa ku-Striatum Ezinxilweni Ezidakamizwa: Ukubandakanyeka Okungenzeka Ngokwe-Orbitofrontal (2007)

J Neurosci. 2007 Nov 14;27(46):12700-6.

I-Volkow ND, Wang GJ, Telang F, UFowler JS, Logan J, UJayne M, UMa Y, Pradhan K, Wong C.

Umthombo

Isikhungo Sikazwelonke Ekuhlukumezeni Izidakamizwa, eBethesda, eMaryland 20892, e-USA. [i-imeyili ivikelwe]

abstract

Inani lemivuzo (imivuzo yemvelo nezidakamizwa) lihambisana nokwenyuka kwe-dopamine kuma-nucleus accumbens futhi kuyahlukahluka njengomsebenzi wesimo. I-cortex yangaphambi kokuqala ifakwe umfutho ekuthembekeni komongo wemivuzo nasenanini eliphakeme elilungiselelwe izidakamizwa ezinomlutha, yize izindlela zingaqondwa kahle. Lapha sivivinya i-hypothesis yokuthi i-cortex yangaphambili ilawula inani lemivuzo ngokulungisa ukwanda kwe-dopamine kuma-nucleus accumbens nokuthi lo mthethonqubo uphazamiseka kwizifundo eziluthayo.

Sisebenzise i-positron emission tomography ukuhlola umsebenzi we-cortex wangaphambili (ukulinganisa umzimba we-glucose metabolism nge [18F] i-fluorodeoxyglucose) nokwanda kwe-dopamine (kulinganiswe ne- [11C] ubuhlanga, a D2/D3 i-receptor ligand ngokubopha okuzwayo ku-endo native dopamine) ethonywa umuthi ovuselelayo we-methylphenidate kuzilawuli ze-20 kanye ne-20 izidakwa eziphuzile, iningi lazo ezazibhema.

Kuzo zonke izifundo, i-methylphenidate inyuse kakhulu i-dopamine ku-striatum. Ku-ventral striatum (lapho i-nucleus accumbens itholakala khona) futhi ku-putamen, ukwanda kwe-dopamine kuhlotshaniswa nemiphumela evuzayo ye-methylphenidate (ukuthanda izidakamizwa nokuphakama) futhi kwakutholakala kakhulu kwizidakwa (i-70 ne-50% ephansi kunezilawuli, ngokulandelana). Ezilawulweni, kepha hhayi ezidakweni zotshwala, i-metabolism ku-orbitofrontal cortex (isifunda esifakwe ne-salivery factor) yayihlotshaniswa ngokungafanele nokukhuphuka kwe-dopamine ye-methylphenidate-ikiwa Le miphumela ihambisana ne-hypothesis yokuthi i-orbitofrontal cortex ilinganisa inani lemivuzo ngokulawula ubukhulu bokwenyuka kwe-dopamine ku-ventral striatum nokuthi ukuphazamiseka kwalesi simiso kungahle kudale ukuzwela okunciphayo kwemivuzo ezifundweni eziyimilutha.

abstract

Inani lemivuzo (imivuzo yemvelo nezidakamizwa) lihambisana nokwenyuka kwe-dopamine kuma-nucleus accumbens futhi kuyahlukahluka njengomsebenzi wesimo. I-cortex yangaphambi kokuqala ifakwe umfutho ekuthembekeni komongo wemivuzo nasenanini eliphakeme elilungiselelwe izidakamizwa ezinomlutha, yize izindlela zingaqondwa kahle. Lapha sivivinya i-hypothesis yokuthi i-cortex yangaphambili ilawula inani lemivuzo ngokulungisa ukwanda kwe-dopamine kuma-nucleus accumbens nokuthi lo mthethonqubo uphazamiseka kwizifundo eziluthayo. Sisebenzise i-positron emission tomography ukuhlola umsebenzi we-cortex wangaphambili (ukulinganisa umzimba we-glucose metabolism nge [18F] i-fluorodeoxyglucose) nokwanda kwe-dopamine (kulinganiswe ne- [11C] ubuhlanga, a D2/D3 i-receptor ligand ngokubopha okuzwayo ku-endo native dopamine) ethonywa umuthi ovuselelayo we-methylphenidate kuzilawuli ze-20 kanye ne-20 izidakwa eziphuzile, iningi lazo ezazibhema. Kuzo zonke izifundo, i-methylphenidate inyuse kakhulu i-dopamine ku-striatum. Ku-ventral striatum (lapho i-nucleus accumbens itholakala khona) futhi ku-putamen, ukwanda kwe-dopamine kuhlotshaniswa nemiphumela evuzayo ye-methylphenidate (ukuthanda izidakamizwa nokuphakama) futhi kwakutholakala kakhulu kwizidakwa (i-70 ne-50% ephansi kunezilawuli, ngokulandelana). Ezilawulweni, kepha hhayi ezidakweni zotshwala, i-metabolism ku-orbitofrontal cortex (isifunda esifakwe ne-salivery factor) yayihlotshaniswa ngokungafanele nokukhuphuka kwe-dopamine ye-methylphenidate-ikiwa Le miphumela ihambisana ne-hypothesis yokuthi i-orbitofrontal cortex ilinganisa inani lemivuzo ngokulawula ubukhulu bokwenyuka kwe-dopamine ku-ventral striatum nokuthi ukuphazamiseka kwalesi simiso kungahle kudale ukuzwela okunciphayo kwemivuzo ezifundweni eziyimilutha.

Isingeniso

Ukwanda kwe-dopamine (DA) kuhlangene nezimpendulo eziqinisayo zezinto zokuhlukumeza kufaka notshwala (I-Koob et al., 1998), kepha indlela (i) yokwenza umlutha oyisisekelo icacile. Kukholakala ukuthi ukusetshenziswa kwezidakamizwa okungamahlalakhona kuphumela ekushintsheni okuguqukayo ezifundeni (amasekethe) okulungiswa yi-DA okwenziwa yi-neurobiology yokulutha (URobbins no-Everitt, i-2002; I-Nestler, i-2004). Kulezi, i-cortex eyandulelayo iya ngokuya ibonwa njengendima enkulu ekuluthweni komlutha (UJentsch no-Taylor, i-1999). Okuphathelene kakhulu nokusebenza kokuqala kokuthile kokuzungeza kwendawo yangaphakathi (i-VTA) nakuyo i-nucleus accumbens (NAc), ebamba iqhaza elikhulu ekulawuleni iphethini yokudubula yamaseli e-DA nokukhishwa kwe-DA, ngokulandelana (UGariano noGroves, 1988; UMurase et al., 1993). Impela, ucwaningo lwangaphambilini lubhale ushintsho kule ndlela ngokuchayeka kwezidakamizwa okungamahlalakhona, okuthe kwagcizelelwa ukuthi kufinyelele ekulahlekelweni kokulawulwa kokudla izidakamizwa okubonisa ukuthi umlutha (I-White et al., 1995; I-Kalivas, i-2004).

Inhloso yalolu cwaningo bekuwukuhlola ukulawulwa kwemisebenzi yobuchopho ye-DA yi-preortalal cortex ebuthweni botshwala. Ukuhlola umsebenzi we-DA wobuchopho, sisebenzise i-positron emission tomography (PET) kanye [11C] i-raclopride (DA D2/D3 i-receptor radioligand ngokubopha okuzwayo kumncintiswano nge-endo native DA) (I-Volkow et al., 1994a) ngaphambi nangemva kwenselelo nge-intylvenous methylphenidate (MP) futhi ngiqhathanise izimpendulo phakathi kwe-20 detoxified alcoholic kanye ne-20 izilawuli ezinempilo. Sisebenzise i-MP njengenselelo yezokwelapha ngoba yandisa iDA ngokuvimba abagibeli be-DA (ama-DAT) futhi ngenxa yalokho ivumela ukuhlolwa okungaqondile komsebenzi we-DA cell (I-Volkow et al., I-2002). Ukuhlola umsebenzi we-cortex eyandulelayo, silinganise umzimba we-glucose metabolism, osebenza njengophawu lomsebenzi wobuchopho (Sokoloff et al., 1977), usebenzisa i-PET ne- [18F] fluorodeoxyglucose (FDG). Ama-hypotheses ethu asebenzayo bekungukuthi ezifundweni ezinotshwala, ukulawulwa komsebenzi wobuchopho be-DA nge-cortex yaphambi kwesikhathi kungaphazamiseka nokuthi ngabe kunciphile umsebenzi we-DA. Futhi ngoba ukwanda kwe-DA okwenzelwe i-MP-indised ye-DA kuhlobene nemiphumela yayo emihle (I-Volkow et al., I-1999), siphinde sacabanga ukuthi ukuncishiswa kokukhishwa kwe-DA kwezidakwa kungaholela ekuqaqeni kokubona okuphathelene nemiphumela emnandi ye-MP.

Izimpahla nezindlela

Izihloko.

Kufundwe izifundo zobudokotela ezingamadoda ezingamashumi amabili kanye ne-20 yezilawuli zokuziphatha ezinempilo zabesilisa. Ama-Alcoholics ayeqashwa emiphakathini eyelapha kanye nezikhangiso. Ithebula 1 ihlinzeka ngezimpawu zabantu kanye nezifundo zokwelapha. Okungenani odokotela ababili baxoxisana neziguli ukuze baqinisekise ukuthi bayahlangana Incwadi Yokuhlola Nezibalo Zezinkinga Zengqondo (DSM), ukubuyekezwa kwesine, izindlela zokuxilonga ukuphuza ngokweqile, ngenhlolokhono ehlelwe ngendlela efanelekile esebenzisa inqubo yeDSM. Izindlela zokufakwa nazo zidinga ukuthi babe nesihlobo sokuqala esasiyisidakwa. Izihloko zazingafakwanga uma zinomlando wokusebenzisa kabi izidakamizwa noma umlutha (ngaphandle kotshwala ne-nicotine). Izindlela zokukhishwa zazihlanganisa nomlando wezifo zengqondo (ngaphandle kokuncika kotshwala) noma isifo semizwa, izimo zezokwelapha ezingashintsha ukusebenza kwe-cerebral (okungukuthi, izifo zenhliziyo, i-endocrinological, i-oncological, noma izifo ezizimele), ukusetshenziswa kwamanje kwemithi enqunyiwe noma ethengiswayo , kanye / noma ukuhlukumezeka ekhanda ngokulahlekelwa ukwazi kwe> 30 min. Zonke izifundo zazinokukhathazeka ngoHamilton (IHamilton, 1959) nokucindezeleka kukaHamilton (IHamilton, 1960) amaphuzu <19 futhi bekufanele ayeke ukuphuza utshwala okungenani ama-30 d ngaphambi kocwaningo. Kuqashwe izilawuli ezivela ezikhangisweni emaphephandabeni endawo; Izindlela zokubekwa eceleni ngaphandle kwesibonelelo sokuncika kotshwala noma ukuhlukunyezwa zazifana nezezifundo ezinotshwala. Ngaphezu kwalokho, izifundo ezilawulwayo zazingafakwanga uma zinomlando womndeni wotshwala. Zonke izifundo zazihlolwa ngokomzimba, ngokwengqondo nangokwezinzwa. Izikrini zezidakamizwa zenziwa ngezinsuku zezifundo ze-PET ukukhipha ukusetshenziswa kwezidakamizwa ezithinta ingqondo. Izihloko zayalwa ukuba ziyeke noma yimiphi imishanguzo ezithengiswa ekhawunteni emasontweni ama-2 ngaphambi kokuthwetshulwa kwe-PET, futhi izilawuli zayalwa ukuthi ziyeke ukuphuza utshwala evikini elandulela ukuskena kwe-PET. Ukudla neziphuzo (ngaphandle kwamanzi) kuyekiswe okungenani i-4 h ngaphambili futhi osikilidi banqanyulwa okungenani i-2 h ngaphambi kocwaningo. Lolu cwaningo luvunyiwe yiBhodi Yezokubuyekeza Isikhungo eBrookhaven National Laboratory, futhi imvume ebhaliwe enolwazi yatholakala kuzo zonke izifundo.

Ithebula 1. 

Izici zobuntu nezomtholampilo zokulawula nezifundo zotshwala

Izinyathelo zokuziphatha nezenhliziyo.

Izilinganiso ezi-Subjective (1-10) zemiphumela yezidakamizwa zabhalwa ngaphambi nangemizuzu ye-27 ngemuva kokulawulwa kwe-placebo noma i-MP (U-Wang et al., I-1997). Le mibiko yokuzazisa ngemiphumela yezidakamizwa ikhonjiswe ukuthi ithembekile futhi ayishintshi ezifundweni zonke (UFischman noFoltin, 1991). Izinga lokushaya kwenhliziyo kanye nomfutho wegazi kwaqashwa ngaphambili nangezikhathi ezithile emva kokuphathwa kwe-placebo noma MP.

Skena.

Izifundo ze-PET zenziwa nge-Nokia (Iselin, NJ) HR + tomograph (isixazululo, i-4.5 × 4.5 × 4.5 mm egcwele isigamu sobukhulu) ngobukhulu obunemikhawulo emithathu. Zonke izifundo zigcwalise ukuskena okubili kwenziwe [11I-C] i-raclopride, kanye ne-19 yezilawuli kanye ne-19 yezidakwa yaqeda iskena sesithathu esenziwe nge-FDG. Iskena siqediwe esikhathini se-2 d, futhi i-oda lahlelwa ngokungahleliwe. Izindlela zishicilelwe i- [11C] i-raclopride (I-Volkow et al., 1993a) naku-FDGU-Wang et al., I-1993). Okwe [11I-C] i-raclopride scans, esinye sezikali ezimbili senziwa ngemuva kwe-placebo engene (i-3 cc ye-saline), kanti enye yenziwa ngemuva kwe-MP envenvenous MP (0.5 mg / kg), enikezwe i-1 min ngaphambili [11C] umjovo we-raclopride. Ucwaningo lwaluwumklamo we-crossover ongaboni. Ukuskena okunamandla kwaqalwa ngokushesha ngemuva kokujova kwe-4-10 mCi ye [11I-C] i-raclopride (umsebenzi othile, i-0.5-1.5 Ci / μm ekugcineni kokuqhuma kwamabhomu) futhi yatholakala ngenani lama-54 amaminithi. Igazi le-Arterial latholakala kuyo yonke inqubo ukulinganisa ukuqoqwa kokungashintshi [11C] i-raclopride ku-plasma njengoba kuchaziwe ngaphambili (I-Volkow et al., 1993a). Ku-FDG, izinyathelo zenziwa ezimweni eziyisisekelo (akukho ukugqugquzela), futhi ukuskena kokukhishwa okungu-20 min kwaqalwa ngemizuzu engama-35 ngemuva kokujova kwe-4-6 mCi ye-FDG, futhi kwasetshenziswa igazi lokulinganisa ukukala i-FDG nge-plasma. Ngesikhathi sokuthatha, izifundo bezihlala endaweni ephakeme amehlo abo evulekile egumbini elimnyama, futhi umsindo ubugcinwa ubuncane. Amanani we-Metabolic abalwa kusetshenziswa isandiso semodeli kaSokoloff (I-Phelps et al., 1979).

Ukuhlaziywa kwesithombe.

Okwe [11Izithombe ze-C] raclopride, izifunda zentshisekelo (i-ROI) zitholwe ngqo kusuka ku- [11C] ubuhlanga izithombe njengoba zichaziwe phambilini (I-Volkow et al., 1994a). Kafushane, sikhethe i-ROI ezithombeni ezifingqiwe (izithombe ezinamandla ezithathwe ku-10 zaya kuma-54 amaminithi) ezaziphindwaphindwa zadonswa ngendiza yokuxhumana lapho sakhetha khona izifunda ku-caudate (CDT), putamen (PUT), i-ventral striatum (VS), ne-cerebellum . Lezi zifunda zabe sezicatshangelwa kusikali esinamandla sokuthola ukugxila kwesikhathi se-C-11 esiphikisana nesikhathi, esasisetshenziselwa ukubala K1 (ukuthutha njalo kusuka ku-plasma kuye kwezicubu) nevolumu yokusabalalisa (i-DV), ehambelana nesilinganiso sokulingana kwesilinganiso sokuxineka kwezicubu kokuhlushwa kwe-plasma ku-CDT, i-PUT, kanye ne-VS isebenzisa inqubo yokuhlaziya enemidwebo yezinhlelo eziguqukayo (Logan et al., 1990). Isilinganiso se-DV ku-striatum kuya ku-cerebellum, ehambelana Bmax'A /Kd′ + 1 (Kd′ No Bmax′ Ziyasebenza vivo ama-constants phambi kwe-endo native neurotransmitter and nonspecific binding), asetshenziswa njengokulinganisa kwe-D2/D3 ukutholakala kwe-receptor (Logan et al., 1990). Imiphumela ye-MP ku- [11I-C] i-raclopride binding inqunyelwe njengoshintsho lwamaphesenti ku Bmax'A /Kd′ Kusuka ku-placebo (okuhlukile okuthembekile).

Ngezithombe ze-metabolic, sikhiphe i-ROI sisebenzisa indlela yokufaka ezenzakalelayo njengoba kuchaziwe ngaphambili futhi kwenziwa isampula (i-1) izifunda ezibekwe kuqala [i-orbitofrontal cortex (OFC), i-cingulate gyrus (CG), i-dorsolateral prefrontal] balawula ukukhishwa kwe-DA; (I-2) izifunda zamazwe athinta ezomnotho (i-CDT, i-PUT, i-VS), ngoba lokhu kuyizisulu eziphambili zamaphethelo we-DA; (3) izifunda ze-limbic (amygdala, hippocampus, insula), ngoba futhi ziyizisulu zezindawo ze-DA; kanye (ne-4) ye-thalamic, temporal, parietal, occipital, ne-cerebellar, esaziphatha njengezindawo zokulawula (I-Volkow et al., I-2006). Kafushane nje, siqale sabeka imephu yezithombe ze-metabolic ku-MNI (Montreal Neurological Institute) isikhala esijwayelekile sobuchopho ukuqeda ukwehluka kobuchopho bomuntu ngamunye. Ukwenza izibalo ze-ROI, sikhiqize imephu ebimboza wonke ama-voxels ahambisanayo wesifunda esinikeziwe ngokulandela izixhumanisi kwisoftware yeTalairach Daemon (I-Collins et al., I-1995; ILancaster et al., 2000) esithombeni se-FDG PET.

Ukuhlaziywa kwesitatimende.

Imiphumela ye-MP ku- K1 naku-D2/D3 ukutholakala kwe-receptor (Bmax'A /KdI-′) nomehluko phakathi kwamaqembu asisekelo kanye nokuphendula kwePhalamende kuhlolwe ne-ANOVA ngento eyodwa ephakathi nesihloko (control vs alcoholics) kanye ne-factor eyodwa engafundeki (placebo vs MP). Thumela hoc t Kusetshenziswe izivivinyo ukuthola ukuthi yimiphi imibandela ehlukile. Ukuhlola ubudlelwane phakathi kwezinguquko ezenzelwe i-MP Bmax'A /KdI-′ (ukuxhomekeka okuthembekile) ku-CDT, i-PUT, ne-VS kanye ne-metabolism yobuchopho besifunda, senze ukucubungula kokuhlangana komkhiqizo wePearson ngezinyathelo ze-metabolic. Ukuhlola ama-hypotheses amathathu amakhulu ocwaningo (i-1) elawula kepha hhayi kuma-alcoholic metabolism ezifundeni zokuqala [CG, OFC, kanye ne-dorsolateral pre kwangaphambilial cortex (DLPFC)] kuzohlotshaniswa nezinguquko ezibangelwe yilungu le-MP Bmax'A /Kd′ (Okuguqukayo okuthembekile), (2) lelo MP elengele ushintsho kuyo Bmax'A /KdI-′ ibe ​​incane kunotshwala kunokulawula, kanye (3) eshintshela ku Bmax'A /KdI-′ ku-VS ingahlotshaniswa nemiphumela ezuzisayo ye-MP bese izilinganiso zokuthi "ukuthanda izidakamizwa" ne "ephezulu" zizobe ziphansi kakhulu kwizidakwa kunokulawula, sibeka izinga lokubaluleka kokuthi p <0.05. Ukuhlaziywa kokuhlola ukuhlola ukuhlangana phakathi kwezinguquko ku- Bmax'A /KdI-′ (ukuxhomekeka okuthembekile) kanye nemetabolism kuma-11 ROIs angachazwanga, sibeka ukubaluleka e- p <0.005. Ukuqinisekisa ukuthi ukuhlangana kukhombisa umsebenzi wesifunda kunokwenza umsebenzi we-metabolic ngokuphelele, siphinde sahlola ukuhlangana kuzindlela ezijwayelekile zesimo semethabolikhi (imetabolism yesifunda / umzimba ophelele wobuchopho). Ukungafani kokuhlangana phakathi kwamaqembu kuhlolwe kusetshenziswa ukuhlolwa okuphelele kokuqondana kokuhlehliswa.

Ngoba ezifundweni ezedlule sibone ukuhlangana phakathi kwezinyathelo eziyisisekelo ze-D2/D3 ukutholakala kwe-receptor kanye nemetabolism yokuqala ye-cocaine ne-methamphetamine abahlukumezi (I-Volkow et al., 1993b, 2001), siphinde sahlola lokhu kuhlangana ukuthola ukuthi inhlangano efanayo yenzeka ezifundweni zotshwala (ukubaluleka kwakuhlelwe p <0.05).

Imiphumela

Ukugxila kwe-Plasma kuka-MP

Ukugxila kwe-Plasma (kuma-nanograms nge millimeter) bekungafani phakathi kwezilawuli kanye nezifundo zotshwala ku-10 min (116 ± 26 vs 107 ± 16, ngokulandelana), i-30 min (85 ± 25 vs 76 ± 12), noma i-45 (65 ( vs 15 ± 59). Ukugxila kwe-MP ye-plasma akuzange kuhambisane nezinguquko ezenziwe nge-MP Bmax'A /Kd′.

Izimpendulo zokuziphatha ku-MP

Kuwo womabili amaqembu, MP kakhulu (p <0.005) kukhuphuke izikolo ekuzibikeni kwakho kokuzizwa ngezidakamizwa, ukuphakama, ukungahlaliseki, ukukhuthazwa, ukusebenzisa izidakamizwa, ukuthanda izidakamizwa, ukungathandi izidakamizwa, isifiso sotshwala, nesifiso sikagwayi (Ithebula 2). Umphumela wokuxhumana wawubalulekile emibikweni eminingi yokuzazisa yemiphumela yezidakamizwa (ngaphandle kokungabi namandla nokufuna utshwala)Ithebula 2). Thumela hoc t izivivinyo ziveze ukuthi imiphumela ye-MP yayinkulu kakhulu ezilawulweni kuneziphuzo zotshwala eziphezulu (p <0.003), kukhuthaziwe (p <0.003), zizwe isidakamizwa (p <0.004), izidakamizwa ezinhle (p <0.04), nokuthanda izidakamizwa (p <0.04) futhi babedlula kakhulu ezidakweni zesifiso sogwayi (p <0.002) nokungathandi izidakamizwa (p <0.05).

Ithebula 2. 

Imiphumela yokuziphatha ngenxa ye-MP eyangena ngaphakathi kuzilawuli nasezifundweni zotshwala futhi F amanani we-etiology ephindaphindwayo ye-elementorial yeqembu, izidakamizwa, nemiphumela yokusebenzisana

I-MP ikhuphule izinga lokushaya kwenhliziyo kanye ne-systolic ne-diastolic blood pressure, futhi le miphumela ibingafani phakathi kwamaqembu (idatha engakhonjisiwe).

Izinyathelo ze-DA D2/D3 ukutholakala kwe-receptor endaweni eyisisekelo (i-placebo)

Ngokwesisekelo, bekungekho mehluko phakathi K1 phakathi kwamaqembu ku-cerebellum, CDT, PUT, noma i-VS (Ithebula 3). Ngokuphambene, D2/D3 ukutholakala kwe-receptor (Bmax'A /Kd′) Kubonise umphumela obalulekile weqembu ku-VS (p <0.007) kepha akukho mehluko ku-CDT naku-PUT. Thumela hoc t ukuhlolwa kukhombisile ukuthi i-VS D2/D3 ukutholakala kwe-receptor kwakuphansi kakhulu kwiziphuzo ezinotshwala (p <0.05) (Ithebula 3).

Ithebula 3. 

Izinyathelo ze K1 futhi Bmax'A /Kd' Okwe [11C] ubuhlanga izithombe zezilawuli kanye nezihloko zotshwala ze-placebo (PL) nezimo ze-MP, kanye p amanani emiphumela ye-ANOVA yeqembu, izidakamizwa, nemiphumela yokusebenzisana

Izinyathelo ze-DA D2/D3 ukutholakala kwe-receptor ngemuva kwe-MP (DA changes)

I-ANOVA ku- K1 izinyathelo ziveze ukuthi awukho umuthi noma imiphumela yokuxhumana ebaluleke kakhulu kwi-CDT, PUT, VS, noma i-cerebellum, okukhombisa ukuthi iLungu lePhalamende alishintshanga ukulethwa kwama-radiotracer nokuthi akukho mehluko phakathi kwamaqembu (Ithebula 3).

ILungu le-MP lehlile Bmax'A /Kd'A, ne-ANOVA iveze umphumela omkhulu wezidakamizwa ku-CDT (F = 19; p <0.001), PUT (F = 54; p <0.0001), kanye ne-VS (F = 41; p <0.001), okukhombisa lokho Bmax'A /KdU-′ wehliswe kakhulu yi-MP kuwo womabili amaqembu (bona I-Fig. 2, Ithebula 3). Umphumela wokuxhumana wawubalulekile ku-PUT (F = 5.5; p <0.03) ne-VS (F = 13; p <0.001), okukhombisa ukuthi izimpendulo kulezi zifunda zehlukile phakathi kwamaqembu. I- iposi hoc t isivivinyo siveze ukuthi ukuncipha nge-MP bekukuncane kakhulu kunotshwala e-PUT (izilawuli, i-21% vs izidakwa, i-11%; p <0.03) ne-VS (izilawuli, i-27% vs izidakwa, 8%; p <0.002) (I-Fig. 1, Ithebula 3).

Umfanekiso we-1. 

Isilinganiso sezithombe ze-DV ratio (DVR) ze- [11C] i-raclopride yezilawuli (n = 20) nezidakwa (n = 20) ezingeni le-striatum ngemuva kwe-placebo nangemva kwe-MP. Qaphela ukwehla kokubopha okuthile (i-DV ratios) nge-MP kanye nempendulo etholwayo ye-MP ezifundweni zotshwala uma kuqhathaniswa nezilawuli.

Ukuhlola ukuthi izinguquko ezincane zingena yini ngaphakathi Bmax'A /KdI-′ (PUT ne-VS) kwizidakwa kunakwizilawuli zibonisa inani labo ababhemayo, siqhathanisa ababhemayo kusukela kwabangabhemi ngokwehlukana kweqembu ngalinye futhi sakhombisa okulandelayo: (1) abalawuli ababhemayo (n = 3) baba nezinguquko ezifanayo kunalezo ezazingenayo (n = 17) e-PUT (20 vs 21%, ngokulandelana) kanye ne-VS (35 vs 26%, ngokulandelana); kanye (2) notshwala obabhemayo (n = 16) baba nezinguquko ezifanayo kunalezo ezazingenayo (n = 4) ku-PUT (11 vs 12%, ngokulandelana) kanye ne-VS (8 vs 6%, ngokulandelana).

Yize amasampula emincane kakhulu ukuthi aveze imiphumela ephelele, akukho kulokhu kulinganiswa kwaba khona ushintsho ku Bmax'A /Kd′ Incinci kubabhemi, okusikisela ukuthi izinguquko ezincane ezidakwayo azibangelwa nje ukubhema.

I-Regional brain glucose metabolism kanye nokuhlangana kwezinguquko ezenziwa yi-MP Bmax'A /Kd′ Kanye nezinyathelo eziyisisekelo ze-D2 ukutholakala kwe-receptor

Noma ubuchopho obugcwele (izilawuli, i-36.4 ± 4 μmol / 100 g / min; izidakwa, i-35.0 ± 4 μmol / 100 g / min) noma i-metabolism yesifunda ihlukile phakathi kwamaqembu (idatha engakhonjisiwe).

Ezilawulweni, kufakwe izinguquko ku-MP Bmax'A /Kd'Ku-VS kwakuhlobene kabi ne-metabolism e-OFC [endaweni kaBrodmann (BA) 11: r = 0.62, p <0.006; BA 47: r = 0.60, p <0.008], i-DLPFC (BA 9: r = 0.59, p <0.01), CG (BA 32: r = 0.50 p <0.04; BA 24: r = 0.52, p <0.03), kanye ne-insula (r = 0.63; p <0.005). (I-Fig. 2). Bmax'A /KdIzinguquko ze-′ ku-CDT ne-PUT zazixhunyaniswa kuphela nokusebenza kwe-metabolism ku-CG (r > 0.51; p <0.03). Kwizidakwa, ukuhlobana phakathi kwezinguquko ezenziwe yi-MP ku- Bmax'A /KdI-′ kanye ne-metabolism yesifunda bekungeyona ebalulekile (I-Fig. 2). Ukuqhathaniswa kwemithambeka yokuqondisa phakathi kwamaqembu kuveze ukuthi ukuhlangana kuhluke kakhulu e-OFC (z = 2.3; p <0.05), i-DLPFC (z = 2.2; p <0.05), CG (z = 2.2; p <0.05), kanye ne-insula (z = 2.6; p <0.01).

Umfanekiso we-2. 

Ukucindezela kwemithambeka phakathi kokushintsha kwamaphesenti ku Bmax'A /KdI-′ (ukuxhomekeka okuthembekile) ku-VS nomsebenzi we-metabolic metabolic ophelele we-OFC (BA 11), i-anterior CG (BA 32), ne-DLPFC (BA 9) ezilawulweni (imibuthano egcwele) nakuma-alcoholic (imibuthano evulekile). Yazi ukuthi iphesenti liyancipha ekubophweni okuthile kwe- [11C] i-raclopride (Bmax'A /Kd′) Bonisa ukwanda kwe-DA okuhlobene, futhi ngakho-ke ukubuyisa kudlulisela ukuhlangana okungalungile: the low the metabolism, the more the DA kuongezeka.

Ukuhlobana ngezindlela ezijwayelekile ze-metabolic (isifunda / umzimba wonke wobuchopho) bekubalulekile ushintsho phakathi Bmax'A /Kd′ Ku-VS ne-OFC (r = 0.62; p <0.006) kuzilawuli kepha hhayi kwizidakwa (I-Fig. 3). Lokhu kuhlangana kuhluke kakhulu phakathi kwamaqembu (z = 2.1; p <0.05).

Ukuxhumeka okuyisisekelo Bmax'A /Kd′ (D2 ukutholakala kwe-receptor) kanye nokudla kwesifunda kwakubalulekile kuma-alcoholic kodwa hhayi izilawuli ku-CG (CDT: r = 0.57, p <0.02; BEKA: r = 0.59, p <0.01; VS: r = 0.57, p <0.02) ne-DLPFC (CDT: r = 0.52, p <0.03; BEKA: r = 0.52, p <0.03; VS: r = 0.50, p <0.03).

Ukuvumelana phakathi kwezinguquko ezibangelwe yilungu le-MP Bmax'A /Kd′ Nemiphumela yayo yokuziphatha kanye nemilando yokuphuza nokubhema

Izinguquko ku Bmax'A /Kd′ Ku-VS exhunyaniswe nephezulu (r = 0.40; p <0.01), izidakamizwa ezinhle (r = 0.33; p <0.05), ujabule (r = 0.33; p <0.05), ukungahlaliseki (r = 0.38; p <0.02), futhi kukhuthaziwe (r = 0.45; p <0.005); ku-PUT nge high (r = 0.32; p <0.05), izidakamizwa ezinhle (r = 0.34; p <0.05), futhi kukhuthaziwe (r = 0.46; p <0.005); naku-CDT okuvuselelwe (r = 0.32; p <0.05).

Umfanekiso we-3. 

Ukucindezela kwemithambeka phakathi kokushintsha kwamaphesenti ku Bmax'A /KdI-′ (ukuxhomekeka okuthembekile) ku-VS nomsebenzi we-metabolic ofanayo ku-OFC (ubuchopho bonke) kulawulo (imibuthano egcwalisiwe) nakwezidakwa (imibuthano evulekile).

Akukho mlando wotshwala noma wokubhema ohambisana noshintsho ku Bmax'A /Kd′ Lapho kufakwe bonke abadakwa. Kodwa-ke, lapho kuhlaziywa kuphela izidakwa eziwubhemayo, bekukhona ukuvumelana okukhulu phakathi kwezinguquko phakathi Bmax'A /Kd′ Kanye neminyaka yokubhema (PUT: r = 0.73, p <0.002) kanye nobudala ekuqalisweni kokubhema (PUT: r = 0.63, p <0.009; VS: r = 0.53, p <0.05).

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Ukulawulwa okungaphambili kokushintshwa yi-MP okuvuswe yi-MP kulawulo kodwa hhayi kubadakwayo

Ezilawulweni, sibonisa ubudlelwane obubi phakathi komsebenzi ophelele we-metabolic ezifundeni zangaphambili (OFC, CG, DLPFC) kanye nezinguquko ezenziwe nge-MP Bmax'A /Kd′ (Ukulinganisa kwezinguquko ze-DA) ku-VS ne-PUT. Ngaphezu kwalokho, lokhu kuhlangana kuhlala ku-OFC ngemuva kokujwayelekile ukuthi kube nomsebenzi we-metabolic womzimba wonke okhombisa ukuthi, okungenani e-OFC, icacisiwe esifundeni esithile. Lokhu okutholakele kuyahambisana nezifundo zokuhlola ukulawulwa kwangaphambili kwamaseli e-DA eVTA kanye nokukhishwa kwe-DA e-NAc (UGariano noGroves, 1988; UMurase et al., 1993).

Ngokuphikisana nabadakwa, i-metabolism ezifundeni zangaphambili ayizange ihambisane nezinguquko ze-DA (njengoba kuhlolwe izinguquko ku Bmax'A /Kd′). Lokhu kuphakamisa ukuthi ezidakweni zotshwala, ukulawulwa kwemisebenzi yeseli ye-DA okwenziwa ngaphambi kokuphazamiseka kuyaphazamiseka nokuthi ukusebenza kwabo okunciphile kweseli le-DA kungabonisa ukulahleka kokulawulwa kwangaphambili kwemigwaqo ye-mesolimbic ye-DA. Okunye okokufaka okusemqoka kumaseli e-DA eVTA wukugcotshwa kwe-glutamatergic kusuka ku-cortex yokuqala (UCarr noSesack, i-2000), futhi kunobufakazi obukhulayo bokuthi badlala indima ebalulekile ekuluthweni (Kalivas noVolkow, i-2005). Ucwaningo lwe-preclinical luphinde futhi lwabonisa ukuthi umthelela we-cortex yangaphambi kokulawulwa kokuziphatha uyancipha ngokuphathwa kwezidakamizwa okungapheli okunomthelela ekulahlekelweni kokulawulwa kokulutha.I-Homayoun neMoghaddam, i-2006). Ngaphezu kwalokho, ukuphazamiseka kwe-OFC (isifunda esifaka phakathi ukuthambekela kokuqina, ukuphazamiseka okuhambisana nokuziphatha okuphoqelelayo) kanye ne-CG (indawo ethinteka nokulawulwa kokuvinjezelwa, ukuphazamiseka okuhambisana nokuphoqelela) kubhekwa njengokuphakathi kwenqubo yokulutha (I-Volkow et al., I-2003).

Ukuhlaziya okwenziwe ngokuhlolisisa kuveze ukuthi kulawulo, izinguquko ze-DA ku-VS nazo zahlotshaniswa nokudla okwenziwe emzimbeni. I-insula ingesinye sezifunda ezinamandla amakhulu ngokufakwa kwe-DA kwaba densest (I-Gaspar et al., 1989), futhi ucwaningo lwakamuva olubika ukuthi ukulimala kokufakelwa kwesokudla luhlotshaniswe nokuyeka ukubhema okungazelelwe kugcizelela ukubaluleka kokuluthwa kwalo (Naqvi et al., 2007).

Kwehliswe ukukhishwa kwe-DA ezifundweni zotshwala

Ezidakweni ezinamandla, i-MP ilinganise ukunyuka okuncane kwe-DA ku-VS ne-PUT kunakulawulo. I-MP iyivimba le-DAT, futhi ezingeni elithile le-DAT blockade, izinguquko ze-DA zibonisa inani le-DA elizenzakalelayo elikhishwe (I-Volkow et al., I-1999). Ngoba ukuhlushwa kwe-MP ku-plasma, obekungafani phakathi kwamaqembu, kubikezela amazinga we-blockade ye-DAT (I-Volkow et al., I-1998, 1999), impendulo engenaphutha ku-MP iphakamisa ukuthi izidakwa zinokukhishwa okuncane kwe-DA kunokulawula. Ukuncishiswa kwakumenyezelwe kakhulu ku-VS (70% ephansi kunezilawuli), elawula ukutholwa kwangaphambilini kokunyuka kwe-DA kwe-VS ngemuva kwe-amphetamine kuma-alcoholic (i-50% ephansi kunokulawula) (U-Martinez et al., 2005). Lokhu okutholakele kubuye kuvumelane nezifundo zangaphambi kokukhombisa ukuncipha okukhulu kokudutshulwa kwamaselula e-DA (UDiana et al., 1993; Bailey et al., 1998; I-Shen et al., I-2007) ku-VTA futhi kwehlise i-DA ku-NAc (Weiss et al., 1996) ngemuva kokuhoxa kotshwala obungamahlalakhona. Ukuhlehliswa kabusha kwendlela ye-DA Vta-eqoqana notshwala kungababeka engcupheni yokuphuza utshwala obuningi ukukhokhela lokhu kusilela. Impela, ukuphathwa kotshwala obukhulu kubuyisela umsebenzi wamaseli we-VTA DA ezilwaneni eziphathwe kabi notshwala (UDiana et al., 1996; Weiss et al., 1996).

I-Alcoholics ibuye ikhombise ukwanda kwe-MP-eyengezwe yi-MP eyenziwe nge-PUT (i-47% ephansi kunakulawulo). Lokhu kungenzeka kukhombise ukubandakanyeka kwamaseli we-DA kuma -antianti nigra, athembela ku-PUT futhi athinteka ekuziphatheni kwezimoto. Ukushoda kwe-DA e-PUT kungachaza ubungozi obukhulu bezimpawu zezimoto eziphuma e-extrapyramidal kwizidakwa.Shen, 1984).

Izifundo zangaphambilini zabahlukumezi be-cocaine futhi zibhale ukwehliswa okukhulu ekunyuseni kwe-DA okwenziwe yi-MP (i-50% ephansi kunezilawuli) (I-Volkow et al., I-1997), okuphakamisa ukuthi ukuncishiswa kwemisebenzi yeseli ye-DA kungabonisa ubuqili obujwayelekile ekuluthweni komlutha.

Yehlisa izimpendulo eziqinisa i-MP entravenous in izidakwa

Izimpendulo ezizuzisayo ze-MP ezilungiselelwe izidakwa bezingaphansi kunezilawuli. Iqiniso lokuthi le miphumela engafani ye-MP yayihlotshaniswa nokwenyuka kwe-DA ku-VS ibonisa ukuthi izimpendulo eziqinisayo ezenziwe ngePhalamende zibonisa ukunciphisa umsebenzi weseli we-VTA DA. Kuze kufinyelela lapho amaseli we-VTA DA, ngokwengxenye yakhe ebekwa khona kwi-NAc, ebamba iqhaza ekuguquleni izimpendulo eziqinisayo zokuqiniswa kwezidakamizwa okwehlile kuncishiswe ukusebenza kweseli ye-DA kungazwela ukuncipha kokuthola imivuzo engalotshwa nakotshwala (Sula et al., 2007).

I-Alcohol / i-nicotine comorbidity

Ezifundweni ezinotshwala ezazibhema, ushintsho olwenziwe yi-MP olwaluhambisana nemibhalo yabo lwaluhambelana nemilando yabo yokubhema. Le nhlangano ingakhombisa impendulo ejwayelekile yotshwala nogwayi ngoba i-nicotine engamahlalakhona iyancipha nokusebenza okuzenzakalelayo kwamaseli we-VTA DA (ULiu noJin, 2004). Kodwa-ke, ngenxa yokuthi izinguquko ze-DA bezingafani phakathi kwababhemayo nabangabhemi noma ababhemayo, akunakwenzeka ukuthi ukwehliswa kwe-DA kubangelwe ukubhema kodwa kungakhombisa ubungozi obujwayelekile (Iqiniso et al., 1999; I-Bierut et al., 2004; I-et et., 2006).

Isisekelo DA D2/D3 izinyathelo ze-receptor

Isisekelo DA D2/D3 ukutholakala kwe-receptor kwakuphansi kunotshwala kunakulawulo lwe-VS, elawula ukucabanga kwangaphambilini (U-Heinz et al., 2004; I-Shen et al., I-2007) kanye ne-postmortem (I-Tupala et al., 2001, 2003) izifundo.

Isisekelo D2/D3 ukutholakala kwe-receptor kuma-alcoholic (kodwa hhayi kwizilawuli) kuhlotshaniswa ne-metabolism ku-CG kanye ne-DLPFC. Lokhu kuyahambisana nokutholakele kwangaphambilini ku-cocaine nakwabahlukumezi be-methamphetamine kanye nasezifundweni ezisengozini enkulu yofuzo kubantu abaphuza utshwala esabika kuyo nobudlelwano phakathi kwesisekelo se-striatal D2/D3 ukutholakala kwe-receptor kanye nemetabolism yokuqala (I-Volkow et al., 1993b, 2001, 2006). Kodwa-ke, iqhathanisa nokuhlobana phakathi kokushintsha kokudla kwasekuqaleni kanye nezinguquko ze-MP-eyenziwe nge-MP, ezazibalulekile zokulawula kepha hhayi zabadakwayo. Lokhu kungakhombisa iqiniso lokuthi bahambelana nezindlela ezahlukahlukene ze-DA neurotransmission; izinguquko ku Bmax'A /Kd"Kubonisa ukukhishwa kwe-DA kusuka kuma-neurons e-DA, okuwumsebenzi wokudubula kwamaseli we-DA futhi kulungiswa ngumsebenzi wangaphambili, kanti u-D2/D3 ukutholakala kwe-receptor kukhombisa kakhulu amazinga we-receptor acatshangelwa ukuthi ahlelwa yizakhi zofuzo neze-epigenetic kodwa, olwazini lwethu, hhayi ngomsebenzi wangaphambilini. Ngakho-ke, ubudlelwano phakathi kwesisekelo D2/D3 ama-receptors kungenzeka abonise ukuguqulwa kwe-dopaminergic kwezifunda zangaphambi kwecortical cortical (I-Oades ne-Halliday, i- 1987). Ngempela, kotshwala, ukuncipha kokutholakala kwe-D2R ku-VS kuboniswe ukuthi kuhlobene nobunzima bokunxanelwa utshwala kanye nokuqalwa okugxilwe kakhulu kwe-cueex ye-medial prefrontal cortex ne-anterior CG njengoba kuhlolwe nge-imaging resonance imaging esebenzayoU-Heinz et al., 2004).

Isisekelo metabolism weglucose yesifunda

Kulolu cwaningo, asikhombisanga ukungezwani komqondo we-glucose metabolism (kufaka phakathi i-cortex yangaphambili) phakathi kwezilawuli nezidakwa. Lokhu kwehluka ocwaningweni lwangaphambilini, olukhombise ukwehliswa kwamandla we-metabolic yangaphambi kotshwala (ngokubukeza, bheka U-Wang et al., I-1998). Kodwa-ke, ngoba ukuncipha kokusebenza kwengqondo kubuyiseleka kakhulu phakathi kwamaviki we-2-4 we-detoxation (ikakhulukazi ku-cortex yangaphambili)I-Volkow et al., 1994b), ukwehluleka ukubona ukuncipha kwezifundo zethu kungakhombisa iqiniso lokuthi babehoxise utshwala okungenani i-30 d ngaphambi kocwaningo.

Ukulinganiselwa

Okokuqala, ngoba [18I-F] FDG, inempilo nengxenye ye-120 min, bekungenakwenzeka ukwenza i- [11Izinyathelo ze-C] ze-raclopride ngosuku olufanayo (i-10 h ziyadingeka phakathi kwemijovo). Kodwa-ke, ngenxa yokuthi izindlela zesisekelo se-metabolic metabolic kanye nezinyathelo zokushintshwa kwe-MP okwenziwe nge-MP kuzinze uma izifundo zivivinywa ngezinsuku ezihlukile (U-Wang et al., 1999a,b), ukuxhumanisa kungenzeka kube okufanayo ukube bekungenzeka ukuthi ungazihlola ngosuku olufanayo.

Okwesibili, ukuxhumeka nge-CG, i-DLPFC, nokufakelwa kwempahla kwakungeyona into ebaluleke kakhulu lapho umsebenzi uthathwa njengowokujwayelekile kumqondo ophelele wobuchopho, ngakho-ke kulezi zifunda, izinhlangano kufanele zithathwe njengezandulela. Futhi, ukuxhumanisa akusho ukuthi izinhlangano ezibandayo futhi azidluliseli ukuqondisa futhi ngakho-ke angeke sikhiphe isinqumo sokuthi usoseshini kunokuba kubonise ukulawulwa kokukhishwa kwe-DA kuqala kukhombisa ukuguqulwa kwe-DA kwezifunda zangaphambili.

Okwesithathu, kuncishisiwe kwesisekelo D2/D3 ukutholakala kwe-receptor uma kulinganiswa ne- [11I-C] i-raclopride ingabonisa amazinga aphansi we-receptor noma ukukhuphuka kwe-DA (UGjedde et al. I-2005). Kodwa-ke iqiniso lokuthi izidakwa, uma zinikezwe iLungu lePhalamende, zikhombise ukukhishwa kwe-DA kukhombisa ukuthi izindlela ezisezingeni eliphansi zika-D2/D3 ukutholakala kwe-receptor kuma-alcoholics, njengoba ngaphambili kwabikwa ngocwaningo lwe-postmortem (I-Tupala et al., 2003), amazinga aphansi we-D2 receptors.

Ekugcineni ukubhema kuyindida, kepha ngoba i-∼90% yabhema yotshwala (Batel et al., 1995), okutholakele kuhambelana nomtholampilo kuningi labadakwa.

Isiphetho

Le miphumela ihambisana nomqondo wokulahleka kokuguqulwa kokuqala komsebenzi we-DA kumaseli otshwala kanye nokwehla okukhulu komsebenzi we-DA kulezi zifundo. Ubudlelwano phakathi kokukhuphuka kwe-DA e-VS kanye nezimpendulo ezibucayi zomvuzo ku-MP buveza ukuthi ukuhlukunyezwa kwe-DA kungabhebhethekisa i-anhedonia ehlangabezana nabadakwa futhi kungafaka engcupheni yabo engcupheni yokusebenzisa kabi utshwala njengendlela yokubuyisa lokhu kusilela. Lokhu okutholakele kusikisela ukuthi ukungenelela ukubuyisa umthetho ongaphambili kanye nokushoda kwe-DA kungazuzisa ngokwelashwa kubadakwa.

Imibhalo yaphansi

  • Yamukelwe ngoJulayi 25, 2007.
  • Ukubuyekezwa kutholwe ngo-Okthoba 2, 2007.
  • Yamukelwe ngo-Okthoba 2, 2007.

  • Lo msebenzi wesekwa ngokwengxenye yohlelo lwe-Intramural Research Programme lweNational Institutes of Health-National Institute on Alcoholism and Alcohol Abuse, nguMnyango Wezamandla (Ihhovisi Lokucwaninga Ngezemvelo kanye Nezemvelo, inkontileka ye-DE-AC01-76CH00016), kanye neNational National Isikhungo se-Mental Health Grant MH66961-02. Sibonga uDonald Warner ngokusebenza kwePET; UDavid Schlyer noMichael Schueller bokusebenza kwe-cyclotron; UDavid Alexoff noPaul Vaska ngokulawulwa kwekhwalithi kwezinyathelo ze-PET; UColleen Shea, uLisa Muench, no-Youwen Xu ngokuqanjwa kwe-radiotracer; Pauline Carter ekunakekelweni kwabahlengikazi; UKaren Apelskog wokusebenzisana kweprothokholi; noLinda Thomas ngosizo lokuhlela.

  • Ukuxhumana kufanele kubhekiswe kuDkt Nora D. Volkow, National Institute on Drug Abuse, 6001 Executive Boulevard, Igumbi 5274, Bethesda, MD 20892. [i-imeyili ivikelwe]

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