NYAYA: Ongororo yekutsvakurudza pamusoro pe tonic (yekutanga) nekushamba (spikes) dopamine.
Neuropharmacology. 2007 Oct; 53 (5): 583-7. Epub 2007 Jul 19.
Goto Y, Otani S, Grace AA.
mabviro
Dhipatimendi re Psychiatry, Yunivhesiti ye McGill, Ongororo Yokuvaka uye Kudzidzisa, 1033 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. [email inodzivirirwa]
ngovepo
Dopamine yakave yakaongororwa zvakadzama pamusana pekuzvibatanidza kwayo kunozivikanwa mune zvinetso zvehutano uye zvepfungwa. Kunyanya, zvidzidzo mumamiriro ehutachiona zvakanyanyisa pamabasa ekukwirira kukuru, phasically yakabvisa dopamine kusunungurwa munzvimbo dzakadai se prefrontal cortex uye striatum. Zvisinei, kutsvakurudza kwakaratidza kuti dopamine kusunungurwa kunogona kunge yakaoma kunzwisisa kupfuura kungosununguka phasic; saka, panewo tanic, background dopamine release, pamwe nekuchinja mu tonic dopamine kusunungurwa kunogona kunge yakasiyana uye inokosha inoshanda basa. Nhamo, zvisinei, tonic dopamine yakasunungurwa yakagamuchira zvishoma nezvishoma. Muchidzidzo ichi, tinopfupikisa zvidzidzo zvedu zvechangobva kuitika uye tinokurukura kuti kushandiswa kweiyo dopamine system, zvose maererano nekushandiswa kwepasic uye kucheneswa kwe tonic dopamine zvakakosha kuti mabasa ehuropi nzvimbo dziwane iyi dopamine kusachengetedzwa, uye kuti kusaenzana mune idzi dopamine zvinosunungura nzira inogona kuita basa rinokosha mukurapa kwepfungwa sezvakaita schizophrenia.
Mashoko ekuti: Limbic System, Prefrontal Cortex, Nucleus Accumbens, Cognitive Functions, Animal Model, Schizophrenia
1. ziviso
Kubva pakurondedzerwa kwaro muuropi naCarlsson mu1957 (Carlsson et al., 1957), mabasa eDopamine (DA) akanyatsodzidza nekuda kwekuratidzwa kwechiitiko ichi chekutumira mumabasa akawanda emakumbo sekudzidza nekuyeuka (Grecksch) uye Matties, 1981), zvinokurudzira (Everitt naRobbins, 2005), uye mafungiro emanzwiro (Nader uye LeDoux, 1999). Uyezve, kuvhiringidzwa kwemasangano eDA kwakabatanidzwa mukusawirirana kukuru kwepfungwa uye kwepfungwa zvinosanganisira Parkinson's disease uye schizophrenia (Hornykiewicz, 1966). Mune zvidzidzo zvedu zvangobva kuitika, tinopa maonero akasiyana-siyana pamusoro pehutano hwehutungamiri hweDA, iyo yatinotaura kuti "kuderera" kwekubudiswa kweDA kunogona kukosha se "kuwedzera" kweDA kusunungurwa mukugadzirisa maitiro.
2. Dopamine spike kufema uye dopamine kusunungurwa
DA neurons inoratidza maitiro maviri akasiyana emasipiramu anotyisa: tonic single spike activity uye kuputika kwemhepo kunokwira (Grace naBunney, 1984a; Grace naBunney, 1984b). Nhasi kutyisa kunongoratidzira kuita basa rekutanga remhepo uye rinotungamirirwa ne pacemaker-semakumbo emakumbo maDon neurons (Grace naBunney, 1984b; Grace naOnn, 1989). Zvisinei, idzi DA neurons dziri pasi pesimba reGABAergic rakasimba zvikuru, kudzivirira dzimwe DA neuroni kuti dzirege kupfura mumamiriro ezvinhu echidiki (Grace naBunney, 1979). Nhasi kutyiswa kweA DA neurons kwave kuchiratidzwa kuti iite pasi ye tonic yekutanga yezinga reDA mukati ye striatum (semuenzaniso 10-20 nM mukati mharaunda inouraya (Keef et al., 1993)). Zvidzidzo zvinoratidza kuti izvi zvinopindirana nekupukunyuka kweDA kubva pane synapse kusvika kune extrasyanptic nzvimbo (Floresco et al., 2003; Grace, 1991). Nokudaro, kuwanda kweDaily extracellular DA kunotarisana nenhamba ye DA neurons inoratidzira basa rinokanganisa tonic spike (Floresco et al., 2003; Grace, 1991).
Mune chibvumirano, kushandiswa kwepasikisi yeDA system inomiririrwa nemhepo inoputika inoputika inokonzerwa ne glutamatergic excitatory synaptic drive kuma DA neurons kubva munzvimbo dzakawanda, kusanganisira pedunculopontine tegmentum (PPTg) (Floresco et al., 2003; Futami et al ., 1995) uye chinonzi subthalamic nucleus (Smith naGrace, 1992). Kuputika kunokonzera kunokonzera kunokonzera kukwirira kwepamusoro (semuzana emamiriyoni emuMM mazinga), nguva duku, kusununguka kweDA kusununguka mukati mematunhu akakurumbira (Floresco et al., 2003; Grace, 1991). Izvi zvakasimudzwa kuti zvive pasi pesimba rakasimba, reuptake inotangira mu-pre-synaptic terminals kuburikidza neDVD vatengesi (Chergui et al., 1994; Suaud-Chagny et al., 1995), saka, phasic DA yakasunungurwa yaizoita nguva inenge iri mukati me synaptic cleft uye pedyo zvikuru ne synapse (Floresco, et al., 2003; Grace, 1991; Chergui et al., 1994; Venton et al., 2003).
Tsamba yezvinyorwa zve electrophysiological zvinyorwa zve Schultz (Schultz et al., 1993; Tobler et al., 2003; Waelti et al., 2001) vakaratidza maitiro ehutano hwehutu hunoputika uye hwechibhakera cheA DA neurons. Nokudaro, DA neurons inoratidza kuputika kwemhepo kunokonzera iyo inokonzerwa nekuratidzwa kwemaropafadzo asina kutarisirwa kana zviratidzo zvekunzwa zvichirondedzera zvikomborero zvakadaro (Schultz et al., 1993). Muchibvumirano, zvidzidzo zvakare zvakaratidza kuti kudarika kwechinguva kwetinic spike kunopisa mu DA neurons kunoitika mukusakanganiswa kwezvikwereti zvinotarisirwa (Tobler et al., 2003) kana chikonzero chekuvhiringidza (Grace naBunney, 1979; Ungless et al., 2004). Schultz anoratidza kuti aya maitiro eDD spike firing anogona kushandiswa sekudzidzira zviratidzo mumagariro akarovedzwa (Waelti et al., 2001). Kunyange zvakadaro, zvakasiyana-siyana zvinokonzerwa nekubudiswa kweDA kunowanikwa mukupindurwa kwekuputika kwemauto kunopesana nekuderedza kushandiswa kwetinic spike basa re DA neuroni munzvimbo yakatarwa yakanga isina kujeka.
3. Dopamine kuenzanisa kwemaonero akasiyana mune nucleus accumbens
Kujekesa kushanda kwebasa reDA kushambadzira maererano nemashoko akabudiswa nekuputika nekupikisa kudonhedzwa kwe tonic kuputika kweA DA neuroni munzvimbo dzakatarirwa, takatsvaga maitiro eTonic uye phasic DA kusunungurwa mukugadzirisa kwezvinhu zvakasiyana mukati memukati accumbens (NAcc), apo DA yakawanda inoshandiswa kubva kune ventral tegmental area (VTA) iripo (Voorn et al., 1986). Iko Nacc inotendwa kurongedza zvinangwa-zvinotungamirirwa (Mogenson et al., 1980) sezvo inogamuchirwa sangano re synaptic kubva kune zvivako zvemuviri uye PFC (Finch, 1966; French uye Totterdell, 2002). Nokudaro, iyo NAcc inowanikwa pane zvinyorwa zvemashoko uye zvepfungwa zvinogadziriswa mumagadzirirwo emagetsi uye nekugadzira motokari zvakagadzirwa mu PFC zvinogona kusanganiswa (Grace, 2000).
Kushandisa in vivo electrophysiology pamwe chete nemagadzirirwo emagetsi eDA system muNacc, takaona kuti kusarudzwa kwemazwi eLimbic uye PFC mafambiro kunopindirana neDA DA D1 uye D2 receptors, maererano (Goto uye Grace, 2005). Nokudaro, kushandiswa kwezvinonzi D1 zvakagadzirisa zvirongwa zvechimbichi kupinda muNacc pasina kuchinja mafungiro ePCC, kunyange kudzivirirwa kweD1 receptors ane mutsigiri weD1 haana kubudisa migumisiro yakawanda kune chimbic kana PFC. Kusiyana neizvi, takaona kuti kushandiswa uye kusagadzirirwa kwevamwe D2 zvakagadziriswa uye zvakagadziriswa, maererano, mhinduro dzakabatanidzwa nePPC zvisizvo zvisingaiti maitiro emakumbo. Izvi zvinoratidza kuti, kusiyana neD1 receptor kukurudzira, vanouraya D2 receptors vari pasi pekutungamirirwa kweDA kumamiriro ekutanga, uye vanogona kuenzaniswa kana kubva pasi kubva munyika ino. Uyezve, isu takashandisa phasic uye tonic DA kusunungurwa muNacc nekuita uye kusagadzikana kwebasal ganglia nuclei iyo inoronga idzi maitiro emabasa akasiyana sezvatakangoita (Floresco et al., 2003). Sarudzo yekufambisa kwechirongwa chechimbichi yakaonekwa apo phasic DA yakasunungurwa (yakagadziriswa ne DA neuron kupisa kupisa) yakawedzerwa, asi, kuwedzerwa uye kuderera mu tonic DA yakasunungurwa yakasarudzwa uye yakagadziriswa, zvichienderana, iyo PFC inobatsira. Zvakatorwa pamwe chete, izvi zvinyorwa zvinoratidza kuti phasic DA yakasununguka inobatsira D1 receptors kuti zvive nemafungiro emakumbo, asi kubudiswa kweDONIC kuve nehutungamiri hwePPC kuburikidza neD2 receptors, uye kuwedzera kwei tonic D2 kukurudzira kuvharidzira PFC kusimbisa maitiro uye kuderera mu tonic D2 kukurudzira kubatsira PFC inobatsira.
Mukuwedzera kumigumisiro yehutano ye tonic uye phasic DA system modulation, idzi idzi dzakasiyana nedzimwe dzezvematongerwo enyika dzeDA dzakawanikwa zvakare kuratidzira maitiro ekutevedza. Nokudaro, tichishandisa shanduko yekunyanya kusarura, takaona kuti kugadziriswa kwechimbichimbi kuAcc na phasic DA kusunungurwa kunobatsira D1 receptors kunodiwa pakudzidza kwegadziriro yekupindura mukusimudzira kudzidzira, asi kuderedzwa kweDONIC kukurudzira kweD2 receptors kunokosha kubvumira kutsvaga nzira itsva yekupindura kana nzira yekuzadzisa zvinangwa ishandurwa (Goto na Grace, 2005). Nokudaro, kubviswa kwetinic spike kuputika kweA DA neurons nekusasikirwa kwemararamiro anotarisirwa, izvo zvinofanira kukonzera kuderedzwa kweDONIC DA kusunungurwa mu NAcc, inogona kushandiswa kusarudza kusarudzira kugadziriswa kwechirongwa chekushaya mararamiro (iyo Meck naBenson, 2002).
4. Mhedziso yekudzvinyirira pane dopamine-inotenderedzwa ne synaptic plasticity
I PFC ndeimwe nzvimbo inogamuchira DA yekuchengetedzwa kubva kuVTA (Thierry et al., 1973). Kusiyana ne-striatum, iyi maDosi yeAIDS anochengetedza kupinda PFC inofananidzwa zvishoma; zvisinei, zvichienderana nenhamba yakaderera yezvivako zvekutsvaga uye dhigirii yepamusoro yeDaily munharaunda iyi, DA inoramba iine hukuru hwemagetsi ehutano nehutano hwehutano munzvimbo ino. DA inosunungurwa muPCC yakaratidza kuti inonyanya kukanganisa kushanda kwepfungwa dzakadai sokushanda pfungwa (Goldman-Rakic, 1995). Uyezve, kuchinjwa kweDA kusunungurwa mu PFC kunonzi kunoitika pazvinenge zvichisvibisa kudzvinyirira. Nokudaro, zvidzidzo zvakaratidza kuti DA yakasunungurwa muFPC inowedzera pasi pechirwere chakanyanya kufungidzirwa (Gresch et al., 1994; Morrow et al., 2000), asi apo kushungurudzika kunogara kusingagumi (semuenzaniso pamusoro pevhiki dze2 dzekutambudzika), kuderera yezvinodiwa DA kusunungurwa mu PFC inoonekwa (Gresch et al., 1994). Kuwedzera kwekuwedzera kwakadaro uye kuderera muDA kubudiswa kwekubudiswa kwe synaptic plasticity mu PFC mitambo yakaongororwa se synaptic plasticity yakadai sekugara kwenguva refu (LTP) uye kuora mwoyo (LTD) muPFC: chirongwa chinozivikanwa kuva DA-chinomiririra (Otani et al., 2003). Takaona kuti chirongwa cheLPP chinonzi hippocampal chinopinda muFPC, chinoenderana neD1 activation (Gurden et al., 2000), yakabatwa nechinguva chiduku chekushungurudzika kwakanyanya, asi apo kusvibiswa kwepfungwa kunowedzera, LTP induction is incaired (Goto uye Grace, 2006). Somugumisiro, kune hukama hwakakonzerwa neU uhu hwakafanana pakati pekuiswa kwe synaptic plasticity mumugwagwa weHippocampal-PFC uye nguva yekushungurudzika kwepfungwa, iyo inopindirana nehuwandu hweDVD kusunungurwa munguva yekudzvinyirira kunetseka. Kunyange zvisinganzwisisike kana kuwedzera kweDA kusununguka kunopfuurira munguva yeLPP induction, kudhindwa kweDA-kunokonzerwa kuchinja kwephosphorylation yechipiri mamiririkemu akadai seC CREB uye DARPP-32 (Greengard, 1999), izvo zvinoda kubudiswa LTP mumugwagwa uyu (Hotte et al., 2007), inozivikanwa kuva nemigumisiro yakanyanya kurera nguva yeDP receptor stimulation (Fig. (Fig.1A1A uyeXXUMUMBBNNXB).
Fgure 1
Kubva pane zvakawanikwa kubva kuongororo yemhuka, mhando dzinoverengeka dzinogona kutorwa kuaccount yezvimwe zvekucherechedzwa kunoitwa maererano nekugona kwekukonzeresa maitiro ehutachiona hwepfungwa senge schizophrenia. (A) Mune zvakajairwa mamiriro pane zvine mwero (zvimwe…)
Mufananidzo 2
Shanduko muhukama hwakasarudzika hwakafanana neU-hunogona kupa kune iyo pathophysiology yeschizophrenia. (A) Zvidzidzo zvinoratidza kuti hukama huripo pakati pekushanda ndangariro uye PFC yekumisikidza inogona zvakare kuratidza seyakagadziriswa U-chimiro. Mumuenzaniso uyu, (more…)
Kushandisa iyo in vitro muchikamu chekugadzirira, takapa dhiyabhorosi iyo inobatanidzwa inoremekedzana nehutano hunoshandiswa nekuderedzwa kwe tonic, ruzivo DA kusunungurwa mu PFC (Matsuda et al., 2006). Nokudaro, muchikamu chekugadzirira apo dhigirii dzeDA dzakagadziriswa kubva mumasero emasero uye yakawanda yeDA yakasara inoshambidzwa kunze panguva yekudzivirira, iyo yakatarwa DA inofungidzirwa inotarisirwa kuva yakanyanya kuderera kupfuura iyo iripo panguva yakajeka, mumamiriro ezvinhu. Takaona kuti pasi pemamiriro ezvinhu akadaro, kukwirira kwepamusoro-soro tetanic kukurudzira iyo inowanzokwanisa kuunza DPP mu vivo panzvimbo pacho kwakaguma mukududzirwa kwe LTD. Zvisinei, apo madiki eDA akashandiswa mubhedha yekushambidza kutevedzera tonic yakasununguka DA kusunungurwa iripo mu vivo, high frequency stimulation zvino inokonzera kubudiswa kweLPP, zvichiratidza kuti nheyo yezera reDonic DA inzwi rinogona kugadzirisa polarity ye synaptic plasticity iyo inogona kukonzerwa mu PFC network (Fig. 1A). Izvozvo zvakaderedzwa mumamiriro ekutanga DA tone inonzi yakasvike kuitika mukati mePCC inotevera kusagadzikana kwekushungurudzika (Gresch et al., 1994). Zvechokwadi, uchapupu hwedu hwepakutanga hunoratidza kuti high frequency stimulation iyo inowanzoita kuti chirongwa chechirwere chechirongwa chechirchi muPPC muzviri mumamiriro ezvinhu chichizoita kuti kuve nekuderedzwa kwe LTD kana zvipfuwo zvichisvikirwa kumavhiki e2 asinganonoki kana kuti kudzivisa kushungurudzika mupfungwa (Goto et al., 2007).
5. Zvinokonzerwa ne tonic uye phasic dopamine kusunungurwa mune zvinetso zvepfungwa
Hunyengeri uye kuvharirwa kweDA kubudiswa muPFC kwakarongedzerwa sezvirwere zvepathophysiological mu schizophrenia (Andreasen et al., 1992; Yang na Chen, 2005), nechisungo chakasiyana nezviratidzo zvisina kunaka zvechirwere ichi (eg anhedonia, social withdrawal) ( Andreasen et al., 1992). Mamiriro ezvinhu akafanana nehupenzi anowanzonziwo kune vanhu vane matambudziko emafungiro emafungiro akadai sekuora mwoyo (Galynker et al., 1998). Tichifunga kuti kusingaperi kunetseka kunozivikanwa kunokonzera kuora mwoyo uye, naizvozvo, kwave kushandiswa semuenzaniso wemhuka yekuodzwa mwoyo (Katz et al., 1981), kushandiswa kusina kuwanikwa kwe LTD nokuregererwa kwetsika yeDONIC DA kusunungurwa mu PFC inogona kubatanidzwa mune zviratidzo zvisina kunaka zvechichichiphrenia uye kuora mwoyo (Fig. 1B).
Kunyange zvazvo kusaremekedza kwakasarudzwa kuti kuvepo mune varwere vechichimba, pane mamwe mitsara inoratidza kuti basa rePFC rinogona kunge rakanyanya kukura muvanhu vane schizophrenia kana vachienzaniswa nedzimwe nharaunda mune zvimwe zviitiko zvakadai mukuita zvakaenzanisira nyore kushanda memori mabasa (Callicott et al., 2003; Manoach, 2003). Nokudaro, zvidzidzo izvi zvinoratidza kuti hukama hwakakonzerwa neU hwakasikwa huripo pakati pekushanda nekurangarira kweFCC, uye kuti schizophrenia varwere vanogona kuratidza kushandiswa kwepamusoro yekugadzirisa kukwanisa kuenzaniswa nekutonga, zvichiita kuti kuwedzerwa kushandiswa nemabasa asina kuoma (Fig 2A) (Manoach , 2003). Zvechokwadi, tawana hukama hwakafanana hwakafanana neU huno pakati peLPP induction mu PFC uye nemigumisiro yekunyanya kunetseka (Goto uye Grace, 2006). Kunyanya, takaonawo kuchinja kwehukama hwakasimudzika u hwakafanana nehutano hwakanyanya hwekunyanya kushungurudzika mumuenzaniso wemhuka we schizophrenia (Fig 2B) (Goto uye Grace, 2006). Zvechokwadi, zvinozivikanwa kuti schizophrenia varwere vanoratidza unhu hwekukanganisa kukuru kwekushungurudzika, kwakabatanidzwa nekunetseka kudzoka zvakare (Rabkin, 1980).
6. Mhedziso
Kuwedzera uye kuderera muDVD kusunungurwa kunogona kunge kwakasiyana zvakasiyana nehuropi hunoita basa, izvo zvinogona kuva "Yin" uye "Yang" zvichienderana nehupenyu hwehupenyu. Nokudaro, kufungisisa kwehupenyu hwekuchinja kweDA kunokosha pamabasa akaenzana emagariro europi anogamuchira DA kusachengetedzwa kusanganisira NAcc uye PFC. Chimwe chikero chisingaenzaniswi chekubudiswa kweDA, kunyanya muFPC, inogona kuita basa rinokosha mukurapa kwepfungwa dzepfungwa dzakadai schizophrenia uye kuora mwoyo.
KUTENDA
Basa iri rakatsigirwa neNARSAD Young Investigator Award, HFSP Short Term Fellowship (YG), Mutungamiri weFrance weKutsvakurudza, Centre National de la Recherche Scientifique (SO), uye USPHS MH57440 (AAG).
Mashoko Omuzasi
Iyi ip file PDF yezvinyorwa zvisingabvumirwi zvakagamuchirwa kuti zvinyorwe. Sevhisi kune vatengi vedu isu tiri kupa iyi shanduro yekutanga yezvinyorwa. Ichinyorwa ichocho chichanyatsogadziridzwa, kufungidzirwa, uye kuongororwa kwehupupuriro hunoguma husati hwabudiswa muhuwandu hwekupedzisira huripo. Ndapota cherechedza kuti munguva yekugadzira mapurogiramu mapepa angangowanikwa iyo inogona kukanganisa zviri mukati, uye zvinyorwa zvose zvemitemo zvinoshanda kumagazini zvine chokuita.
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