Qalong D2 Dopamine Receptor Sensitivity e bolela esale pele hore na Cocaine e na le kutloisiso ea mofuta ofe le moputso oa Rats (2015)

Kathryn E. Merritt,

Kopanelo: Lefapha la Psychology le Neuroscience, Yunivesithi ea Colorado, Boulder, Colorado, United States of America

Ryan K. Bachtell

[imeile e sirelelitsoe]

Kopanelo: Lefapha la Psychology le Neuroscience, Univesithi ea Colorado, Boulder, Colado, United States of America,
Setsi sa Neuroscience, Univesithi ea Colado, Boulder, Colado, United States of America,
Institute for Behaeveal Genetics, Univesithi ea Colado, Boulder, Colado, United States of America

PLOS
  • E phatlalalitsoe: November 4, 2013
  • ETSA: 10.1371 / journal.pone.0078258

inahaneloang

Ts'ebetso ea li-receptor tsa dopamine kahare ho sisteme ea mesolimbic dopamine e tsejoa e nka karolo ho qala le ho boloka ts'ebeliso ea koae. Polelo ea D2 dopamine receptor subtype e hlahisitsoe e le ntho e rerang pele le sephetho sa tšebeliso ea koae e sa foleng. Ha ho hlake hore na ho na le kamano ea ho bonela pele lipakeng tsa D2 dopamine receptor function le sensitivity ea koae e ka lumellang ho hlekefetsoa ha koae. Ka hona, re sebelisitse monyetla oa karohano ea boits'oaro ho D2 dopamine receptor e hlohlelletsang ho leka kamano ea eona le boits'oaro bo kopanetsoeng ba koae. Ba kentse letsoho, likhoto tsa banna tsa Sprague-Dawley qalong li ne li khetholloa ka ho arabela ha bona ka moferefere ho D2 dopamine receptor agonist, quinpirole, lenaneong la karabelo ea tekanyetso (0, 0.1, 0.3 & 1.0 mg / kg, sc). Likhoto li ne li khetholloa e le ba arabelang ba phahameng kapa ba tlase ba quinpirole (HD2 le LD2, ka tatellano) ka karohano e mahareng ea mosebetsi oa bona oa quinpirole o kenyellelitsoeng hare. Likhoto li ile tsa hlahlojoa kamora nako ea phapang litlamorao tsa psychostimulant tsa cocaine ka ho lekanya liphetoho mesebetsing ea cocaine-induction locomotor (5 le 15 mg / kg, ip). Likhoto li ile tsa boela tsa lekoa bakeng sa ho se tšoane ha nts'etsopele ea sebaka se ikhethileng sa lethal dose e tlase ea cocaine (7.5 mg / kg, ip) e sa hlahiseng mofuta oa koae ea boemo ba koae ka ts'epo. Kamora nako, likhoto li ile tsa lekoa bakeng sa ho fumana boits'ebetso ba koae le ho li lokisa ho latela tekanyo e tsitsitseng ea 1 le kemiso ea 5 ea matlafatso, ka ho latellana. Liphetho li bonts'a HD eo2 likhoto li ntlafalitse kutlo ea thepa ea cocaine e matlafatsang, e bonts'a boikhethelo ba sebaka sa cocaine, le ho ithaopa cocaine e ngata ha e bapisoa le LD2 liphoofolo. Liphumano tsena li fana ka maikutlo a hore liphapang tsa motho ka mong ho D2 dopamine receptor sensitivity e kanna ea ba ponelopele ea maikutlo a cocaine le moputso.

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Tlhaloso:Merritt KE, Bachtell RK (2013) Qalong D2 Dopamine Receptor Sensitivity Predicts Cocaine Sensitivity and Reward in Rats. PloS ONE 8 (11): e78258. Doi: 10.1371 / journal.pone.0078258

mohlophisi: Abraham A. Palmer, Univesithi ea Chicago, United States of America

Re amohetse: Kajeno 28, 2013; E amohetse: September 10, 2013; E phatlalalitsoe: November 4, 2013

Copyright: © 2013 Merritt, Bachtell. Ena ke sengolo se bulehileng se fihletsoeng tlasa tumellano ea Lichelete ea Tlhahiso ea Creative Commons Attribution, e lumellang tšebeliso e sa thibeloang, phetiso, le tlhahiso hape ka mofuta o mong le o mong, ha feela mongoli oa mantlha le mohloli ba ngoliloe.

Lithuso:Mosebetsi ona o tšehelitsoe ke R03 DA 029420; CU Tlhahiso ea Peo e Ncha. Bafani ba lichelete ba ne ba sena karolo morerong oa ho ithuta, ho bokella data le ho hlahlobisisa, qeto ea ho phatlalatsa, kapa ho hlophisa sengoloa.

Lithahasello tse tsitsitseng: Bangoli ba boletse hore ho na le lithahasello tsa tlhōlisano tse teng.

Selelekela

Ho utloisisa hore na hobaneng batho ba bang ba qhekella ts'ebeliso e mpe ea lithethefatsi kapa mekhoa ea ts'ebeliso e mpe ea lithethefatsi ha ba bang e se e 'ngoe ea likarolo tse sa utloisiseng hantle tlhahisong ea bokhoba ba lithethefatsi. Liphuputso tsa Epidemiological li tlaleha hore hoo e batlang e le 17% ea batho ba sebelisang koae ba tla fetoha k'hok'heine kamora lilemo tsa 10 tsa tšebeliso ea koae ea pele [1]. Sena se fana ka maikutlo a hore batho ba bang ba hlaseleha habonolo, ha ba bang ba hanyetsa ho nts'etsapele lithethefatsi leha ba na le nalane ea ts'ebeliso ea lithethefatsi. Leha ho na le mabaka a mangata a ka kenyang ts'epahalo ea lithethefatsi (mohlala, ho fumaneha hoa lithethefatsi, khatello ea sechaba, jj.) Phapang pakeng tsa batho ba tlokotsing le ba hanyetsanang le bona e ka hlalosoa ka ho fapana ha ts'ebetso ea methapo ea methapo e bakang karabelo ea lithethefatsi tsa lithethefatsi. tlhekefetso [2]. Ho utloisisa likarohano tsena ho ka fana ka leseli ho e 'ngoe ea lipotso tse batloang haholo ho nts'etsopele ea kholo ea litheko.

Sisteme ea mesolimbic dopamine (DA) e na le lisele tsa dopamine tse sebakeng sa ventral tegmental tse sebelisang li-neuron tsa spiny tse bohareng ba likarolo tsa methapo ea methapo. [3]. Cocaine e phahamisa kapele DA e tsoang libakeng tsa "terminal" tsa mesolimbic tseleng ka ho thibela transporter ea DA, e tlatsetsang ho matlafatseng koae [4]. Ts'ebetso ea tsela ea mesolimbic e tsejoa haholo ho kenya letsoho ho qala le ho boloka ts'ebeliso ea koae le ts'ebeliso ea lithethefatsi tse ling tsa tlhekefetso [5]. Liphetoho tse ka har'a mesolimbic DA circry li bontšitsoe e le litlamorao tsa tšebeliso ea phetisetso ea psychostimulant hape e le ntho e rerang esale pele. Mohlala, tšebeliso ea koae e sa foleng e amahanngoa le D e fokotsehileng2 Maemo a receptor a DA ho ventral striatum ea ba hlekefetsang koae [6], ho fana ka maikutlo a hore fokotsehile D2 Polelo ea receptor ea DA ke litholoana tsa tsamaiso ea koae e sa foleng. Ho bile le ngangisano e telele ea hore na ho fokotseha ha D2 Polelo ea receptor ea DA e hlokometsoeng ho batho ba hlekefetsang koae ka lebaka la ts'ebeliso e mpe ea koae kapa hore phetoho ena e emela boemo bo neng bo ka 'na ba etsa hore motho a se ke a ba le bothata ba koae.

Mosebetsi oa morao-rao ho batho le liphoofolo o fana ka maikutlo a hore fokotse D2 Ha e le hantle polelo ea DA receptor e ka ba sesosa sa ho ba kotsing. Kahoo, batho ba sa lemalleng ba nang le litekanyetso tse tlase tsa D2 DA receptor e tlaleha lithethefatsi tse kholo tse "ratang" bakeng sa psychostimulant, methylphenidate [7]. Litoeba tsa Mutant tse haelloang ke D2 DA receptor e ipeha koae e ngata ho feta ha e bapisoa le liphoofolo tse hlaha [8], ha a ntse a hlahisa maikutlo D2 Li-receptors tsa DA ka har'a ventral striatum li fokotsa ho sebelisa k'hok'heine [9]. Ka bobeli lithuto tsena li fana ka maikutlo a hore liphetoho tse neng li le teng pele ho D2 Polelo ea receptor ea DA e kanna ea bolela esale pele litlamorao tse matlafatsang tsa koae, leha ho ntse ho ena le ho hloka bonnete mabapi le karolo e tobileng ea D2 Lisebelisoa tsa DA e le sesosa sa ho ba kotsing.

Ho na le thahasello e hlahang ho karohano pakeng tsa D2 Polelo ea receptor ea DA le D2 Mosebetsi oa receptor oa DA le kutloelo-bohloko. Ha tsamaiso ea li-cocaine tse kang li-cocaine libakeng tse busang likhoto li fokotsehile D2 Polelo ea receptor ea DA, joalo ka ha e bonoa ho batho ba hlekefetsang batho ba koae, ho na le lintlha tse ling tse makatsang tsa hore protheine ea G e ka sebetsa.2 DA receptor e tsosang [10]. Ka mokhoa o ts'oanang, taolo ea koae e phahamisa polelo ea bosebeletsi bo phahameng D2 Li-receptors tsa DA [10], [11]. Liphetoho tsena li supa hore ha polelo ea D2 Li-receptors tsa DA li ka fokotseha, kutloisiso ea D2 Li-receptors tsa DA li ka nyoloha ho latela koae e pheta-phetoang. Mohopolo ona o bonahala liketsong tse 'maloa tsa boitšoaro moo cocaine e sa foleng e hlahisang maikutlo a phelisang le litla-morao tsa psychostimulant tsa D2 DA receptor agonists [12], [13], [14], [15], le tshusumetso ea D2 Lisebelisoa tsa DA li hlahisa phepo e matla ea ho batla koae ka mefuta e ikemetseng ea tsamaiso ea koae [16], [17], [18], [19], [20], [21]. Ha ho tsejoe hore na phapang e teng pele ho kutlo ea D2 Li-receptors tsa DA li amana le litlamorao tsa boitšoaro ba koae.

Lithutong tse teng hona joale, re sebelisitse mohlala oa mokhoa oa ho phopholetsa ho khetholla ho fapana ha maikutlo le boits'oaro ba D2 Li-receptors tsa DA li amana le boitšoaro bo susumetsoang ke koae. Tsamaiso ea D2 DA receptor agonist, quinpirole, e hlahisa phapang e phahameng ho likarabo tsa locomotor ho liphoofolo tsa na drugve tsa lithethefatsi. Kahoo, re ile ra sebelisa hampe liphapang tsena ho karabelo ea mantlha ea "ratin" ea quinpirole e le mohlala oa ho etsa liteko tsa D.2 Boikemisetso ba DA receptor e le sesosa sa tlokotsi bakeng sa boits'oaro bo latelang bo kopanetsoeng ke koae. Liphoofolo tseo tse bonts'ang keketseho e matla mesebetsing e susumetsoang ea quinpirole li ne li tšoauoa ka hore li na le D e phahameng2 Boikemisetso ba DA receptor (HD2), ha likhoto tse nang le ts'ebetso e nyane haholo li bonts'oa li le tlase2 Sensitivity ea DA receptor (LD2). Kamora sebopeho sena sa pele, likhoto tse tsoang sehlopheng ka seng li ile tsa bapisoa le sehlahisoa sa koae se khothalletsoang ke koae, se ratoang ke k'hok'heine, le ho itaola.

Lisebelisoa le mekhoa

Animals

Male Sprague-Dawley rats (Charles River, Portage, MI) a boima ba 275-325 g a ne a bolokiloe ka bonngoe ha a fihla. Ho fuoe litoeba ad libitum lijo le metsi, ntle le moo ho bontšitsoeng. Liteko tsohle li entsoe nakong ea leseli la (12: 12) potoloho ea leseli / lefifi.

Boitšoaro ba Melao

Lithuto tsena li ile tsa etsoa ho latela tataiso e thehiloeng ke Tataiso ea Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro tsa Setsi sa Naha sa Bophelo mme e amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso Univesithing ea Colado ho Boulder.

Tloaelo tikolohong ea Novel

Ts'ebetso ea locomotor e tlalehiloe ka likamoreng tsa ho hlapela (San Diego Lisebelisoa, San Diego, CA, USA) e lekanya 16 x 16 × 15 ka 16 lipara tsa li-photobeams tse arohaneng 1 ka thoko ho lifofane ka bobeli. Liteko tsohle tsa locomotor li ne li etsoa likamoreng tsa ts'ebetso tse senngoeng nakong ea leseli la (12: 12) lebone / lefifi potoloho. Liphoofolo li ne li lula malapeng a boithuto ba li-locomotor tsa mofuta oa li-2 hrs pele ho tlhahlobo ea quinpirole e kenyellelitsoeng ho entomotor (bona ka tlase).

Sebopeho sa Quinpirole-induction Locomotor Behaeve

Karabelo ea pele ea mofere-fere ho D2 DA receptor agonist, quinpirole e ne e sebelisoa ho arola liphoofolo ka lihlopha pele ho teko e 'ngoe ea boitšoaro. Liteko li qalile bonyane matsatsi a 7 kamora hore liphoofolo li fihle ho tsoa ho morekisi 'me li khanneloe ka liphapusing tse lefifi tsa lefifi nakong ea leseli la (12: 12) potoloho ea leseli / lefifi. Liphoofolo tsohle li ne li sebetsoa ka nako e ka bang metsotso ea 5 letsatsi le letsatsi bakeng sa matsatsi a 4 pele a qala lits'ebetso tsena ho felisa tšitiso efe kapa efe e ka bang teng. Liphoofolo tsohle li ile tsa lula pele ho lisebelisoa tsa tlhahlobo ea li-locomotor bakeng sa 2 hrs letsatsi pele ho tlhahlobo ea quinpirole (bona ka holimo). Quinpirole-induction locomotion e ile ea hlahlojoa ka har'a protocol ea karabo ea 5-hr ka nako e latelang: 1-hr habituation e lateloang ke litekanyetso tsa hora tsa agonist (0, 0.1, 0.3 le 1.0 mg / kg, sc). Ho arotsoe litheko tse akaretsang tsa "quinpirole-ikiwa-" tse hlahisoang e le Area Under the Curve, bona ka tlase) ho khetholla likhoto tsena ka hore ke D e phahameng2 ba arabelang (HD2) kapa tlase D2 babuelli (LD2). Ts'ebetso tsena li ne li etsoa ka mokhoa o ts'oanang liphoofolong tse 'maloa tsa liphoofolo (lihlopha tsa likhoto tse tsoang ho morekisi a le mong ka nako e lekanang le boima) ho e ngoe le e' ngoe ea mehato ea boits'oaro e hlalositsoeng (mohlala: cocaine locomotion, maemo a sebaka le boits'oaro). Karolong e 'ngoe le e' ngoe ea liphoofolo, phoofolo e nang le lintlha tse mahareng e ile ea lekoa, empa ea felisoa tlhahlobisong e meng ea data. Kabo ea lipalo ka har'a sehlopha se seng le se seng e ne e tšoana hantle, empa re hlokometse phapang lipakeng tsa bongata le lipalo tsa bohareng ba liphoofolo tse etsang quinpirole tse khothalletsoang lipakeng tsa liphoofolo. Ka hona, HD2 le LD2 linthla li entsoe kahare ho sehlopha ka seng.

Khokahano ea tšiea ea Cocaine

Karolong e le 'ngoe ea liphoofolo (N = 39), likarabo tsa locomotor li ile tsa lekanngoa ho sebelisoa protocol ea karabo ea 3-hr kahare ho nako. Liteko tsena li ile tsa etsoa likamoreng tsa lefifi tsa lefifi nakong ea leseli la (12: 12) potoloho ea leseli / lefifi. Liphoofolo li ile tsa lekoa matsatsi a 5-7 kamora sebopeho sa pele sa kutloisiso ea tsona ea quinpirole likamoreng tse ts'oanang tsa ts'ebetso. Ka letsatsi la liteko, liphoofolo li ne li lula ka kamoreng ea locomotor bakeng sa 1 hr ebe li fuoa litekanyetso tsa hora tsa cocaine (5 le 15 mg / kg, ip).

Boemo ba Sebaka sa Cocaine

K'honeng e 'ngoe ea liphoofolo (N = 37), maemo a sebaka a ile a lekanngoa molemong oa lisebelisoa tsa kamore ea 3 e sa sebelisoeng e sebelisang mokhoa oa 3-phase. Teko e qalile matsatsi a 7 ka mor'a tšobotsi ea pele ea kutlo ea quinpirole. Likamore tse peli tsa maemo (15 cm x 25 cm x 35 cm) li ne li ikhethile ka mekhoa ea lebota (mela e moputsoa le metsero e tšoeu le e ntšo) le mekhabiso ea fatše (grid vs. hole). Kamore e bohareng (15 cm x 10 cm) e ne e e-na le mabota a masoeu le mokato o holimo. Likamore li na le lifoto tsa infrared ho bona boemo ba liphoofolo le motsamao oa lisebelisoa. Ho tloha ho 1000-1500 hrs ka letsatsi pele ho boemo (pre-conditioning), likhoto li ile tsa lumelloa ho fihlella likarolo tsohle tse tharo tsa 20 min ho ea lekola khetho ea pele. Phoofolo e le 'ngoe ha e aroloe tlhahlobong hobane e bontšitse nako ea 92% ea nako ka lekaleng le le leng. Likhoto li fumane likarolo tse tharo tsa boemo ba saline ea 30-min le li-cocaine tse tharo tsa 30-min (7.5 mg / kg, ip). Boemo ba saline bo etsahetse pakeng tsa 0800-1100 hrs, ha boemo ba koae bo ne bo etsahala lipakeng tsa 1500-1700 hrs. Motsoako oa cocaine oa 7.5 mg / kg o ile oa khethoa hobane lithuto tsa pele ho lab tsa rona li bonts'a hore ha e hlahise khetho ea libaka litepising tsohle. Ka hona, tekanyetso ena ea koae e ne e loketse ho khetholla phapang e teng ntlafatsong ea khetho ea sebaka pakeng tsa lihlopha tsena tse peli. Seboka sa ho qetela sa liteko (boemo ba morao-rao) se ile sa etsoa pakeng tsa 1000 hrs le 1500 hrs mme likhoto li ile tsa boela tsa lumelloa ka mokhoa o sa lefelloeng likomphutheng tseo tse tharo mme khetho e ile ea khethoa ha nako e sebelisitsoeng komporong ea lithethefatsi nako e sebelisitsoeng lekaleng la saline (ratang maemo (CPP) lintlha.

Ts'ebetso ea Sucrose le Cocaine

Cohort e 'ngoe ea liphoofolo (N = 29) e ile ea lekoa bakeng sa ts'ebetso e arabang bakeng sa li-pellets tsa sucrose ka mor'a tšobotsi ea pele ea kutlo ea quinpirole. Ts'ebetso ea boits'ebetso e ile ea etsoa likamoreng tsa maemo a sebetsang (Med-Associates, St Albans, VT) e nang le ba arabang ba babeli. Matsatsi a supileng kamora tlhahlobo ea quinpirole ea pele, likhoto tsena li ne li beoa lijo ho thibela boima ba 'mele,' me li koetliselitsoe ho tobetsa lisebelisoa tsa pentets ka mokhoa o tsitsitseng oa 1 (FR1) kemiso ea ts'ebetso ho fihlela litekanyetso tsa ho fumana li fumanoe (50 sucrose pellets). Latency ea ho fihlela sekhahla sena e sebelisitsoe e le phapang e itshetlehileng litekong tsena. Likhoto tsohle li fihletse tekanyetso kamora matsatsi a 8 a ho ikoetlisa 'me a feptjoa ad libitum kamora moo.

Ka mor'a boits'oaro bo itekanetseng le bonyane letsatsi la ad libitum fepa, liphoofolo li ne li kenelletsoa ka li-catheter tse jugular tlasa anesthesia ea halothane (1-2.5%), joalo ka ha ho hlalositsoe libakeng tse ling [22]. Kamora matsatsi a 5-7 a ho hlaphoheloa opereisheneng, liphoofolo li ipeha k'hok'heine (0.5 mg / kg / 100 µl, iv) tlasa kemiso ea ntlafatso ea XXUMUMX, nako ea 1 ea nako ea 20 letsatsi le letsatsi. Liphoofolo li ile tsa fetisetsoa ho FR6, nako ea 2 s ea ho matlafatsa bakeng sa li-5 tsa letsatsi le letsatsi tsa 20-h. Litlolo tsa cocoaine li ile tsa tlisoa ka nako e tšoanang ka 5 s ka ho emisoa ha leseli la ntlo le khanya ea leseli la cue le kaholimo ho moqomo o kentsoeng lithethefatsi.

lithethefatsi

Quinpirole [(- - - Quinpirole hydrochloride] le cocaine hydrochloride li ile tsa rekoa ho Sigma (St. Louis, MO). Lithethefatsi tsohle li ile tsa qhaloa ka letsoai le silafetseng la 'mele (0.9%).

Boitsebiso ba Lintlha

Lintlha tsa locomotor tsa cocaine tse kenyellelitsoeng (liqhomane tsa maballo) li ile tsa hlahlojoa ke 2-factor factor design ANOVA e nang le sehlopha sa quinpirole (HD2 le LD2) le lethal dose ea cocaine (5 & 15 mg / kg) e le lisosa. Lits'oants'o tse fapaneng li ile tsa etsoa hape ho data ea locomotor ho khetholla matla a hlalosang kutloisiso ea quinpirole ts'ebetsong ea cocaine. Lintlha tsa boemo ba sebaka (lintlha tsa CPP = lipara tse nang le letsoai tse nang le letsoai) li ile tsa hlahlojoa ho sebelisoa moralo o kopaneng oa lintlha tse 2 ANOVA le sehlopha sa quinpirole (HD2 le LD2) le maemo (Boemo ba pele le Boemo ba Kamora) e le lintlha. Lintlha tsa boits'oaro ba Cocaine (infracine infusions) li ile tsa hlahlojoa ke moetso o kopaneng oa 2-factor motsoako ANOVA o nang le sehlopha sa quinpirole (HD2 le LD2) le matsatsi e le mabaka, kapa tlhahlobo e ikemetseng ea tlhahlobo lipakeng tsa li-quinpirole lihlopha (HD2 le LD2) ha infraine ea koae e ile ea putlama ka matsatsi a mangata. Maemong kaofela, litlamorao tsa bohlokoa le tse kopaneng li ile tsa lateloa ke litlhahlobo tse bonolo tsa tlhahlobo le liteko tsa post hoc (Teko ea bohlokoa ea Bonferroni). Bohlokoa ba lipalo bo ne bo hlophisitsoe pele ho p

Results

Tšoaetso ea Lihlopheng tsa Sensitivity tse phahameng le tse tlase tsa Quinpirole

Ho na le phapang e kholo ea ho araba lethathamo le leng le le leng la quinpirole nakong ea tlhahlobo ea karolo e kahare ea thutoSetšoantšo sa S1). Ka kakaretso, lethal dose le tlaase ka ho fetisisa la quinpirole (0.1 mg / kg, sc) le hatella mofuta o mong ha o bapisoa le ho araba koloi, ha litekanyetso tse phahameng (0.3 le 1.0 mg / kg, sc) activate locomotion. Ena ke karabelo ea tekanyetso ea quinpirole ea prototypical, moo litekanyetso tse tlase tsa quinpirole ka mohlomong li tsosang D2 li-autoreceptors litsing tsa dopamine le litekanyetso tse phahameng tsa quinpirole saturate D2 autoreceptors le ho hlohlelletsa li-postynaptic D2 Li-receptors [23], [24], [25]. Boitekong ba ho fumana ho rarahana ha boitshwaro ba pre- le postynaptic D2 ho hlohlelletsa li-receptor, re balile sebaka se katlasehong ea khoele (AUC) bakeng sa phoofolo e ngoe le e ngoe ho pholletsa le litekanyetso tsohle tsa quinpirole (Setšoantšo sa S1). Lenane la quinpirole AUC le ile la sebelisoa ho arola sehlopha se seng le se seng hore se be le kutloisiso e phahameng ea "quinpirole"2) le kutloisiso e tlase ea quinpirole (LD2) lihlopha tse thehiloeng karohanong e akaretsang ea sehlopha sohle. Setšoantšo sa 1A le 1B etsa papiso ka bobeli kabo ea lenane la quinpirole AUC 'me sehlopha se bolela ho latela mokelikeli o arotsoe ho HD2 le LD2 lihlopha. Setšoantšo sa 1C le 1D e bonts'a lipehelo le mekhoa ea sehlopha ea thomello ho tekanyetso e le 'ngoe ea quinpirole. Ha ho nts'etsopele lihlopha, lenane le tsamaisanang le lintlha tsa moemeli le ile la tlosoa tlhahlobisong e 'ngoe, empa ho bontšoa setšoantšong ho supa motho ka mong le moelelo oa phapang ho tsoa lipakeng tsa kakaretso.

ponahalo e nyane

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Setšoantšo sa 1. Tsamaiso le lipalo tsa ts'ebetso ea mofuta oa quinpirole e kentsoeng ke LD2 le HD2 lihlopha.

(A) Khokahano ea sehlopha sa libaka tse baloang tsa quinpirole tlasa li-curve (AUC) tse sebelisoang ho khetholla likhoto ho LD2 le HD2 lihlopha. Mohala o nang le matšoao o bontša lintlha tse bohareng (M = 15460). (B) Karolelano ea sehlopha (± sem) ea lenane la quinpirole AUC le sebelisitsoeng ho hlahisa LD2 le HD2 lihlopha. Mohala o nang le matšoao o bontša lintlha tse bohareng (M = 15460). (C) Tsamaiso ea litekanyetso tsa mesebetsi ea popomotor (li-break break / hr) nakong ea tlhahlobo ea karabelo ea quinpirole ea lethathamo la kahare ho LD2 (likerese tse putsoa) le HD2 (lihlopha tse khubelu) lihlopha. (D) Karolelano ea lihlopha (± sem) ea karabelo ea karabelo ea quinpirole ea LD2 le HD2 lihlopha.

doi: 10.1371 / journal.pone.0078258.g001

Kaha likabelo tsa sehlopha li susumetsoa haholo ke ts'ebetso ea locomotor e hlahisoang ke ts'ebetso ea quinpirole ea li-postynaptic D2 li-receptors, re boetse re batla ho tseba hore na lihlopha li fapana ka karabelo ea tsona ho ea tlase, lethal dose ea khatello ea quinpirole (0.1 mg / kg). Ho hapa ka botlalo boholo ba litlamorao tse hatellang tsa lethal dose le tlase la quinpirole, re lekantse litlamorao tsa quinpirole e le liperesente tsa basement (ketsahalo e susumetsoang ke letsoai; Setšoantšo sa S2). Ho ne ho se na phapang ho khatello ea quinpirole-induction locomotor e hlahisitsoeng ke 0.1 mg / kg quinpirole (t36 = 1.01, p = 0.3183), e fana ka maikutlo a hore kutloisiso ea phapang ea ho qekisa pakeng tsa HD2 le LD2 liphoofolo haholo-holo li bonts'a kutloisiso ea postynaptic D2 Li-receptors tsa DA.

Phatlalatso e Phahameng ea Quinpirole e Phahameng ea Keketseho e Atlehileng ea Cocaine

Ha re sebelisa likarolo tsa sehlopha tse arohaneng tsa karabelo ea quinpirole, re ile ra leka hore na kutloisiso ea quinpirole e ne e amana le thepa e sebelisang koae. Setšoantšo sa 2 e supa HD eo2 liphoofolo li ne li e-na le ts'ebetso e kholo ea koae ea cocaine e kenyellelitseng lethal dose ea 15 mg / kg ea cocaine, empa e sa latele tekanyetso ea koae ea 5 mg / kg. Moralo o kopaneng oa likarolo tse peli ANOVA ea lintlha tsena o senola tšebelisano e kholo lipakeng tsa lethal dose ea koae le sehlopha sa quinpirole (F1,36 = 7.17, p = 0.0111), le litlamorao tse kholo tsa cocaine (F1,36 = 88.43, p <0.0001) le sehlopha (F1,36 = 6.86, p = 0.0128). Setšoantšo sa 2 e boetse e bonts'a sephetho sa methapo e melelele e etsitsoeng lethathamong le leng le le leng la koae ho palo eohle ea liphoofolo. Ho ne ho e-na le kamano ea bohlokoa pakeng tsa sensiniviro ea quinpirole le 15 mg / kg mosebetsi oa lococotine oa cocaine-ikiwa1,36 = 8.62, p = 0.0058), empa eseng 5 mg / kg ts'ebetso ea ts'ebetso ea koae1,36 = 1.91, p = 0.1761). Kahoo, ho bonahala eka letsoalo la quinpirole la pele le bonahala le bolela esale pele hore ho tla ba le lethathamo la cocaine le matla le le matla.

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Setšoantšo sa 2. HD2 diphoofolo di bonts'a kutlwisiso e matla mabapi le ketsahalo ya locomotor e etsoang ke koae.

(A) Likhoto li ile tsa lekoa ka makhetlo a mabeli a litekanyetso tsa koae (5 le 15 mg / kg, ip) ts'ebetsong ea nako e telele. HD2 liphoofolo li bontšitse ts'ebetso ea koae e kholo haholo ea koae ho 15 mg / kg cocaine, empa eseng 5 mg / kg cocaine. * HD2 bohlokoa ho LD2, p <0.05 (B le C) Litlhahlobo tsa sehlopha sohle se entsoe ho netefatsa kamano lipakeng tsa lintlha tsa quinpirole AUC le locomotion e susumetsoang ke cocaine. Kamano e senang bohlokoa e ile ea khetholloa bakeng sa tšebetso e susumetsoang ke k'hok'heine ka tekanyetso e tlase (B, 5 mg / kg k'hok'heine) mme kamano e ntle e ile ea khetholloa bakeng sa ts'ebetso e susumetsoang ke cocaine ka lethal dose le phahameng (C, 15 mg / kg cocaine ).

doi: 10.1371 / journal.pone.0078258.g002

Mosebetsi o fetileng o bonts'a hore ts'oarelo e ncha e susumetsoang ke bompoli e rerese ho arabela ka koae nakong e tlang [26], [27]. Ka hona, re ne re batla ho hlahloba hore na ho na le phapang pakeng tsa LD2 le HD2 lihlopha tse ts'ebetsong ea popomotor e ncha. Ho ne ho se na phapang pakeng tsa HD2 le LD2 Lihlopheng tsa puo e ncha e khothalelitsoeng nakong eohle ea thuto (Setšoantšo sa 3A: t36 = 0.44, p = 0.6601) kapa nakong ea metsotso ea pele ea 30-60 (Setšoantšo sa 3B), ha ho se utloane ho arohaneng ka mokhoa o hlakileng ho le thata ka ho fetisisa. Ho tseba hore na ts'ebetso e nchafalitsoeng ea ts'usumetso e ncha e ne e rerile D2 Maikutlo a ho amoheloa ke DA, re tšoaea likhoto tsa rona e le tšebetso ea maiketsetso e tlaase kapa e phahameng haholo. Kahoo, re thehile likhoto tse tlase tsa karabo (LR) le likhoto tse arabelang tse phahameng (HR) re ipapisitse le karohano ea methati ea karabelo ea bona ea pele mabapi le lisebelisoa tsa tlhahlobo ea locomotor nakong ea tlhahlobo ea tikoloho. Ka mor'a moo re ile ra fumana hore na lihlopha tsena li fapane tšebetsong ea sephethephethe sa quinpirole. Joalokaha ho bontšitsoe Setšoantšo sa 3, LR le likhoto tsa HR li ne li sa fapana haholo ka tekanyetso efe kapa efe ea litekanyetso tsa quinpirole (Sehlopha: F1,108<1, NS; Quinpirole: F3,108 EA-69.61, le <0.0001; Tšebelisano: (F3,108<1, NS), leha lihlopha li ne li fapane hofeta ka locomotion e bakoang ke cocaine (Sehlopha: F1,36 = 10.49, p = 0.0026; Cocaine: F1,36 EA-84.86, le <0.0001; Tšebelisano: (F1,36 = 5.02, p = 0.0313). Ka bobeli, tlhaiso-leseling ena e fana ka maikutlo a hore le ha tšebeliso e ncha-e susumetsoang e le bokhopo ba ho arabela ka tšebeliso ea koae, mekhoa e amanang le kamano ena e kanna ea fapana le e amanang le D.2 Boikemisetso ba DA receptor.

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Setšoantšo sa 3. Boikutlo ba Quinpirole ha bo amanang le ts'ebetso ea popomotor e iqapetsoeng.

Ho lekola pherekano e nchafalitsoeng nakong ea tlhahlobo ea liteko ho ile ha senola phapang e kholo lipakeng tsa LD2 le HD2 lihlopha. (A) Ho ajoa ha lintlha tsa mosebetsi o mocha o qobelloang oa tlhahlobo ea maiketsetso nakong ea tlhahlobo ea 2-hr. (B) Thupelo ea nako e bonts'a tšebetso e ncha e bululetsoeng e nchafatsang lipakeng tsa LD2 le HD2 lihlopha. Liphoofolo tse tsoang sehlopheng sena li ile tsa hlophisoa bocha ho ba sehlopha se arabelang tlaase (LR) le sehlopha sa ba arabelang haholo (HR) ho ipapisitsoe le ts'ebetso ea bona ea bohahlauli e hlohlellelitsoeng. (C) LR le likhoto tsa HR ha lia ka tsa bolela esale pele phapang ea ts'ebetso ea locomotor ho pholletsa le liteko tsa quinpirole. (D) Likhoto tsa HR li bonts'itse tšebetso e kholo ea li-cocaine tse hlohlellelitsoeng ke cocaine maemong a mabeli a cocaine. * HR e bohlokoa ho tsoa ho LR, p <0.05.

doi: 10.1371 / journal.pone.0078258.g003

Kaha liphapang tsa karabelo ea pele ea k'hok'heine le tsona li bontšitsoe hore li tsamaisana le liphetoho ntlafatsong ea maikutlo a koae, moputso oa koae le boitlhokomelo ba koae, re tsebahala ka likhoto tsa rona hore re na le ts'ebetso e tlase kapa e phahameng ea tšusumetso ea koae. [28], [29], [30], [31]. Ts'ebetso ena e ntlafalitsoeng e ne e ipapisitse le ho bala AUC bakeng sa tšebeliso ea koae ka litekanyetso ka bobeli tsa cocaine nakong ea tlhahlobo ea karabelo ea koae ea kahare. Likhoto tse nang le litekanyetso tsa AUC ka tlase ho median li ile tsa beoa sehlopheng se tlase sa k'hok'heine ea k'hok'heine (LCR) ha ba nang le litekanyetso tsa AUC kaholimo ho Median ba ne ba behiloe sehlopheng se phahameng sa 'cocaine responder (HCR). Joale re ile ra fihlela qeto ea hore na phello ea pele e khothalletsoang ke koae e ne e reretsoe ho etsa mosebetsi oa quinpirole kapa che. Likhoto tsa HCR li ne li e-na le ts'ebetso e kholo ea quinpirole ka kakaretso ha e bapisoa le litoeba tsa LCR li sebelisa palo ea quinpirole AUC (t36 = 3.585, p <0.0010, data ha e bontšoe). Ho hlahlojoa ha ts'ebetso ea liteko tsa quinpirole ho fana ka maikutlo ho fana ka maikutlo a hore liphapang tsena li ne li bonoa haholo moetlong o sebelisang li-quinpirole tekanyetso (Setšoantšo sa 4). Kahoo, tlhahlobo ea karabo ea tekanyetso ea quinpirole lipakeng tsa lihlopha e senotse litlamorao tsa bohlokoa tsa sehlopha (F1,108 = 14.05, p = 0.0006), lethal dose la quinpirole (F3,108 = 85.93, p <0.0001) le tšebelisano (F3,108 = 7.64, p = 0.0001). Re boetse re lekotse kamano e teng lipakeng tsa maikutlo a koae ka kakaretso le kutloisiso ea quinpirole re sebelisa lintlha tsa AUC bakeng sa lithethefatsi ka seng moo ho neng ho e-na le kamano ea bohlokoa lipakeng tsa lintlha tse peli tsa ts'ebetso (Setšoantšo sa 4). Ka bobeli liphuputso tsena li bonts'a hore ho na le phapano ea bohlokoa lipakeng tsa kutlo ea pele ea koae le kutloelo-bohloko ba pele ba quinpirole.

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Setšoantšo sa 4. Kutloahalo ea "cocaine" ea pele e lumellana le phapang ea D2 Boikemisetso ba DA receptor.

Sebaka se ka tlasa mothinya (AUC) se ne se baloa bakeng sa ts'ebetso e 'ngoe le e' ngoe ea rat ea kh'ok'heine e susumetsoang ke k'hok'heine ka har'a litekanyetso tse 5 le 15 mg / kg. Ho sebelisa lintlha tsena tse baliloeng bakeng sa tšebetso ea basebetsi ba pele ba bakoang ke k'hok'heine, likhoto li ile tsa aroloa sehlopheng se tlase sa batho ba arabelang k'hok'heine (LCR) le sehlopha se phahameng sa ba arabelang k'hok'heine (HCR). (A) Likhoto tsa HCR li bonts'itse ts'ebetso e kholo ea li-quinpirole-induction locomotor litekong tsa 0.3 le 1.0 mg / kg. * HCR e bohlokoa ho tsoa ho LCR, p <0.05. (B) Ho ile ha etsoa tlhahlobo ea sehlopha sohle sa sehlopha ho tseba kamano pakeng tsa lintlha tsa quinpirole AUC le lintlha tsa cocaine AUC. Kamano e ntle e ntle e ile ea fumanoa lipakeng tsa kutlo ea "quinpirole" ea mantlha le kutloisiso ea "cocaine" ea pele.

doi: 10.1371 / journal.pone.0078258.g004

Lipapatso tse phahameng tsa Quinpirole Sensitivity Eketsehileng Moputso oa Cocaine

Ka sehlopheng se ikemetseng sa liphoofolo, ho arotsoe likarolo tse arohaneng tsa sehlopha sa karabo ea quinpirole (data e sa bontsitsoeng) le boemo ba sebaka sa cocaine (7.5 mg / kg) li ile tsa lekoa. Tekanyetso ena e sebelisitsoe tlhahlobong ena hobane ha e hlahise maemo a phetseng hantle a liphoofolo tsohle. Setšoantšo sa 5 e bonts'a mofuta oa ts'oarelo ea letsoai le cocaine le motsoako nakong ea maemo a 30 min. Ho ne ho se na phapang ea bohlokoa ea sehlopha ho ferekantsoeng ke letsoai (F1,66 = 0.51, p = 0.4784). Ho bile le phokotseho e kholo ea sebaka sa tlhahiso-leseling se nang le letsoai ho pholletsa le setsi se seng le se seng sa maemo2,66 = 10.91, p <0.0001) leha ho ne ho se na tšebelisano e bohlokoa lipakeng tsa lihlopha le mananeo (F2,66 = 0.59, p = 0.5567). HD2 likhoto li ne li e-na le tšusumetso e matla haholo ea koae ka nako ea maemo ha e bapisoa le LD2 likhoto (F1,66 = 4.29, p = 0.0462). Ha ho na phello e ka sehloohong ea seboka (F2,66 = 0.77, p = 0.4595) mme ha ho na litlamorao tse kholo tsa tšebelisano (F2,66 = 0.60, p = 0.5535), leha ho ne ho bonahala eka ho na le ntlafatso e ntlafalitsoeng ea tšebeliso ea koae nakong ea likopano tse peli tsa pele tsa maemo (Setšoantšo sa 5). O ile a phahamisa tlhoko ea koae ea cocaine e phahameng2 liphoofolo nakong ea maemo a maemo li hlakisa seo re se fumaneng (Setšoantšo sa 2) mme e supa hore HD2 liphoofolo li tsotella thepa ea "cocaine" e matlafatsang, le eo e ka bang mohopolo oa moputso oa koae. Ha sehlopha sohle sa cohort se hlahlobisisoa bakeng sa nts'etsopele ea sebaka se ratoang sa cocaine, ho bile le keketseho e kholo ea nako e sebelisitsoeng kamoreng ea ho phomola ka koae36 = 2.27, p = 0.0295). Ha sehlopha se ne se kenngoa tlhahlobisong, ho bile le phello e kholo ea maemo (F1,34 = 6.31, p = 0.0169), e boetse e fana ka maikutlo a hore ka kakaretso, liphoofolo li hlahisitse khetho bakeng sa kamore e tsamaeang ka koae. Ha ho na phello ea sehlopha (F1,34 = 3.27, p = 0.0793), empa ho bile le tšebelisano ea bohlokoa lipakeng tsa maemo le sehlopha (F2,34 = 4.36, p = 0.0443). Litlhahlobo tse latelang li senotse hore HD2 liphoofolo li bonts'a sebaka se ikhethileng sa 7.5 mg / kg cocaine ha e bapisoa le LD2 liphoofolo ka tlhahlobo ea kamora maemo (t34 = 2.33, p = 0.0258), empa e ne e sa fapana ka tlhahlobo ea maemo a pele (t34 = 0.31, p = 0.7619). Liphumano tsena li fana ka maikutlo a hore maikutlo a pele a quinpirole a amahanngoa le moputso o phahameng oa koae.

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Setšoantšo sa 5. HD2 diphoofolo di bonts'a kutlwisiso e kholo ho litlamorao tse khahlisang tsa koae.

(A) Ho ne ho se na phapang pakeng tsa sehlopha sa tšebetso ea locomotor ea saline nakong ea liteko. (B) Ho bile le phapang e kholo ea sehlopha ts'ebetsong e khothalletsoang ke koae nakong ea liteko tsa maemo moo HD2 liphoofolo li bonts'a tšebetso e kholo ea cocaine e ntšitsoeng ka har'a cocaine nakong eohle ea thupelo. * HD2 bohlokoa ho LD2, p <0.05. (C) Liphuputso tsa liphoofolo tsohle tse teng ka har'a sehlopha li bonts'a sebaka sa bohlokoa, se ikokobelitseng se khethiloeng ke cocaine se latelang maemo. † Post-conditioning ea bohlokoa ho tloha ho pre-conditioning, t36 = 2.27, p = 0.0295. (D) Tlhahlobo ea sehlopha e bonts'itse hore ke liphoofolo feela ho HD2 sehlopha se hlahisitse khetho ea bohlokoa bakeng sa kamore e koahetsoeng ka koae ha e bapisoa le liphoofolo tse ho LD2 sehlopha se sa kang sa hlahisa boemo bo bong le bo bong phapusing ea letsoho la koae. * HD2 bohlokoa ho LD2, p <0.05.

doi: 10.1371 / journal.pone.0078258.g005

Liphetoho tse phahameng tsa Quinpirole Sensitivity Eketsa Boiteko ba Cocaine

Ka sehlopheng se ikemetseng sa liphoofolo, likabelo tsa sehlopha tse arohaneng tsa karabelo ea quinpirole li ile tsa thehoa 'me ho ile ha etsoa liteko tsa ho ipopa tsa sucrose kapa cocaine. Setšoantšo sa 6 e bontša hore ho ne ho se na phapang ea sehlopha ho fumaneheng ha tsamaiso ea boipuso (F1,176 = 0.39, p = 0.5406) le lihlopha tseo ka bobeli li fumanoe ka mokhoa o tšoanang (Liemo: F8,176 = 18.00, p <0.0001; Tšebelisano ea sehlopha: Seboka: F8,176 = 1.81, p = 0.0775), a fana ka maikutlo a hore lihlopha tsena ha li fapana ho thuto e matlafalitsoeng ea karabelo e sebetsang. Joale tsona liphoofolo tsena li ile tsa kenngoa ka sethopo se sa feleng sa ho lula 'me tsa lumelloa ho ipeha koae. Pele, liphoofolo li ile tsa ipusa tsa koae ka lenaneo la FR 1. Ho ne ho e-na le mokhoa oa HD2 ho ikhalemela koae ho feta LD2 liphoofolo tse lenaneong la FR 1 li hlahlobiloe ho pholletsa le linako tsohle (F1,95 = 3.31, p = 0.0846). Ha lithuto li ne li karolelanoa ho linako tsohle tsa X 1, HD2 liphoofolo li iphekole ka koae haholo ho feta LD2 liphoofolo (t19 = 2.63, p = 0.0164, data ha e bontšoe). Ha kemiso e ne e se e hatetse pele ho kemiso ea FR 5 ea ntlafatso ea HD2 liphoofolo li iphekola ka ho eketsehileng koae ka linako tsohle joalokaha ho bontšitsoe ke tšebelisano e kholo (F4,76 = 3.465, p = 0.0118), leha phello ena e sa ka ea bonoa ha e kengoa libakeng tsohle tsa FR 5 (t19 = 1.51, p = 0.1484, data ha e bontšoe). Kahoo, kutloelo-bohloko ea pele ea "quinpirole" e amanang le tšebeliso ea matla e amanang le tšebeliso ea "cocaine" e eketsehileng.

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Setšoantšo sa 6. HD2 liphoofolo li iphekola koae ho feta LD2 liphoofolo.

(A) Ho ne ho se na liphapang tsa sehlopha ho fumane karabelo ea ts'ebetso ea ho fumana li-pellets tsa sucrose. . #tloaelo ea bohlokoa lipakeng tsa HD2 le LD2 lihlopha, p = 0.08, * HD2 bohlokoa ho LD2, p <0.05.

doi: 10.1371 / journal.pone.0078258.g006

Cocaine e Eketsa Quinpirole Sensitivity ka bobeli ba HD2 le LD2 Animals

Ho thehiloe hantle hore phekolo ea koae e sa foleng e eketsa maikutlo a D2 Li-receptors tsa DA [12], [13], [14], [15]. Ka hona, re lekile kutloelo-bohloko ea quinpirole ho liphoofolo tsohle tse latelang ts'ebetso ea ho ithekisa ka koae ho bona hore na phapang e teng ho D pele2 Boikutlo ba DA receptor bo ile ba phehella ho latela taolo ea koae e sa foleng. Sena se entsoe ho liphoofolo tsohle empa tsa 3 tse ileng tsa lahleha ka lebaka la ho hloleha ha catheter. Setšoantšo sa 7 e bontša hore ho itlhokofatsa ka koae ho ntlafatsa phokotso ea quinpirole ha e bapisoa le ho araba ka liphoofolo tse tšoanang pele ho tsamaiso ea koae. ANOVA e tsoakiloeng habeli e senola hore ho ne ho e-na le phello e ka sehloohong ea ho hlahisoa ha koae (F1,104 = 17.46, p <0.0001) le quinpirole dose (F2,104 = 66.73, p <0.0001). Ho ne ho boetse ho e-na le tšebelisano 'moho (F2,104 = 10.61, p <0.0001). Liphetho tse tšoanang li fumanoe ho sebelisoa lintlha tsa quinpirole AUC tse hlahisitsoeng pele le kamora ho pepesetsoa k'hok'heine (t24 = 5.56, p <0.0001). Re boetse re hlahlobile phapang lipakeng tsa HD2 le LD2 lihlopha tse mabapi le kutloelo-bohloko ea Quinpirole pele le ka mor'a ho itaola ka koae (Setšoantšo sa 7). Ho khahlisang, liphapang tsa sehlopha se neng se le teng pele li lula li ntse li ntlafalitsoe le tlatsetso ea koae ho D2 sensitivity sensept ka lihlopha tsena ka bobeli. Kahoo, tlhahlobo e senola phello e kholo ea sehlopha (F3,98 = 24.21, p <0.0001), tekanyo ea quinpirole (F2,98 = 117.50, p <0.0001) le tšebelisano (F6,98 = 16.03, p <0.0001). Ka mokhoa o ts'oanang, liphetho li fumanoe hape ho sebelisoa lintlha tsa quinpirole AUC tse hlahisitsoeng pele le kamora ho pepesetsoa k'hok'heine. Litlhahlobo li senola phello e kholo ea sehlopha (F1,23 = 46.05, p <0.0001) le ponahalo ea cocaine (F1,23 = 36.26, p <0.0001), empa eseng tšebelisano (F1,23 = 3.45, p = 0.0760). Liphumano tsena li bonts'a hore leha kutloelo-bohloko ea Quinpirole pele ho ts'ebetso ea koae e hakanya karabelo ea nako e tlang ea koae, batho ka bobeli ba hlaolela ho ts'oaroa hoa maikutlo ka ho latela ts'ebetso ea koae.

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setšoantšo sa mantlha (1.17MB)

Setšoantšo sa 7. Ts'ebetso ea Cocaine e ntlafatsa D2 Tlhokomeliso ea li-receptor tsa DA ho LD ka bobeli2 le HD2 likhoto.

(A) Lintlha tsa Quinpirole AUC li ntlafalitsoe ho pholletsa le sehlopha sohle sa liphoofolo tse lekiloeng kamora ho ipusa ha cocaine. Kamora hore cocaine e be bohlokoa ho Pele ho cocaine, p <0.05 (B) Ka mokhoa o ts'oanang, ntlafatso ena e ile ea bonoa litekong tsohle tsa quinpirole. Kamora k'hok'heine e bohlokoa ho Pele ho cocaine, p <0.05. (C le D) Lintlafatso tse kentsoeng ke Cocaine ho D2 Tlhokomeliso ea DA receptor e ne e bonahala ka bobeli ho LD2 le HD2 lihlopha tse sebelisang likhahla tsa AUC tsa quinpirole le lintlha tse tala tsa locomotor ka kotara ea quinpirole dose response. Kamora k'hok'heine e bohlokoa ho Pele ho cocaine, p <0.05. Ho khahlisang ke hore liphapang tsa sehlopha li ile tsa tsoela pele leha a se a pepesitsoe ka cocaine. † HD2 bohlokoa ho LD2, p <0.05.

doi: 10.1371 / journal.pone.0078258.g007

Puisano

Liphumano tse tlalehiloeng mona li bonts'a phapang ea karabelo ea motho ea ts'oaroang ke quinpirole esale pele. Ena ke pontšo ea pele e bontšang phapang e mabapi le kutloisiso ea D2 Barekisi ba DA ba bolela esale pele phapang e khothalletsoang ke koae, ho khetha le ho itaola. Likhoto li arotsoe e le HD2, ho ba le ts'ebetso e phahameng ea ts'ebetso mabapi le kalafo ea quinpirole, ho bonts'a ts'ebetso ea ts'ebetso ea cocaine e khothalletsoang, ho eketsa moputso oa koae, le ts'ebetso ea koae ka bongata bo bongata ha bo bapisoa le likhoto tse khethiloeng e le LD2 tse fokotsitseng ts'ebetso ea locomotor ho araba quinpirole. Habohlokoa, mekhahlelo ea HD2 le LD2 ha ea ka ea bapisoa le phapano ea ho sibolla tikoloho ea nalane, e bonts'itsoeng e le ponelo-pele ea ho arabela koae. Ho beha likarolo ho likhakanyo ho latela maikutlo a bona a pele a cocaine (HCR le LCR) ho tsamaisane le phapang ea maikutlo a quinpirole a fanang ka maikutlo a hore ho ka ba le mekhoa e tloaelehileng e tlatsetsang phapang pakeng tsa litšobotsi tsena tse peli tsa boits'oaro. Ho ile ha khethoa hore mekhahlelo ea HD2 le LD2 ha e lumellane le khatello e matla e khothalletsoang ke quinpirole eo mohlomong e kopantsoeng le presynaptic D2 DA receptor e tsosang [23], [24], [25]. Ka hona, re belaella hore HD2 le LD2 sebopeho sa sehlopha sebakeng sa quinpirole se kanna sa bonts'a phapang ea kutloisiso ea postynaptic D2 Li-receptors tsa DA. Leha ho le joalo, quinpirole e boetse e tsejoa ho hokahana le khetho e itseng ho D3 Li-receptors tsa DA [32]. Ebile, ho phatlalalitsoe hore litekanyetso tse tlase tsa quinpirole li etsa hore ho be le boits'oaro bo bongata ba molomo le boits'oaro ba manonyeletso likhotong tsa banna ka ho sebelisana le D.3 Li-receptors tsa DA [33], [34]. Kahoo, ha re ntse re nahana hore tlhonamo ea quinpirole e susumetsoang e bonts'a postynaptic D2 DA receptor susumetsang, ho ka etsahala hore D3 Li-receptors tsa DA li ka bapala karolo ea karabelo ea boitšoaro ho quinpirole.

Liphetoho tse ka har'a mesocorticolimbic DA circry li bile le tšusumetso e telele e le lebaka le rerang tšebeliso ea psychostimulant le phello ea tšebeliso ea psychostimulant e phetoang. D2 Receptor ea DA e amohetse tlhokomelo e makatsang ka lebaka la ho elelloa hore taolo e sa feleng ea lithethefatsi tse ngata tsa tlhekefetso e fokotsa D2 DA receptor e tlamang ho striatum, e fana ka maikutlo a hore ts'ebeliso ea lithethefatsi e hlahisa liphetoho tsena [6]. Leha ho le joalo, lintlha tse ling tsa bopaki li bontša hore D2 Polelo ea receptor ea DA e kanna ea lumellana le ntho e ka bang kotsing. Kahoo, batho ba sa sebeliseng lithethefatsi ba tlalehileng lintlha tse phahameng tsa "litend" tsa methylphenidate le tsona li ne li le maemong a tlase a D2 Li-receptors tsa DA kahare ho striatum [7]. Sebelisa mohlala oa phoofolo, ho ile ha bonoa hore e bua haholo ka D2 Receptor ea DA ho ventral striatum e fokotsa ho itaola ha koae [9]. Liphumano tsena li fana ka maikutlo a polelo ea D2 Li-receptors tsa DA li ka bolela esale pele tšebeliso ea koae nakong e tlang, leha ho se na mokhoa oa ho ithuta o buang ka maikutlo a D2 Receptor ea DA e ka tsamaellana le karabelo ea li-psychostimulants.

Ho na le lintlha tse 'maloa tse fanang ka maikutlo a hore maemo a polelo a li-receptor tsa metabotropic a ka qheleloa ka thoko ho sensitivity ea receptor ho qala ts'ebetso ea ho saena le ho susumetsa mesebetsi ea maqhubu. Mohlala, ho ikarola ho ile ha bonoa litoebeng kamora ts'ebetso e kang ea ho itlopa lijo ea koae. Kahoo, fokotseha ho D2 DA receptor B, max li ile tsa bonoa li bontša ho fokotseha ha D2 Polelo ea receptor ea DA kamora ho tsamaisoa ha koae, ha litheko tse ngata tsa protheine ea G li bonts'itsoe ha a araba D2 DA receptor e tsosa liphoofolo tsena tse tšoanang [10]. Sena se tsamaisana le khopolo ea hore boikoetliso ba koae e eketsa tšebeliso ea tumellano e phahameng ea D2 Li-receptors tsa DA ntle le ho susumetsa polelo e akaretsang ea D2 Li-receptors tsa DA [11]. Lithuto tsa rona li fana ka maikutlo a hore phapang ea motho ka mong boitekong ba boits'oaro ho D2 Ho hlohlelletsa litefiso tsa DA ho bolela esale pele karabelo ea morusu o khothalletsoang ke koae, moputso le matlafatso. Ka ho khetheha, liphoofolo tse nang le D e phahameng2 DA receptor sensitivity boitšoaro, ekaba ke ka lebaka la polelo e kholo ea tumellano e phahameng ea D2 Li-receptor tsa DA, ts'ebetso ea protheine e ntlafalitsoeng ea G kapa mochine o mong oa selefouno, e etsa hore liphoofolo li utloe matla a koae ka ho feta, li putse le ho li matlafatsa. E ntse e sa thibeloe hore na HD ke eona2 le LD2 likhoto li fapana polelong ea D2 Li-receptors tsa DA le / kapa ts'ebetso ea protheine ea G.

Ho etsa lipatlisiso ka phapang ea motho ka mong e le selelekela sa kutloisiso ea lithethefatsi, moputso le nts'etsopele ea liphetoho tse tšoanang le tšebeliso ea boitšoaro e seng e le mokhoa oa nako e telele oa ho fumana lintlha tse ka bang kotsing. E 'ngoe ea mehlala ea liphoofolo tse thehiloeng ka ho fetesisa e sebelisa karabelo ea ho lula tikolohong ea lipale ho khetholla liphoofolo e le ba arabelang tlaase kapa ba phahameng (LR kapa HR, ka ho latellana; [26]). Mohlaleng ona, likhoto tsa HR li bonts'a karabelo e kholo ea tšebeliso ea k'hok'heine le ho sebelisa litekanyetso tse tlase tsa li-psychostimulants ha li bapisoa le likhoto tsa LR [26], [27], [35], [36]. Ho khahlisang, likhoto tsa HR le LR le tsona li bonts'a phapang ho D2 Polelo ea receptor ea DA moo likhoto tsa HR li fokotse B, max of 3H-raclopride e tlamang le ho D2 DA receptor mRNA ho li-nucleus tsa li-nucleus [37]. Phapang ena ha e bonahatsoe ke boits'oaro ba boits'oaro ho D2 Ho hlohlelletsoa ha DA receptor kaha ha re a ka ra bona phapang lipakeng tsa HR le LR rats ka ts'oants'o e khothalelitsoeng ea quinpirole e netefatsang sephetho [38]. Ho fapana le hoo, phuputso e makatsang moo likhoto li ileng tsa khethoa ka mokhoa o fapaneng bakeng sa karabelo ho bo-ralitaba, ba arabelang holimo ba bontšitse karolo e kholo ea tumellano e phahameng ea D2 Li-receptors [39], [40]. Likhoto tse reretsoeng ho arabela ka boiphihlelo bo bongata hape li bonts'a kutloisiso e kholo ea quinpirole, ho arabela ka mokhoa o hlakileng ho li-cices tse amanang le koae le ts'ebeliso e ntlafalitsoeng ea boitšoaro, liphumano tse lumellanang le tse ling tsa lintho tseo re li boneng. Ha ho hlake hore na phapang pakeng tsa likhoto tsa HR le LR ho D2 Polelo ea receptor ea DA e bonts'a liphetoho tsa pele kapa tse ling tsa morao-rao kapa liphetoho lipakeng tsa batho ba babeli ba D2 Li-receptors tsa DA. Phuputso e 'ngoe e tlaleha hore likhoto tsa HR li na le subsensitivity ea D2 li-autoreceptors sebakeng se potolohileng ka hare ho ventral, leha ho le joalo ha ho tsejoe hore na maikutlo a post-synaptic D2 Li-receptors tsa DA libakeng tsa sepetlele sa striatal li fapane pakeng tsa likhoto tsa HR le LR [41]. Ha re fuoa tse ling tsa ho se lumellane lithutong tsa rona le lits'ebetsong tse fetileng re belaela hore D2 Ts'oaetso ea sehlopha sa DA receptor e kanna ea ts'oana le mekhoa e arohaneng le karabelo tse akaretsang tsa locomotor le boits'oaro bo bobebe.

E 'ngoe hape, phoofolo ea morao-rao e tsoetseng pele e sebelisang phapang ea motho ka mong e sebelisa karabelo ea pele ea cocaine ho fumana likhoto tsa HCR le LCR [28]. Moetso ona o thehile hore likhoto tsa LCR li bonts'a ntlafatso e kholo ea maikutlo a koae [29], sebaka se ntlafalitsoeng se ratoang ke koae [30], hape o na le litheko tse phahameng tsa keketseho e fetang ea likhoto tsa HCR [31]. Liphumano tsena li fana ka maikutlo a hore liphoofolo tse nang le karabelo e fokolang ea qalong ea koae li ka ba kotsing ea ho lemalla koae. Re hlokometse HD eo2 likhoto li na le karabelo ea pele ho koae, li ntšetsa pele koae e le maemo a bonolo ho feta, hape li ithaopela ho sebelisa koae e ngata ka nako e ts'oanang le ea LD2 likhoto. Ha re leka ho hokahanya seo re se fumaneng le ba sebelisang sebopeho sa HCR / LCR, re ile ra supa liphoofolo tsa rona ho latela karabelo ea bona ea pele ea koae. Re sebelisa mokhoa ona, re hlokometse hore likhoto tsa HCR li ne li na le D e phahameng haholo2 Sensitivity ea DA receptor ha e bapisoa le litoeba tsa LCR. Ha lipatlisiso tsena li ntse li hanyetsana ho tloha ha re fumana hore D e phahameng2 Boikemisetso ba DA receptor bo tsamaisana le boits'oaro bo hopotsang litheko tsa LCR lithutong tse fetileng (mohlala, khokahano e phahameng ea koae, k'hok'heine ea k'hok'heine, ho itaola hantle ha koae), li lumellana le liphumano tse tsoang melaong e kholo ea ho qoba libaka moo likhoto li bonts'ang karabelo e kholo ea tšebeliso ea sebaka. Iketsetse k'hok'heine e eketsehileng [42], [43].

Ho ka 'na ha e-ba le litlatsetso tse sa sebetseng tsa "neurobiological" tse tsamaellanang le phapang ena kapa e kanna ea ba lipontšo tsa liphapang tse' maloa. Taba ea mantlha, ha rea ​​ka ra pheta hantle lits'ebetso tse phatlalalitsoeng bakeng sa sebopeho sa HCR / LCR. Re sebelisitse mokhoa o mongata oa karabelo ea pele ea koae. Kahoo, re ile ra oela ka kotloloho ho litekanyetso tsa cocaine tsa 2 (5 le 15 mg / kg) mme tlhahlobo e ile ea etsoa ka nako e fetang lihora tse peli. Sena se fapane haholo le tlhahlobo ea metsotso ea 30 kamora 10 mg / kg cocaine e neng e sebelisoa lithutong tsa HCR / LCR tse fetileng. Taba ea bobeli, tlhahlobo ea "cocaine locomotor" e entsoe kamora tlhahlobo ea pele ea kutlo ea quinpirole kamoreng e le 'ngoe ea li-locomotor. Ha ho hlake hore na boiphihlelo bona bo ka be bo ile ba ferekanya joang teko e ileng ea latela ea koae. Kamora nako, re ile ra sebelisa mekhoa e fapaneng ho lekola likhetho tsa libaka (ip vs iv cocaine ente) mme lithuto tsa rona tsa ho itaola li ile tsa etsoa kamora ho itaola haholo. Ebile, phuputso e 'ngoe ea morao-rao e sebelisang koetliso ea lijo pele ho taolo ea koae e ile ea ama likhopotso tsa seo re se fumaneng se fana ka maikutlo a hore ena e ka ba tlhahlobo ea bohlokoa ea ts'ebetso [44]. Ka kakaretso, liphapang tsena tsa tsamaiso li ka sitisa bokhoni ba rona ba ho bapisa lithuto tsa rona ka kotloloho le ba sebelisang sebopeho sa HCR / LCR

Leha ho le joalo, kutloisiso ea pele e matlafalitsoeng ea D2 Ho hlohlelletsoa ha li-receptor tsa DA ho ka bonts'a sesosa sa tlokotsi se kenyang ts'ebeliso e matla ea ts'ebeliso ea psychostimulant. Lintho tseo re li boneng li sebelisa phapang ho D2 DA receptor sensitivities in a outfred, drug-naïve baahi ba litoeba. Ho ka etsahala hore liphatsa tsa lefutso kapa tikoloho li ka susumetsa D2 Sensitivity DA e fana ka batho ba bang ba hlaselehang habonolo kapa ba hanyetsanang le litlamorao tsa boits'oaro ba psychostimulants. Mohlala, maemo a ho holisa le maemo a sechaba a bontšitsoe ho susumetsa polelo ea D2 Li-receptors tsa DA. Matlo a ikhethileng a amanang le D a fokotsehile2 Polelo ea receptor ea DA [45], leha ba bang ba tlaleha phetoho ea polelo ea receptor mme ha ho phetoho maikutlong a boits'oaro ba D2 Li-receptors tsa DA [46]. Liphoofolong tse bolokiloeng kahara batho, matla a puso a ka susumetsa polelo ea D2 Li-receptor tsa DA moo liphoofolo tse hlahelletseng li bonts'ang li eketsehile D2 Polelo ea receptor ea DA 'me e hana ho itaola [47], [48]. Ka lebaka la hore liphoofolo tsa rona li lula ka tlung ka bomong, menyetla ea ho ba le maemo a bophelo e ne e se eona e tlatsetsang, leha bophelo ba pele ba bophelo ba setjhaba le / kapa bo sithabetsang bo ne bo ka ama D2 Litšeho tsa receptor tsa DA [49], [50], [51], [52], [53], [54], [55].

Ka kakaretso, re bontša hore likhoto tse nang le maikutlo a phahameng a mantlha litlamorao tsa D2 DA e hlohlelletsa receptor, HD2 likhoto, li tsamaisana le kutloisiso e kholo ea kutlo ea cocaine locomotor sensitivity, moputso oa koae, le cocaine e bapisoang le LD2 likhoto tse nang le kutloisiso ea boemo bo tlase ho litlamorao tse hlahisoang ke D2 DA receptor e tsosang. Ena ke pontšo ea pele eo D2 Sensitivity ea DA ke mofuta oa tlhaho o emelang tšebeliso ea koae, kaha ho eketsoa ha litlamorao tsa boitšoaro ba koae. Lithuto tsa nako e tlang li tla rereloa ho tseba hore na D2 Boikemisetso ba DA receptor bo amana le kholo ea kholo ea boits'oaro ba maikutlo le ts'oaetso ea ts'ebeliso ea koae hammoho le liphetoho tse amanang le tsona kahare ho neurobiology ea tsamaiso ea mesocorticolimbic DA.

Ho tšehetsa Boitsebiso

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feiekabelo ea

jarolla

Ho ajoa ha tlhaselo ea quinpirole e kentsoeng ka har'a sehlopha se le seng sa liphoofolo. (A) Ho ajoa ha lintlha tsa ts'ebetso ea li-locomotor (likheo tsa beam / hr) nakong ea tlhahlobo ea karabelo ea karabelo ea quinpirole ea nako e kenang kahare. Mehala e lefifi ea 'mala o moputsoa ka har'a lihlopha tsa data e bonts'a kakaretso ea "Medi" ho "lethal" le leng le le leng. (B) Tsamaiso ea sebaka se baliloeng tlasa khoele (AUC) bakeng sa phoofolo ka 'ngoe ho feta tekanyetso ea quinpirole e meraro. Nete ​​ea lefifi e tlatsitsoeng ka lefifi le mola o nang le matheba li emela palo ea bohareng (M = 15460).

Setšoantšo S1.

Ho ajoa ha tlhaselo ea quinpirole e kentsoeng ka har'a sehlopha se le seng sa liphoofolo. (A) Ho ajoa ha lintlha tsa ts'ebetso ea li-locomotor (likheo tsa beam / hr) nakong ea tlhahlobo ea karabelo ea karabelo ea quinpirole ea nako e kenang kahare. Mehala e lefifi ea 'mala o moputsoa ka har'a lihlopha tsa data e bonts'a kakaretso ea "Medi" ho "lethal" le leng le le leng. (B) Tsamaiso ea sebaka se baliloeng tlasa khoele (AUC) bakeng sa phoofolo ka 'ngoe ho feta tekanyetso ea quinpirole e meraro. Nete ​​ea lefifi e tlatsitsoeng ka lefifi le mola o nang le matheba li emela palo ea bohareng (M = 15460).

doi: 10.1371 / journal.pone.0078258.s001

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Setšoantšo S2.

LD2 le HD2 lihlopha li ne li sa fapana ka D2 dopamine Autoreceptor sensitivity. (A) Tsamaiso ea lipalo tse baliloeng (Baseline) bakeng sa 0.1 mg / kg quinpirole kahare ho LD2 le HD2 lihlopha. Ts'ebetso ea motheo e tsamaisana le ts'ebetso ea locine ea morine e khothalletsoang ka saline hora pele ho taolo ea quinpirole ea 0.1 mg / kg ho ts'ebetso ea tekanyetso ea karabelo ea tekanyetso ea karolo. (B) Litekanyetso tsa sehlopha (± sem) bakeng sa D2 Likolo tsa sensitivity sensitivity ha li senole liphapang tse kholo tsa sehlopha.

doi: 10.1371 / journal.pone.0078258.s002

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Menehelo ea Mongoli

O ile a amohela le ho hlophisa liteko: RKB KEM. O entse liteko: KEM. Ho hlahlobisisa lintlha: RKB. Li-reagents tse kentsoeng / lisebelisoa / lisebelisoa tsa tlhahlobo: RKB KEM. Ngola pampiri: RKB.

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