BMB Rep. 2013 Nov; 46 (11): 519-526.
doi: 10.5483 / BMBRep.2013.46.11.207
PMCID: PMC4133846
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Dopamine (DA) e laola boikutlo ba maikutlo le bo susumetsang ka tsela ea mahlakoreng a dopaminergic. Batho ba bangata ba lumela hore liphetoho tsa DA ho bontša hore ho na le meriana ea ho itšireletsa ka matla ho fetola boitšoaro bo amanang le melemo 'me ka hona bo amana haholo le ho lemalla lithethefatsi. Bopaki ba morao-rao hona joale bo fana ka maikutlo a hore joaloka ho lemalla lithethefatsi, botenya le boitšoaro bo qobelloang ba ho ja bo akarelletsa potoloho ea moputso ea boko, haholo-holo ho potoloha ho amanang le dopaminergic neural substrates. Litlaleho tse eketsehileng tsa lithuto tsa batho tsa ho nahana, hammoho le tlhahlobo ea liphatsa tsa lefutso, li bontšitse hore batho ba mahlahahlaha le ba lemaletseng lithethefatsi ba atisa ho bontša ho fetoloa ha li-receptor tsa DA D2 libakeng tse itseng tsa boko, 'me libaka tse tšoanang tsa boko li susumetsoa ke lijo tse amanang le lijo le lithethefatsi- litokomane tse amanang le tsona. Tlhahlobo ena e lebisa tlhokomelo mesebetsing ea tsamaiso ea DA, e tsepamisitseng maikutlo ka ho toba ka tlhaloso ea 'mele le karolo ea pontšo ea DA D2 ho amohela ho lemalla lijo. [BMB e tlaleha 2013; 46 (11): 519-526]
Keywords: Tlhekefetso, Dopamine, Dopamine receptor, Lijo tsa lijo, Moputso oa potoloho
SELELEKELA
Hangata Catecholamines e hokahantsoe le mafu a boitšoaro a mafu a mangata a kelello le a kelello a joalo ka lefu la Parkinson, lefu la Huntington, bokhoba ba lithethefatsi, khatello ea maikutlo le schizophrenia. Dopamine (DA) ke catecholamine e hlaheletseng bokong 'me e entsoe ke mesencephalic neurons sebakeng sa substantia nigra (SN) le sebakeng sa ventral tegmental (VTA). Morero oa DA neurons ho tloha SN le VTA ho ea libakeng tse fapaneng tsa boko. Lihlopha tsena tsa lisele tsa dopaminergic li khethiloe e le lisele tsa sehlopha sa 'A', tse bontšang lisele tse nang le DA tse nang le aminergic, 'me li arotsoe ka lihlopha tsa lisele tsa A8 ho isa ho A14. Lisele tsa DA kahare ho pars compacta (A8) le libaka tse haufi (sehlophaA9) tsa morero oa SN ho ea basal ganglia (striatum, globus pallidus, le nucleus ea subthalamic). Tlhaloso ena ke mokhoa oa nigrostriatal, o amehang haholo-holo ho laola moithaopi oa boithatelo empa hape le mekhoa e tsamaisoang ke morero (Feie. 1). Ho tloha ho VTA, merero ea lihlopha tsa lihlopha tsa A10 ho ea nucleus accumbens (NAc), prefrontal cortex, le libaka tse ling tsa maoto. Ka hona, sehlopha sena sa lisele li bitsoa tsela ea mesolimbic le mesocortical (Feie. 1). Li-neurons tsena li phetha karolo ea bohlokoa mekhoeng e amanang le moputso le ho susumetsa. Sehlopha se seng se ikhethang sa lisele ke sona tsela ea tubero-infundibular. Lisele tsena li hlaha ho tswa ho nucleus (cellgroupA12) le kakarese ea periventricular (cellgroupA14) ea hypothalamus le morero ho pituitary. Tsela ena e tsejoa ho laola ho lokolloa le ho sebelisoa ha hormone ea pituitary, haholo-holo prolactin (1-4).
DAergic e tsamaea bokong. Ho na le litsela tse kholo tse tharo tsa dopaminergic: Tsela ea pele, ea nigrostriatal moo lisele tsa DA li leng teng pars compacta (A8) le sebaka sa boahelani (sehlopha sa A9) se tsoang SN project ho striatum, ketsahalo ena e ameha boholo ba taolo ...
Tsamaiso ea tsamaiso ea DA bakeng sa mekhoa e amanang le moputso e tsamaisana le litsela tsa mesolimbic le mesocortical. Karolo ea DA e ts'oanang le boitšoaro bo amanang le moputso e ile ea hlokomeloa haholo ka liphello tse matla tsa ho se sebetse ho potlakileng ho potoloha maoto a meriana le mesocortical, a kenyeletsang ho lemalla lithethefatsi le ho tepella maikutlong. E sa tsoa amoheloa hore moputso oa lijo-phetisano oa DA o kopantsoe le botenya, bothata bo boholo ba bophelo bo botle ba sechaba.
Hoa tsebahala hore setsi sa melao-motheo sa homeostatic bakeng sa mekhoa ea ho fepa se teng ka boko, haholo-holo hypothalamus, 'me se kopanya lipontšo tse fapaneng tsa hormone le neuronal tse laolang takatso ea lijo le matla a maholo a ho laola boima ba' mele. Melao ena ea homeostatic ea boima ba 'mele e shebile boemo ba' mele ka ho sebelisa basebelisi ba fapaneng ba kang leptin, insulin le ghrelin (5). Leha ho le joalo, tšusumetso ea lijo e amana haholo le moputso, 'me ho arabela lihlahisoa tsa hedonic tsa lijo tse kang ho bona, monko, le tatso li ka amahanngoa le maemo a boemo bo botle. Litšoaneleho tsena tsa hedonic li ka fetela tsamaiso ea homeostatic (6). Ka lebaka leo, ho hlalosa hore na lijo tsena tsa moputso oa potoloho boko bo ka khona ho laola takatso ea lijo le mekhoa ea ho ja e amanang le homeostatic ea matla a tekanyo ea matla a thata ho thata.
Bopaki bo bongata bo fana ka maikutlo a hore synaptic e fetoletsoeng ea tsamaiso ea DA ea mahlo a maholo e amana haholo le liphello tse putsang tsa lithethefatsi tsa tlhekefetso hammoho le moputso oa lijo (7-9). Leha ho le joalo, moputso oa DA o bontšang moputso ke o rarahaneng haholo ho feta kamoo o hlahang kateng, hape o ameha ka mekhoa ea ho ithuta le maemo, joalokaha ho pakoa ke liphuputso tse bontšang hore lipontšo tsa moputso oa dopaminergic li kenyelletsoa ho ngolisa phoso ea ho bolela esale pele molemong oa ho ithuta (10-13). Ho lemalla lithethefatsi, ho tsebahala hore liphello tse atlehang tsa lithethefatsi li bakoa haholo ke ho eketsoa ha DA ha ho etsoa lihlahisoa tsa substrate e itseng, joaloka mokhanni oa DA ha ho na le cocaine. Leha ho le joalo, ho lemalla lijo, ho ntse ho le joalo ho ntse ho hlokomoloha kamoo moputso oa lijo o ka sebelisang letšoao la moputso oa DA ka tsela e tšoanang le ea ho lemalla lithethefatsi. Ke habohlokoa ho utloisisa mekhoa eo lits'ebetso tsena li nang le tsona li baka liphetoho tse feto-fetohang ho potoloha ha DA tse ikarabellang bakeng sa mekhoa ena ea ho lemalla (7-9).
Tlhahlobisong ena, ke tla fana ka kakaretso e khutšoanyane ea pontšo ea dopaminergic mekhoeng e amanang le moputso oa lijo, ka ho tsepamisa maikutlo lipatlisong tsa morao-rao ka karolo ea li-DA receptor subtypes, haholo-holo li-receptors tsa D2, ts'ebetsong ena.
LITABA TSA LITABA TSA D2
DA e sebelisana le li-receptor tsa membrane tsa lelapa la li-receptor tse likarolo tse supileng tsa G-protein tse kopanetsoeng. Sena se lebisa tlhophisong ea manģosa a bobeli le ts'ebetso kapa khatello ea litsela tse tobileng tsa ho paka. Ho tla fihlela joale, lihlopha tse hlano tse sa tšoaneng tsa mokete oa DA li entsoe ka mefuta e sa tšoaneng. Ho aroloa ka likarolo tse peli ho lihlopha tse peli ho thehiloe ho latela mekhoa ea bona ea mohaho le oa G-protein: li-receptor tse kang D1, tse susumetsang litekanyetso tsa masapo a intracellular le tse nang le D1 (14,15) le D5 (16,17) li-receptor, le li-receptor tse kang D2, tse thibelang litekanyetso tsa CAMP tsa intracellular ebe li kenyelletsa D2 (18,19), D3 (20), le D4 (21) li-receptors.
D1 le li-receptor tsa D2 ke tsona tse ngata tse fumanoang ke DA bokong. Mantsoe a D3, D4, le li-receptors tsa D5 bokong ke tse fokolang haholo le tse fokolang ho feta tsa D1 le D2 receptors. Mokelikeli oa D2 o emeloa ke li-isoform tse peli tse hlahisoang ke mefuta e meng ea liphatsa tsa lefutso (18,22). Li-isoforms tsena, tse kang D2L le D2S, li ts'oana le ntle le ho kenngoa ha 29 amino acid e hlahang sethaleng ea boraro ea intracellular ea D2L, e hatisitsoeng ke exon 6 ea liphatsa tsa lefutso la D2, sebaka se entracellular se nahanang ho ba le karolo ka ho kopanya sehlopha sena sa ho amohela ho manģosa a itseng a bobeli. Sehlopha se seholo sa isoform se bonahala e le mofuta o ka sehloohong o teng libakeng tsohle tsa boko, le hoja palo e nepahetseng ea li-isoform tse peli e ka fapana (22). Ha e le hantle, phantotype ea D2 receptor litho tsohle tsa ho kokota e ile ea senoloa e le e fapaneng haholo le litoeba tsa ho kokota D2L (23-25), e leng se bontšang hore li-isoform tse peli tsa mofuthu oa D2 li ka 'na tsa e-ba le mesebetsi e fapaneng ka ho feletseng. Liphello tsa morao tjena tsa Moyer le basebetsi-'moho le tsona li tšehetsa phapang pakeng tsa bobeli ba D2 receptor isoform boko ba motho. Ba bonts'a mefuta e 'meli ea liphatsa tsa lefutso la D2 (Drd2), e bakoang ke D2 receptor alternative splicing, e na le li-single-nucleotide polymorphisms (SNPs) tse sa tloaelehang tse neng li amahanngoa le tlhekefetso ea cocaine Caucasians (26,27). D2S le methapo ea meriana ea D2L e ne e lekanngoa ka lisele tse tsoang bokoeng ba likopi tsa motho (prefrontal cortex le putamen) tse fumanoang ho bahlaseluoa le li-control tsa cocaine, 'me kamano pakeng tsa liphatsa tsa lefutso tsa liphatsa tsa lefutso tsa D2S / L le ho sebelisoa hampe ea cocaine e ile ea hlahlojoa. Liphello li tšehetsa phello e matla ea phapang ea SNP e tobileng ho fokotsa pontso e lekanyelitsoeng ea D2S ho batho, e emelang lisosa tse matla tsa likotsi maemong a ho noa ha cocaine (26). Kaha ho na le li-isoform tse peli tse hlahisoang ke mefuta e meng ea liphatsa tsa lefutso, ho tla ba monate ho bona hore na karolelano ea li-isoform e mabeli e ka ba eng e bakang lefu lena.
Li-receptor tsa D2 li boetse li na le presynaptically sebakeng seo, joalokaha ho bontšoa ke liteko tse hlahlobang polelo ea li-receptor le libaka tsa ho tlama li-neurons tsa DA ho pholletsa le midbrain (28). Li-autoreceptor tsena tsa D2 e ka 'na ea e-ba li-autoreceptor tse se-somendodendritic, tse tsejoang ho fokotsa ho khotsofatsa ha neuronal (29,30), kapa li-autoreceptor tse qetellang, tseo boholo ba tsona li fokotsang tlhahiso ea DA le ho pata (31,32) le ho thibela ho lokolloa ha DA (33-35). Ho 'nile ha boleloa hore sethaleng sa bobeli, motlakase oa D2 a ka phetha karolo ea nts'etsopele ea DA neuronal (36-38).
Bello le basebetsi-'moho le eena ba sa tsoa etsa hore litoeba li se ke tsa hlola li amoheloa ke D2 receptor meleng ea li-neurons (e bitsoang litoeba tsa autoDrd2KO). Likarabo tsena tsa autoDrd2 KO ha lia na likarabo tsa DA-mediated somatodendritic synaptic le ho thibela ho lokolloa ha DA (39) le ho hlahisa ts'ebetso e phahameng ea DA le ho lokolloa, ho phekola ha likokoana-hloko, le ho fetela holimo ho liphello tsa cocaine. Litoeba li boetse li bonts'itse sebaka se eketsehileng sa sebaka sa cocaine le tšusumetso e ntlafatsang bakeng sa moputso oa lijo, ho bonts'ang bohlokoa ba li-autoreceptor tsa D2 tsamaisong ea tšebetso ea phekolo ea meriana ea DNA le ho bontša hore li-autoreceptor tsa D2 ke tsa bohlokoa bakeng sa motlakase o tloaelehileng, boitšoaro bo batlang lijo, le kutloisiso ho moetsi le moputso oa cocaine (39). Ka hona, karolo ea bohlokoa ea li-autoreceptors tsena e bonahala e le thibelo le ho feto-fetoha ha phetoho ea phekolo ea AIDS. Joalokaha ho bontšoa ke litoeba tse senyehileng tsa D2, ho ka etsahala hore motho a be le maikutlo a hore ho ikamahanya le kutloisiso ea moputso ka karabelo ea presynaptic D2 e ka 'na ea e-ba habohlokoa likarolong tsa boitšoaro bo susumelletsang lithethefatsi tse lemalloang hammoho le meputso ea lijo, le hoja karolo ea cellular le ea limolek'hule li-receptor tsena tsa presynaptic tsa D2 li ntse li lokela ho batlisisoa ka ho eketsehileng.
BOPHELO BA BOPHELO BA HO BONTŠA MOKHATLO OA LITABA
Joalokaha ho boletsoe ka holimo, lithethefatsi tsa tlhekefetso li ka fetola mekhoa ea rona ea moputso oa boko, haholo-holo dopaminergic mesolimbic system. Ho phaella moo, ho 'nile ha bontšoa hore lijo tse monate tse nang le mafura a phahameng le tsoekere li ka etsa hore moputso oa moputso oa DA o sebelisoe haholo. Liphuputso tsena li fana ka maikutlo a hore li-substrate tse tloaelehileng li teng bakeng sa lithethefatsi tsa lithethefatsi le lithethefatsi, 'me tse peli li itšetlehile ka lipotoloho tsa dopaminergic. Ho feta moo, boko ba motho bo nahanang ka lithuto li tšehetsa ka matla karolo ea bohlokoa bakeng sa lipotoloho tsa dopaminergic tse laolang lijo (40-43).
Lithethefatsi tsa tlhekefetso li baka kgolo e kholo ea li-synaptic tsa mahlahahlaha a lefats'e ka tsela ea mesolimbic (44). Ka mokhoa o ts'oanang, ho 'nile ha tlalehoa hore lijo tse khotsofatsang li susumetsa phetiso ea dopaminergic ho NAc (45-47). Ha DA e ne e lekantsoe ke microdialysis nucleus accumbens ea likhoto tse tsamaeang ka bolokolohi ha ho na le meputso ea lijo, ho ile ha hlokomeloa hore ente ea amphetamine le cocaine e eketsehile maemong a DA NAC, eo hangata e sebetsang ka ho ja; ka hona, ho fana ka maikutlo a hore ho lokolloa ha DA ka ho ja e ka ba sesosa sa ho lemalla lijo (46). Ho phaella moo, ho sebelisa li-voltammetry tse potlakileng tsa li-carbon-fiber microelectrodes ho NAc ea likhoto tse koetliselitsoeng ho hatella lever bakeng sa sucrose, Rotiman le basebetsi-'moho ba bontšitse hore ho na le monyetla oa ho arabela moputso oa sucrose, kapa tlhahiso e sa lebelloang ea sucrose, e hlahisitsoe DA ho lokolloa ho NAc (47);; kahoo, ho na le maikutlo a matla a ho bontša hore DA e na le nako ea sebele ea moetlo oa ho batla lijo. Leha ho le joalo, lipatlisiso tse ling li senola bohlokoa ba dorsal striatum, ho e-na le NAc, ho laola lijo. Ka mohlala, ente ea mohanyetsi oa DA ea cis-flupenthixol ho dorsal striatum empa e se NAC, amygdala, kapa foreal cortex ea rats e hlahisa ho fokotseha ha lijo tse amanang le moputso oa lijo (48). Ho phaella moo, litoeba tse senyehileng tsa DA li na le tšireletso, 'me ho tsosolosoa ha liphatsa tsa lefutso tsa DA ka likokoana-hloko tsa DA tse fokolang feela ha ho ne ho tsosolosoa DA ha ho etsoa letšoao la ho hlahisa li-cassate-putamen le li-storum. Ka lehlakoreng le leng, ho tsosolosoa ha dopaminergic ho ea ho NAc ha hoa ka ha fetola alagia, le hoja karabo ea mohahlauli tikolohong e ncha kapa amphetamine e tsosolositsoe ke ho fana ka likokoana-hloko ho NAc (49,50).
Ho batho, haholo-holo ts'ebetso ea li-dorsal striatum e 'nile ea hlokomeloa hore e tsamaisane le mekhoa ea ho fepa. Ka mohlala, Ba banyenyane le basebetsi-'moho ba ne ba sebelisa positron emission tomography (PET) ho batho ba nang le likoloto tsa batho ba bontšang hore ho phalla ha mali ho ea ka tekano ha ba ntse ba ja chokolete e amanang le monate oa likarolo tsa dorsal caudate le putamen, empa eseng NAc (41). Phuputsong ea papiso ea PET ea lihlooho tsa batho ba phetseng hantle, ho ile ha e-ba le kamano pakeng tsa ho fokotsa tšebetso ea li-ligand ea DA ho ea ka lehlakoreng le leng le ho fepa (42). Tumellanong le sena se fumanoeng, polelo ea ho amoheloa ha D2 e fokolang e ne e fokotsehile ho batho ba mafura ka ho lekanang le sekhahla sa 'mele oa' mele oa bona (40);; sehlooho sena se tla tšohloa haholo karolong e latelang.
Li-receptor tsa D2 lijong tsa lijo
Le hoja ho fepa ho eketsa mohopolo oa DA oa extracellular mokokotlong oa accumbens ka likhoto, (45,46), joaloka lithethefatsi tsa tlhekefetso, Ho senyeha ha DA ho NAC ka likhoto ka mor'a hore liente tse peli tsa motsoako oa neurotoxic 6-hydroxydopamine (6-OHDA) ho nucleus accumbens feela ha e fetohe ho fepa (51). Ho thibeloa ha litšebeletso tsa D1 le li-receptor tsa D2 ho NAc ho ama boitšoaro ba motlakase le nako le nako ea ho fepa, empa ha ho fokotsa bongata ba lijo tse jeoang (52). Phuputso e 'ngoe e tlalehile hore ha e e-na le lijo tse lekaneng haholo tsa mafura, litoeba tse nang le methapo e fokolang ea ho amohela D2 ka putamen e nkoa e le boima ho feta litoeba tse nang le matla a phahameng a ho amohela D2 (53), ho bontša hore tsamaiso ea dopaminergic e arabela lijo tse monate. Davis le basebetsi-'moho ba ile ba hlahloba khopolo-taba ea hore botenya bo bakoang ke ho ja lijo bo fokotsa mosebetsi oa DA oa mahlo (54). Ba ile ba bapisa ts'ebetso ea DA ho ea mahlahahlaha a tsamaiso ea DA pakeng tsa likhoto tse fepa lijo tse ngata tse mafura le ba jang lijo tse tlaase tse tlaase. (54). Liphello li bontšitse hore liphoofolo tse jang lijo tse phahameng haholo, tse ikemetseng ho nts'etsopele ea botenya, li bontšitse ho fokotseha ha thekiso ea DA ho NAC, ho fokotsa khetho ea sekheo sa amphetamine, le ho fokotsa likarabo tsa basebetsi bakeng sa sucrose. Bangoli ba ile ba boela ba hlokomela hore botenya bo bakoang ke lijo tse ngata tse mafura li ne li haelloa ke li-DA tse nucleus accumbens, ha ho ne ho se na phapang pakeng tsa ts'oaetso ea DA kapa phetoho ea orbitofrontal cortex, e leng se bontšang phello e tobileng ea lijo tse mafura tse fokolang feela NAC (54).
Morao tjena, Halpern le basebetsi-'moho ba ile ba hlahloba phello ea boko bo tebileng ba boko (DBS) ea shell ea NAc (55). Kaha mokhoa ona o ntse o etsoa lipatlisiso ho batho bakeng sa phekolo ea ho tepella maikutlo ho tebileng, boloetse bo feteletseng ba ho qobella, le ho lemala, ba ne ba nahana hore e ka boela ea atleha ho fokotsa ho ja joala. Ho thahasellisang ke hore DBS ea shell ea NAC e fumanoe ho fokotsa ho ja lijo tsa ho itlopa lijo le ho eketsa litekanyetso tsa c-Fos sebakeng sena. Raclopride, mohanyetsi oa DA D2 ea amohelang batho ba bangata, o ile a hlokomelisa liphello tsa DBS, athe mohanyetsi oa D1 ea amohelang batho ba bangata SCH-23390 o ne a sa sebetse, a fana ka maikutlo a hore pontšo ea DA e amang li-receptor tsa D2 e hlokahalang bakeng sa phello ea DBS ka shell ea NAc (55). Ha ba hlahloba phello ea lefu le sa feleng la NAC le DBS litlhaselong tse nang le bothata ba ho ja lijo tse ngata, li fumanoe li fokotsa ho ja lijo tsa caloric le ho fokotsa boima ba 'mele, ka hona, ho tšehetsa ho kenngoa ha litsela tsa DA tse nang le li-DA tse fumanehang ka lijo tse tlatsetsang botenya , hammoho le katleho ea NAC shell DBS ho tsamaisa tsamaiso ena (55).
Phuputso ea morao-rao e entsoeng ke Johnson le Kenny e ile ea fana ka maikutlo a ho lumellana ka matla pakeng tsa lipolelo tsa li-receptor tsa D2 le boitšoaro bo qobelloang ba ho ja (56). Phuputsong ena, ho ile ha hlokomeloa hore liphoofolong tse fanoeng ka 'lijo tsa ho ja lijo', tse nang le lijo tse nang le matla a maholo, tse nang le matla a matla a matla a fumanehang lik'hafeteng bakeng sa ho sebelisoa ha batho, liphoofolo tsena li ile tsa theola 'mele' me tsa bontša boitšoaro bo boima ba ho ja (56). Ntle le ho ba boemong bo feteletseng ba ho ja le ho qobella ho ja, likhofu tlas'a lijo tsa ho ja lijo li fokotsehile polelo ea D2 e amohelang mofuthu ka striatum. Phuputsong e 'ngoe ea morao tjena, ho khethoa ha li-insulin li-receptor ka har'a methapo ea li-dopaminergic neurons ho litoeba ho bontšitse hore ho laola hona ho etsa hore boima ba' mele bo eketsehe, ho eketseha ha mafura le hyperphagia (57). Ho thahasellisang ke hore litlhaselong tsena, polelo ea DA D2 e amohelehang ho VTA e ne e fokotseha ha e bapisoa le eona ho litoeba tsa taolo, e bontšang hore ho ka khoneha ho thibela lisele tsa VTA / SN tsa dopaminergic ka mokhoa o itšetlehileng ka D2 (57). HLeha ho le joalo, ka laboratori ea rona, re hlokometse hore ha re bapisoa le litoeba tsa mofuta oa mofuta (WT), litoeba tsa D2 receptor KO li na le phenotype e mahlahahlaha 'me pontšo e fokotseha ho ja lijo le boima ba' mele ka pontšo ea hypthalamic leptin e ntlafetseng. (58). Ho itšetlehile ka liphuputso tsena, re ke ke ra hlokomoloha hore mokelikeli oa D2 o phetha karolo ea taolo ea homeostatic ea metabolism ka ho sebelisana le homeostatic regulators of energy balance, joaloka leptin, ho phaella mosebetsing oa eona boitšoarong bo susumetsang lijo. Tka hona, ho bonahala eka polelo ea D2 receptor e amana haholo le moputso oa lijo le mekhoa ea ho ja, 'me hoo ho itšetlehile ka ho ba teng ha batho ba amohelang D2 bokong, sena se ka lebisa liphetong tse fapaneng lipakeng tse sebetsang.
Ma-DA D2 a amohelang botenya ba motho
Liphuputso tse ngata tsa batho li bontšitse bohlokoa ba mokete oa DA D2 ha o laola moputso oa lijo ho latela bothata ba ho nona haholo, haholo-holo ho bontša phetoho ea mosebetsi oa ho amoheloa ha D2 le polelo (59,60). Batho ba bangata ba nang le lithethefatsi le ba lemalloang lithethefatsi ba atisa ho bontša palo e fokolang ea li-receptor tsa DA D2 libakeng tse hlaselang, 'me lipatlisiso tsa litšoantšo li bontšitse hore libaka tse tšoanang tsa boko li tsosoa ke litlhaloso tse amanang le lijo le tse amanang le lithethefatsi (61,62). Liphuputso tsa PET li bontša hore ho fumaneha ha li-receptor tsa DA D2 ho fokotsehile ho batho ba mafura ka ho lekanang le lintlha tsa 'mele oa tsona. (40);; ka hona, ho fana ka maikutlo a hore ho haella ha DA ho batho ba mafura ho ka 'na ha tsoela pele ho ja lijo tsa mafu e le mokhoa oa ho lefella ho fokotsa ts'ebetso ea lipotoloho tsa moputso oa dopaminergic. Tlhaloso e 'ngoe ke hore batho ba nang le lipalo tse fokolang tsa li-receptor tsa D2 ba ka ba kotsing ea ho itšoara ka tsela e tsitsitseng, ho kenyeletsa ho noa lijo, mme, ka hona, ho fana ka bopaki bo tobileng ba phoso ho batho ba DA D2 ba amohelang batho ba mahlahahlaha (40).
Ho itšetlehile ka ho fumaneha ha likhahla tsa D2 ho fumanoa sebakeng se hlaselang sa batho ba mafura haholo, e leng se bontšang hore ho na le karolo e ka khonehang bakeng sa ba amohelang D2 ho laola mekhoa e metle ea ho ja, Volkow le basebetsi-'moho ba ile ba hlahloba hore na ho fumanoa ha D2 ho fumanoa lihloohong tse ngata ho tla amahanngoa le metabolism ho prefrontal libaka tse kang cingulate gyrus (CG), dorsolateral prefrontal cortex (DLPFC), le orbitofrontal cortex, e leng libaka tsa boko bo kentsoeng likarolong tse sa tšoaneng tsa taolo ea thibelo (63). Phuputso ea bona e senola mokhatlo oa bohlokoa o pakeng tsa li-receptor tsa D2 le statum le ts'ebetsong DLPFC, medial OFC le CG lihloohong tse ngata. Kaha libaka tsena tsa boko li kenngoa ka taolo ea ho thibela tšebetso, ho fana ka matla, le ho ts'oaroa ha maikutlo, ho fumanoa hona ho fana ka maikutlo a hore ho senyeha ha libaka tsena ho ka bakela boitšoaro bo sa tsitsang le bo qobelloang, le hore ena e ka ba e 'ngoe ea mehato eo maemong a tlaase a D2 a amohelang botenya ka eona tlatsetsa ho feta-ho ja le botenya (63).
Kamano pakeng tsa D2 receptor genotype le botenya ho batho e entsoe lipatlisiso, 'me ho' nile ha boleloa hore mefuta e meng ea allelic ea Taq1A polymorphism lefapheng la liphatsa tsa lefutso la D2 e ama polelo ea D2 ea ho amohela (64,65). Polymorphism ena e na le 10 kb ka tlaase ho sebaka sa coding sa lefutso 'me e oela ka har'a sebaka sa protheine-encodeing ea liphatsa tsa lefutso domain domain ea ankyrin hape ea kinase e nang le 1 (ANKK1). The Taq1A polymorphism e na le mefuta e meraro ea allelic: A1 / A1, A1 / A2, le A2 / A2. Lipatlisiso tsa Postmortem le tsa PET li bontša hore batho ba nang le likopi tse le 'ngoe kapa tse peli tsa A1 allele ba na le 30-40% tse fokotsehang ha li amoheloa ke D2 ha li bapisoa le ba se nang A1 allele (64) mme mokhatlo oa A1 o felisitsoeng le tahi e 'nile ea etsoa tlhahiso (64,66). Hoa thahasellisa hore ho tlalehiloe hore ho matlafatsa lijo ho na le phello e kholo tabeng ea ho kenngoa ha matla, mme phello ena e lekanyelitsoe ke A1 allele (67,68). Epstein le basebetsi-'moho ba ile ba hlahloba lijo tse matlafatsang lijo, li-polymorphisms dopamine D2 receptor le liphatsa tsa lefutso tsa DA, le matla a laboratori a fumanoang ka batho ba batenya haholo le ba seng bobebe. Ts'ehetso ea lijo e ne e le khōlō ho feta ho feta batho ba seng bobe haholo, haholo-holo ho batho ba nang le bobebe ba nang le eona TaqI A1 e phethehile. Ho ja matla a matla a matla ho batho ba nang le maemo a phahameng a ho matlafatsa lijo le ba bohlokoa ho ba nang le matla a phahameng a lijo le a TaqI A1 e phethehile (68). Leha ho le joalo, ha ho na phello ea liphatsa tsa lefapha la DA tse fumanoang thuputsong ena, e bonts'a mokhatlo pakeng tsa liphatsa tsa lefutso tsa liphatsa tsa lefutso tsa D2 le ho matlafatsa lijo.
Tumellanong le thuto ena, Stice le basebetsi-'moho ba ile ba sebelisa litšoantšo tse sebetsang ka matla a motlakase (fMRI) ho bontša hore ho batho ba nang le kakaretso ea A1 ea TaqIA polymorphism liphatsa tsa lefutso tsa D2, ho fokolloa ho fokolang ka matla ho arabela ha lijo tse kenang lijo li ne li amana haholo le boima ba 'mele le bokamoso bo tlang nakong ea selemo sa 1, ho bapisoa le ba haelloang ke A1. (59,69,70). Ba sebelisa feme e fapaneng ea tekanyetso ea fMRI, Stice le basebetsi-'moho ba ile ba bontša hore ho fokolisa ho matla ha opalulum, ka pele ho eona kapa orbitofrontal cortex, le striatum ka lebaka la ho nahana ka ho ja lijo tse monate, ho fapana le ho nahana ka ho ja lijo tse fokolang haholo kapa metsi a nooang, ho boleloa hore boima bo phahameng fumana bakeng sa ba nang le A1 (71). Ho ts'oaroa ha weaker ea foreal operculum, lateral orbitofrontal cortex, le striatum ho arabela ka ho noa ho nahanang ha lijo tse monate hape ho boletse ho eketseha ha nako e tlang ea boima ba 'mele bakeng sa ba nang le TaqIA A1 phetoho ea liphatsa tsa lefutso tsa D2 (71), ho fana ka maikutlo a hore ba sa hlokeng sena ba atlehe, tlhokomelo e kholo ea libaka tsena tsa moputso oa lijo e boletse esale pele ho eketseha ha nakong e tlang ea boima ba 'mele.
Hoa thahasellisa hore tlaleho ea morao tjena ea Davis le basebetsi-'moho le eona e bontšitse karolo e 'ngoe ea kamano pakeng tsa matšoao a amohelang D2 le boitšoaro bo qobelloang ba ho ja (72). Ba ile ba bontša hore batho ba baholo ba nang le bothata ba ho ja lijo tse itekanetseng ba fapana haholo le balekane ba bona ba sa jeng. Ha e le hantle, batho ba baholo ba nang le bothata ba ho ja lijo tse ngata ba ne ba e-na le tšoaetso e matla ea DA ha ba bapisoa le balekane ba bona ba mafura empa ba sa sebetsane le bona, phapang e neng e amahanngoa le liphatsa tsa lefutso tsa liphatsa tsa lefutso tsa lefutso TaqIA ea liphatsa tsa lefutso tsa D2 (72).
Ho phaella moo, le hoja ho amoheloa ha D2 ho thothokiso ea li-storum ho bonahala eka ho ameha ka taolo ea ho thibela ho itima lijo, Caravaggio le basebetsi-'moho haufinyane ba ile ba tlaleha hore ho na le kamano e ntle pakeng tsa 'mele le D2 / D3 e amohelang li-agonist e tlamang ka ventral striatum (NAc) ea batho bao e seng batho ba bolileng, empa ha ba fumane kamano le mohanyetsi ea tlamang. Litlaleho tsena li bontša hore ho batho ba seng bobebe, boima ba 'mele bo ka' na ba amahanngoa le likamano tse eketsehileng tsa methapo ea D2 ho NAc, le hore ho ba le kamano e ntseng e eketseha ho ka ba le matla a ho susumetsa lijo le ho eketsa tšusumetso ea ho ja lijo tse monate (73).
Ka hona, le hoja bopaki bo bongata bo bontša hore litekanyetso tse fokolang tsa li-D2 li kopanngoa le keketseho ea ho ja lijo, ho ba le boima ba 'mele, le kotsi ea ho lemalla lijo, joalokaha ho fumanoe bathong ba nang le mathata a ho sebelisa lithethefatsi hampe (74), e tla ba ea bohlokoa ho fumana hore na polelo ea D2 e amohelehang le pontšo ea eona e ka tlase e ka laola mokhatlo ona.
LIPOTSO TSA MOKHOA OA HO FUMANA
Ho na le bopaki bo ntseng bo eketseha ba ho hlahisa potoloho ea boko e laolang taolo ea homeostatic ea ho ja lijo. Liphuputso tsa morao-rao li thusitse ho bonts'a tsela e tsotehang pakeng tsa lipotoloho tsa homeostatic le moputso oa mekhoa ea ho fepa. Lithuto tsa batho li bontša ka ho hlaka bohlokoa ba mekhoa ea moputso, haholo-holo tsamaiso ea DA, ho laola boitšoaro ba ho ja le botenya. Ho itšetlehile ka li-susceptibilities tse hlahisitsoeng tsa lefutso le taolo ea mokelikeli oa D2 ha ho etsoa lithuto tsa moputso oa lijo, ho hlakile hore mosebetsi oa D2 mokelikeli ke oa bohlokoa bakeng sa tšusumetso ea lijo le ho bontša boko bo feteletseng. Leha ho le joalo, ho ntse ho le thata ho hlalosa moralo oa lipotoloho tsa boko tse akarelletsang li-substrate tsa molecular tse sebetsang ho laola ho lemalla lijo. Lipatlisiso tsa morao-rao tse tsoang laboratori ea rona li bontšitse hore mokelikeli oa D2 ha oa hlokeha bakeng sa ho fumana lithethefatsi tsa lithethefatsi, empa o phetha karolo ea bohlokoa ho laola liphetoho tsa synaptic tse hlahisitsoeng ke liphihlelo tse kang khatello ea kelello. Ka hona, mokamoli oa D2 o sebetsa ho e-na le mokena-lipakeng oa boiphihlelo-ho susumelletseha, ho batla lithethefatsi, le ho khutlela boitšoarong (75), e bontšang karolo ea eona e tobileng boitšoarong bo hlephileng.
Ha e le ho lemalla lithethefatsi, ho bonahala eka lijo li etsa hore VTA-NAc dopaminergic mesolimbic circuit e sebetse, 'me bohlokoa ba phenotypic ba mekhoa ea ho fepa e fetoleloa ka ho bontša pontšo ea caudate putamen le dorsal striatum, e sebelisanang le prefrontal cortex bakeng sa ho etsa liqeto le ho phethahatsa boitšoaro ba lijo . Li-controller homeostatic tse boletsoeng ka holimo, tse kang leptin, insulin le ghrelin, li ama tšusumetso ea tsona har'a li-midrand DA systemby e laolang kamano pakeng tsa mefuta ea homeostatic le hedonic ea ho ja lijo, (6,9,76) (Feie. 2). Ha ho pelaelo hore lintlha tsena tsa lipatlisiso li fane ka motheo bakeng sa lithuto tsa nakong e tlang ho ba potoloho ea neural ea tsamaiso ea DA, e tla thusa ho lemoha ha pathophysiology e ka sehloohong ea ho lemalla lijo. Liphetoho tsa morao-rao lisebelisoa tse kang optogenetics le DREADD (li-receptors tse entsoeng ka moqapi feela tse sebelisitsoeng ke lithethefatsi tsa moqapi) li tla tsamaisa lithuto tsena ka ho lumella ho fihlella lisele tse itseng tsa neuronal kapa lipotoloho tse laolang boitšoaro bo amanang le moputso.
Mokhoa oa lijo oa potoloho o amanang le tsamaiso ea DA le li-receptors tsa D2. E le ho lemalla lithethefatsi, ho bonahala eka lijo li etsa hore VTA-NAc DA e hlokomele potoloho le phantotypic bohlokoa ba mekhoa ea ho fepa e fetoletsoeng ka ho etsoa ka letsoho ho e-na le litlhaku tse fokolang. ...
lumela hore baa fokola
Mosebetsi ona o ne o tšehelitsoe ke thuso ea Morero oa R&D oa Korea Health Technology (A111776) o tsoang Lefapheng la Bophelo le Boiketlo, mme karolo e 'ngoe ke Lenaneo la Patlisiso ea Brain ka National Research Foundation of Korea (NRF) e tšehelitsoeng ke Lefapha la Saense, ICT. & Moralo oa Bokamoso (2013056101), Rephabliki ea Korea.
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