Nucleus accumbens dopamine e sebelisana le amphetamine e bakoang ke ho ba le bothata ba ho kopanngoa ha sechaba le mefuta e mengata ea li-rodent (2010)

Likhoba tse joalo tse joalo ka bokhoba ba ho sheba litšoantšo tse litšila tse tsosang takatso ea boitšoaro bo bobeNuklea e bokellang dopamine mediates amphetamine e khelositse ho senyeha ha tlamahano ea setsoalle le mofuta oa monogamous rodent

Proc Natl Acad Sci US A. Jan 19, 2010; 107 (3): 1217-1222.

E phatlalalitsoe ka marang-rang Dec 29, 2009. Doi:  10.1073 / pnas.0911998107

PMCID: PMC2824263

Khopolo-taba

Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.

Eya ho:

inahaneloang

Thomello e rorisang (Microtus ochrogaster) ke mofuta oa bophelo ba batho ba litso tse fapaneng ba ratoang kamora hore ba ts'oaroe. Mona, re sebelisitse libaka tsa banna tsa ho rorisa banna ho hlahloba litlamorao tsa ho pepesetsoa lithethefatsi ho kopaneng le ho potoloha ka neural. Boitekong ba rona ba pele, boitšoaro bo susumetsang ba amphetamine (AMPH) bo ile ba hlahlojoa ba sebelisa mokhoa o hlophisitsoeng oa sebaka sa boikhethelo (CPP) mme ba bonts'oa ba kenelletsoa ke ts'ebetso ea li-receptors tsa D1-like DA. Ka mor'a moo, re ile ra hlahloba litlamorao tsa ho pepesetsoa khafetsa AMPH mabapi le maqhama a mabeli. Banna ba tloaetseng ho laola balekane le ba letsoai ba bonts'itseng liqeto tse tlisoang ke balekane ba bona, athe ba batona ba iketselitsoeng le AMPH ka litekanyetso tse atlehang tsa ho susumetsa CPP ba sitiloe ho bonts'a likhetho tsa balekane. Phekolo e joalo ea AMPH le eona e ntlafalitse D1, empa eseng D2, polelo ea receptor ea DA ho li-nucleus accumbens (NAcc). Ntle le moo, lithibelo tsa bongaka tsa li-receptor tsa D1 tse kang DA ho NAcc li pholositse likhetho tsa molekane tse matlafatsang tsa batšehali ho banna ba tšoaroang ke AMPH. Ka kopanelo, lintlha tsa rona li bonts'a hore ho pepesetsoa khafetsa ha AMPH ho ka fokotsa boitšoaro ba maqhubu a rorisang banna ka mokhoa o ikhethileng oa DA receptor e itseng ho NAcc, mme ea baka ho senyeha ha sebopeho sa maqhama a mabeli.

Keywords: vole, CPP, D1 Receptor

Ho amoheloa hohle hore boits'oaro bo susumetsang le bo nang le maikutlo bo khothalletsang boikoetliso bo laoloa ke ho potoloha ha moputso oa boko ho kenyeletsa le mesolimbic dopamine (DA) system (1, 2). Leha tsamaiso ena e lula e na le tšusumetso ho litekanyetso tsa lijo le boits'oaro ba thobalano (3, 4), hape e bile le tšusumetso mekhoeng e meng e atileng ea tlhaho e susumetsoang, joalo ka papali ea setso pakeng tsa bana le tlamahano ea kamano pakeng tsa motsoali le bana (5-9). Hangata ho hlahisoang khafetsa lipatlisisong ke litlamo tsa kahisano pakeng tsa balekane ba baholo, ke hore, maqhama a mabeli. Patlisiso ea morao-rao e sebelisa mofuta o mong oa bophelo bo botle ba litoeba, setopo sa prairie (Microtus ochrogaster) (10-12), e bonts'a hore boholo ba melaoana ea methapo e tlasa motheo oa tlamahano le tokiso ea mabotho li etsahala kahare ho li-nucleus accumbens (NAcc) (13-15) - sebaka sa boko ba mesolimbic se bohlokoa bakeng sa boitšoaro bo matla bo arolelanang (1, 2, 16).

Le ha li-circry tse susumetsang li bile teng ho khothaletsa boikoetliso bo matlafatsang bo kang ho fepa, ho kopanya le ho tlamahana le lelapa (1, 17), e kotsing ea ho ipolaea ka litlhare ke tlhekefetso (8). Mohlala, tsamaiso ea lithethefatsi tsa psychostimulant tsa tlhekefetso, joalo ka koae le amphetamine (AMPH), e baka phetoho e phehellang ea mosebetsi oa mesolimbic DA (18, 19). Kameho e matla potolohong ena ke lithethefatsi tsena tse ling tse tlatsetsang e khothalelitsoe ho fokotsa boleng bo ananeloang ba litheko tsa tlhaho (20), ho kenyelletsa le tsa setsoalle (8). Leha ho tsebahala hore bokhoba ba lithethefatsi bo bontša boitšoaro bo bobe ba setšo (21), taolo ea neural ea ts'ebelisano lipakeng tsa boiphihlelo ba lithethefatsi le ho ikamahanya le sechaba ha e utloisisehe hantle. Lebaka ke hore, ka tsela e 'ngoe, ho thata ho etsisa litšebelisano tse joalo lipontšong tsa setso tsa laboratori tse sa bontsheng kamano pakeng tsa batho ba baholo.

Neurobiology ea khokahano e joalo ea sechaba, haholo-holo maqhama pakeng tsa batho ba baholo, e ithutile haholo bukaneng ea prairie (10-12), mme haufinyane, mofuta ona o thehiloe e le mohlala o sebetsang ho hlahloba boleng bo susumetsang ba AMPH (22). Ntle le moo, ho theha maqhama a mabeli le ntlafatso ea AMPH li arolelitsoe, bonyane ka karolo, ka phetiso ea DA ka har'a NAcc (14, 15, 23). Ka hona, thuto ea hona joale e sebelisitse mofuta oa mofuta oa tlotliso ho theha mofuta oa boitšoaro ho ithuta litlamorao tsa ho pepesetsoa lithethefatsi khokamanong ea sechaba mme e tsepamisitse ts'ebetso ea ho saena ea NAcc DA ho senola mochine oa neural o tlasa litlamorao tsa boitšoaro bona.

Results

AMPH-Induction Conditioned Place Preference (CPP) E Ikarola ka DA ho Receptor -pecific Manner.

Ho thehoa ha CPP ho hlalositsoe ke keketseho e kholo ea nako e sebelisitsoeng khubung e kolobelitsoeng ea AMPH nakong ea morao-rao, kamora matsatsi a 3 ea boemo ba AMPH, bo amanang le botle ka ho fetisisa. Ha ho na liente tsa saline kapa saline e nang le litekanyetso tse peli tse tlase tsa AMPH tse lekiloeng (0.1 le 0.5 mg / kg) likhethong tse fetotsoeng tsa likhaba (Feie. 1A). Leha ho le joalo, banna ba boemong bo nang le litekanyetso tse phahameng tsa AMPH, ho kenyeletsoa 1.0 (t = 2.87, P <0.01), 3.0 (t = 3.63, P <0.01), kapa 5.0 mg / kg (t = 3.03, P <0.01), e bonts'itsoeng CPP (Feie. 1A).

Setšoantšo sa 1.

(A) Ba batona ba amohetseng li-ente tsa saline kapa litekanyetso tse tlase tsa AMPH (0.1 kapa 0.5 mg / kg) nakong ea matsatsi a 3 ea maemo ha ea ka ea bontša CPP. Leha ho le joalo, ba batona ba boemong ba AMPH ka litekanyetso tse phahameng (1.0, 3.0, le 5.0 mg / kg) ba sebelisitse nako e ngata haholo ...

Hobane AMPH e eketsa haholo neurotransication ea DA libakeng tsa prairie (24), mme DA Mediates matlafatsa ntlafatso ea AMPH ho mefuta e meng (23), hape re hlahlobile molao oa tšebetso oa DA receptor (DAR) oa AMP e kenyellelitsoeng lipuong tsa basali tse rorisang basali. Litaba li ile tsa etsoa pele ho CPP paradigm, tsa phekoloa ka saline kapa saline e nang le litekanyetso tse fapaneng tsa motsoako oa khatello ea DAR antagonist (haloperidol) pele ho li-ente tsa AMPH (1.0 mg / kg) nakong ea matsatsi a 3, 'me ea hlahlojoa CPP ka mora nako e telele. Lintho tse tšoaroang ka letsoai (t = 2.69, P <0.01) kapa letsoai le nang le litekanyo tse peli tse tlase tsa haloperidol (0.1 mg / kg; t = 3.62, P <0.01; 1.0 mg / lik'hilograma; t = 3.89, P <0.01) pele boemo ba AMPH bo bonts'a CPP e susumetsoang ke AMPH, athe haloperidol ho 5.0 mg / kg e thibetse CPP e susumetsoang ke AMPH, e bonts'a ho nka karolo ha li-DAR liphellong tsa boits'oaro ba AMPH (Feie. 1B). Ho fumana hore na DAR subtype e sebelisang li-CPP tse kenyellelitsoeng ke li-DP, re boetse re laetse mofuta o itseng oa D1-like antagonist (SCH23390) kapa D2-like antagonist e khethehileng (eticlopride) pele ho ente tsa AMPH nakong ea maemo. Diphetoho tse kang D2-like antikonism ha lia ka tsa thibela CPP e kenyellelitsoeng (AMPH)t = 3.15, P <0.01 bakeng sa 0.5 mg / kg le t = 2.60, P <0.05 bakeng sa 5.0 mg / kg eticlopride) empa thibelo ea li-receptor tse kang tsa D1 e felisitse CPP e susumetsoang ke AMPH (Feie. 1B), e bonts'ang hore CPP e kenyellelitsoeng ke AMPH e tsamaisoa ke ts'ebetso ea D1-e joalo, empa eseng joalo ka D2-receptors ma-voirs a banna ba rorisang.

Thupelo ea Tlhahlobo ea AMPH e Fenya Mathatla a Ts'oants'itsoeng.

Le ha CPP e kenyellelitsoe CPP e hloka ts'ebetso ea li-receptors tse kang D1 (Feie. 1B), re kile ra bonts'a hore ts'ebetso ea li-receptor tsa D1 tse kang e thibela ho thetsoa hoa tlamahano ea likamano (14). Ka hona, re na le maikutlo a hore boikaketsi ba AMPH bo ka kena-kenana le ho kopanya ho kopantseng ha balekane le li-voles tsa banna tsa praemia. Ba batona ba ile ba aroloa ka lihlopha tse 'ne tse sa kang tsa entoa (intact), ente ea saline, kapa liente tsa 1.0 kapa 5.0 mg / kg AMPH ka matsatsi a 3 (paradigm ea sindano e lekaneng ho kenya CPP). Ka letsatsi la bone, ba batona bohle ba ne ba penta le mosali ea amohelang thobalano bakeng sa 24 h mme ba ile ba hlahlojoa hore na ba khetha eng. E lumellana le lithuto tse fetileng (14, 25-27), banna ba batona le ba batšehali ba amohetseng ente ea saline bakeng sa matsatsi a 3 pele ba emoloa ba bonts'a likhetho tsa balekane (ba batšehali ba sa tsitsang; t = 3.05, P <0.01, banna ba nang le letsoai le nang le letsoai; t = 3.21, P <0.01; Feie. 2A). Leha ho le joalo, ba batona ba neng ba entsoe ka lethal la mofuta oa AMPH bakeng sa matsatsi a 3 pele ho nako ea botšehali ba sitoa ho bonts'a khetho ea molekane (Feie. 2A). Habohlokoa, ts'ebetso ea AMPH ha e ea ka ea ama khafetsa ea nako ea ho emolisa nakong ea ho phomola (F(3, 26) = 0.26, P = 0.85; Feie. 2B) kapa ketsahalo ea mofuta o mong nakong ea tlhahlobo ea khetho ea molekane.F(3, 26)= 2.34, P = 0.10; Feie. 2C), e bonts'a hore AMPH e kena-kenana ka kotlolloano le litabatabelo tsa mofani.

Setšoantšo sa 2.

(A) Kamora 24 h ea ho tlolelana, banna ba sa tsitsang ba bonts'itse khetho ea molekane ka ho qeta nako e ngata haholo ba le kopanong le molekane ea tloaelaneng le mosali ea sa mo tsebeng. Tlhahiso ena e khahlisang ea molekane e ile ea bontšoa ke ba batona ba amohetseng ...

Boiphihlelo ba AMPH bo Phahamisa D1 Receptors ho NAcc.

Kaha ho na le likhetho tsa molekane oa mofutsana tsa AMPH preexposure le li-CPP tse tsamaeang ka bobeli (bona ka holimo) le li-bonding (14) li laoloa ke NAcc DA, re kholoa hore AMPH e ne e ka fetola haholo potoloho ea mesolimbic DA libakeng tsa basali tsa prairie. Borena ba lithuto tse tsoang tlhahlobong e boletsoeng ka holimo ea boitšoaro bo ile ba sebetsoa bakeng sa ho ngola mabitso a li-mRNA tsa DA. Ba batona ba tšoaroang ke AMPH (1.0 mg / kg) ba bontšitse keketseho e kholo ho D1 receptor (D1R; t = 3.06, P <0.01), empa eseng D2 receptor (D2R), mRNA e ngolang kahare ho NAcc, ha e bapisoa le banna ba fumanang kalafo ea letsoai pele ho nako (Feie. 3 A-C). Leha ho le joalo, ha ho liphapang tsa sehlopha tse fumanoeng ka bongata ba ho ngoloa ha mRNA bakeng sa tyrosine hydroxylase (TH), Transporter ea DA (DAT), kapa D2Rs kahare ho sebaka sa ventral tegmental (VTA) - sebaka sa boko se fanang ka kenyelletso ea mantlha ea dopaminergic ho NAcc (Feie. 3 D-G). Polelo e ntseng e eketseha ea li-D1Rs ho NAcc e tiisitsoe hape ke ho thibeloa ha Bophirimela (t = 1.90, P <0.05; Feie. 3 H 'me I). Mmoho, datha tsena li bonts'a hore ho pepesetsoa ha AMPH ho na le litlamorao tse amanang le li-site-system ho mesolimbic DA system ea li-voerendes tsa banna - ho eketsa boemo ba D1R ho NAcc.

Setšoantšo sa 3.

Litšoantšo tse bonts'oang ka ho ngoloa ha D1R (A) le D2R (B) mRNA ho NAcc le caudate putamen (CP) ea li-voes prairie tsa banna tse fumaneng liente tsa ip ea saline kapa AMPH (1.0 mg / kg) bakeng sa matsatsi a 3. Phekolo ea AMPH e ile ea eketsa letsoalo la ...

Li-Receptors tsa D1 ho NAcc Mediate AMPH Ho Fokotsa Likhetho tsa Partner.

Re kile ra bonts'a hore, ka li-voes tsa prairie tsa banna, ts'ebetso ea D1Rs kahare ho NAcc e thibetse mofuta oa khetho ea molekane (14), mme lipatlisiso tsa morao-rao li bonts'a hore tlhahiso ea AMPH e hlahisa li-D1Rs ho NAcc (Feie. 3). Ka hona, re lekile khopolo-taba ea hore ho sitisoa ha AMPH ho kenyelletsang litakatso tsa molekane ho kopantsoe le li-D1R ka har'a NAcc. Tse tona li fuoe monokotšoai o koetsoeng ka kotloloho ho polokelong ea NAcc (Feie. 4A). Artificial cerebrospinal fluid (CSF) e le 'ngoe kapa CSF e nang le litekanyetso tse fapaneng tsa D1-like receptor antagonist SCH23390 e ile ea kenngoa ka har'a NAcc pele ho entoa ea AMPH (1.0 mg / kg) nakong ea matsatsi a 3. Kamora moo, lithuto li ile tsa penta le mosali bakeng sa 24 h ebe li hlahlojoa hore na li khetha eng. Joalo ka teko e kaholimo (Feie. 2), Ho pepesetsoa AMPH ho thibetse likhetho tsa balekane ba tlatselletsang ho balekane ba amohelang li-ente tsa NAF tsa intra-NAcc kapa lethalinyana le tlase la SCH23390 (Feie. 4B). Leha ho le joalo, banna ba neng ba kentsoe ente ka tekanyetso e phahameng ea SCH23390 (100 ng / kg) ba bontšitse likhetho tsa molekane (t = 2.55, P <0.05), e bonts'a thibelo ea D1R ho NAcc e felisitse tšenyo e bakiloeng ke AMPH ea sebopeho sa khetho ea molekane (Feie. 4B). Ha ho na liphapang tsa sehlopha tse fumanoeng khafetsa nakong ea teko ea ho kopanya kapa ho etsa lintho tse tšoanang nakong ea tlhahlobo ea khetho ea molekane.

Setšoantšo sa 4.

(A) Setšoantšo sa setšoantšo le setšoantšo se reriloeng se bonts'a sebaka sa ente ho NAcc ea boko ba monna ea semmuso. Re tsepamisitse maikutlo holim'a mokokotlo oa NAcc hobane "subregion" ena e ikamahanya le litabatabelo tsa balekane. (B) Ba batona ba amohetseng intra-NAcc ...

Puisano

Thutong ena, re pheta mantsoe a rona a fetileng a hore ho pepeseha hoa AMPH ho hohela CPP maemong a banna ba rorisang (22) hape e bonts'a hore ts'ebetso ea D1R ho NAcc ea hlokahala bakeng sa boits'oaro bona, sephetho se lumellanang le lipatlisiso mefuteng e meng ea litoeba:28). Phumano ena, hammoho le lithuto tsa pejana, e fana ka maikutlo a hore mekhoa e ikhethileng ea DAergic ho NAcc e laola boitšoaro ba AMPH- le bo susumetsoang ke molekane: boitšoaro bo khothalletsoang ke AMPH (CPP) bo kopantsoe ke D1R, athe boitšoaro bo susumetsoang ke molekane (lithahasello tsa molekane) bo tsamaisoa ke D2R ts'ebetso le ho thibeloa ke ts'ebetso ea D1R kahare ho NAcc (13-15). [Ho bohlokoa ho hlokomela hore, ho NAcc, D2R activation e sebelisana le li-CPP tse kentseng lithethefatsi tlasa maemo a itseng (29) le ts'ebetso ea D1R e kenella mekhoeng e meng e susumetsoang ke sechaba, joalo ka e lebisitsoeng ho bana (7, 30)].

Phapang e fapaneng ea taolo ea DAergic ea CPP le sebopeho sa khetho ea molekane e ka fumaneha haholo ke phapang e teng tekong ea khatello ea DA e khothalletsang li-subtypes tse fapaneng tsa DAR. Ka lebaka la liphapang tse tlamang, likolo tse phahameng tsa khatello ea DA li hlokahala ho kenya tšebetsong li-D1Rs tse tlase, athe keketseho e nyane moqoqong oa DA o khetha ts'ebetso e phahameng ea D2R (31). Ka li-voes tsa prairie, AMPH e tsosa keketseho e kholo ho khatello ea DA (24) bapisoa le se ts'oeroetsoeng ke mating (15, 25). Lintlha tsena li fana ka maikutlo a hore keketseho e itekanetseng ea mahloriso a DA nakong ea lipuisano tsa sechaba (15, 25) lumella ho kengoa tšebetsong e itseng ea li-D2R tse haufi haholo 'me ka hona e nolofalletse ho theha maqhama a mabeli. Ka lehlakoreng le leng, keketseho e matla litlamong tsa DA kamora hore Tsamaiso ea AMPH e lekane ho kenya tšebetsong li-D1R tse tlase, ka ho etsa joalo ho tsamaisa CPP e susumetsang.

Taolo ea boitšoaro e ikhethileng ea receptor e entsoeng ke DA e lumellana le lithuto tse tsoang kantle ho ramatiki lithutong tse tsamaeang ka bolokolohi tse bonts'ang hore lithethefatsi le litheko tsa tlholeho li sebetsoa ke mefuta e ikhethileng ea neuronal kahare ho NAcc (32). Leha lithuto tse joalo tsa elektrophiki li sa khone ho tseba taba e nyane ea li-receptor tsa DA tse hlahisitsoeng ho li-neuron ka bomong, lithuto tsa sebopeho li bontša hore NAcc e entsoe ka li-neuron tsa projeke tse hlahisang D1R kapa D2R tse nang le coexpression e nyane haholo (33). Psychostimulants ka mokhoa o khethollang o kenya ts'ebetsong mats'oao a ho tsepamisa mohopolo a theoha molemong oa D1Rs (joalo ka qeto ea phosphorylation ea limolek'hule tse bontšang ()34) mme re kile ra bonts'a hore ts'ebetso e eketsang ea lits'ebetso tse saenang e thibela ho khethoa ha balekane (35). Kahoo, leha phetisetso ea DA ka hara NAcc e bapala karolo ea bohlokoa karabong ea AMPH le ho theoa ha lithahasello tsa balekane, mekhoa ena e kanna ea kopanngoa ka li-microcircuitries tse ikhethileng tse nang le litsamaiso tsa projeke ea striatal33, 36). Hona ke ho khahlisang hobane ho theha maqhama a kopantsoeng ho kopanngoe ka ts'ebetso ea li-neuron tse hlahisang D2R tse ikemiselitseng pele ho proven pallidum (33), karolo e 'ngoe ea boko e bohlokoa bakeng sa tlamo26).

Thutong ena, re fana ka bopaki ba hore boiphihlelo ba AMPH bo thibela ho tlamahana ha balekane. Ha liteko tsa khetho ea molekane litekong tsena li entsoe 48 h ka mor'a ho pepesetsoa AMPH ea ho qetela (ke hore, ka mor'a hore moriana o sebelisoe ka botlalo), datha tsena li hlahisa phello e phehellang ea AMPH khokahanong ea sechaba. Mochine o mong o ka sebelisoang, o lumellanang le litlamorao tsa AMPH ho mefuta e meng (37, 38), eo AMPH e ka sitisang khoebisano ka bobeli ka ho eketseha ha polelo ea D1R ka har'a NAcc. Tlhahiso ena e tšehetsoa ke karolo ea bohanyetsi ea NAcc D1Rs ka sebopeho sa khetho ea balekane (14, 24) le ka data e teng hona joale e bonts'ang pholoso ea khetho ea molekane ea tsoang ho motho ea kenang lenyalong ka intra-NAcc D1R blockade ho liphoofolo tse tšoaroang ke AMPH (Feie. 4). Ho khahlisang ke hore re kile ra bonts'a hore, mananeong a banna a ho rorisa, taolo-leseling ea NAcc D1Rs kamora libeke tsa 2 tsa bonto li thusa ho khetha moferefere ho batho bao ba sa ba tsebeng, ho kenyeletsa le basali ba amohelang thobalano, ba fanang ka maikutlo a hore mokhoa ona oa neural oa polasetiki ke mokhoa o fetotsoeng oo li-voles tsa banna li sebetsang ka tsona boloka maqhama a seng a tiisitsoe (14). Boithuto ba hona joale bo fana ka maikutlo a hore AMPH e baka ts'ebetso ea neuroplasticity ena, e lebisang ho senyeheng ha AMPH ea bonase. Hape hoa etsahala hore banna ba tšoaroang ke AMPH ba ka kopanya mosali le mosali ea tlosoang ke ho tlosoa ha AMPH, ka hona kamano ena e mpe e ka baka tšenyo ea AMPH ea tlamahano ea lenyalo. Phuputso e fetileng e bontšitse hore ho ikarola lenaneong le ntseng le eketseha la d-amphetamine le boitšoaro bo bobe ba thobalano ho likhoto tsa banna (39). Thutong ea rona, leha ho le joalo, lihlopha tsa lihlopha tse fapaneng tsa kalafo li bontšitse mekhoa e tšoanang ea ho holisa (Feie. 2B), ho supa hore mohlomong ba ne ba se boemong ba ho tsoa ho amphetamine. Leha ho le joalo, monyetla ona o tiisa hore ho hlokahala patlisiso e eketsehileng.

Ho thehiloe ka nepo hore ts'ebetso ea "neural" e khothalletsoang ke lithethefatsi e bohlokoa bakeng sa bokhoba ba lithethefatsi (40). Psychostimulants e fetola haholo polasetiki ea sebopeho tsamaisong ea mesolimbic DA (41) mme ho na le bopaki ba ho fana ka maikutlo a hore liphetoho tse joalo li mamelletse ho D1 e hlalosang li-neurons (37). Ntle le moo, lithuto tsa electrophysiological li bontšitse hore boiphihlelo ba koae bo ka fokotsa neuroplasticity e latelang kahare ho NAcc (42). Ka sebele, tlhophiso e hlophisitsoeng e entsoeng ka litlhare ea Nacc e bonts'a tlhophiso ea tlhaho ea tlhaho e hlahang kamora ho pepesehela pale e ncha ea tikolohong e rarahaneng (43). Ka hona, leha tšebeliso ea lithethefatsi e tsejoa hohle e le bothata ba ho ithuta le ho hopola (1, 40, 44), hangata hoa ananeloa hore tahlehelo e bakoang ke lithethefatsi ea menyetla ea liphetoho tse eketsehileng makaleng a mesolimbic le eona e ka ba bohlokoa bakeng sa ho lemalla. Phokotso e joalo ea polasetiki e kanna ea beha boitšoaro bo botle ho batho ba batlang lithethefatsi. Ha ho makatse hore ebe li-voles tse tšoeroeng ke AMPH li bonts'itse boitšoaro bo fokolisitsoeng ba kopane. Litlamorao tsa ho pepesetsoa hoa AMPH ho tlamahanong ea bobeli li lumellana le lithuto tse fetileng tse bontšang litlamorao tsa li-psychostimulants litloaelong tse ling tsa bophelo, ho kenyeletsoa boits'oaro ba bo-mme.45-47) le papali ea boithabiso (48-50). Ka kopanelo, mosebetsi o joalo o fana ka ts'episo ea hore ho hlahloba hore na lithethefatsi le ts'usumetso ea sechaba li kenella joang bokong, li ka holisa kutloisiso ea rona ea tšebelisano e matla lipakeng tsa boits'oaro ba sechaba le tšebeliso ea lithethefatsi ho batho (21).

Lisebelisoa le mekhoa

Taba.

Lintho tseo e ne e le likamano tsa botona le botšehali tsa banna ba tsoang ka thobalanong e tsoang koloneng e ikatisang. Lintho li ile tsa khoesoa ka nako ea matsatsi a 21 'me tsa bolokoa ka ba babeli ho ngoan a ngoanana a le mong ka mekotleng ea polasetiki (12 x 28 × 16 cm) moo metsi le lijo li neng li fuoa lib libitum. Litsela tsohle li ne li bolokoa tlasa 14: 10 potoloho e lefifi, 'me mocheso o ne o batla o le 20 ° C. Lithuto tsohle li ne li ka ba matsatsi a 90 a lilemo ha a ne a lekoa. Tlhatlhobo ea Stereotaxic le ts'oaetso e ikhethileng ea libaka tsa DA li hlalositsoe ka botlalo libakeng tse ling (14).

Teko ea Boitšoaro.

Teko ea CPP e entsoe joalo ka ha ho hlalositsoe pele (22) le mekhelo e latelang. Khetho ea pele ea kharebe bakeng sa thuto e ngoe le e ngoe e ne e khethiloe ho 30-min preest ka letsatsi 1. Litaba li ile tsa fanoa ka nako eo, ka nako ea li-40 tsa metsotso, le AMPH ho ea terakeng e sa khetholloang le saline ho ea teropong e ratoang (li-injection tsa AMPH le tsa saline li fanoe ka letsatsi le ts'oanang, 6 h ka thoko) bakeng sa matsatsi a 3 a latellanang (matsatsi a 2-4). Kamora moo, lithuto li ile tsa lekoa (morao-rao) bakeng sa ho ba teng ha CPP ka letsatsi 5.

Teko ea khetho ea balekane e entsoe joalo ka ha ho hlalositsoe pele (14). Ka bokhutšoanyane, lisebelisoa tsa tlhahlobo e ne e le k'haravene e bohareng (12 × 28 × 16 cm) e kopantsoeng le methapo ea methapo (7.5 × 16 cm) litsing tse peli tse ts'oanang tse tšoanang le e 'ngoe ea matlo e le phoofolo e khothalletsang. Liphoofolo tse hlohlelletsang e ne e le "molekane" ea tloaetseng (molekane oa mosali eo ho buuoang ka eena) le "osele" (mosali ea neng a e-so ka a kopana le taba eo) ​​ea neng a kenelletsoa ka kotloloho kahara matlo a hae a arohaneng ntle le ho buisana ka kotloloho. Ha ho qala tlhahlobo ea 3-h, lithuto li ile tsa kenngoa ka har'a terata e bohareng mme tsa lumelloa ho tsamaea ka bolokolohi ho lisebelisoa tsohle. Behaeve e tlalehiloe ho sebelisoa sistimi ea ho rekota ea video e liehang ho fihla. Litsebi tse sa boneng ho thetsa li ile tsa hlahloba sethepu mme li tlaleha boitšoaro ba sehlooho. Khetho ea molekane e hlalositsoe e le taba e sebelisang nako e ngata ho hokahana le molekane ntle le motho eo a sa mo tsebeng, joalo ka ha ho bonts'itsoe ke mehlala t tlhatlhobo (27).

Ho Situ Hybridization le Western Immunoblotting.

Mefuta e khethehileng ea antisense riboprobes (Lethathamo 1) e ne e sebelisoa bakeng sa D1R, D2R, TH, le DAT ho ngol mRNA labeling. Labeling e ile ea etsoa le 35S-labels phenes le li-control tsa mRNA bakeng sa letšoao le leng le le leng la DA joalo ka ha ho hlalositsoe pele (51). Bakeng sa tlhahlobo ea ho fifala ea Bophirimela, protheine ea DAR e nkiloe ho supernatant ea li-punch tsa tishu tsa NAcc mme e ts'oaroe joalo ka ha ho hlalositsoe pele (52).

Tafole 1.

cDNA e batlana le letšoao la DA la mRNA e ngotsoeng bokong ba prairie vole

Tlhatlhobo ea Tlhahlobo le Tlhahlobo.

Likhetho tsa CPP le balekane li khethoa ke mehlala ea lipara t liteko. Phapang pakeng tsa lihlopha tsa ho ruruha nakong ea tlhahlobo ea pele ea 6 h ea ho tsamaea le mosali le ente nakong ea tlhahlobo ea khetho ea molekane e ile ea hlahlojoa ke ANOVA. Methapo ea optical ea D1R le D2R mRNA e ngotsoeng ho NAcc hammoho le TH, DAT, le D2R mRNA e ngolisitsoeng ho VTA li ile tsa hlakoloa ho tsoa ho li-autoradiograms ka ho sebelisa lenaneo la setšoantšo sa k'homphieutha (NIH IMAGE 1.64). Lintlha li hlahisitsoe e le phetoho ea liperesente tsa moelelo oa sehlopha sa taolo ea letsoai le ho fapana ha lihlopha ho ileng ha hlahlojoa ke t liteko. Qetellong, methapo ea mahlo ea D1R le D2R e hlahang filiming ea x-ray ho tsoa liteko tsa West blotting li ile tsa hlahlojoa ke t liteko.

Moralo oa Teko.

Teko 1a e thehile lekhapetla la karabo ea lethal dose bakeng la CPP e kenyellelitsoeng ke AMP. Lintho li ile tsa etsoa pele ka har'a lisebelisoa tsa CPP ka letsatsi la 1, ka mokhoa o sa abeloang sehlopha se le seng sa liteko tse tšeletseng tse ileng tsa amohela liente tsa ip (ip) tsa saline tse nang le mefuta e fapaneng ea AMPH [0 (n = 12), 0.1 (n = 8), 0.5 (n = 9), 1.0 (n = 12), 3.0 (n = 12), kapa 5.0 mg / kg (n = 13)] matsatsing a 3 (ka letsatsi 2-4) ea boemo bo itseng, 'me ka mor'a moo e ile ea lekoa bakeng sa CPP ka mor'a letsatsi la 5.

Teko 1b e senotse likarolo tsa li-receptor tsa DA ho CPP e kenyellelitsoeng ke AMP. Litaba li ile tsa etsoa pele ka har'a lisebelisoa tsa CPP 'me ka mokhoa o sa abeloang tsa aroloa ho e' ngoe ea lihlopha tse robeli tsa liteko tse amohetseng ente ea sc (sc) ea saline (n = 10) kapa saline e nang le likhopolo tse fapaneng tsa mohanyetsi oa DA receptor antagonist [haloperidol; 0.1 (n = 8), 1.0 (n = 8), kapa 5.0mg / kg (n = 8)], kapa mofuta o kang D1-joaloka (SCH23390; 0.5 (n = 7) kapa 5.0 mg / kg (n = 7)] kapa D2-joalo ka DA receptor antagonist [eticlopride; 0.5 (n = 8) kapa 5.0 mg / kg (n = 8)]. Metsotso e mashome a mararo hamorao, lethal dose la AMPH (1.0mg / kg), le neng le kenyelletsa CPP ho Teko ea 1a, le ile la sebelisetsoa boemo ba AMPH. Kamora matsatsi a 3 a boemo ba AMPH, lithuto tsohle li amohetse postPest ea CPP.

Teko ea 2 e ile ea hlahloba hore na boiphihlelo ba AMPH bo kena-kenana le maqhama a mabeli. Bafetsi ba ile ba abeloa sehlopha se seng sa liteko tse ileng tsa amohela liente tsa saline (n = 8) kapa letsoai le nang le 1.0 mg / kg (n = 8) kapa 5.0 mg / kg (n = 7) AMPH hang ka letsatsi bakeng sa matsatsi a 3 a latellanang — paradigm e ileng ea qobella CPP ho li-voes tsa praemae tsa banna. Ka letsatsi la bone, lithuto li ile tsa penta le mosali ea holisitsoeng ka estrogen ea 24 h (14), mme ka nako eo ba ile ba lekoa tlhahlobong ea balekane ba 3-h. Ho laola litlamorao tse ka hlahisoang ke liente tsa li-bonding, sehlopha sa bone sa liteko sa banna ba sa ts'oaroang ba sa fumanang liente (n = 6) e ne e ngotsoe ka basali ka estrogen-primed bakeng sa 24 h mme ea nto e lekoa bakeng sa khetho ea molekane. Liteko tsohle tsa boits'oaro li ile tsa khethoa video bakeng sa netefatso ea ho emoloa. Nako ea lithuto tse haufi le molekane le motho eo a sa ba tsebeng e ne e le eona e lekantsoeng. Ntle le moo, khafetsa maqhubu a ho tlolelana ha nako ea 6 h ea ho hira le ho etsa lintho tse ling (tse bonts'itsoeng ke ho tšelella) nakong ea liteko tsa khetho ea molekane oa 3-h li ile tsa hlakoloa. Kamora tlhahlobo ea khetho ea molekane, bafo ba ile ba bolaoa hanghang. Mabali ohle a ne a kotuloa, a hoamisoa leqhoeng le omileng, 'me a bolokiloe ho −80 ° C bakeng sa ho ngolla mofuta oa li-mRNA tsa DA.

Teko ea 3 e ile ea lekola hore na bonding e senyehileng ea AMPH e amana le liphetoho mesebetsing ea mesolimbic DA. Borena ba lithuto tse amohelang saline (n = 8) kapa 1.0 mg / kg AMPH (n = 8) ho Teko ea 2 e ile ea khaoloa holima crystat hore e be likarolo tsa coronal (botenya ba 14 μm) tse neng li qopetsoa ho Superfrost / plus slides (Fisher Science science). Likarolo tsa methapo ea methapo ea 98-μm e ile ea sebetsoa bakeng sa ho ngolisoa ha li-hybridization tsa D1R, D2R, TH, le DAT mRNA. Hobane li-voles tse nang le 1.0 mg / kg AMPH li bonts'itse keketseho ea D1R, empa eseng D2R, ho ngolisoa ha mRNA ho NAcc, ha ho bapisoa le taolo e kentsoeng letsoai, lihlopha tse peli tse eketsehileng tsa lithuto tse ileng tsa fumana liente tsa saline (n = 6) kapa 1.0 mg / kg AMPH (n = 6), 24 h ea mating, le tlhahlobo ea khetho ea balekane, joalo ka ha ho hlalositsoe kaholimo. Lintho li ile tsa hlakoloa 'me masapo a sefahleho a ne a lisoa ka cryostat ho botenya ba 300 μm. Lithapo tsa lithapo li nkuoe ka bobeli ho NAcc li ile tsa sebetsoa bakeng sa D1R le D2R Western blotting.

Teko ea 4 e ile ea hlahloba hore na ts'ebetso ea li-receptors tsa mofuta oa D1 ho NAcc e ne e ikarabella bakeng sa ho senyeha hoa matla a AMPH. Lintho li ile tsa kenngoa ka tataiso ea cannulae ka linaha tse peli tse etselitsoeng khetla ea NAcc. Kamora matsatsi a 3 a ho hlaphoheloa, ba ile ba abeloa ka tšohanyetso ho ba se seng sa lihlopha tse tharo tsa liteko moo ba ileng ba fumana li-ente tsa NAcc tsa CSF (200 nL / side, n = 11), kapa CSF e nang le 0.4 (n = 6) kapa 100 ng / lehlakoreng (n = 7) SCH23390. Metsotso e mashome a mararo hamorao, ba ile ba amohela liente tsa ipN ea 1.0 mg / kg AMPH. Ts'ebetso ena e ile ea phetoa matsatsi a 3 a latellanang. Ka letsatsi la bone, lithuto li ile tsa penta le mosali ea emisitsoeng pele oa estrogen bakeng sa 24 h mme a ntoo hlahlojoa hore na o rata eng.

lumela hore baa fokola

Bangoli ba leboha Kyle Gobrogge, Claudia Lieberwirth, Kelly Lei, le Melissa Martin ka ho bala ka mokhoa o nyatsoang buka ena e ngotsoeng ka letsoho. Mosebetsi ona o tšehelitsoe ke National Institutes of Health Grants MHR01-58616, DAR01-19627, le DAK02-23048 ho ZW

Mongolo o botlaaseng ba leqephe

Bangoli ba phatlalatsa hore ha ho na likhohlano tsa thahasello.

Sengoliloeng sena ke Tlhahiso ea Direct ea PNAS.

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