LIPOTSO: Tlhahlobo ea lipatlisiso mabapi le "tonic" (baseline) le phasic (spikes) dopamine.
Neuropharmacology. 2007 Oct; 53 (5): 583-7. Epub 2007 Jul 19.
Goto Y, Otani S, Mohau AA.
mohloli o moholo
Lefapha la Psychiatry, Univesithi ea McGill, Setsebi sa Lipatlisiso le Koetliso, 1033 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. [imeile e sirelelitsoe]
inahaneloang
Dopamine e entse tlhahlobo e batsi ka lebaka la ho kenya letsoho ha eona ho tsejoang mathateng a mangata a kelello le a kelello. Haholo-holo, lithuto tsa maemo a bophelo ba methapo li shebile karolo ea bophahamo bo phahameng, phaphatso ea phallo ea dopamine libakeng tse kang preortalal cortex le striatum. Leha ho le joalo, lipatlisiso li bontšitse hore ho lokolloa ha dopamine ho ka ba thata ho feta feela ho lokolloa ha phasic; ka hona, ho na le tokollo ea dopamine ea tonic, ea morao-rao, e nang le liphetoho litokollong tsa tonic dopamine tse ka bang le likarolo tse ikhethang le tsa bohlokoa tsa tšebetso. Ka bomalimabe, leha ho le joalo, tokollo ea tonic dopamine e amohetse tlhokomelo e fokolang. Thutong ena, re akaretsa lithuto tsa rona tsa morao-rao 'me re buisana ka hore na modulation ea sistimi ea dopamine e sebetsa joang mabapi le phasic activation le attenuation ea tonic dopamine ho bohlokoa mesebetsing ea libaka tsa boko tse fumanang ts'ebetso ea dopamine, le hore ho se lekane lits'ebetsong tsena tsa dopamine. e ka bapala karolo ea bohlokoa lithutong tsa mafu a kelello tse kang schizophrenia.
Mantsoe a bohlokoa: Sistimi ea Limbic, Cortex ea Pele, Li-Accumbens tsa Nyutlelie, Mesebetsi ea Khethollo, Mohlala oa Phoofolo, Schizophrenia
1. Selelekela
Ho tloha ka litlhaloso tsa eona bokong ke Carlsson ho 1957 (Carlsson et al., 1957), likarolo tsa dopamine (DA) li ithutoe haholo ka lebaka la ts'ebetso e bonts'itsoeng ea ts'ebetso ena ea transmitter mesebetsing e mengata ea boko joalo ka ho ithuta le ho hopola (Grecksch le Matties, 1981), khothatso (Everitt le Robbins, 2005), le boits'oaro ba maikutlo (Nader le LeDoux, 1999). Ho feta moo, ho sitisoa ha lits'ebetso tsa DA ho kentsoe ts'ebetsong e kholo ea methapo ea kelello le mafu a kelello ho kenyeletsa lefu la Parkinson le schizophrenia (Hornykiewicz, 1966). Lithutong tsa rona tsa morao-rao, re fana ka pono e ikhethang mabapi le bohlokoa bo sebetsang ba molao oa tsamaiso ea DA, moo re fanang ka maikutlo a hore "fokotseha" ea tokollo ea DA e kanna ea ba bohlokoa joaloka "keketseho" ea tokollo ea DA ka boits'oaro ba boitšoaro.
2. Dopamine spike firing le tokollo ea dopamine
Li-neurons tsa DA li bonts'a mekhoa e 'meli e ikhethileng ea ho thunya spike: ts'ebetso ea spike e le' ngoe le ho phatloha ha spike (Mohau le Bunney, 1984a; Mohau le Bunney, 1984b). Ho thunya ka tonic ho bolela ketsahalo e etsahalang ka boeona e etsahalang ka tšohanyetso 'me e khannoa ke maqhubu a kang membemane a kopaneng a li-neuron tsa DA (Mohau le Bunney, 1984b; Mohau le Onn, 1989). Leha ho le joalo, li-neuron tsena tsa DA li tlas'a tšusumetso ea tšubuhlellano e matla ea GABAergic, e thibela li-neuron tse ling tsa DA hore li se ke tsa thunya ka mokhoa o ikemetseng maemong a basal (Mohau le Bunney, 1979). Ho thunngoa ha Tonic ka li-neurons tsa DA ho bontšitsoe ho tlatsa boemo ba motheo ba tonic ea DA ka har'a striatum (mohlala 10-20 nM ka hare ho setereke (Keef et al., 1993). Boithuto bo fana ka maikutlo a hore sena se hokahanngoa le ho pholoha ha DA ho tloha synapse ho ea sebakeng sa extrasyanptic (Floresco et al., 2003; Mohau, 1991). Ka hona, ho ts'oaroa ha DA-tonic extracellular DA ho ipapisitse le palo ea li-neuron tsa DA tse bonts'ang mesebetsi ea spikeane ea tonic spike (Floresco et al., 2003; Mohau, 1991).
Ka konteraka, ts'ebetso ea phasic ea ts'ebetso ea DA e emeloang ke mokhoa oa ho phatloha ha spike fensetere e its'etleha ho glutamatergic thabo e matla ea synaptic drive ho li-neurons tsa DA ho tsoa libakeng tse 'maloa, ho kenyelletsa le pedunculopontine tegmentum (PPTg) (Floresco et al., 2003; Futami et al. ., 1995) le subthalamic nucleus (Smith le Grace, 1992). Ho phatloha ka sekhahla ha sefofane ho baka boemo bo phahameng (mohlala, makholo a μM ho ea ho li-mM), nako e khuts'oane, phasic DA e lokolla intrasynaptically kahare ho libaka tse boletsoeng (Floresco et al., 2003; Mohau, 1991). Ts'oaetso ena e phahameng ea DA e fana ka maikutlo a hore e ka ba tlasa maemo a matla, a ho khutlisetsa hang-hang litsing tsa pre-synaptic ka batsamaisi ba DA (Chergui et al., 1994; Suaud-Chagny et al., 1995), ka hona, phasic DA e tla sebetsa. nako le nako kahare ho teropo ea synaptic ebile e haufi haholo le synapse (Floresco, et al., 2003; Mohau, 1991; Chergui et al., 1994; Venton et al., 2003).
Letoto la lithuto tsa electrophysiological tse entsoeng ke Schultz (Schultz et al., 1993; Tobler et al., 2003; Waelti et al., 2001) li bonts'itse mekhoa ea boitšoaro mabapi le ho thunya hoa tonic le ho phatloha ho matla ha li-neurons tsa DA. Ka hona, li-neurons tsa DA li bonts'a ho thunya ha sepakapaka ho lebisoang ke tlhahiso ea meputso e sa lebelloang kapa matšoao a bonohang a boletseng moputso o joalo (Schultz et al., 1993). Ka konteraka, liphuputso li boetse li senotse hore khatello ea nakoana ea ho thunya ha litoniki kahare ho li-neuron tsa DA e etsahala ka lebaka la ho se tloheloe ha meputso e lebelletsoeng (Tobler et al., 2003) kapa sepheo sa maikutlo (Mohau le Bunney, 1979; Ungless et al., 2004). Schultz e fana ka maikutlo a hore mekhoa ena ea ho thunya ha spike ea DA e ka sebelisoa e le lipontšo tsa ho ithuta metsong e boletsoeng (Waelti et al., 2001). Leha ho le joalo, ts'oaro e hlakileng ea ts'ebetso ea ho lokolloa ha DA e etsahalang ka lebaka la ho phatloha ho matla ha leqhubu ha e bapisoa le khatello ea tšebetso ea spike ea tonic sebakeng sa morero e ne e sa hlakile.
3. Dopamine modulation ea kenyelletso e kenyellelitsoeng ka har'a li-nucleus tsa li-nucleus
Ho hlakisa bohlokoa ba ts'ebetso ea phetisetso ea sistimi ea DA ho latela melaetsa e tsamaisitsoeng ke ho phatloha ho hoholo le ho hatelloa ha thunya ea tonic ho li-neuron tsa makala libakeng tse amehang, re fuputse tšusumetso ea tokollo ea DA ea tonic le ea phasic mabapi le phetoho ea liphihlelo tse amanang le phallo ea bohlokoa. accumbens (NAcc), moo ho nang le lefapha le leholo la DA le tsoang sebakeng se kenellang hare sa teropo (VTA) se leng teng (Voorn et al., 1986). NAcc e lumela ho laola boitšoaro bo lebisitsoeng ho sepheo (Mogenson et al., 1980) ha e ntse e amohela litlatsetso tse fetolelang tsa converaptic tse tsoang metsong ea li-limbic le PFC (Finch, 1966; French le Totterdell, 2002). Ka hona, NAcc e teng moo tlhahisoleseling le maikutlo a maikutlo a sebetsanang le litaba tsa maoto le merero ea koloi e hlophisitsoeng ho PFC li ka kopanngoeng (Mohau, 2000).
Re sebelisa vivo electrophysiology e kopantsoeng le mananeo a meriana a tsamaisanang le meriana ea DA ho NAcc, re fumane hore ho feto-fetoha ha khetho ea maiketsetso le litho tsa PFC ho kenelletsoa ke li-receptor tsa DA D1 le D2, ka ho latellana (Goto le Mohau, 2005). Kahoo, ts'ebetso ea li-receptors tsa D1 e nolofalitse ho kenella ha limbic ho NAcc ntle le ho ama mats'oao a PFC, leha blockade ea li-receptor tsa D1 e nang le mohanyetsi oa D1 ha ea ka ea hlahisa litlamorao tse ngata ho kenngoeng ha limbic kapa PFC. Ho fapana le hoo, re fumane hore ts'ebetso le ts'ebetso ea li-receptors tsa D2 li kengoe li bile li tataisoa, ka ho tšoanang, likarabo tse arolelanoang le liphetho tsa PFC ntle le ho ama lipehelo tsa maoto. Sena se fana ka maikutlo a hore, ho fapana le ts'usumetso ea li-receptor tsa D1, li-receptor tsa D2 tsa striat li tlas'a tšusumetso ea DA maemong a motheo, mme li ka fetoloa holimo kapa tlase ho tsoa mmuso ona. Ntle le moo, re boetse re thetsitse phasic le tonic DA ho lokolloa ho NAcc ka ts'ebetso le ts'ebetso ea basal ganglia nuclei e laolang mekhoa ena e ikhethileng ea mesebetsi joalo ka ha re sa tsoa tlaleha (Floresco et al., 2003). Ho hlophisetsoa ha litlatsetso tsa litho tsa maoto ho ile ha bonoa ha ho lokolloa ha phasic DA (e kopantsoeng le tumellano ea DA ea mokokotlo), ha e ntse e eketseha le ho fokotseha ha litokollo tsa DA tsa khethoa le ho nolofalloa, ka ho latellana, liphetho tsa PFC. Ha ho kopanngoa hammoho, lipatlisiso tsena li bonts'a hore phasic DA e lokolla li-receptor tsa D1 ho thusa ho kenya letsoho litlatsetso, athe tokollo ea DA ea tonic e na le litlamorao tse amanang le liphetho tsa PFC ka li-receptor tsa D2, ka lipallo tse eketsehang tsa D2 tse fumanehang liphuthehong tsa PFC le ho fokotseha ha ts'usumetso ea tonic D2 Likenyelletso tsa PFC.
Ntle le litlamorao tsa mmele tsa ho feto-fetoha ha tsamaiso ea tonic le phasic DA, libaka tsena tse ikhethileng tsa ts'ebetso tsa DA li ile tsa fumanoa li bonts'a litlamorao tse ikhethileng. Ka hona, ka ho sebelisa mosebetsi oa khethollo ea cue ea boitšoaro, re fumane hore ts'ebetso ea ho kenya letsoho ha litho tsa litho tsa letsoho tsa letsoho ho NAcc ka ho lokolloa ha phasic DA ho kenya letsoho li-receptors tsa D1 hoa hlokahala bakeng sa ho ithuta leano la karabelo ho matlafatsong ho ithuta, athe phokotso ea tšusumetso ea tonic DA ea li-receptors tsa D2 e bohlokoa. ho lumella ho fetohela ho leano le lecha la karabo hang ha mekhoa ea ho fihlela lipheo e fetotsoe (Goto le Mohau, 2005). Ka hona, khatello ea ho thunya ha methapo ea tonic ka li-neuron tsa DA ka ho tlohela meputso e lebelletsoeng, e lokelang ho fella ka phokotso ea tokollo ea DA ea tonic ho NAcc, e ka sebelisoa ho khetha ka mokhoa o ikhethileng ts'ebetso ea tlhahisoleseling ea cortico-striatal e sebetsanang le maemo a phetoho ea boitšoaro (Meck le Benson, 2002).
4. Tšusumetso ea khatello ea maikutlo ho dopamine-inthanete e itšetlehileng ka synaptic
PFC ke sebaka se seng se amohelang bolulo ba DA ho tsoa VTA (Thierry et al., 1973). Ho fapana le striatum, ts'ebetso ena ea mesocortical DA ho PFC e fapane hanyane feela; Leha ho le joalo, ka lebaka la palo e tlase ea libaka tse nkang sebaka le tlhahiso e phahameng ea DA tikolohong ena, DA e ntse e hlahisa litlamorao tse tummeng tsa elektroloxia le boits'oaro sebakeng sena sa boko. Ho lokolloa ha DA ho PFC ho bontšitsoe ho le bohlokoa bakeng sa mesebetsi e hlokolosi joalo ka memori e sebetsang (Goldman-Rakic, 1995). Ho feta moo, liphetoho tse lokollotsoeng ho DA ho PFC li tlalehoa li etsahala ha ho hlaha khatello ea maikutlo. Kahoo, liphuputso li bonts'itse hore ho lokolloa ha DA ho PFC ho eketseha ka tlasa bonts'a khatello ea maikutlo (Gresch et al., 1994; Morrow et al., 2000), ha khatello ea maikutlo e ba e sa foleng (mohlala, ka libeke tsa 2 tsa maemo a sithabetsang), ho fokotseha ea mantlha ea ho lokolloa ha DA ho PFC ho bonoe (Gresch et al., 1994). Kameho ea keketseho e joalo le ho fokotseha ha ho lokolloa ha DA ho kenngoeng ha polasetiki ea synaptic ho marang-rang a PFC ho ile ha hlahlojoa e le polasetiki ea synaptic joalo ka ts'ebetso ea nako e telele ea ts'ebetso (LTP) le khatello ea maikutlo (LTD) ho PFC: ts'ebetso e tsejoang e le ho its'etleha ho DA (Otani et al., 2003). Re fumane hore ho kenella kahare ho LTP lithahasellong tsa hippocampal ho PFC, ho latela ts'ebetso ea D1 (Gurden et al., 2000), e ile ea ntlafatsoa ka nako e khuts'oane ea ho pepesoa ha khatello ea maikutlo, athe ha ts'ebetso ea khatello ea maikutlo e lieha, (Goto le Mohau, 2006). Ka lebaka leo, ho na le kamano e potiloeng ka U e pakeng tsa ho kenella ka polasetiki ea synaptic tseleng ea hippocampal-PFC le nako ea phumaneho ea khatello, e amanang le palo ea DA e lokolloang nakong ea khatello ea khatello. Le ha ho sa tsejoe hantle hore na keketseho ea ho lokolloa ha DA e tsoela pele nakong ea kenyelletso ea LTP, liphetoho tse hlahisitsoeng ke DA ho phosphorylation ea limolek'hule tsa molaetsa oa bobeli tse kang CREB le DARPP-32 (Greengard, 1999), tse hlokahalang bakeng sa ho kenyelletsa LTP tseleng ena (Hotte et al., 2007), e tsejoa e na le litlamorao tse hole le nako ea ho hlohlelletsoa ha li-receptor tsa DA (Fig. (Fig.1A1A le and2B2B).
Figure 1
Ho ipapisitsoe le liphuputso tse tsoang liphuputsong tsa liphoofolo, mefuta e 'maloa e ka nkuoa ho ikarabella bakeng sa tse ling tse hlokometsoeng tse mabapi le mekhoa e ka bang teng ea likokoana-hloko ea mafu a kelello a joalo ka schizophrenia. (A) Boemong bo tloaelehileng boemong bo itekanetseng (more…)
Setšoantšo sa 2
Liphetoho likamanong tse sothehileng tse bopehileng joaloka U li ka kenya letsoho ho pathophysiology ea schizophrenia. (A) Boithuto bo fana ka maikutlo a hore kamano lipakeng tsa memori ea ts'ebetso le ts'ebetso ea PFC le eona e ka hlahisa sebopeho sa U se sothehileng. Mohlala ona, (more…)
Re sebelisa tlhophiso ea karolo ea in vitro, re fane ka datha tse nang le liphetho tsa bohlokoa mabapi le ts'usumetso e sebetsang e hlahisitsoeng ke phokotso ea tokollo ea tonic, ea morao-rao ea DA ho PFC (Matsuda et al., 2006). Ka hona, litokisetsong tsa matlapa moo litlamo tsa DA li qhalakantsoeng ho tsoa mefuteng ea sele, 'me palo e kholo ea masala a DA e hlatsuoa nakong ea ho kenella, maemo a ka morao a DA a ka lebelloa ho ba tlase haholo ho feta a neng a le teng mothating, maemong a vivo. Re fumane hore tlasa maemo a joalo, tšusumetso e phahameng ea "tetanic" e atisang ho lekana ho khothaletsa LTP ho vivo ho fapana le moo e felletse ka tlhahiso ea LTD. Leha ho le joalo, ha palo e tlase ea DA e kenngoa tharollong ea ho hlapela ho ts'oara litekanyetso tsa morao-rao tsa DA tse hlahisitsoeng ho vivo, ts'usumetso e phahameng ea hona joale e baka ho kenngoa ha EPP, e fana ka maikutlo a hore boemo ba molumo oa toni ea DA bo ka bonts'a phapang ea polasetiki ea synaptic e ka kenelloang marangrang a PFC (sa feiga. 1A). Phokotso e ts'oanang ea molumo oa mokokotlo oa DA ho tlalehoa hore e etsahala kahare ho PFC kamora ho pepeseha ha khatello ea maikutlo (Gresch et al., 1994). Ho joalo, bopaki ba rona ba pele bo bonts'a hore tšusumetso e phahameng ea hangata e ts'oarang LTP libakeng tsa hippocampal tse kenang ho PFC maemong a vivo ho fapana le moo e tla etsa hore ho kenngoe LTD ha liphoofolo li pepesoa le libeke tsa 2 tsa serame tse sa feleng kapa ho thibela khatello ea maikutlo (Goto et al., 2007).
5. Litlamorao tsa tokollo ea dopamine ea tonic le phasic dopamine mathateng a kelello
Hypofrontality le tokollo e lumellanang ea DA ho PFC e hlahisitsoe e le mabaka a pathophysiological ho schizophrenia (Andreasen et al., 1992; Yang le Chen, 2005), ka kamano e itseng le matšoao a mabe a bothata bona (mohlala, anhedonia, ho tlosoa ha sechaba) ( Andreasen et al., 1992). Boemo bo tšoanang ba hypofrontal bo boetse bo tlaleheloa ho batho ba nang le mathata a ho feto-fetoha ha maikutlo joalo ka khatello ea maikutlo (Galynker et al., 1998). Ka lebaka la hore khatello ea maikutlo e sa foleng e tsejoa ho susumetsa boemo bo sithabetsang 'me, ka hona, e sebelisitsoe e le mohlala oa phoofolo ea khatello ea maikutlo (Katz et al., 1981), ho kenella ka mokhoa o sa tloaelehang oa LTD ka tumello ea tokollo ea tonic e ka morao ea DA ho PFC e ka ameha matšoao a fosahetseng a lefu la kelello le khatello ea maikutlo (feiga. 1B).
Leha ho kopantsoe hypofrontality hore e be teng ho bakuli ba schizophrenia, ho na le litlaleho tse fanang ka maikutlo a hore ts'ebetso ea PFC e ka ba e phahameng haholo ho bakuli ba schizophrenia ha e bapisoa le lithuto tse tloaelehileng maemong a itseng joalo ka ho etsa mesebetsi e bonolo ea memori e sebetsang (Callicott et al., 2003; Manoach, 2003). Kahoo, lithuto tsena li fana ka maikutlo a hore ho na le kamano e pakeng tsa U-sebopeho se pakeng tsa memori ea ts'ebetso le ts'ebetso ea PFC, le hore bakuli ba schizophrenia ba ka bonts'a memori e tlase ea ho sebetsa ha e bapisoa le taolo, e lebisang ts'ebetsong e phahameng le mesebetsi e bobebe (Fig 2A) (Manoach , 2003). Kannete, re fumane kamano e tšoanang le e nang le sebopeho sa U pakeng tsa ts'ebetso ea LTP ho PFC le litlamorao tsa khatello ea maikutlo e matla (Goto le Mohau, 2006). Haholo-holo re hlokometse phetoho ea kamano ena e nang le sebopeho sa U e lebisang tlokotsing ea khatello ea maikutlo ho phoofolo ea mofuta oa schizophrenia (Fig 2B) (Goto le Grace, 2006). Ha e le hantle, hoa tsebahala hore bakuli ba schizophrenia ba bonts'a ts'oaetso e kholo ea khatello ea maikutlo, e kopantsoeng le ts'ebetso ea ho khutla hape (Rabkin, 1980).
6. Qetello
Ho eketseha le ho fokotseha ha tokollo ea DA ho ka ba le litlamorao tse fapaneng ho ts'ebetso ea boko, e ka bang "Yin" le "Yang" ho latela boemo ba setho. Ka hona, ho nahanisisoa ka mofuta oa bi-mwelekeo oa liphetoho tsa DA ho bohlokoa mesebetsing e tloaelehileng ea libaka tsa boko tse fumanang bolulo ba DA ho kenyelletsa NAcc le PFC. Tekano e sa tloaelehang ea ho lokolloa ha DA, haholo-holo ho PFC, e ka bapala karolo ea bohlokoa ho pathophysiology ea mafu a mafu a kelello a kang schizophrenia le khatello ea maikutlo.
Liteboho
Mosebetsi ona o ne o tšehelitsoe ke Moputso oa NASAAD oa Mofuputsi oa Bacha, HFSP Short term Fellowship (YG), Letona la Fuputso la Fora, Center National de la Recherche Scientifique (SO), le USPHS MH57440 (AAG).
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