Ho batla ho sebelisa lithethefatsi ka mekhoa e mengata ea ho sebelisa lithethefatsi sebakeng sa boemo bo tlase ba Dopamine (2014)

Biol Psychiatry. 2014 Sep 22. pii: S0006-3223 (14) 00703-3. Doi: 10.1016 / j.biopsych.2014.09.004. RC1, Wheeler DS2, Ebben AL2, Jacobsen AJ2, Robble MA2, Mantsch JR2, Wheeler RA2.

inahaneloang

Background

Ho sithabela ha khatello ea maikutlo ho ama boemo ba maikutlo le ho khanna ho batla lithethefatsi, ka karolo e itseng, ka ho fetola tšebetso ea sistamine ea mesolimbic dopamine. Ka bomalimabe, taolo e potlakileng ea dopamine e boletsoeng ke boiphetetso e bakang ho batla lithethefatsi ha e hlahelle. Litekong tse 'maloa, re ile ra hlahlobisisa melaoana ea thibelo ea dopamine ka ho hlohlelletsa, quinine,' me ra leka bokhoni ba eona ba ho baka ho batla koae. Ntle le moo, re ile ra hlahloba molao oa bohareng ba dopamine ka bobeli ba ho tšoaea dopamine le ho batla koae ka peptide e nang le khatello ea maikutlo, corticotropin releasing factor (CRF).

mekhoa

Ho kopanya voltlicet e potlakileng ea scan ninemokrase le boitšoaro ba tlhahlobo ea meriana, re ile ra hlahloba phello ea tsamaiso ea methapo ea kutlo ho li-nucleus accumbens dopamine signaling le polelo ea hedonic ho likhoto tsa 21 tsa banna tsa Sprague-Dawley. Re lekile karolo ea CRF ho fetoheng liphetoho tse tlisoang ke ho tsilatsila ho tsebisoang ka har'a dopamine le k'hok'heine e batlang ka ho kenella kahare ho CRF antagonist, CP-376395, ho kena sebakeng sa ventral tegmental (VTA).

Results

Re fumane hore quinine e ile ea fokotsa dopamine ka potlako ho supa maemong a mabeli a ikhethileng. Re ikemiselitse hore CRF e sebelisane le VTA ho kopanya phokotso ena ho e le ngoe feela ea likala tsa nako. Ho feta moo, re fumane hore phokotso ea "dopamine tone" le "quinine" e khothalletsoang ke "cocaine" e felisitsoe ka ho thibela liketso tsa CRF ho VTA nakong ea boiphihlelo.

Nahanisisa

Lintlha tsena li bonts'a hore ho batlana le lithethefatsi tse bakoang ke khatello ea maikutlo ho ka hlaha tikolohong ea lentsoe le tlase la dopamine le itšetlehileng ka phokotso ea CRF e hlahisang ts'ebetso ea midbrain dopamine.

Keywords:

Liketsahalo tse sithabetsang tsa bophelo ke li-modulators tse fetolang maikutlo mme li ka baka mekhoa e fapaneng ea boits'oaro e kenyelletsang ts'ebeliso e mpe ea lithethefatsi (1). Le ha bokhoba ke bokuli bo kopanetsoeng, ho 'nile ha fanoa ka maikutlo a hore liketsahalo tse fapaneng tsa bophelo li ka khothaletsa ho khutla hape ho lithethefatsi ka ho hohela tse mpe le ka ho lakatsa (2, 3, 4, 5). Ka mokhoa o ts'oanang, tšusumetso e amanang le lithethefatsi e etsa hore motho a be le ts'ebeliso e mpe ea tšebeliso ea tšebeliso ea lino tse tahang ("cocaine").2, 4, 6). Qetellong lithahasello tsena ho nahanoa hore li khothaletsa boitšoaro bo bobe boo ho bona batho ba sebelisang lithethefatsi hampe, ba lekang ho lula ba sa thibe, ba khothalletsoang ho lokisa boemo bo bobe ba tikoloho bo hlohlelletsang tikoloho ka ho qala ts'ebeliso ea lithethefatsi (7, 8, 9, 10, 11).

Liketsahalo tse feto-fetohang le maemo a bona a ho hlasela li ka 'na tsa khanna ho batla lithethefatsi ka ho kenya tšebetsong sisteme ea mesolimbic dopamine, empa tsela eo ba etsang sena ka eona ha e utloisisehe hantle. Ebile, ha bopaki bo ntse bo eketseha hore ts'usumetso e mpe ke qeto e hlakileng ea ho qalella ha lithethefatsi ho latela linako tse latelang tsa ho tsila, lingoliloeng li hanyetsanoa ka potso ea mantlha ea hore na karabelo ea dopamine e susumetsoa joang (12, 13). Lithuto tsa electrophysiological le electrochemical tse lekanyang ts'ebetso ea dopamine neuron le ho lokolloa ha dopamine, ka ho latellana, li lumellana le maikutlo a kapele le pono ea susumetsang e khahlapetsang. khafetsa a tšoaea liphokotso tse potlakileng ho lets'oao la dopamine ho araba maikutlo a khutsitseng le ba boletsoeng esale pele (14, 15, 16, 17, 18, 19). Tphokotso ea hae ea ts'ebetso ea dopaminergic ho tlalehoa e susumetsoa, ​​ka karolo e 'ngoe, ke li-neuromodulators tse nang le khatello ea maikutlo tse kang corticotropin-releasing factor (CRF) (20, 21). Ka bomalimabe, lirekoto tsa electrophysiological tsa dopamine neurons li bonts'a hore ho fokotseha ho bakoang ke ts'usumetso ea dopamine neuron kapa taelo ea CRF ea karabelo eo ha e tšoane. (22, 23, 24, 25), ho hlokahala mokhoa o tla hlahloba ho saena ho potlakileng ha lipalo tsa li-prooption tsa neurophene tsa dopamine.

Hanyane hanyane ho tsejoa ka mofuta oa lipapatso tsa dopamine tse potlakileng, tse hlohlelletsang le tse tsoang libakeng tse loketseng. Ha ho hlake hore na tšusumetso e joalo e ka baka phokotseho joang ho lets'oao la dopamine le hore na dopamine e fokotsehileng e ka khothatsa joang boits'oaro bo bobe ba khatello ea maikutlo, joalo ka ho batla lithethefatsi. Ho li-nucleus accumbens (NAc), sebaka sa bohlokoa sa potoloho ea moputso, sea eketseha ebile se fokotseha ka har'a khatello ea dopamine ka mokhoa o loketseng activate D1- le D2-receptor-e hlalosang li-katiba tsa "spiny neurons" (MSNs), ka ho latellana, tse nang le litlamorao tse khahlanong le boits'oaro bo susumetsang (26, 27). Ts'ebetso ea li-circuits tsena tse ikhethileng e se e le nako e telele e tsejoa ho laola mefuta e fapa-fapaneng ea boits'oaro bo susumetsang, ho kenyelletsoa le likarabo tsa lithethefatsi tsa tlhekefetso. (28, 29, 30, 31, 32, 33). Ka hona, ho khetholla hore na maikutlo a susumetsang a matla a eketseha kapa a fokotseha NAC dopamine e ka ba bohlokoa ho tseba hore na liketsahalo tse sithabetsang tsa bophelo li etsa hore ho khutla tšebelisong ea lithethefatsi ho tsose ts'ebeliso ea lithethefatsi joang. Pele re ne re hlokometse hore tšusumetso ea boikhopotso ba koae e ka baka boemo bo bobe ba ts'ebetso, ha ka nako e ts'oanang e fokotsa tšoaetso ea dopamine ho NAc (19). Leha ho le joalo, tšusumetso ea boiphihlelo ba e 'ngoe ea lipono tsena e ntse e lokela ho hlahlojoa. Lipotso tsa bohlokoa tsa hore na sepheo se khopisang se laola taolo ea dopamine ka mokhoa o fosahetseng le hore na mochine ona ke o mong o ka lebisang boits'oarong bo batlang lithethefatsi litonong o tlameha ho arajoa. Lithutong tsena, re hlahlobisitse litšitiso tse hlakileng tsa moea tse fokotsang tšibollo ea dopamine signature, molaoana ka khatello ea khatello ea CRF sebakeng se phephetsang (VTA), le tšusumetso ea boits'oaro ho ts'ebetsong ea hedonic le ho tsoma lithethefatsi. Ka kakaretso, seo re se fumaneng se senola ho rarahana ha nakoana ho ho saena ka dopamine le bokhoni ba CRF ba ho laola molumo oa dopamine le ho khothaletsa ho batla lithethefatsi.

Mekhoa le Lisebelisoa

Lihlooho

Liroto tse mashome a mabeli a motso o mong tsa Sprague-Dawley rats (275-300 g; Harlan Laboratories, St. Louis, Missouri) li ne li bolokiloe ka bonngoe mochesong o laoloang ke mocheso le mongobo, Mokhatlo oa Tlhatlhobo le Kamohelo ea Laboraro ea Tlhokomelo ea Liphoofolo. Likhoto li ile tsa bolokoa mokolokong oa nako ea 12 / 12-hora e khutliselitsoeng morao (mabone a ile a fihla 7 am) mme a na le phihlello ea lipapatso (ntle le ha ho boletsoe ka tsela e 'ngoe) ka metsi le lijo (Teklad; Harlan Laboratories). Liprotheine tsohle tsa liteko li amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso Univesithing ea Marquette ho latela Setsi sa Naha sa Tataiso ea Bophelo bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro.

 Phekolo

Ts'ebetso tsohle tsa ts'ebetso ea opereishene li ne li etsoa tlas'a ketamine / xylazine (100 mg / kg / 20 mg / kg, intraperitoneal) anesthesia. Ho kenella ka hare ho intraoral le intrajugular catheter ho entsoe joalo ka ha ho hlalositsoe pele (11). Tataiso ea li-cannulas tsa li-microinjections (26-gauge; Plastics One, Roanoke, Virginia) li ile tsa kenngoa ka kotloloho kahare ho VPS (anterior-posterior: −5.6; medial-lateral: ± 2.2 at 11º; dorsal-ventral: −7.0). Ho itokisetsa lirekoto tsa voltammetric, li-cannulas tsa li-elektrode li kentsoe kaholimo ho polasetiki ea NAc ntle le tšohanyetso (anterior-posterior: + 1.3; medial-lateral: ± 1.3), 'me li-electrode tsa silevera / tsa silevera ea chloride li ile tsa beoa ka boikhethelo ho cannula ea tataiso. Ntle le moo, setsi se kopaneng sa "bipolar" se kopantseng "" polasetiki "se kopaneng se ile sa beoa kapele ho ipsilateral VTA, 'me" cannula "ea tataiso e ile ea beoa kaholimo ho tumellano ea VTA. Bakeng sa lits'ebetso tsohle tsa ts'ebetso ea opereishene, likhoto li ile tsa phekoloa ka anti-inflammatory med-cam (1% ho emisoa ka molomo) ka letsatsi le bakeng sa matsatsi a 2 kamora ho buuoa ho fokotsa ho ruruha le bohloko ba morao. Ho boloka patency, li-catheters tse kenang kahare le tse kenang kahare li ne li fepuoa letsatsi le letsatsi ka metsi a qhibilihileng (kahare) kapa letsoai le nang le heparinised le cephazolin (intravenous [IV]) ka ho latellana.

Microinjections

Microinjectors e atolositsoe .5 mm ho tloha qetellong ea cannula ea tataiso. Artificial cerebrospinal fluid (aCSF) (.3 µL / min) kapa selekane sa CRF receptor antagonist CP-376395 (.3 µg / .3 µL / min) se ile sa kenngoa kahare ho VTA (n = 6 aCSF, n = 6 CP-376395). CP-376395 ke mohanyetsi ea khethiloeng oa CRF-R1, empa litšebelisano le R2 li kanna tsa ba le tekanyetso ena. Li-Microinjectors li ile tsa siuoa li le sebakeng sa metsotso ea 2 ka mor'a ente ho lumella phallo. Ts'ebetsong ka bobeli, ho tsamaisoa ka quinine e ile ea qala ho qalisoa hang kamora ho entoa.

Rekoto ea Voltammetric

Kamora ho hlaphoheloa opereisheneng, likhoto li ile tsa lula bakeng sa lihora tsa 2 tikolohong ea ho rekota ea voltammetric, e nang le kamore e hlakileng ea Plexiglas (Med Associates, St. Albans, Vermont) e kentsoeng mokotleng o hahiloeng ka mokhoa oa Faraday. Electrode e susumetsang ea VTA e ne e hokahantsoe ka mochini o potolohang (Crist Instrument Co, Hagerstown, Maryland), 'me cannula e le' ngoe e kenang e ile ea kenngoa mokelikeli o tsoang mokelikeli (Instech Laboratory, Plymouth Assembly, Pennsylvania) e neng e ka amohela metsi ho tsoa pompong ea syringe (Razel , St. Albans, Vermont). Letsatsing le latelang, lirekoto tsa voltammetric li ile tsa etsoa joalokaha ho hlalositsoe pele (16). Lintlha tsa mokhoa oa ho rekota le ho sekaseka li hlalositsoe ho Tlatsetsa 1. Ka bokhutšoanyane, electrode ea carbon fiber e theotsoe khetla ea NAc, mohala oa metsi o ile oa kenngoa ka har'a cannula ea kahare, 'me seboka sa boits'oaro sa qala. Teko e ne e le karolo ea 30 ea motsotsoana oa ho hlahloba dopamine (phase 1); nako ea tlhahiso ea quinine ea metsotso ea 30 (phase 2); li-virinjection tse peli tsa VTA; le nako ea ho tsamaisoa ha quinine ea metsotsoana ea 50 ea metsotso ea 3 (phase 6). Ho pholletsa le likarolo tsohle tsa tlhahiso ea quinine, tlhahiso ea 2-ea bobeli ea .001 mL quinine (.XNUMX mmol / L) e ile ea hlahisoa hoo e ka bang motsotso o mong le o mong.

Tlhahlobo ea Tlhahlobo ea Voltammetry

Lintlha tsa boitsebahatso ba ho hlahloba li hlalositsoe ho Tlatsetsa 1. Lintlha tse tsoang ho teko e 'ngoe le e' ngoe (−20 sec pele le 30 sec postinfusion ukuqala) li ne li nts'itsoe ka morao-rao ka sekepe sa 1-bobeli ho minima ea lehae metsaneng ea 20 pele ho ts'itiso. Bakeng sa rat e 'ngoe le e' ngoe, datha e ne e lekantsoe ho pholletsa le liteko tsa infinine infusion ka metsotsoana ea 10 kamora ho qalisoa ha nako ea infinine infusion (quinine) ha e bapisoa le nako ea 10-ea bobeli (prequinine) le nako e latelang ea 10-bobeli (postquinine). Liphetoho tse hlahisitsoeng hona joale ha nako e ntse e feta li ile tsa hlahlojoa bakeng sa liphetoho tsa dopamine li sebelisa motsoako oa motheo. Bakeng sa likhoto tsohle (n = 12), phokotso ka sebopeho sa dopamine ka tlhaho e neng e sa sebetse (e seng nako e notlelitsoeng) e ile ea hlalosoa 'me ea hlahlojoa ka ho bapisa liteko tsa 5 tsa pele (pele) ka liteko 11 ho 15 (bohareng) le liteko tsa 5 tsa ho qetela (morao) nakong ea prequinine , Metsotsoana ea 10 pele ho ts'oaetso ea quinine, o sebelisa tlhahlobo e pheta-phetoang ea phapang (ANOVA). Liphetoho tsa bohlokoa ho khatello ea dopamine ha nako e ntse e tsamaea, e koaletsoeng nako ho kenngoa infinine, li ile tsa hlahlojoa ho sebelisoa mehato e 'meli e phetoang ea li-ANOVA tse arohaneng (motheo, quinine, le quinine + drug [aCSF kapa CP-376395]) x nako (prequinine, quinine, postquinine). Ha ho fumanoe litlamorao tse kholo kapa tse kopanetsoeng, lipapiso tsohle tsa joala tse peli li entsoe ka liteko tsa Tukey tsa post tsa hoc bakeng sa papiso e ngata le alpha e behiloeng ho .05.

Liketsahalo tsa tokollo ea Dopamine li etsahetse ntle le ts'usumetso kapa ts'ebetso efe kapa efe ea ts'ebetso e laoloang ka nako ea motheo. Ho tseba hore na tšusumetso e matla e ammeng monyetla oa liketsahalo tse phahameng tsa tlhahiso ea dopamine, sampuli e 'ngoe le e' ngoe ea 100-msec tekong e 'ngoe le e' ngoe e lekantsoeng e ne e bolokiloe nako haeba khatello ea eona e ne e le 40 nmol / L kapa e phahame. Monyako ona o kahara mefuta e fapaneng ea li-affinities tsa li-receptor tse phahameng tsa D1 mme ke boleng bo lekanyelitsoeng ba liketsahalo tsa tokollo ea dopamine tse tsoang kantle.34, 35). Ho tsoa ho sebopeho sena, khafetsa le bolelele ba nakoana bo ne bo hlalosoa le ho hlahlojoa. ANOVA ea mekhoa e 'meli e sebelisitsoe ho supa litlamorao tsa mantlha tsa nako (quinine versus postquinine) le lithethefatsi (aCSF vs. CP-376395). Liteko tsa Tukey tsa ho hoc tsa ho bapisa lintho tse ngata li ile tsa sebelisoa ho khetholla liphapang tsa bohlokoa nakong le sethethefatsi. Maemong kaofela, boemo ba alpha ba bohlokoa e ne e le .05. Lipapiso tsa lipalopalo li entsoe ka software e fumanehang khoebong (Statistica; StatSoft, Tulsa, Oklahoma).

Leketso tsa Tlhahlobo ea Tatso

Ho pheta-pheta ho ile ha hlahlobisisoa tlhahlobisong ea sebopeho ka sebopeho se sebelisitsoeng video ea dijithale e tlalehiloeng ka letsatsi la liteko ho likhakanyo tse kentsoeng tsa CSF- le CP-376395 (n = 5 sehlopheng ka seng). Reacuction ea monate le e sa thabiseng e ile ea baloa matsatsing a prequinine le quinine ho sebelisoa mokhoa oa Grill le Norgren (36). Ho sisinyeha ha molomo ho tšoanang le sebopeho sa borarong nako e telele ho feta 90 msec ho baliloe e le ho phephetsang. Litekanyetso tsena li ne li sa kenyele ho sisinyeha hohle ha molomo le ho kenella ka hare, tse neng li baloa ka thoko. Lits'ebeletso tseo leleme le ileng la tsoa le ho tšela bohareng ho ne ho thoe li monate. Boitšoaro bo setseng ba ho nyeka bo ile ba nkoa e le ho nyeka ho se nke lehlakore. Litlhahlobo tsa boithuto ba data eohle ea boits'oaro li entsoe ka software e fumanehang khoebong (Statistica).

Boitlhotlhollo le Boitlamo

Likhoto tse thibetsoeng lijo tse bobebe (15-18 g / ka letsatsi) li ile tsa koetlisetsoa ho tobetsa moferefere bakeng sa li-pellets tsa sucrose. Ha ho fumanoa khatello ea lever (matsatsi a ~ 3-5), li-catheters tse kenang kahare le tse kenang methapong li ile tsa kenngwa joalo ka ha ho hlalositsoe kaholimo. Kamora ho fola, likhoto li ile tsa thibeloa lijo hape tsa koetlisetsoa ho iphelisa ka cocaine (.3 mg / .2 mL / infusion, IV) lenaneong le sa fetoheng la 1 likamoreng tse sebetsanang le likhomphutha tse kentsoeng likamoreng tse thibelang molumo (Med Metsoalle). Ha lenaneo la k'hok'heine le qala, lebone la ntlo le ile la bonesa kamore eo, 'me lebone la leseli le kaholimo ho lever le ne le bontša ho fumaneha ha cocaine. Phallo e 'ngoe le e' ngoe ea k'hok'heine e ne e tsamaisana le ho tima lebone la ntlo le leseli la ntlo, le nako ea ho phomola e tšoarellang metsotsoana e 20, nakong eo lelepe le ileng la lula le atolositsoe mme likarabo tsa ngoloa empa tsa se ke tsa matlafatsoa. Ho araba lever ea bobeli e sa sebetseng le hona ho tlalehiloe. Kamora nako ea ho tsoa, ​​lebone la ntlo le lebone la ntlo li ile tsa buloa 'me tsa bontša ho fumaneha ha cocaine. Likarolo tsa boipheliso li etsahetse letotong la matsatsi a 6 a laoloang ke liteko tse nang le matsatsi a 3 a ts'ebetsong ea cocaine le matsatsi a 3 a se na k'hok'heine ntlong ea lapeng. Kamora potoloho ea boraro, likhoto tsohle li ile tsa fuoa opereishene ea VTA mme ba qala potoloho ea bona ea bone kamora libeke tsa 2 tsa ho fola. Lenaneo le leng le le leng la k'hok'heine letsatsi le leng le le leng le ile la fela ha likhoto li fumana palo e lekantsoeng ea infusions ea cocaine (25 infusions bakeng sa matsatsi a 9 a ho fihlella pele ho thibelo ea VTA le li-infusions tse 30 bakeng sa linako tse tharo tsa ho qetela tsa cocaine kamora ho tlosoa ha VTA). Ho felisoa ho ne ho na le mananeo a letsatsi le letsatsi a lihora tse 2 nakong eo mochini o mong le o mong oa khatiso o ile oa baka tšelo ea letsoai empa ho se na leseli la leseli kapa phepelo ea k'hok'heine. Hang ha sekhahla sa ho felisoa se fihlelletsoe (<15 likarabo tse sebetsang tsa lever bakeng sa karolelano ea matsatsi a 2; Letlapa la S1 in Tlatsetsa 1), Rate e 'ngoe le e' ngoe e ile ea lekoa bakeng sa ho khutlisetsoa ka har'a quinine. Ho thibela pherekano e ka bang teng ea ho hlaphoheloa ha boiketsetso, ho ile ha etsoa tlhahlobo e khutlisetsang phoofolo e 'ngoe le e' ngoe ka le hlahlamang ka mor'a hore e felisoe. Pele ho karolo e 'ngoe le e' ngoe ea ho khutlisetsoa ka likhoto, likhoto li ile tsa amohela li-microinjections tsa intra-VTA tsa aCSFn = 4) kapa CP-376395 (n = 5). Lithupelo tsa boiphetetso li qalile ka infusions tsa intinine tsa 15 tsa quinine tse fanoeng ka phapusing ea boiketsetso ea koae ka mokhoa o ts'oanang le tekong e fetileng ea metsotso ea 15. Metsotso e mehlano ka mor'a ho tsamaisoa ka quinine, lvers e ile ea eketsoa 'me likarabo tsa hatisoa bakeng sa hora ea 1.

Tlhahlobo ea Tlhahlobo ea Boitsebiso

Liphetoho tsa boits'ebetso ba khatello ea lever ka hora ea pele ea thupelo e ngoe le e ngoe li ile tsa hlahlojoa ho sebelisoa mekhoa e 'meli ea ANOVA e fapaneng pakeng tsa lintlha tsa lithethefatsi (aCSF, CP-376395) le ntho ea ka hare ea lithuto (ho felisoa, ho khutlisoa, ho khutlisetsoa morao-rao) . Karabelo ea ho felisoa ha limela e hlalositsoe e le letsatsi la ho qetela la thupelo ea ho timela, 'me karabelo ea morao-rao e ne e le thuto ea hoqetela e lekoa tlas'a maemo a ho timela ntle le taolo ea quinine. Phapang e kholo mekhoeng ea ho batla lithethefatsi e ile ea bonoa ha ho loketse ke liteko tsa Tukey tsa post tsa hoc tsa lipapiso tse ngata le alpha e behiloeng ho .05.

Histology

Kamora ho phetheloa ha lits'ebetso tsa liteko, lithuto tsohle li ile tsa khothaletsoa ka khabone. Ho netefatsa ho behoa ha li-electrode tsa ho rekota, liso tse nyane tsa elektrone li thehiloe ka ho tsamaisa sejoale-joale (250 µA) ka motlakase oa motlakase oa tšepe o kentsoeng botebong ba moo ho rekota ho etsahetseng. Li-brains li ile tsa tlosoa 'me tsa kenngoa kahare ho 10% formaldehyde bakeng sa matsatsi a 14. Ka mor'a moo ba ne ba kentsoe likarolo tsa 40-µm, ba beoa, ba hloekisoa ka .25% thionin, 'me e koaetsoe. Litšoantšiso tsa cannula le li-electrode li beiloe ho tsoa voltammetry le liteko tsa ho khutlisetsoa li hlahisoa ho Litšoantšo S1 'me S2 in Tlatsetsa 1, ka ho latellana (37).

Results

Ho fumana matla a nakoana a phokotso ea dopamine e bakiloeng ke liketsahalo tse makatsang, re ile ra sebelisa li-volclic tse lebelo ka potlako ho likhoto tse tsamaeang ka bolokolohi litšoantšong tse kantle tsa tatso e sa rateheng le e bohloko ea quinine. Moralo ona o lumella leihlo le ts'oanang la karabelo ea phoofolo e kopanetsanang le tlhahlobo ea ho lokolloa ha dopamine ho NAc ka nako e ka tlase ho nako (16, 19). Joalo ka ha ho lebelletsoe, ho pholletsa le nako ea tlhahlobo ea metsotso ea 30 (1 infusion / min), ho pepesetsoa ha quinine ho ile ha tsosa polelo ea ho kheloha tatso e khutsitseng nako e notlelletsoeng ho fokotsa litheko tsa ho lokolloa ha dopamine (Setšoantšo sa 1B; phase 2, prequinine ha e bapisoa le linako tsa quinine / postquinine, ka ho le letšehali le ka ho le letona; Setšoantšo sa S3 in Tlatsetsa 1). Ka mokhoa o tsotehang, phokotso ea dopamine e bonts'itse matšoao a mabeli a nakoana a setšoantšo: mokokotlo o hlakileng kapele, nako le nako ha o pepesetsoa quinine, hammoho le phokotso ea nako e telele ea lentsoe la dopamine ka tlhaho e hlahang feela kamora ho pepesehela quinine khafetsa. Phello ena ea morao e ile ea hlalosoa e le phokotso ea bohlokoa bohareng (liteko tsa 11-15) le liteko tsa morao-rao (liteko tsa 26-30), ha li bapisoa le liteko tsa pele (tsa pele tsa 5) nakong ea prequinine ea metsotsoana ea 10 pele ho infinine infusions (Setšoantšo sa 1B, hantle). Lintlha tsena li netefatsa bokhoni ba tšusumetso ea maikutlo a ho theola khatello ea methapo ea dopamine mme bo senola ho rarahana ha nakoana karabong ena.

Setšoantšo sa setšoantšo sa Figure 1. E bula setšoantšo se seholo    

Setšoantšo sa 1

Corticotropin-releasing factor regulation of dopamine signing nakong ea boiphihlelo bo matla bo ke keng ba qojoa. (A) Ho feto-fetoha ha maemo molemong oa tlhaho ea dopamine ka khetla ea khetla ea nucleus e bokellanang ho taolo ea boitšoaro (ka ho le letšehali) le tekong (ka ho le letona) mo molatong oa motheo (phase 1). (B) Alopidine ea dopamine e fetotsoeng ha e araba tsamaiso ea methapo ea quinine (phase 2). Phokotso e ka bonoa ka bobeli ka mokhoa o hlakileng ha o arabela quinine (x axis) hape o pharaletse ho pholletsa le liteko (y axis, prequinine [Nako ea Q]. (B) (ka ho le letona) Phallo ea methapo ea kutlo ea quinine e fokotsehileng e emisitsoeng ho feta litekong nakong ea prequinine nako ea phase 2 (tlhahlobo ea phapang ea mantlha: liteko F2,22 = 11.73, p <.01; Poso ea Tukey, *p <.05, phokotso e kholo ea liteko tsa bohareng le tsa morao ho bapisoa le liteko tsa pele). (C) Phokotso ea Quinine e kenyellelitsoeng ho lets'oao la dopamine e ile ea fumanoa ke li-entraventral tegmental sebakeng sa ente ea corticotropin-releasing factor antagonist, CP-376395 (phase 3). aCSF, mokelikeli oa k'holeseterole ea maiketsetso; DA, dopamine; Post Q, postquinine.

Ka mor'a moo re ile ra botsa hore na ho theoha dopamine ho sa feleng ho susumetsoa ke tšoaetso ea CRF ho VTA (21). Karolong ea 3, liphoofolo li fumane li-microinjection tsa intra-VTA tsa CRF antagonist CP-376395 (.3 µg / .3 µL / min) kapa aCSF (.3 µL / min), ha ho tsamaisoa ka har'a quinine ea ho tsoa kahare le ho rekota ka sekhahla ha li-cyclic cytlic li ntse li tsoela pele. (Setšoantšo sa 1C, ho lokile; Setšoantšo sa S1 in Tlatsetsa 1). Bofetoheli ba CRF ho VTA bo ne bo sena tšusumetso ho bokhoni ba quinine ea ho baka ho fokotseha ka sekhahla ha nako ea khatello ea dopamine nakong ea ts'ebetso ea quinine intraoral infusion.Setšoantšo sa 1C). Ka lehlakoreng le leng, ho hanyetsa ka CRF ho VTA ho felisitse phello ea inhibitory ea quinine e sa koaletsoeng nako ea "dopamine" nakong ea prequinine le linako tsa postquinine (Setšoantšo sa 1C). Ka ho pheta-pheta litekong, khatello ea dopamine e atolositsoeng nako e ka bonoa (Setšoantšo sa 2A, B), hammoho le phokotso e matla e bakoang ke infinine infusion. Ho bona karabelo ea karabo ena ho ka bonoa ka mora khang ea CRF (Setšoantšo sa 2D) hape e hlalositsoe tlhahlobo e latelang ea chemometric (Setšoantšo sa 3A, B).

Setšoantšo sa setšoantšo sa Figure 2. E bula setšoantšo se seholo    

Setšoantšo sa 2

Phetoho ea khatello ea dopamine e atamelaneng le nako nakong ea infinine infusion le ho latela corticotropin-releasing factor receptor blockade. Lipontšo tsa mebala e likarolo li peli tsa data ea cyclic voltammetric e bokelletsoeng metsotsoana ea 50 ho potoloha infusions tsa quinine, ka karolelano ea liteko bakeng sa mohato ka mong oa teko. The supplement ke motlakase o kentsoeng (Eapp) mme abscissa ke nako (metsotsoana) e. Liphetoho tse etsahalang hona joale ho li-electrode tsa carbon fiber li bontšoa ka 'mala. Karolong ea 2, infinine infusion e ile ea fokotsa khatello ea nako ea nako ea dopamine (A) le liteko (B) liphoofolo. (C) Phokotso ena e ile ea phehella ho litoeba tse amohelang inferior cerebrospinal fluid (aCSF) ka kotlolloho kahare ho sebaka sa ho putlama. (D) Litaba tse tlisoang ke corticotropin-releasing factor antagonist tsa CP-376395 li fumane phokotso ena. Lithapo tse otlolohileng tse otlolohileng li bonts'a lintlha tsa nako tseo li-cyclic voltammograms li hlophiselitsoeng ho bontša boteng ba dopamine (ka ho le letšehali), phokotso ea eona ka quinine (bohareng), le phetoho ea pH e latelang ho kenella ka hare ho intraoral (ka ho le letona).

Setšoantšo sa setšoantšo sa Figure 3. E bula setšoantšo se seholo    

Setšoantšo sa 3

Ho kenella ka hare ho tatso e hohelang, quinine, ho fokotsa khatello ea dopamine ka tsela e itšetlehileng ka corticotropin. Liphetoho likhatisong tsa dopamine (DA), tse reriloeng ka tlhaiso ea karolo e kholo, li reretsoe ho (A) 'me (B). (A) Quinine e fokotsitse khatello ea dopamine haholo ho tsoa ho basement (phase 1) ho likhakanyo tsa methapo ea methapo ea methapo (aCSF) - litekanyetso tse kenelletseng (tlhahlobo ea nako ea phokotso ea phallo ea lithethefatsi x; F4,20 = 10.683, p <.001; Poso ea Tukey, *p <.05). (B) Phokotso ea dopamine e theotsoeng ka quinine e kenyellelitsoeng ho likhakanyo tsa li-injine tsa CP-376395-e kenelletse (tlhahlobo ea nako ea phapanyetsano x ho sebelisana ha lithethefatsi; F4,20 = 6.77, p <.01; Poso ea Tukey, *p <.05, phokotso e kholo ea liphoofolo tse phekotsoeng tsa CP-376395 feela nakong ea quinine). Phokotso ea dopamine e khutlisitsoe ke liente tsa sebaka sa intraventral tegmental tsa CP-376395 empa feela nakong ea prequinine (Pre-Q) le postquinine (Post-Q) moo quinine e neng e le sieo. Lintlha li hlahisoa e le tsa bohlokoa + SEM.

Liphetoho likhatisong tsa dopamine tsa ho kula liphoofolong li ka tsamaisoa ke liphetoho hangata kapa liketsahalong tsa dopamine.38). Mona, re hlokometse hore quinine e fokotsitse molumo oa dopamine ka ho khetha ka mokhoa o ikhethileng oa ho theola maqhubu, mme phello ena e ile ea khutlisoa ka ho thibela li-receptor tsa CRF ho VTA (Setšoantšo sa 4A). Ha li kopantsoe, lintlha tsena li bonts'a hore ho ts'usumetso e matla, CRF e tšoaeang VTA e hatella molumo oa dopamine ho NAc ka ho feto-fetoha ha liketsahalo tsa tokollo ea dopamine.

Setšoantšo sa setšoantšo sa Figure 4. E bula setšoantšo se seholo    

Setšoantšo sa 4

Quinine e ile ea fokotsa makhetlo a liketsahalo tsa tokollo ea dopamine. (A) Khokahano ea quinine e khopisang e fokolitse ho tsoaloa hangata ha dopamine ka nako e latelang ts'ebetso ea ho kenella kahare, mme phello ena e ile ea khutlisoa ke sesosa sa corticotropin-depasing factor antagonist [li-baser tsa cerebrospinal fluid (aCSF) ha se bapisoa le aCSF postquinine (F1,10 = 10.21, Tukey post hoc, *p <.05]. (B) Ts'oaetso ea quinine e ne e sena matla ho lokolloeng hoa matla nakong ena e le ngoe (F1,10 = .75, p > .05). Lintlha li hlahisoa e le tsa bohlokoa + SEM.

Menahano e susumetsang e ka laolang eseng feela maemo a amanang empa le boitšoaro bo bobe ba ho batla lithethefatsi (3, 9, 39, 40), e tlamahantsoeng haufi le midbrain dopamine signaling (41, 42) hape e laoloa ke CRF (43, 44, 45, 46). Ka hona, re ile ra leka hore na ho pepeseha hoa quinine le ho theoha ha eona ea manonyeletso a NAc dopamine ho lekane ho khanna ho ts'oara ha lithethefatsi ho paradigm e khutliselitsoeng. Likhoto li ile tsa koetlisetsoa ho hatisa lever bakeng sa infuse ea koae ea IV. Kamora nako ea ho itaola hantle, boits'oaro bo hatellang bo ile ba felisoa ka ho tlohela ho fumaneha ha koae. Kamora ho felisoa, likhoto li amohetse infusions ea quinine infusions e kenang (1 infusion / min bakeng sa metsotso ea 15) e lateloang ke monyetla oa ho tobetsa lever eo pele e neng e fana ka koae. Tsamaiso ea Quinine e matlafalitse lever e tobetsa feela ho lever e sebetsang (Setšoantšo sa 5A; Setšoantšo sa S4 in Tlatsetsa 1), ho bontša hore tšusumetso e matla e hatellang molumo oa dopamine le eona e ka khutlisa boitšoaro ba ho batla lithethefatsi. Ho feta moo, boits'oaro bo khutlisetsang bo ne bo thibetsoe ka botlalo ka ho thibela li-receptor tsa CRF ho VTA (Setšoantšo sa 5A; Setšoantšo sa S2 in Tlatsetsa 1). Ho makatsang ke hore, leha e le hore mohanyetsi oa CRF o thibetse ho khutlisetsoa ka hare ho boits'oaro, o ile a pholosa lintho tse bonojoana tsa quinine, joalo ka ha ho bonts'oa ke polelo e phehellang ea ho fetoha hape ha tatso e monate (Setšoantšo sa 5B). Ha re e nka hammoho, lintlha tsena li bonts'a hore tšusumetso e matla e hatellang molumo oa dopamine le eona e ka khutlisetsa boitšoaro bo batlang lithethefatsi mme likarabo tsena ka bobeli li ka qojoa ka ho thibela li-receptor tsa CRF ho VTA.

Setšoantšo sa setšoantšo sa Figure 5. E bula setšoantšo se seholo    

Setšoantšo sa 5

Mekhoa ea ho susumetsa, empa eseng polelo ea hedonic, e ne e laoloa ke ho lokolla ha corticotropin. (A) Ka mor'a ho nyamela (Ext), infusions ea tlhaho ea quinine e bakile ho batla ha koae ka tlhahlobo e khutlisetsang (Rein) ho likhofu tsa maiketsetso tsa mokokotlo oa mokokotlo (aCSF), phello e ileng ea khutlisoa ka liente tsa intraventral tsa likarolo tse ling tsa CP-376395 × tšebelisano ea letsatsi; F2,16 = 5.83, p <.05; Poso ea Tukey, *p <.05). (B) Quinine e kenang kahare bakeng sa tatso e hohelang, quinine, e hlahisitse polelo e khathollang ea tatso e kantle ho likhoto tse tšoaroang ke aCSF. Phello ena ha ea ka ea fetoloa ke li-entraventral tegmental sebakeng sa li-CP-376395 (t1,9 = .98, p > .05). Lintlha li hlahisoa e le tsa bohlokoa + SEM. Poso, poso.

Puisano

Tlaleho ena e bonts'a mokhoa o ka etsang hore tšusumetso e matla e ka susumetsang potoloho hore e susumetse boitšoaro ba ho batla lithethefatsi. Litlolo tse kenang kahare tsa tastant e makatsang, quinine, li bakile phokotso ea phasic le tonic ho polelo ea dopamine ea terminal (ke hore, liphokotso metsotso le metsotso e seng mekae). Litlaleho tsa pejana li hlalositse ho fokotseha ho potlakileng, phasic, le ho hlohlelletsoa ha dopamine ho lokolloe ha dopamine (16). Leha ho le joalo, ka ha ho se na tšusumetso e tobileng ea maikutlo, liketsahalo tsa nakoana tse lokolloang tse nang le letšoao la tonic le tsona li ka nka nako e fetang metsotso e itseng.47). Re sebelisa mokhoa ona, re fumane hore tšusumetso ea koae e ka baka tšusumetso e mpe ha ka nako e tšoanang e fokotsa tšoaetso ea phasic le tonic dopamine ho NAc (19). Ho khahlisang, re hlokometse hore tonic, empa eseng phasic, phokotso e khutlisitsoe ka ho thibela li-receptor tsa CRF ho VTA. Le ha boqhekanyetsi bona bo ne bo sa ame thepa ea quinine e makatsang, e ile ea khutlisa tlhaku e khothalletsoang ke quinine, e bonts'a hore mehopolo e sa laoleheng e ka khanna ho batla lithethefatsi boemong ba molumo o tlaase oa dopamine. Lithuto tse ling li tla hlokahala ho supa mochine le bohlokoa ba boitšoaro bo ka fokotsoang phasic ea dopamine ho arabela sepheo se setle.

Liphumano tsena li hatisa tlhokahalo ea ho hlahlobisisa mokhoa o totobetseng oo ba bang ba tsosang takatso ea ho etsa lintho ka sepheo sa ho khothaletsa boitšoaro, ho phahamisa dopamine ho supa maemong a mang le ho fokotsa ho saena hoa dopamine ho ba bang. Mohlala, footshock ea motlakase e khelohileng e bontšitsoe ho eketsa ts'ebetso ea CRF ho VTA (45, 46), e leng eona e ka eketsang tšebetso ea dopamine neuron (25, 44, 45, 48) ake khutlisetsa ho batla lithethefatsi (43, 45, 46). Le ha liphumano tsena li bonahala li sa lumellane le tlaleho ea hajoale, li lumellana le mehato e bolaeang ea dopamine e sebelisang microdialysis eo ka tloaelo e tlalehang maemo a phahameng a tlatsetso ea dopamine metsotso e 'maloa nakong le kamora ho hlohlelletsa ho hlohlelletsa ho batla ho cheka. (49, 50, 51, 52). Tdata ea hajoale e tsosa takatso hobane e bonts'a hore maikutlo a susumetsang a fokotsang ho supa dopamine a ka tsamaisa ho batla lithethefatsi le hore liketsahalo tsena ka bobeli li tlas'a taolo ea CRF.

Tlhaloso e le 'ngoe ea hore na ho eketseha le ho fokotseha ha ho saena ka dopamine ho ka lebisa ho batleng lithethefatsi ho ka fumanoa mokhatlong oa cellular oa libaka tsa sepheo sa dopamine.

Phenotypically ikhethang ea striatal neuron pops li hlophiselitsoe hore li amehe ka mokhoa o fapaneng mabapi le ho eketseha kapa ho fokotseha ha khatello ea dopamine.

  • Ka dorsal striatum, li-DNNUMX-receptor-expression tse amanang le maemo a tlase tse tsamaisang tsela e tobileng ea sephethephethe sa koloi e hlahisoa ke maemo a phahameng a dopamine a khothalletsang motsamao oa boithaopo..
  • Ka mokhoa o ts'oanang, li-DNNUMX-receptor-expression tse hlahisang maemo a phahameng, li kenyelletsa tsela e sa tsejoang ka kotloloho ea koloi, li thibeloa ke molumo o phahameng oa dopamine empa li tsotella, ebile li susumetsoa ke ho khefutsa ha phasic ho dopamine e hatellang boitšoaro [bakeng sa tlhahlobo, bona (26)].

Tmona ho na le bopaki bo ntseng bo eketseha ba hore mokhatlo ona o ts'oantsoe ho isa boholeng bo kholo ho ts'ebetsong ea ventral. Ho NAc, keketseho ea phasic ea dopamine signaling activate dopamine receptor-expression e hlahisang li-MSN tse khothalletsang thuto ea moputso.

Ka lehlakoreng le leng, ho fokotseha ha dopamine ho supa ho kenya tšebetsong dopamine receptor e hlahisang li-MSN le ho khothaletsa ho nyatsa. (27, 30, 53).

Lithutong tsa morao-rao, quinine e kanna ea kopanya potoloho ea morao, e sebetsa joalo ka khatello ea maikutlo ea tikoloho e fokotsehileng ho saena ka dopamine ka mokhoa o itšetlehileng ka CRF le ho khothaletsa ho batla lithethefatsi.. Boiphetohelo bo bong bo amanang le tikoloho bo amanang le tikoloho bo ka eketsa ho bonts'a dopamine ho NAc mme bo ka lebisa sephethong se ts'oanang sa boits'oaro ka ho etsa mekhahlelo e fapaneng.

NAc dopamine signaling e kentse letsoho haholo mekhoeng e khothalletsang bokhoba ba tahi. NAc dopamine e bohlokoa bakeng sa thuto e amanang le moputso (54) le likarabo tse nepahetseng litabeng tsa tšusumetso (55), e ts'ehetsang mohopolo oa hore ho ts'oaea dopamine ho fana ka ts'usumetso kapa litempe ho boleng bo susumetsang ba ho matlafatsa mohopolo (42) hape e kenya letsoho haholo ho qobelloang ho batla lithethefatsi (41, 56).

Ho amohela sena, ho ka ba bohlale ho nahana ka tšusumetso e phahameng ea dopamine e bakang lithethefatsi tsa lithethefatsi empa re sa fokotse ho nahana ka hore na li susumetsa ka matla hakae tse fokotsang dopamine ho hlahisa sena.

Leha ho le joalo, tse ling tsa likhopolo tsa pele tsa tlhekefetso ea lithethefatsi li khothalelitse hore tloso ea lithethefatsi e sebelisoe ka mekhoa e mebe ea ho khothaletsa batho ba sebelisang lithethefatsi ba lekang ho lula ba sa thibele.57, 58, 59). Le ha liteko tsa morao-rao tsa likhopolo tsena li belaela hore na ho itokolla ka matla ho ka baka tlokotsi e khetholloang ke ho khutlela morao ka nako e telele kamora nako e teletsana ea ho tlohela lithethefatsi (60, 61, 62, 63), lits'ebetso tse mpe tsa ho matlafatsa li hlakile hore li na le karolo.

Neuroadaptations e ngata e tsamaeang le tšebeliso e mpe ea lithethefatsi le ho khothaletsa ho hloka teboho le mamello (7, 56, 64, 65, 66) e ka etsa hore kutloisiso ea likhatello tsa tikoloho e be taba ea bohlokoa le ho feta ea ho khothaletsa ho khutlisetsoa hoa batho ba sa tloheleng lithethefatsi.

I'Nete ke hore, le nako ea hona joale ea ho itlhokofatsa ea koae e bonahala e kenyelletsa thuto e matlafatsang e kopantsoeng le ho saena hoa dopamine. Ha khatello ea dopamine e putlama, boipuso bo tsoela pele ka mokhoa o ts'epahalang 'me liphoofolo li sebelisa k'hok'heine ea koae ho boloka khatello ea kelello ea dopamine e lutlang (67, 68). Nakong ea boitaolo, liphoofolo li ka ithuta ho arabela ho qoba boemo ba dopamine e tlase, mme sehlahisoa sa thuto ena e matlafatsang se ka ts'oaroa ke ts'usumetso e nyarosang ea molumo o tlase oa dopamine. Tlaleho ea hajoale e supa mokhoa o ka 'nang oa fetoha oa dopaminergic oa tšusumetso ena e mpe e kenyelletsang CRF, e leng neuromodulator e sebetsanang le khatello ea maikutlo.

Boholo bo susumetsang bo fokotsa ho bonts'a dopamine, bo kenya mochine ona le liphatlalatso tsa lona tsa maikutlo (mohlala, ho ama hampe kapa ho lakatsa) ho sa fumanehe ha lithethefatsi. Ka sebele, lipatlisiso tsa hona joale li fana ka maikutlo a hore batho ba hlekefetsang lithethefatsi ba ithuta ho lokisa khatello ea maikutlo ba fokotseha ka ho supa dopamine ka mokhoa o sebetsang ka ho fetisisa ka ho ithaopela k'hok'heine.

Liteboho le liphatlalatso

Mosebetsi ona o ne o tšehelitsoe ke US National Institutes of Health (R01-DA015758, JRM, le R00-DA025679, RAW).

Re leboha M. Gilmartin, M. Blackmore, P. Gasser, J. Evans, le E. Hebrone ka menehelo ea letsoho.

Bangoli ha ba phatlalatse lithahasello tsa lichelete tse sa lumellaneng kapa likhohlano tse ka bang teng.

Sehlomathiso A. Lisebelisoa tse tlatsetsang

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