Ho itšireletsa ho tsoa k'hok'heine e sa foleng ea botho ho fetola tsamaiso ea ho bolaoa ha dopamine ho rhesus monkeys. (2009)

¹Lefapha la Fisiks le Pholoji, Setsi sa Patlisiso ea Neurobiological ea Tlhekefetso ea Lithethefatsi, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Sengoloa: Ngaka LJ Porrino, Lefapha la Physiology le Pharmacology, Setsi sa Patlisiso ea Neurobiological ea Tlhekefetso ea Litlhare, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA. Mohala: +1 336 716 8575; Fekse: +1 336 716 8501; Lengolo-tsoibila: [imeile e sirelelitsoe]

E amohetse 29 Mmesa 2008; E ntlafalitsoeng ka la 25 Phupu 2008; E amohetse 30 Phupu 2008; E phatlalalitsoe marang-rang ka la 3 Loetse 2008.

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inahaneloang

Le ha dysregulation ka hara dopamine (DA) e le sesupo sa ho pepeseha hoa koae e sa foleng, potso ea hore na liphetoho tsena li phehella ho setseng e ntse e sa arabeloe haholo. Li-primates tse se nang botho li emela mohlala o motle oo ho wona ho ka hlahlojoang litlamorao tsa ho ila ts'ebetso ea DA ka mor'a ho pepesetsoa koae. Thutong ena, litšoelesa tse tona tsa boea li itlhomme kocaine (0.3 mg/kg ka ente e ngoe, li-reinforcers tse 30 ka nako e le ngoe) tlasa nako e tsitsitseng ea metsotso e 3chedule ka matsatsi a 100 e lateloang ke ho tsuba matsatsi a 30 kapa a 90. Nako ena ea ho ipusa ea koae e kile ea bontšoa ho fokotseha ha methapo ea li-receptor ea DA D2 le ho eketsa maemo a li-receptors tsa D1 joalo ka baeti ba DA (DAT). Ho arabela ke litšoene tse laolang ho ne ho bolokoa ke tlhahiso ea lijo tlasa protocol e ts'oanang le linako tse tšoanang tsa ho itima lijo. [³H]SCH 23390 tlama ho Lisebelisoa tsa DA D1 tse latelang matsatsi a 30 a ho tsuba li ne li phahame haholo likarolong tsohle tsa striatum, ha li bapisoa le ho laola liphoofolo, athe [³H]lebelo la raclopride le tlamang li-receptors tsa DA D2 le ne le sa fapana lipakeng tsa lihlopha. [³H]WIN 35 428 e tlamang ho DAT e ne e boetse e phahame haholo ho hoo e ka bang likarolo tsohle tsa dorsal le ventral striatum kamora matsatsi a 30 a ho tsuba. Kamora matsatsi a 90 a ho khaotsa ho tsuba, leha ho le joalo, litekanyetso tsa li-receptor tsa DA D1 le DAT li ne li sa fapana le litekanyetso tsa taolo. Le ha litholoana tsena li supa hore ho na le monyetla oa ho ntlafatsoa ha likarolo tse fapaneng tsa tsamaiso ea DA, li boetse li supa sebopeho sa likarolo tsena nakong ea mekhahlelo ea pele ea ho se ikhethe ho taolo e sa feleng ea koae.

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SELELEKELA

Tšebeliso e sa feleng ea koae har'a batho ba lemaletseng batho e amana le neuroadaptations tsamaisong ea dopamine (DA) (Malison et al a, 1998; Volkow et al a, 1993, 1997). Tsena li kenyelletsa keketseho ea boteng ba batsamaisi ba DA (DAT) mme ea fokotseha maemong a likeleli tsa DA D2-like receptors (Little et al a, 1999; Mash et al a, 2002; Volkow et al a, 1993). Ntle le moo, liphetoho tsa tokollo ea DA le tsona li hlokometsoe. Mohlala, bafuputsi ba sebelisang lithuto tsa positron emission tomography (PET) le [¹¹C]raclopride le methylphenidate li bontšitse ho fokotseha ha tokollo ea DA maemong a batho ba sebelisang koae ka nako e telele (Volkow et al a, 1997; Wong et al a, 2006). Bothata bo bong, leha ho le joalo, ke hore hangata ho thata ho khetholla tšusumetso ea lintlha tse ling tse joalo ka tšebeliso ea lithethefatsi tse ling tse seng molaong le tsa molao, phapang ea maro a lithethefatsi le mekhoa ea tšebeliso, le phapang ea mokhoa oa bophelo. Liphapang tsena, hammoho le ho ba teng ha maemo a ka 'nang a rera tšebeliso ea lithethefatsi, ho ka fokotsa ho hlalosoa ha lithuto ho bakuli ba batho.

Mefuta ea litheko tsa batho bao e seng ba motho, eo ka tsona mekhoa e fapaneng e ka fetoloang ka mokhoa o hlophisehileng, e emela mokhoa o mong oa ho ithuta ka litlamorao tsa ho itaola ho feta tsa koae le ho ila ka morao ho moo. Liphuputso tse fetileng li bontšitse hore ho pepeseha koae ka ho sa feleng ho tsamaisana le ho fokotseha ho hoholo hoa li-receptor tsa D2 hammoho le maemo a phahameng maemong a li-D1 receptors le boteng ba letsatsi la DAT (Letchworth et al a, 2001; Moore et al a, 1998a, 1998b; Nara et al a, 2002, 2006). Litlamorao tsena li supa tse bonoang bathong, ka hona li tiisa ts'ebeliso ea mefuta ena ea tšebeliso ea lithethefatsi.

Leha ho na le bopaki bo bongata ba ho senyeha ha litsamaiso tsa DA, ho ipakile ho le thata ho lekola hore na ho na le bopaki ba ho fola kamora ho khaotsa ts'ebeliso ea lithethefatsi (Malison et al a, 1998; Jacobsen et al a, 2000; Volkow et al a, 1993) kapa hore na liphetoho tsena li ntse li tsoela pele ntle le nako ea ho pepesetsoa koae. Hape, mefuta ea batho bao e seng batho e ka ba leseli mohato ona oa ho lemalla. Farfel et al a (1992) e tlalehiloe e fokotsehile ho tsepamisa mohopolo ho li-DAT le li-receptor tse kang D1 ho striatum ea litšoene ka mor'a ho itšireletsa khafetsa mabapi le koae. Leha ho le joalo, karolo e ikhethileng ea ho itima lijo e ne e le thata ho tseba ka lebaka la khaello ea litekanyo sehlopheng se se nang nako ea thibelo. Ka mokhoa o ts'oanang, Melega et al a (2008) e tlalehiloe e fokotsehile haholo litekanyetso tsa DAT maemong a litonki tsa vervet tse latelang libeke tse 3 tsa ho ila thipa ho mofuta o ntseng o eketseha oa methamphetamine. Tsamaiso ea li-stimulants lithutong tsena ka bobeli, leha ho le joalo, e ne e se litaba. Tsela ea tsamaiso (contingent vs noncontingent) ho bonts'itsoe ho ama kelello ka mokhoa o fapaneng mabapi le tokollo ea DA (Boitšoaro et al a, 1997) le metabolism ea tsoekere (Graham le Porrino, 1995; Porrino et al a, 2002). Kahoo, ts'ebeliso ea boitaolo lithutong tse teng hona joale e thibela taba ena. Ntle le moo, litlamorao tsa ho itaola ka nako e telele ho lits'ebetso tsa boko tsa DA li ithutile haholo ho sebelisa mokhoa ona oa ho itaola ho litšoene tsa rhesus, ka hona, ho fana ka motheo oa ho hlahloba li-neuroadaptations tse etsahalang nakong ea thobalano.

Morero oa lithuto tsena, ka hona, e ne e le ho bona hore na liphetoho tse mabapi le li-DAT le DA D1 le D2 le li-receptor tsa DXNUMX tse bonts'itsoeng pejana ho liphoofolo li pepesitsoe ke ho itaola ka mokhoa oa cocaine (Letchworth et al a, 2001; Moore et al a, 1998a, 1998b; Nara et al a, 2002) e tla khutlisoa kamora nako e telele ea ho itšila. Motheong oa lithuto ho basebelisi ba lithethefatsi tsa batho (cf Volkow et al a, 1993), re fane ka maikutlo a hore liphetoho tsena tsamaisong ea DA li tla tsoela pele le kamora likhoeli tse 3 tsa ho tlohela mosebetsi. Ho fihlela sena, litšoene li ipeha k'hok'heine ka makhetlo a 100, ka kakaretso ea 900 mg/kg, e lateloa ke matsatsi a 30 kapa a 90 a ho tlohela lithethefatsi. DA D1 le li-receptor tsa D2, hammoho le DAT, li ne li lekantsoe ka bongata a vitro li-receptor autoradiography.

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METHODA

Lihlooho

Kakaretso ea litšoene tse tona tse rhesus tse 17 tse se nang litekoMacaca mulatta) boima ba pakeng tsa 7.7 le 13 kg (bolela ± SD, 10.2 ± 1.32) qalong ea thuto e ne e le lithuto. Ts'ebetso tsohle li entsoe ho latela mekhoa e tiisitsoeng joalokaha ho hlalositsoe ho Tataiso ea Sechaba ea Tataiso ea Bophelo bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro. Ntle le moo, lits'ebetso tsohle li ile tsa hlahlojoa le ho amoheloa ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Yunivesithi ea Wake Forest. Litšoene ka bomong li ne li bolokiloe ka har'a mekotla ea tšepe e se nang tšepe ka metsi ad libitum; liphoofolo li ne li kopana ka mahlo le ka pono. Boima ba 'mele ea bona bo ne bo bolokoa nako e ka bang 90-95% Boima ba 'mele bo fepeloang mahala ke li-pellets tse nang le litholoana tsa banana tse fumanoeng nakong ea liteko le ka ho fepa ka tlatsetso ea Lab Diet Monkey Chow, haufinyane hofeta 30 metsotso kamora seboka. Ho feta moo, ba ne ba fuoa litholoana tse ncha kapa liperekisi bonyane makhetlo a mararo ka beke. Tšoene e 'ngoe le e' ngoe e ne e imaloa hang ka beke, 'me haeba ho hlokahala, lijo tsa bona li ne li fetoloa ho boloka boima bo tsitsitseng.

Lisebelisoa tsa Boitšoaro

Ho ile ha etsoa lithuto tsa liteko ka likamoreng tse sebetsang tsa moea tse kenang moea o mongata tse nang le molumo (1.5 × 0.74 × 0.76 m; Med Associates Inc., East Fairfield, VT) e etselitsoe ho lula setulong sa litulo (Model R001; Lihlahisoa tsa Primate, Redwood City, CA). Kamore eo e ne e na le phanele ea bohlale (48 × 69 cm), e neng e e-na le levers tse peli tse ka khutloang (5 cm ka bophara) le mabone a mararo a susumetsang. Lisepa li ne li le ka har'a bonolo ba tšoene e lutseng setulong se haufi. Li-pellets tsa lijo tsa banana tse nang le banana haholo (1 g; Bio-Service, Frenchtown, NJ) li ile tsa tlosoa ntlong ea phepelo e ka holim'a kamore. Pompo ea infusion ea peristaltic (7531-10; Cole-Parmer Co, Chicago, IL) e sebelisitsoe ho fana ka liente tsa lithethefatsi ka tekanyo e ka bang 1 ml ka 10 s ho liphoofolo tseo tse ipapisang ka koae. Ts'ebetso ea likamore le ho fumana data ho phethiloe ka sistimi ea khomphutha ea Power Macintosh e nang le sehokelo (Med Associates Inc.).

Mekhoa ea Ts'ebetso

Litšoene tsohle, ho kenyeletsoa le taolo, li ne li hlophisitsoe hantle ka tlasa maemo a se nang thipa, tse nang le li-catheter tse kenang kahare le likharetene tsa phihlello ea methapo (Model GPV; Access Technologies, Skokie, IL). Litšoene li ile tsa bolaoa ka mokhoa o sa kopaneng le ketamine (15 mg/kg, im) le butorphanol (0.03 mg/kg, im) mme incision e entsoe haufi le mothapo oa botšehali. Kamora ho phatloha ho hoholo le ho arohana ha mothapo, pheletso e hlakileng ea catheter e ile ea kenngoa methapong bakeng sa sebaka se lekantsoeng sa ho emisa kahare e tlaase ea vena cava. Bofelo ba distal ba catheter bo ile ba tlangoa ka mokhoa o sa ts'oaneng le ts'oaetso e entsoeng hanyane bohareng ba mokokotlo. Boema-kepe ba ho kena ka methapo e kentsoe ka pokothong e thehiloeng ke monko o haufi le ts'ebetso ena. Litšoene li fuoe 24-48 h nako ea ho hlaphoheloa pele a khutlela ho karabelo e matlafatsang ea lijo. Hoo e ka bang matsatsi a 5 pele ho ts'ebetso ea sepetlele, tšoene e 'ngoe le e' ngoe e ile ea kenngoa kahare e sa foleng ea methapo e kenang kahara mothapo o haufi oa basali bakeng sa ho bokella mehlala ea mali ea khale ea nako. Ts'ebetso ea ts'ebetso ea ts'ebetso e ne e tšoana le e hlalositsoeng bakeng sa li-catheter tsa venous. Ka letsatsi la karolo ea hoqetela, ho ile ha etsoa thuto ea "metabolism" ea "glucose metabolism" moo litšoene li ileng tsa kenngoa ka 2-[¹⁴C]deoxyglucose (2-DG) hoo e ka bang 2 Metsi kamora ho fela ha seboka le disampole tsa mali li ile tsa fumaneha ka arctial catheter tse fetang 45 nako ea metsotso (bona Beveridge et al a, 2006 bakeng sa lintlha). Lintlha tsa metabolism tse tsoang lithutong tsena ha li hlahisoe mona.

Mekhoa ea Boitšireletso

Qalong litšoene li koetliselitsoe ho arabela ho e 'ngoe ea likhama tse peli ka ho tiisa karabo e' ngoe le e 'ngoe ho lever e nepahetseng le pellet ea lijo. Hoo e ka bang nako ea libeke tse 3 karohano pakeng tsa ho fumaneha ha lipente tsa lijo e ile ea eketsoa hanyane ka hanyane ho fihlela nako ea metsotso e 3 e fihletsoe (ke hore kemiso ea tumellano ea metsotso e 3 ea ho matlafatsa; FI 3-min). Tlas'a maemo a kemiso ea ho qetela, karabelo ea pele ho lever kamora 3 min e ile ea fella ka ho tsamaisoa ha pellet ea lijo; Linako li felile kamora tlhahiso ea lijo tse 30. Qetellong ea karolo ka 'ngoe, batho ba arabang ba ile ba hlakoloa, mabone a ntlo le mabone a ho hlohlelletsa a tima,' me liphoofolo li ile tsa lula kamoreng e lefifi ka nako e ka bang 30 metsotso pele ba khutlisetsoa mabokoseng a bona. Litšoene tsohle li ile tsa arabela tlasa kemiso ea lijo ea metsotso e 3 ea ho fana ka lijo bakeng sa bonyane linako tse 20 le ho fihlela tšebetso e tsitsitseng (± 20% moelelo oa likarolo tse tharo tse latellanang, ntle le litekanyetso tsa maemo a karabelo). Ha karabelo e bolokiloeng ke lijo e tsitsitse, se fepehang se ne se sa fuoe 'me litlamorao tsa ho felisoa ha ho arabeloa li ile tsa hlahlojoa linako tse hlano tse latellanang, ka mor'a moo ho araba ho ile ha hlophisoa bocha le ho bolokoa ke tlhahiso ea lijo.

Kamora hore ts'ebetso ea mantlha e thehiloe, litšoene tsohle li ile tsa hlophisoa ka mokhoa o fapaneng le li-catheter, joalo ka ha ho hlalositsoe kaholimo, 'me ka tšohanyetso tsa abeloa se seng sa lihlopha tse tharo. Sehlopha se le seng sa litšoene se sebelitse e le taolo 'me sa tsoelapele ho araba tlasa lenane la lijo la metsotso e 3 ea FI bakeng sa tlhahiso ea lijo bakeng sa lithuto tse 100 kaofelaN=6). Litšoene tse 11 tse setseng li ile tsa abeloa sehlopha sa boikoetliso ba koae (0.3 mg/kg ka ente). Hobane 0.3 mg/kg cocaine ka ente e ne e nkuoa e le tekanyetso e phahameng bakeng sa litšoene tse seng li ntse li le ka har'a koae, hobane liphoofolo tse ngata lethalinyana lena le ile la fumaneha ka nako ea likarolo tse peli ka ho lumella monkey hore e itaole ka makhetlo a mabeli. mg/kg cocaine. Ts'ebetso e bolokiloeng ke lijo e ile ea lumelloa ho tsitsa kamora ts'ebetso ea ho buoa (e ka bang matsatsi a 4-6) pele liboka tsa boikoetliso ba koae li qala. Pele ho karolo e 'ngoe le e' ngoe ea liteko, mokokotlo oa phoofolo o ile oa hloekisoa ka 95% ethanol le betadine scrub le 22 gege Huber Point needle (Model PG20-125) li ile tsa kenngoa koung e lebisang sebakeng sa venous catheter, se hokela pompo ea ho kenella e nang le tharollo ea koae ho catheter. Pele ho qala ha seboka, pompo e ne e sebelisitsoe nako e ka bang 3 s, ho tlatsa koung ka tekanyetso ea koae e neng e fumaneha nakong ea liteko. Likarolo li ile tsa fela kamora liente tse 30; ha e le tlasa maemo a taolo, litšoene li lutse ka kamoreng e lefifi nako e ka bang 30 mets. Qetellong ea karolo ka 'ngoe, boema-kepe bo ne bo tletse ka saline e tsoakiloeng (100) U/ml) ho thusa ho thibela ho hoama.

Lithupelo tsa liteko li ile tsa etsoa ka nako e ts'oanang letsatsi le leng le le leng 'me tsa tsoela pele ka kakaretso ea lithuto tse 100. Kamora ho phetheloa ha lisupa tse 100, ho ile ha hlahisoa nako ea ho itima lijo ka matsatsi a 30 kapa a 90 ka nako eo ka nako eo li-catheter li neng li sutumetsoa letsatsi le leng le le leng ka letsoai le ikhethileng, empa ho ne ho se na lithuto tsa koae kapa tsa tsamaiso ea lijo. Bakeng sa sehlopha sa taolo, linako tse 30 tsa ho itima lijo li ile tsa kenngoa liphoofolong tse 'ne le matsatsi a 90 ho tse ling tse peli. Bakeng sa sehlopha sa cocaine, linako tse 30 tsa ho itima lijo li ne li beoa liphoofolong tse robeli le matsatsi a 90 liphoofolong tse tharo. Qetellong ea nako ea ho ila ntho e le 'ngoe ea ho itaola (taolo ea lijo kapa koae) ho ile ha etsoa mme ts'ebetso ea 2-DG e ile ea qalisoa hang kamora thuto. Litsong tse peli tsa taolo le liphoofolo tse 'ne tse ipehang tsa koae ka sehlopha sa matsatsi a 30 sa ho itima lijo, ha ho cocaine e ileng ea fumanoa sehlopheng sa ho qetela. Liphoofolo li ile tsa bolaoa ka nama ka mokhoa o feteletseng oa pentobarbital (100 mg/kg, iv) qetellong ea 45 Nako ea ho ts'oara nako ea ho ts'oara.

Ho sebetsa ka lisele

Kamora ho bolaea, methapo ea kutlo e ile ea tlosoa hang-hang, ea koaloa, 'me ea hoamisoa ke isopentane ka −35 ho −55 ° C ebe e bolokoa ho −80 ° C. Litšiea tse nang le striatum li ne li khaoloa ka sekepeng ka −20 ° C ka sefofane sa "coronal" hore se fihle ho 20 μlikarolo, tse bokelletsoeng ka har'a li-slide tse khaotsoang ka motlakase, li kentsoe ka tlasa bosiu ho 4 ° C, ebe li bolokoa ka −80 ° C ho fihlela e sebetsoa bakeng sa autoradiography. Likarolo tsa methapo e ile ea bokelloa likarolong tsa "caudate nucleus" putamen le "nucleus" tse bokellaneng holima karolo ea bokantle ba kantle. Sebaka sena se bitsoa sekhahla sa prommissural striatum. Ho feta moo, litekanyetso tsa rostral le tsa caudal tsa striatum ea mantlha li ile tsa khethoa ho ipapisitsoe le li-nucleus accumbens. Rostral precommissural striatum ke sebaka seo boksi bo bokellanang bo sa khetholloang ho likhetla tse ikhethileng le li-subcompartments tsa mantlha. The caudal precommissural striatum ke tikoloho e kopaneng le ponahalo ea khetla le konokono ea li-nucleus accumbens, e ka morao ho ho hlaha ha tubercle ea olgicory. Bakeng sa thuto e 'ngoe le e' ngoe e tlamang, likarolo tse peli tse haufi li ile tsa nkuoa maemong ohle a mahlano (rostral le tse tharo tsa caudal) ka striatum ea mantlha bakeng sa likarolo tsohle tse 10 ka phoofolo e ngoe.

D1 Receptor Ho Kopanya

DA D1 receptor bindingensens densens e ile ea etsoa qeto ka [³H]SCH 23390 (tšebetso e khethehileng — 85 Ci/mmol; PerkinElmer, Boston, MA) ka bongata a vitro receptor autoradiography ho latela lits'ebetso tse fetotsoeng ho Mohlolohadi et al a (1991) 'me Nara et al a (2002). Likarolo li ne li entsoe ka 20 mets ho buffer (50 MM Tris, 120 Monghali NaCl, 5 Monghali KCl, 2 mC CaCl₂, 1 Monghali MgCl₂, pH 7.4, 25 ° C) ho tlosa mofuta oa DA oa khale, koae le [¹⁴C] ho tsoa ts'ebetsong ea 2-DG. Likarolo li ne li kengoe bakeng sa tse 30 min ho buffer e tšoanang, pH 7.4, 25 ° C, e nang le 1 mM ascorbic asiti, 40 nM ketanserin, le 1 nM [³H]SCH 23390. Kamora ho kenella, likarolo li ile tsa ts'oaroa habeli bakeng sa 20 s buffer 1 mM ascorbic acid ho pH 7.4, 4 ° C, ebe e kenngoa ka metsing a tlotsitsoeng ka 4 ° C, ebe e oma ka molatsoana oa moea o pholileng. Ho tlama ka mokhoa o sa hlonepheng ho hlalositsoe ke ho kenella ha likarolo tse haufi le tharollo ea ho incubation moo ho nang le 5 μM (+) -butaclamol. Likarolo, hammoho le likhakanyo [³H] litekanyetso tsa autoradiographic (Amersham, Piscataway, NJ), li ile tsa kenngoa filimi ea Kodak Biomax MR (Fisher Science science, Pittsburgh, PA) bakeng sa libeke tse 6.

D2 Receptor Ho Kopanya

Matšoenyeho le ho ajoa ha libaka tsa khokahano ea li-receptor tsa DA D2 li ile tsa beoa le [³H]raclopride (ketsahalo e ikhethileng, 87 Ci/mmol; PerkinElmer) ho latela lits'ebetso tse ikhethileng ho tloha Mohlolohadi et al a (1991) 'me Nara et al a (2002). Likarolo li ne li entsoe ka 20 mets ho buffer (50 MM Tris, 120 Monghali NaCl, 5 mM KCl, pH 7.4, 25 ° C) ho tlosa li-DA tsa semmuso, koae, le [¹⁴C] ho tsoa ts'ebetsong ea 2-DG. Li-slide li ile tsa kenngoa tse 30 min ho buffer e le 'ngoe, e nang le 5 mM ascorbic asiti le 2 nM [³H]lebala. Likarolo li ile tsa ts'oaroa 3 × 2 min ka buffer ho pH 7.4, 4 ° C, ebe e kenngoa ka metsing a tlotsitsoeng ka 4 ° C, mme e omisitsoe tlas'a molatsoana oa moea o pholileng. Ho tlamisa Nonspecific ho hlalositsoe ke ho kenella ha likarolo tse haufi le tharollo ea poloko boteng ba 1 μM (+-Butaclamol. Likarolo, hammoho le likhakanyo [³H] litekanyetso tsa autoradiographic, li ile tsa kenngoa filimi ea Kodak Biomax MR bakeng sa libeke tse 8.

Dopamine Transporter Ho kopanya

Matšoenyeho a libaka tse tlamang tsa DAT li ne li ikemiselitse ho sebelisoa [³H]WIN 35,428 (tšebetso e ikhethileng, 87 Ci/mmol; PerkinElmer) Autoradiography ho ea ka lits'ebetso tse fetotsoeng ho Canfield et al a (1990) 'me Letchworth et al a (2001). Likarolo tsa likarolo li ne li entsoe ka buffer (50 MM Tris, 100 mM NaCl, pH 7.4, 4 ° C) bakeng sa 20 min ho tlosa leha e le efe DA e setseng, cocaine, le [¹⁴C] ho tsoa ts'ebetsong ea 2-DG. Likarolo li ne li kengoe bakeng sa tse 2 h ho 4 ° C ho buffer e le 'ngoe e nang le 5 nM [³H]WIN 35 428. Likarolo li ile tsa hlakoloa ka kakaretso ea 2 min ka buffer ho 4 ° C, ebe e kenngoa ka metsing a halikiloeng ka 4 ° C, mme e omisitsoe tlasa moea o batang. Ho tlama ka mokhoa o sa hlonepheng ho hlalositsoe ke ho kenella ha likarolo tse haufi le tharollo ea ho kenella ka pele ho ba 30 μM koae. Likarolo, hammoho le likhakanyo [³H] litekanyetso tsa autoradiographic, li ile tsa kenngoa filimi ea Kodak Biomax MR bakeng sa libeke tse 6.

Densitometry le Tlhahlobo ea data

Lifilimi li ile tsa hlahisoa ka moqapi oa Kodak GBX, Stopaba le Rapid Fixer (VWR, West Chester, PA), 'me ea ntšoa. Ts'ebetso ea li-autoradiograms e entsoe ke densitometry ea bongata ka ts'ebetso ea ts'ebetso ea ts'ebetso ea likhomphutha (MCID, Imaging Research; InterFocus Imaging Ltd, Cambridge, UK). Melao ea letsoalo ea Optical e ile ea fetoloa hore e be fmol/mg (ea lithane tse boima ba metsi) ka ho supa calibrate [³H] litekanyetso. Ho tlama ka mokhoa o ikhethileng ho ile ha khethoa ke litšoantšo tse nkang litšoantšo ka mokhoa o hlakileng oa litšoantšo tse sa kopaneng tsa litšoantšo tse haufi tse kopantsoeng. Meetso e ile ea bonoa ke Nissl ho boloka likarolo tsa haufi le tseo ho hlahlojoang li-receptor binding. Lintlha tse tsoang mohopolong o mong le o mong li ile tsa hlahlojoa ka mokhoa o ikemetseng ka tlhahlobo e le 'ngoe ea phapang e lateloang ke liphapang tse fokolang post hoc liteko tsa ho bapisoa tse ngata. Sebaka ka seng se ne se e-na le tlhahlobo e fapaneng. Hobane data e tlamang e fumanoeng ho liphoofolo tse laoloang e sa sebetse matsatsi a 30 le 90 e ne e sa fapana haholo le e 'ngoe, e ts'oanang le lithuto tse fetileng (Nara et al a, 2002), data e tsoang ho lihlopha tsa taolo e ne e kopantsoe. Ntle le moo, ho ne ho se na phapang e kholo lipakeng tsa data e tsoang ho liphoofolo tseo tse amohetseng koae le tseo e neng e le sieo kopanong ea tsona ea hoqetela, ka hona lintlha tsa lihlopha tsena li ne li boetse li kopantsoe.

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LIPOTSO

Litlamorao tsa ho Thibela ho Tsamaea ho sa Ts'oaneng le Boitšoaro ba Cocaine bo sa Feleng ka matsatsi a 30

Likhakanyo tsa [³H]SCH 23390 e tlamang li-receptors tsa DA D1 ka har'a striatum ea semmuso e bontšoa ho Lethathamo 1. E tlamang e khethehileng ea [³H]SCH 23390 e tlaleha ho feta 90% ea tlama ka botlalo. E lumellana le litlaleho tse fetileng (Moore et al a, 1998a; Nara et al a, 2002), tlamo ea [³H]Li-receptor tsa SCH 23390 ho D1 liphoofolong tse laoloang ke lithethefatsi ntle le lithethefatsi li ne li le ngata ka phapang e kholo maemong a tlamahanong pakeng tsa litekanyetso tsa striatum. Labelling e ne e le morusu likarolong tse ngata tsa bophelo le tsa bongaka ho pholletsa le striatum.

Kamora matsatsi a 30 a ho khaotsa ho pepesetsoa koae, ho tlama li-receptor tsa D1 ho ile ha tšoauoa ka maemo a phahameng hohle ka nqa eohle ea rostral-caudal ea stommatum ea pele, ha e bapisoa le masene a tlama liphoofolo tse laoloang tse senang litlhare (Lethathamo 1; Setšoantšo sa 1). Ho rostral striatum, ho tsepamisa mohopolo ho ne ho phahame haholo mokokotlong oa caudate ho kenyelletsa dorsolateral (+27%), bohareng (+27%, dorsomedial (+27%), le ventromedial (+23%) likarolo, hammoho le ka har'a dorsal (+17%), bohareng (+22%), le ventral (+23%) likarolo tsa putamen, ha li bapisoa le letsoalo liphoofolong tse sa laoloeng ke lithethefatsi. Lintho tse phahameng tsa bohlokoa li ne li boetse li bonahala ho li-nucleus accumbens (+23%) boemong bona. Boemong ba striatum moo konokono le khetla ea li-nucleus li bokellanang haholo, methapo ea li-receptor tsa D1-e ne e phahame haholo ho feta dorsolateral (+31%), bohareng (+29%, dorsomedial (+30%), le ventromedial (+18%) motsoako oa caudate, hammoho le dorsal (+23%), bohareng (+29%), le ventral (+28%) putamen, bapisoa le mathata a taolo e senotsoeng lithethefatsi. Ka har'a striatum ea boemo bona bo maemong ana, khatello ea D₁ libaka tsa "receptor" tse tlamang li ne li phahame moholong oa "nucleus accumbens" (+45%) le shell (+20%), hammoho le ka tubercle ea olodoory (+26%), bapisoa le bongata ba taolo.

Likhakanyo tsa [³H]raclopride e tlamang li-receptor tsa DA D2 ka har'a striatum ea mantlha e bontšitsoe ho Lethathamo 2. E tlamang e khethehileng le [³H]lebala le leholo le fetang 90% ea tlama ka botlalo. Kabo ea [³H]raclopride e tlamang li-receptor tsa D2 e ​​ne e boetse e le ntho e majabajaba litulong tse tlase tsa dorsal le ventral striatum joalo ka litlalehong tse fetileng (Moore et al a, 1998b; Nara et al a, 2002). Ka har'a taolo e senang lithethefatsi ntle le lithethefatsi, lits'ebetso tse phahameng tsa libaka tse tlamang tsa D2 li ne li le teng ka har'a dorsal ha li bapisoa le ventral striatum. Ntle le moo, ho ne ho e-na le bopaki ba hore ho na le maikutlo a morusu ho tse ling tse lumellanang le libaka tse tlamang tse neng li le teng likarolong tse ling tsa striatum.

Kamora matsatsi a 30 a ho khaotsa ho tsuba, litekanyetso tsa D2 receptor e tlamang ho liphoofolo tse pepesitsoeng koae le tse matlafatsoang ke lijo li ne li sa fapana haholo ho tsoa libakeng tse ngata tsa striatum. Likarolo tse phahameng tsa libaka tse tlamang li ile tsa bonoa ho "ventral putamen"+10%) le anterior nucleus+12%) ka linama tse tsoang ho litšoene tse pepesitsoeng koae ha li bapisoa le taolo. Ha ho phapang e 'ngoe e hlokomelehang.

Likhakanyo tsa [³H]WIN 35428 e tlamang ho isa ho DAT maemong a mantlha a bontšitsoeng ho Lethathamo 3. E lumellana le litlaleho tse fetileng (Letchworth et al a, 2001), ho tlamahanya le libaka tsa DAT ho liphoofolo tse sa senngoeng lithethefatsi ho ne ho phahame haholo dorsal ha ho bapisoa le ventral striatum. Ka har'a li-bokellit tsa nucleus, methapo e phahameng e ne e bonoa kahare ha e bapisoa le karohano ea likhetla. Qetellong, ho se kopane ho ikhethileng ho ikarabelletse ka tlase ho 10% ea kakaretso.

Kamora matsatsi a 30 a ho khaotsa ho pepesetsoa k'hok'heine, ho tlama ho ea ho DAT ho ne ho phahame haholo ho pholletsa le libaka tse ngata tsa striatum rostral ho ea moketeng oa ka ntle ha ho bapisoa le ho tlama liphoofolo tse laoloang tse senang lithethefatsi (Setšoantšo sa 1). Ka ho khetheha, likhatiso tsa libaka tse tlamang tsa DAT maemong a rostral li ne li phahame haholo bohareng.+22%, dorsomedial (+25%), le ventromedial (+28%) motsoako oa caudate le ka har'a dorsal (+16%) le bohareng (+23%) putamen, ha e bapisoa le taolo e matlafatsang ea lijo. Ntle le moo, ho ne ho boetse ho na le tlamo e phahameng haholo ho DAT ho anterior nucleus accumbens (+37%) cocaine- ha e bapisoa le litšoene tse matlafatsang lijo. Kahare ho likarolo tse ling tsa bohlophisi ba semmuso, li-density tsa libaka tsa binding tsa DAT li ne li phahame haholo ka har'a "caudate nucleus" e bohareng.+21%), le putamen, bohareng (+20%) le ventral (+19%; Setšoantšo sa 1). Ka har'a "ventral striatum" ena e neng e le maemong ana, "binding" e ne e phahame haholo mokokotlong oa "nucleus accumbens" (+20%) le tuber Fun+24%) Lisele tse tsoang ho koae- vs litšoene tse matlafatsang lijo.

Litlamorao tsa ho Thibela ho Tsamaea ho sa Ts'oaneng le Boitšoaro ba Cocaine bo sa Feleng ka matsatsi a 90

Ho fapana le phapang e atileng haholo boteng ba libaka tse kopanyang li-D1 receptor tse bonoang liphoofolong tse pepesitsoeng ke koae ka mor'a matsatsi a 30 a ho tsuba, kamora matsatsi a 90 a ho tlohela, ho ne ho se na phapang e kholo ha ho bapisoa le taolo e matlafatsoang ke lijo karolong efe kapa efe ea 'mele e tloaelehileng. striatum (Lethathamo 1; Setšoantšo sa 1). Ka mokhoa o ts'oanang, likhakanyo tsa [³H]morabe o kopanang le li-receptor tsa DA D2 maemong a tloaelehileng kamora matsatsi a 90 a ho khaotsa, le tsona li ne li sa fapana haholo le tsa liphoofolo tse senotsoeng ke lithethefatsi (Lethathamo 2).

Likhakanyo tsa [³H]WIN 35428 e tlamang ho DAT e bonts'itse mokhoa o ts'oanang le o boneng ka D1 le D2 receptors. Ho ne ho se na phapang e kholo litekanyetsong tsa DAT lipakeng tsa litšoene tse pepesitsoeng ke koae ka mor'a matsatsi a 90 a ho khaotsa ho bapisoa le maemo maemong a taolo e senotsoeng ke lithethefatsi (Lethathamo 3; Setšoantšo sa 1), leha ho lokela ho hlokomeloa hore ho ne ho e-na le mokhoa o lebisang lipakeng tse phahameng tsa ho tlama ka har'a li-nucleus tsa anterior.

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TŠOHLOA

Boithuto ba pejana bo tsoang sehlopheng sa rona bo bonts'itse hore ho pepeseha ho itaola ka mokhoa o sa ts'oaneng ho tsamaisana le taolo e kholo ea sistimi ea DA ea li-primates tse seng tsa motho (Letchworth et al a, 2001; Moore et al a, 1998a, 1998b; Nara et al a, 2002, 2006). Liphetho tsa boithuto ba hona joale li bonts'a hore khatello ena e lula e bonahala kamora ho hlakoloa ha koae. Kamora matsatsi a 30 a ho khaotsa ho tsuba, likhakanyo tsa li-receptors tsa DA D1 le DAT li ile tsa phahamisoa haholo ho pholletsa le litšoene tse nang le nalane ea boits'oaro bo matla ba koae ha bo bapisoa le taolo e matlafatsang ea lijo. Leha ho le joalo, thuto ea hona joale e boetse e fana ka bopaki bo hlakileng ba ho hlaphoheloa kahare ho sistimi ea DA kamora nako e telele ea ho itima lijo (matsatsi a 90), joalo ka ha ho bonahetse ho hloka phapang e kholo lipakeng tsa liphoofolo tse senotsoeng ke koae le koae ka nako ena. Lintlha tsena li fana ka maikutlo a hore ho pepesetsoa ha koae ho ka se hlahise liphetoho tse sa feleng tsamaisong ea DA, empa pholoso e ka hlaha ka ho tlohela nako e telele tšebeliso ea lithethefatsi.

Ts'isinyeho ea lintho tse tsepamisitsoeng ho DAT tse bonts'itsoeng mona ka mora ts'ebeliso e lumellana le litlaleho tsa nakong e fetileng litlalehong tse seng tsa botho (Letchworth et al a, 2001), e bonts'eng liphahamiso tse kholo mathateng a libaka tse tlamang tsa DAT libakeng ka bobeli le ka har'a dorsal striatum. Le ha e sa lekoa ka kotloloho, ho bonahala eka kamora ho pepesetsoa hoa lithethefatsi litheko tse phahameng tsa setsi sa marang-rang se kopanyang bonyane li leholo haholo ebile li atile haholo libakeng tsohle tsa striatum ho feta tse tlalehiloeng ntle le nako ea ho tlohela.Letchworth et al a, 2001). Ka mokhoa o ts'oanang, likhakanyo tse phahameng tsa libaka tse tlamang tsa D1 receptor tse bonoang mona kamora matsatsi a 30 a ho khaotsa ho ts'oaroa hape li lumellana le lithuto tse fetileng tse bonts'itseng li-densens tse tlatselletsang tse tšoanang le D1 receptor maemong a tšoanang le a motho a sa bonahaleng a fumanehang ka mokhoa o tšoanang oa tsamaiso ea koae.Nara et al a, 2002). Ho fapana le hoo ho ne ho se na phapang e kholo e bonts'itsoeng lipakeng tsa methapo ea methapo e kang D2-receptor e kopanyang methapo ea liphoofolo tse pepesitsoeng le koae. Ho hloka taolo hona ho ne ho le teng, leha ho fokotsehile haholo litekanyetsong tsa li-receptor tsa D2 tse tlalehiloeng litlalehong tsa batho ka bobeli (Volkow et al a, 1993) le mefuta ea liphoofolo ea ho itlhokofatsa ka koae (Moore et al a, 1998a, 1998b; Nara et al a, 2002, 2006). Lintlha tse teng hona joale li fana ka maikutlo a hore maemo a potlakile ho laola maemo tsamaisong ena ha a bapisoa le li-receptor tse kang D1 le DAT. Ha ho kopantsoe hammoho, liphetoho tse fumanoang ho li-receptor tsa DA le DAT li bontša ka ho hlaka hore nako e latelang ho felisoa ha ts'ebetso ea koae e sebetsa haholo ka liphetoho tse ngata taolong ea tšebetso ea DA e etsahalang, empa hore sena se lateloa ke tokiso ea tsamaiso ea sistimi e atamelang phepelo e tloaelehileng ho feta ea li-receptor tsa DA le DAT kamora ho khaotsa nako e telele.

D1 Receptor Liphetoho

Phahamiso e pharalletseng boteng ba li-receptor tsa D1 tse bonoang mona kamora ho khaotsa ts'ebeliso ea koae e lumellana le litlaleho tse bonts'ang maikutlo a eketsehang a li-receptor tsa D1 nakong ea ho tlohela. Tekanyo ea maikutlo a D1 e entsoe thutong ke Henry le White (1991), moo rekoto e le 'ngoe ea li-neurons tse bokellaneng ea li-nucleus e fumanoeng e ameha haholo ho D1 receptor agonist SKF 38393 ka mor'a ho enta cocaine ea letsatsi le letsatsi ea cocaine ha e bapisoa le taolo e entsoeng ke saline. Tšusumetso ena e ne e phehella, ka hore kutloelo-bohloko e ntseng e eketseha e ile ea lula e bonahala ho fihlela khoeli e le ngoe ho tlohela. Bangoli ba ile ba tiisa hore tlhokomeliso ea D1 receptor e ne e le ka lebaka la subsensitivity ea D2 autoreceptor sebakeng sa somatodendritic A10, ka tsela eo, e fokotsa phallo ea tšusumetso ho ts'ebetso eohle ea sesebelisoa sa DA (Henry le White, 1991). Lintlha tse tsoang thutong ea hona joale li fana ka maikutlo a hore libaka tse tlamang tsa D1 receptor li tebile, tse ka hlalosang kutloisiso ena e eketsehang ea methapo ea methapo ho dopaminergic neuron ho ea sebetsang ka kotloloho ea D1 receptor agonist. Ntle le moo, phello e ntlafalitsoeng ea SKF 38393 ka li-neuron tsa nucleus e ne e sa bonahale likhoeli tse peli kamora ho khaotsa, ho fana ka maikutlo a hore ho na le pholoso ea sensitivity ea D1Henry le White, 1991); sephetho se tsamaellanang le ho hlaphoheloa ha methapo ea methapo ea D1 tse boletsoeng thupelong ea morao tjena kamora matsatsi a 90 a ho khaotsa ho tsuba. Litlaleho tse ling li boetse li tšehetsa karolo ea bohlokoa bakeng sa li-receptor tsa D1 ho khutla hape. Ho hlohlelletsa ka kotlolloho li-receptor tsa D1 ka khetla ea li-nucleus bokone ho ka khutlisa ho batla koae ka litoeba tse thibelang (Schmidt et al a, 2006). Leha ho le joalo, lingoliloeng li batla li sa lumellane hobane litumelo le bohanyetsi ba D1 ka bobeli li ka bonts'a lithethefatsi tse tsosang takatso ea maikutlo a koae kapa tšusumetso e amanang le cocaine (Tlotlisang et al a, 2002; DeVries et al a, 1999; Khroyan et al a, 2000; Self et al a, 1996; Weiss et al a, 2001). Morao tjena, Khroyan et al a (2003) e tlaleha hore lingaka tsa lefutso tsa D1 le bahanyetsi li fokotsa ho khutlisetsoa ka mokhoa o sa tloaelehang oa batho ba batlang koae. Bangoli bana ba khothalelitse hore ho ka ba le mefuta e fapaneng ea ts'ebetso ea D1 receptor e hlokahalang bakeng sa ho batla koae, le hore bahanyetsi ka bobeli le bo-agonist ba ka tlosa ts'ebetso ka fensetere ena. Khatello e eketsehileng ea li-receptor tsa D1 tse tsamaeang le ho ila li ka fetola bongata bona, ea baka phetoho ho kutlo ea tsamaiso ena. Taba e 'ngoe ke hore ts'ebetso ea D1 e ka sebetsa ho fetola tšebetso ho li-receptor tsa D2 (Nolan et al a, 2007; Ruskin et al a, 1999; Walters et al a, 1987). Lintlha tse teng hona joale li fana ka maikutlo a hore karolelano ea li-receptor tsa D1 ho D2 e ​​fetoha nakong ea thibelo mme ka hona e ka fetola ho sebetsa ha moelelo ona.

Le ha ho le joalo, ho fapana le tlhaiso-leseling e teng hona joale, ho bile le litlaleho tsa litekanyetso tse fokotsehileng tsa li-receptor tsa D1 kamora ho itaola ho sa feleng ha k'hok'heine (Moore et al a, 1998a), ho na le phapano e kholo lipakeng tsa lithuto tsena, joalo ka tekanyetso le bolelele ba ho pepesetsoa koae, ho ja ka botlalo, le lihlopha tsa taolo. Kahoo, ha ho kopanngoa, bopaki bo bo kopanyang bo bonts'a ka mokhoa o hlakileng hore sisteme ea D1 e ntse e eketseha haholo kamora ho ikarola ho tsamaiso e sa foleng ea koae.

Dopamine Transporter Liphetoho

Liphumano tsa lipalo tse phahameng tsa DAT ho theosa le liphoofolo tse senotsoeng ke koae ka mor'a ho tlohela ts'ebeliso ea lithethefatsi li atolosa lithuto tsa rona tse fetileng tse bonts'ang litekanyetso tse eketsehang tsa libaka tsa ho ikatisa tsa DAT tse tsamaeang le boits'oaro ba koae maemong a seng a motho. Lintlha tse teng hona joale li bonts'a hore khatello ena e phehella nakong ea mokhahlelo oa pele oa ho ila. Ho feta moo, ba fana ka maikutlo a hore ho hlaphoheloa maemong a taolo ho latela nako e telele (ho fihlela matsatsi a 90 thupelong ena). Lithutong tsa rona tsa pejana re bonts'itse hore le hoja qalong e ne e le lithibelo ho libaka tse nang le moea o kenang ka hare ho naha feela, liphetoho matsatsing a tlamahano ea libaka tse kopantsoeng tsa DAT li atolositsoe ho kenyelletsa likarolo tse ling tsa dorsal le rostral tsa striatum tse nang le nako e telele ea ho pepesetsoa cocaine (Letchworth et al a, 2001; Porrino et al a, 2004). Phuputsong ea hona joale ho khutlela maemong a taolo ea ho tsepamisoa hoa DAT ka nako ea ho itima lijo ho ile ha bonahala e le kholo ebile ho potlakile haholo ho dorsal striatum ho feta ka har'a ventral striatum, 'me ka hona ho ne ho bonahala eka ho latela mokhoa o sa reroang oa morao-rao oa mokhoa oa litlamorao tse hlahisoang ke ho pepesoa ke koae e sa foleng. .

Lintlha tsa hona joale li tsamaisana le litlaleho ho basebelisi ba koae ea batho (Little et al a, 1999; Malison et al a, 1998; Mash et al a, 2002; Staley et al a, 1994) tse bonts'itseng maemo a phahameng a ho tlama ho libaka tsa DAT ho striatum ha li bapisoa le li-control, ka lipalo tse nang le matšoao a mangata a fumanehang ka har'a ventral striatum. Haufinyane, maemo ana a phahameng a bonts'itsoe a tsamaisana le ho fokotseha ho hoholo ha vesicular monoamine transporter 2 (VMAT2) binding (Little et al a, 2003), e khothalletsang tahlehelo ea 'nete ea li-neuron tsa DA. Bangoli ba phethile ka hore letsatsi le phahamisitsoeng la DAT le kanna la hlaha ka kotloloho ka lebaka la karabelo e tlatselletsang ho motsoako oa litlatse ka koae, athe ho fokotseha ha VMAT2 ho ka etsahala ho bonts'itse liphetoho tse akaretsang tsa metabolism ea DA, ho fella ka ts'ebetso ea hypodopaminergic.

Batho ba lemaletseng koae ba batho ba 'nile ba tlalehoa hore ba fokotse ho tsepamisa maikutlo ha DA kahare ho litekanyetso, joalo ka PET, ho arabela phephetso ea methylphenidate ha e bapisoa le taolo e phetseng hantle (Volkow et al a, 1997). Morao tjena, Martinez et al a (2007) e tlaleha hore basebelisi ba koae ba ile ba arabela ka mokhoa o sa tobang phephetsong ea amphetamine ka har'a ventral striatum le putamen. Ntle le moo, ho fokotseha hona ha tlhahiso ea DA e hlahisitsoeng ke amphetamine ho ile ha lumellana le khetho ea koae ka linako tse fapaneng tsa tsamaiso, hoo basebelisi ba nang le tekanyo e tlase haholo ea ho lokolloa ha DA ka karabelo ho amphetamine ba neng ba ka khona ho khetha koae ka lebaka la mofuta o mong o matlafatsang (Martinez et al a, 2007). Boithuto ba morao-rao ba mefuta ea litoeba tsa koae bo ts'ehetsa mohopolo ona. Mateo et al a (2005), mohlala, ho tlaleha hore ho pepesehela boits'ebetso bo sa tsitsang ba koae ho amana le liphetoho lipakeng tsa tšebetso ea DAT. Bafuputsi bana ba bonts'itse hore ho nka litheko tsa mantlha tsa DA ho ile ha eketsoa, ​​'me ha fella ka ho pepeseha ha synaptic DA,' me ka hona, ea theoha litekanyetso tsa basel tsa extracellular DA, kapa naha ea hypodopaminergic. Kahoo, ho ka etsahala hore likhatiso tse eketsehang tsa DAT tse latelang ho khaotsa ho itaola ho sa feleng ha cocaine tse bonoang thutong ea hona joale li bonts'a karabelo, e lebisang maemong a tlase a DA a kantle ho naha.

D2 Receptor Liphetoho

Sephetho se seng ho tsoa thutong ea morao-rao ke hore litekanyetso tsa li-receptor tsa D2 li ne li khutletse taolong litekanyetso tse latelang matsatsi a 30 a ho ts'oaroa, ha ho bapisoa le phokotseho e kholo e bonoang liphoofolong tse se nang nako ea ho tlohela (Nara et al a, 2002). Ho fapana le lipatlisiso tsa hona joale, lithuto tsa batho tse nahanang ka kakaretso li fumane hore litekanyetso tsa D2 receptor li tlase ho feta tsa taolo kamora ho khaotsa nako e telele ho pepeseng koae (cocaine) e sa feleng.Martinez et al a, 2004; Volkow et al a, 1993). Litlhaloso tse ka bang tsa phapano lipakeng tsa lithuto tsena tsa batho le lipatlisiso tsa hona joale tse seng tsa botho li kenyelletsa phapang ea sebopeho le nako ea ho ja koae, hammoho le monyetla oa ho fumana maemo a tlase a li-receptor tsa D2 ho batho ba lemaletseng batho.

Tumellanong le mohopolo oa morao-rao, ho na le bopaki ba ho fana ka maikutlo a hore maemo a tlase a li-receptor tsa D2 ho batho ba phetseng hantle a bolela esale pele ts'ebetso e matlafatsang ea litlatsetso tse kang methylphenidate (Volkow et al a, 1999), mme joalo ka litšoene, maemo a mantlha a li-receptor tsa D2 a boletse esale pele botebo ba ho tsamaisa koae (Morgan et al a, 2002; Nara et al a, 2006). Ho tsamaisana le sebopeho se tšoanang sa lintho tsena tse fumanoeng ka mefuta eohle ea batho, (Volkow et al a, 1993) le maemo a seng a bothoNara et al a, 2006) lithuto tsa ho nahana li bonts'itse maemo a tlase a ho fumaneha ha D2 receptor kamora ho itlhahisa ho pepesoa koae. Haholo-holo, kemiso ea ho itlhokofatsa ka koae tekong ea morao-rao (Nara et al a, 2006) e ne e tšoana le kemiso ea matlafatso e sebelisitsoeng thutong ena. Kahoo, litlamorao tse sa lumellaneng tse tsoang lipatlisisong tsena tse peli ha li na monyetla oa ho ba teng ka lebaka la phapang ea mekhoa, joalo ka kemiso ea ho matlafatsoa kapa ho kenella ka bongata nakong ea boikoetliso ba koae.

Tlhaloso e ka bang teng e kenyelletsa tšebetso ea tšebetso ea DA. Mehato ea ho fumaneha ha li-D2 receptor le PET e 'nile ea hlalosoa e le' e sebetsang 'hobane lets'oao le amana le palo ea protheine (boemong bona densities tsa D2 receptors) le maemo a methapo ea methapo ea methapo (bona Laruelle, 2000; Nader le Czoty, 2008 bakeng sa lipuisano tse ling). Ika lehlakoreng le leng, receptor autoradiography ha e silafatsoe ke maemo a potoloha ho DA. Kahoo, thuto ea hona joale, hammoho le mosebetsi oa rona oa pejana, li fana ka maikutlo a hore litekanyetso tsa D2 receptor li fokotsehile ka ho itaola, empa litekanyetso tsa li-receptor li bonahala li ntlafala nakong ea ts'ebeliso. Phuputsong e entsoeng ka mokhoa o tšoanang oa PET (Nara et al a, 2006), ho hlaphoheloa ho ile ha hlokomeloa ho litšoene tse tharo ho tse hlano. Liphumano tse teng hona joale li bonts'a hore litšoene tsena li kanna tsa fapana maemong a D2 receptor density, empa mohlomong karabelo ea sistimi ea DA (ke hore maemo a ho potoloha ha DA nakong ea thibelo) a arohantsoeng lipakeng tsa lithuto tsa 'pholoso' le 'tse sa sibolloang.'

sheba mefokolo ea

Tekanyetso e 'ngoe ea bohlokoa ea lithuto tsa hona joale ke hore lithuto tsa rona li ke ke tsa sebetsana le ts'ebetso ea li-receptor tsa D1 le D2 kapa tsa DAT. Ho fapana le moo re ile ra hlahloba feela liphetoho tse boteng ba liprotheine tsa receptor. Leha liphetho li na le moelelo bakeng sa karolo e ka bang teng ea litsamaiso tsena, lithuto tse ling li tla hlokahala ho fana ka leseli mabapi le litlamorao tsa boits'oaro ba liphetoho tse bontšitsoeng mona. Ntho e 'ngoe e sitisang boithuto ba hona joale ke hore hangata li-autoradiographic ligands li sitoa ho khetholla libaka tsa lipheo tsa bona, ka ha bahanyetsi ba radiolabeled hangata ba khonahala. Little et al a (2002) e bontšitse hore ho pepesehela cocaine e sa foleng ho lebisa ho ho eketseha ho hoholo ha DAT sebakeng sa membrane, ka nako e tšoanang le ho fokotseha ha sehokelo sa intracellular ea DAT, liseleng tse fetotsoeng. Haufinyane, Samuvel et al a (2008) ho tlaleha phumano e ts'oanang litokisetsong tsa rat striatal synaptosomal. Liphetho tsena li fana ka maikutlo a hore liphetoho tse ho ajoang ka mokhoa oa DAT tse hlokometsoeng thupelong ea hona joale li ka emela liphetoho sebakeng sa membrane, ho fapana le libaka tse ikhethileng.

Kamora nako, ho tlameha ho fanoe ka tlhokomeliso e mabapi le ho toloka lithuto tsa ho se sebetse ka nako e telele (matsatsi a 90), kaha liphumano tsena li thehiloe ho sehlopha se fokolang sa liphoofolo (N=3). Leha ho na le palo e nyane ea lithuto, lintlha tse fumanoeng sehlopheng sena li ne li sa feto-fetohe, joalo ka ha ho bonoa ka leano la hasanya le bonts'itsoeng Setšoantšo sa 2. Khatello ea libaka tse tlamang tsa D1 receptor kahar'a striatum li bontšitse phapang e nyane ka har'a lihlopha, ho fana ka maikutlo a ho ts'epahala ha liphetho tsena. Ho ts'oana ho ts'oanang ho ile ha bonahala le datha ho tsoa ho D2 receptor le li-assays tse tlamang tsa DAT. Le ha ho lokela ho sebelisoe tlhokomeliso, lintlha tsena li khothaletsa ka matla hore ho khutlisetsoa ha li-DAT le li-receptor tsa DA kahare ho striatum ho ka etsahala ka ho khaotsa nako e telele.

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CONCLUSIONS

Qetellong, ho pepeseha ho itaola ea koae ho hlahisitse liphetoho tse kholo taolong ea litsamaiso tsa DA tse ileng tsa tsoela pele nakong ea mekhahlelo ea pele (matsatsi a 30 a pele) a ho tlohela. Sena se ne se bonahala haholo taolong ea khatello ea li-receptor tsa D1 le DAT, ka bobeli ho latela boholo ba liphetoho tsa tsona le boholo ba tsona. Ho fapana le hoo, ho ne ho na le bopaki ba hore bo ne bo tloaelehile bo bile le nako e telele ea ho khaotsa ho pepesetsoa koae, ka hore litekanyetso tsa DAT, D1, le li-D2 tse amohelang kamora matsatsi a 90 tsa ho khaotsa li ne li sa fapana le tsa taolo e senotsoeng lithethefatsi. Tmekhoa ea hese, leha ho le joalo, ha e hlile e latela tsela e tšoanang ea nakoana ea ho hlaphoheloa, ho fana ka maikutlo a hore ho na le monyetla oa hore ho ka ba le tsitsipano molaong oa maemo a DA haholo pele ho ts'ebeletso.. Tekanyetso ena ea dopaminergic e ka ama katleho ea ts'ebetso efe kapa efe ea meriana e ka sebelisoang ho litlhare tse lemalloang ke koae, haholo-holo haeba meriana e itšetleha ka sistimi ea DA bakeng sa ts'ebetso ea eona.

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Notes

QETHA/TŠEBELETSO EA BATHO

Bangoli ha ba na likhohlano tsa thahasello ea ho li senola.

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References

1. Alleweireldt AT, Weber SM, Kirschner KF, Bullock BL, Neisewander JL (2002). Ho thibela kapa ho hlohlelletsoa ha D1 dopamine receptors ho tiisa ho khutlisetsoa ha boitšoaro bo tsubang ba ho batla koae ka likhoto. Psychopharmacology (Berl) 159: 284–293. | Sehlooho se | E fetotsoe | ChemPort |
2. Beveridge TJ, Smith HR, Daunais JB, Nader MA, Porrino LJ (2006). Boitšoaro bo sa feleng ba koae bo amahanngoa le ts'ebetso e fetotsoeng mesebetsing ea nakoana ea mekhatlo ea nakoana ea batho. Eur J Neurosci 23: 3109–3118. | Sehlooho se | E fetotsoe |
3. Canfield DR, Spealman RD, Kaufman MJ, Madras BK (1990). Autoradiographic lehae la libaka tse tlamang koae ka koae ke [3H] CFT ([3H] WIN 35428) bokong ba monkey. Synapse 6: 189–195. | Sehlooho se | E fetotsoe | ChemPort |
4. De Vries TJ, Schoffelmeer AN, Binnekade R, Vanderschuren LJ (1999). Mechine ea Dopaminergic e tsamaisang tšusumetso ea ho batla koae le heroin kamora ho tlosoa ha nako e telele hoa taolo ea lithethefatsi tsa IV. Psychopharmacology (Berl) 143: 254–260. | Sehlooho se | E fetotsoe | ChemPort |
5. Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD (1992). Liphello tsa liente tse pheta-phetoang tsa koae libakeng tse tlamang tsa catecholamine receptor, libaka tsa tlama tsa dopamine transporter le boitšoaro ho monkey ea rhesus. Resin ea Boko 578: 235–243. | Sehlooho se | E fetotsoe | ChemPort |
6. Graham J, Porrino LJ (1995). Likarolo tsa Neuroanatomical tsa Cocaine Boitšoaro. CRC: Boca Raton, FL.
7. Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997). Phapang lipapaling tsa dopamine tsa extracellular dopamine ka har'a li-nucleus tse bokellanang nakong ea tsamaiso e itšetlehileng ka karabo ea k'hok'heine le karabelo e ikemetseng ho rat. Psychopharmacology (Berl) 133: 7–16. | Sehlooho se | E fetotsoe | ChemPort |
8. Henry DJ, White FJ (1991). Ts'ebetso e phetoang ea koae e baka ntlafatso e tsoelang pele ea sensitivity ea D1 dopamine receptor kahare ho li-nucleus tsa rubus. J Pharmacol Exp Ther 258: 882–890. | E fetotsoe | ChemPort |
9. Jacobsen LK, Staley JK, Malison RT, Zoghbi SS, Seibyl JP, Kosten TR et al a (2000). Phahamisoa ka sekepeng sa transotter e tlamang ho fumaneha hoa bakuli ba ts'ehetsang k'hok'heine. Am J Psychiatry 157: 1134–1140. | Sehlooho se | E fetotsoe | ISI | ChemPort |
10. Khroyan TV, Barrett-Larimore RL, Rowlett JK, Spealman RD (2000). Dopamine D1- le D2-like receptor mochine o khutlisetsa boits'oaro bo batlang cocaine: litlamorao tsa bahanyetsi ba ikhethileng le agonists. J Pharmacol Exp Ther 294: 680–687. | E fetotsoe | ISI | ChemPort |
11. Khroyan TV, Platt DM, Rowlett JK, Spealman RD (2003). Boikemisetso ba ho khutlela bothateng ba ho tsuba koae ke ba dopamine D1 receptor agonists le bahanyetsi lithutong tse seng tsa batho. Psychopharmacology (Berl) 168: 124–131. | Sehlooho se | E fetotsoe | ChemPort |
12. Laruelle M (2000). Ho etsisa li-neurotransication tsa synchingic le Ka vivo mekhoa e tlamang ea tlholisano: tlhahlobo e mahlonoko. J Cereb flow flow Metab 20: 423–451. | Sehlooho se | E fetotsoe | ISI | ChemPort |
13. Letchworth SR, Nader MA, Smith HR, Friedman DP, Porrino LJ (2001). Ts'ebetso ea liphetoho lipakeng tsa dopamine transporter e tlamang letsoalo ka lebaka la ho itaola ha koae ho litšoene tsa rhesus. J Neurosci 21: 2799–2807. | E fetotsoe | ISI | ChemPort |
14. Lidow MS, Goldman-Rakic ​​PS, Gallager DW, Rakic ​​P (1991). Tsamaiso ea li-receptor tsa dopaminergic ho cortex ea khale ea likhalase: tlhahlobo ea maikutlo ea autoradiographic e sebelisang [3H] raclopride, [3H] spiperone le [3H] SCH 23390. Khopolo-taba 40: 657–671. | Sehlooho se | E fetotsoe | ChemPort |
15. Little KY, Elmer LW, Zhong H, Scheys JO, Zhang L (2002). Cocaine induction ea ts'ebetso ea dopamine transporter ho fetisa membrane ea plasma. Mol Pharmacol 61: 436–445. | Sehlooho se | E fetotsoe | ISI | ChemPort |
16. Little KY, Krolewski DM, Zhang L, Cassin BJ (2003). Ho felloa ke protheine ea "striatal vesicular monoamine transporter" (VMAT2) ho basebelisi ba koae. Am J Psychiatry 160: 47–55. | Sehlooho se | E fetotsoe |
17. Little KY, Zhang L, Desmond T, Frey KA, Dalack GW, Cassin BJ (1999). Litšitiso tsa Striatal dopaminergic ho basebelisi ba koae ea batho. Am J Psychiatry 156: 238–245. | E fetotsoe | ChemPort |
18. Malison RT, Best SE, van Dyck CH, McCance EF, Wallace EA, Laruelle M et al a (1998). Barekisi ba dopamine ba phahamisitsoeng ba dopamine nakong ea ho ithibela koae ka mokhoa o matla joalo ka ha e lekantsoe ke [123I] beta-CIT SPECT. Am J Psychiatry 155: 832–834. | E fetotsoe | ChemPort |
19. Martinez D, Broft A, Foltin RW, Slifstein M, Hwang DR, Huang Y et al a (2004). Ho itšetleha ka cocoaine le ho fumaneha ha d2 receptor likarolong tse sebetsang tsa striatum: kamano le boits'oaro bo batlang cocaine. Neuropsychopharmacology 29: 1190–1202. | Sehlooho se | E fetotsoe | ISI | ChemPort |
20. Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang DR, Broft A et al a (2007). Khokahano ea dopamine ea Amphetamine: e fositse haholo ho ts'etsong ea koae le ho nahana esale pele ka khetho ea ho ikhalemela koae. Am J Psychiatry 164: 622–629. | Sehlooho se | E fetotsoe | ISI |
21. Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S (2002). Ts'ebetso ea ho tsamaisa Dopamine e phahame ho basebelisi ba koae. J Neurochem 81: 292–300. | Sehlooho se | E fetotsoe | ChemPort |
22. Mateo Y, Cack ea CM, Morgan D, Roberts DC, Jones SR (2005). Fokotsa tšebetso ea dopamine, le ho se tsotelle ho koahelang k'hok'heine ka mor'a ho itlhokofatsa ka koae. Neuropsychopharmacology 30: 1455–1463. | Sehlooho se | E fetotsoe | ISI | ChemPort |
23. Melega WP, Jorgensen MJ, Lacan G, Tsela ea BM, Pham J, Morton G et al a (2008). Tsamaiso ea methamphetamine ea nako e telele lithutong tsa litšoelesa tsa vervet likarolo tsa phumaneho ea motho: neurotooticity ea bongoana le boits'oaro bo botle ba boitšoaro. Neuropsychopharmacology 33: 1441–1452. | Sehlooho se | E fetotsoe | ChemPort |
24. Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998a). Kameho ea ho itaola ka koae ho li-striatal dopamine Deptors ho litšoelesa tsa rhesus. Synapse 28: 1–9. | Sehlooho se | E fetotsoe | ChemPort |
25. Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998b). Kameho ea ho itaola ka koae ho li-receptor tsa dopamine D2 ho litšoene tsa rhesus. Synapse 30: 88–96. | Sehlooho se | E fetotsoe | ChemPort |
26. Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O et al a (2002). Bolaoli ba sechaba ho litšoene: Dopamine D2 receptors le ho itaola ka koae. Nat Neurosci 5: 169–174. | Sehlooho se | E fetotsoe | ISI | ChemPort |
27. Nader MA, Czoty PW (2008). Mehopolo ea kelello ka litsoeng tse seng tsa botho: temohisiso ea bokhoba ba lithethefatsi. ILAR J 49: 89–102. | E fetotsoe | ChemPort |
28. Moetapele MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR et al a (2002). Litlamorao tsa ho itlhokofatsa ka koae ka lits'ebetso tsa dopamine litšoeneng tsa litšoelesa: ho pepeseha pepenene le ho sa foleng. Neuropsychopharmacology 27: 35–46. | Sehlooho se | E fetotsoe | ISI | ChemPort |
29. Moetapele MA, Morgan D, Gage HD, Nader SH, Calhoun TL, Buchheimer N et al a (2006). PET ea ho nahana ka li-receptor tsa dopamine D2 nakong ea boits'oaro bo sa feleng ba koae ka litšoene. Nat Neurosci 9: 1050–1056. | Sehlooho se | E fetotsoe | ChemPort |
30. Nolan EB, Harrison LM, Lahste GJ, Ruskin DN (2007). Sehaenderal synergism lipakeng tsa D (1) le D (2) li-dopamine receptors ho litoeba ha lia itšetleha ka likheo tsa likheo. Synapse 61: 279–287. | Sehlooho se | E fetotsoe | ChemPort |
31. Porrino LJ, Lyons D, Miller MD, Smith HR, Friedman DP, Daunais JB et al a (2002). 'Mapa oa metabolism oa litlamorao tsa koae nakong ea mekhahlelo ea pele ea boitaolo maemong a seng a botho. J Neurosci 22: 7687–7694. | E fetotsoe | ChemPort |
32. Porrino LJ, Lyons D, Smith HR, Daunais JB, Nader MA (2004). Ts'ebetso ea Cocaine e hlahisa karolo e tsoelang pele ea likarolo tsa maoto le mekhahlelo ea sensorimotor. J Neurosci 24: 3554–3562. | Sehlooho se | E fetotsoe | ISI | ChemPort |
33. Ruskin DN, Bergstrom DA, Walters JR (1999). Multisecond oscillations ka sekhahla sa ho thunya ho globus pallidus: synergistic modulation ka D1 le D2 dopamine receptors. J Pharmacol Exp Ther 290: 1493–1501. | E fetotsoe | ISI | ChemPort |
34. Samuvel DJ, Jayanthi LD, Manohar S, Kaliyaperumal K, Bona RE, Ramamoorthy S (2008). Phokotso ea thekiso ea dopamine transporter le ts'ebetso kamora ho khaotsa ho itaola ka har'a koae ho litoeba: bopaki ba phapang e fapaneng ho caudate putamen le li-nucleus tsa rubus. J Pharmacol Exp Ther 325: 293–301. | Sehlooho se | E fetotsoe | ChemPort |
35. Schmidt HD, Anderson SM, Pierce RC (2006). Ho hlohlelletsa li-receptor tsa D1 tse kang D2 kapa DXNUMX dopamine khetla, empa eseng ntho ea mantlha, ha li-nucleus tsa li-nucleus li khutlisetsa boits'oaro ba ho ts'oara koae ka har'a rat. Eur J Neurosci 23: 219–228. | Sehlooho se | E fetotsoe |
36. Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996). Phetohelo e hanyetsang ea boitšoaro bo batlang koae ka koae ke D1- le D2-like dopamine receptor agonists. Science 271: 1586–1589. | Sehlooho se | E fetotsoe | ISI | ChemPort |
37. Staley JK, Hearn WL, Ruttenber AJ, Wetli CV, Mash DC (1994). Libaka tse phahameng tsa tumello ea koae ho "transporter" ea dopamine li phahamisetsoa ho batho ba bolailoeng ke koae. J Pharmacol Exp Ther 271: 1678–1685. | E fetotsoe | ChemPort |
38. Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ et al a (1993). Ho fumaneha ha dopamine D2 receptor ho theoha ho amana le metabolism e fokotsitsoeng ea botlokotsebe ba koae. Synapse 14: 169–177. | Sehlooho se | E fetotsoe | ISI | ChemPort |
39. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A et al a (1999). Phatlalatso ea ho matlafatsa likarabo ho li-psychostimulants ho batho ka maemo a dopamine D2 receptor. Am J Psychiatry 156: 1440–1443. | E fetotsoe | ISI | ChemPort |
40. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R et al a (1997). Karabelo e theohileng ea dopaminergic e theohile lithutong tse itšetlehileng ka koae. Nature 386: 830–833. | Sehlooho se | E fetotsoe | ISI | ChemPort |
41. Walters JR, Bergstrom DA, Carlson JH, Chase TN, Braun AR (1987). D1 dopamine receptor activation e hlokahalang bakeng sa tlhahiso ea postynaptic ea litlamorao tsa D2. Science 236: 719–722. | Sehlooho se | E fetotsoe | ChemPort |
42. Weiss F, Martin-Fardon R, Ciccocioppo R, Kerr TM, Smith DL, Ben-Shahar O (2001). Ho mamella ho hanela ho felisoa hoa boitšoaro bo batlang koae ka koae bo khothalletsoang ke litloaelo tse amanang le lithethefatsi. Neuropsychopharmacology 25: 361–372. | Sehlooho se | E fetotsoe | ISI | ChemPort |
43. Wong DF, Kuwabara H, DJ ea Schretlen, Bonson KR, Zhou Y, Nandi A. et al a (2006). Keketseho ea ho lula ha li-dopamine receptors lithutong tsa batho nakong ea litakatso tsa cueine tse phahameng. Neuropsychopharmacology 31: 2716–2727. | Sehlooho se | E fetotsoe | ChemPort |