Ndemanga: Ndemanga iyi inapangidwa ndi mutu wa NIDA, Nora Volkow, ndi gulu lake. Zimakayikira kuti mankhwala osokoneza bongo komanso makhalidwe oipa amakhala ndi njira zofananamo kapena zowonongeka. Izi zimakhala zomveka chifukwa chizoloŵezi cha mankhwala osokoneza bongo chikuphwanyidwa ndi oyang'anira dera la neural kuti agwirizane, kugonana, ndi kudya. Popeza kugonana kumatulutsa dopamine mobwerezabwereza monga kudya zakudya zomwe mumazikonda, ndipo wogwiritsa ntchito zolaula angathe kusunga dopamine kwa maola ambiri, ndizowononga kuti kusokoneza bongo sikungakhaleko.
Behav Neurosci yapamwamba. 2011 Oct 21.
Volkow ND, Wang GJ, Fowler JS, Tomasi D, R. Baler
gwero
National Institute on Drug Abuse, 6001 Executive Boulevard 6001, Chipinda 5274, Bethesda, MD, 20892, USA, [email protected].
Kudalirika
Kumwa mankhwala osokoneza bongo ndi kunenepa kwambiri kungatanthauzidwe ngati matenda omwe phindu la mtundu umodzi wa mphotho (mankhwala ndi chakudya, motsatana) limakula kwambiri poyerekeza ndi ena. Chitsanzochi chikugwirizana ndi mfundo yakuti mankhwala ndi chakudya zonse zimakhala ndi mphamvu zolimbitsa thupi - zomwe zimayendetsedwa ndi kuwonjezeka kwa dopamine mu limbic system - zomwe, nthawi zina kapena mwa anthu omwe ali pachiwopsezo, zimatha kuwononga njira zowongolera ubongo. Kufanana kotereku kwapanga chidwi chachikulu pakumvetsetsa zofooka zomwe zimagawidwa komanso njira zomwe zimayambira pakati pa chizolowezi ndi kunenepa kwambiri. Tsopano, kupeza zithunzi za ubongo kwayamba kuvumbula zinthu zomwe zimafanana pakati pa mikhalidwe iwiriyi ndikuwonetsa zina mwa ma circuits a ubongo omwe kusowa kwa ntchito kwawo kungafotokoze zolakwika zamalingaliro ndi zokhudzana ndi khalidwe mwa anthu. Zotsatirazi zikusonyeza kuti anthu onenepa kwambiri komanso omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo amavutika ndi zovuta m'njira za dopaminergic zomwe zimawongolera machitidwe a neuronal omwe amagwirizanitsidwa osati ndi kukhudzidwa ndi mphotho komanso chilimbikitso, komanso ndi kuwongolera (kukumbukira/kuphunzira), kuwongolera kukhudzika (kuletsa khalidwe), kuchitapo kanthu pamavuto, komanso kuzindikira kwa malingaliro. Apa, tikuphatikiza zomwe zapezeka makamaka kuchokera ku positron emission tomography zomwe zimawunikira ntchito ya dopamine mu chizolowezi cha mankhwala osokoneza bongo komanso kunenepa kwambiri, ndikupereka njira yogwirira ntchito yatsopano kuti ithandize kuzindikira njira zochiritsira zomwe zingapindulitse matenda onsewa.
1 Mbiri Yachiyambi
2 Udindo wa Dopamine mu Mphotho Yoopsa ya Mankhwala ndi Chakudya
3 Kujambula DA Poyankha Mankhwala Osokoneza Bongo ndi Zizindikiro Zokhazikika mu Kuledzera
4 Zotsatira za Kulephera Kugwira Ntchito Pakuletsa Ku ...
5 Kutenga nawo mbali kwa Ma Circuits Olimbikitsa
6 Kutenga nawo mbali kwa Interceptive Circuitry
7 Kuzungulira kwa Chizolowezi
8 Mphotho ya Mankhwala ndi Chakudya Choyambitsa Matenda: Chitsanzo Chogwira Ntchito Chosinthidwa
1 Background
Dopamine (DA) imaonedwa kuti ndi chinsinsi cha zotsatira zabwino za mphotho zachilengedwe ndi mankhwala osokoneza bongo. Komabe, udindo wake pakutaya ulamuliro ndi machitidwe okakamiza omwe amagwirizanitsidwa ndi chizolowezi ndi kunenepa kwambiri sadziwika bwino. Maphunziro a PET achita gawo lofunika kwambiri pofotokoza udindo wa machitidwe a ubongo a DA mu chizolowezi (kuphatikiza udindo wake mu mphotho ya mankhwala osokoneza bongo) komanso kunenepa kwambiri. Zoonadi, mankhwala osokoneza bongo (kuphatikizapo mowa) amamwedwa ndi anthu kapena amaperekedwa ndi nyama za labotale chifukwa amapindula mwachibadwa, zomwe zimachitika kudzera mu mphamvu zawo zowonjezera DA mu mesolimbic system (Wise 2009 ). Komabe , pankhani ya chizolowezi, maphunziro ojambula zithunzi awonetsa kuti vutoli silikhudza kokha dera la mphotho ya DA komanso njira zina za DA zomwe zimakhudzidwa ndi kusintha kwa makhalidwe/zizolowezi, chilimbikitso, ndi ntchito zoyang'anira (kulamulira koletsa, kupereka mphamvu, ndi kupanga zisankho), ndipo kuti kusowa kwa DA kungatenge nawo gawo pakuwonjezera kupsinjika ndi kusokoneza kuzindikira kwa malingaliro okhudzana ndi chizolowezi. Kafukufuku wa preclinical ndi chipatala wavumbulanso ma neurotransmitters ena (ndi ma neuropeptides) omwe amagwira ntchito yofunika kwambiri pa mphotho ya mankhwala ndi kuledzera (monga, cannabinoids, opioids) ndipo amakhudzidwa kwambiri ndi kusintha kwa mitsempha komwe kumachitika pambuyo pogwiritsa ntchito mankhwala mobwerezabwereza (monga, glutamate, opioids, GABA, corticotropin-releasing factor). Dongosolo la glutamatergic ndilodziwika kwambiri pankhaniyi chifukwa limayambitsa kusokonezeka kwa mphamvu ya nthawi yayitali komanso kupsinjika kwa nthawi yayitali komwe kwawonedwa m'mitundu ya nyama yogwiritsira ntchito mankhwala nthawi yayitali (Thomas et al. 2008 ). Ndemanga zokhudzana ndi machitidwe ena owonjezerawa zitha kupezeka kwina (Kalivas 2009 ; Koob 1992 ).
Popeza mankhwala osokoneza bongo amayambitsa machitidwe omwewo a mphotho omwe amayambitsa mphotho ya chakudya, sizodabwitsa kuti, kawirikawiri, maphunziro ofufuza za ubongo athandizira lingaliro lakuti zolakwika m'magawo oyendetsedwa ndi DA zimakhudzidwanso ndi machitidwe olakwika a kudya . Zizindikiro za chakudya, monga zizindikiro za mankhwala osokoneza bongo, zimawonjezera DA yakunja kwa thupi ndikulimbikitsa chilimbikitso chochita machitidwe ofunikira kuti mupeze ndikudya chakudyacho, kupereka umboni wokhudza kutenga nawo mbali kwa DA osati pa mphotho ya chakudya chokha komanso pazinthu zolimbikitsa zopanda mphamvu za chakudya (mwachitsanzo, zofunikira zama caloric) komanso kuchepa kwa mphamvu zoletsa zomwe zimawonedwa mukudya mopitirira muyeso mopitirira muyeso (Avena et al. 2008 ; Volkow et al. 2008a ).
Pano, tikuwunikanso zomwe zapezeka kuchokera ku kafukufuku wokhudza zithunzi zomwe zimayang'ana kwambiri kuphatikizika kwa ma circuits a ubongo omwe amasokonezeka chifukwa cha kunenepa kwambiri komanso kugwiritsa ntchito mankhwala osokoneza bongo. Komabe, ndikofunikira kukumbukira kuti kuwongolera machitidwe a kudya ndi kovuta kwambiri kuposa kuwongolera kudya mankhwala osokoneza bongo. Chomalizachi chimayang'aniridwa makamaka ndi zotsatira zabwino za mankhwala osokoneza bongo pomwe choyambacho chimasinthidwa osati ndi zotsatira zake zabwino (hedonic factors) komanso ndi zinthu zingapo zamkati ndi zapakati zomwe zimazindikira zosowa za michere m'thupi zomwe zimafunikira kuti munthu akhale ndi moyo (homeostatic factors). Chosangalatsa ndichakuti, pali umboni wokulirapo wakuti zinthu za homeostatic (monga insulin, leptin, ghrelin) zimasinthasintha kudya chakudya pang'ono mwa kuwonjezera kapena kuchepetsa kukhudzidwa kwa ma circuits a mphotho ya ubongo ku zoyambitsa chakudya (Volkow et al. 2011a ).
2 Udindo wa Dopamine mu Mphoto Yambiri kwa Mankhwala Osokoneza Bongo ndi Zakudya
Kaya mwachindunji kapena mwanjira ina, mankhwala onse osokoneza bongo amasonyeza kuthekera kowonjezera DA mu nucleus accumbens (NAc) kudzera mu kuyanjana kwina ndi zolinga zosiyanasiyana za ma molekyulu (Nestler 2004 ) (Chithunzi 1 ). Njira ya mesolimbic DA [maselo a DA mu ventral tegmental area (VTA) yomwe imalowa mu NAc] ikuwoneka kuti ndi yofunika kwambiri pa mphotho ya mankhwala (Wise 2009 ). Komabe, monga tafotokozera pansipa, njira zina za DA [mesostriatal (maselo a DA mu substantia nigra omwe amalowa mu dorsal striatum) ndi mesocortical (maselo a DA mu VTA omwe amalowa mu frontal cortex)] zimathandizanso pa mphotho ya mankhwala ndi chizolowezi (Wise 2009 ). Ponseponse, zikuwoneka kuti zotsatira zabwino komanso zolimbitsa thupi za mankhwala osokoneza bongo zimayendetsedwa kwambiri ndi kuwombera kwa phasic DA cell, zomwe zimapangitsa kuti DA ikule kwambiri komanso kwakanthawi. Mosiyana ndi zimenezi, kusintha kwa ntchito ya executive komwe kumachitika mu chizolowezi kumalumikizidwa ndi kusintha kwa kuwombera kwa tonic DA cell ndipo kumabweretsa milingo yotsika koma yokhazikika ya DA (Grace 2000 ; Wanat et al. 2009 ). Izi, zikusonyeza kuti ma D1 receptors (D1R), omwe ndi ma DA receptors otsika omwe amalimbikitsa cyclic AMP signaling, omwe amagwira ntchito pochiza matenda amisala komanso pakulimbitsa thupi, chifukwa izi zimagwirizanitsidwa ndi kuchuluka kwa DA kofunikira kuti D1R ilimbikitse. Mosiyana ndi zimenezi, ma D2R, omwe amaletsa cyclic AMP signaling, amalimbikitsidwa ndi phasic ndi tonic DA. Dziwani kuti, chifukwa cha kusowa kwa ma radiotracers enieni a PET imaging a ma DA receptors amitundu ya D1, D3, D4, ndi D5, maphunziro ambiri okhudza zotsatira za mankhwala osokoneza bongo komanso kuledzera muubongo wa munthu amayang'ana kwambiri ma D2R.
Chithunzi 1 Mankhwala osokoneza bongo amagwira ntchito pa mphoto ndi ma circuits owonjezera kudzera mu njira zosiyanasiyana, komabe, zonse zimapangitsa kuti pakhale zotsatira zofanana za dopaminergic mu VTA ndi NAc . Chifukwa chake, zolimbikitsa zimathandizira DA mwachindunji, pomwe ma opiates amachita izi pochepetsa kamvekedwe koletsa ka GABAergic interneurons pa DA signaling yonse mu VTA kapena mu NAc. Ngakhale njira za mankhwala ena osokoneza bongo sizikudziwika bwino, pali umboni wosonyeza kuti nicotine ikhoza kuyambitsa VTA DA mwachindunji kudzera mu nicotinic acetylcholine receptor (nAChR) pa ma neuron amenewo komanso mwanjira ina kudzera mu kusonkhezera ma receptors ake pa glutamatergic nerve terminals zomwe zimasunga maselo a DA. Mowa umawoneka kuti umaletsa ma GABAergic terminals mu VTA, zomwe zimapangitsa kuti ma DA neurons achotsedwe mu VTA. Cannabinoids amagwira ntchito, pakati pa ena, kudzera mu kuyatsa ma CB1 receptors pa glutamatergic ndi GABAergic nerve terminals mu NAc, komanso pa ma NAc neurons okha. Phencyclidine (PCP) ikhoza kugwira ntchito poletsa postsynaptic NMDA glutamate receptors mu NAc. Kuphatikiza apo, pali umboni wina wosonyeza kuti nicotine ndi mowa zimathanso kuyanjana ndi njira za endogenous opioid ndi cannabinoid (sizinawonetsedwe). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum. Yosindikizidwanso ndi chilolezo cha Nestler ( 2005 )
Mwa anthu, kafukufuku wa PET wasonyeza kuti mankhwala angapo [olimbikitsa (Drevets et al. 2001 ; Volkow et al. 1999b ), nikotini (Brody et al. 2009 ), mowa (Boileau et al. 2003 ), ndi chamba (Bossong et al. 2009 )] amawonjezera DA mu dorsal ndi ventral striatum (komwe NAc ili). Maphunziro awa amagwiritsa ntchito ma radiotracer angapo, monga [ 11 C]raclopride, omwe amamangirira ku D2R koma pokhapokha ngati awa sakumangirira DA ya endogenous (yopanda anthu), yomwe pansi pa mikhalidwe yoyambira ikufanana ndi 85-90% ya striatal D2R (Abi-Dargham et al. 1998 ). Chifukwa chake, kufananiza kwa [ 11 C]raclopride kumangirira pambuyo pa placebo ndi pambuyo pa kupereka mankhwala kungatithandize kuyerekeza kuchepa kwa kupezeka kwa D2R komwe kumachitika chifukwa cha mankhwalawa (kapena zinthu zina zomwe zingawonjezere DA). Kuchepa kumeneku mu [ 11 C] raclopride binding kumagwirizana ndi kuwonjezeka kwa DA (Breier et al. 1997 ). Kafukufukuyu wasonyeza kuti kuwonjezeka kwa DA komwe kumabwera chifukwa cha mankhwala osokoneza bongo mu striatum kumagwirizana ndi kukula kwa chidziwitso cha euphoria kapena "high" [onani ndemanga (Volkow et al. 2009a )] (Chithunzi 2 ).
Chithunzi 2 Zotsatira za methylphenidate (MP) m'mitsempha mu raclopride kumangirira ndi ubale pakati pa kuwonjezeka kwa DA komwe kumachitika chifukwa cha MP mu striatum ndi malipoti odziwonetsa kuti ndi "high". Zosinthidwa kuchokera ku Volkow et al. ( 1999b )
Kafukufuku wa PET wavumbulutsanso ubale womveka bwino pakati pa mbiri ya mankhwala (monga liwiro lomwe amalowa ndi kutuluka muubongo) ndi mphamvu zake zolimbitsa thupi. Makamaka, mankhwala akafika mofulumira kwambiri muubongo, amakhala ndi "mphamvu" (Volkow et al. 2009a ). Mwachitsanzo, pa mlingo wofanana wa cocaine wofika muubongo (woyesedwa kudzera mu PET), pamene cocaine inalowa muubongo mwachangu (yomwe imaperekedwa ndi kusuta kapena iv), inakhala ndi "mphamvu" kwambiri kuposa pamene inalowa pang'onopang'ono (yomwe inafufuzidwa) (Volkow et al. 2000 ). Izi zikugwirizana ndi maphunziro a preclinical omwe akuwonetsa mgwirizano wofanana pakati pa mbiri ya mankhwala ndi mphamvu zake zolimbitsa thupi (Balster ndi Schuster 1973 ). Ndizomveka kuganiza kuti kuwonjezeka kwadzidzidzi komanso kwakukulu kwa DA komwe kumachitika chifukwa cha mankhwala osokoneza bongo kungafanane ndi kuwonjezeka kwachangu komanso kwakukulu kwa DA komwe kumachitika chifukwa cha DA yomwe yakhala ikugwiritsidwa ntchito, muubongo, ndi kukonza chidziwitso chokhudza mphotho ndi kusakhazikika (Schultz 2010 ). Kuwonjezeka kwa DA komwe kumachitika chifukwa cha mankhwala osokoneza bongo mu NAc kungakhale kofunikira pa chizolowezi, koma mfundo yakuti kumachitikanso mwa anthu omwe si osokoneza bongo imasonyeza kuti sikukwanira kufotokoza momwe kugwiritsa ntchito mankhwala osokoneza bongo mopupuluma komanso mokakamiza kumakhudzira chizolowezi.
Pali umboni tsopano wakuti mayankho ofanana a dopaminergic akugwirizana ndi mphotho ya chakudya ndipo njira zimenezi zingathandizenso kudya kwambiri komanso kunenepa kwambiri. Ndizodziwika bwino kuti zakudya zina, makamaka zomwe zili ndi shuga ndi mafuta ambiri, zimapindulitsa kwambiri (Lenoir et al. 2007 ). Zakudya zokhala ndi ma calories ambiri zimatha kulimbikitsa kudya mopitirira muyeso (kudya komwe sikukugwirizana ndi zosowa zamphamvu) ndikuyambitsa mgwirizano wophunziridwa pakati pa zolimbikitsa ndi mphotho (kukonza). M'mawu osinthika, khalidwe ili la zakudya zokoma linali lothandiza m'malo omwe magwero a chakudya anali osowa komanso/kapena osadalirika, chifukwa linkaonetsetsa kuti chakudya chimadyedwa chikapezeka, zomwe zimathandiza kuti mphamvu zisungidwe m'thupi (ngati mafuta) kuti zigwiritsidwe ntchito mtsogolo. Mwatsoka, m'madera ngati athu, komwe chakudya chimakhala chochuluka komanso chimapezeka nthawi zonse, kusintha kumeneku kwakhala vuto.
Ma neurotransmitters angapo, kuphatikizapo DA, cannabinoids, opioids, ndi serotonin, komanso mahomoni ndi ma neuropeptides omwe amagwira ntchito yolamulira homeostatic ya kudya, monga insulin, orexin, leptin, ndi ghrelin, akhala akukhudzidwa ndi zotsatira zabwino za chakudya (Atkinson 2008 ; Cason et al. 2010 ; Cota et al. 2006 ). Mwa izi, DA yakhala ikufufuzidwa bwino kwambiri ndipo ndiyo yodziwika bwino kwambiri. Kuyesera kwa makoswe kwawonetsa kuti, akayamba kukhudzidwa ndi chakudya, kuwombera kwa ma neuron a DA mu VTA kumawonjezeka zomwe zimapangitsa kuti DA itulutsidwe mu NAc (Norgren et al. 2006 ). Mofananamo, mwa anthu athanzi, olemera bwino, kudya chakudya chokoma kwawonetsedwa kuti kumamasula DA mu dorsal striatum molingana ndi kuchuluka kwa kusangalatsa kwa chakudya (Small et al. 2003 ) (Chithunzi 3 ). Komabe, monga momwe taonera m'maphunziro okhudza anthu omwe amagwiritsa ntchito mankhwala osokoneza bongo, kuwonjezeka kwa DA komwe kumachitika chifukwa cha chakudya kokha sikungathe kufotokoza kusiyana pakati pa kudya chakudya mwachizolowezi ndi kudya mopitirira muyeso chifukwa izi zimachitikanso mwa anthu athanzi omwe sadya mopitirira muyeso. Chifukwa chake, monga momwe zilili ndi chizolowezi choledzera, kusintha kwina kumatha kubweretsa kutayika kwa ulamuliro pa kudya chakudya.
Chithunzi 3 Kutulutsidwa kwa dopamine komwe kumachitika chifukwa cha kudya. Gawo la coronal kuchokera ku T-map la kuchepa kwakukulu kwa [ 11 C]raclopride's binding potential (BP) pambuyo pa kudya. Mtundu wa bala ukuyimira ziwerengero za t. (Yosindikizidwanso ndi chilolezo Small et al. 2003 )
3 Kujambula DA pakuyankha kwa mankhwala osokoneza bongo komanso kufotokoza zida zolimbitsa thupi
Udindo wa DA pakulimbikitsa mphamvu ndi wovuta kwambiri kuposa kungolemba kuti munthu alandire mphotho (chisangalalo cha hedonic); mwachitsanzo, zolimbikitsa zomwe zimayambitsa kuwonjezeka kwa DA mwachangu komanso kwakukulu zimayambitsanso mayankho okhazikika ndikupereka chilimbikitso chofuna kuzipeza (Owesson-White et al. 2009 ). Izi ndizofunikira chifukwa, kudzera mu ndondomeko yolimbikitsa, zolimbikitsa zopanda tsankho zomwe zimalumikizidwa ndi cholimbikitsa (kaya chachilengedwe kapena cholimbikitsa mankhwala) zimapeza mphamvu zokha zowonjezera DA mu striatum (kuphatikiza NAc) poyembekezera mphotho, motero zimapangitsa kuti munthu akhale ndi chilimbikitso champhamvu chofunafuna mankhwala (Owesson-White et al. 2009 ). Komabe, kulumikiza njira zolipirira mphotho ndi zolimbikitsa mphamvu mu ndondomeko ya kuledzera kwa mankhwala osokoneza bongo ndikovuta kwambiri kuposa kudya chifukwa mankhwala osokoneza bongo, kudzera mu zotsatira zake zamankhwala, amayatsa mwachindunji ma neuron a DA (mwachitsanzo, nikotini) kapena kuwonjezera kutulutsidwa kwa DA (mwachitsanzo, amphetamine).
Kafukufuku wokhudza ubongo womwe unayerekeza kuwonjezeka kwa DA komwe kumachitika chifukwa cha mankhwala olimbikitsa a methylphenidate (MP) kapena amphetamine (AMPH) pakati pa anthu omwe ali ndi vuto la cocaine poyerekeza ndi omwe amalamulira anasonyeza kuchepa kwakukulu kwa kuwonjezeka kwa DA komwe kumachitika chifukwa cha MP kapena AMPH mu striatum (50% yotsika mwa anthu omwe amaletsa kugwiritsa ntchito mankhwala osokoneza bongo ndi 80% mwa anthu omwe amalamulira kugwiritsa ntchito mankhwala osokoneza bongo) komanso kuchepa kwa malipoti a zotsatira zabwino za mankhwalawa poyerekeza ndi omwe sagwiritsa ntchito mankhwala osokoneza bongo (Martinez et al. 2007 ; Volkow et al. 1997 ) (Chithunzi 4 ). Izi zinali zodabwitsa popeza MP ndi AMPH zimafanana ndi cocaine ndi methamphetamine, motsatana, ndipo anthu omwe amagwiritsa ntchito mankhwala osokoneza bongo sangathe kusiyanitsa pakati pawo akapatsidwa kudzera m'mitsempha. Popeza kuchepa kwakukulu kwa kuchuluka kwa DA komwe kumachitika chifukwa cha mankhwala osokoneza bongo kunawonedwa ngati anthu omwe amaletsa kugwiritsa ntchito mankhwala osokoneza bongo a cocaine adachotsedwa kapena ayi, izi zikusonyeza kuti momwe munthu amasiya kumwa mankhwalawo si chinthu chosokoneza (Volkow et al. 2011b ). Zotsatirazi ndi zina zokhudzana nazo (Volkow et al. 2009a ) zikugwirizana ndi lingaliro lakuti yankho la hedonic limakhala lochepa mwa anthu omwe ali ndi vuto la mankhwala osokoneza bongo, ndipo zimalimbitsanso lingaliro lakuti zotsatira za mankhwala osokoneza bongo zomwe zimapangitsa kuti DA ikule mu NAc sizingathe kufotokoza zokha chifukwa chowonjezera chilimbikitso chowagwiritsa ntchito.
Chithunzi 4 Kusintha kwa DA komwe kumachitika chifukwa cha iv MP m'ma control ndi mwa anthu omwe ali ndi cocaine . zithunzi za avareji ya nondisplaceable biding potential (BPND) za [ 11 C]raclopride mwa anthu omwe ali ndi cocaine (n = 19) ndi m'ma control (n = 24) zomwe zayesedwa pambuyo pa placebo ndi pambuyo pa iv MP. b Kupezeka kwa D2R (BPND) mu caudate, putamen, ndi ventral striatum pambuyo pa placebo (buluu) ndi pambuyo pa MP (wofiira) m'ma control ndi mwa anthu omwe ali ndi cocaine. MP yachepetsa D2R m'ma control koma osati mwa anthu omwe ali ndi cocaine. Dziwani kuti ogwiritsa ntchito cocaine molakwika akuwonetsa kuchepa kwa kupezeka kwa D2R yoyambira (muyeso wa placebo) ndi kuchepa kwa kutulutsidwa kwa DA akapatsidwa iv MP (kuyezedwa ngati kuchepa kwa kupezeka kwa D2R kuchokera ku baseline). Ngakhale munthu angakayikire kuti kupezeka kwa D2R yochepa m'thupi mwa anthu omwe ali ndi vuto la cocaine kumalepheretsa bwanji kuzindikira kuchepa kwina kuchokera ku MP, mfundo yakuti anthu omwe ali ndi vuto la cocaine amasonyeza kuchepa kwa kupezeka kwa D2R akakumana ndi zizindikiro za cocaine imasonyeza kuti zotsatira zochepa za MP pa [ 11 C] raclopride binding zimasonyeza kuchepa kwa kutulutsidwa kwa DA. Yosindikizidwanso ndi chilolezo (Volkow et al. 1997 ; Wang et al. 2010 )
Yankho la VTA DA neurons lopindulitsa kusintha kosintha ndi kubwereza mobwerezabwereza.
Ngakhale maselo a DA amayaka moto akangoyamba kulandira mphotho yatsopano, kuwonekera mobwerezabwereza ku DA kumapangitsa kuti ma neuron asiye kuwombera akangolandira mphotho ndi moto m'malo mwake akakumana ndi zinthu zomwe zimaneneratu mphothoyo (Schultz et al. 1997 ). Izi mwina zingathandize DA pakuphunzira ndi kukonza. Zoonadi, kusintha kwa DA komwe kumachitika chifukwa cha mankhwala osokoneza bongo kumatha kuyambitsa kusintha kwa ma neurodecapitations m'magawo ena omwe amagwirizana ndi kupanga zizolowezi ndi machitidwe a khalidwe. Kusintha kumeneku kumachitika makamaka chifukwa cha kusintha kwa D1R signaling ndi synaptic mu ma receptors a NMDA ndi AMPA omwe amasinthidwa ndi glutamate (Luscher ndi Malenka 2011 ; Zweifel et al. 2009 ). Kulemba ma circuits awa ndikofunikira kwambiri pakukula kwa matenda chifukwa mayankho omwe amatsatira amathandizira kufotokoza chilakolako chachikulu cha mankhwala osokoneza bongo (chilakolako) ndi kugwiritsa ntchito mokakamiza komwe kumachitika pamene anthu omwe ali ndi vutoli akumana ndi zizindikiro zokhudzana ndi mankhwala osokoneza bongo. Lingaliro ili likugwirizana ndi zomwe zawonedwa paokha (Volkow et al. 2006b ; Wong et al. 2006 ) zomwe zikuwonetsa mphamvu ya cocaine-yogwirizana ndi cue yomwe imakweza milingo ya DA mu dorsal striatum ndikuyambitsa kuwonjezeka kwa chilakolako cha anthu omwe amagwiritsa ntchito mankhwala osokoneza bongo a cocaine (Chithunzi 5 ). Popeza dorsal striatum imagwira ntchito pophunzira zizolowezi (Belin et al. 2009 ; Yin et al. 2004 ), mgwirizanowu ukhoza kuwonetsa kulimba kwa zizolowezi pamene chizolowezi choledzera chikupitirira. Izi zikusonyeza kuti kusokonezeka kwakukulu mu chizolowezi kungagwirizane ndi mayankho omwe amayamba chifukwa cha DA omwe amabweretsa zizolowezi zomwe zimapangitsa kuti munthu azilakalaka kwambiri komanso kumwa mankhwala osokoneza bongo mopitirira muyeso. Chochititsa chidwi n'chakuti, pogwiritsa ntchito anthu omwe ali ndi vuto la cocaine, kuchuluka kwa DA komwe kumachitika chifukwa cha zizindikiro zokhazikika kumawoneka kuti ndi kwakukulu kuposa komwe kumapangidwa ndi mankhwala olimbikitsa okha monga momwe tawonera m'magulu awiri osiyana a anthu (Volkow et al. 2011b , 2006b ), zomwe zikusonyeza kuti mayankho okhazikika amatha kuyambitsa chizindikiro cha DA chomwe chimasunga chilimbikitso chomwa mankhwalawa ngakhale zotsatira zake zamankhwala zikuwoneka kuti zachepa . Chifukwa chake, ngakhale kuti mankhwala osokoneza bongo poyamba angayambitse malingaliro a mphotho mwachangu kudzera mu kutulutsidwa kwa DA mu ventral striatum, pogwiritsa ntchito mobwerezabwereza, ndipo chizolowezi chikakula, zikuwoneka kuti pali kusintha kuchokera ku mankhwala kupita ku chilimbikitso chokhazikika. Malinga ndi kafukufuku wa nyama za labotale, ma glutamatergic projections kuchokera ku prefrontal cortex ndi kuchokera ku amygdala kupita ku VTA/SN ndi NAc amayang'anira mayankho okhazikika awa (Kalivas 2009 ). Mwanjira imeneyi, kuneneratu mphotho kumatha kukhala mphotho yomwe imalimbikitsa khalidwe lofunikira pakumwa mankhwala osokoneza bongo (kapena chakudya).
Chithunzi 5 Kusintha kwa DA komwe kumachitika chifukwa cha zizindikiro zomwe zimakhazikika mwa anthu omwe ali ndi vuto la cocaine . zithunzi zapakati pa nondisplaceable binding potential (BPND) za [11C]raclopride mwa anthu omwe ali ndi vuto la cocaine (n = 17) zomwe zayesedwa poonera kanema wosalowerera (zochitika zachilengedwe) komanso powonera kanema wa cocaine-cues (anthu omwe akumwa cocaine). b Kupezeka kwa D2R (BPND) mu caudate, putamen, ndi ventral striatum ya kanema wosalowerera (buluu) ndi kanema wa cocaine-cues (wofiira). Zizindikiro za cocaine zinachepetsa D2R mu caudate ndi putamen. c Kugwirizana pakati pa kusintha kwa D2R (kuwonetsa kuwonjezeka kwa DA) ndi malipoti odziwonetsa okha a chilakolako cha cocaine chomwe chimayamba chifukwa cha kanema wa cocaine-cues. Yasinthidwa kuchokera ku ref. (Volkow et al. 2006b )
Chosangalatsa n'chakuti, mtundu uwu wa "switch" yogwira ntchito wanenedwanso za zolimbitsa thupi zachilengedwe, zomwe zingayambitse kusintha kofanana komanso pang'onopang'ono kwa kuwonjezeka kwa DA, kuchokera ku ventral regions kupita ku dorsal regions zambiri za striatum panthawi yosintha kuchokera ku stimulus yatsopano yomwe imapindulitsa mwachibadwa kupita ku zizindikiro zogwirizana zomwe zimaneneratu. Kusinthaku kumachitika kudzera mu DA signaling, yomwe ikuwoneka kuti ikuwonetsa "cholakwika cholosera mphotho" (Schultz 2010 ). Ma glutamatergic afferents ambiri ku ma neurons a DA ochokera kumadera omwe akukhudzidwa ndi kukonza sensory (insula kapena primary gustatory cortex), homeostatic (hypothalamus), mphotho (NAc), emotional (amygdala ndi hippocampus), ndi multimodal (orbitofrontal cortex for salience attribution), amasintha zochita zawo poyankha mphotho ndi ma conditioned cues (Geisler ndi Wise 2008 ). Makamaka, ma projection ochokera ku amygdala ndi orbitofrontal cortex (OFC) kupita ku ma neurons a DA ndi ku NAc amakhudzidwa ndi mayankho okhazikika ku chakudya (Petrovich 2010 ). Zoonadi, kafukufuku wokhudza kujambula zithunzi anasonyeza kuti pamene amuna omwe si onenepa kwambiri anapemphedwa kuti aletse chilakolako chawo cha chakudya - pamene anali kukumana ndi zizindikiro za chakudya - anasonyeza kuchepa kwa ntchito ya kagayidwe kachakudya mu amygdala ndi OFC (komanso mu hippocampus), insula ndi striatum, ndipo kuchepa kwa OFC kunagwirizanitsidwa ndi kuchepa kwa chilakolako cha chakudya (Wang et al. 2009 ). Kuletsa kofanana kwa ntchito ya kagayidwe kachakudya mu OFC (komanso mu NAc) kwawonedwa mwa ogwiritsa ntchito cocaine pamene anapemphedwa kuti aletse chilakolako chawo cha mankhwala osokoneza bongo akakumana ndi zizindikiro za cocaine (Volkow et al. 2009b ).
Komabe, kutuluka kwa zilakolako zoterezi, zomwe zimadyanso chakudya mwa anthu abwino omwe samadya kwambiri, sizingakhale zopweteka kwambiri ngati sizikuphatikizana ndi kuchepa kwa ubongo kuti zitha kulepheretsa makhalidwe oipa.
4 Mphamvu ya Kulephera Kuletsa Kutetezedwa
Kutha kuletsa mayankho obwera mwadzidzidzi kumathandizira munthu kupewa kuchita zinthu zosayenera, monga kumwa mankhwala osokoneza bongo kapena kudya asanakhute, motero kumawonjezera chiopsezo chake cha chizolowezi (kapena kunenepa kwambiri) (Volkow ndi Fowler 2000 ; Volkow et al. 2008a ).
Kafukufuku wa PET wapeza kuchepa kwakukulu kwa kupezeka kwa D2R mu striatum ya anthu omwe ali ndi vuto la kugwiritsa ntchito mankhwala osokoneza bongo omwe amapitilira kwa miyezi ingapo atatha kuchotsa poizoni m'thupi kwa nthawi yayitali [kuwunikidwa mu (Volkow et al. 2009a )]. Mofananamo, maphunziro okonzekera matenda a makoswe ndi anyani omwe si a anthu awonetsa kuti kupezeka mobwerezabwereza kwa mankhwala osokoneza bongo kumakhudzana ndi kuchepa kwa milingo ya D2R m'mimba (Nader et al. 2006 ; Thanos et al. 2007 ; Volkow et al. 2001 ). Mu striatum, ma D2R amalumikiza chizindikiro mu njira yosalunjika ya striatal yomwe imasintha madera a prefrontal; ndipo kuchepa kwake kwawonetsedwa kuti kumawonjezera chidwi cha zotsatira za mankhwala m'mitundu ya nyama (Ferguson et al. 2011 ). Mwa anthu omwe amamwa mankhwala osokoneza bongo, kuchepa kwa D2R yoyambira kumalumikizidwa ndi kuchepa kwa ntchito za m'madera oyambira monga momwe zikuwonekera ndi kuchepa kwa kagayidwe ka shuga m'magazi (chizindikiro cha ntchito ya ubongo) mu OFC, anterior cingulate gyrus (ACC), ndi dorsolateral prefrontal cortex (DLPFC) (Volkow et al. 2001 , 1993 , 2007 ) (Chithunzi 6 ). Popeza OFC, ACC, ndi DLPFC zimakhudzidwa ndi kuyika mphamvu, kuletsa kulamulira/kukhudzidwa, komanso kupanga zisankho, motsatana, zanenedwa kuti kulamulira kwawo kosayenera ndi chizindikiro cha DA chothandizidwa ndi D2R mwa anthu omwe ali ndi vutoli kungayambitse kufunikira kwakukulu kwa mankhwala m'makhalidwe awo komanso kutayika kwa ulamuliro pa kumwa mankhwala osokoneza bongo (Volkow ndi Fowler 2000 ). Kuphatikiza apo, chifukwa zovuta mu OFC ndi ACC zimagwirizanitsidwa ndi machitidwe okakamiza komanso kusakhazikika (Fineberg et al. 2009 ), kusokonekera kwa DA m'madera awa kungayambitse kumwa mankhwala osokoneza bongo komanso osakhazikika omwe amapezeka mu chizolowezi (Goldstein ndi Volkow 2002 ). Zoonadi, mwa ogwiritsa ntchito mankhwala osokoneza bongo a methamphetamine, D2R yotsika kwambiri idalumikizidwa ndi kusakhazikika (Lee et al. 2009 ), ndipo idaneneratunso kuti kuperekedwa kwa cocaine mosakhazikika m'makoswe (Everitt et al. 2008 ). Chochitika chosiyana, momwe chiopsezo choyamba chogwiritsa ntchito mankhwala osokoneza bongo chimakhalapo m'madera a prefrontal, ndipo pomwe kugwiritsa ntchito mankhwala mobwerezabwereza kumayambitsa kuchepa kwakukulu kwa D2R ya striatal, n'kothekanso. Inde, kafukufuku wochitidwa mwa anthu omwe, ngakhale ali ndi chiopsezo chachikulu cha uchidakwa (mbiri yabwino ya banja la uchidakwa) sanali zidakwa, adawonetsa kupezeka kwa D2R ya striatal kuposa kwachizolowezi komwe kumalumikizidwa ndi kagayidwe kabwinobwino mu OFC, ACC, ndi DLPFC (Volkow et al. 2006a ). Izi zikusonyeza kuti, mwa anthu omwe ali pachiwopsezo cha uchidakwa, ntchito yabwinobwino ya prefrontal inalumikizidwa ndi kuwonjezeka kwa chizindikiro cha D2R cha striatal, chomwe mwina chinawateteza ku kumwa mowa mopitirira muyeso.
Chithunzi 6 Kugwirizana pakati pa kupezeka kwa D2R mu ubongo ndi kagayidwe kachakudya m'madera a ubongo wa prefrontal. zithunzi za ubongo wa Axial zowongolera ndi za munthu wokonda cocaine pazithunzi zoyambira za kupezeka kwa D2R mu striatum (yomwe idapezeka ndi [ 11 C]raclopride) ndi kagayidwe ka shuga m'magazi mu OFC (yomwe idapezeka ndi [ 18 FDG). b Kugwirizana pakati pa D2R mu ubongo ndi kagayidwe kachakudya mu OFC mwa anthu omwe ali ndi vuto la cocaine komanso omwe ali ndi vuto la methamphetamine. Yosindikizidwanso kuchokera ku Volkow et al. ( 2009a ) Copyright (2009), ndi chilolezo kuchokera kwa Elsevier
Mosakayikira, umboni wa kusokonekera kwa kayendedwe ka kayendetsedwe ka thupi wapezekanso pakati pa anthu onenepa kwambiri. Maphunziro onse a preclinical ndi clinic apereka umboni wa kuchepa kwa chizindikiro cha striatal D2R, chomwe, monga tafotokozera pamwambapa, chikugwirizana ndi mphotho (NAc) komanso kukhazikitsidwa kwa zizolowezi ndi machitidwe (dorsal striatum) mu kunenepa kwambiri (Geiger et al. 2009 ; Wang et al. 2001 ). Chofunika kwambiri, kuchepa kwa kupezeka kwa striatal D2R kwalumikizidwa ndi kudya mokakamiza m'makoswe onenepa (Johnson ndi Kenny 2010 ) komanso kuchepa kwa kagayidwe kachakudya mu OFC ndi ACC mwa anthu onenepa kwambiri (Volkow et al. 2008b ) (Chithunzi 7 a–c). Popeza kuti kusokonekera kwa OFC ndi ACC kumabweretsa kukakamizidwa [onani ndemanga (Fineberg et al. 2009 )], izi zitha kukhala gawo la njira yomwe chizindikiro chochepa cha striatal D2R chimathandizira hyperphagia (Davis et al. 2009 ). Kuphatikiza apo, popeza kuchepa kwa chizindikiro chokhudzana ndi D2R kungachepetsenso kukhudzidwa ndi mphotho zina zachilengedwe, kusowa kumeneku mwa anthu onenepa kwambiri kungathandizenso kudya mopitirira muyeso (Geiger et al. 2008 ).
Chithunzi 7 Hyperphagia ikhoza kuchitika chifukwa cha chilakolako chofuna kulipira gawo lofooka la mphotho (lokonzedwa kudzera m'magawo a corticostriatal olamulidwa ndi dopamine) kuphatikiza ndi chidwi chowonjezeka cha kumveka bwino (makhalidwe a hedonic a chakudya chokonzedwa pang'ono kudzera mu somatosensory cortex) . Zithunzi zapakati za kupezeka kwa DA D2 receptor (D2R) mu zowongolera (n = 10) komanso mwa anthu onenepa kwambiri (n = 10). b Zotsatira kuchokera ku (Statistical Parametric Mapping) SPM yodziwitsa madera omwe D2R imagwirizanitsidwa ndi kagayidwe ka shuga, izi zikuphatikizapo medial OFC, ACC, ndi dorsolateral PFC (dera lomwe silinawonetsedwe). c Kutsika kwapakati pakati pa striatal D2R ndi ntchito ya kagayidwe kachakudya mu ACC mwa anthu onenepa kwambiri. d Zithunzi za SPM zojambulidwa m'magawo atatu zomwe zikuwonetsa madera omwe ali ndi kagayidwe kachakudya kwambiri mwa anthu onenepa kuposa anthu osanenepa (P < 0.003, osakonzedwa). e Zotsatira za SPM zokhala ndi utoto zomwe zikuwonetsedwa mu korona yokhala ndi chithunzi chowonekera cha somatosensory homunculus. Zotsatira zake (z value) zaperekedwa pogwiritsa ntchito sikelo ya utawaleza pomwe wofiira > wachikasu > wobiriwira. Poyerekeza ndi anthu ochepa thupi, anthu onenepa anali ndi kagayidwe kabwino ka thupi m'malo omwe amamva thupi komwe pakamwa, milomo, ndi lilime zimayimiriridwa ndipo zomwe zimakhudzana ndi kukonza chakudya zimakoma. Zasinthidwa, ndi chilolezo, kuchokera kwa Volkow et al. ( 2008a ) (a–c) ndi Wang et al. ( 2002 ) (d, e)
Lingaliro ili likugwirizana ndi umboni woyambirira wosonyeza kuti kuchepa kwa ntchito ya DA mu VTA kumabweretsa kuwonjezeka kwakukulu kwa kudya zakudya zokhala ndi mafuta ambiri (Stoeckel et al. 2008 ). Mofananamo, poyerekeza ndi anthu olemera bwino, anthu onenepa omwe adawonetsedwa zithunzi za chakudya chokhala ndi ma calories ambiri (cholimbikitsa chomwe ali nacho) adawonetsa kuwonjezeka kwa mphamvu ya mitsempha m'madera omwe ali gawo la magawo a mphotho ndi chilimbikitso (NAc, dorsal striatum, OFC, ACC, amygdala, hippocampus, ndi insula) (Killgore ndi Yurgelun-Todd 2005 ). Mosiyana ndi zimenezi, muzowongolera kulemera kwabwinobwino, kuyambitsa kwa ACC ndi OFC (madera omwe akukhudzidwa ndi salience attribution yomwe imayambira mu NAc) panthawi yopereka chakudya chokhala ndi ma calories ambiri kunapezeka kuti sikukugwirizana ndi body mass index yawo (BMI) (Stice et al. 2008b ). Izi zikusonyeza kuyanjana kwamphamvu pakati pa kuchuluka kwa chakudya chomwe chimadyedwa (chomwe chimawonetsedwa pang'ono mu BMI) ndi momwe madera opindulitsa amagwirira ntchito ndi chakudya chokhala ndi ma calories ambiri (chomwe chimawonetsedwa mu kuyambika kwa OFC ndi ACC) mwa anthu olemera bwino, zomwe zimatayika chifukwa cha kunenepa kwambiri.
Chodabwitsa n'chakuti, anthu onenepa kwambiri sanawonetse mphamvu zochepa zopezera mphotho kuchokera ku chakudya chenicheni (chomwe chimatchedwa mphotho ya chakudya chokwanira) kuposa anthu opanda mafuta, pomwe adawonetsa mphamvu zambiri za madera a cortical omwe amalandira kukoma kokoma akamayembekezera kudya (Stice et al. 2008b ). Kuwona komalizaku kunagwirizana ndi madera omwe kafukufuku wakale adawonetsa mphamvu zowonjezera mwa anthu onenepa omwe adayesedwa poyambira (osalimbikitsa) (Wang et al. 2002 ) (Chithunzi 7 d, e). Ntchito yowonjezera ya madera omwe amalandira kukoma kokoma ingapangitse anthu onenepa kukhala okonda chakudya kuposa zinthu zina zachilengedwe zolimbitsa thupi, pomwe kuchepa kwa mphamvu zopezera dopaminergic chifukwa cha kudya kwenikweni kungayambitse kumwa mopitirira muyeso ngati njira yolipirira chizindikiro chofooka cha D2R (Stice et al. 2008a ). Kuyankha kocheperako kwa mphamvu zopezera mphotho pakudya kwa anthu onenepa kumakumbutsa kuchepa kwa DA komwe kumachitika chifukwa cha kumwa mankhwala osokoneza bongo mwa anthu omwe ali ndi vuto loledzera poyerekeza ndi anthu omwe alibe vuto loledzera.
Prefrontal cortex (PFC) imagwira ntchito yofunika kwambiri pa ntchito yoyendetsa, kuphatikizapo kuletsa kulamulira (Miller ndi Cohen 2001 ). Njirazi zimasinthidwa ndi D1R ndi D2R (mwina D4R) motero, kuchepa kwa ntchito mu PFC, ponse paŵiri mu chizolowezi ndi kunenepa kwambiri, kungapangitse kuti munthu asamalamulire bwino komanso kuti azichita zinthu mopitirira muyeso. Kupezeka kochepa kwa D2R m'thupi la anthu onenepa kwambiri, komwe kwagwirizanitsidwa ndi kuchepa kwa ntchito mu PFC ndi ACC (Volkow et al. 2008b ) chifukwa chake kungathandizire kuti munthu asalamulire bwino kudya chakudya. Zoonadi, kugwirizana kolakwika pakati pa BMI ndi striatal D2R komwe kwanenedwa mwa anthu onenepa kwambiri (Wang et al. 2001 ) komanso mwa anthu onenepa kwambiri (Haltia et al. 2007a ) kumathandizira izi. Kumvetsetsa bwino njira zomwe zimapangitsa kuti PFC isamagwire bwino ntchito mu kunenepa kwambiri (kapena kuledzera) kungathandize pakupanga njira zochepetsera, kapena mwina kusintha, zolakwika zinazake m'magawo ofunikira a chidziwitso. Mwachitsanzo, kuchedwetsa kuchotsera, komwe ndi chizolowezi chochepetsa mtengo wa mphotho chifukwa cha kuchedwetsa kwakanthawi kwa kupereka kwake, ndi chimodzi mwa ntchito zofufuza kwambiri zokhudzana ndi matenda okhudzana ndi kusakhazikika maganizo ndi kukakamiza. Kuchedwetsa kuchotsera kwafufuzidwa kwambiri mwa ogwiritsa ntchito mankhwala osokoneza bongo omwe amawonetsa kukonda kwambiri mphotho zazing'ono koma mwachangu kuposa zazikulu koma mochedwa (Bickel et al. 2007 ). Komabe, maphunziro ochepa omwe adachitidwa ndi anthu onenepa kwambiri apezanso umboni wa kukonda mphotho zazikulu, mwachangu, ngakhale kuti pali mwayi wokulirapo wovutika ndi kutayika kwakukulu mtsogolo (Brogan et al. 2010 ; Weller et al. 2008 ). Ndipo posachedwapa, kafukufuku wina adapeza mgwirizano wabwino pakati pa BMI ndi kuchedwetsa kwa hyperbolic, komwe kubweza koyipa mtsogolo kumachepetsedwa pang'ono kuposa kubweza kwabwino mtsogolo (Ikeda et al. 2010 ). Chochititsa chidwi n'chakuti, kuchepetsa kuchedwa kumawoneka kuti kumadalira ntchito ya ventral striatum (Gregorios-Pippas et al. 2009 ) ndi ya PFC, kuphatikizapo lateral OFC (Bjork et al. 2009 ), ndipo kumakhudzidwa ndi kusintha kwa DA (Pine et al. 2010 ). Makamaka, kukulitsa chizindikiro cha DA (ndi chithandizo cha L DOPA) kumawonjezera kutengeka ndi kuchepetsedwa kwa nthawi.
5 Kuphatikizidwa kwa Makonzedwe Otsitsimula
Kulankhulana kwa dopaminergic kumakhudzanso chilimbikitso. Makhalidwe monga mphamvu, kupirira, ndi kuyesetsa kupitiriza kukwaniritsa cholinga, zonse zimayendetsedwa ndi DA kudzera m'madera angapo omwe akufunidwa, kuphatikizapo NAc, ACC, OFC, DLPFC, amygdala, dorsal striatum, ndi ventral pallidum (Salamone et al. 2007 ). Kulankhulana kwa DA molakwika kumagwirizanitsidwa ndi chilimbikitso chowonjezeka chofuna kugula mankhwala osokoneza bongo, chizindikiro cha chizolowezi, ndichifukwa chake anthu omwe ali ndi vuto la mankhwala osokoneza bongo nthawi zambiri amachita zinthu zoopsa kuti apeze mankhwala osokoneza bongo, ngakhale atakhala ndi zotsatirapo zoopsa komanso zoyipa (Volkow ndi Li 2005 ). Chifukwa kumwa mankhwala osokoneza bongo kumakhala chilimbikitso chachikulu chofuna kugwiritsa ntchito mankhwala osokoneza bongo (Volkow et al. 2003 ), anthu omwe ali ndi vuto la chizolowezi amadzuka ndikulimbikitsidwa ndi njira yopezera mankhwala osokoneza bongo koma nthawi zambiri amakhala odzipatula komanso osamvera akakumana ndi zinthu zosagwirizana ndi mankhwala osokoneza bongo. Kusinthaku kwaphunziridwa poyerekeza machitidwe ogwirira ntchito ubongo omwe amapezeka ndi kuwonetsedwa ndi zizindikiro zokhazikika ndi zomwe zimachitika popanda zizindikiro zotere. Mosiyana ndi kuchepa kwa zochita za prefrontal zomwe zanenedwa mwa ogwiritsa ntchito mankhwala osokoneza bongo a cocaine omwe adachotsedwa poizoni akapanda kusonkhezeredwa ndi zizindikiro za mankhwala osokoneza bongo kapena mankhwala osokoneza bongo [onani ndemanga (Volkow et al. 2009a )], madera awa a prefrontal amayamba kugwira ntchito pamene ogwiritsa ntchito mankhwala osokoneza bongo a cocaine akumana ndi zinthu zomwe zimayambitsa chilakolako (kaya mankhwala osokoneza bongo kapena zizindikiro) (Grant et al. 1996 ; Volkow et al. 1999a ; Wang et al. 1999 ). Zotsatirazi zikukumbutsa zomwe zawonedwa kuti ogwiritsa ntchito mankhwala osokoneza bongo a cocaine, omwe adaphunziridwa patangopita nthawi yochepa atamwa cocaine, adawonetsa kuwonjezeka kwa ntchito ya metabolic mu OFC ndi ACC (komanso dorsal striatum) zomwe zimagwirizanitsidwa ndi chilakolako (Volkow et al. 1991 ).
Komanso, pamene mayankho a iv MP ayerekezeredwa pakati pa anthu omwe ali ndi vuto la cocaine ndi omwe alibe vuto la cocaine, oyambawo adayankha ndi kuchuluka kwa kagayidwe kachakudya mu ventral ACC ndi medial OFC (zotsatira zokhudzana ndi chilakolako), pomwe omalizawa adawonetsa yankho losiyana, lomwe ndi kuchepa kwa kagayidwe kachakudya m'madera awa (Volkow et al. 2005 ). Izi zikusonyeza kuti kuyambika kwa madera awa a prefrontal omwe ali ndi vuto la mankhwala osokoneza bongo kungakhale kwapadera kwa chizolowezi ndipo kumakhudzana ndi chilakolako chowonjezeka cha mankhwala osokoneza bongo. Kuphatikiza apo, kafukufuku yemwe adalimbikitsa anthu omwe ali ndi vuto la cocaine kuti aletse dala chilakolako akakumana ndi zizindikiro za mankhwala osokoneza bongo adawonetsa kuti anthu omwe adapambana poletsa chilakolako adawonetsa kuchepa kwa kagayidwe kachakudya mu medial OFC (yomwe imapanga phindu lolimbikitsa la reinforcer) ndi NAc (yomwe imaneneratu mphotho) (Volkow et al. 2009b ). Zomwe zapezekazi zikugwirizananso ndi kutenga nawo mbali kwa OFC, ACC, ndi striatum mu chilimbikitso chowonjezereka chopeza mankhwala omwe amapezeka mu chizolowezi.
Mosakayikira, OFC yakhala ikukhudzidwanso ndi kuyika mphamvu ya chakudya pamlingo wa mphamvu (Grabenhorst et al. 2008 ; Rolls ndi McCabe 2007 ), kuthandiza kuwunika kukongola kwake komanso kumveka bwino kwake malinga ndi momwe zinthu zilili. Maphunziro a PET ndi FDG kuti ayesere kagayidwe ka shuga m'magazi mwa anthu omwe ali ndi kulemera kwabwinobwino adanenanso kuti kuwonetsedwa ku zakudya kumawonjezera ntchito ya kagayidwe kachakudya mu OFC, zomwe zinali zotsatira zogwirizana ndi malingaliro a njala ndi chilakolako cha chakudya (Wang et al. 2004 ). Kuwonjezeka kwa OFC chifukwa cha kukondoweza kwa chakudya kungawonetse zotsatira za dopaminergic ndikutenga nawo mbali mu gawo la DA pakulimbikitsa kudya. OFC imagwira ntchito pophunzira mgwirizano wolimbikitsa ndi kulimbitsa thupi (Cox et al. 2005 ; Gallagher et al. 1999 ), imathandizira kudya mothandizidwa ndi zizindikiro zokhazikika (Weingarten 1983 ), ndipo mwina kumathandizira kudya mopitirira muyeso mosasamala kanthu za zizindikiro za njala (Ogden ndi Wardle 1990 ). Zoonadi, kusagwira bwino ntchito kwa OFC kwalumikizidwa ndi kudya mopitirira muyeso (Machado ndi Bachevalier 2007 ).
Ngakhale kuti pali kusagwirizana pakati pa kafukufuku, deta yokhudza kujambula ubongo imathandizanso lingaliro lakuti kusintha kwa kapangidwe ka thupi ndi ntchito m'madera a ubongo komwe kumakhudzidwa ndi ntchito ya executive (kuphatikizapo kuletsa kulamulira) kungagwirizane ndi BMI yapamwamba mwa anthu athanzi. Mwachitsanzo, kafukufuku wa MRI wochitidwa mwa akazi okalamba, pogwiritsa ntchito voxel-based morphometry, adapeza mgwirizano woipa pakati pa BMI ndi kuchuluka kwa imvi (kuphatikizapo madera akutsogolo), omwe, mu OFC, anali okhudzana ndi ntchito yolakwika ya executive (Walther et al. 2010 ). Pogwiritsa ntchito PET poyesa kagayidwe ka shuga m'magazi m'magulu athanzi, tinanena za mgwirizano woipa pakati pa BMI ndi ntchito ya kagayidwe ka thupi mu DLPFC, OFC, ndi ACC. Mu kafukufukuyu, ntchito ya kagayidwe ka thupi m'madera a prefrontal inaneneratu momwe anthuwa amagwirira ntchito poyesa ntchito ya executive (Volkow et al. 2009c ). Mofananamo, kafukufuku wa nuclear magnetic resonance (NMR) spectroscopic mu azaka zapakati ndi okalamba omwe ali ndi thanzi labwino adawonetsa kuti BMI inali yogwirizana molakwika ndi milingo ya N-acetyl-aspartate (chizindikiro cha umphumphu wa mitsempha) mu frontal cortex ndi ACC (Gazdzinski et al. 2008 ; Volkow et al. 2009c ).
Kafukufuku woyerekeza anthu onenepa ndi ochepa thupi wanenanso kuti kuchuluka kwa imvi m'madera akutsogolo (frontal operculum ndi pakati pa frontal gyrus) komanso mu post-central gyrus ndi putamen (Pannacciulli et al. 2006 ). Kafukufuku wina, sanapeze kusiyana pakati pa kuchuluka kwa imvi pakati pa anthu onenepa ndi ochepa thupi, komabe, adalemba ubale wabwino pakati pa kuchuluka kwa zinthu zoyera m'mapangidwe a ubongo wa basal ndi chiuno ndi chiuno, zomwe zidasinthidwa pang'ono ndi kudya (Haltia et al. 2007b ). Chochititsa chidwi n'chakuti, madera a cortical, monga DPFC ndi OFC omwe amagwira ntchito yoletsa kuletsa, apezekanso kuti ayamba kugwiritsidwa ntchito mwa anthu opambana omwe amadya bwino poyankha kudya (DelParigi et al. 2007 ), zomwe zikusonyeza kuti pali njira yophunzitsiranso khalidwe pochiza kunenepa kwambiri (komanso kuledzera).
6 Kuphatikizidwa kwa Zokambirana zapakati
Kafukufuku wa ubongo wavumbulutsa kuti insula yapakati imagwira ntchito yofunika kwambiri pakulakalaka chakudya, cocaine, ndi ndudu (Bonson et al. 2002 ; Pelchat et al. 2004 ; Wang et al. 2007 ). Kufunika kwa insula kwawonetsedwa ndi kafukufuku yemwe adanenanso kuti osuta omwe adawonongeka m'derali (koma osati osuta omwe adakumana ndi zilonda zakunja kwa intramuscular) adatha kusiya kusuta mosavuta komanso popanda kukumana ndi chilakolako kapena kubwereranso (Naqvi et al. 2007 ). Insula, makamaka madera ake akutsogolo, imalumikizidwa motsatizana ndi madera angapo a limbic (monga ventromedial prefrontal cortex, amygdala, ndi ventral striatum) ndipo ikuwoneka kuti ili ndi ntchito yolumikizirana, kuphatikiza chidziwitso cha autonomic ndi visceral ndi malingaliro ndi chilimbikitso, motero imapereka chidziwitso chodziwa bwino za zilakolako izi (Naqvi ndi Bechara 2009 ). Zoonadi, kafukufuku wa zilonda za muubongo akusonyeza kuti PFC ya m'magazi ndi insula ndi zinthu zofunika kwambiri m'magawo ogawidwa omwe amathandizira kupanga zisankho zamaganizo (Clark et al. 2008 ). Mogwirizana ndi lingaliro ili, maphunziro ojambula zithunzi nthawi zonse amasonyeza kusintha kwa mphamvu ya insula panthawi ya chilakolako (Brody et al. 2009 ; Goudriaan et al. 2010 ; Naqvi ndi Bechara 2009 ; Wang et al. 1999 ). Chifukwa chake, reactivity ya dera la ubongo ili yanenedwa kuti imagwira ntchito ngati chizindikiro chothandizira kulosera kubwereranso (Janes et al. 2010 ).
Chipindacho chilinso malo ofunikira kwambiri, omwe amachita nawo mbali zambiri za machitidwe odya, monga kukoma. Kuphatikiza apo, rostral insula (yolumikizidwa ndi primary taste cortex) imapereka chidziwitso ku OFC chomwe chimakhudza mawonekedwe ake ambiri a kukongola kapena phindu la mphotho ya chakudya chomwe chikubwera (Rolls 2008 ). Chifukwa cha kulowerera kwa chipindacho m'malingaliro ozindikira thupi, mu kuzindikira zamaganizo (Craig 2003 ) komanso mu chilimbikitso ndi malingaliro (Rolls 2008 ), chopereka cha insular impair mu kunenepa kwambiri chingayembekezeredwe. Zoonadi, kutsekeka kwa m'mimba kumabweretsa kuyambitsa kwa posterior insula, komwe kungawonetse ntchito yake pakuzindikira momwe thupi lilili (pankhaniyi ya kudzaza) (Wang et al. 2008 ). Kuphatikiza apo, mwa anthu ochepa thupi, koma osati mwa anthu onenepa kwambiri, kutsekeka kwa m'mimba kunapangitsa kuti amygdala iyambe kugwira ntchito ndikuletsa anterior insula (Tomasi et al. 2009 ). Kusowa kwa mayankho a amygdala mwa anthu onenepa kungasonyeze kuzindikira kofooka kwa momwe thupi limagwirira ntchito ndi kukhuta (mimba yonse). Ngakhale kuti kusintha kwa ntchito ya DA sikunafufuzidwe bwino, zikudziwika kuti DA imagwira nawo ntchito poyankha kulawa zakudya zokoma zomwe zimayendetsedwa kudzera mu insula (Hajnal ndi Norgren 2005 ). Kafukufuku wa anthu awonetsa kuti kulawa zakudya zokoma kunayambitsa madera a insula ndi midbrain (DelParigi et al. 2005 ; Frank et al. 2008 ). Komabe, chizindikiro cha DA chingakhalenso chofunikira kuti muzindikire kuchuluka kwa kalori m'chakudya. Mwachitsanzo, akazi olemera bwino akalawa sweetener yokhala ndi ma calories (sucrose), madera onse a insula ndi dopaminergic midbrain adayamba kugwira ntchito, pomwe kulawa sweetener yopanda ma calories (sucralose) kumangoyambitsa insula (Frank et al. 2008 ). Anthu onenepa kwambiri amawonetsa insular activation yayikulu kuposa njira zowongolera wamba akalawa chakudya chamadzimadzi chomwe chili ndi shuga ndi mafuta (DelParigi et al. 2005 ). Mosiyana ndi zimenezi, anthu omwe achira matenda a anorexia nervosa amasonyeza kuti sakusangalala kwambiri ndi chakudya chochokera ku insula akamadya sucrose ndipo sakusangalala ndi chakudya chochokera ku insula monga momwe zawonedwera m'magawo olamulira (Wagner et al. 2008 ). Zotsatirazi zikaphatikizidwa, zimapangitsa kuti zikhale zotheka kuti kusokonekera kwa chakudya chochokera ku insula chifukwa cha kukoma kungakhale chifukwa cha kulephera kwa machitidwe osiyanasiyana a chilakolako.
7 The Circuitry of Aversion
Monga tanenera kale, kuphunzitsa (kukonza) pa chizindikiro chomwe chimaneneratu mphotho kumabweretsa kuphulika kwa maselo a dopaminergic poyankha kulosera kwa mphotho, osati mphotho yokha. Kumbali ina, komanso mogwirizana ndi mfundo imeneyi, zawonedwa kuti maselo a dopaminergic adzaphulika mochepa kuposa mwachizolowezi ngati mphotho yomwe ikuyembekezeka ilephera kuchitika (Schultz et al. 1997 ). Umboni wochuluka (Christoph et al. 1986 ; Lisoprawski et al. 1980 ; Matsumoto ndi Hikosaka 2007 ; Nishikawa et al. 1986 ) ukuwonetsa kuti habenula ndi imodzi mwa madera omwe amayang'anira kuchepa kwa kuwombera kwa maselo a dopaminergic mu VTA komwe kungatsatire kulephera kulandira mphotho yomwe ikuyembekezeka (Kimura et al. 2007 ). Chifukwa chake, kukhudzidwa kwakukulu kwa habenula, chifukwa cha kupezeka kwa mankhwala osokoneza bongo nthawi yayitali, kungayambitse kuyankha kwakukulu ku zizindikiro za mankhwala osokoneza bongo. Zoonadi, kuyambika kwa habenula, mwa anthu omwe ali ndi vuto la cocaine, kwakhala kukugwirizana ndi kubwerera m'mbuyo kwa khalidwe la kumwa mankhwala osokoneza bongo akangoyamba kumwa mankhwala osokoneza bongo (Brown et al. 2011 ; Zhang et al. 2005 ). Pankhani ya nikotini, ma α5 nicotinic receptors mu habenula amawoneka kuti amasintha mayankho otsutsa ku mlingo waukulu wa nikotini (Fowler et al. 2011 ); ndipo ma α5 ndi ma α2 receptors mu habenula amakhudzidwa ndi kusiya nikotini (Salas et al. 2009 ). Chifukwa cha yankho losiyana la habenula ndi la ma neurons a DA kuti alandire mphotho (kuletsa) ndi kuyambika kwake akangoyamba kumwa mankhwala osokoneza bongo, tikutanthauza pano chizindikiro cha habenula ngati chimodzi chomwe chimapereka "kubwezera".
Habenula ikuwoneka kuti imagwira ntchito yofanana pankhani ya mphotho ya chakudya. Zakudya zokoma kwambiri zimatha kuyambitsa kunenepa kwambiri mwa makoswe, pomwe kulemera kumawonjezeka komwe kumayenderana ndi kuwonjezeka kwa μ-opioid peptide binding mu basolateral ndi basomedial amygdala. Chochititsa chidwi n'chakuti, medial habenula inawonetsa μ-opioid peptide binding yapamwamba kwambiri (pafupifupi 40%) atatha kudya chakudya chokoma mwa makoswe omwe adanenepa (omwe adadya chakudya chochuluka) koma osati mwa omwe sanadye (Smith et al. 2002 ). Izi zikusonyeza kuti habenula ikhoza kukhala ndi gawo pakudya mopitirira muyeso ngati chakudya chokoma chilipo. Kuphatikiza apo, ma neuron omwe ali mu rostromedial tegmental nucleus, omwe amalandira gawo lalikulu kuchokera ku lateral habenula, amafikira ku ma neuron a VTA DA ndipo amayamba kugwira ntchito atatha kusowa chakudya (Jhou et al. 2009 ). Zomwe zapezekazi zikugwirizana ndi gawo la habenula poyankha mayankho ku zoyambitsa zotsutsa kapena zochitika monga zomwe zimachitika panthawi yodya kapena kusiya mankhwala osokoneza bongo.
Kuphatikizidwa kwa habenula ngati malo oletsa mphotho mkati mwa maukonde amalingaliro kumagwirizana ndi zitsanzo zakale za chizolowezi chomwe chinkanena kuti mayankho oletsa mphotho (omwe amachokera ku kukhudzidwa kwakukulu kwa amygdala ndi kuwonjezeka kwa chizindikiro kudzera mu corticotropin releasing factor) ndi omwe amachititsa kuti munthu ayambe kugwiritsa ntchito mankhwala osokoneza bongo (Koob ndi Le Moal 2008 ). Mayankho ofanana ndi a chizolowezi angathandizenso kudya kwambiri anthu onenepa kwambiri.
8 Mankhwala Osokoneza Matenda ndi Mphoto ya Chakudya: Njira Yopangidwira Yogwira Ntchito
Kutha kukana chilakolako chogwiritsa ntchito mankhwala osokoneza bongo kapena kudya mopitirira muyeso kumafuna kugwira ntchito bwino kwa ma neuron circuits omwe amagwira ntchito yolamulira kuchokera pamwamba kupita pansi kuti atsutsane ndi mayankho okhazikika omwe amalosera mphotho kuchokera mukudya chakudya/mankhwala ndi chilakolako chodya chakudya/mankhwala. Pano, tawunikira ma circuits asanu ndi limodzi awa: mphotho/kusala, chizolowezi/zizolowezi, kuwongolera/ntchito yoletsa/kulamulira, chilimbikitso/chilimbikitso, kulowerera mkati, ndi kupewa kukana/kupsinjika maganizo (Chithunzi 8 ). Kutengera ndi deta yojambulidwa yomwe yaperekedwa pano, tikuganiza kuti kusiyana pakati pa kuyembekezera zotsatira za mankhwala/chakudya (mayankho okhazikika) ndi zotsatira za neurophysiological zomwe zimasunga kumwa mankhwala osokoneza bongo kapena kumwa kwambiri zakudya pofuna kupeza mphotho yomwe ikuyembekezeka. Komanso, kaya ayesedwa nthawi yoyambirira kapena yayitali yodziletsa/kudya zakudya zochepa, anthu omwe ali ndi vuto la kunenepa kwambiri amasonyeza kuti D2R yotsika mu striatum (kuphatikiza NAc), zomwe zimagwirizanitsidwa ndi kuchepa kwa ntchito yoyambira m'madera a ubongo omwe amakhudzidwa ndi salience attribution (orbitofrontal cortex) ndi inhibitory control (ACC ndi DLPFC), zomwe zimasokoneza zomwe zimapangitsa kuti munthu azichita zinthu mopitirira muyeso komanso mopanda chidwi. Mwachidule, umboni wawonekeranso pa ntchito ya interceptive ndi aversive circuitry mu kusalingana kwa dongosolo komwe kumabweretsa kumwa mankhwala osokoneza bongo kapena chakudya mokakamiza.
Chithunzi 8 Chitsanzo chopereka lingaliro la netiweki ya ma circuit olumikizana, kusokonezeka komwe kumathandizira ku gulu lovuta la machitidwe osagwirizana omwe amayambitsa chizolowezi cha mankhwala osokoneza bongo komanso kudya mopitirira muyeso kosatha: mphotho (nucleus accumbens, VTA, ndi ventral pallidum), conditioning/memory (amygdala, medial OFC yokhudza saliency, hippocampus, ndi dorsal striatum ya zizolowezi), ulamuliro wotsogola (DLPFC, ACC, inferior frontal cortex, ndi lateral OFC), chilimbikitso/drive (medial OFC yokhudza saliency, ventral ACC, VTA, SN, dorsal striatum, ndi motor cortex). Nac, nucleus accumbens, interception (Insula ndi ACC), ndi kukana/kupewa (Habenula). a Ma circuit awa akamayenderana, izi zimapangitsa kuti pakhale kuwongolera koyenera komanso kupanga zisankho. b Panthawi yoledzera, pamene kuyembekezera kwakukulu kwa mankhwala m'ma circuit a mphotho, chilimbikitso, ndi kukumbukira kumagonjetsa dera lolamulira, zomwe zimapangitsa kuti pakhale njira yabwino yoyankhira yomwe imayambitsidwa ndi kumwa mankhwalawa ndikupitilizidwa ndi kuyambitsa bwino kwa ma circuit a chilimbikitso/drive ndi memory. Ma circuits amenewa amalumikizananso ndi ma circuits omwe amakhudzidwa ndi kulamulira maganizo, kuphatikizapo stress reactivity (yomwe imaphatikizapo amygdala, hypothalamus, habenula) ndi interception (yomwe imaphatikizapo insula ndi ACC ndipo imathandizira kuzindikira chilakolako). Ma neurotransmitters angapo amakhudzidwa ndi neuroadaptations izi, kuphatikizapo glutamate, GABA, norepinephrine, corticotropin-releasing factor, ndi opioid receptors. CRF, corticotropin-releasing factor; NE, norepinephrine. Yasinthidwa ndi chilolezo kuchokera kwa Volkow et al. ( 2011b )
Chifukwa cha kusokonezeka kotsatizana m'magawo awa, anthu amatha kukumana ndi 1) kuwonjezeka kwa chilimbikitso cha mankhwala/chakudya (chogwirizana ndi kuphunzira kudzera mu machitidwe ndi zizolowezi) potengera zinthu zina zolimbikitsa (chogwirizana ndi kuchepa kwa chidwi cha gawo la mphotho), 2) kulephera kuletsa zochita mwadala (zotsogozedwa ndi zolinga) zomwe zimayambitsidwa ndi chikhumbo champhamvu chomwa mankhwala/chakudya (chogwirizana ndi kulephera kwa ntchito yoyang'anira) zomwe zimapangitsa kuti munthu ayambe kumwa mankhwala/chakudya mokakamiza, ndi 3) kuwonjezeka kwa kupsinjika maganizo komanso kupewa kusokonezeka komwe kumabweretsa kumwa mankhwala mopupuluma kuti athawe mkhalidwe wosokonezeka.
Chitsanzochi chimapereka njira zambiri zothandizira mankhwala ozunguza bongo omwe amachititsa kuchepetsa mphamvu zowonjezereka za mankhwala / chakudya, kubwezeretsanso / kupititsa patsogolo zopindulitsa zowonjezera zachilengedwe, kulepheretsa mayanjano ophunzitsidwa bwino, kulimbikitsanso ntchito zosagwiritsidwa ntchito ndi mankhwala / kuchepetsa nkhawa. , kusintha maganizo, komanso kulimbitsa mphamvu zowonongeka.
Kuvomereza
Olembawo angafune kuyamika thandizo la NIAAA pulogalamu yazitsulo ya National Institutes of Health.
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