MAFUNSO: kafukufuku wa kafukufuku wokhudzana ndi tonic (zofunikira) motsutsana ndi phasi (spikes) dopamine.
Neuropharmacology. 2007 Oct; 53 (5): 583-7. Epub 2007 Jul 19.
Goto Y, Otani S, Grace AA.
gwero
Dipatimenti ya Psychiatry, Yunivesite ya McGill, Zomangamanga ndi Zomangamanga, 1033 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. [imelo ndiotetezedwa]
Kudalirika
Dopamine yayamba kufufuzidwa kwakukulu chifukwa cha kugwiriridwa kwake kodziŵika m'maganizo angapo a m'maganizo ndi m'maganizo. Makamaka, kufufuza m'matendawa kumagwira ntchito zapamwamba zamakono, phasically inachotsa dopamine kumasulidwa m'madera monga prefrontal cortex ndi striatum. Komabe, kafukufuku wasonyeza kuti dopamine kumasulidwa kungakhale kovuta kwambiri kuposa kumasulidwa kwa phasic; Choncho, palinso kutulutsa, kutuluka kwa dopamine kumasulidwa, ndi kusintha kwa tonic dopamine kumasulidwa kukhala ndi ntchito yapadera komanso yofunika kwambiri. Mwatsoka, komatu, tonic dopamine kumasulidwa sadalandira chidwi pang'ono. Phunziroli, timafotokozera mwachidule maphunziro athu atsopano ndikukambirana momwe dongosolo la dopamine likuyendera, palimodzi potsatsa phokoso ndi kuchepa kwa dopamine ya tonic ndizofunikira kuti ntchito za m'madera a ubongo zikhale ndi malo osungiramo dopamine, komanso kusagwirizana kumeneku mu njira zotulutsira dopamine zingathandize kwambiri m'maganizo a maganizo monga schizophrenia.
Mfundo zofunikira: Limbic System, Prefrontal Cortex, Nucleus Accumbens, Cognitive Functions, Animal Model, Schizophrenia
1. Introduction
Malinga ndi kufotokozedwa kwake mu ubongo ndi Carlsson mu 1957 (Carlsson et al., 1957), maudindo a dopamine (DA) akhala akuphunzira kwambiri chifukwa cha kuwonetseratu kwa kayendedwe kotereku mu ntchito zambiri za ubongo monga kuphunzira ndi kukumbukira (Grecksch ndi Matties, 1981), chilimbikitso (Everitt ndi Robbins, 2005), ndi machitidwe a maganizo (Nader ndi LeDoux, 1999). Kuphatikizanso apo, kusokonezeka kwa machitidwe a DA kwaphatikizidwa ndi matenda aakulu a ubongo ndi matenda omwe amaphatikizapo matenda a Parkinson ndi schizophrenia (Hornykiewicz, 1966). Phunziro lathu laposachedwapa, timapereka maonekedwe apadera pazomwe ntchito ya DA ikuyendera, zomwe timati "kuchepa" kwa DA kumasulidwa kungakhale kofunikira ngati "kuwonjezeka" kwa DA kumasula khalidwe.
2. Dopamine akuthamanga ndi kutulutsa dopamine
DA neurons amasonyeza njira ziwiri zochepetsera zida zowonongeka motere: Chingwe cha tonic chosasunthika ndipo chimathamanga kwambiri (Grace ndi Bunney, 1984a; Grace ndi Bunney, 1984b). Kuwotcha kwa Tonic kumakhala kochita zokhazokha ndipo kumayendetsedwe ndi mpweya wamagetsi a DA (Grace ndi Bunney, 1984b; Grace ndi Onn, 1989). Komabe, madokotala a DA awa amachititsidwa ndi mphamvu yotchedwa GABAergic, yomwe imalepheretsa kuti ma DA neononi asathamangidwe pokhapokha (Grace ndi Bunney, 1979). Kuwonetsa kwa Tonic kuwombera kwa DA neurons kumasonyezedwa kuti ndilowetse pansi mphamvu ya tonic ya DA yomwe ili mkati mwa statum (mwachitsanzo 10-20 nM mkati mwa dera lopweteka (Keef et al., 1993)). Kafukufuku akusonyeza kuti izi ndizopambana ndi DA kuchoka ku synapse kupita ku dera la extrasyanptic (Floresco et al., 2003; Grace, 1991). Choncho, kuchuluka kwa toniclularla DA kumadalira chiwerengero cha DA neurons zomwe zimasonyeza zochitika zokhazokha (Floresco et al., 2003; Grace, 1991).
Mu mgwirizano, ntchito ya DA yomwe ikuyimiridwa ndi kuphulika kwazomwe zimapangidwira zimadalira mphamvu yamagetsi yokhala ndi mphamvu ya glutamateric yomwe imachokera ku madera osiyanasiyana a DA, kuphatikizapo pedunculopontine tegmentum (PPTg) (Floresco et al., 2003; Futami et al ., 1995) ndi pulogalamu yachinsinsi (Smith ndi Grace, 1992). Kuphulika kumathamanga kumayambitsa matalikidwe apamwamba (mwachitsanzo mamita mazana a mamita mpaka mamita), kutuluka kwa DA, nthawi yochepa, kumasulidwa kwa DA kumalo ena omwe amaloledwa (Floresco et al., 2003; Grace, 1991). Izi zikutanthauza kuti apolisi akuluakulu a DA amawomboledwa kuti adziwomboledwe mwatsatanetsatane kudzera m'mabuku a DA otsatsa malonda (Chergui et al., 1994; Suaud-Chagny et al., 1995). mofulumira mkati mwa synaptic cleft komanso pafupi kwambiri ndi synapse (Floresco, et al., 2003; Grace, 1991; Chergui et al., 1994; Venton et al., 2003).
Zolemba zambiri za electrophysiological za Schultz (Schultz et al., 1993; Tobler et al., 2003; Waelti et al., 2001) adziwonetsa khalidwe labwino la kuwombera minofu ya DA neurons. Momwemonso, ma DA neonons amayamba kuwombera chifukwa cha mphoto zosayembekezereka kapena zizindikiro zowonongeka zowonetsera mphoto zotere (Schultz et al., 1993). Mu mgwirizano, kafukufuku adawonetsanso kuti kusokonezeka kwa toniki koopsa kwa DA neononi kumachitika chifukwa cha kuchepa kwa madalitso (Tobler et al., 2003) kapena chisokonezo (Grace ndi Bunney, 1979; Ungless et al., 2004). Schultz akusonyeza kuti zida za DA zothamanga zingagwiritsidwe ntchito ngati zizindikiro zozizwitsa m'magulu a ubongo (Waelti et al., 2001). Ngakhale zili choncho, ntchitoyi imakhala yovuta kwambiri chifukwa cha kuwomboledwa kwa DA komwe kumachitika chifukwa cha kupwetekedwa kwapadera kwa ntchito ya tonic ya DA tonopera m'madera omwe sankadziwa.
3. Dopamine kusinthika kwa zochitika zomwe zimalowetsa mu nucleus accumbens
Pofuna kudziwa momwe ntchito ya DA ikugwiritsira ntchito poyendetsera mauthenga omwe amafalitsidwa ndi kuwombera mowonjezereka ndi kuwombera kwa tonic ya DA neurons m'madera omwe akuwunikira, tafufuza zotsatira za kumasulidwa kwa DA tonic ndi phasic kuwonjezera pa zomwe zimayambira mkati (accumulated) (NAcc), kumene DA wodalirika kuchokera ku ventral tegmental (VTA) alipo (Voorn et al., 1986). The NAcc imakhulupirira kuti imayendetsa khalidwe lotsogolera zolinga (Mogenson et al., 1980) pamene amalandira mphamvu za synaptic zopangidwa kuchokera ku ziwalo zam'mimba ndi PFC (Finch, 1966; French ndi Totterdell, 2002). Choncho, NAcc ilipo pomwe mauthenga ndi zochitika zamaganizo zomwe zimagwiritsidwa ntchito m'miyendo yamagetsi ndi kukonza magalimoto zomwe zimagwiritsidwa ntchito mu PFC zikhoza kuphatikizidwa (Grace, 2000).
Kugwiritsira ntchito in vivo electrophysiology kuphatikizapo mankhwala opangidwa ndi DA m'kati mwa NAcc, tinapeza kuti kusintha kwa maselo ndi PFC kumagwirizanitsa ndi DA D1 ndi D2 receptors, motero (Goto ndi Grace, 2005). Choncho, kuyambitsidwa kwa madokotala a D1 kunathandiza kuti ziwalozo zikhale zopangidwa ndi feteleza ku NAcc popanda kuthandizira ziphuphu za PFC, ngakhale kutsekedwa kwa D1 kulandira mankhwala ndi mdani wa D1 sikunapangitse zotsatira za zimbamu kapena PFC. Mosiyana ndi zimenezi, tinapeza kuti kusinthidwa ndi kulepheretsa anthu odwala D2 kuti athandizidwe komanso kuwathandiza, motero, mayankho omwe amathandizidwa ndi PFC popanda kuthandizira ziwalo zambidzi. Izi zikusonyeza kuti, mosiyana ndi kukakamizidwa kwa D1 kulandira, kulandira D2 receptors kuli pansi pa ulamuliro wa DA pa chikhalidwe choyambirira, ndipo akhoza kusinthidwa kapena kutsika kuchokera ku dziko lino. Kuwonjezera pamenepo, tinagwiritsanso ntchito ntchikiti ndi tonic DA kumasulidwa mu NAcc ndi kutsegula ndi kusokoneza basal ganglia nuclei omwe amachititsa zochitika zosiyana ntchito monga momwe posachedwa (Floresco et al., 2003). Kusankhidwa kwa ziwalo za maimbambo kunayang'anitsitsa pamene kupulumutsidwa kwa DA (kupitilizidwa ndi DA neuron kuwombera kuwombera) kukuwonjezeka, komabe, kuwonjezeka ndi kuchepa kwa kutulutsa kwa DA kwachisawawa kwachinyengo ndikuwathandiza, motsogoleredwa ndi PFC. Zowonongeka, izi zikuwonetsa kuti kumasulidwa kwa DAs kumapangitsa kuti D1 receptors ikhale ndi mphamvu zozizwitsa, pamene kumasulidwa kwa DAI kumatulutsa zotsatira za PFC kudzera mwa mapepala a D2, ndipo kuwonjezereka kwa D2 kumapangitsa kuti PFC iwonongeke komanso kumachepetsa kuchititsa chidwi kwa D2. PFC.
Kuphatikiza pa zotsatira za thupi la kusintha kwa mphamvu za DA ndi phasic DA, zigawo zosiyana siyana za DAzi zinapezedwanso kuti ziwonetsetse khalidwe. Choncho, pogwiritsa ntchito khalidwe lopangira chisankho, tinapeza kuti kuyendetsa ziwalo za limbic ku NAcc ndi phasic DA kumasula ma D1 receptors n'kofunika kuti aphunzire njira yowonetsera polimbikitsana kuphunzira, koma kuchepetsa kuthamanga kwa DIYNX kwa DIYNUMX n'kofunika kulola kusintha kwa njira yatsopano yowonetsera pokhapokha ngati mutha kukwaniritsa cholinga chanu (Goto ndi Grace, 2). Choncho, kuchotseratu kuthamanga kwa tononi za DA kuwonjezera pa malipiro oyembekezeredwa, zomwe ziyenera kuchepetsa kuchepetsedwa kwa DAC ku kampani ya NAcc, ingagwiritsidwe ntchito poyambitsa njira yowonongeka yowonongeka yomwe imaphatikizapo kusintha kwa khalidwe (Meck ndi Benson, 2005).
4. Zotsatira za kupsinjika pa dopamine-amadalira syntaptic plastiki
PFC ndi dera lina limene limalandira ufulu wothandizidwa ndi DA kuchokera ku VTA (Thierry et al., 1973). Mosiyana ndi striatum, madandaulo a DA awa mu PFC ndi ochepa; Komabe, chifukwa cha malo ochepa omwe amapezeka ndi malo opambana a DA muderali, DA idakali ndi zotsatira zapamwamba zamagetsi komanso zochitika mu ubongo. DA yamasulidwa mu PFC yasonyezedwa kuti ndi yovuta kwambiri kuti azidziŵa zinthu monga kugwiritsira ntchito ntchito (Goldman-Rakic, 1995). Komanso, kusintha kwa DA kumasulidwa mu PFC kunanenedwa kuti kumachitika pokhapokha atakhala ndi nkhawa. Choncho, kafukufuku wasonyeza kuti DA yatuluka mu PFC yowonjezereka mwachangu (Gresch et al., 1994; Morrow et al., 2000), pamene mavuto amakhala aakulu (mwachitsanzo kuposa masabata a 2 ovuta), kuchepa za kumasulidwa kwa DA ku PFC zikuwonetsedwa (Gresch et al., 1994). Zotsatira za kuwonjezeka kotereku ndi kuchepa kwa DA kuchoka pa mapuloteni a chipanichi m'mipando ya PFC anayesedwa monga syntaptic plastiki monga momwe angathere nthawi yaitali (LTP) ndi kuvutika maganizo (LTD) mu PFC: njira yomwe imadziwika kuti ndi DA (Otani et al., 2003). Tapeza kuti pulojekiti ya LTP yomwe imagwira ntchito ku PFC, yomwe imadalira D1 activation (Gurden et al., 2000), imathandizidwa ndi nthawi yochepa kwambiri ya nkhawa, pamene nthawi yowonjezera yowonjezereka imawonjezereka, kulembedwa kwa LTP kuli kovuta (Goto ndi Grace, 2006). Zotsatira zake, pali mgwirizano wofanana ndi U womwe umakhala pakati pa pulogalamu ya syntaptic plasticity mu msewu wa hippocampal-PFC komanso nthawi ya kupsinjika maganizo, yomwe ikugwirizana ndi kuchuluka kwa DA kutulutsidwa pakadutsa nkhawa. Ngakhale sizikudziwikanso ngati kuwonjezeka kwa DA kumasulidwa panthawi ya kulumikizidwa kwa DPP, kusintha kwa DA kumasintha phosphorylation ya mamolekyu amtundu wachiwiri monga CREB ndi DARPP-32 (Greengard, 1999), zomwe zimafunikila kudulidwa LTP mumsewu uwu (Hotte et al., 2007), amadziwika kuti ali ndi zotsatira zomwe zimatulutsa nthawi ya DA yomwe imakopeka (mkuyu (fig. 1A1A ndiXXUMUMB2B).
Fsungani 1
Kutengera zomwe apeza kuchokera ku kafukufuku wazinyama, mitundu ingapo ingatengeredwe pazomwe zinawonetsedwa pazomwe zingayambitse zovuta zamatenda amisala monga schizophrenia. (A) Momwe zimakhalira pang'onopang'ono (More…)
Chithunzi 2
Kusintha kwa maubwenzi omwe adasandulika U kumatha kuyambitsa matenda am'mimba mwa schizophrenia. (A) Kafukufuku akuwonetsa kuti ubale womwe ulipo pakati pokumbukira kugwira ntchito ndi kuyambitsa kwa PFC amathanso kukhalanso mawonekedwe a U. Mu chitsanzo ichi, (more…)
Pogwiritsa ntchito majekiti a vitamini, tapereka deta yomwe ili ndi zofunikira zokhudzana ndi ntchito zomwe zimachitidwa ndi kuchepetsedwa kwa tonic, kumasulidwa kwa DA ku PFC (Matsuda et al., 2006). Kotero, mu kukonzekera kagawo komwe DA amagwirizanitsa ndi chitetezo kuchokera ku matupi ndi kuwerengeka kwakukulu kwa DA kumatsuka panthawi yopuma, chiwerengero cha DA chiyenera kukhala chochepa kwambiri kuposa chomwe chiripo panopa, mwachikhalidwe. Tapeza kuti m'mikhalidwe yotereyi, kuthamanga kwapamwamba kwa tetanic komwe kumakhala kokwanira kuchititsa LTP mu vivo mmalo mwake kunabweretsa kudulidwa kwa LTD. Komabe, pamene DA inagwiritsidwa ntchito m'kati mwa madzi osambira kuti azitsanzira mchitidwe wa DA womwe umatulutsidwa mu vivo, kuthamanga kwapamwamba komwe kumachititsa kuti pulogalamu ya LTP ipangidwe, kutanthauza kuti msinkhu wa tonic DA tone ukhoza kuzindikira Synaptic plasticity yomwe ingagwiritsidwe ntchito mu PFC (Fig. 1A). Zomwe zimachititsanso kuchepetsa chikhalidwe cha DA zikufotokozedwa kuti zikuchitika mkati mwa PFC pambuyo pozizira kwambiri (Gresch et al., 1994). Inde, umboni wathu woyambirira umasonyeza kuti kuthamanga kwapamwamba komwe kumapangitsa kuti pulogalamu ya pulogalamu ya phokoso ku PFC ikhalepo mu chikhalidwe chake chidzabweretsa kudulidwa kwa LTD pamene zinyama zidzatuluke ku masabata a 2 omwe amazizira kwambiri (Goto et al., 2007).
5. Zotsatira za kutulutsa ndi kutulutsa dopamine kumasulidwa mu matenda a maganizo
Andreasen et al., 1992; Yang ndi Chen, 2005), ali ndi mgwirizano wapadera ndi zizindikiro zosokoneza za matendawa (mwachitsanzo, anhedonia, chikhalidwe cha anthu) ( Andreasen et al., 1992). Chikhalidwe chofanana chachinyengo chimanenedwa ndi anthu omwe ali ndi matenda a maganizo monga kuvutika maganizo (Galynker et al., 1998). Chifukwa chakuti kupanikizika kosayembekezereka kumadziwika kuti kumapangitsa kuti anthu azivutika maganizo, choncho, akhala akugwiritsidwa ntchito ngati chinyama cha kuvutika maganizo (Katz et al., 1981), kusowa mwadzidzidzi kwa LTD ndi kuchepetsa chikhalidwe cha tonic DA kutuluka mu PFC kungakhalepo mu zizindikiro zoipa za schizophrenia ndi kuvutika maganizo (mkuyu 1B).
Ngakhale kuti anthu amakhulupirira kuti ali ndi mtima wosadzikonda, amakhala ndi zifukwa zina zomwe zikusonyeza kuti ntchito ya PFC ingakhale yapamwamba kwambiri kwa anthu odwala matenda a schizophrenia poyerekeza ndi zinthu zomwe zimakhala bwino monga momwe zimakhalira ndikugwira ntchito zosavuta kuzikumbukira (Callicott et al., 2003; Manoach, 2003). Choncho, kafukufukuyu akusonyeza kuti ubale wofanana ndi U ulipo pakati pa kugwiritsira ntchito kukumbukira ndi kutsegula kwa PFC, ndipo odwala schizophrenia angasonyeze kuchepetsa mphamvu yogwira ntchito poyerekeza ndi kulamulira, zomwe zimapangitsa kuti apite patsogolo ndi ntchito zosavuta (Mkuyu 2A) (Manoach , 2003). Inde, tapeza mgwirizano wofanana ndi womwe uli pakati pa LTP kudulidwa mu PFC komanso zotsatira za vuto lalikulu (Goto ndi Grace, 2006). Makamaka, tawonanso kusintha kwa ubalewu wofanana ndi U womwe umagwirizanitsa ndi zovuta zowonjezereka zovuta zowonongeka mu zinyama za schizophrenia (mkuyu 2B) (Goto ndi Grace, 2006). Ndipotu, zimadziwika kuti odwala schizophrenia amasonyeza khalidwe lalikulu la kuvutika maganizo, lomwe lagwirizana ndi kuganiza kuti abwerere (Rabkin, 1980).
6. Kutsiliza
Kuwonjezeka ndi kuchepa kwa kumasulidwa kwa DA kungakhale ndi zotsatira zosiyana kwambiri pa ubongo, zomwe zingakhale zonse "Yin" ndi "Yang" malingana ndi chikhalidwe cha zamoyo. Choncho, kulingalira za chikhalidwe chotsatira cha kusintha kwa DA n'kofunika kwambiri kuti ntchito zachigawo za ubongo zilandire chipulumutso cha DA kuphatikizapo NAcc ndi PFC. Kusiyanitsa kwa DA, makamaka mu PFC, kungathandize kwambiri pa matenda opatsirana pogonana monga schizophrenia ndi kuvutika maganizo.
Zothokoza
Ntchitoyi inalimbikitsidwa ndi mphoto ya NARSAD Young Investigator, HFSP Short Term Fellowship (YG), Minister of France Research, Center National de la Recherche Scientifique (SO), ndi USPHS MH57440 (AAG).
Mawu a M'munsi
Imeneyi ndi fayilo ya PDF ya zolembedwa zosavomerezeka zomwe zavomerezedwa kuti zifalitsidwe. Monga ntchito kwa makasitomala athu ife tikupereka malemba oyambirira a zolembedwazo. Mipukutuyi idzayambanso kujambula, kufotokozera, ndi kubwereza umboni umene umapezekapo musanatulutsidwe mawonekedwe ake omalizira. Chonde dziwani kuti panthawi yopanga zolakwika zingapezeke zomwe zingakhudze zomwe zili, komanso zotsutsana ndi malamulo zomwe zimagwiritsidwa ntchito pa magaziniyo.
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