lē faʻatino
tua
O faʻalavelave faʻalavelave e aʻafia ai le tulaga faʻalagona ma faʻamalosia le sailia o fualaau faasaina, i se vaega, e ala i le faʻaogaina o le gaioiga o le mesolimbic dopamine system. O le mea e leaga ai, o le faʻatonutonu vave o le faʻailoga o le dopamine e ala i mea faʻamalosi e mafua ai le suʻeina o vailaʻau e le o faʻamaonia lelei. I se faasologa o faʻataʻitaʻiga, na matou suʻesuʻeina le tulafono lalo lua o le dopamine faʻailoga e ala i le aversive stimulus, quinine, ma faʻataʻitaʻiina lona gafatia e mafua ai le suʻeina o cocaine. E le gata i lea, na matou suʻesuʻeina le tulafono ole midbrain ole dopamine faʻailoga ma le cocaine e sailia e le peptide maʻaleʻale, corticotropin releasing factor (CRF).
Metotia
Faʻatasia vave-scan cyclic voltammetry ma faʻataʻitaʻiga faʻataʻitaʻiga, matou suʻesuʻeina le aʻafiaga o le intraoral quinine administration i luga o le nucleus accumbens dopamine signaling ma le faʻaaliga faʻapitoa i 21 male Sprague-Dawley rats. Na matou faʻataʻitaʻiina le matafaioi a le CRF i le faʻaogaina o suiga faʻafefe i le dopamine concentration ma le cocaine e ala i le faʻaogaina o le CRF antagonist, CP-376395, i totonu o le ventral tegmental area (VTA).
i'uga
Na matou iloa o le quinine na vave faʻaitiitia le faʻailoga o le dopamine i luga o le lua taimi maʻoti. Na matou fuafuaina o le CRF na galue i le VTA e faʻatalanoaina lenei faʻaitiitiga i luga o le tasi o nei fua taimi. E le gata i lea, na matou iloa o le faʻaitiitia o le dopamine leo ma le quinine-induced cocaine na faʻaumatia e ala i le polokaina o gaioiga a le CRF i le VTA i le taimi o le poto masani o le faʻaosofia o le aversive.
faaiuga
O nei faʻamatalaga o loʻo faʻaalia ai e mafai ona tupu le suʻesuʻeina o vailaʻau faʻaosoina i totonu o se siʻosiʻomaga e maualalo le leo dopamine lea e faʻalagolago i le faʻaitiitia o le CRF i le midbrain dopamine.
uputatala:
O fa'alavelave fa'alavelave e tutupu i le olaga o ni suiga malosi o lagona ma e mafai ona fa'aoso ai le tele o amioga fa'aleagaina, e aofia ai le fa'aaogaina o fualaau fa'asaina (1). E ui o le tagofia o mea ua fai ma vaisu o se maʻi e tele, ua fautuaina e faʻapea o mea leaga e tutupu i le olaga e mafai ona faʻateleina ai le toe faʻafoʻi i vaisu e ala i le faʻaosofia o aʻafiaga leaga ma le manaʻo (2, 3, 4, 5). E faʻapea foʻi, o faʻamalosi e fesoʻotaʻi ma vailaʻau e faʻaalia ai se tulaga le lelei i tagata faʻaaogaina cocaine e faʻamaonia le toe faʻafoʻi (2, 4, 6). Mulimuli ane, o nei fa'aosofiaga ua manatu e fa'atupuina ai le si'osi'omaga o amioga fa'aletonu lea e fa'atupu ai le fa'aaogaina o vaila'au, taumafai e tumau i le fa'asao, e fa'asa'o ai se tulaga le lelei fa'alesiosiomaga e ala i le toe fa'aaogaina o fualaau fa'asaina (7, 8, 9, 10, 11).
O fa'alavelave fa'alavelave ma o latou lagona fa'alagona e ono fa'aosoina ai le su'eina o fualaau fa'asaina e ala i le fa'atupuina o le mesolimbic dopamine system, ae o le auala latou te faia ai e le o malamalama lelei. O le mea moni, a'o fa'atupula'ia fa'amaoniga e fa'apea o a'afiaga leaga ose fa'ai'uga taua lea o le toe fa'aauauina o fualaau fa'asaina pe a mae'a vaitaimi o le fa'amama, o loʻo feteʻenaʻi tusitusiga i luga o le fesili autu o le faʻatonuga o le tali atu o le dopamine i faʻalavelave faʻafefe (12, 13). Electrophysiological ma electrochemical suʻesuʻega e fua ai le dopamine neuron activity ma le faʻamalolo o le dopamine, i le faasologa, e fetaui lelei ma le lagona vave ma le iloa o faʻalavelave faʻafefe. e masani ona faʻaalia le faʻaitiitia vave o le dopamine faʻailoga e tali atu ai i faʻalavelave faʻafefe ma a latou vaʻaiga (14, 15, 16, 17, 18, 19). To lona faʻaitiitia o le gaioiga o le dopaminergic ua lipotia mai e faʻaosoina, i se vaega, e neuromodulators faʻalavelave faʻalavelave e pei ole corticotropin-releasing factor (CRF) (20, 21). O le mea e leaga ai, o faʻamaumauga eletise o dopamine neurons e faʻaalia ai e le o le faʻaitiitia o le faʻaitiitia o le gaioiga o le dopamine poʻo le tulafono a le CRF o lena tali e tutusa. (22, 23, 24, 25), e manaʻomia ai se auala e suʻesuʻe ai faʻailoga vave i le dopamine neuronal projection targets.
E itiiti se mea e iloa e uiga i le natura o le vave, aversion-induced dopamine release patterns i vaega faʻamautu talafeagai. E le o manino pe faʻafefea ona faʻatupuina le faʻaitiitiga o faʻailoga o le dopamine ma pe faʻafefea ona faʻaititia le dopamine e mafai ai ona faʻamalosia amioga faʻaleagaina, pei o le sailia o fualaau faasaina. I totonu o le nucleus accumbens (NAc), o se nofoaga taua o le matagaluega o taui, faʻateleina ma faʻaitiitia le faʻaogaina o le dopamine e faʻagaoioia ai le D1- ma le D2-receptor-faʻaalia ai neu spiny medium (MSNs), taʻitasi, o loʻo i ai aʻafiaga faʻafeagai i amioga faaosofia. (26, 27). O le fa'agaoioia o nei ta'amilosaga ma'oti ua leva ona iloa e fa'atulafonoina ai le tele o ituaiga o amioga fa'aosofia, e aofia ai tali i vaila'au fa'aleagaina. (28, 29, 30, 31, 32, 33). O le mea lea, o le faʻamalamalamaina pe faʻatuputeleina pe faʻaitiitia le faʻatupuina o le NAc dopamine e foliga mai e taua i le fuafuaina pe faʻafefea ona faʻagasolo faʻalavelave faʻalavelave faʻalavelave faʻalavelave faʻapitoa e mafua ai le toe faʻaaogaina o fualaau faasaina. I le taimi muamua, na matou matauina e mafai e le cocaine-predictive stimuli ona faʻaosofia se tulaga le lelei, ae faʻaititia i le taimi lava e tasi le dopamine faʻailoga i le NAc (19). Ae ui i lea, o le aʻafiaga o amioga a se tasi o nei faʻamatalaga o loʻo tumau pea e suʻeina. O fesili ogaoga pe faʻafefea ona faʻafefeina e faʻamalosi faʻamalosi le faʻatonutonuina o le dopamine faʻailoga ma pe o lenei faiga o se tasi e mafai ona taʻitaʻia ai amioga e pei o fualaau faʻasaina i rodents. I nei suʻesuʻega, matou te suʻesuʻeina le faʻaogaina o le tino o le faʻaitiitia o le faʻaitiitia o le dopamine, o le tulafono faatonutonu e ala i le faʻamaʻiina o le CRF faʻamalosi i totonu o le ventral tegmental area (VTA), ma le aʻafiaga o amioga i le faʻaogaina o vailaʻau ma le sailia o fualaau. I le aotelega, oa matou suʻesuʻega o loʻo faʻaalia ai le lavelave faaletino i le dopamine signaling ma le gafatia o le CRF e faʻatonutonu le leo o le dopamine ma faʻalauteleina le sailia o fualaau faasaina.
Metotia ma Mea
Mataupu
E lua sefulu tasi tamaʻi iole Sprague-Dawley (275-300 g; Harlan Laboratories, St. Louis, Missouri) na faʻapipiʻiina taʻitoʻatasi i totonu o le vevela-ma le susu-pulea, Association for Assessment and Accreditation of Laboratory Animal Care accredited vivarium. Na tausia iole i luga o le 12/12-itula fesuia'i taamilosaga (pe moli i le 7 am) ma maua ad libitum avanoa (se'i vagana ua matauina) i vai ma meaai (Teklad; Harlan Laboratories). O fa'ata'ita'iga fa'ata'ita'iga uma na fa'amaonia e le Komiti Fa'atonu Fa'atonu ma Fa'aoga Manu i le Iunivesite o Marquette e tusa ai ma le National Institutes of Health Guide mo le tausiga ma le fa'aogaina o manu su'esu'e.
Togafitiga
O taotoga uma na faia i lalo o le ketamine / xylazine (100 mg / kg / 20 mg / kg, intraperitoneal) faʻamaʻi. O le fa'apipi'iina o le fa'ama'i toto ma totonu o le gutu sa faia e pei ona fa'amatalaina muamua (11). Guide cannulas mo microinjections (26-gauge; Plastics One, Roanoke, Virginia) na faʻapipiʻiina i luga aʻe o le VTA (tua-tua: -5.6; medial-lateral: ± 2.2 i le 11º angle; dorsal-ventral: -7.0). Ina ia saunia mo le pueina o le voltammetric, na faʻapipiʻi i luga aʻe o le atigi NAc faʻapipiʻi faʻatasi (tua-tua: +1.3; medial-lateral: ± 1.3), ma sa tuʻuina se faʻailoga eletise siliva / siliva chloride faʻasaga i le taʻiala taʻiala. E le gata i lea, o le tu'ufa'atasiga bipolar stimulating electrode/microinjection guide cannula (Plastics One) na tu'u tonu lava i luga a'e o le VTA ipsilateral, ma tu'u ai se ta'iala ta'iala i luga a'e o le VTA contralateral. Mo taotoga uma, na togafitia iole i le anti-inflammatory med-cam (1% oral suspension) i le aso ma le 2 aso talu ona uma le taotoga e faʻaitiitia ai le mumū ma le tiga pe a uma le taotoga. Ina ia faatumauina le pateni, o le intraoral ma intrajugular catheters na fufulu i aso uma i le vai faʻafefe (intraoral) poʻo le saline heparinized ma le antibiotic cephazolin (intravenous [IV]), i le faasologa.
Microinjections
Microinjectors fa'alautele .5 mm mai le pito o le ta'iala ta'iala. Ole sua ole cerebrospinal (aCSF) (.3 µL/min) po'o le CRF fa'afete'ena'i filifilia CP-376395 (.3 µg/.3 µL/min) na tui fa'alua ile VTA (n = 6 aCSF, n = 6 CP-376395). CP-376395 ole CRF-R1 fa'afeagai, ae o fegalegaleaiga ma R2 e foliga mai i lenei fua. Microinjectors tu'u i le nofoaga mo le 2 minute ina ua uma le tui ina ia mafai ai ona faʻasalalau. I taualumaga uma e lua, o le tu'uina atu o le quinine sa (toe) amata loa ina ua mae'a le tui.
Voltammetric Recordings
Ina ua maeʻa ona toe faʻaleleia mai le taotoga, na masani ai iole mo le 2 itula i totonu o le voltammetric recording environment, e aofia ai se potu manino Plexiglas (Med Associates, St. Albans, Vermont) o loʻo tuʻuina i totonu o se faʻailoga faʻapitoa Faraday. O le VTA stimulating electrode sa fa'apipi'iina i se commutator feliuliua'i (Crist Instrument Co., Hagerstown, Maryland), ma le tasi cannula intraoral sa fa'aogaina i se sua swivel (Instech Laboratory, Plymouth Meeting, Pennsylvania) e mafai ona maua mai le vai mai se pamu tui (Razel). , St. Albans, Vermont). I le aso na soso'o ai, na fa'atautaia ai fa'amaumauga voltammetric e pei ona fa'amatalaina muamua (16). O fa'amatalaga o le fa'amaumauga ma le au'ili'iliga o lo'o fa'amatalaina i totonu Faʻaopoopo 1. I se faapuupuuga, na tu'u ifo i lalo se eletise kaponi i totonu o le atigi NAc, o se laina vai na fa'apipi'i i le intraoral cannula, ma amata ai le sauniga o amioga. O le faʻataʻitaʻiga na aofia ai le 30-minute baseline dopamine mataʻituina vaega (vaega 1); 30-minute le tu'uina atu o le quinine (vaega 2); VTA microinjection lua; ma le 50-minute pe a uma ona tu'uina le kuini (vaega 3). I le taimi atoa o le tu'uina atu o le kuini, o le 6-lua fa'ainu o le .2 mL quinine (.001 mmol/L) na tu'uina atu e tusa ma minute uma.
Voltammetry Fa'amatalaga Fa'amatalaga
O faʻamatalaga faʻamatalaga faʻamaonia o loʻo faʻamatalaina i totonu Faʻaopoopo 1. O faʻamatalaga mai faʻataʻitaʻiga taʻitasi (-20 sec muamua ma le 30 sec postinfusion onset) na toesea le talaaga e faʻaaoga ai se poloka 1-lua i le pito i lalo ole lotoifale ile 20 sekone aʻo leʻi amataina le infusion. Mo iole taʻitasi, o faʻamaumauga na faʻatatau i le quinine infusion faʻataʻitaʻiga i le 10 sekone pe a maeʻa le amataina o le quinine infusion period (quinine) faʻatusatusa i le 10-second period (prequinine) ma le isi 10-second period (postquinine). O suiga o loʻo i ai nei i le aluga o taimi na suʻesuʻeina mo suiga o le dopamine e faʻaaoga ai le faʻasologa o vaega. Mo isumu uma (n = 12), faʻaitiitiga o le leo dopamine masani (e le o lokaina) na faʻatusatusaina ma suʻesuʻeina e ala i le faʻatusatusaina o faʻataʻitaʻiga muamua 5 (vave) ma faʻataʻitaʻiga 11 i le 15 (ogatotonu) ma faʻataʻitaʻiga 5 mulimuli (tuai) i le vaitaimi muamua. , 10 sekone aʻo lumanaʻi le faʻaogaina o le quinine, faʻaaogaina o suʻesuʻega faifaipea o le eseesega (ANOVA). O suiga taua i le dopamine concentration i luga o le taimi, taimi-loka i le quinine infusion, na iloiloina e faʻaaoga ai le lua i totonu-mataupu faʻataʻitaʻiga fua ANOVAs eseese vaega (baseline, quinine, ma quinine + vailaʻau [aCSF poʻo CP-376395]) × vaitaimi (prequinine, quinine, postquinine). Ina ua iloa a'afiaga taua po'o fa'afeso'ota'i, na faia uma fa'atusatusaga fa'alua i su'ega post hoc a Tukey mo le tele o fa'atusatusaga ma le alpha seti i le .05.
Dopamine fa'amalolo mea na tutupu tuto'atasi mai so'o se fa'aosofiaga fa'atatau po'o fa'ata'ita'iga fa'ata'ita'iga fa'atonuga amio i le taimi fa'avae. Ina ia iloa pe faʻafefea ona aʻafia faʻamalosi faʻamalosi le faʻaalia o mea e faʻamalolo ai le dopamine maualuga, o faʻataʻitaʻiga 100-msec uma i faʻataʻitaʻiga uma mo iole taʻitasi na faʻamauina taimi pe afai o lona faʻatonuga o le 40 nmol / L pe sili atu. O lenei tapulaa o loʻo i totonu o le tele o fesoʻotaʻiga mo le maualuga o le D1 faʻafeiloaʻi ma o le tau faʻatatau o le tuʻuina atu o le dopamine faʻafuaseʻi (34, 35). Mai lea fa'amatalaga, sa fa'atatauina ma au'ili'ili le alaleo le tumau ma le amplitude. O le ANOVA e lua-auala na faʻaaogaina e iloa ai aʻafiaga autu o le vaitaimi (quinine versus postquinine) ma vailaʻau (aCSF vs. CP-376395). Tukey's post hoc suʻega mo le tele o faʻatusatusaga na faʻaaogaina e iloa ai eseesega taua i totonu ole vaitaimi ma vailaʻau. I tulaga uma, o le alpha level mo le taua o le .05. Fa'atusatusaga fa'amaumauga na faia i le fa'aogaina o polokalama fa'apisinisi (Statistica; StatSoft, Tulsa, Oklahoma).
Su'esu'ega Fa'amatalaga Fa'amatalaga Tofo
Na suʻesuʻeina le gaioiga o le tofo i se suʻesuʻega faʻavaa-i-faʻavaa e faʻaaoga ai le vitio numera na puʻeina i le aso o le suʻega i aCSF- ma le CP-376395-injected rats (n = 5 i vaega taitasi). O le fa'amalieina o le tofo ma le fa'aleagaina na faitaulia i vaitaimi o le prequinine ma le quinine e fa'aaoga ai le metotia a Grill ma Norgren (36). O gaioiga o gutu e fetaui ma foliga tafatolu mo se umi e sili atu i le 90 msec sa faitauina o le tetee. O nei ta'iala e le'i aofia uma ai le fa'aituau ma gaioiina gutu, lea sa faitauina fa'atasi. O taimi na fa'aoso ai le laulaufaiva ma laasia le laina ogatotonu sa faitauina o se fia'ai. O le isi amioga licking sa faitaulia e le faaituau. O su'esu'ega fa'afuainumera o fa'amaumauga uma o amioga na fa'atinoina i le fa'aogaina o polokalame fa'apisinisi (Statistica).
Puleaina e le tagata lava ia ma Toe Fa'aola
Na a'oa'oina isumu e fa'atapula'aina mea'ai (15-18 g/aso) e oomi se leve mo pelleti sucrose. I le mauaina o le lever oomiina (~ 3-5 aso), o le intraoral ma intravenous catheters na totoina e pei ona faamatalaina i luga. A maeʻa ona toe faʻaleleia, o isumu na toe faʻasaina meaʻai ma aʻoaʻoina e faʻatonuina e le tagata lava ia cocaine (.3 mg / .2 mL / infusion, IV) i luga o se faʻatulagaga faʻatulagaina 1 i totonu o potu faʻapipiʻi faʻafesoʻotaʻi komepiuta o loʻo faʻapipiʻiina i totonu o potu faʻamaʻi leo (Med). Associates). Ina ua amata le sauniga cocaine, o se moli o le fale na faʻamalamalamaina le potu, ma o se moli faʻaaliga o loʻo i luga aʻe o le leve malosi na faʻaalia ai le maua o le cocaine. O fa'ainu uma o cocaine na fa'atasi ma le tapeina o le moli o le fale ma le moli fa'ailoa, ma se taimi fa'agata e 20 sec, lea na fa'aauau pea le fa'alautele ma fa'amaumau tali ae leai se fa'amalosia. Sa faamaumauina foi le tali atu i luga o le lever lona lua ua le toaga. Ina ua mae'a le taimi e malolo ai, sa ki le moli o le fale ma le moli fa'ailoga ma fa'ailo ai le maua o cocaine. O fa'atonuga a le tagata lava ia na tupu i se fa'asologa o fa'ata'ita'iga fa'ata'ita'iga 6-aso ta'amilosaga e aofia ai aso 3 o le fa'atonuga a le tagata lava ia ma le 3 aso e aunoa ma le cocaine i totonu o le fale. Ina ua mae'a le taamilosaga lona tolu, na maua uma e iole le taotoga VTA ma amata ai le latou taamilosaga lona fa ina ua uma le 2 vaiaso o le toe fa'aleleia. O sauniga cocaine taʻitasi na faʻamutaina ina ua maua e isumu se numera maualuga maualuga o faʻamaʻi koko (25 infusions mo le 9 aso muamua o le avanoa aʻo leʻi faia le VTA cannulation ma 30 infusions mo le tolu cocaine sauniga mulimuli pe a uma le VTA cannulation). O le faʻaumatia e aofia ai i aso taʻitasi 2-itula sauniga i le taimi o loʻo lolomi taʻitasi na maua ai le faʻafefeteina o le saline ae leai se faʻailoga malamalama poʻo le tuʻuina atu o cocaine. O le taimi lava na ausia ai le fa'ai'uga fa'aumatia (<15 tali leve malosi mo le laina 2-aso averesi; Ripoti S1 in Faʻaopoopo 1), o iole ta'itasi na fa'ata'ita'iina mo le toe fa'atūina o le quinine. Ina ia puipuia le fa'alavelave fa'afuase'i o le toe fa'afo'isia, na faia su'esu'ega mo manu ta'itasi i le aso na fa'ataunu'uina ai fa'atonuga fa'aumatia. A'o le'i toe fa'afo'i sauniga ta'itasi, na maua e iole ni tui fa'a-VTA microinjection o le aCSF (n = 4) poʻo le CP-376395 (n = 5). Toe fa'afouina sauniga na amata i le 15 intraoral infusions o le quinine na tu'uina atu i totonu o le potu e pulea e le tagata lava ia cocaine i le faiga tutusa e pei o le su'ega muamua mo 15 minute. I le lima minute talu ona tuʻuina atu le quinine, na faʻalautele le lever ma faʻamaumau tali mo le 1 itula.
Toe fa'afou Su'esu'ega Fa'amatalaga
Suiga i le lever oomi amioga i le itula muamua o vasega taʻitasi na suʻesuʻeina e faʻaaoga ai se ANOVA e lua auala e fesuiaʻi ai le va o mataupu o vailaʻau (aCSF, CP-376395) × o totonu o mataupu autu o le aso (faʻaumatia, toe faʻaleleia, posttest) . O le tali atu o le fa'aumatia na fa'amatalaina o le aso mulimuli o a'oa'oga fa'aumatia, ma o le tali mulimuli ane o se vasega mulimuli na fa'ata'ita'iina i lalo o tulaga fa'aumatia e aunoa ma le fa'atonuina o le kuini. O le tele o eseesega i le su'esu'eina o fualaau faasaina na iloa pe a talafeagai e Tukey's post hoc suʻega mo le tele o faʻatusatusaga ma le alpha seti i le .05.
Talafaasolopito
A mae'a fa'ata'ita'iga fa'ata'ita'iga, na fa'amama uma mata'upu i le carbon dioxide. Ina ia faʻamaonia le tuʻuina o mea faʻapipiʻi eletise, na faia ni faʻamaʻi eletise laiti e ala i le faʻaogaina o le taimi nei (250 μA) e ala i se eletise uamea e tuʻu i le loloto na faia ai le pueina. Ona aveese lea o fai'ai ma faagoto i le 10% formaldehyde mo le 14 aso. Ona tipi lea i ni vaega 40-µm, fa'apipi'i, fa'ailoga i le .25% thionin, ma ufiufi. O faʻamatalaga o le cannula ma le faʻaogaina o le eletise mai le voltammetry ma le toe faʻaleleia o suʻega o loʻo tuʻuina atu i totonu. Ata S1 ma S2 in Faʻaopoopo 1, fa'asologa (37).
i'uga
Ina ia suʻesuʻeina le malosi faaletino o le faʻaitiitia o le dopamine e mafua mai i mea faʻalavelave, na matou faʻaaogaina le voltammetry cyclic faʻavavevave i isumu feʻaveaʻi saoloto e faʻaalia i totonu o le gutu puupuu o le tofo oona o le quinine. O lenei mamanu e mafai ai mo le mataʻituina faʻatasi o le tali a le manu e fetaui lelei ma le iloiloga o le tuʻuina atu o le dopamine i le NAc i luga o se taimi faʻatulagaina (16, 19). E pei ona faʻamoemoeina, i le 30-minute suʻega faʻataʻitaʻiga (1 infusion / min), o le faʻaalia o le quinine na faʻaalia ai le faʻaalia o le faʻafefe o le tofo i le taimi-lokaina i le faʻaitiitia o mea e faʻamalolo ai le dopamine (Ata 1B; Vaega 2, prequinine fa'atusatusa i vaitaimi o le quinine/postquinine, agavale ma taumatau; Ata S3 in Faʻaopoopo 1). O le mea e mataʻina ai, o le faʻaitiitia o le dopamine na faʻaalia ai ni saini tuʻufaʻatasiga e lua: o se pa'ū faʻafuaseʻi, faʻafuaseʻi i taimi taʻitasi e faʻaalia i le quinine, faʻapea foʻi ma le faʻaitiitia o le umi o le leo o le dopamine na tupu faʻafuaseʻi pe a uma ona faʻaalia pea i le quinine. O lenei aʻafiaga mulimuli na faʻatusatusaina o se faʻaitiitiga taua i le ogatotonu (faʻataʻitaʻiga 11-15) ma le tuai (faʻataʻitaʻiga 26-30) faʻataʻitaʻiga, faʻatusatusa i le amataga (muamua 5) faʻataʻitaʻiga i le vaitaimi o le prequinine 10 sekone aʻo leʻi faia le quinine infusion (Ata 1B, tauagavale). O nei faʻamaumauga e faʻamaonia ai le gafatia o faʻamalosi faʻamalosi e faʻaitiitia ai le faʻaogaina o le dopamine ma faʻaalia ai se faʻalavelave faʻaletino i lenei tali.
Ata 1
Corticotropin-faʻasaʻoina mea faʻatonutonu tulafono ole dopamine faʻailoga i le taimi o le poto masani o se faʻalavelave faʻafefe e le maalofia. (A) O fesuiaiga o sui o le dopamine faʻanatura o loʻo tupu i totonu o le atigi o le nucleus e faʻapipiʻi i le pulea o amioga (agavale) ma le suʻega (taumatau) iole i le vaega faʻavae (vaega 1). (B) Suia le faʻailoga o le dopamine e tali atu i le faʻaogaina o le quinine (vaega 2). O fa'aitiitiga e mafai ona va'aia fa'apitoa i le tali atu i le quinine (x axis) fa'apea fo'i ma le lautele i fa'ata'ita'iga (y axis, prequinine [Pre Q] vaitaimi). (B) (taumatau taumatau) Tuuina atu i totonu o le gutu o le quinine faʻaititia le tonic dopamine faʻatonuga faʻataʻitaʻiga i faʻataʻitaʻiga i le vaitaimi muamua o le vaega 2 (suʻesuʻega o eseesega aʻafiaga autu: faʻataʻitaʻiga F2,22 = 11.73, p < .01; Tukey's post hoc, *p <.05, faʻaitiitiga taua i le ogatotonu ma le tuai o faʻataʻitaʻiga faʻatusatusa i faʻataʻitaʻiga muamua). (C) O faʻaitiitiga faʻaosoina o le Quinine i le faʻailoga o le dopamine na faʻaititia e le tui o le vaega o le corticotropin-releasing factor antagonist, CP-376395 (vaega 3). aCSF, sua ole cerebrospinal; DA, dopamine; Post Q, postquinine.
Na matou fesili mulimuli ane pe o lenei pa'ū fa'aoso-fa'aosoina i le terminal dopamine e a'afia e le CRF fa'ailoga i le VTA (21). I le vaega 3, na maua ai e manu le intra-VTA microinjections o le CRF antagonist CP-376395 (.3 µg/.3 µL/min) poʻo le aCSF (.3 µL/min), aʻo faʻaauau le tuʻuina atu o le quinine intraoral ma faʻataʻitaʻiga vave cyclic voltammetry pueina. (Ata 1C, tauagavale; Ata S1 in Faʻaopoopo 1). O le CRF antagonism i le VTA e leai se aafiaga i le gafatia o le quinine e mafua ai le vave, faʻaitiitia le tumau i le faʻaogaina o le dopamine i le taimi o le quinine intraoral infusion period (Ata 1C). I se faʻatusatusaga, o le CRF antagonism i le VTA na faʻaumatia ai le faʻaogaina o le quinine i luga o le leo dopamine e le o lokaina i le taimi o le prequinine ma le postquinine vaitaimi (Ata 1C). E ala i le averesi i faʻataʻitaʻiga, e mafai ona vaʻaia le faʻatonuga o le dopamine i le taimi (Ata 2A,B), faʻatasi ai ma le faʻaitiitia o le faʻaitiitia e mafua mai i le tui o le quinine. O se faʻaitiitia o lenei tali e mafai ona vaʻaia pe a maeʻa le faʻalavelave CRF (Ata 2D) ma fa'atatau ile su'esu'ega chemometric (Ata 3A,B).
Ata 2
Su'i le fa'aogaina o le dopamine i le taimi i le taimi o le tui o le quinine ma le mulimulitaia o le corticotropin-releasing factor receptor blockade. Fa'atusa lanu e lua o fa'amaumauga voltammetric cyclic na aoina mo le 50 sekone fa'ata'amilo i quinine infusions, fa'atatau i fa'ata'ita'iga mo vaega ta'itasi o le su'ega. O le ordinate o le voltage faʻaaogaina (Eapp) ma le abscissa o le taimi (sekona [s]). Suiga i le taimi nei i le electrode fiber carbon o loʻo faʻaalia i le lanu. I le vaega 2, quinine infusion na faʻaitiitia ai le taimi-aveve faʻatonuga o le dopamine i le puleaina (A) ma faataitai (B) manu. (C) O lenei fa'aitiitiga na fa'aauau pea i isumu na maua mai fa'asusu fa'atosina (aCSF) fa'alava i totonu o le va'a. (D) O faʻamaʻi faʻatasi o le corticotropin-releasing factor antagonist CP-376395 na faʻaitiitia ai lenei faʻaititia. O laina tu'u sa'o e fa'ailoa mai ai taimi o lo'o fa'ata'amilo ai voltammograms e fa'ailoa ai le iai o le dopamine (agavale), lona fa'aitiitiga i le quinine (ogatotonu), ma le suiga o le pH pe a mae'a fa'asuavai totonu (taumatau).
Ata 3
Tuuina atu i totonu o le gutu o le tofo aversive, quinine, faʻaitiitia le faʻaogaina o le dopamine i se auala faʻalagolago i le corticotropin-releasing factor. Suiga i le dopamine (DA) faʻatonuga, fuafuaina e ala i suʻesuʻega autu, o loʻo faʻatulagaina i totonu (A) ma (B). (A) Quinine faʻaitiitia le faʻaogaina o le dopamine mai le laina faʻavae (vaega 1) i le faʻaogaina o le cerebrospinal fluid (aCSF) -iole (suʻesuʻega o le vaeluaga taimi × fefaʻatauaʻiga fualaau; F4,20 = 10.683, p < .001; Tukey's post hoc, *p <.05). (B) O le quinine-induced dopamine faʻaitiitia na faʻaititia i CP-376395-tuiina imoa (suʻesuʻega o le vaeluaga taimi × fefaʻatauaʻiga fualaau; F4,20 = 6.77, p < .01; Tukey's post hoc, *p <.05, fa'aitiitiga taua i CP-376395-togafitiga manu na'o le vaitaimi o quinine). O le fa'aitiitiga o le dopamine na toe fa'afo'i e ala i tui fa'apitonu'u o le CP-376395 ae na'o le taimi muamua (Pre-Q) ma le postquinine (Post-Q) e le'i iai le quinine. O faʻamatalaga o loʻo tuʻuina atu o le uiga + SEM.
Suiga i le faʻaogaina o le dopamine faʻamaʻi i manu feʻaveaʻi e mafai ona faʻaosofia e ala i suiga i le taimi poʻo le tele o mea e faʻamalolo ai le dopamine (38). O iinei, na matou matauina ai o le quinine na faʻaitiitia le leo o le dopamine e ala i le faʻaitiitia o le faʻasaʻoina o taimi, ma o lenei aʻafiaga na suia e ala i le polokaina o le CRF receptors i le VTA (Ata 4A). Faʻatasi, o nei faʻamatalaga o loʻo faʻaalia ai i luga o le faʻamalosia o le faʻamalosi, o le CRF faʻailoga i le VTA e taofiofia le leo o le dopamine i le NAc e ala i le faʻavasegaina o taimi o faʻamalologa o le dopamine.
Ata 4
Quinine na faʻaititia le tele o mea e faʻamalolo ai le dopamine. (A) O le aversive quinine stimulus na faʻaititia ai le dopamine le tumau i le vaitau na sosoo ai ma le intraoral infusion, ma o lenei aʻafiaga na fesuiaʻi e le corticotropin-releasing factor antagonist [artificial cerebrospinal fluid (aCSF) baseline faʻatusatusa i le aCSF postquinine (F1,10 = 10.21, Tukey post hoc, *p <.05]. (B) O le tui o le quinine e leai se aoga i le faʻasaʻolotoina o le amplitude i lenei lava vaitaimi (F1,10 = .75, p > .05). O faʻamatalaga o loʻo tuʻuina atu o le uiga + SEM.
O fa'aoso fa'aleaga e fa'atulafonoina e le gata i le tulaga fa'aa'afia ae fa'apea fo'i ma amioga fa'atupu fa'aletonu ole su'esu'eina o vaila'au (3, 9, 39, 40), lea e vavalalata vavalalata i le midbrain dopamine signaling (41, 42) ma fa'atulafonoina e le CRF (43, 44, 45, 46). O lea na matou faʻataʻitaʻia ai pe o le faʻaalia o le quinine ma le pa'ū o le NAc dopamine e lava e ave ai le suʻeina o vailaʻau i se faʻataʻitaʻiga toe faʻaleleia. Na a'oa'oina iole e oomi se leve mo se fa'ainu IV cocaine. Ina ua maeʻa se vaitaimi o le pulea e le tagata lava ia, na faʻaumatia le amio faʻamalosi e ala i le taofia o le maua o cocaine. Ina ua uma ona faʻaumatia, na maua e isumu le faʻaogaina o le quinine intraoral infusions (1 infusion / min mo 15 minute) sosoo ai ma le avanoa e oomi ai le leve na tuʻuina atu muamua cocaine. O le pulega o le Quinine ua faateleina le leve oomi na'o le leve malosi (Ata 5A; Ata S4 in Faʻaopoopo 1), faʻaalia o se faʻamalosi faʻafefe e taofiofia ai le leo o le dopamine e mafai foi ona toe faʻafoʻisia amioga suʻesuʻe fualaau. E le gata i lea, o le toe faʻafoʻisia o amioga na puipuia atoatoa e ala i le polokaina o le CRF receptors i le VTA (Ata 5A; Ata S2 in Faʻaopoopo 1). O le mea e mataʻina ai, e ui lava na taofia e le CRF antagonism le toe faʻaleleia o amioga, ae na faʻasaoina ai mea leaga o le quinine, e pei ona faʻaalia e le faʻaalia faifaipea o le tofo aversive reactivity (Ata 5B). I le tuʻufaʻatasia, o nei faʻamaumauga o loʻo faʻaalia ai o se faʻamalosi faʻamalosi e taofiofia ai le leo o le dopamine e mafai foi ona toe faʻafoʻi mai amioga suʻesuʻe fualaau ma o nei tali uma e lua e mafai ona puipuia e ala i le polokaina o le CRF receptors i le VTA.
Ata 5
O faiga faʻaosofia, ae le o le faʻaaliga faʻapitoa, na faʻatonutonuina e le corticotropin-releasing factor. (A) Ina ua maeʻa (Ext), o le tui o le quinine na mafua ai le suʻeina o le koko i le suʻega toe faʻaleleia (Rein) i le sua o le cerebrospinal fluid (aCSF) -togafitiga o isumu, o se aafiaga na fesuiaʻi e tui intraventral tegmental vaega o le CP-376395 (suʻesuʻega o vailaʻau eseese. × aso fegalegaleai; F2,16 = 5.83, p < .05; Tukey's post hoc, *p <.05). (B) O le tu'uina atu i totonu o le gutu o le tofo aversive, quinine, na mafua ai le faʻaalia o le faʻafefe o le tofo i totonu o isumu aCSF. O lenei a'afiaga e le'i suia e ala ile tui ole vaega ole intraventral tegmental ole CP-376395 (t1,9 = .98, p > .05). O faʻamatalaga o loʻo tuʻuina atu o le uiga + SEM. Post, postquinine.
Talanoaga
O lenei lipoti o loʻo faʻamaonia ai se faiga e mafai ai e faʻamalosi faʻafefe ona faʻaosoina le taʻavale faʻamalosi e faʻaosofia ai amioga suʻesuʻe fualaau. O le tui i totonu o le gutu o le aversive tatant, quinine, na mafua ai le faʻaitiitia o le phasic ma le tonic i le faʻamauina o le dopamine faʻamau (faʻataʻitaʻiga, faʻaititia i sekone ma minute atoa). O lipoti talu ai na faʻamatalaina ai le faʻaitiitia vave, faʻasolosolo, faʻafefe-faʻaosoina faʻaitiitia le faʻamalolo o le dopamine (16). Ae ui i lea, i le leai o se faʻaosofia tuusaʻo faʻamalosi, o faʻasalalauga faʻafuaseʻi e aofia ai se faʻailoga tonic e mafai foi ona faʻatupuina le taimi i luga o minute (47). I le faʻaaogaina o lenei auala, na matou iloa ai o faʻamaʻi faʻamaʻi-cocaine e mafai ona faʻaosoina ai aʻafiaga leaga aʻo faʻaititia i le taimi e tasi le phasic ma le tonic dopamine faʻailoga i le NAc (19). O le mea e malie ai, na matou matauina o le tonic, ae le o le phasic, faʻaitiitiga na fesuiaʻi e ala i le polokaina o le CRF receptors i le VTA. E ui o lenei togafiti e leʻi aʻafia ai uiga leaga o le quinine, na suia ai le suʻeina o cocaine, faʻaalia ai e mafai e faʻamalosi faʻamalosi ona faʻamalosia le suʻeina o fualaau faasaina i se tulaga maualalo le leo dopamine. O suʻesuʻega faʻaopoopo o le a manaʻomia e faʻaalia uma ai le masini ma le taua o le amio o le faʻaitiitia o le dopamine i le tali atu i faʻalavelave faʻafefe.
O nei suʻesuʻega o loʻo faʻamamafaina ai le manaʻoga e suʻesuʻe le auala e foliga mai e lavelave lea e faʻaalia ai le faʻalavelave faʻafefe i luga o le taʻavale taui e faʻaosofia ai amioga, faʻaleleia le faʻailoga o le dopamine i nisi tulaga ma faʻaitiitia le faʻailoga o le dopamine i isi. Mo se faʻataʻitaʻiga, ua faʻaalia le faʻaogaina o vae eletise eletise e faʻateleina ai le CRF i le VTA (45, 46), lea, i le isi itu, e mafai ona faateleina le gaioiga o le dopamine neuron (25, 44, 45, 48) mama toe fa'afo'i le su'eina o vaila'au (43, 45, 46). E ui o nei suʻesuʻega e foliga mai e feteʻenaʻi ma le lipoti o loʻo i ai nei, e ogatasi ma fua faʻatatau o le dopamine faʻailoga e faʻaaoga ai le microdialysis lea e masani ona lipotia ai le maualuga o le dopamine concentration mo ni nai minute i le taimi ma le maeʻa ai o le faʻamalosi faʻamalosi e faʻamalosia ai le sailia o le eli. (49, 50, 51, 52). To fa'amatalaga o lo'o iai nei e fa'aoso fa'aoso ona latou fa'aalia ai o fa'atupu fa'alavelave e fa'aitiitia ai le fa'ailoga o le dopamine e mafai fo'i ona fa'aoso ai le su'eina o vaila'au ma o fa'alavelave uma e lua o lo'o i lalo o le pule a le CRF.
O se tasi faʻamatalaga talafeagai mo le faʻafefea ma le faʻaititia o le dopamine faʻailoga e mafai ona taʻitaʻia ai le sailia o fualaau faasaina e mafai ona maua i totonu o le telefoni feaveaʻi o le dopamine target regions.
Ole faitau aofaʻi ole striatal neuron e faʻalogoina e ese le maʻaleʻale i le faʻateleina poʻo le faʻaititia o le dopamine concentration.
- I totonu o le pito i tua, D1-receptor-faʻaalia MSNs maualalo e aofia ai le auala tuusaʻo afi e faʻagaoioia e le maualuga o le dopamine e faʻaleleia ai le gaioiga ofo..
- E tutusa lelei, maualuga-affinity D2-receptor-expressing MSNs, e aofia ai le auala e gaosia ai le afi, e faʻalavelaveina e le maualuga o le leo dopamine ae e maaleale i, ma faʻagaoioia e, phasic taofi i le dopamine e taofiofia amioga [mo iloiloga, vaʻai ((26)].
To lo'o fa'atupula'ia fa'amaoniga o lenei fa'alapotopotoga e fa'atusaina i se tulaga taua i le ventral striatum. I le NAc, faʻateleina le faʻatupuina o le dopamine faʻailoga e faʻagaoioia ai le maualalo o le dopamine receptor-faʻaalia MSNs e faʻaleleia ai le aʻoaʻoina o taui.
I le isi itu, o le faʻaitiitia o le faʻailoga o le dopamine e faʻagaoioia ai le maualuga-affinity dopamine receptor-faʻaalia MSNs ma faʻateleina le faʻafefe. (27, 30, 53).
I suʻesuʻega o loʻo i ai nei, e foliga mai o le quinine na faʻaaogaina le matagaluega mulimuli, e avea o se faʻalavelave faʻafefe o le siosiomaga lea na faʻaitiitia ai le faʻailoga o le dopamine i se auala faʻalagolago i le CRF ma faʻalauteleina le sailia o fualaau faasaina.. O isi fa'aupuga o le si'osi'omaga talafeagai e mafai ona fa'ateleina ai le fa'ailoga o le dopamine i le NAc ma e mafai ona ta'ita'ia ai le i'uga tutusa o amioga e ala i le fa'aaogaina o matagaluega eseese.
NAc dopamine faʻailoga ua matua aʻafia i faiga e faʻaleleia ai vaisu. NAc dopamine e taua mo aʻoaʻoga faʻatatau i taui (54) ma tali sa'o i fa'ailoga fa'aosofia (55), lagolagoina le manatu o le dopamine faʻailoga e maua ai le faʻamalosi mo poʻo faʻailoga i le taua faʻaosofia o le faʻamalosia o faʻamalosi (42) ma e tele sona sao i le taumafai malosi o fualaau faasaina (41, 56).
O le taliaina o lenei mea, atonu e faigofie ona mafaufau i mea e faʻateleina ai le dopamine e mafua ai le suʻeina o vailaʻau ae faʻaitiitia ai le mafaufau pe faʻafefea ona faʻafefeteina faʻamalosi e faʻaitiitia ai le faailo o le dopamine e ausia ai lenei mea.
Ae ui i lea, o nisi o manatu muamua o le faʻaaogaina o vailaʻau na fautua mai e faʻaaogaina fualaau faʻasaina e ala i faiga faʻamalosia le lelei e faʻamalosia ai le toe faʻafoʻi i tagata faʻaaogaina vailaʻau o loʻo taumafai e tumau le faʻamaʻi (57, 58, 59). E ui lava o suʻesuʻega mulimuli ane o nei aʻoaʻoga na fesiligia pe mafai ona saofagā le faʻamaʻi faʻamaʻi i se faʻafitauli e faʻaalia i le toe faʻafoʻi masani pe a maeʻa le umi o le faʻaaogaina o fualaau faasaina (60, 61, 62, 63), o faiga fa'amalosi le lelei e manino lava le sao.
Le 'au o neuroadaptations e faʻatasi ma le faʻaaogaina masani o fualaau faasaina ma faʻaleleia le le mautonu ma le faapalepale (7, 56, 64, 65, 66) e mafai ona avea le maaleale i faʻalavelave faʻaleagaina o le siʻosiʻomaga o se mea e sili atu ona taua i le faʻalauiloaina o le toe faʻafoʻi i le faitau aofaʻi o tagata faʻatau fualaau faasaina.
IO le mea moni, e o'o lava i lea taimi ma lea taimi cocaine pulea e le tagata lava ia e foliga mai e aofia ai le le lelei o le faʻamalosia o aʻoaʻoga faʻatalanoaina e ala i le faʻailoga o le dopamine. A o paʻu le faʻaogaina o le dopamine, e faʻaauau le faʻatonuina o le tagata lava ia ma faʻateleina e manu le taumafa cocaine e faʻamautu ai le faʻaogaina o le dopamine o loʻo manaʻomia. (67, 68). I le taimi o le pulea e le tagata lava ia, e mafai e manu ona aʻoaʻo e tali atu e aloese mai se tulaga o le faʻaititia o le dopamine, ma o le oloa o lenei aʻoaʻoga faʻamalosia le lelei e mafai ona mulimuli ane faʻaaogaina e ala i le faʻafefe o le leo o le dopamine. O le lipoti o loʻo iai nei o loʻo faʻaalia ai se faʻaogaina o le dopaminergic mechanism o lenei faʻaosofiaga faʻafefe e aofia ai le CRF, o se neuromodulator faʻamalosia.
Aversive fa'aosofia e fa'aitiitia ai le fa'ailoga o le dopamine, fa'aogaina lenei masini ma ona lagona fa'alagona (fa'ata'ita'iga, a'afiaga leaga po'o le mana'o) i le leai o se vaila'au e maua. O le mea moni, o suʻesuʻega o loʻo i ai nei o loʻo fautua mai ai e aʻoaʻo e le au faʻaaogaina vailaʻau e faʻasaʻo le faʻaitiitia o le faʻaosoina o le dopamine i le auala sili ona lelei e ala i le faʻaaogaina e le tagata lava ia cocaine.
Fa'afetai ma Fa'ailoa
O lenei galuega na faʻatupeina e le US National Institutes of Health (R01-DA015758, JRM, ma le R00-DA025679, RAW).
Matou te faafetai atu ia M. Gilmartin, M. Blackmore, P. Gasser, J. Evans, ma E. Heperona mo sao i tusitusiga.
E fa'ailoa mai e le au tusitala e leai ni aia tau tupe fa'alesoifua maloloina po'o ni fete'ena'iga e ono tula'i mai.
Fa'aopoopo A. Mea Fa'aopoopo
mau faasino
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