DeltaFosB ho kenngoa ha orbitofrontal cortex ho ka etsa hore motho a hlokomele le ho feta ha a hlokomoloha ho se sebetse hantle ho bakoang ke cocaine. (2009)

LIPOTSO: Boithuto bo bontša hore DelatFosB cand lebaka ka bobeli sensitization and desensitization (mamello).

Pharmacol Biochem Behav. 2009 Sep; 93 (3): 278-84. Epub 2008 Dec 16.

Winstanley CA, Green TA, Theobald DE, Renthal W, LaPlant Q, DiLeone RJ, Chakravarty S, Nestler EJ.

mohloli o moholo

Lefapha la Psychiatry, Setsi sa Bongaka sa Texas Southwestern Medical, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, United States. [imeile e sirelelitsoe]

inahaneloang

Liphetho tsa ho lemalla lithethefatsi li fetoha ha li sebelisoa khafetsa: batho ba bangata ba mamella litlamorao tsa tsona tse khahlisang empa ba ameha haholo ka tatellano e mpe (mohlala, ho tšoenyeha, ho hlonama, le takatso ea lithethefatsi). Ho utloisisa mekhoa e tlatselletsang mamello le maikutlo a joalo ho ka fana ka leseli la bohlokoa molemong oa ts'ebeliso ea lithethefatsi le lemalla ntho. Haufinyane re supile hore tsamaiso ea koae e sa foleng e fokotsa bokhoni ba ente ea cocaine e matla ea ho ama ho kenella ho likhoto. Le ha ho le joalo, liphoofolo li ba leqe ho feta nakong ea ho tlohela ho itaola. Re boetse re bonts'a hore taolo e sa foleng ea cocaine e eketsa polelo ea transcript factor DeltaFosB ho orbitof Pambal cortex (OFC). Ho etsisa bophahamo bona bo susumetsoang ke lithethefatsi ho OFC DeltaFosB ka phetiso ea lefutso e fetisoang ke vaerase e etsisa lintlafatso tsena tsa boits'oaro: DeltaFosB e bua haholo ka OFC e etsa hore motho a mamellehe litlamorao tsa phephetso e matla ea koae empa o anela likhoto ho latela tsela eo a utloang ka eona.. Mona re fana ka tlaleho ea tlhahlobo e bonts'ang hore DeltaFosB e ntseng e eketseha ho OFC e boetse e hlokomelisa liphoofolo ka thepa ea "cocaine" e khothalletsang batho hore ba ts'oarehe. Analysis ea li-nucleus tse bokellaneng lisele tse nkiloeng ho likhoto ho feta DeltaFosB ho OFC mme e alafshoang ka mokhoa o sa foleng ka letsoai kapa cocaine ha e fane ka ts'ehetso bakeng sa mohopolo oa hore ho eketseha ha OFC DeltaFosB ho ka matlafatsa maikutlo ka li-nucleus accumbens. Lintlha tsena li fana ka maikutlo a hore ho mamellana le ho matlafatsoa ke litlamorao tse ngata tsa k'hok'heine, leha li bonahala e le likhanyetso, li ka susumetsoa ka mokhoa o ts'oanang ka ts'ebeliso e ts'oanang ea tikoloho sebakeng se le seng sa boko, le hore liphetoho tse bakiloeng ke lithethefatsi liphatsong tsa lefutso ka har'a OFC li bapala karolo ea bohlokoa. likarolong tse ngata tsa lemalla ntho.

1. Selelekela

TKetsahalo ea mamello le maikutlo a thellisang lipelong tsa likhopolo tsa hona joale mabapi le bokhoba ba lithethefatsi. Ha ho nahanoa ka litekanyetso tsa Diagnostic and Statistical Manual (American Psychiatric Association DSM IV) (1994) bakeng sa bothata ba tšebeliso e mpe ea lithethefatsi, e 'ngoe ea matšoao a bohlokoa ke hore mosebelisi oa lithethefatsi o mamella litlamorao tsa lithethefatsi mme o hloka lithethefatsi tse ngata ho fihlela se tšoanang "Phahameng". Leha ho le joalo, mamello ha e tsoele pele ka potlako ho litlamorao tsa lithethefatsi, e leng se lebisang lipolaong tse feteletseng ha basebelisi ba eketsa tšebeliso ea lithethefatsi. Basebelisi ba lithethefatsi tse sa feleng ba boetse ba qobelloa, ho fapana le ho mamella likarolo tse ling tsa boiphihlelo ba lithethefatsi. Leha thabo e fumanoeng ho lithethefatsi e sa fokotsehe e ntse e fokotseha butle-butle, takatso ea ho sebelisa lithethefatsi e ea eketseha, 'me batho ba lemaletseng lithethefatsi hangata ba lemoha litlamorao tse mpe tsa lithethefatsi (mohlala, ho tšoenyeha, paranoia) le matla a likotsi tse tsamaeang le lithethefatsi ho baka lithethefatsi. boits'oaro le boits'oaro bo bobe (Robinson le Berridge, 1993). Ka ho utloisisa mekhoa ea likokoana-hloko e hlokofatsang maikutlo le mamello ho moriana, ho ts'epahetse hore mekhoa e tla fumanoa e khutlisetsa kapa e sitise ts'ebetso ea bokhoba.

Ka lebaka leo, ts'ebetso ea sensomization ea locomotor e entsoe lipatlisiso tse tebileng, haholoholo litoebeng tsa laboratori (bona (Pierce le Kalivas, 1997) bakeng sa tlhahlobo). Lithethefatsi tsa Psychostimulant tse kang cocaine le amphetamine li eketsa ts'ebetso ea locomotor. Kamora ho tsamaisoa khafetsa, karabelo ena e ea hlaka ebe phoofolo e ba le khatello e matla haholo kamora phephetso e matla ea lithethefatsi. Ha joale e se e thehiloe hantle hore locomotor sensitization crha e le hantle ho latela liphetoho lipontšo tsa dopaminergic le glutamatergic ka har'a nucleus accumbens (NAc) (bona (Kalivas le Stewart, 1991; Karler et al., 1994; Wolf, 1998). Ho fumanoe karolo e ngata ea protheine ea limolek'hule e ka bakang karabo ea karabelo ena e matla ea koloi. Protein e 'ngoe e joalo ke "transenti factor" e ntseng e eketseha ho NAc le dorsal striatum kamora ho kula ho sa foleng, empa e seng ho le thata, taolo ea lithethefatsi tse ngata tse lemalloang (Nestler, 2008). KeTekreasing NAc maemo a ΔFosB e eketsa sensitization sensacotine ho cocaine, e eketsa maemo a ratang lithethefatsi hape e nolofalletsa boikoetliso ba koae. (Colby et al., 2003; Kelz et al., 1999). Ka hona ho tla bonahala eka ho kenella ha ΔFosB ho NAc ho thusa nts'etsopele ea mmuso o lemaletseng.

Ho hlokomeleha le ho feta hore ho pepesehela lithethefatsi tse lemalloang ho ama mesebetsi e mengata e hlokolosi joaloka ho etsa liqeto le taolo e potlakileng, le hore sena se na le tšusumetso e kholo ea ho khutlela bothateng ba ho batla lithethefatsi (Bechara, 2005; Garavan le Hester, 2007; Jentsch le Taylor, 1999). Khaello ea taolo ea ts'usumetso e se e bonoe ho batho ba lemaletseng koae haufinyane, le basebelisi ba lithethefatsi tse ling (mohlala (Hanson et al., 2008; Lejuez et al., 2005; Moeller et al., 2005; Verdejo-Garcia et al., 2007). Ho 'nile ha nahanoa hore ts'usumetso ena e hlaha ho tsoa ho hypoactivity ho orbitofrontal cortex (OFC) e hlokometsoeng bathong ba joalo (Kalivas le Volkow, 2005; Roger et al., 1999; Schoenbaum et al., 2006; Volkow le Fowler, 2000). Haufinyane re hlokometse hore taolo ea koae e pheta-phetoang e eketsa maemo a ΔFosB ka har'a OFC, le hore e etsisa ts'ebetso ena ka ho kenya vaerase e amanang le adeno (AAV) e etselitsoeng ho hlahisa ΔFosB ka bongata ho OFC (phetisetso ea bongaka e fetotsoeng) lipotoloho (Winstanley et al., 2007). Maemo a phahameng a OFC ΔFosB ka hona a ka kenya letsoho ka matla ho liphetoho tse khothalletsoang ke lithethefatsi taolong ea tšusumetso.

Haufinyane re qetile lithuto tse ngata ho leka tlhahlobo ena ea maikutlo, le ho tseba litlamorao tsa taolo e matla le e sa foleng ea koae ka mehato e 'meli ea ho se tsitse litekong: boemo ba pele ho nako (bo sa qobelloang) ho arabela mosebetsing oa nako ea bohlano oa ho khetha ( 5CSRT) le khetho ea moputso o nyane kapele holim'a moputso o liehang ho lieha mosebetsing oa ho fokotsa nako (Winstanley et al., 2007). Re hlokometse hore cocaine e hlobaetsang e eketsehile ho arabela ka 5CSRT leha ho le joalo e fokotse khetho e potlakileng ea moputso o monyane kapele ho paradigm ea ho liehisa, ho etsisa litlamorao tsa amphetamine. Mokhoa ona oa boits'oaro — keketseho ea ketso e sa tsotelleng empa ho fokotseha ha khetho e sa qobelloang-o hlalositsoe e le keketseho ea tšusumetso ea moputso (Uslaner le Robinson, 2006). Leha ho le joalo, kamora ho tsamaisoa ha koae khafetsa, likhoto ha li sa bontša liphetoho tse joalo, joalo ka ha eka li mamelletse litlamorao tsa lithethefatsi tsena. Sena se fapane haholo le karabelo ea locomotor e ts'oarehang ea koae e bonoang kamora hore ho be le taolo e sa feleng e boletsoeng ka holimo. Ntle le moo, ho hlahisoa ha ΔFosB ho OFC ho hlalositse litlamorao tsa kalafo ea koae e sa foleng: litlamorao tsa koae e mpe haholo mabapi le ts'ebetso ea 5CSRT le mesebetsi ea ho theola nako ea ho liehisa li ile tsa fumaneha liphoofolong tsena, joalo ka ha eka li se li qalile ho mamella lithethefatsi. litlamorao.

Leha ho le joalo, le ha ΔFosB e ntseng e eketseha ho OFC e ne e thibela k'hok'heine e matla hore e se ke ea kenella, ho thetsoa hona ho ile ha eketsa ho hloka matla nakong ea ho tlohela ho tsoa ho 'muso oa ho iphelisa ka koae oa nako e telele (Winstanley et al., 2008). Ts'ebetso ea kelello ea liphoofolo tsena e ne e sa amehe ha cocaine e le teng, leha ho le joalo ba ne ba le kotsing ea ho qobella ho fokola ha nako ea ho tlohela. Ho laola ka mokhoa o le mong-ho eketsa ΔFosB ho OFC - ka hona ho ka eketsa mamello kapa ho ba le maikutlo a likarolo tsa litlamorao tsa koae. Mona re tlaleha tlhaiso-leseling e ncha e bonts'ang liphoofolo tse bonts'ang karabelo e fositseng ho phephetso e matla ea koae litekong tsa ho se ts'oarehe kamora ho hlahisoa ha ΔFosB ho OFC le tsona li ile tsa hlokomelisoa liketso tse tsosang takatso ea koae. Ka hona, mamello le ho susumetsa likarolo tse fapaneng tsa litlamorao tsa koae li ile tsa bonoa lithutong tse tšoanang. Ha re nahana ka karolo e boletsoeng ea NAc ho kopanyeletsa maikutlo a locomotor, le ho se be teng ha datha tse kenyang OFC tsamaisong ea makoloi, re ile ra nahana hore ho eketsa ΔFosB ho OFC ho kanna ha ntlafatsa karabelo ea makoloi ho koae ka ts'ebetso ea phetoho sebakeng sena se ts'oanang. Ka hona re entse tlhahlobo e ikhethileng re sebelisa PCR ea 'nete ea ho etsa lipatlisiso hore na ho eketsa ΔFosB ponts'ong ea mofuta oa OFC ho NAC ka mokhoa o bonts'ang ho ntlafatsa sensitization ea locomotor.

2. Mekhoa

Liteko tsohle li entsoe ho latela tataiso ea NIH bakeng sa Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro mme e amohetsoe ke Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso ho UT Southwestern.

2.1. Lihlooho

Male Long Evans litoeba (boima ba pele: 275-300 g; Charles River, Kingston, RI) li ne li kentsoe ka bobeli ka tlase ho potoloho ea mabone (mabone ho tloha 21.00-09.00) ka kamoreng ea kolone e laoloang ke maemo a leholimo. Liphoofolo boitekong ba boitšoaro (n= 84) e ne e le lijo tse lumelloang ho 85% ea boima ba bona ba ho fepa mahala ebile e bolokiloe ho 14 g ea rat chow ka letsatsi. Metsi a ne a le teng ad libitum. Teko ea boits'oaro e etsahetse lipakeng tsa 09.00 le 19.00 matsatsi a mahlano ka beke. Liphoofolo tse sebelisetsoang ho hlahisa lisele tsa boko bakeng sa liteko tsa qPCR li ne li fihlella mahala ho lijo le metsi (n= 16). Liphoofolo tsena li ne li ka fumana lijo le metsi mahala.

2.2. Ho buuoa

Lits'ila li fumane liente tsa intra-OFC tsa AAV-GFP, AAV-ΔFosB, kapa AAV-ΔJunD li sebelisa mekhoa e tloahelehileng ea stereotaxic joalo ka ha ho hlalositsoe (Winstanley et al., 2007). Likhoto li ne li sa phekoloe ka ketamine (Ketaset, 100 mg / kg intramuscular (im) ente) le xylazine (10 mg / kg im; lithethefatsi ka bobeli tse tsoang ho Henry Schein, Melville, NY). Li-AAV li ile tsa kenngoa ka har'a OFC li sebelisa ente ea tšepe ea 31 ea tšepe e se nang tšepe (Likarolo tse Nyane, Florida, USA) e kopantsoeng le pompo ea Hamilton microinfusion ka polyethylene tubing (Instech Solomon, Pennsylvania, USA). Lirosa tsa vaerase li ile tsa kenngoa ka tekanyo ea 0.1 μl / min ho latela lihokela tse latelang tse nkiloeng ho setsi sa li-stereotaxic atlas (Paxinos le Watson, 1998): saete 1 AP + 4.0, L ± 0.8, DV −3.4, 0.4 μl: sebaka 2 AP + 3.7, L ± 2.0, DV −3.6, 0.6 μl: sebaka 3 AP ± 3.2, L ±XNN 2.6 μl (bona (Hommel et al., 2003) bakeng sa lintlha tsa tokisetso ea AAV). Khokahano ea AP (anteroposterior) e nkuoe ho bregma, khokahano ea L (ea morao-rao) ho tloha bohareng le DV (dorsoventral) e hokahanya ho tsoa ho dura. Liphoofolo li ile tsa lumelloa beke e le 'ngoe hore li fole ho buuoa pele ho etsoa liteko tsa boitšoaro (liteko tsa 1) kapa tsamaiso ea lithethefatsi (liteko tsa 2).

2.3. Moralo oa liteko

Lintlha tsa tebello ea tebello ea phenomotor li fumanoe ho liphoofolo tse neng li entse tlhahlobo ea liteko tsa boitšoaro ho lekola tatellano ea tlhaiso ea litlolo tse sa feleng, mme lintlha tsena li hatisitsoe pele (Winstanley et al., 2007). Ka bokhutšoanyane, likhoto li ile tsa koetlisetsoa ho etsa 5CSRT kapa mosebetsi oa ho theola sekhahla. Joale ba ile ba aroloa ka lihlopha tse tharo tse lekantsoeng bakeng sa ts'ebetso ea motheo. Vaerase e amanang le adeno (AAV2) e hlahisang ΔFosB ka ho feteletsengZachariou et al., 2006) e kentsoe ka mokhoa o khethiloeng ho OFC ea sehlopha se le seng e sebelisa mekhoa e tloaelehileng ea ho buoa ("bona ka tlase)" Sehlopha sa bobeli se fumane infusions-OFC infusions ea AAV-ΔJunD. AAV-GFP (protheine e tala ea fluorescent) e ne e sebelisetsoa sehlopha sa taolo. Hang ha ho thehiloe motheo o tiileng oa ts'ebetso ea ts'ebetso, litlamorao tsa cocaine e mpe (0, 5, 10, 20 mg / kg ip) li ile tsa ikemisetsa ho sebetsa. Ho lekola hore na taolo e sa foleng ea cocaine e fetola litlamorao tsa ho pepesetsoa hoa koae, liphoofolo li ile tsa ts'oaroa kahare le lipakeng tsa lihlopha tsa bona tsa opereishene ka lihlopha tse peli tse lekanang. Sehlopha se seng se ile sa tšoaroa ka mokhoa o sa tloaelehang ka letsoai, se seng ka koae (2 × 15 mg / kg) ka matsatsi a 21. Libeke tse peli kamora hore kalafo ea lithethefatsi e sa khaotseng e felise, liphephetso tse mpe tsa cocaine li ile tsa phetoa. Beke hamorao, karabelo ea locomotor ho koae e ile ea hlahlojoa.

2.4. Karabelo ea locomotor ho koae

Ts'ebetso ea locomotor e ile ea hlahlojoa mekotla e le 'ngoe (25 cm × 45 cm × 21 cm) e sebelisa sistimi ea ts'ebetso ea photobeam (PAS: San Diego Instruments, San Diego, CA). Ts'ebetso ea koleche ka 'ngoe e ne e lekantsoe ke 7 photosbeams e tšela bophara ba khokhoe, 6 cm ka thoko le 3 cm ho tloha mokatong oa likhomo. Lintlha li ne li kentsoe holim 'a likenke tsa 5 min sebelisa software ea PAS (mofuta oa 2, Lisebelisoa tsa San Diego, San Diego, CA). Kamora metsotso ea 30, liphoofolo li ile tsa kenngoa ka koae ka koae (15 mg / kg ip) mme ts'ebetso ea locomotor e behiloe leihlo bakeng sa metsotso e meng ea 60.

2.5. Quanifying of mRNA

Lits'ila li fumane liente tsa intra-OFC tsa AAV-GFP kapa AAV-ΔFosB, tse lateloang ke 21 ka makhetlo a mabeli letsatsi le leng le le leng la saline kapa cocaine, hantle feela joalokaha ho hlalositsoe litekong tsa boits'oaro. Liphoofolo li ile tsa sebelisoa 24 h ka mor'a ente ea ho qetela ea saline kapa cocaine. Likhoto li ile tsa bolaoa ke decapation. Mabali a ile a ntšoa ka potlako 'me likarolo tse peli tsa 1 mm tse boima ba 12 li-punch tsa NAc li ile tsa fumanoa' me hang-hang tsa hoamisoa le ho bolokoa ho −80 ° C ho fihlela RNA e arotsoe. Li-punches tse tsoang OFC le tsona li tlositsoe hore li hlahlojoe ke li-Micracar microarray tse netefalitseng phetisetso ea liphatsa tsa lefutso e atlehileng sebakeng sena (bona (Winstanley et al., 2007) bakeng sa liphetho tse hlakileng haholoanyane. RNA e ntšoa sampoleng ea NAc e sebelisang RNA Stat-60 reagent (Teltest, Houston, TX) ho latela litaelo tsa moetsi. DNA e silafatsang e tlositsoe ka kalafo ea DNase (DNA-Free, catalog # 1906, Ambion, Austin TX). RNA e hloekisitsoeng e ile ea fetisetsoa ho CDNA (Superscript ea Pele Strand Synthesis, Catalog # 12371-019; Invitrogen). Lingoloa tsa mofuta oa lithahasello li ile tsa emisoa ho sebelisoa qPCR ea 'nete (SYBR Green; Li-biosystems tse sebelisitsoeng, Foster City, CA) ho Stratagene (La Jolla, CA) Mx5000p 96-hantle thermocyste. Li-primers tsohle li ne li etsoa ka tloaelo ke Operon (Huntsville, AL; bona Lethathamo 1 bakeng sa tatelano) mme e netefalitsoe bakeng sa tatellano le tatellano pele ho liteko. Lintlha tsohle tsa PCR li ne li etselitsoe maemo a glyceraldehyde-3-phosphate dehydrogenase (GAPDH), e sa fetoloang ke kalafo ea koae, ho latela foromo e latelang: ΔC_t =C_t(mofuta oa phahlo) - C_t (GAPDH). Maemo a fetotsoeng a fetotsoeng bakeng sa likhoto tsa AAV-ΔFosB le AAV-GFP tse amohetseng koae, le litoeba tsa AAV-ΔFosB tse fumaneng letsoai le sa feleng, li ile tsa lekanyetsoa ho latela taolo (sehlopha sa AAV-GFP se fuoeng saline e sa feleng) ka tsela e latelang: ΔΔC_t = ΔC_t - ΔC_t (sehlopha sa taolo). Ho tsamaisana le tloaelo e khothalletsoang tšimong (Livak le Schmittgen, 2001), maemo a polelo a amanang le taolo a ne a baloa ho sebelisoa polelo e latelang: 2^−ΔΔ^C^t.

Lethathamo 1

Ho ts'oaroa ha li-primers tse sebelisitsoeng ho phahamisa maemo a cDNA ka PCR ea nako ea nnete.

2.6. Lithethefatsi

Cocaine HCl (Sigma, St. Louis, MO) e ile ea qhibiliha ka saline ea 0.9% ka bongata ba 1 ml / kg mme ea tsamaisoa ka ente ea ip. Lidao li ne li baloa joalo ka letsoai.

2.7. Tlhahlobo ea lintlha

Lintlha tsohle li ile tsa hlahlojoa ho sebelisoa software ea SPSS (SPSS, Chicago, IL). Lintlha tsa locomotor li ile tsa kenngoa ka bongata ba multifactorial ANOVA ka ho buoa (mekhahlelo e 'meli: GFP vs ΔFosB kapa ΔJunD) le kalafo e sa foleng (mekhahlelo e' meli, saline e sa foleng le cocaine e sa foleng) joalo ka lipakeng tsa lintlha, le nako ea bin e le karolo ea lithuto. Lintlha tse tsoang litekong tsa PCR tsa nako ea nnete li ile tsa hlahlojoa ke ANOVA e sa sebetseng ka ho buoa (mekhahlelo e 'meli: GFP vs ΔFosB) le kalafo e sa foleng (mekhahlelo e' meli, saline e sa foleng le cocaine e sa foleng) e le lintlha tse tsitsitseng. Litlamorao tse kholo li ile tsa lateloa ke mehlala e ikemetseng t-Liteko moo ho loketseng.

3. Liphetho

Leka 1

Tsamaiso ea koae e sa foleng e hlahisa maikutlo litlamorao tsa hyperlocomotor tsa cocaine e mpe e emeloang ke ΔFosB

Joalokaha ho ne ho ka lebelloa, sensitization sensorotor e matla e ile ea bonoa e le taolo ea liphoofolo kamora ho pepesetsoa koae ka nako e telele, 'me liphoofolo tse tšoaroang hampe ka koae li bonts'a ts'ebetso e kholo ea karohano ka lebaka la phephetso e matla ea cocaine (Setšoantšo sa 1A, kalafo e sa foleng: F_1,34 = 4.325, p<0.045). Liphoofolo li bua ka mokhoa o fetelletseng ΔJunD, phetoho e matla ea JunD e sebetsang joalo ka mohanyetsi oa ΔFosB (Zachariou et al., 2006), ho OFC li ne li sa khetholloe ho tsoa ho liphoofolo tse laoloang (Setšoantšo sa 1C, GFP vs ΔJunD, sehlopha: F_{1, 56} = 1.509, NS). Leha ho le joalo, liphoofolo tse hlalosang ΔFosB ka bongata ho OFC e neng e fumane liente tsa saline khafetsa li hlahile "li tsebisitsoe": li bonts'itse karabelo e ntlafalitsoeng ea kankere e matla e neng e sa hlaka karabelo ea balekane ba bona ba tšoaroang ke koae e sa foleng.Setšoantšo sa 1B, GFP vs ΔFosB surge × kalafo e sa foleng: F_{1, 56} = 3.926, p<0.052; OsBFosB feela: kalafo e sa foleng: F_1,22 = 0.664, NS). Liphoofolo tsa ΔFosB li ne li le ngata haholo kamora metsotso ea 15 ea pele ho ho beoa mabokoseng a locomotor (GFP vs ΔFosB: F_1,56 = 4.229, p <0.04), empa litekanyetso tsa ts'ebetso ea baetsi ba likoloi li ne li ts'oana le taolo ho 15 min pele ho tsamaiso ea koae (ho buuoa: F_{1, 56} = 0.138, NS).

Feie. 1

Sensorization ea locomotor ho koae. Acoca cocaine e hlahisitse keketseho e kholo ea ts'ebetso ea locomotor ho laola liphoofolo tse tšoaroang nako e telele le koae ea cocaine le saline (phanele ea A). Liphoofolong tse hlalosang ΔFosB (phanele B), tse fanoang khafetsa letsoai (Hape …)

Ka ho nahana hore, ha e fuoa cocaine nakong ea 5CSRT, liphoofolo tse tšoanang li bonts'itse bokhoni bo ntlafalitsoeng ba ho se thibele likarabo tsa makoloi pele ho nako, ts'ebetso ena e bonahala e ikhethile ho mofuta oa ho ts'oaroa ke mofuta oa motsamao o tlalehiloeng lithutong tsa maikutlo tsa locomotor. Leha ts'ebetso e ntlafalitsoeng ho arabela lithethefatsi tse susumetsang e ka bonts'a profil ea tsoekere, ho buoa ha -FosB ha ho eketse matšoenyeho ha ho lekantsoe ho sebelisoa maze e phahameng kapa tlhahlobo e bulehileng ea (data e sa bonts'itsoeng). Liphoofolo li ne li boetse li lula lijelong tsa IP, 'me liente tsa saline li sa fetole tšebetso ea tsona ea kutloisiso (Winstanley et al., 2007), ka hona, ts'ebetso ena ea motor e ke ke ea hlahisoa ka karabelo e akaretsang ea ente ea IP. Ka kakaretso, liphuputso tsena li bonts'a hore ho kenella ha ΔFosB ho OFC ho lekane (empa ha ho hlokahale) bakeng sa sensomisedor sensitotor e arabela cocaine, leha ΔFosB e le sebakeng se ts'oanang e baka mamello ho litlamorao tsa cocaine ho susumetso le ho ts'oaroa (1).Winstanley et al., 2007).

Leka 2

Ts'ebetso ea ts'ebetso ea koae e sa foleng e fetolela mofuta oa mofuta oa NAc

Haeba molek'hule e itseng ho NAc e ne e kenya letsoho karabong e khahlisang maikutlo e bonoang sehlopheng se tšoaroang letsoai la AAV, re ka lebella ho bona karabelo e ts'oanang ea biochemical ho liphoofolo tsena ha re bapisoa le liphoofolo ho AAV-GFP le Lihlopheng tsa AAV-ΔFosB li ile tsa phekoloa ka thata ke koae. Ntle le moo, liphoofolo tse sehlopha sa AAV-GFP tse tšoaroang ka letsoai ha lia lokela ho bonts'a karabelo kaha liphoofolo tsena ha li khothalelitsoe ke koae. Mokhoa ona oa liphetho o ne o tla bonts'oa ts'ebelisanong e kholo ea ts'ebeliso ea lithethefatsi x, e tšehetsoeng ke sampuli ea bohlokoa e ikemetseng t-e ka bapisa mekhoa ea sehlopha sa phekolo sa AAV-GFP le AAV-ΔFosB, hammoho le lihlopha tsa phekolo ea koae ea AAV-ΔFosB le AAV-GFP. Litlamorao tse kholo tsa kalafo ea lithethefatsi kapa ho buuoa li ka netefatsa hore cocaine e sa foleng kapa polelo e fetang ea ΔFosB ho OFC e ka fetolela molek'hule e lebisitsoeng ho NAc, empa tlhokomeliso ena ha e na ho hlalosa karabelo ea locomotor e hlokometsoeng sehlopheng sa kalafo sa AAV-ΔFosB . Lithapo tse tsoang phoofolo e le 'ngoe tse fumaneng infra-OFC infusions ea AAV-GFP le li-ente tsa cocaine tse sa khaotseng ha li na ho hlahlojoa ka lebaka la tlhahiso e tlase ea RNA. Boitekong bona, re ile ra shebisisa mefuta e 'maloa e' nileng ea ameha ka maikutlo a locomotor ho cocaine (bona Puisano).

3.1. ΔFosB / FosB

Maemo a FosB mRNA ho NAc ha aa ka a fetoloa ke kalafo e sa foleng ea lithethefatsi (Setšoantšo sa 2A, lithethefatsi: F_1,14 = 1.179, ns) kapa polelo ea ΔFosB ho OFC (ts'ebetso ea bongaka: F_{1, 14} = 0.235, ns). Leha ho le joalo, maemo a ΔFosB a ne a phahame haholo ho liphoofolo tse phekoloang ka ho sa feleng ka koae ho latela litlaleho tse fetileng (Chen le al., 1997); Setšoantšo sa 2B, lithethefatsi: F_1,14 = 7.140, p<0.022). Ho khahlisang ke hore palo ea ΔFosB mRNA ho NAc ea liphoofolo tse tšoaroang ka letsoai e ne e le tlase ho tseo ho tsona sengoloa sena se neng se hlalositsoe hofeta ho OFC (sethethefatsi: F_1,14 = 9.362, p<0.011). Leha ho le joalo, ho ba sieo ha ts'ebelisano 'moho le ts'ebeliso ea lithethefatsi ho bontša hore kalafo e sa foleng ea cocaine e ne e na le phello e tšoanang ho lihlopha tse tšoaroang tsa AAV-GFP le AAV-ΔFosB, e phahamisa maemo a ΔFosB ka mokhoa o ts'oanang (ts'ebeliso ea lithethefatsi ×: F_{1, 14} = 0.302, ns).

Feie. 2

Liphetoho mRNA ka hara NAc ea liphoofolo e bontša ka kotloloho GFP kapa ΔFosB ho OFC, 'me e phekoloa hampe ka letsoai kapa cocaine. Lintlha li bonts'a liphetoho tse emeng motsamaong oa polelo e le karolo ea boleng ba taolo. Lintlha tse bontšitsoeng li (Hape …)

3.2. Arc / CREB / PSD95

Ha ho na bopaki ba keketseho ea "protein" e amanang le cytoskeleton e amanang le cytoskeleton 24 h kamora ho pepeseha ha lithethefatsi tsa ho qetela, ebile ha ea ka ea eketseha ka osFosB maemong a phetoho a OFC a Arc mRNA ho NAc (Setšoantšo sa 2C, lithethefatsi: F_1.14 = 1.416, ns; opereishene: F_1,14 = 1.304, ns). Ka mokhoa o ts'oanang, ha ho liphetoho tse ileng tsa bonoa ho polelo ea CREB (cAMP Karabelo e tlamang protein)Setšoantšo sa 2D, lithethefatsi: F_1,14 = 0.004, ns; opereishene: F_1,14 = 0.053, ns). Leha ho le joalo, tsamaiso e sa foleng ea cocaine e ile ea eketsa haholo maemo a mRNA bakeng sa PSD95 (protynaptic density protein of 95 kD) (Setšoantšo sa 2E, lithethefatsi: F_1,14 = 11.275, p <0.006), empa keketseho ena e ne e tšoana le lihlopheng tsa AAV-GFP le AAV-ΔFosB (opereishene: F_{1, 14} = 0.680, ns; drug × surge: F_1,14 = 0.094, ns).

3.3. D₂/ GABA_B/ GluR1 / GluR2

Maemo a mRNA bakeng sa dopamine D₂ li-receptors li ile tsa eketseha ka mor'a taolo ea koae e sa folengSetšoantšo sa 2F, lithethefatsi: F_1,14 = 7.994, p<0.016), empa keketseho ena e ne e sa angoa ke polelo e fetelletseng ea ΔFosB ho OFC (ts'ebetso: F_{1, 14} = 0.524, ns; drug × surge: F_1,14 = 0.291, ns). maemo a MRNA a GABA_B receptor e bontšitse boemo bo ts'oanang, 'me maemo a eketseha ka tekanyo e nyane empa e le a bohlokoa kamora ho pepesetsoa koae ka ho sa tsotelehe ka bongataSetšoantšo sa 2G, lithethefatsi: F_1,14 = 5.644, p <0.037; ho buoa: F_{1, 14} = 0.000, ns; drug × surge: F_1,14 = 0.463, ns). Leha ho le joalo, litekanyetso tsa AMPA glutamate receptor subunits GluR1 le GluR2 ha lia ka tsa angoa ke ho qhekelloa ho hong, leha ho ne ho e-na le mokhoa o fokolang oa keketseho ea GluR2 kamora kalafo ea koae e sa foleng (Setšoantšo sa 2H, GluR1: sethethefatsi: F_1,14 = 0.285, ns; opereishene: F_{1, 14} = 0.323, ns; drug × surge: F_1,14 = 0.224, ns; Setšoantšo sa 2I, GluR2: sethethefatsi: F_1,14 = 3.399, p <0.092; ho buoa: F_{1, 14} = 0.981, ns; drug × surge: F_1,14 = 0.449, ns).

Ka kakaretso, le ha kalafo ea koae e sa foleng e fetotse maemo a MRNA bakeng sa mefuta e 'maloa e lekiloeng ho NAc, ha rea ka ra bona keketseho e ts'oanang ea polelo ea mefuta ena ho litoeba tse phekotsoeng ka saline e hlalosang ΔFosB ho OFC. Liphumano tsena li fana ka maikutlo a hore mefuta ena e sa kenelle karabelong e atolositsoeng ea sehlopha.

4. Puisano

Mona re bonts'a polelo e fetisang ea ΔFosB ho OFC e khothalelitseng likhakanyo tsa liketso tse tsosang takatso ea koae, e ts'oants'a liketso tsa ts'ebetso ea cocaine e sa foleng. Re kile ra bonts'a hore ts'ebetso ea liphoofolo tse tšoanang ho 5CSRT le litheko tsa ho liehisa ho liehisoa ha li anngoe haholo ke koae e mpe haholo, le hore mamello e ts'oanang le e ts'oanang e bonoa kamora ho pepesetsoa ha koae. Kahoo, maikutlo le mamello liketsong tse fapaneng tsa koae li ka bonoa ho liphoofolo tse ts'oanang, ka li-adaptation tsena ka bobeli ka molek'hule e ts'oanang, ΔFosB, e sebetsang sebakeng se le seng sa boko. Taba ea hore liketsahalo tsena ka bobeli li ka susumetsoa ka nako e le ngoe ka ho etsisa e 'ngoe ea liketso tsa koae sebakeng se le seng sa kereke e totobatsa bohlokoa ba libaka tse amanang le lithethefatsi tse sa feleng. Ntle le moo, datha tsena li fana ka maikutlo a hore mamello le maikutlo li bonts'a likarolo tse peli tse fapaneng empa li amana haufi-ufi, karabelo ea litlhare tse lemalloang.

Ka lebaka la polelo e nyolohileng ea BFosB ho NAc e ameha ka matla ho ntlafatseng maikutlo a locomotor sensotization, khopolo e le 'ngoe e ka be e le hore ho buoa haholo ka ΔFosB ho OFC pele ho hlokomelisa liphoofolo cocaine ka ho eketsa maemo a ΔFosB ho NAc. Leha ho le joalo, sephetho se makatsang se fumanoe: maemo a ΔFosB ho NAc a ne a le tlase haholo ho liphoofolo tse hlalosang ΔFosB haholo ho OFC. Litlamorao tsa boitšoaro ba ho fokotseha hona ha NAc ΔFosB ha li thata ho e hlalosa, joalo ka ho thibela liketso tsa ΔFosB ka polelo e fetelletseng ea unJunD tikolohong ena e fokotsa litlamorao tse ngata tsa koae ho litoeba (Peakman et al., 2003). Ho na le ho tšoana ho teng lipakeng tsa lipatlisiso tsena le tse entsoeng mabapi le sistimi ea dopamine. Mohlala, ho fokola ka tsela e itseng ea dopamine ho NAc ho ka lebisa ho phahametseng tlhaho ka mokhoa o ka tataisang ts'ebeliso ea lingaka tsa dopamine sebakeng sena (Bachtell et al., 2005; Costall et al., 1984; Parkinson et al., 2002; Winstanley et al., 2005b). Ka mokhoa o ts'oanang, taba ea hore maemo a cortical a ntseng a eketseha a ΔFosB a ka fokotseha polelo ea subcortical e ts'oana le ho fumana hore keketseho ea phetiso ea dopaminergic hangata e tsamaisana le ho fokotseha ho hoholo ha maemo a dopamine (striatal dopamine)Deutch et al., 1990; Mitchell le Gratton, 1992). Mochine o joalo oa ho fana ka maikutlo o ka sebetsa joang limolek'huleng tsa cellular tse sa tsebeng letho hajoale ha ho hlaka, empa ho ka bonts'a liphetoho mesebetsing e akaretsang ea li-network tsa neuronal tse bakoang ke phetoho ea bongaka ba gene. Mohlala, ho eketsa ΔFosB ho OFC ho lebisa ho nyoloheng hoa tšebetso ea thibelo ea lehae, joalo ka ha ho pakoa ke keketseho ea maemo a GABA_A receptor, mGluR5 receptor le ntho P, joalo ka ha li sibolotsoe ke tlhahlobo ea microarray (Winstanley et al., 2007). Phetoho ena ea ts'ebetso ea OFC e ka ama ts'ebetso libakeng tse ling tsa boko, tse ka lebisang phetohong ea lehae ea polelo ea expressionFosB. Hore na litekanyetso tsa ΔFosB li bonts'a liphetoho tse lekanang tšebetsong ea dopamine ke taba e hlokang hore ho etsoe lipatlisiso tse ling.

Liphoofolo tsohle li bontšitse keketseho e kholo ea maemo a ΔFosB mRNA ho NAc ho latela kalafo ea koae e sa foleng, ho latela litlaleho tse fetileng tsa maemo a liprotheine a eketsehang (Chen le al., 1997; Hope et al., 1992; Nye et al., 1995). Leha ho le joalo, tlaleho ea morao-rao e fumane hore maemo a osFosB mRNA a ne a se a sa phahamisoe haholo 24 h kamora kalafo ea amphetamine e sa foleng, leha keketseho e kholo e ile ea bonoa 3 h kamora ho ente ea ho qetela (Alibhai et al., 2007). Phapang ena e kanna ea bakoa ke phapang ea moriana oa psychostimulant o sebelisitsoeng (cocaine vs amphetamine), empa ha o fuoa halofo e khuts'oane ea bophelo ba cocaine, e tla ba ho utloahalang ho lebella hore litlamorao tsa eona ho polelo ea gene li tla tloaeleha ka potlako ho feta tsa amphetamine, ho fapana le ho fapana. Lebaka le hlakileng haholoanyane la liphetho tsena tse fapaneng ke hore liphoofolo liphuputsong tsa hona joale li ile tsa kenngoa ka tekanyetso e lekanang ea lithethefatsi habeli ka letsatsi bakeng sa matsatsi a 21 ha a bapisoa le ente e le 'ngoe e phahameng ea matsatsi a 7 (Alibhai et al., 2007). Mokhoa oa kalafo o atolositsoeng o ka fella ka liphetoho tse boletsoeng mona.

Leha liphetoho tse hlahisitsoeng ho mofuta oa gene tse bonoang ka har'a NAc e latelang cocaine e sa lumellaneng li lumellana ka kakaretso le liphumano tse tlalehiloeng pele, boholo ba litlamorao bo nyane thutong ea hona joale. Lebaka le leng la sena ke hore liphoofolo li ile tsa etsoa sehlabelo feela 24 h kamora jekiseni ea ho qetela ea koae, athe boholo ba lithuto li sebelisitse li-tiske tse ileng tsa fumana libeke tse peli ho tloha ponahalong ea ho qetela ea lithethefatsi. Boithuto bo fumanang nako ea sensomotor sensitization bo bonts'a hore liphetoho tse boletsoeng ho feta boitsoaro le polelo ea liphatsa tsa lefutso li bonoa nakong ena ea morao-rao. Leha re tlaleha keketseho e nyane mRNA bakeng sa dopamine D₂ receptor ho NAc, tumellano e akaretsang ke hore maemo a polelo a D₂ kapa D₁ li-receptor ha li fetoloe ka ho sa feleng nts'etsopele ea sensomization ea sensomotor, le ha ka bobeli bo eketseha ebile bo fokotseha ho D₂ palo ea li-receptor e tlalehiloe nakoana kamora ho fela ha puso ea maikutlo (bona (Pierce le Kalivas, 1997) bakeng sa lipuisano). Phihlelo ea rona ea hore GluR1 le GluR2 mRNA li ne li sa fetoloe ka mor'a kalafo e sa foleng ea koae ka nako ena ea pele le eona e lumellana le tlaleho ea pejana (Fitzgerald et al., 1996), leha keketseho ea GluR1 mRNA e fumanoe nakong ea morao-rao-lintlha kamora ho khaotsa kalafo e sa foleng ea psychostimulant (Churchill et al., 1999).

Leha ho le joalo, re bone keketseho e nyane ho PSD95 mRNA ho NAc ea liphoofolo e tšoaroang hampe ke koae. PSD95 ke molek'hule e hlaselang, 'me ke e' ngoe ea liprotheine tse kholo ka har'a mesaletsa ea postynaptic ea li-synapses tse thabisang. E hloa li-receptor tse 'maloa tsa glutamate le liprotheine tse tsamaeang le eona ho "synapse",' me keketseho ea polelo ea PSD95 ho nahanoa hore e bonts'a ts'ebetso e eketsehang ea synaptic le ho kenyelletsa ho eketsang le ho tsitsisa ha li-receptor tsa glutamate ho li-synapses (van Zundert et al., 2004). Karolo ea PSD95 ho nts'etsopele ea sensomization ea locomotor e khothalelitsoe pele (Yao et al., 2004).

Keketseho ea polelo ea Arc e boetse e hokahane le ho eketseha ha mosebetsi oa synaptic. Leha ho le joalo, ha keketseho ea polelo ea Arc ho NAc e hlokometsoe 50 min kamora ho kenngoa ka ente le amphetamine (Klebaur et al., 2002), data ea rona e bonts'a hore taolo e sa foleng ea cocaine ha e phahamise Arc ho NAc ka ho sa feleng, leha keketseho ea Arc e hlokometsoe 24 h kamora ho hlonama ho sa feleng ka lithethefatsi tsa antidepressant (Larsen et al., 2007) le amphetamine (Ujike et al., 2002). Keketseho ea phosphorylation ea CREB e boetse e bonoa ho NAc kamora tsamaiso e mpe ea cocaine le amphetamine (Kano et al., 1995; Konradi et al., 1994; Boithati le al., 1998), empa mohlomong ha ho makatse hore ebe ha ho na keketseho ea CREB mRNA e ileng ea bonoa ka mor'a taolo ea koae e sa foleng. Ho supa tseleng ea CREB ho nahanoa hore ke ntho ea bohlokoa ho feta maemong a qalang a ho sebelisa lithethefatsi, ka lintlha tse ngotsoeng joalo ka ΔFosB e tla busa ha ts'ebetso ea ts'ebeliso ea lithethefatsi e tsoela pele (McClung le Nestler, 2003). Le ha CREB e kentse letsoho litlamorao tse thabisang tsa koae (Carlezon et al., 1998), ha ho be le litlaleho tsa hore polelo ea CREB e ntseng e eketseha e ama maikutlo a locomotor, le ha e le hore viral-mediated e eketseha ho mohanyetsi ea matla oa "CREB", protheine ea morao-rao ea cAMP kapa "ICER" e eketsa hyperacaction e bakoang ke ente e mpe ea amphetamine (Green le al., 2006).

Ka kakaretso, leha boholo ba liphetoho tse tlisitsoeng ke lithethefatsi tseo re li boneng li lumellana le litlatsetso tse tsoang ho lingoliloeng, ha rea fumana liphetoho lipapatsong tsa mofuta oa NAc tse ka hlalosang karabelo ea locomotor mabapi le koae e bonoang liphoofolong tse sebelisoang ke lithethefatsi ka intra-OFC AAV-ΔFosB. Sena se hlahisa monyetla oa hore increasingFosB e eketsehang ho OFC e kanna ea se ke ea ama maikutlo a motor ka NAc, leha mefuta e meng e mengata e sa ithutoang mona e kanna ea ba le seabo. Bopaki bo bonts'ang bo fana ka maikutlo a hore ho feto-fetoha ha medial prefrontal cortex (mPFC) ho ka fetola liketsahalo tsa litheko, ka ho etsa joalo, ho kenya letsoho ho hoheleng ha boitsoaro ho psychostimulants (Steketee, 2003; Steketee le Walsh, 2005), leha e le tse fokolang tse tsebahalang ka karolo ea libaka tse tlang pele ho sebaka sa mantlha tse kang OFC. NAc e amohela tse ling tse tsoang ho OFC (Berendse et al., 1992). Leha ho le joalo, tlhahlobo ea morao-rao le e qaqileng e bontsitse likhakanyo tse 'maloa tse tobileng haholo tsa OFC-NAc: ho ngolla ka nqane ho karolo ea morao-rao ea khetla ea NAc ho ile ha bonoa ka morao ho entetsoa ha ente ea anterograde tracer libakeng tsa OFC, le tse ka hare-hare tsa OFC tikoloho e romela likhakanyo tse nyane ho mantlha ea NAc (Schilman et al., 2008). Bohareng ba bo-caudate-putamen bo fuoa bolulo bo bongata haholo. Ka lebaka la bopaki bona bo nang le boiphihlelo, boholo ba li-tisc tsa NAc tse hlahlobiloeng ho ts'ebetso ea rona ea PCR li ka be li sa ka tsa ngolisoa ka kotloloho ke OFC, ho fokotsa menyetla ea hore liphetoho leha e le life tsa polelo ea gene li ka bonoa ka katleho.

OFC e hola haholo ho libaka tseo ka botsona li amanang le NAc, joalo ka mPFC, basolateral amygdala (BLA), caudate putamen le subthalamic nucleus (STN). Hore na liphetoho ho OFC li ka fetola ts'ebetso ea NAc ka tsela e sa tobang ka tšusumetso ea tsona libakeng tsena ke potso e bulehileng. Ho bonts'itsoe hore ts'ebetso ho BLA e fetoloa ka mor'a lesapo la OFC, le hore sena se thusa haholo ho fokotseng thuto e khutlisetsang morao e bakiloeng ke tšenyo ea OFC (Stalnaker et al., 2007), empa litlamorao tse teng libakeng tse kang NAc ha li sa tla boleloa. E kanna ea hlahisa litholoana tse ngata ho tsepamisa maikutlo libakeng tse ling tse hokahaneng haholo le OFC le tse amehang haholo taolong ea makoloi. STN ke sepheo se ts'episang haholo, hobane ha se feela hore lesapo la STN le OFC ha le hlahise litlamorao tse tšoanang ho ho ithuta le ho ithuta tsa Pavlovian (Baunez le Robbins, 1997; Chudasama et al., 2003; Uslaner le Robinson, 2006; Winstanley et al., 2005a), empa sensostization ea psychostimulant-ikiwa e amanang le maikutlo e amahanngoa le keketseho ea polelo ea c-Fos sebakeng sena (Uslaner et al., 2003). Liteko tsa nako e tlang li reretsoe ho fumana hore na liphetoho tse fetotsoeng ke lithethefatsi ho mofuta oa gene ka har'a OFC li ama ts'ebetso ea libaka tse tlase joalo ka STN li lokeloa. OFC e boetse e romela mohopolo o nyane sebakeng sa ho kenella ka hare (Geisler et al., 2007), tikoloho e tsejoang e nka karolo ka botebo ho ntlafatseng maikutlo a locomotor sensitization. Ho ka etsahala hore tlhahiso ea ΔFosB ea OFC ka lebaka leo e ka susumetsa maikutlo a locomotor tseleng ena.

Sebopeho se tobileng sa kamano lipakeng tsa liphetoho tse susumetsoang ke lithethefatsi ts'ebetsong ea kelello le sensitization ea locomotor ha li sa hlaka, 'me ha joale re se re tsepamisitse maikutlo ho OFC. Ka lebaka la liphumano tsena, ho ka etsahala hore liphetoho lipuong tsa gene tse amanang le nts'etsopele ea sensomization ea locomotor libakeng tse ling tsa boko li ka ba le tšusumetso e itseng karabong ea kutloisiso ea koae. Litlhahlobo tse lekolang tšebelisano lipakeng tsa libaka tsa cortical le subcortical kamora ho tsamaisoa ha lithethefatsi tse lemalloang li ka hlahisa leseli le lecha mabapi le hore na naha e lemaletseng e hlahisoa le ho bolokoa joang, le likarolo tse kopanetsoeng tse bapaloang ka maikutlo le mamello ts'ebetsong ena.

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