Lintlha tse tsamaisitsoeng le boikutlo ba ho khothatsa batho liphoofolo le batho (2009)

Neuropharmacology. Sengoloa se ngotsoeng; e fumaneha ho PMC 2010 Jan 1.

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PMCID: PMC2635339

NIHMSID: NIHMS86826

Moetso oa khatiso oa ho qetela oa mohatisi o fumaneha ho Neuropharmacology

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Eya ho:

inahaneloang

Ho pepeseha khafetsa ho li-psychostimulants ho ka lebisa tlhokomelong ea nako e telele ea litlamorao tsa lithethefatsi le boits'oaro. Liphuputso tse joalo li bohlokoa haholo likhopolong tsa morao-rao tsa bokhoba ba lithethefatsi tse sisinyang hore sensitized nucleus accumbens (NAcc) dopamine (DA) e phalla ka ho khetheha liketsong tse kopaneng le liphetoho tse ling ho neurochemistry ea khubu ena ho khothaletsa ho batla lithethefatsi le ho itaola. Leha ho le joalo, liteko tsa litoeba, litšoene tse seng tsa botho le batho ha se ka mehla li lemotseng boits'oaro kapa boits'oaro ba lik'hemik'hale kamora ho pepeseha ha lithethefatsi, ho tlisa lipelaelo ts'ebeliso ea mofuta ona. Ka boiteko ba ho hokahanya liphapang tse hlahang ho lingoliloeng, tlhahlobo ena e lekola maemo a ka amang polelo ea ts'ehetso nakong ea liteko. Haholo-holo, karolo e bapaloang ke lintlha tse hlophisitsoeng e ea hlahlojoa. Litlaleho tse 'maloa li tšehetsa ka matla karolo e matla le ea bohlokoa bakeng sa tšusumetso e matla molemong oa ho matlafatsa. Liphuputso li fana ka maikutlo a hore tšusumetso e amanang le boteng kapa ho ba sieo ha lithethefatsi e ka nolofalletsa kapa ea thibela karabelo e matlafatsang. Ho phetheloa hore boteng kapa ho ba sieo ha tšusumetso e joalo nakong ea liteko tsa ho matlafatsa lithuto tsa liphoofolo le tsa batho ho ka ama haholo litholoana tse fumanoeng. Hoa hlokahala ho nahana ka monyetla ona haholoholo ha ho tolokoa sephetho sa lithuto tse sa atleheng ho bona karabelo e matlafatsoang.

Keywords: maemo a thibelo, boemo, dopamine, bokhoba ba lithethefatsi, ho itaola lithethefatsi, ho ts'oara maemo a thabo a Paplovian

1. Sensitization ho liphoofolo le batho

Ho na le tumellano e akaretsang ea hore likhoto li pepesitsoe khafetsa ke li-psychostimulants tse kang amphetamine li tla bontša ho matlafatsa - ho matlafatsa - moahloli ea arabang ha a se a phephetsoa ke sethethefatsi nakoana hamorao. Liphoofolong tsena, ts'ebetso ea li-neurone tsa mesoaccumbens dopamine (DA) phephetsong ea lithethefatsi le eona ea ntlafatsoa (bakeng sa litlhahlobo tse hlokolosi tsa lingoliloeng tsa pele ho nako, bona Kalivas le Stewart, 1991; Vanderschuren le Kalivas, 2000; Vezina, 2004). Tsena ke litlamorao tsa nako e telele ho rat. Sensitised locomotor arabela e tlalehiloe ho fihlela selemo se le seng (Paulson et al., 1991) le li-nucleus accumbens (NAcc) tse ntlafalitsoeng tsa DA li ngatafala ho fihlela likhoeli tse tharo kamora ho pepesetsoa lithethefatsi (Hamamura et al., 1991). Haholo-holo, boholo ba amphetamine-induction DA bo bongata ho NAcc bo eketseha ka nako kamora ho pepesetsoa sethethefatsi (Vezina, 2007).

Ka lebaka la bohlokoa ba mesocorticolimbic DA pathways molemong oa boits'oaro ba takatso ea lijo ho kenyelletsa ho batla le ho sebelisa lithethefatsi tse hlekefelitsoeng, ho latela hore litlatsetso tsa nako e telele tšebetsong ea mekhoa ena li ka lebisa ntlafatsong ea nako e telele boits'ebetsong ba boitsoaro bo botle. Monyetla ona o hlahisitse bohlokoa ba sebopeho sa tšusumetso ea maikutlo a tšusumetso ea bokhoba ba litlatsetso bo fanang ka maikutlo a NAcc DA a khaphatsehang a etsa lintho ka tumellano le liphetoho tse ling ho neurochemistry ea nucleus ena ho ntlafatsa litlamorao tsa lithethefatsi le ho khothaletsa ho phehella le ho itaola (Robinson le Berridge, 1993). Ka lebaka leo, palo e kholo ea lits'ebetso, lipatlisiso tsa cellular le limolek'hule li tsepamisitse mohopolo lits'ebetsong tse ka fetolang ts'ebeliso ea methapo ea methapo ea methapo ea DA le lits'ebetso tseo li sebelisanang le tsona (Hyman et al., 2006).

Ho ntse ho le joalo, hore tšehetso e ngata ea liteko tse ntlafalitsoeng tsa DA li tsoa litekong tse entsoeng ka litoeba, ha liphumano tse fumanoeng metseng ea khale e se motho le batho li lekane. Mohlala, lithuto tse sebetsang tsa neuroimaging li fana ka maikutlo seterekeng sa maoto a fokotsitsoeng ho e-na le likarabelo tsa DA tse khothalletsoang ke lithethefatsi ho bakuli ba lemaletseng koae ha ba bapisoa le taolo (mohlala, Volkow et al., 1997). Sena se lebisitse ho khang ea hore sensitization ea karabelo ea NAcc DA e le mokhoa oa ts'ebeliso e mpe ea lithethefatsi le mefuta e meng ea pathology ha e na boleng bo lekanyelitsoeng kaha e sa fetelle ho boemo ba motho. Bopaki ba morao-rao bo hlahile, leha ho le joalo, bo bonts'a hore tokollo ea DA e hlahisitsoeng ke amphetamine ho tsoa ho ventral striatum e kanna ea khahloa ke lithuto tsa batho (Boileau et al., 2006).

Ka tlase re qala ho hlahloba bopaki ba boits'oaro le dopaminergic ho liphoofolo le ho batho ka moo ho amanang le ho batla lithethefatsi le ho ts'oara lithethefatsi. Bopaki ba hore polelo ea ho susumetsa maikutlo e ka laoloa ke likhakanyo tse nang le maemo e ea hlahlojoa. Tlhahlobo ea lingoliloeng tsa liphoofolo e felletsoe feela litlalehong tsa liteko tse etsoang ho likhoto kaha tsena li file bopaki bo bongata ba mantlha libakeng tsena. Ha re leka ho boelanya liphapang tse hlahang ka har'a lingoliloeng, re hlahloba ka ho hlaka monyetla oa hore polelo ea maikutlo e ka tsamaisoa maemong a mang mme ea sitisa ba bang. Ho boleloa hore litlamorao tse joalo li tlameha ho nahanoa ha ho tluoa liphetho tsa lithuto tse sitoang ho bona karabelo e susumetsoang.

1.1. Sensitization ho liphoofolo

Amphetamine e eketsa maemo a tsoang ho DA maemong a mokokotlo le a sele ea lithoaccumbens li-neurons tsa DA ka ho khutlisa ho tsamaisa thepa ea DA le ho thibela ho tsubella ha eona ka morekisi oa DA (Seiden et al., 1993). Ho NAcc, phello ena e amahantsoe le bokhoni ba eona ba ho hlahisa mesebetsi ea li-locomotor le ho tšehetsa boits'oaro (Hoebel et al., 1983; Vezina le Stewart, 1990). Litla-morao tsena ka bobeli li thibetsoe ke bahanyetsi ba DA receptor kapa li-6-OHDA lesapo la methapo ea methapo ea DA ho NAcc (Joyce le Koob, 1981; Lyness et al., 1979; Phillips le al., 1994; Vezina, 1996).

Ho litoeba tse neng li pepesetsoa liente tsa psychostimulant tse phetoang khafetsa, liphetho tsena lia ntlafatsoa (bona lebokose 1). Tikoloho ea nako e telele ea sensitisedor le NAcc DA e arabang e tlalehiloeKalivas le Stewart, 1991; Vanderschuren le Kalivas, 2000; Vezina, 2004). Maemong a morao-rao, bokhoni bo ntlafalitsoeng ba lithethefatsi tse kang amphetamine ho eketsa maemo a tsoang kantle ho DA ho NAcc bo emela neuroadaptation e amanang haholo le polelo ea boits'oaro. E eketseha ha nako e ntse e feta, 'me e' nile ea bonoa ka vitro le libekeng tsa vivo ho isa likhoeli tse latelang ho pepesetsoa lithethefatsi (Hamamura et al., 1991; Kolta et al., 1989; Paulson le Robinson, 1995; Robinson, 1988, 1991; Segal le Kuczenski, 1992; Wolf le al., 1994; Vezina, 2007; cf, Kuczenski et al., 1997). Ho kenyelletsoa ha maikutlo ke li-psychostimulants, ka lehlakoreng le leng, ho fumanoe hore ho etsahala sebakeng sa ventral tegmental (VTA), sebaka sa litho tsa lisele tsa mahloaccumbens DA neurons. Ka bobeli locomotor le NAcc DA sensitization e hlahisoa ke amphetamine ho VTA ka mokhoa o itšetlehileng oa D1 DA receptor.Bjijou et al., 1996; Cador et al., 1995; Dougherty le Ellinwood, 1981; Hooks et al., 1992; Kalivas le Weber, 1988; Perugini le Vezina, 1994; Vezina, 1993, 1996; Vezina le Stewart, 1990). Ho ka etsahala hore mefuta e 'meli ea maikutlo e hlahisoe ke liketsahalo tsa "neuronal liketsahalo" tse qalileng ka keketseho ea maemo a holimo ho DA ho VTA (Kalivas le Duffy, 1991). Sena se kenyelletsa ts'ebetso ea glutamate-DA e le ts'ebetso ea li-subtypes tsohle tse tharo tsa glutamate (NMDA, AMPA le metabotropic) e hlokahalang bakeng sa ho kenyelletsa sensorization ea locomotor ke amphetamine (Vanderschuren le Kalivas, 2000; Vezina le Suto, 2003; Wolf, 1998).

lebokose 1 

Lipehelo le Litlhaloso

Ho boetse ho na le bopaki bo kholisang ba hore ho pepesehela li-psychostimulants khafetsa ho lebisa ho tsamaiso ea bona e ntlafalitsoeng. Joalo ka sebopeho sa maoto le maoto (Mogenson, 1987) e amohela mohopolo oa "encoding encoding" o tsoang ho VTA le libakeng tse ka pele ho eona joaloka preortal cortex, hippocampus le basolateral amygdala, NAcc e boemong bo botle ba ho bapala karolo ea mantlha molokong oa likarabo tsa makoloi tse lumellanang le boits'oaro bo loketseng. Hobane ts'ebetso ho li-neurons tsa DA tse kopantsoeng eseng feela le phumants'o e hlahisoang empa le tsamaiso ea boits'oaro e ts'ehetsoeng ke lithethefatsi tse joalo ka amphetamine, hoa utloahala ho lebella hore ts'ebetso e ntlafalitsoeng ho li-neurons tsena e tla ama ho tsoma lithethefatsi le ho itaola ha lithethefatsi. Ho phehisanoa ka hore ketsahalo ea machoaccumbens li-neurons tsa DA li kenyelletsa ts'usumetso ea phello ea lithethefatsi (Robinson le Berridge, 1993; Stewart et al., 1984; Vezina et al., 1999). Haeba ho ne ho le joalo, maikutlo a methapo ena ea kutlo a lokela ho matlafatsa le tsusumetso ea ho phehella moriana le ba o susumetsang o amanang le ona. Litlaleho tse ngata tse tšehetsang pono ena joale li thehile hore ho pepesetsoa lithethefatsi tse 'maloa ho lebisa ho khethoeng ea maemo a ntlafalitsoeng (Gaiardi et al., 1991; Lett, 1989; Shippenberg le Heidbreder, 1995) hammoho le mokhoa o fumanehang oa ho iphumanela lithethefatsi (Horger et al., 1990, 1992; Piazza et al., 1989, 1991; Pierre le Vezina, 1997; Valadez le Schenk, 1994) mme hang ha boitšoaro bo fumanoe, khothatso e ntlafalitsoeng ea ho fumana moriana (Lorrain et al., 2000; Mendrek et al., 1998; Vezina et al., 2002). Joalokaha ho hlokometsoe ka mofere-fere o khothalelitsoeng le NAcc DA e khaphatseha, nts'etsopele ea litlamorao ho tsamaiso ea lithethefatsi e boetse e hloka ts'ebetso ea D1 DA le li-receptor tsa glutamatergic ho VTA (Pierre le Vezina, 1998; Suto et al., 2002, 2003).

1.2. Sensitization bathong

Lilemong tsa ho qetela tsa 10-15, ho ntlafalitsoe mekhoa e sebetsang ea neuroimaging e kang positron emission tomography (PET) e sebelisang li-ligands tsa benzamide ka radioxly bakeng sa D2 / 3 DA receptors mme e ka kopanngwa le matla a boselamose a monahanyo (MRI). Sena se lumelletse lithuto tsa litlamorao tsa lithethefatsi tse hlekefelitsoeng ho reactivity ea DA matsohong a batho bao haufinyane ba fihletseng qeto e lekaneng ea sebaka ho lumella tlhahlobo ea litlatsetso tse fapaneng tsa litereke. Joalokaha ho thehiloe ka litoeba, lithuto tsena li bonts'a hore maemo a tsoang kantle ho DA a boetse a eketseha maemong a batho (haholo-holo subralion) kamora taolo e mpe ea lithethefatsi tse fapaneng tse hlekefelitsoeng ho kenyeletsa amphetamine (Volkow et al., 1994, 1997, 1999, 2001; Laruelle et al., 1995; Breier et al., 1997; Drevets et al., 2001; Leyton et al., 2002; Martinez et al., 2003, 2007; Abi-Dargham et al., 2003; Oswald et al., 2005; Riccardi et al., 2006a; Boileau et al., 2006, 2007; Munro le al., 2006; Casey et al., 2007) le cocaine (Schlaepfer et al., 1997; Cox et al., 2006). Keketseho ena e bakiloeng ke lithethefatsi ho DA ea kantle ho naha e fumanoe e lumellana le maemo a monate a maikutlo le ho lakatsa hammoho le ho batla bocha le ho batla.

Le ha lithuto tsa batho li rarahane ka tsela e utloisisang ho feta se entsoeng ka litoeba, bopaki ba hore maikutlo a ka hlaha litlamorao tsa lithethefatsi bo tlalehiloe, leha e se ka mabaka a itseng a sa lumellaneng (bakeng sa tlhahlobo e thata ea lingoliloeng tsa batho, bona Leyton, 2007). Ha likhakanyo tse phahameng tsa amphetamine li ne li fanoa ho lihlooho tse sa itšetleheng ka lithethefatsi (bona lebokose 2), tlhokomeliso ea litlamorao tse ngata tsa lithethefatsi e ile ea bonoa, ho kenyelletsa le lits'ebetso tse ka bang mafolofolo le maemo a matla hammoho le likarabo tse ka 'nang tsa baka mahlo le maikutlo tse phahamisang maikutlo (Strakowski et al., 1996, 2001; Strakowski le Sax, 1998; Boileau et al., 2006). Phuputsong e le 'ngoe (Sax le Strakowski, 1998), e bonts'ang tlhoko e tlisoang ke lithethefatsi mokhoeng o tsamaisanang hantle le tšobotsi ea botho ea ho batla bocha. Phuputsong e telele ka ho fetisisa, ho eketseha ho matlafalitsoeng ha amphetamine ho ile ha bonoa selemo se felletseng hamorao (Boileau et al., 2006). Sensitization hore na lihlooho li ratile amphetamine hakae ha e so ka e bonoa lithutong tsena, sepheo se lumellanang le bopaki bo bonts'a hore NAcc DA e hokahane haholo le tšusumetso ea lithethefatsi le litheko tse amanang le tsona ho fapana le thabo e tlisoang ke tšebeliso ea tsona (Stewart et al., 1984; Stewart, 1992; Blackburn et al., 1992; Robinson le Berridge, 1993; Berridge le Robinson, 1998; Ikemoto le Panksepp, 1999; Leyton, 2008). Ho khahlisang, mamello ho litlamorao tsa litla-morao tsa lithethefatsi tsa psychostimulant ho tlalehiloe ho barekisi ba ts'ebeliso ea koae le ha ba batlana le lithethefatsi tse matlafalitsoeng (Volkow et al., 1997; Mendelson et al., 1998). Batho bana ba boetse ba tlalehiloe ba sitoa ho bonts'a likarabo tsa maikutlo tsa bophelo bo botle tsa 'mele kapa tsa mmele tse latelang 2-4 ea tsamaiso ea koae ea letsatsi le letsatsi (Nagoshi et al., 1992; Rothman et al., 1994; Gorelick le Rothman, 1997).

lebokose 2 

Nts'etsopele ea tekanyetso ea kutlo ea kutlo e pheta-phetoang d-amphetamine lithutong tse phetseng hantle

Boithuto bo lekanyang maikutlo a litlamorao tsa DA tsa li-psychostimulants li nyane haholo ka palo empa liphumano tsa bona li batla li lumellana le sephetho sa boitšoaro se hlahliloeng ka holimo. Ha ho etsoa lithutong tse sa sebeliseng tlhekefetso e seng lithethefatsi, tokollo ea DA ea amphetamine e khothalletsoang haholo e hlahisitsoeng libeke tse peli le selemo se le seng ka mor'a ts'ebetso ea litekanyetso tse tharo tsa lithethefatsi ka nako ea beke e le 'ngoe (Boileau et al., 2006). Bophahamo ba sensitization ea DA bo amana hantle le maikutlo a boemo ba matla le sekhahla sa leihlo-mahlo hammoho le botho ba ho batla bocha. Leha ho le joalo, ha ho etsoa ho bakuli ba tloheletsoeng ba nang le nalane ea ho itšepa koae, ho sa natsoe ho lokolloa ho matla ha DA ho arabela phepheng ea phepo ea psychostimulant (Volkow et al., 1997; Martinez et al., 2007). Habohlokoa, karabelo ena e fokotsehileng ea DA e ke ke ea hlalosoa e le ho sitoa ha mokhoa oa DA ho araba kaha batho bana ba khona ho bonts'a keketseho e bakoang ke lithethefatsi tokollong ea DA (e tlalehiloe ka mokhoa o ikhethileng ho dorsal striatum; Volkow et al., 2006; Wong et al., 2006).

Ho na le liphapang tse ngata lipakeng tsa lithuto tse entsoeng lithutong tse phetseng hantle le bakuli ba hlekefetsang lithethefatsi tse ka bakang liphetho tse fapaneng tse tlalehiloeng. Khethong ea morao-rao, lithuto li hlahisitsoe ka bongata ba lithethefatsi mme ho ka etsahala hore esita le ho bakuli ba tlohetseng boemo bo boholo ba ponaletso ena ho ka kena-kenana le polelo e latelang ea maikutlo. Ka hara rat, ntlafatso e ntlafalitsoeng ea lithethefatsi ea NAcc DA ha e bonoe matsatsing a latelang a ho pepeseha empa ho e-na le libeke ho isa likhoeling hamorao (Hamamura et al., 1991; Hurd et al., 1989; Segal le Kuczenski, 1992; Paulson le Robinson, 1995). Nako ea ho khaotsa e hlokahalang ho bonahatsa maikutlo e ka ba telele ho batho mme e telele e ntse e latela ho pepesetsoa ha lithethefatsi nako e telele (bona Dalia et al., 1998; Vezina et al., 2007). Phapang e 'ngoe e tebileng lipakeng tsa lipatlisiso tse entsoeng lithutong tse sebelisang bophelo bo botle ba tlhekefetso ea lithethefatsi e ka kenyelletsa maikutlo a fapaneng a tikoloho a potolohileng ho sebelisa lithethefatsi le ao e leng maemo a liteko. Lits'oants'o tse entsoeng ka lithethefatsi le tse se nang lithethefatsi li ka ba le tšusumetso e fapaneng ea karabelo ea DA ea lithethefatsi lihlopheng tsena tse peli. Sehlopha sa linaleli se khothalletsoang ke tikoloho ea tlhahlobo ea PET, ka mohlala, se ka lebelloa ho hlahisa litlamorao tse fapaneng ho batho ba amohetseng lithethefatsi boteng ba bona feela, ha ba bapisoa le ba bang ba amanang le lintlha tsena le ho ba sieo ha moriana. Bopaki bo tšehetsang monyetla ona bo hlalositsoe ka tlase.

2. Lits'oants'o tse nang le maemo le polelo ea maikutlo

E 'nile ea tsejoa ka nako e telele hore polelo ea boits'oaro ea boitšoaro e ka ba tlasa taolo e matla ea tikoloho. Bopaki ba mantlha ba sena bo tsoa litekong tse bonts'ang hore likhoto li ne li pepesitsoe lithethefatsi tikolohong e le 'ngoe (li tšehelitsoe) li bonts'a karabo e kholo ea lithethefatsi tekong ea sensitization e etsoang tikolohong ena ha e bapisoa le likhoto tse neng li kile tsa pepesetsoa lithethefatsi kae kapa kae. ) kapa Laola likhoto tse neng li kile tsa pepesetsoa letsoai libakeng tse peli. Kannete, tlasa maemo ana, likhoto tse sa lefelloeng li sitoa ho bonts'a bopaki ba maikutlo a locomotor ha li hlahlojoa le moriana, leha ba kile ba fumana phello e tšoanang ea khemisi ka sethethefatsi joalo ka likhoto tsa Paired. Polelo e joalo e ikhethileng ea tikoloho ea sensomotor sensitization e tlalehiloe le lithethefatsi tse fapaneng ho kenyeletsa morphine, amphetamine le cocaine (Vezina le Stewart, 1984; Stewart le Vezina, 1987; Vezina et al., 1989; Pert et al., 1990; Stewart le Vezina, 1991; Anagonstaras le Robinson, 1996; Anagnostaras et al., 2002; Wang le Hsiao, 2003; Mattson et al., 2008; bakeng sa litlhahlobo, bona Stewart le Vezina, 1988; Stewart, 1992). Haufinyane, mokhoa ona o sebelisitsoe ho bonts'a maikutlo a ikhethang a tikoloho ea amphetamine-e hlahisang NAcc DA e pharalletseng joalo ka (Guillory et al., 2006).

Litekong tsena, mokhoa oa khethollo hangata o sebelisetsoa ho pepesetsa liphoofolo lithethefatsi le ho lumella mekhatlo hore e thehe lipakeng tsa motsoako o senang tšusumetso ea lithethefatsi (UCS) le tikoloho e nang le maemo a ntlafatsang (CS) tataiso (Setšoantšo sa 1). Litekong tsa ts'ebetso ea locomotor, likhoto sehlopheng sa Paired li fumana lithethefatsi likamoreng tsa ts'ebetso ea ts'ebetso ka letsatsi le le leng le saline tikolohong e 'ngoe (hangata e le ntloana ea lehae) ka le hlahlamang. Likhoto sehlopheng se sa lefelloeng li fumana palo e lekanang ea ente ea lithethefatsi empa tikolohong e ngoe le saline likamoreng tsa ts'ebetso; likhoto tsena li pepesetsoa lithethefatsi empa li sa pepesehe ka likamore tsa tšebetso. Kamora nako, sehlopha sa boraro sa liphoofolo tse laoloang se pepesoa ka mokhoa o ts'oanang tikolohong ka bobeli empa ha ho mohla sethethefatsi. Ts'ebetso ena e lumella tlhahlobo e latelang ea likarabo tse nang le maemo ha likhoto lihlopheng tsohle li fanoa ka letsoai pele ho tlhahlobo 'me li utloa maikutlo a arabela ha likhoto tsohle li fuoa phephetso ea lithethefatsi tsa lithethefatsi pele ho tlhahlobo (Setšoantšo sa 1). Ka mokhoa o sa khaotseng, karabelo e ntlafalitsoeng e bonoa ho liphoofolo tse Paired ka bobeli litlhahlobong tsena: mokhoa o tsitsitseng tekong ea boemo le boikemisetso bo ikhethileng ba tikoloho tlhahlobong ea sensitization (Setšoantšo sa 2).

Setšoantšo sa 1 

Lethathamo la mekhoa ea khethollo e atisang ho sebelisoa maemong a lithethefatsi le boitekong ba maikutlo. Ka nako ya Boemo / Phihlelo, liphoofolo li ka kenngoa ka liente tse 'maloa ka ente e' ngoe le e 'ngoe e nang le liente tse peli, ...
Setšoantšo sa 2 

Liphetho tse fumanoeng litlhahlobong tsa boemo (A) le sensitization (B) likotong tseo pele li neng li pepesetsoa letsoai (Taolo) kapa amphetamine (1.0 mg / kg, IP) e ka ba Paired kapa e sa lefelloang ka likamore tsa ts'ebetso ea locomotor. Lintlha li bontšoa e le kakaretso ea 2-hr ...

2.1. Boemo bo khahlisang ba Pavlovian le polelo ea maikutlo

Ha ho makatse hore ebe liteko tsa pele tsa ho ikarabella bakeng sa taolo ea ts'usumetso ea tikoloho ea polelo ea maikutlo li khothalelitse hore li bakoa ke tšibollo ea sehlahisoa sa UCS le karabelo e ntseng e hola ea CS e huloang ke lithethefatsi (Hinson le Poulos, 1981; Pert et al., 1990). Koteng, likarabo tse 'maloa tsa boemo bo holimo tsa CS li bontšitsoe ka mor'a li-coupings tsa lithethefatsi ho kenyelletsa ts'ebetso ea locomotor, stereotypy le boitšoaro ba ho potoloha (Beninger le Hahn, 1983; Vezina le Stewart, 1984; Tlhokomelo, 1986; Drew and Glick, 1987; Hiroi le White, 1989; Pert et al., 1990; Stewart le Vezina, 1991; Anagnostaras le Robinson, 1996) hammoho le NAcc DA e khaphatseha (Fontana et al., 1993; Gratton le Wise, 1994; Di Ciano et al., 1998; Ito et al., 2000). Ka mokhoa o ts'oanang, likarabo tse 'maloa tsa maemo a phahameng ka ho fetisisa tsa CS li tlalehiloe bathong, ho kenyelletsa takatso le matla a eketsehang a matla, ho rata lithethefatsi, takatso ea lithethefatsi, sekhahla sa pelo le khatello ea mali ea systolic (Foltin le Haney, 2000; Panlilio et al., 2005; Berger et al., 1996, Leyton et al., 2005; Boileau et al., 2007). Ho lokolloa hoa boemo bo phahameng ba maemo a leholimo a litaba tsa DA le hona ho tlalehiloe ho batho (Volkow et al., 2006; Wong et al., 2006; Boileau et al., 2007). Leha ho le joalo, leha litlamorao e le litla-morao tsa lithethefatsi li khothalelitsoe ho bapala karolo ea bohlokoa ho susumetseng ho batla lithethefatsi ho liphoofolo le bathong (Stewart et al., 1984; Childress et al., 1988; Stewart, 2004), tlatsetso ea bona tlhokomatsong e ikhethileng ea tikoloho ha e hlake. Mohlala, motsoako o bonolo oa karabelo e nang le maemo le UCS ea lithethefatsi ha e felle khafetsa mabapi le karabelo e lemohuoang (Anagnostaras le Robinson, 1996). Ntle le moo, mefuta e meng ea tlhahiso-leseling, e kang ho kenya amphetamine ho VTA, ha e hlahise sensomotor le NAcc DA sensitization empa ha e hlahise karabelo e sa reroang kapa e lebise ho nts'etsopele ea karabelo e nang le maemo, e le hore polelo ea maikutlo ke taba e ikemetseng (Vezina le Stewart, 1990; Perugini le Vezina, 1994; Vezina, 1996; Scott-Railton et al., 2006). Ka mokhoa o ts'oanang, liteko tsa "vitro striatal slice" tse bonts'itsoeng tse lokollotsoeng ha DA li hlile li etsa joalo ha ho hloka tšusumetso ea maemo a teng (Castaneda et al., 1988; Robinson le Becker, 1982), ho etsa hore ho hlokehe ho nahana ka litlhaloso tse ling bakeng sa kamoo lithethefatsi tse amanang le lithethefatsi tsa tikoloho li laolang polelo ea maikutlo. Liphumano tsena li bonts'a ka mokhoa o hlakileng hore maikutlo a ho susumetsa ke ntho e sa amaneng le eona e ka bang tlasa taolo ea ts'usumetso ea tikoloho.

2.2. Phokotso le maemo a thibeloang a ka laola ho hlahisoa ha maikutlo

Anagnostaras le Robinson (1996) e tlaleha liphumano tse qobellang tse tšehetsang mohopolo oa hore ba susumetsang ba sebetsang joaloka batšehetsi (bao hape ho thoeng ke bahlophisi ba liketsahalo) ba ka ikarabellang bakeng sa maikutlo a ikhethang a tikoloho. Thepa ea ho tataisa e fanoa ka tšusumetso e tlisoang ke maemo a tšohanyetso a ba lumellang ho bolela esale pele ka ts'ohanyetso se tla etsahala kapa tšusumetso e 'ngoe. Ha e se e thehiloe, mehopolo ena e ka sebetsa e le sethala sa liketsahalo ka ho fetola matla a nyakallo a susumetsang a mang. Ho fapana le basomi ba maemong a felletseng, batataisi ha ba hlile ha ba batle likarabo tse maemong a tlase empa ba laola bokhoni ba tse ling tsa ho susumetsa ho etsa joalo (Rescorla, 1985; Holland, 1992). Tabeng ea ho susumetsa maikutlo, Anagnostaras le Robinson (1996) e bonts'a hore ts'ebetso ea ts'usumetso ea tikoloho e tlang ho bolela ho ba teng ha moriana e ka ba le bokhoni ba ho beha ketsahalo bakeng sa karabelo e susumetsoang ka letsatsi la tlhatlhobo ntle le tlhokeho ea ho arabela karabelo e thabisang ea eona. Ka hona, karabelo e khahlisang e ne e bonoa feela ho liphoofolo tse lekiloeng boteng ba tšusumetso ea tšusumetso ea (liphoofolo tse pentiloeng ka Setšoantšo sa 1). Re lokela ho hlokomela hore liphetho tsa Anagnostaras le Robinson (1996) bonts'a hore batataisi ha ba hlophise monyetla oa li-CS feela empa ba ka etsa joalo le ka li-UCS tsa lithethefatsi (bona lebokose 1).

Ho sa tsotelloeng e bile monyetla o mong oa hore litekanyetso tse sa sebetseng hantle ka lithethefatsi li ka sebetsa e le li-inhibitors tse maemong (Rescorla, 1969; LoLordo le Fairless, 1985) ho thibela polelo ea karabelo e susumetsoang. Mefuta e fapaneng ea bopaki e tšehetsa monyetla ona, o khothalletsoang ke Stewart le Vezina (1988, 1991; Stewart, 1992). Taba ea pele, mokhoa oa khethollo o boletsoeng ho Setšoantšo sa 1 mme e sebelisitsoe lithutong tsa maemo a lithethefatsi le litlhahlobo ho tsebahala ho theha tšusumetso e hlakileng ntle le ts'ebetso ea UCS joalo ka li-inhibitors tse nang le maemo (Mackintosh, 1974). Taba ea bobeli, ha e sebelisoa ts'ebetsong ea likhetho, li-inhibitors li nang le maemo li fokotsa ho arabela eseng feela ho batho ba thabileng ba nang le maemo empa hape le tse susumetsang ntle le tumello (Rescorla, 1969; Thomas, 1972). Kahoo, joalo ka ha ho hlahisitsoe ke Anagnostaras le Robinson (1996) bakeng sa bathusi, li-inhibitors tse maemong a ka lekanang ka mokhoa o ts'oanang li ka arabela ka litlamorao tse seng ntle tsa lithethefatsi (Stewart, 1992). Taba ea boraro, mekhoa e tsejoang ka ho tima thibelo e nang le maemo (Lysle le Fowler, 1985; Kasprow et al., 1987; Hallam et al., 1990; Fowler et al., 1991) e ka khetha ka mokhoa o khethollang polelo ea locomotor le NAcc DA sensitization ka amphetamine ho senola karabelo e susumetsoang ho liphoofolo tse sa fuoang letho (Guillory et al., 2006;; bona hape Stewart le Vezina, 1991). Qetellong, Anagnostaras et al. (2002) e bonts'a hore ho sebelisa tšabo ea elektroconvulsive ho etsa hore ho khutlisetsoe amnesia disinhibited ho arabela ka mokhoa o ikhethileng ho likhoto tse sa lefelloeng molemong oa tlhahlobo ea maikutlo, ho fana ka maikutlo a hore liphoofolo tsena ka tloaelo li ne li hlile li khothalelitsoe empa li sa thibeloe ho hlahisa karabelo e ntlafalitsoeng. Ntle le thibelo ea boemo ba maikutlo a maikutlo, bopaki bakeng sa thibelo e nang le maemo ea nts'etsopele ea mamello ho analgesic (Siegel et al., 1981), sedativeFanselow le Sejeremane, 1982le hypothermic (Hinson le Siegel, 1986) litlamorao tsa lithethefatsi tse ling le tsona li tlalehiloe.

Ka kopanelo, liphumano tse kaholimo li bonts'a hore polelo ea ts'usumetso e ka ba tlasa taolo e matla ea ts'usumetso ea tikoloho. Kahoo, polelo ea karabelo e susumetsoang ke maikutlo e ka khothaletsoa ke litakatso tse bileng teng ho bolela boteng ba lithethefatsi le tse thibeloang ke tšusumetso e reng e bontša ho ba sieo ha eona. Ho feta moo, ha ho na lebaka la ho belaela hore lits'ebetso tse joalo li ikhethile ka bobeli. Le ha e le hantle e rarahane haholo, ts'usumetso e joalo e tataisang le e thibelang maikutlo e ka lebelloa hape ho ba le taolo e matla holim'a ponahatso ea maikutlo bathong.

2.3. Litlamorao tsa ponahatso ea maikutlo ho batho

Hoa khahlisa ho lekola tse ling tsa liphumano tse tlalehiloeng lithutong tsa bosebeletsi ba batho ba lithethefatsi ka lebaka la se fumanoeng ka holimo. Leha e se karohano feela, phapang e le 'ngoe e atileng haholo lipakeng tsa liteko tse sebelisitsoeng lithutong tse mpe tsa tlhekefetso ea lithethefatsi mabapi le ts'usumetso ea taolo ea lithethefatsi nakong ea ho pepeseha le maemo a kopanyang nakong ea liteko. Ho isa tekanyong ea hore tšusumetso e amanang le tlhekefetso ea batho ba sebelisang lithethefatsi ka theko ea lithethefatsi le tšebeliso ea lithethefatsi mohlomong e fapana haholo le e teng ka nako ea tlhahlobo, monyetla oa ho thibela kapa ho hloka ts'ebetso ea ts'ebetso ea maikutlo le boits'oaro ba DA bo ka sitisang polelo. ea sensitization ha ho etsoa liteko (mohlala, Nagoshi et al., 1992; Rothman et al., 1994; Gorelick le Rothman, 1997; Volkow et al., 1997; Mendelson et al., 1998). Ka lehlakoreng le leng, ha batho ba sa laoloe ke lithethefatsi ba fuoa lithethefatsi ka mokhoa o khethehileng moo ho nang le litekanyetso tsa tlhahlobo, maemo a ho tataisa boits'oaro bo ntlafalitsoeng le karabelo ea DA bo ka khothaletsa polelo ea ho susumetsa maikutlo tekong (mohlala, Strakowski et al., 1996, 2001; Strakowski le Sax, 1998; Boileau et al., 2006). Tumellanong le tlhaloso ena, ha mabaka a susumetsoang a amanang le tlhekefetso ea lithethefatsi a ne a fumaneha nakong ea tlhahlobo (seipone, lehare, lehlokoa le phofo ea koae) le lithuto li ile tsa lumelloa ho lokisa phofo e le mela e le 'ngoe kapa tse peli le ho e kenella kahare ho tloaelo ea bona e tloaelehileng, ts'ebeliso ea lithethefatsi tsa psychostimulant tse fetileng e lumellane hantle le karabelo ea DA ea bootsoa (Cox et al., 2006). Liteko tse ts'oanang moo mekhoa ena e neng e le sieo (phephetso ea lithethefatsi e ne e sa sebetsanoe ntle le khang ka sekhukhu sa nondescript se hlalositsoeng e le moriana; ha ho lithethefatsi kapa litla-morao tsa lithethefatsi tse neng li le teng), ts'ebeliso ea lithethefatsi tsa psychostimulant tse boletsoeng esale pele e ile ea bolela karabelo e nyane ea DA e matlaCasey et al., 2007). Ho khahlisang ke hore phuputso ea haufinyane e tlalehile tšusumetso e amanang le lithethefatsi eo - ho fapana le e ho Cox et al. (2006) - ha ea lebisa ho ts'ebeliso ea lithethefatsi, e sa atlehe ho hlahisa tokollo ea DA e matlafalitsoeng lithutong tse sebelisang lithethefatsi hampe (Volkow et al., 2008). Liphumano tsena li boetse li tiisa bohlokoa ba ts'usumetso ea tikoloho ho arabela ka lithethefatsi hobane ho ts'oara mothusi ea lebelletsoeng ho tsejoa ho fokotsa ho arabela ha DA (Schultz et al., 1997).

3. Liphello

Lingoliloeng tsa liphoofolo tse bokellanang li bonts'a hore polelo ea ho susumetsa maikutlo e ka angoa ke lintho tse ngata ho fapana le ho nahanoang hangata. Haholo-holo ke likarolo tsa semmuso tsa ponaletso ea lithethefatsi pele ho tlhahlobo (mohlala, botebo ba ho pepesetsoa hoa lithethefatsi le nako ea ho ikhula) hammoho le ho ba teng kapa ho se be teng hoa litumelo tse amanang le lithethefatsi nakong ea liteko (bakeng sa litlhahlobo, bona Leyton, 2007; Vezina et al., 2007). Thutong ena, ho hlahisoa bopaki bo bonts'ang maikutlo a ho khothaletsa lithethefatsi tsa tlhekefetso a ka ba tlasa taolo e matla ea tikoloho. Stimuli e bolelang esale pele ho fumaneha ha lithethefatsi (bathusi, bahlalosi ba liketsahalo) ba khothaletsa karabelo e khahlisang empa tse susumetsang tse bolelang ho ba sieo ha tsona (li-inhibitors) li thibela tlhahiso ea maikutlo. Le ha qalong li ne li haella ka mokhoa oa ho arabela ka litoeba ka litoeba, liphetho tsena li sa tsoa atolosoa ho kenyelletsa le maemo a thibelitsoeng a likarabo tsa methapo ea kutlo le methapo.

Ho phehisanoa mona hore litlamorao tse tšoanang li etsahala ho batho. Liphetho tsa liteko tse 'maloa bathong li fana ka maikutlo a hore ho ba teng hoa likhakanyo tse boletsoeng esale pele ka ts'ebeliso ea lithethefatsi ho amana le ho arabela ha maikutlo ha ho ba sieo hoa lintlha tsena kapa ho ba teng hoa tšusumetso ea ho ba teng ha moriana ho amana le ho ba sieo ha karabelo ea maikutlo. Litloaelo tse joalo tse ka amang polelo ea maikutlo li ka baka tsietsing ea ho lemalla, ho thefuleha le ho batla ho oela hape bothateng, le litšila tse fetelletseng tse khomaretsoeng ke lithahasello tsa lithethefatsi. Lithuto tse sa laoleheng bakeng sa lintlha tsena li kanna tsa se ke tsa bonahatsa maikutlo le ha li-neuroadaptations tse loketseng li etsahetse le monyetla oa tsona oa ho fetola boits'oaro o le teng.

Liteboho

Tlhahlobo ena e ile ea khoneha ka lithuso ho tsoa ho National Institutes of Health (DA09397, PV) le Canadian Institutes for Health Research (MOP-36429 le MOP-64426, ML).

Mongolo o botlaaseng ba leqephe

Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.

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