Li-substrate tsa likokoana-hloko tsa moputso le ho ferekanya: ntho e nucleus accumbens tlhahiso-pele ea maikutlo (2009)

A. Bopaki ba pharmacological

Ho thehiloe hantle hore lithethefatsi tsa tlhekefetso (Di Chiara le Imperato, 1988) le meputso ea tlhaho (Fibiger et al., 1992; Pfaus, 1999; Kelley, 2004) ba le ketso e tloaelehileng ea ho phahamisa likhahla tse tsoang ho dopamine ho NAc. Ho feta moo, liso tsa NAc li fokotsa litlamorao tse matlafatsang tsa li-stimulants le opiates (Roberts le al., 1980; Kelsey et al., 1989). Lithuto tsa thuto ea meriana literekeng (mohlala, Caine et al., 1999) le litšoene (mohlala, Caine et al., 2000) fana ka maikutlo a hore ts'ebetso ea receptor e kang D2 e bapala karolo ea bohlokoa moputsong. Leha ho le joalo, e bile lithuto tse kenyelletsang ho kenella ha lithethefatsi ka kotloloho sebakeng sena tse faneng ka bopaki bo matla haholo bakeng sa karolo ea bona ho linaha tse nang le moputso. Mohlala, likhoto li tla ikarabella ho moemeli oa phepo ea dopamine amphetamine ka kotloloho ho NAc (Hoebel et al., 1983), ho bonts'a litlamorao tse matlafatsang tse phahamisang extracellular dopamine sebakeng sena. Likhoto li tla boela li tsamaise k'hok'heine ea dopamine reuptake inhibitor ho NAc, leha phello ena e fokola ka mokhoa o makatsang ha e bapisoa le e tlalehiloeng le amphetamine (Carlezon et al., 1995). Tlhatlhobo ena e lebisitse ho khopolong ea hore litlamorao tse khahlisang tsa koae li kopantsoe ka ntle ho NAc, libakeng tse kenyelletsang tubercle ea olodoory (Kemoto, 2003). Leha ho le joalo, likhoto li tla ikatisa ka nepo ea dopamine reuptake inhibitor nomifensine ho NAc (Carlezon et al., 1995), e fana ka tlhahiso ea hore litheko tsa koae tse kopanyang tsa koae moo moriana o kenang ka kotloloho ho li-neuron. Ho kenella ka har'a dopamine D2-khetha antagonist sulpiride e ipehela ts'ebetso ea boithati ea nomifensine, ho bonts'a karolo ea bohlokoa bakeng sa li-receptors tsa D2 joalo ka litlamorao tse thabisang tsa intra-NAc microinfusions tsa sehlahisoa sena. Ha ho nahanoa hammoho le bopaki bo tsoang lipatlisisong tse ling tse fapaneng (bakeng sa tlhahlobo, bona Rompré le Wise, 1989), lithuto tsena li lumellana ka ho felletseng le likhopolo tse teng ho 1980's hore dopamine liketso ho NAc li bapala karolo e hlokahalang le e lekaneng ea moputso le khothatso .

Leha ho na le khang e nyane ea hore liketso tsa dopamine ho NAc li lekane bakeng sa moputso, mosebetsi o mong o ile oa qala ho phephetsa maikutlo a hore ba hlokahala. Mohlala, likhoto li tla ikatisa morphine ka kotloloho ho NAc (Maqheku, 1982), hole le "trigger zone" (VTA) eo ho eona lithethefatsi li nkang karolo ho phahamisa dopamine ea extracellular ho NAc (Leone et al., 1991; Johnson le North, 1992). Ho nahanoa hore li-receptors tsa μ- le δ-opioid li fumaneha ka kotloloho ho li-NAc MSNs (Mansour et al., 1995), datha tsena e bile tsa pele ho fana ka maikutlo a hore moputso o ka hlahisoa ke liketsahalo tse etsahallang ka hofitisisa le (kapa ho theohela ka tlase ho) tse tlisoang ke dopamine. Likhoto li tla itlhahisa hape ka phencyclidine (PCP), sethethefatsi se rarahaneng seo e leng dopamine reuptake inhibitor le mohanyetsi ea seng oa tlholisano oa NMDA, ka kotloloho ho NAc (Carlezon le Wise, 1996). Ho na le lintlha tse peli tse bontšang hore phello ena ha ea itšetleha ka dopamine. Taba ea pele, ho ipusa ka botsona ha PCP ha ho amehe ke ho ts'oaroa ha dopamine D2-khetha antagonist sulpiride; 'me ea bobeli, likhoto li tla ikarabella ho tse ling tse se nang tlholisano (MK-801) kapa tlholisano (CPP) bahanyetsi ba NMDA ba se nang litlamorao tse tobileng litsing tsa dopamine ka kotloloho ho NAc (Carlezon le Wise, 1996). Lintlha tsena li fane ka bopaki ba pejana ba hore blockade ea li-receptor tsa NMDA ho NAc e lekane bakeng sa moputso mme, ka ho eketsa, moputso o ka ikemela ka dopamine. Blockade ea li-receptor tsa NMDA e ka lebelloa ho hlahisa phokotso e akaretsang ea thabo ea li-NAc MSN ntle le ho ama tlhahiso ea motheo ea thabo e kopantsoeng ke li-receptors tsa AMPA (Uchimura et al., 1989; Pennartz et al. 1990). Habohlokoa, likhoto le tsona li ikarabelle ho bahanyetsi ba NMDA ka likarolo tse tebileng tsa PFC (Carlezon le Wise, 1996), projeke eo ka kotloloho ho NAc (bona Kelley, 2004) 'me ba tsebisoe e le karolo ea potoloho ea lintho tse khothatsang ("STOP!")Ngoana, 2006). Ha ho nahanoa hammoho, lithuto tsena li fane ka lintlha tse peli tsa bohlokoa tse nkileng karolo e kholo ho theweng ha maikutlo a rona a sebetsang: pele, moputso o itšetlehileng ka dopamine o fumanoa ke blockade ea D2-receptors, e leng li-receptors tse thibelang lintho ka bongata. ho NAc ho li-MSN tsa tsela e sa tsejoeng; mme ea bobeli, ke hore liketsahalo tse neng li ka lebelloa ho fokotsa thabo eohle ea NAc (mohlala, tšusumetso ea G_i- Li-receptor tse amohelang opioid, tse fokotsang ho tsosa li-receptors tsa NMDA tse nyakallisang, tlhahiso e fokotsoang ea lethathamo) li lekane bakeng sa moputso. Tlhaloso ena e lebisitse ho nts'etsopele ea mofuta oa moputso moo ketsahalo e bohlokoa e fokotsoang ts'ebetso ea li-MSN ho NAc (Carlezon le Wise, 1996).

Bopaki bo bong ba pharmacological bo tšehetsa khopolo ena, mme bo hlahisa calcium (Ca2 +) le tšebetso ea eona ea bobeli ea len messengerosa. E butsoe ke NMDA receptors gate Ca2 +, molek'hule e bonts'ang maikutlo e ka amang depolarization ea membrane, tokollo ea neurotransmitter, phetiso ea matšoao, le molao oa liphatsa tsa lefutso (bona Carlezon le Nestler, 2002; Carlezon et al., 2005). Microinjection ea L-mofuta Ca2 + antagonist diltiazem ka kotloloho ho NAc e eketsa litlamorao tse thabisang tsa cocaine (Chartoff et al., 2006). Ha ho tsejoe hore na mekhoa e sebelisang menyetla e tlisoang ke liphetoho tse fetisisang mabapi le phaello ka Ca2 + e le bohlokoa. Monyetla o mong ke oa hore blockade ea Ca2 + protocol ka liteishene tsa mofuta oa L-e tsamaisang motlakase e fokotsa sekhahla sa ho thunya ha li-neuron kahare ho Navc ea ventral (Cooper and White, 2000). Ho bohlokoa ho tseba, leha ho le joalo, hore littiazem feela e ne e se moputso, bonyane ho litekanyetso tse lekiloeng litekong tsena. Sena se ka bonts'a hore maemo a motheo a Ca2 + protocol ka L-mofuta oa L-mofuta ka har'a NAc hangata a tlase, mme ho thata ho a fokotsa. Monyetla o amanang le ona ke hore microinjection ea diltiazem e fokotsa liketso tse fapaneng tsa koae tse kopantsoeng le NAc, moputso o sa thekeseleng. Mohlala, ketsahalo ea "transaction factor cAMP reaction element binding protein" (CREB) ka hara NAc e amana le linaha tse khelohang le phokotso ea moputso oa koae (Pliakas et al., 2001; Nestler le Carlezon, 2006). Ts'ebetso ea CREB e its'etleha ho phosphorylation, e ka hlahang ka ts'ebetso ea l-mofuta oa L-mofuta oa Ca2 + (Rajadhyaksha et al., 1999). Phosphorylated CREB e ka susumetsa polelo ea dynorphin, e leng neuropeptide e ka tlatsetsang ho linaha tse feto-fetohang ka ts'ebetso ea li-receptor tsa κ-opioid ho NAc (bakeng sa tlhahlobo, bona Carlezon et al., 2005). Karolo e ka bang teng ea intra-NAc Ca2 + ho laola linaha tse nang le moputso le tse phetetsang maikutlo ke sehlooho se tloaelehileng mosebetsing oa rona o tla hlalosoa ka botlalo ka tlase.

B. Bopaki ba limolek'hule

Lisebelisoa tse haellang tsa dopamine D2-like receptors li fokolisitse kutlo ea litlamorao ho litlamorao tse khahlisang tsa koae.Welter et al., 2007). Ho felisoa ha li-receptor tse kang D2 hape ho fokotsa litlamorao tse atlehang tsa morphine (Maldonado et al., 1997) - Haholo-holo ka ho fokotsa bokhoni ba moriana o hlasimollang dopamine ka mekhoa ea VTA: Leone et al., 1991; Johnson le North, 1992) - le ea morao-rao hypothalamic boko bo susumetsang (Elmer et al., 2005). Tlhaloso e le 'ngoe ea liphumano tsena ke hore tahlehelo ea li-receptor tse kang D2 ho NAc e fokotsa matla a dopamine ho thibela tsela e sa tsejoeng, mokhoa o behang moputso. Liphumano tsena, ha li kopantsoe le bopaki ba hore batho ba lemaletse batho ba fokotse dopamine D2-like receptor e tlamang ho NAc, ba fana ka maikutlo a hore li-receptor tsena li bapala karolo ea bohlokoa ho foleng moputso (Volkow et al., 2007).

Tsoelo-pele e 'ngoe ea bioloji ea limolek'hule e thusitse hore ho fumanoe likarabo tsa neuroadaptative ho lithethefatsi tsa tlhekefetso le bokhoni ba ho etsisa liphetoho tse joalo libakeng tsa boko bo fokolang ho hlahloba bohlokoa ba tsona. Phetoho e ngoe e joalo e ka polelo ea li-receptors tsa AMPA-mofuta oa glutamate, tse hlahisoang ka mokhoa o hlakileng bokong mme li entsoe ka mefuta e fapaneng ea li-receptor subunits GluR1-4 (Hollmann et al., 1991; Malinow le Malenka, 2002). Lithethefatsi tsa tlhekefetso li ka fetola polelo ea GluR ho NAc. Mohlala, ho pepesehela khafetsa khafetsa cocaine ho phahamisa polelo ea GluR1 ho NAc (Churchill et al., 1999). Ntle le moo, polelo ea GluR2 e phahame ho NAc ea litoeba tse etselitsoeng ho bontša ΔFosB, neuroadaptation e amanang le kutloelo-bohloko ea lithethefatsi tsa tlhekefetso (Kelz et al., 1999). Boithuto boo ho bona livaerase tsa vaerase li neng li sebelisoa ho phahamisa GluR1 ka mokhoa o ikhethileng ho NAc li bonts'a hore neuroadaptation ena e tloaetse ho etsa cocaine e le phapanyetsano litekong tsa maemo a sebaka, athe GluR2 ea NAc e eketsa moputso oa cocaine (Kelz et al., 1999). Litlhaloso tse ka bang teng bakeng sa mokhoa ona oa liphumano li kanna tsa kenyelletsa Ca2 + le phello ea eona mesebetsing ea neuronal le ho saena lipakeng. Ho eketseha ha polelo ea GluR1 ho rata ho etsoa ha GluR1-Homomeric (kapa GluR1-GluR3 heteromeric) AMPAR, e leng Ca2 + -permeable (Hollman et al., 1991; Malinow le Malenka, 2002). Ka lehlakoreng le leng, GluR2 e na le motif e thibelang Ca2 + influx; polelo e nyolohileng ea GluR2 e ka thabela ho etsoa ha GluR2-e nang le Ca2 + -impermeable AMPAR (mme ka theoretic e fokotsa palo ea Ca2 + -permeable AMPAR). Ka hona li-AMPAR tse nang le li-GPR2 li na le thepa ea 'mele e li etsang hore li sebetse hantle ho fapana le ba haelloang subunit ena, haholoholo mabapi le tšebelisano ea bona le Ca2 + (Feie. 1).

Feie. 1

Schematic e bonts'ang sebopeho sa subunit ea li-receptors tsa AMPA (glutamate). Bakeng sa bonolo, li-receptors li bontšoa ka li-subunits tsa 2. GluR2 e na le motif e thibelang Ca2 + flux ka har'a receptor, ka hona li-receptor tsa heteromeric tse nang le ...

Lithuto tsena tsa pele li ne li kenyelletsa lithuto tsa maemo a bophelo, tseo hangata li hlokang ho pepesetsoa lithethefatsi tsa tlhekefetso mme mohlomong li kenyelletsa menyetla ea moputso le boiphetetso. Boithuto ba morao-rao bo ile ba hlahloba hore na liphetoho lipuisanong tsa polelo ea GluR tse bontšang tse fumanoeng ka ho pepesetsoa lithethefatsi khafetsa li ama ho intlafatsa (ICSS), e leng mosebetsi o sebetsang oo ho oona matla a matla a tšehelitsoeng a laoloang ka nepo (Bohlale, 1996). Polelo e phahamisitsoeng ea GluR1 ka har'a khetla ea NAc e eketsa likotsi tsa ICSS, athe GluR2 e phahameng e li theola (Todtenkopf et al., 2006). Matla a GluR2 ho ICSS a tšoana hantle le a hlahisoang ke lithethefatsi tsa tlhekefetso (Bohlale, 1996), ho fana ka maikutlo a hore e bontša ho eketseha ho phello e ntle ea khothatso. Ka lehlakoreng le leng, litlamorao tsa GluR1 li tšoana hantle le tse hlahisoang ke kalafo ea prodepress ho kenyeletsa ho tlosoa hoa lithethefatsi (Markou et al., 1992) le κ-opioid receptor agonists (Pfeiffer et al., 1986; Wadenberg, 2003; Todtenkopf et al., 2004; Carlezon et al., 2006), ho fana ka maikutlo a hore e bontša ho fokotseha ho hoholo hoa moputso. Liphumano tsena li bonts'a hore polelo e phahameng ea GluR1 le GluR2 ka har'a khetla ea NAc li na le litlamorao tse fapaneng ho boits'oaro bo susumetsang. Ho feta moo, ba netefatsa lipatlisiso tse boneng li phahamisitse polelo ea GluR1 le GluR2 ka har'a khetla ea NAc li na le litlamorao tse fapaneng lithutong tsa maemo a koae ea cocaine (Kelz et al., 1999), le ho holisa kakaretso ea mathata ana ho litloaelo tse sa susumetsoang ke lithethefatsi tsa tlhekefetso. Mohlomong ho bohlokoa ka ho fetisisa, ba fana ka bopaki bo eketsehileng ba ho kenya Ca2 + flux kahare ho NAc ka moputso o fokotsoeng kapa boikhohomoso bo phahameng. Hobane Ca2 + e bapala karolo ea bobeli ho fokotseng ha methapo ea kutlo le tsamaiso ea liphatsa tsa lefutso, liphetoho lipuisanong la GluR le sebopeho sa tšebeliso ea karolo ea AMPAR ho NAc shell li ka hlahisa likarabo tsa mmele le molek'hule, tseo mohlomong li kopanang ho fetola tšusumetso. Hape, mekhoa e sebelisang phetisetso ea Ca2 + e ka tsosang mefuta e amanang le linaha tse phetseng hantle e hlalositsoe ka botlalo.

A. Bopaki ba pharmacological

Bo bong ba bopaki ba pele-pele ba hore NAc e bapala karolo ea linaha tse khelohileng e tsoa lithutong tse amanang le bahanyetsi ba opioid receptor. Microinjections of a wide-spectrum opioid receptor antagonist (methylnaloxonium) ho NAc ea likhoto tse itšetlehileng ka opiate e theha libaka tse khahlano le sebaka (Stinus et al., 1990). Ho litoeba tse itšetlehileng ka opiate, ho itlhahisa pele ho nako ho ka tsosa liphatsa tsa lefutso tsa pele-pele le lintlha tsa ho ngola ho NAc (Gracy et al., 2001; Chartoff et al., 2006), ho fana ka tlhahiso ea ts'ebetso ea li-MSN. Li-agonists tse khethiloeng tsa κ-opioid, tse etsisang litlamorao tsa endo native κ-opioid ligand dynorphin, le tsona li hlahisa libaka tse khelohang. Microinjections ea agonist ea κ-opioid ho NAc e etsa hore ho be le libaka tse feto-fetohang (Bals-Kubik et al., 1993) le ho phahamisa likotlo tsa ICSS (Chen le al., 2008). Inhibitory (G_i-coupled) Li-ept-opioid receptors li fumaneha literonkong tsa lipetlele tsa VTA dopamine ho NAc (Svingos et al., 1999), moo ba laolang tokollo ea dopamine ea lehae. Ha ho le joalo, khafetsa li se li ntse li sebelisoa ho li-receptor tsa μ- le δ-opioid (Mansour et al., 1995), le ho tsosa ho hlahisa litlamorao tse fapaneng le tsa agonists ho li-receptor tsa othr tsena litekong tsa boits'oaro. Ho joalo, lintho tse ngata haholo tse amanang le dopamine li fokotsehile ho NAc ke mokhoa o hlophisitsoeng (DiChiara le Imperato, 1988; Carlezon et al., 2006) kapa li-microinfusions tsa lehae tsa κ-opioid agonist (Donzati et al., 1992; Spanagel et al., 1992). Ts'ebetso e fokotsehileng ea lits'ebetso tsa dbamine ea midbrain e amana le linaha tse sithabetsang ho kenyelletsa anhedonia ea litoeba (Bohlale, 1982) le dysphoria bathong (Mizrahi et al., 2007). Kahoo tsela e le 'ngoe ea ho kheloha e bonahala e fokotseha tlhahiso ea dopamine ho NAc, e neng e tla fokotsa ts'usumetso ea li-inhibitory dopamine D2-like receptors tse shebahalang li le bohlokoa bakeng sa moputso (Carlezon le Wise, 1996).

Boithuto bo bong bo bonahala bo netefatsa karolo ea bohlokoa ea li-receptor tsa dopamine D2-like ho hatella likarabo tse khelohang. Microinjections ea dopamine D2-joaloka antagonist ho NAc ea likhoto tse itšetlehileng ka opiate e fana ka matšoao a ho khaotsa ha motho ka mong (1)Harris le Aston-Jones, 1994). Le ha litlamorao li ne li sa lekantsoe thutong ena, kalafo tse fanang ka maikutlo a ho khaotsa ho khaotsa khafetsa li baka linaha tse nang le maikutlo a matla ho feta ha li baka matšoao a ho tlohela (Gracy et al., 2001; Chartoff et al., 2006). Ho khahlisang, leha ho le joalo, li-microinjection tsa dopamine D1-agonist e tšoanang le NAc le eona e hlahisa matšoao a ho khaotsa ho litoeba tse itšetlehileng ka opoate. Lintlha li bonts'a hore tsela e 'ngoe ea ho feto-fetoha le maikutlo e eketseha ha li-receptor tse thabisang tsa dopamine D1-like recensor ka likhoto tse nang le ts'ehetso ea opiate e thehiloeng neuroadaptations ho NAc. Mohlomong ha ho makatse hore e 'ngoe ea litlamorao tsa D1-receptor e susumetsang ho likhoto tse itšetlehileng ka opiate ke phosphorylation ea GluR1 (Chartoff et al., 2006), e neng e tla lebisa ponts'etsong e eketsehileng ea li-receptor tsa AMPA ho li-MSN tsa tsela e otlolohileng.

B. Bopaki ba limolek'hule

Ho pepesehela lithethefatsi tsa tlhekefetso (Turgeon et al., 1997) le khatello ea maikutlo (Pliakas et al., 2001) kenya ts'ebetso ea mantlha e ngotsoeng CREB ho NAc. Matlafatso ea veal e hlohlelletsoang ke vaerase mosebetsing oa NAc e fokotsa litlamorao tsa lithethefatsi (Carlezon et al., 1998) le tšusumetso ea kelello ea hypothalamic (Parsegian et al., 2006), e bonts'a litlamorao tse kang anhedonia. E boetse e etsa hore litekanyetso tse tlase tsa "cocaine aversive" (letšoao le hlakileng la dysphoria), le ho eketsa boits'oaro bo sa sebetseng litekong tse qobelloang tsa ho sesa (letšoao le hlalosang la "ho nyahama ka boitsoaro") (Pliakas et al., 2001). Bongata ba litlamorao tsena li ka hlahisoa ke keketseho e laoloang ke CREB mosebetsing oa dynorphin (Carlezon et al., 1998). Ka sebele, li-agonist tse khethang li-lic-opioid receptor-khetha li na le litlamorao tse tšoanang hantle le tse hlahisoang ke tšebetso e phahameng ea CREB ho NAc, ho hlahisa matšoao a anhedonia le dysphoria ka mehlala ea moputso le ho eketseha ho sa lekeng teko e qobelloang ea ho sesa (Bals-Kubik et al., 1993; Carlezon et al., 1998; Pliakas et al., 2001; Mague et al., 2003; Carlezon et al., 2006). Ka lehlakoreng le leng, bahanyetsi ba khethang lic-velate ba hlahisa mofuta oa antidepressant-like phenotype o tšoanang le o bonoang ho liphoofolo tse nang le ts'ebetso ea CREB ho NAc (Pliakas et al., 2001; Newton et al., 2002; Mague et al., 2003). Liphumano tsena li bonts'a hore sephetho se seng sa bohlokoa sa ts'ebetso ea ts'ebetso ea lithethefatsi kapa khatello ea maikutlo ea CREB ka hara NAc ke sengoloa sa dynorphin, se baka matšoao a bohlokoa a khatello ea maikutlo. Litlamorao tsa Dynorphin li kanna tsa kopanngoa ka ho hlohlelletsa li-receptor tsa κ-opioid tse sebetsang ho thibela ts'ebetso ea neurotransmitter ho tsoa ho mesolimbic dopamine neurons, ka ho etsa joalo e fokotsa ts'ebetso ea li-neurons tsa VTA, joalo ka ha ho hlalositsoe kaholimo. Tsela ena ea ho kheloha e bonahala e fokotseha tlhahiso ea dopamine ho NAc, e neng e tla hlahisa phokotso mohopolong oa inhibitory dopamine D2-like receptors tse shebahalang li le bohlokoa bakeng sa moputso (Carlezon le Wise, 1996). Joalokaha ho hlalositsoe ka tlase, ho boetse ho na le bopaki ba hore polelo e phahameng ea CREB ho NAc ka kotloloho e eketsa thabo ea li-MSN (Dong et al., 2006) ntle le tahlehelo ea thibelo ea D2-regluated inhibition, ho tsosa menyetla ea hore litlamorao tse ngata li kenya letsoho karabong e khopameng.

Ho pepesetsoa hangata hoa lithethefatsi tsa tlhekefetso ho ka phahamisa polelo ea GluR1 ho NAc (Churchill et al., 1999). Bophahamo ba vaerase bo hlohlelletsang bophahamo bo phahameng ba GluR1 ho NAc e eketsa ho ts'oaroa ha lithethefatsi lithutong tsa maemo a sebaka, mofuta oa "atypical" oa maikutlo a lithethefatsi (ke hore, ho phahamisa kutloisiso ho ba iphapanyetsang ho fapana le likarolo tse khahlisang tsa koae). Phekolo ena e boetse e eketsa likotsi tsa ICSS (Todtenkopf et al., 2006), e bonts'a litlamorao tse kang anhedonia-le dysphoria. Ho khahlisang, litlamorao tsena tse susumetsang li batla li tšoana hantle le tse hlahisoang ke tšebetso e phahameng ea CREB ho NAc. Lintho tsena tse tšoanang li phahamisa monyetla oa hore litlamorao ka bobeli ke karolo ea ts'ebetso e kholo. Sebakeng se le seng se ka hlahang, ho pepesetsoa ha lithethefatsi ho ka baka liphetoho ponahalong ea GluR1 ho NAc, e tla lebisa ho eketseho ea lehae ponong ea sefahleho ea Ca2 + -permeable AMPA receptors, e leng ho eketsang Ca2 + protx le ho kenya CREB, e lebisang ho diphetoho ho sodium. polelo ea selelekela e amang motheo le e khothalelitseng thabo ea li-MSN ho NAc (Carlezon le Nestler, 2002; Carlezon et al., 2005; Dong et al., 2006). Ntle le moo, liphetoho tsa pele tsa ts'ebetso ea CREB li ka etella pele liphetoho ho polelo ea GluR1. Likamano tsena hajoale li tlas'a thuto e matla litubelong tse 'maloa tse tšehelitsoeng ke NIDA, ho kenyeletsoa le tsa rona.

A. Ho leka hypothesis ka electrophysiology

Lebaka le leng le lebisang ho thibelo ea moputso / moputso ke hore thibelo e pharalletseng le ea nako e telele ea NAc ea ho thunya, joalo ka lithuto tsa inactivation kapa lesion, ha e hlahe e hlahisa litholoana tse ntle (mohlala. Yun et al., 2004b). Sena se hlahisa monyetla oa hore ha se thibelo ea NAc, ka se, e kenyetsang moputso empa ho fapana le phetoho ho tloha ho litheko tse tloaelehileng tsa basal ho ea ho litefiso tse tlase tse etsahalang ha maemo a nang le moputso a le teng. Ho thibela nako e telele ho ka senya tlhahisoleseling e matla eo hangata e ts'oaroang ho maikutlo a nakoana a NAc ea ho thunya.

Liteko tse thehiloeng ho electrophysiology tsa likhakanyo tsa hypothesis ena li oela ka mekhahlelo e 'meli ea bohlokoa. Mokhahlelo oa pele o kenyelletsa ho laola sebopeho sa phoofolo hore e hlahise liphetoho tse tsitsitseng karabelong ea maikutlo le meputso e lateloang ke liteko tsa motlakase oa naha ena o fetotsoeng oa moputso. Mohlala, boemo ba pele ba ho tlohela ho tloha ho pepesehelang nako e telele ho li-psychostimulants bo tšoauoa ka anhedonia le ho se arabele ka sepheo sa tlhaho se atlehang sa moputso. Na thibelo ea moputso / moputso e ne e tla bolela eng esale pele ka boemo ba electrophysiological ba li-neuron tsa NAc nakong ea mmuso ona? Phatlalatso e kholo ke hore li-neuron tsa NAc li tla bonts'a ho fokotseha ha khatello ea ts'ebetso e atisang ho hlahisoa ke ho ba le tšusumetso e ntle (mohlala, sucrose). Ho tsebo ea rona, sena ha se e-so fumanoe lipatlisiso. Mekhoa e ka bang teng ea ho fokotseha hoa thibelo, haeba ho ka etsahala, e ka kenyelletsa keketseho e akaretsang ea thabo ea neuronal e hlahisoang ke motsoako ofe kapa ofe oa liphetoho menahanong ea methapo (mohlala, lipalo tsa Na + kapa Ca2 +, phallo ea K +) kapa phetiso ea synaptic (mohlala, fokotseha ka glutamatergic kapa keketseho ea phetisetso ea GABAergic). Ka lehlakoreng le leng, data e fumanehang ho NAc MSN thabo nakong ea ho tlosoa ha psychostimulant ea pele e fana ka maikutlo a hore ehlile e fokotsehile nakong ea karolo ena (Zhang et al., 1998; Hu et al., 2004; Dong et al., 2006; Kourrich et al., 2007). Joalokaha ho boletsoe kaholimo, ho ka etsahala hore khatello ea maikutlo e telele ka lebaka la thabo e ka nyenyefatsa tlhahisoleseling e amanang le moputso e fumanehang lithutong tsa nakoana tsa ho thunya, mohlomong ka ho theha phello ea "fatše" le ho fokotsa boholo ba litšitiso tsena. Monyetla ona o ntse o lokela ho lekoa.

Ha re nahana ka khokahano e hlakileng pakeng tsa NAc le ventral pallidum ho encoding ea moputso (bona ka holimo), re ne re ka bolela esale pele hore liphetoho life kapa life tsa thabo e hlahisoang ke ho feto-fetoha ha boemo ba moputso oa phoofolo li ka bonahala haholo ho li-neurons tsa striatopallidal / D2. Leha ho ithuta likarolo tse hlakileng tsa 'mele tsa li-neuron tsena ho bile thata nakong e fetileng, nts'etsopele ea morao-rao ea mola oa litoeba tsa BAC tse hlahisang GFP ho li-neuron tsena (Gong et al., 2003; Lobo et al., 2006) e entse hore ho khonehe ho li bona kahare a vitro litokisetso tsa methapo, li nolofalletsa haholo monyetla oa tlhaiso ea mmele ea lisele tsa D2.

Mokhahlelo oa bobeli oa liteko tse thehiloeng ho electrophysiology li kenyelletsa ho sebelisa boenjiniere ba liphatsa tsa lefutso (bona ka tlase) ho fetola polelo e sebetsang ea likarolo tsa bohlokoa tsa mochini oa cellular bakeng sa thabo kapa modumo ea ho feto-fetoha ha li-neuron tsa NAc. Ka khopolo, sena se ka thusa ho feto-fetoha ha lithibelo kapa menyaka e amanang le moputso kapa ho hloea, ka ho latellana, ka li-neuron tsa NAc. Ka sena kelellong, mohlomong limolek'hule tse fumanehang ka ho fetisisa e kanna ea ba karolo ea ts'ebetso e its'epahalletseng ea ts'ebetso ea thabo ea mothong, ho fapana le ho boloka litefiso tsa ho thunya ho basal. Lipheo tsena li kanna tsa fana ka monyetla o betere oa ho fetolela karabelo ea susumetso ho feta lipehelo tse akaretsang (mohlala: tšekamelo ea Na +), ka ho etsa joalo ho thusa ho lekola tlhahlobo ea maqhubu / moputso. Mohlala, khafetsa ho thunya ha li-neuron tse sebetsang ho ka laoloa ke mekhoa e sa tšoaneng ea ionic e hlahisang spike kamora-hyperpolarizations (AHPs). Ka ho shebella li-neuron tsa NAc tse nang le liphatsa tsa lefutso (kapa mohlomong le pharmacologic) tse reretsoeng merero e hlahisang AHPs, ho ka etsahala hore li fokotse boholo ba likarabo tse amanang le maikutlo a nyarosang mabapi le li-neurons tsena mme ka tsela ena ho lekola hore na phetoho ee ea 'mele e lumellana le boits'oaro bo fokotsehileng. matšoao a ho khopisa.

B. Ho etsa tlhahlobo ea maikutlo ka litekanyetso tsa boitšoaro

E 'ngoe ea liteko tse totobetseng tsa meriana e ne e tla tseba hore na likhoto li iphekola ka dopamine D2-like agonists ka kotloloho ho NAc. Ho khahlisang, mosebetsi oa nakong e fetileng o bonts'a hore le ha litheko li ikatisa ho kopanya li-D1-and d2-like agonists into NAc, ha ba iphelise ekaba karolo ea lithethefatsi ba le bang, bonyane ho tekanyetso.Ikemoto et al., 1997). Ha lintho li ntse li fumaneha feela, ho ka bonahala eka li senya mosebetsi oa rona oa tšebetso, empa bopaki ba hore li-activation tsa D1 le D2 receptors ho li-neuron tsa Nac, maemong a mang li ka baka phokotso ea thabo ea bona ea membrane e sa boneng karabelo ho e 'ngoe le e' ngoe. agonist feelaO'Donnell le Mohau, 1996). Ntle le moo, ho hlokahala mosebetsi o eketsehileng ho ithuta litlamorao tsa boitšoaro ba li-agonists tsa GABA; Nalane, mosebetsi ona o 'nile oa sitisoa ke benzodiazepines e seng e sebetsane le eona.Griffiths le Ator, 1980) ho sa tsotellehe tloaelo ea bona ea ho fokotsa ts'ebetso ea dopamine ho NAc (Wood, 1982; Finlay et al., 1992: Murai et al., 1994) - le palo e nyane haholo ea bafuputsi ba sebelisang lits'ebetso tsa boko microinjection mmoho le mehlala ea moputso. Mekhoa e meng hape ea ho leka mokhoa oa rona oa ho nahana e ka ba ho ithuta litla-morao tse tsoang libakeng tsa bokong tlase ho D2 receptor-e nang le li-MSN. Hape, bopaki ba pele bo bonts'a moputso bo kopantsoe ke ts'ebetso ea "ventral pallidum", sephetho se nahannoeng sa thibelo ea li-MSN tsa tsela e sa tsejoeng (Tindell et al., 2006).

C. Ho leka hypothesis ka boenjiniere ba lefutso

Nts'etsopele ea mekhoa ea boenjiniere ea liphatsa tsa lefutso e lumellang tsela ea liphetoho tse sa hlokeng kapa tsa maemo ho ea libakeng tse itseng tsa boko e tla ba sesebelisoa sa bohlokoa seo re ka lekang maikutlo a rona ka sona. Linyeoe ka ho tlosoa hoa GluRA (lebitso le fapaneng la GluR1) li bonts'a liphetoho tse ngata mabapi le kutloisiso ea lithethefatsi tsa tlhekefetso (Vekovischeva et al., 2001; Dong et al., 2004; Mead et al., 2005, 2007), tseo tse ling tsa tsona li tsamaisanang le tšebeliso ea maikutlo ea rona e sebetsang 'me tse ling tsa tsona ha li joalo. Tahlehelo ea GluR1 qalong ea nts'etsopele e ka fetola haholo karabelo ea mefuta e mengata ea mehopolo, ho kenyeletsa le lithethefatsi tsa tlhekefetso. Ntle le moo, litoeba tsena tsa GluR1-mutant ha li na protheine eohle bokong, athe lipatlisiso tse ntlafalitsoeng mona li bua haholo ka lits'ebetso tse etsahalang ka hare ho NAc. Lintlha tsena ke tsa bohlokoa haholo hobane tahlehelo ea GluR1 libakeng tse ling tsa boko e ka lebelloa ho ba le litlamorao tse mpe, 'me ka linako tse ling li fapane haholo litloaelong tse amanang le tlhekefetso ea lithethefatsi. Joalo ka mohlala o le mong feela, re bonts'itse hore modumo ea ts'ebetso ea GluR1 ho VTA e fana ka phello e fapaneng karabo ea likarabo tsa lithethefatsi ha e bapisoa le modumo ea GluR1 ho NAbc (Carlezon et al., 1997; Kelz et al., 1999). Se fumanoeng ho litoeba tse haelloang ke GluR1 ha se lumellane le liphetho tse kopaneng tsa NAc le VTA: litoeba tsa mofuta oa GluR1 li tsotella litlamorao tsa morphine (phello e ka hlalosoang ke tahlehelo ea GluR1 ho NAc) , empa ha ba hlahise keketseho e tsoelang pele ea karabelo ea morphine (phello e ka hlalosoang ke tahlehelo ea GluR1 ho VTA) tlhahlobo e etsahala tlasa maemo a khothalletsang maikutlo le ho kenyelletsa likarolo tse eketsehileng tsa boko. Ka hona, motho o tlameha ho ba hlokolosi ha a fana ka litlhaloso tsa libaka le tsa nakoana ho data ho tsoa ho litoeba tse kengoang: lingoliloeng li ntse li phetheloa ka mehlala ea liprotheine tse nang le litlamorao tse fapaneng (mme ka linako tse ling tse fapaneng) le boitšoaro ho ipapisitse le likarolo tsa boko tse tlas'a thuto (bona Carlezon et al., 2005).

Lithuto tsa pele ho litoeba tse nang le polelo e sa sebetseng ea mofuta o matla oa CREB — e leng thetso e fokotsang thabo ea NAc MSNs-e nahanisisa ka litlamorao tse khahlisang tsa koae ha e ntse e sa nahanele litlamorao tse tlatselletsang tsa mofumahali oa κ-opioid (DiNieri et al., 2006). Le ha liphumano tsena li lumellana le tšibollo ea rona ea tšebetso, lithuto tse ling (mohlala, electrophysiology) li ka thusa ho supa sebopeho sa 'mele oa litlamorao tsena. Leha ho le joalo, bokhoni bo eketsehang ba taolo ea tlhaho le ea nakoana ea liphatsa tsa lefutso bo laolang thabo ea li-NAc MSNs bo tla etsa hore liteko tse tsoelang pele tsa nalane ea rona ea ts'ebetso li sebetse.

E tšehelitsoe ke National Institute on Drug Abuse (NIDA) ka lithuso ho DA012736 (ho WAC) le DA019666 (ho MJT) le moprofesa oa McK Night-Land Grant (ho MJT). Re leboha MJ Kaufman, B. deB. Fredrick, le SS Negus bakeng sa tumello ea ho qaqisa datha e sa hlahisoang ho tsoa lithutong tsa bona tsa ho nahana ka bokong ho litšoene.