Ho ba le tšusumetso e feteletseng ea mokhopi ho lebisa phetoho ho Dorsolateral Dopamine Dopamine Control ea Cocaine Ho batla (2014)

Likokoana-hloko tsa likokoana-hloko Buka ea 76, Khatiso ea 1, Maqephe 15–22, Phupu 1, 2014

E amohetse: May 21, 2013; E amohetse ka foromo e ntlafalitsoeng: Loetse 18, 2013; E amohetsoe: September 18, 2013; E phatlalalitsoe marang-rang: Mphalane 23, 2013
 
 

Background

Nts'etsopele ea mekhoa e mebe ea ho batla lithethefatsi e etsahala hammoho le phetoho ea khatello ea maikutlo ho dopaminergic taolong ea boitšoaro. Leha litloaelo tsena li ntlafala habonolo ha ts'ebeliso ea lithethefatsi e ntse e tsoela pele, ho susumetsoa ka matla ke bosholu ba taolo ea taolo holim'a ho batla le ho sebelisa lithethefatsi. Leha ho le joalo, hore na ho se ts'oanelehe ho nolofalletsa phetoho mekhoeng e lebisang ho koae ea dorsolateral striatum (DLS) kapa hore na ho kenella le ho ts'oaroa ke cocaine e kenyellelitsoeng phetolelong ea ts'ebetso ke mekhoa e tlatsetsang ha e tsejoe.

mekhoa

Likhoto tse phahameng le tse sa tsamaeeng letho tse khethiloeng mesebetsing ea nako e mehlano ea khetho ea makhetlo a mahlano li ile tsa koetlisetsoa ho ipeha cocaine (.25 mg / infusion) ka infusions e etsahalang boteng ba tšusumetso ea khanya ea cue-light. Phetisetso ea Dopamine e ne e koetsoe DLS kamora mehato e meraro ea boikoetliso: pele, phetoho, le mohato oa morao-rao, ka infusions ea methapo e kenang ea α-flupenthixol (0, 5, 10, kapa 15 μg / lehlakoreng) nakong ea 15-min cocaine-batla litlhahlobo tsa teko tseo karabelo e 'ngoe le e' ngoe e neng e matlafatsoa ka nepo ea tšusumetso e amanang le koae.

Results

Litekong tsa pele-pele, ha ho sehlopha se ileng sa angoa ke DLS dopamine receptor blockade. Litekong tsa phetolelano ea methati, likhoto tse sa ts'epahalang li bonts'itse phokotso e kholo ea ho ts'oara litheko tsa koae, athe likhoto tse phahameng haholo li ne li ntse li sa angoe ke infusions ea α-flupenthixol. Teko ea ho qetela, e batlang e le morao haholo, lihlopha tsena ka bobeli li bonts'itse kutloisiso ea tekanyo ea tekanyetso ho dopamine receptor blockade.

Nahanisisa

Liphetho li bonts'a hore ho qobella ho phahameng ho amana le phetoho e liehang ho taolo e thehiloeng ho DLS-dopamine mabapi le ho batla koae. Sena se fana ka maikutlo a hore, haeba ho qobelloa ho etsa hore motho a lemale, ha e tsoele pele feela ka nts'etsopele ea mekhoa e mengata empa ho e-na le hoo, e tsamaisana le mekhoa ea bootsoa e qetellang ka mekhoa e mebe ea ho batla lithethefatsi.

Bopaki bo ntseng bo eketseha bo fana ka maikutlo a hore bokhoba ba litlamorao bo bakoa ke ho fetoha hoa liphetoho tse fapaneng tsa methapo ho lithuto tse tlokotsing, qetellong ho felletseng ka tahlehelo ea taolo holim'a ho batla lithethefatsi tse mpe (1, 2, 3). Ho pepesehela lithethefatsi tse lemalloang, joalo ka koae, ha ho senye feela lits'ebetso tse kholo, ho felletseng ka bofokoli ba taolo le tšusumetso ea boitšoaro (4), empa e boetse e thusa nts'etsopele ea mekhoa ea ho batla lithethefatsi (3, 5, 6), ka ho etsa liketso tse matla tse hananang le litlamorao tsa bona le bohlokoa ba tsona (6, 7). Lithethefatsi tse tlatsetsang li baka ho ikamahanya le maemo ka har'a potoloho ea corticostriatal, ho kenyelletsa le phokotso ea tšebetso ea metabolic le li-receptor tsa D2 dopamine, tse qalang ho khutlisetsoa libakeng tse ka hare tsa striatum le preortal cortex empa qetellong li kenyeletsa libaka tse eketsehileng tsa dorsolateral, Associative and cognitive.8, 9, 10). Phetoho ena e tsoelang pele ho tloha ho li-network tsa "limbic" ho ea ho corticostriatal network tse etsahalang nakong ea ts'ebeliso ea lithethefatsi (11) e etsahala haufi le phetoho ho tloha ho li-nucleus tse bokellang ho dorsolateral striatum (DLS) sebakeng sa taolo ea ho batla le ho ts'oara lithethefatsi (12) le ho se leka-lekane ho amanang le ts'ebetso ea ho kopanya ea fronto-striatal le striato-striatal13) e bonts'itsoeng ke batho ba khale le ba lemaletseng lithethefatsi.

Boithuto ho liphoofolo bo bontšitse hape hore sebaka sena sa phetoho ea DLS taolong ea ho batla lithethefatsi (14, 15) ha e amane feela le nts'etsopele ea karabelo ea tloaelo bakeng sa moriana joalo ka tlhahlobo ea mekhoa ea tlhatlhobo (3, 6) empa hape e bonts'a ho hlaha hoa ho qobella ho batla koae (16). Ea bobeli ke tšobotsi e ikhethang ea bokhoba ba tahi (17), e boletsoe esale pele ka mokhoa oa boitšoaro oa ho susumetsoa haholo (18), e amanang le ho fumaneha ho tlase ha D2 / 3 dopamine receptor ho ventral striatum (19). Sena se lebisitse ho li-hypotheses tse fanang ka maikutlo a hore ho susumetsa le mekhoa, le likarolo tsa bona tse qalang tsa dopaminergic, lia sebelisana nakong ea ho theha lithethefatsi tsa koae, empa motheo oa ts'ebelisano ena ha o tsejoe. Lithuto tse thehiloeng ho thuto tsa kelello tse thehiloeng ho 'mele, litšoantšiso tsa basekaseki ba ts'ebetso ea basal ganglia (20) fana ka maikutlo a hore ho ba le ts'usumetso e phahameng le ho fumaneha ha eona habonolo tsa D2 dopamine receptor ho proral striatum ho thusa phetoho ho taolo ea DLS mabapi le taolo ea lithethefatsi. Leha ho le joalo, rona le ba bang re khothalelitse hore ho batla lithethefatsi ho tlatsetsang bokhobeng ho ka re bakela taolo e fokolang ea ts'ireletso holim'a tloaelo e ikemiselitseng e ikemiselitseng, e susumetsoang ke lithethefatsi, e mpe.4, 21).

Ka hona, re ile ra etsa lipatlisiso ka kotloloho hore na ho kena lipakeng ho laola ho imeloa ke DLS e thehiloeng ho dopamine ka nako e telele. Ho etsa sena, re fuputse litlamorao tsa infusions ea methapo ea kutlo ea dopamine receptor antagonist α-flupenthixol ho DLS ea likhoto tse khethiloeng e le phahameng (HI) le tse tlase tse kenang (LI) mesebetsing ea nako ea 5-serial reaction-time (5-CSRTT ), litekanyetsong tse laoloang ke koae tse laoloang ke cue ka nako ea pele, ea nakoana le ea morao-rao ea koetliso tlasa kemiso ea tatellano ea bobeli ea matlafatso ea koae (22). Tlas'a maemo ana re bontšitse pejana hore ho batla koae ho fetoha ka lebaka la phetisetso ea dopamine ho DLS (14, 18, 23), le tšebetso e sebetsang ea ho hira mochine ona oa dopaminergic ke letšoao la neurobiological la ho hlaha ha mekhoa ea ho batla lithethefatsi (3, 6).

Mekhoa le Lisebelisoa

Lihlooho

Lats Hooded tse tona tse mashome a mane tsa banna (Charles River Laboratories, Kent, United Kingdom) tse boima ba hoo e ka bang 300 g ha li fihla li ne li kengoe joalo ka ha ho hlalositsoe pele (23). Liteko li entsoe ho latela Molao oa Liphoofolo tsa Tsamaiso ea Liphoofolo tsa Saense 1986 tsa United Kingdom.

5-CSRTT

Lisebelisoa le Tsamaiso. Lisebelisoa tsa 5-CSRTT li hlalositsoe ka botlalo libakeng tse ling (24, 25) (Tlatsetsa 1). Ts'ebetso ea koetliso e ne e ts'oana le e hlalositsoeng pele (18). Seboka se seng le se seng sa boikoetliso se qalile ka ho bonesa ka kamore e sebetsang ke khanya ea ntlo le ho tsamaisoa ha pellese ea lijo makasineng. Ho sututsa ho bula karolo ea limakasine mme ho bokella pellet ena ho qalile nyeoe ea pele. Kamora nako e telele ea ho kenella lipakeng (ITI), leseli ka morao ho e 'ngoe ea lintho tse neng li arabeloa ka karabo e ile ea bonesoa hanyane ka hanyane. Likarabo tse ka hara aperture ena ka nako e sa lekanyetsoang (5 sec) li ile tsa matlafatsoa ke ho tsamaisoa ha pellet ea lijo makasineng (likarabo tse nepahetseng). Likarabo ka har'a aperture e sa fetoloang li tlalehiloe e le likarabo tse sa nepahalang mme li ile tsa otloa ke nako ea 5-sec nako ea ho tsoa. Ho sitoa ho araba ka nako e lekanyelitsoeng e lekantsoeng e sa tloheloa 'me le eona ka ho tšoanang e ile ea fuoa kotlo. Likarabo tse ling tlatsong leha e le efe ea lijo pele ho pokello ea lijo (likarabo tse phehellang) li tlalehiloe empa li sa fuoe kotlo. Likarabo tse entsoeng ka aperture efe kapa efe pele ho qala ts'usumetso ea sepheo, kapa likarabo tsa pele ho nako, li ile tsa fuoa kotlo ke nako ea ho tsoa 5-sec. Nako eohle ea koetliso, ITI e ile ea eketsoa hanyane ka hanyane, 'me nako ea khothatso e ile ea fokotseha butle-butle (25). Lihlooho li ne li nkuoa li fumane mosebetsi ha ho nepahala e ne e le> 75% mme ho siuoa ho ne ho le ka tlase ho 20% ha nako ea ts'usumetso e ne e le .5 sec le 5-sec ITI.

Kamora libeke tsa 2 tsa karabelo e tsitsitseng, likhoto li bile le phephetso ea 60-sec ITI makhetlo a mararo (nako e telele ea maqhubu a mahareng [LITI]), e arotsoeng ke mananeo a 7-sec ITI (18, 26). Li-LITI ka mokhoa o hlakileng li eketsa karabelo pele ho nako, ka tsela eo e thusa ho tsebahatsoa ha liphapang tse fapaneng tsa batho ba le bong le ho feta. Palo ea likarabo tsa pele ho nako nakong ea lithuto tsa LITI e fana ka index ea taolo ea tšusumetso (18, 19, 24, 25, 26), e sebelisetsoang ho khetholla litoeba tsa HI kapa LI. Likarolo li ne li behiloe ho latela palo ea likarabo tse potlakileng nakong ea likopano tse peli tsa ho qetela tsa LITI (10, 18). Ba nang le likarabo tsa <20 kapa> 50 pele ho nako ba khethiloe e le likhoto tsa LI le HI, ka ho latellana (n = 8 / sehlopha) (Setšoantšo sa S1 in Tlatsetsa 1).

Ntle le moo, likarabo tsa pele ho nako, likarolo tsa makasine li hatisa, likarabo tse nepahetseng le tse fosahetseng, liteko tse sa tloheng, le ho bokella li-latency (li-milliseconds ho bokella pellet ea lijo) li ile tsa kenyelletsoa likarolong tsohle tsa motheo pele ho karolo e 'ngoe le e' ngoe ea ho qetela ea LITI ho bapisa ts'ebetso ea boits'oaro ea mantlha ho LI le likhoto tsa HI

Phekolo

Joale litoeba li ile tsa etsoa liopereishene tse tloaelehileng tsa methapo le e rarahaneng tlasa ngaka e loantšang likokoana-hloko ka kakaretso (Tlatsetsa 1). Cannulae e kentsoe habeli 2 mm ka holimo ho dorsolateral striatum (anterior / posterior + 1.2, medial / lateral ± 3, dorsal / ventral-3 [15]; Mananeo a AP le a ML a lekantsoe ho tsoa bregma, DV e hokahanya ho tloha mokokotlong oa sefahleho, bareng ea incisor ho −3.3 mm [27]).

lithethefatsi

Cocaine hydrochloride (Macfarlan-Smith, Edinburgh, United Kingdom) e felisitsoe ka letsoai le lengata .9%. α-Flupenthixol (Sigma Aldrich, Poole, United Kingdom) e ile ea qhibiliha ka metsing a phallang habeli. Litekanyetso tsa lithethefatsi li tlalehoa ka foromo ea letsoai.

Cocaine Boitšoaro

Lisebelisoa. Likamore tse 12 tsa maemo a sebetsang tse hlalositsoeng ka botlalo libakeng tse ling (15) li ne li sebelisoa (Mekhoa ea ho Tlatsetsa 1).

Tsamaiso. Lethathamo la mekhoa ea ho itaola le ho bontšoa ho Setšoantšo sa 1. Ka bokhutšoanyane, linako tsa ho ikoetlisa tsa koae li ile tsa qala matsatsi a 7 kamora ho buuoa. Cocaine (.25 mg / infusion; .1 mL / 5 sec) e ne e fumaneha tlasa kemiso e tsitsitseng ea 1 (FR1) (e ntseng e ts'oaroa) ts'ebetso ea ts'ebetso eo ho eona mochine o le mong o sebetsang oa lever o ileng oa baka ts'ebetso le ho qala 20-sec nako ea ho tsoa . Nakong ea sekhukhu seo sa 20, leseli la "cue-light (" le nang le moea o khothatsang [CS]) le neng le le ka hofitisisa le ne le bonesitsoe, lebone la ntlo le ne le tima, 'me litšepe ka bobeli li hlakoloe. Ho phehella ho lever e sa sebetseng e tlalehiloe ho fana ka index ea ts'ebetso e akaretsang empa ha e-ba le litholoana tse boletsoeng. Boemo bo phahameng ba infomine ea koae ea 30 e ne e fumaneha sethaleng sena. Kabelo ea lever e sebetsang le e sa sebetseng e ne e hanyetsoa.

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

Setšoantšo sa 1

Lethathamo la liteko tsa ho itaola. Litho li ile tsa etsa kalafo e kenelletseng ea catheter le ea cannulae bohareng beke pele a qala ho ikoetlisa. Ho bile le lithuto tse hlano tsa koetliso ea boemo bo tsitsitseng ea 1 (FR1) e ileng ea lateloa ke liteko tsa ho fumana thepa esale pele. Ho tloha matsatsing a 13 ho isa ho 17, tlhoko ea karabelo e ile ea eketseha ho pholletsa le linako ho ea lenaneong la thupelo ea bohareng ba FR10 (FR4: S). Likhoto li ile tsa lula kemisong eo tse hlano pele li kenella tlhahlobo ea mahareng. Tlhokahalo ea karabelo e ile ea eketseha hape ka Mats'oa a 30 le 31 lenaneong la ho qetela la thupelo ea bobeli, FI15 (FR10: S). Liraka li ile tsa lekoa hape kamora linako tsa thupelo ea 15 ho tloha matsatsing a 32 ho ea 46 lenaneong la ho qetela la matlafatso. Teko ea morao-rao e qalile ka Letsatsi la 37. d, letsatsi; FI, nako ea nakoana.

Kamora linako tse hlano tsa koetliso tlasa kemiso ea FR1 ea matlafatso, litlamorao tse tlisoang ke litheko tsa driamine dopamine receptor blockade mabapi le ho batla cocaine ea pele-pele li ile tsa lekoa. Li-infusions tsa bilateral tsa α-flupenthixol li entsoe ho DLS. Likopano tsena tsa liteko tsa 15-min [FI15 (FR10: S)] li thehile phetoho ea maemo a tšohanyetso hobane mochine o mong le o mong o sebetsang oa lever o hlahisitse tlhahiso ea 1-sec light CS, 'me cocaine e ile ea hlahisoa feela mochineng oa pele oa lever ka mor'a 15-min karohano (23). Kahoo, liteko tsa ts'ebetso ea pele li ile tsa etsoa pele mme ka hona li ne li sa angoe ke k'hok'heine e itlhommeng pele ka linako tsena, hobane li ile tsa hlahlojoa ka ho hlaka bakeng sa ho batla koae ka nako e behiloeng ho fapana le karolelano e tsitsitseng. Seboka se seng le se seng sa tlhahlobo se ile sa lateloa hang-hang ke seboka sa koetliso ea ho itlhokomela ka koae ea FR1 (30) ka lihora tse 2), 'me likhoto li fuoe seboka pakeng tsa matsatsi a liteko e le ho netefatsa le ho boloka sethala se nkang koae.

Kamora liteko tse hlahlobang ts'ebetso ea pele ea ho ts'oha koae, tlhoko ea karabelo e ile ea eketseha ho pholletsa le linako tsa koetliso ea letsatsi le letsatsi ka li-kemiso tse latelang tsa ho matlafatsa: FR1; FR3; FR5 (FR2: S); FR10 (FR2: S); ebe ho FR10 (FR4: S). Tlas'a moralo o mong le o mong oa bohareng oa tatellano ea bobeli, ho phethoa ha kemiso ea yuniti (e fanoeng ka har'a li-parentheses) ho felletse ka tlhahiso ea leseli la 1-sec CS; cocaine infusions le nako ea 20-sec li fuoe feela ha ho phetheloa kemiso eohle. Ka hona, bakeng sa litlhahlobo tsa sethala sa phetoho, likhoto li ne li koetliselitsoe tlasa maemo a ntlafatsang ts'ebelisano lipakeng tsa karabo ea lipina le li-firmforts: maemo a hanyetsanang le CS a amanang le koae a etsahetse kamora likarabo tsa 4 (FR4: S); 'me koae e ile ea tlisoa ha ho phethoa mochini oa 10th oa mechine e mene ea lever. Likhoto li ile tsa lula lenaneong lena la lithuto tse hlano pele li qala liteko tsa ho batla koae. Nakong ea tlhahlobo e ngoe le e ngoe ea 15-min le infusions ea α-flupenthixol ho DLS, likhatiso tse ling le tse ling tse 'ne tse sebetsang tsa lever li ile tsa tsoela pele ho hlahisa tlhahiso ea 1-sec light CS,' me cocaine e ile ea hlahisoa feela khatisong ea bone ea lever ka mor'a nako ea 15-min [ ke ho re, FI15 (FR4: S)]. Kahoo, liteko tsa tšebetso ea phetoho li ile tsa boela tsa etsoa pele 'me li ne li sa angoe ke cocaine ea letsatsi le letsatsi. Seboka se seng le se seng sa liteko se ile sa lateloa hang-hang ke seboka sa koetliso ea koae ea FR10 (FR4: S) ka nako ea lihora tsa 30, mme likhoto li fuoe seboka pakeng tsa matsatsi a liteko e le ho netefatsa le ho boloka sethala se nkang koae. .

Kamora ho qeta liteko tse hlahlobang ho batla koae ka sethaleng sa phetoho, litlhoko tsa karabelo li ile tsa eketsoa hape ka linako tsa koetliso ea letsatsi le letsatsi ho latela linako tsohle tse latelang tsa ho matlafatsa: FR10 (FR6: S); FR10 (FR10: S); 'me qetellong ke kemisong e akaretsang ea nako e lekanyelitsoeng ea karolelano ea nako ea FI15 (FR10: S) e sebelisitsoeng lithutong tse fetileng (23, 28). Nakong ea kemiso ea ho qetela ea FI15 (FR10: S), ho araba ho ile ha bolokoa ka ho hlahisa maikutlo a amanang le CS ea amanang le koae ka mor'a likarabo tsa 10 (FR10: S); cocaine e ile ea tlisoa ha ho phethoa mochini oa khatiso oa 10 oa pele ka mor'a ho felloa ke nako ha nako e telele ea 15-min e tsitsitseng. Mothating ona oa ho qetela, ho ne ho e-na le moeli oa infusions ea koae e mehlano. Likhoto li ile tsa koetlisoa tlasa kemiso ena ea FI15 (FR10: S) ea ho matlafatsa mananeo a 15 pele ho nako ea liteko tse thehiloeng hantle, kapa tsa morao-rao, moo litlamorao tsa infusions tsa α-flupenthixol ho DLS li ileng tsa hlahlojoa hape. Nako ea pele (FI15) ea kemiso ea tatellano ea bobeli e fana ka nako eo ho sa sebelisoeng koae ka eona, leha ho le joalo likhoto li ntse li batla moriana ka mafolofolo. Likhoto tse peli li ile tsa tlosoa pele ho liteko tsa ho qetela, ka lebaka la li-catheters tse fosahetseng. Liroto li fuoe bonyane karolo e le 'ngoe ea koetliso tlasa maemo a FI15 (FR10: S) pakeng tsa tlhahlobo e ngoe le e' ngoe ea ensi-flupenthixol ho netefatsa maemo a botsitso a motheo.

Litšusumetso tse fapaneng

Bakeng sa mehato eohle e meraro ea tlhahlobo, infusionsriatal infusions (.5 μL / lehlakoreng) ea α-flupenthixol (0, 5, 10, and 15 μg / infusion in an antibalanced, Latin-square order of kalafo) li entsoe ka 28-gauge ironododic li-injection (Plastics One, Roanoke, Virginia) li theoleloa libakeng tsa ente 2 mm ventral ho fihlela qetellong ea tataiso ea cannulae (ke hore, DV-5 mm). Litaba tse tlotsitsoeng ka bonna li entsoe ka 90 sec ka pompo ea syringe (Harvard Apparatus, Holliston, Massachusetts) mme tsa lateloa ke nako ea ho kenyelletsa 60-sec pele li-injector li tlosoa 'me li-deturators li nkeloa sebaka. Linako tsa liteko li qalile 5 min hamorao.

Histology

Qetellong ea liteko, histology e ile ea etsoa joalo ka ha ho hlalositsoe pele (23) (Tlatsetsa 1).

Lipatlisiso tsa Statistical

Likarabo tsa pejana ho 5-CSRTT li ile tsa hlahlojoa ka mokhoa oa 2-tlhahlobo ea li-variance (ANOVA) le Session joalo ka karolo ea sehlooho, le Sehlopha (HI kapa LI) e le taba ea lipakeng. Likarabo tsa pele ho nako li ne li hokahanngoa le mehato e khethiloeng ea boikoetliso ho tsoa ho 5-CSRTT, 'me ho ile ha tiisoa hore ho na le lipehelo tsa bohlokoa lipakeng tsa taba-pakeng t liteko.

Ho amoheloa ha karolo ea DLS dopaminergic ea ho batla koae e netefalitsoe ka tsela e meraro ea ANOVA e nang le Stage (ea pele, phetoho, mme e thehiloe hantle), Dose (0, 5, 10, le 15 μg), le Lever (ea sebetsang le ea sa sebetseng) joalo ka ka har'a lintlha. Ho haptjoa hoa phapang ea ho nka karolo ha DLS dopaminergic ho batleng koae pakeng tsa HI le LI likhoto ho fumanoe lipatlisiso ka ANKA ea tsela e meraro e nang le phapang e reriloeng (29) le Session (boima ba 'mele 2 vs. 1) le Dose (boima ho litekanyetso tsa 10 le 15 µg / side vs. koloi) e le lintlha tsa kahare le Sehlopha (HI kapa LI) e le taba ea pakeng tsa lithuto. Phapang pakeng tsa likhoto tsa HI le LI bakeng sa sethala ka seng e ile ea hlahlojoa le ANOVA e nang le Dose le Lever e le lintlha tse kahare. Litšebelisano tsa bohlokoa li ile tsa hlahlojoa ho ea pele ka liteko tsa bohlokoa tsa Tukey (HSD) ka botšepehi. Bohlokoa bo behiloe ho α = .05.

Results

5-CSRTT

Likhoto tse khethiloeng e le HI (n = 8) ho 5-CSRTT e bontšitse kutloisiso e kholo ea ho eketsa nako ea ITI ho feta LI (n = 8) likhoto joalo ka ha li tšehelitsoe ke keketseho ea likarabo tsa pele ho nako bakeng sa liteko tse tharo tsa LITI tsa HI ha li bapisoa le litoeba tsa LI (Setšoantšo sa 2) (litlamorao tse kholo tsa Sehlopha: F1,14 = 65.20, p <.001, Seboka: F14,196 = 59.34, p <.001, le Group × Seboka sa kopano: F14,196 = 25.44, p <.001). Tlhahlobo ea Post hoc e senotse hore liphapang tsa sehlopha li hlahile ka lebaka la ho lelefatsa ITI (HSD = 14.477).

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

Setšoantšo sa 2

Likhoto tse phahameng haholo ha li hlahisoe ke likarabo tse ngata tse entsoeng pele ho tšusumetso ea sepheo nakong ea liteko tse mahareng tsa liteko (LITIs) empa eseng nakong ea lithuto tsa motheo. *Phapang ea bohlokoa ho tloha ho likhoto tse sa keneng nako e telele nakong ea LITI e le 'ngoe.

Ho ts'oaroa ka mokhoa o phahameng (o lekantsoeng joalo ka tekanyo ea likarabo tsa pele ho nako nakong ea likarolo tse peli tsa ho qetela tsa LITI) ho ne ho amana le palo e kholo ea ho ts'oara sepheo (e lekantsoeng joalo ka ha lipampiri li sutumetsa makasineng) le latency ea ho bokella li-pellets tse fumanoeng joalo ka ha li senotsoe ke kamano e ntle lipakeng tsa karabelo ea pele ho nako le solar panel nakong ea boikoetliso (ed = .481, p = .010) (Setšoantšo sa 3A); sena se tiisitsoe hape ke tlhahlobo t teko e bapisa palo ea li-panus tsa li-rits tsa HI le LI (t14 = 2.36, p = .033). Tšusumetso e ne e se, leha ho le joalo, e amanang le tšusumetso ea matlafatso, joalo ka ha ho senotsoe ke ho hloka botsitso pakeng tsa palo ea likarabo tsa pele ho nako le latency ea ho bokella li-pellets kamora teko e nepahetseng (τ = −.211, p = .259) (Setšoantšo sa 3B) le ho se be teng phapang molemong ona oa ho qetela lipakeng tsa likhoto tsa HI le LI (t14 = 1.14, p = .273). Litekanyetso tsa boitšoaro tsa motheo tse tlalehiloeng nakong ea lithuto tsa pele tsa LITI 2 le 3 li bonts'oa Letlapa la S1 in Tlatsetsa 1.

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

Setšoantšo sa 3

Likarabo tsa pele ho nako nakong ea liteko tse mahareng tsa liteko (LITI) li ne li hokahantsoe le lipampiri tsa lipapatso tsa limakasine (ho latela sepheo) (A) le latency ho bokella li-reinforcers (khothatso) (B) nakong ea lithupelo. Likhoto tse nang le tšusumetso e phahameng li bonts'itse maemo a phahameng a tšebelisano le makasine, empa a sa susumetsoe haholo ho fumana moputso, ho feta likhoto tse sa qobelloang.

Litlhahlobo tsa nalane

Likhoto tsohle li ne li le cannulae e fumanehang kahare ho DLS (Setšoantšo sa 4) (27).

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

Setšoantšo sa 4

Litekanyetso tsa Schematic tsa lehae la libaka tsa entetso ka boemo bo phahameng (A) hape ha e susumetsehe habonolo (B) likhoto tse nang le li-cannulae tse tataisang li kenngoa kahare ea dorsolateral striatum. E ngotsoe hape ho tloha Paxinos le Watson (27) ka tumello e tsoang ho Elsevier, copyright ea 1998.

Ho amoheloa hape ha taolo ea DLS Dopamine taolong ea Ho Batla Cocaine

Ho hloa mohato ka mokhoa o tsoetseng pele oa mekhoa ea DLS e ts'ehetsang taolo ea litekanyetso tse tsitsitseng, tse tloahelehileng, tse laoloang ke koae ho ile ha bonoa ho tloha litekong tsa pele ho ea morao haholo joalo ka ha ho bonts'oa ke keketseho e tsoelang pele ea phello ea bilatal intra-DLS α-flupenthixol infusions mechini e hatellang ea lever nakong ea ha 15-min e sa sebetse lithethefatsi e sa sebetsanoe le maemo (Stage × Dose × Lever tšebelisano: F6,78 = 3.50, p = .004), e netefatsa liphetho tsa rona tsa pejana (15, 23). Kahoo, le ha dopamine receptor blockade ho DLS e ne e sa sebetse nakong ea mohato oa pele oa ho ts'oaka koae (Setšoantšo sa 5A) (phello ea Dose: F3,45 = 1.03, p = .389 le tšebelisano ea Lever × Dose: F3,45 = 1.06, p = .375), e ile ea fokotsa tekanyetso ea koae ka ho ts'epahala ha e etsoa mothating oa phetoho (Setšoantšo sa 5B) (Phello e kholo ea Dose, F3,45 = 3.41, p = .025; le tšebelisano ea Lever × Dose, F3,45 = 3.45, p = .024). Patlisiso ea hoc ea hoc e senotse hore phello ena e hlahisitsoe ke 10- le 15-μg / litekanyetso tsa lehlakore tsa α-flupenthixol (HSD = 26.59). Ha ho batla koae e laoloang ke koae ho ne ho thehiloe hantle, infusions ea DLS α-flupenthixol e ileng ea hlaha e ile ea fella ka ho fokotseha le ho feta ha likarabo tsa ho batla koae tse lekantsoeng nakong ea karohano ea mahala ea lithethefatsi ea 15-minSetšoantšo sa 5C) (Phello e kholo ea Dose: F3,39 = 9.69, p Tšebelisano ea <.001 le Lever × Dose: F3,39 = 9.01, p <.001). Mothating ona, litekanyetso tsohle tsa α-flupenthixol li fokolitse haholo k'hok'heine e batlang ho amana le koloi (HSD = 40.30).

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

Setšoantšo sa 5

Ho bokella butle-butle ho laola dopamine e thehiloeng ho dorsolateral striatum mabapi le ho tsoma koae e laoloang ke cueine. Mechine ea khatiso e sebetsang le e sa sebetseng (± 1 SEM) nakong ea liteko tsa (tsa koae tse se nang koae) tse sebelisang lithethefatsi tse nang le ente ea α-flupenthixol ka har'a dorsolateral striatum ea likhoto tse phahameng le tse tlase tse sa kopaneng ho hang. (A), phetoho (B), 'me e thehiloe hantle (C) methati ea boikoetliso. *Phapang ea bohlokoa ho lever e sebetsang ho tsoa tlhahlobong ea 0 μg. +Phapang ea bohlokoa pakeng tsa likarabo tsa lever tse sebetsang le tse sa sebetseng bakeng sa lethal dose le leng le le leng tse lekiloeng. FI, nako ea nako e tsitsitseng; FR, karolelano ea linako.

Ho susumetsa ho kopantsoe le phetoho e liehang ho DLS Dopamine Taolo holima ho ts'oaroa ha Cocaine

Ho amoheloa ka mokhoa o tsoelang pele oa taolo ea dopamine ea DLS holim'a ho tsoma koae ho hlokometsoeng ho sechaba sohle ho fetotsoe ke boemo ba ho se tsitse. Kahoo, litoeba tsa HI le LI li bonts'a linako tse fapaneng tsa kutlo ea bona ea DLS dopamine receptor blockade holim'a phetoho ho tloha pele ho ea ho ea pele e qalileng hantle, e le tloaelo, e laoloang ke k'hok'heine ea koae: F1,12 = 8.07, p <.05). Kahoo, athe li-infusions tsa DLS α-flupenthixol li ne li se na tšusumetso e kholo mochineng oa khatiso oa lever ho HI (Setšoantšo sa 6A) le likhoto tsa LI (Setšoantšo sa 6B) nakong ea liteko tsa pele tsa ho batla (litlamorao tsa Dose kapa Dose × Lever. Fs ≤ 2.83, p ≥ .063) ba fokotsa ho ts'oara koae ka litoeba tsa LI (Setšoantšo sa 6C) (Phello e kholo ea Dose: F3,21 = 3.89, p = .023, le tšebelisano ea Dose × Lever: F3,21 = 3.86, p = .024) empa eseng ho litoeba tsa HI (Setšoantšo sa 6D) (Fs <1) nakong ea liteko tse batlang liteko. Liphuputso tsa Post hoc li senotse hore ts'ebetso ea "cocaine" e batlang boits'oaro ba likhoto e fokotsoe kamora ho tšoaetsoa ha 10- le 15-μg / lehlakoreng la lehlakore la α-flupenthixol mabapi le koloi le likhatiso tse sa sebetseng tsa lever (HSD = 40.62).

Setšoantšo sa setšoantšo sa Figure 6. E bula setšoantšo se seholo 

Setšoantšo sa 6

Ho lieha ho fetoha hoa taolo ea dorsolateral striatum holim'a boitšoaro bo batlang koae ka koae ka likhoto tse phahameng tse sa tsamaeeng. Mechine ea khatiso e sebetsang le e sa sebetseng (± 1 SEM) nakong ea liteko tsa (tse senang koae) tsa lithethefatsi tse nang le ente ea α-flupenthixol ka har'a dorsolateral striatum ea li-rats tse tlase le tse phahameng haholo qalong.A, B, ka tatellano), phetoho (C, D, ka tatellano)E, F, ka tatellano) methati ea boikoetliso. *Phapang ea bohlokoa ho lever e sebetsang ho tsoa tlhahlobong ea 0 μg. +Phapang ea bohlokoa pakeng tsa likarabo tsa lever tse sebetsang le tse sa sebetseng bakeng sa lethal dose le leng le le leng tse lekiloeng. FI, nako ea nako e tsitsitseng; FR, karolelano ea linako.

Litekong tse batlang li thehiloe hantle, kamora hore litoeba li koetlisoe ho batla koae tlas'a taolo ea li-CSs tse amanang le lithethefatsi, nakong ea mohato oa FI15 (FR10: S) lenaneong la tatellano ea bobeli, ho arabela ho ne ho fokotsehile. ka infusions habeli ea α-flupenthixol ho DLS ka bobeli ho HI le LI likhoto. Lieti tsa LI li ntse li tsoela pele ho bonts'a litlamorao tse tlisoang ke tekanyetso ea infusions ea α-flupenthixol ho DLS (Setšoantšo sa 6E), ha kutloisiso ena ea DLS dopamine receptor blockade joale e hlahile ho litoeba tsa HI (Setšoantšo sa 6F) (Phello e kholo ea Dose: F3,15 = 5.23, p = .011 le F3,21 = 4.11, p = .019, ka ho latellana, tšebelisano ea Dose × Lever: F3,15 = 5.20, p = .012 le F3,21 = 3.59, p = .031, ka ho latellana). Kahoo, 10 le 15 μg / litekanyetso tsa mahlakore a α-flupenthixol tse nang le lintlha tse fokolisitsoeng tse sebetsang li lever tse amanang le koloi hoo liphapang tse kholo lipakeng tsa khatello e sebetsang ea lever e neng e se e sa boneloe (HSD = 69.58 le HSD = 55.62 bakeng sa LI le li-RI HI , ka tatellano).

Leha phetoho nakong ea karolelano ea taolo ea dopamine e itšetlehileng ka DLS holim'a ho ts'oara koae e laoloang ke cueine e ile ea bonoa pakeng tsa likhoto tsa HI le LI, lihlopha tsena tse peli ha lia fapana ka tekanyo ea ho qala ts'ebetso ea boikoetliso ba koae ka makhetlo a mahlano a FR1 (sephetho sa mantlha sa thuto: F4,56 = 3.124, p = .022 empa ha ho na phello ea Sehlopha: F1,14 = 1.606, p = .226, kapa tšebelisano ea Sehlopha × F <1) kapa ts'ebetsong ea bona ho litlhoko tse ntseng li eketseha tsa boits'oaro tse amanang le mohato o mong le o mong oa ho theha lenane la tatellano ea bobeli ea matlafatso bakeng sa sethethefatsi. Ho joalo, ha ho na liphapang tse bonoeng likarabong tse batlang k'hok'heine lipakeng tsa likhoto tsa HI le LI nakong ea liboka tse hlano tsa FR10 (FR4: S) tse neng li etella pele tekolo ea lipakeng (tsohle Fs <1) kapa nakong ea liboka tsa FI15 (FR10: S) tse etelletseng pele tekolo ea morao-rao (phello e kholo ea Sehlopha: F1,12 = 1.367, p = .265, le tšebelisano ea Sehlopha × F14,168 = 1.167, p = .305), leha ho na le keketseho e akaretsang ea likhatiso tsa lever tse sebetsang nakong ea lithuto, tse bonts'ang keketseho e tsoelang pele ea tšusumetso ea lipuo tse khanyetsanoang ho CS mabapi le likarabo tse batlang koketso ea koae ka mor'a nako (phello e ka sehloohong ea Karolo ea Sontaha: F14,168 = 1.872, p = .033).

Puisano

Ts'ebetso ea tlhaho e kopantsoeng ke cocaine e qetella e hlahisitse mekhoa ea ho batla lithethefatsi ka dLamine dopamine.3, 14, 15, 23, 30, 31) tse ntseng li nkuoa e le mochini oa bohlokoa nakong ea ntlafatso ea bokhoba ba tahi (16). Leha e le hore impulsivity e tšoauoa ka phumaneho e tlase ea "trralatal" D2 / 3 dopamine receptor (19) e khethiloe e le lets'oao la bohlokoa la boikemelo ba motho ka mong ho fetoha ho tloha ho laoloang ho la ts'ebeliso e mpe ea lithethefatsi (18), mekhoa eo ho haella le ho kenella ka tlase ho eona ka tumellano e tsamaisanang le lithethefatsi ha e tsejoe. Ho latela monahano oa rona oa pejana (28) le mohlala oa papatso ea ho lemalla ho latela ts'ebetso ea litheko (20), tšobotsi ea ho qhekella ho phahameng le ho amana ka tlase le dopamine D2 / 3 ventral striatal dopamine receptors (19) ho fanoe ka maikutlo a ho nolofalletsa ho haptjoa ke lithethefatsi tsa taolo e tloahelehileng ea DLS holim'a boitšoaro bo batlang koae. Ka lehlakoreng le leng, litekanyetso tse kopanyang li fana ka maikutlo a hore bokhoba bo fetoha ha ts'ebetso ea methapo ea molaoli ea holofetseng, ea itšetleha ka corticostriatal, taolo ea inhibitory, e leng mothating oa ho susumetsoa, ​​eketsa le ho hokahana le ba amanang le liphetoho tse tlisoang ke lithethefatsi tse fanang ka nts'etsopele ea cue- sethethefatsi se laoloang-tloaelo ea ho batla (6, 7, 21, 32, 33).

Se fumanoeng thutong ea morao-rao se ts'ehetsa pono ea morao-rao ka ho fana ka bopaki ba hore ho ts'oaroa ho eketsehileng ha ho tsamaise kapa ho potlakisa ho hira ho tsoelang pele ha taolo ea DLS e thehiloeng ho dopamine mabapi le boits'oaro bo bonts'itsoeng maemong a tlase a ho batla lithethefatsi le ho tsoma koae (3, 6, 15, 16, 23). Sebakeng seo, ho ts'oaroa ho hoholo ho ne ho amahanngoa le ho lieha ha neuroadaptations ea striato-striatal e lebisang ho ts'ebetsong ea taolo e tsoelang pele ea taolo ea koae e batlang lits'ebetso tse itšetlehileng ka DLS. Sena se bontša hore tšebelisano lipakeng tsa ho ts'oaroa le ho ts'oaroa ke koae ka lebaka la ts'usumetso ea ts'ebetso ea dopoline e thehiloeng holim'a ts'ebetso e tlisitseng phetoho ea ts'ebetso e tlamang ea ho batla lithethefatsi (16) ho ka its'etleha holima ts'ebetso ea li-corticostriatal le li-striato-striatal tse sebetsang. Ka hona ho ka nahanoa hore ho batla lithethefatsi ho tlama ho hlaha ka nts'etsopele ea bojaki e sa tsitsitseng, e thata, e seng kotsi bathong ba tlokotsing ba khetholloang ka liphetoho tse amanang le taolo ea corticostriatal-inhibitory.

Kahoo, likotong tsa HI, ho bile le phetoho ea nako ea nako ea litla-morao tsa methapo ea methapo ea kutlo ea DLS ea dopamine receptor antagonist α-flupenthixol ho fokotsa likhatiso tsa lever tse sebetsang nakong ea liteko tsa 15-min tsa ho batla lithethefatsi. Le ha DLS dopamine receptor blockade e ne e sena tšusumetso ho likarabo tse laoloang ke koae nakong ea tlhahlobo ea pele, e ile ea fokotseha haholo mochini oa khatiso o sebetsang nakong e tlang, sethaleng sa liteko, mekhahlelo e 'meli ea tlhahlobo ha ho ne ho se na phapang ea letho lipakeng tsa HI le LI likhoto. Lintlha tsena, li lumellana le mosebetsi oa rona oa pele (23), ka tsela eo re bonts'a hore - ho sa tsotelehe phapang ea taolo ea tšusumetso - lithuto tsohle li qetella li nts'etsapele mekhoa ea ho batla koae ka DLS e fuoang motho ka mor'a ho etsa ts'ebetso ea ho batla lithethefatsi (3, 8, 15, 23). Leha ho le joalo, setsing sa bohareng sa thupelo, likarabo tse batlang k'hok'heine li ile tsa fokotsoa ke DLS dopamine receptor blockade ka ho khetheha ho LI empa eseng litoeba tsa HI.

Sena se liehisitse ho hira DLS taolong ea ho batla koae e fana ka maikutlo a hore ho fumaneha ha li-ventral striatum dopamine D2 receptors ho ka ba le tšusumetso ea liphetoho tse tlisoang ke lithethefatsi tlasa ts'ebetso e tsoelang pele ea ts'ebetso ea ts'ebetso ea dorsal striatal switch e etsahalang nakong ea ho lemalla batho.12, 34) le nakong ea nako e teletsana ea ho itlhokofatsa ea koae ka mefuta ea khale ea batho (8, 9, 11, 35) le likhoto (10). Rona le ba bang re khothalelitse hore ts'ebetso ena ea "" ventral to dorsal striatal switch 'e its'etleha holima ts'ebetso ea "dopamine" e nyolohang ka linako tsohle36, 37) ka nepo e hokahanya ventral le dorsolateral striatum (13, 15, 31, 38), leha mekhoa ea ho qala mosebetsi ona e ntse e tlameha ho theha. Eketsoa ponts'o ea morao-rao ea hore tekanyo e tsoelang pele ea k'hok'heine e fokotsang matla a dorsal striatum ea dopamine D2 receptors le li-messenger RNA (mRNA) li bonts'itsoe lipapaling (39, 40, 41) le likhoto (10) e lieha ho HI ha e bapisoa le litoeba tsa LI10), leha ho na le litekanyetso tsa motheo tsa D2 mRNA ka har'a nucleus e bokellang li-shell le dopaminergic neurons tsa mehleng (10), liphetho tsa hona joale li fana ka maikutlo a hore ho fumaneha ha li-receptor tse tlase tsa D2 lits'ebetsong tsa "criineal" tse bakoang ke koae. Sena se lumellana le pontšo ea hore ho ba kotsing ea ho itlhahisa e le koae ka ho lemalla joala, hoo re bonts'itseng hore o rereloa esale pele ka ho susumetsoa haholo (18), e amahanngoa le polasetiki e nang le bothata ba koae ea cocaine e fumanehang ho "ventral striatum"42).

Le ha ho pepesetsoa ha koae ho hlahisa mats'oao a ho fokotseha hoa litheko tsa "DopNUMX" dopamine receptor le li-mRNA.39, 43, 44, 45), ho itlhompha ka k'hok'heine ho litoeba tsa HI tse bonts'ang maemo a tlase a D2 mRNA le li-receptor maemong a li-ventral striatum ho etsa hore maemo a tloaelehileng a D2 receptor (46) e tsamaellanang le phokotso ea ho hloka toka. Tlhahlobo ena e fana ka maikutlo a hore ho lieha ho lieha ho hira dorsal striatal kamora ho pepesetsoa ha koae ho litheko tsa HI ho ka hlahisoa ka lebaka la khalemelo e fokolang ea koae ka dXamine e tlase ea "troporous" le "infulsivity" e amanang le eona e etsahalang pejana kamora ho ikamahanya le koae. Ka sebele, ts'ebetso ena ea tšehetso ea kelello e tšehetsoa ke thuto ea morao-rao ea "positron emission topology" ea LI le RI (46). Sena se na le moelelo oa bohlokoa maemong a kelello ka hore se fana ka maikutlo a hore, bakeng sa likhoto tsa HI, liketso tse sebetsang bakeng sa koae li ka lula li tataisoa nako e telele ho feta ho litoebeng tsa LI, sephetho se ikemiselitsoeng ke boemo ba bofokoli ba dopamine ka hara ventral striatum. Sena se lumellana le tlhokomeliso ea hore likhoto tsa HI li shebile haholo sepheo sa lijo ho feta likhoto tsa LI, e qeta nako e ngata makasineng ea phepelo ea lijo ha e koetlisoa ho 5-CSRTT. Ho feta moo, batho ba ipatileng ka sepheo sa ho etsa mosebetsi oa boemo bo holimo ba Pavlovia ba susumetsoang ke lijo ba ne ba qobelloa ho etsa mosebetsi oa ho theola ho liehisa ho feta batho ba sa etseng morao (47), tekanyo ea ho qobelloa e bonts'itsoeng hape ke litoeba tsa HI tse khethiloeng ho 5-CSRTT (48). Litlhokomeliso tsena li bonts'a hore ho iketelletsa pele ho tsamaisana le tšebeliso ea boits'oaro bo tataisoang ke merero nakong ea boiphihlelo ba pele mesebetsing ea lipina le ea Pavlovian.

Liphetho tsa hona joale li bonts'a hore mekhoa ea kelello eo ka eona ts'usumetso le litloaelo li tlatsetsang bokhobeng ha li ea itšetleha ka nts'etsopele ea nts'etsopele ea ea pele. Leha ho le joalo, ho bohlokoa ho khetholla matla a ho ntlafatsa mekhoa, eo ka boyona e seng ts'ebetso e fetelletseng, ho tloha ho se khone ho fumana taolo hape mekhoeng e mebe e seng e sa sebetse, joalo ka e bonoang ho batho ba lemaletseng lithethefatsi ba batlang le ho nka lintho ka hloko. lithethefatsi. Sena se fana ka maikutlo a hore ho ba kotsing ea ho lemalla ha motho ha ho bolele hore motho o na le mekhoa e metle empa ho e-na le hoo o lula a le maemong a thata a tloaelo ea ho batla lithethefatsi le ho sitoa ha motho hore a boele a laole litloaelo tsena tse mpe. Ho fokotseha hona ha mekhoa ea ho batla lithethefatsi ho ka hlaha ho tsoa ho e mong le e mong (49) kapa likarolo tsa striatal tsa taolo e fokolang ea thibelo ea methapo kapa ho phehelleng ha liphetoho tsa methapo ea kutlo tse bokellaneng nakong ea ho haptjoa ha taolo ea dorsolateral striatal taolo ea boits'oaro ho hlola ho bonahala ho haella ha "striatal neuroplasticity" e bonts'ang likhoto tsa HI (10).

Mosebetsi ona o tšehelitsoe ke lithuso tsa Lekhotla la Patlisiso ea Bongaka (MRC) ho BJE le JWD (G1002231, G0701500) le ka moputso o kopaneng oa mantlha o tsoang ho MRC le Wellcome Trust (MRC G1000183; WT 093875 / Z / 10 / Z) ho ts'ehetsa Setifikeiti sa Behaeveal and Clinical Neuroscience Univesithing ea Cambridge.

Re amohela tšehetso ea chelete ka har'a MRC Imperial College-Cambridge University-Manchester University (ICCAM) leano la ts'ebetso ea ts'ebetso ea ts'ebeliso ea taolo (G1000018). DB ke setho sa Groupe de Recheche (GDR) 3557 mme e tšehelitsoe ke chelete ea INSERM AVENIR, ANR "heraddictstress," IREB le Univesithi ea Poitiers. Re leboha Emily Jordan, David Theobald, le Alan Lyon ka thuso ea bona ea tekheniki.

Bangoli ha baa tlaleha lithahasello tsa lichelete tsa lichelete kapa likhohlano tse ka bang teng.

Sehlomathiso A. Tlhahisoleseling e tšehetsang

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