Proc Natl Acad Sci US A. 2007 Mar 20; 104 (12): 5181-6. Epub 2007 Mar 9.
Ventura R, Morrone C, Puglisi-Allegra S. Tšebeliso
mohloli o moholo
Santa Lucia Foundation, Setsi sa Europe sa Patlisiso ea Brain (CERC), Via del Fosso di Fiorano 65, 00143 Roma, Italy. [imeile e sirelelitsoe]
inahaneloang
Bopaki ba morao-rao bo fana ka maikutlo a hore mehopolo e thabisang le e nyenyefatsang e ama likarolo tse tšoanang tsa boko, ho kenyelletsa le medial preambilial cortex le nucleus accumbens. Le ha li-nucleus accumbens li tsebahala ho arabela ho ts'usumetso e kholo, ho sa tsotelehe valence ea bona ea hedon, ka khetho e eketsehang ea dopamine, ha ho tsejoe ka karolo ea preortal ea cortex ho moputso- le tšusumetso e amanang le ho hlohlona kapa mabapi le li-neurotransmitters tse amehang. Mona re fumana hore boikhethelo ba norepinephrine bo ikhethileng ka mokhoa oa pele oa cortex ea mace o felisitse keketseho ea ho lokolloa ha norepinephrine ke preortal cortex le dopamine ka nucleus accumbens e khothalletsoang ke lijo, cocaine, kapa lithium chloride mme e sitisitse boemo ba maemo bo hlahisitsoeng ke lithium ka bobeli. chloride (aversion) le lijo kapa cocaine (ratang). Hona ke bopaki ba hore phetisetso ea pele ea cortical norepinephrine e hlokahala bakeng sa sepheo sa ho susumetsoa ke sesosa sa ho susumetsoa ke moputso le tšusumetso e amanang le phallo ka ho feto-fetoha ha dopamine ho li-nucleus accumbens, sebaka sa boko se kenyelletsang boits'oarong bohle bo susumetsoang.
Liphoofolo le batho ba na le matla a ho batla meputso le ho qoba likotlo. Boitšoaro bona bo hlakileng bo kenyelletsa bokhoni ba ho emela boleng ba moputso le ho otla, ho theha likhakanyo mabapi le bona, le ho sebelisa boitlamo ho tataisa boitsoaro (1). Ha feela maikutlo a ka hlalosoa e le "lipuo tse khothalelitsoeng ke bahlophisi (meputso le bahlahisi)" (2), ho utloisisa likarolo tsa boko tse kenyelletsoang ts'ebetsong ho fana ka meputso e sa ts'oaneng kapa e nyarosang e ka ba molemong oa ho utloisisa liphoso tse ngata tsa maikutlo ho batho.
Lintlha tsa morao-rao li bonts'a hore li-nucleus accumbens (NAc) le preortal cortex (pFC) li etsa karoloana e le 'ngoe ea ts'ebetso ea ts'ebetso e khothatsang le e khahlisang (3-7). Ventral striatum (kapa NAc) e kenella ho ts'ebetsong tlhaiso-leseling e tlasa taolo e susumetsang ea boitšoaro bo tataisoang ke sepheo, 'me lithuto tsa batho le liphoofolo li tšehetsa karolo e akaretsang bakeng sa sebaka sena sa boko ho ts'ebetsong mehopolo e monate le e nyarosang, ho sa tsotelehe valence (3-8 ).
Ho feta moo, bopaki bo bongata bo fana ka maikutlo a hore pFC e kenella ka kotloloho boits'oarong bo tataisoang ke sepheo le ts'ebetsong e sebetsang (1, 9). Leha ho le joalo, leha phetisetso ea dopamine ho NAc e kopantsoe hore e kopanye ts'ebetso e arolelanoang ea "susumetso ea ts'usumetso" ho valence e ntle le e mpe (3, 6), karolo ea pFC ts'ebetsong ena le subocate ea methapo e amehang.
Phetisetso ea Norepinephrine ho pFC e hlahisoa ke maikutlo a susumetsang (10, 11) mme a susumetsa takatso ea maikutlo le ea maemo (12, 13). Ho feta moo, norepinephrine ho medial pFC (mpFC) e sa tsoa bontšoa ho kenya letsoho litlamorao tse khotsofatsang tsa lithethefatsi tse ling tse tloaeloang ho hlekefetsoa ka ketso ea eona ea ho feto-fetoha ha tlhahiso ea dopamine ho NAc (14, 15). Sena se fana ka maikutlo a hore phetisetso ea pele ea cortical norepinephrine e kenya dopamine hore e sebetse hantle ka mokhoa o susumetsang.
Mona, re sebelisa litoeba, re qalile ho lekola hore na mokhoa oa pele oa cortical norepinephrine / mesoaccumbens dopamine ke mofuta o tloaelehileng oa neural o kentsoeng ts'ebetsong ho latela tšusumetso e ntle le e fosahetseng. Haholo-holo re fuputse hore na norepinephrine ho mpFC, ka ts'ebetso ea eona ea modulating tsamaisong ea dopaminergic mesolimbic, e hlokahala bakeng sa tšusumetso ea sepheo sa ho susumetsa sa ho khothaletsa moputso- le sepheo se amanang le ho hlohlona.
Hobane boiphihlelo ke bona bo hlakileng ba tšusumetso ea khothalletso e fe kapa e fe e fuoeng (7), re ile ra lekola litlamorao tsa ho pepesehela lijo tsa tlhaho tse monate (tse fumanehang habonolo, chisi ea lebese) le tšusumetso ea motsoako oa litlhare (cocaine) le tšusumetso e matla ea motsoako oa pharmacological [lithium chloride] (LiCl)] on prepaleal cortical norepinephrine le dumbamine e tlisoang ke dopamine e tsoa ka intracerebral micodialysis. Ntle le moo, ho fumana hore na phetisetso ea pele ea norepinephrine e laola ho eketseha ha tlhahiso ea dopamine e kenyellelitsoeng ke ho pepesoa hoa tšusumetso ea maikutlo a mantlha, re boetse re sekasekile litlamorao tsa khetho e mpe ea norepinephrine ho mpFC mabapi le tokollo ea dopamine ho NAc le tokollo ea norepinephrine ho mpFC e hlahisitsoeng ke pepenyo ea pele. ho tsena.
Kamora nako, re ile ra etsa lipatlisiso ka litlamorao tsa ho tepella ho ho khetheha ha tlhoekiso ea noradrenergic pele ho maemo a khethiloeng (CPP) a susumetsoang ke chokolete le koae hape le sebakeng se phephetsang (CPA) se hlohlellelitsoeng ke LiCl. Mokhoa oa ho lokisa maemo o ile oa khethoa bakeng sa boithuto bona hobane bo ne bo lumella tlhahlobo ea thepa e fumanehang le litheko tse khahlisang ho susumetsoa ka meputso ea mantlha le liketsahalo tse feto-fetohang mme hobane bopaki bo bongata bo supa hore ke mohato o ka tšeptjoang oa lits'ebetso tse ka tlase. tšusumetso e susumetsang ea ho susumetsa (3, 16).
LIPOTSO
Leka 1.
Ho lekola hore na ho ba le tšusumetso ea pele ho litheko tse monate le tse sa tsotelleng tse amang tšusumetso ea pele ea norepinephrine le hypopal dopamine, re ile ra hlahloba, ka ts'ebetso ea microgalbric, litlamorao tsa systemca cocaine kapa LiCl le tšebeliso ea chokolete ka ho lokolloa ha norepinephrine ho mpFC le dopamine outflow ea NAc. Ntle le moo, ho tseba hore na phetiso ea cortical noradrenergic e hlokahala bakeng sa tlhahiso ea dopamine e kentsoeng ka sepheo sa ho hlahisa maikutlo ana a susumetsang, re ile ra lekola litlamorao tsa ho tepella ho hoholo ha noradrenergic ho karabelo ea dopamine e tlisoang ke cocaine, chokolete, le LiCl. Cocaine, chokolete, le LiCl li hlahisitse keketseho e lebelletseng ea nako ea norepinephrine e tsoang mpFC ea lihlopha tse tšoaroang ke sham, e fihla keketseho e kholo ea ≈200% ho 40 min, ≈70% ho 120 min, le ≈100% ho 60 min, ka ho latellana (sa feiga. 1a). Leha ho nts'etsopele ea norepinephrine e ntseng e eketseha ka har'a pFC mabapi le koae ho tlalehiloe haholo, ho tsebo ea rona ena ke tlaleho ea pele ea norepinephrine e tsoetseng pele e hlahisoang ke ho pepesetsoa ke chokolete kapa systemic LiCl ka har'a mpFC. Tsena li boetse li hlahisitse keketseho e lebelletseng ea nako ea dopamine ho tsoa ho NAc ea liphoofolo tse tšoaroang ke sham (sa feiga 1b), tumellanong le pono ea hore sebaka sena se bapala karolo e kholo ts'ebetsong ea litheko tse kholo ho sa tsotelehe maemo a tsona a makatsang (3 , 6). Litlamorao tsa bofokoli bona mabapi le ho lokolloa ha norepinephrine ho mpFC le tsona li ile tsa hlahlojoa. Preleal norepinephrine depletion e ile ea fumanoa ka ho khetha masapo a methapo a methapo ea methapo ea methapo ea methapo (li-norepinephrine-depleted lihlopha) ho mpFC kamora ts'ireletso ea dopamine ke inhibitor e ikhethileng. Mokhoa ona o hlahisitse phello e matla ea litekanyo tsa lisele tsa norepinephrine (≈90%), e siea litekanyetso tsa lisele tsa dopamine li sa sebetse. Liphoofolo tse laolang (lihlopha tse tšoaroang ke sham) li ne li tšoaroa ka tsela e tšoanang le litoeba tse senyehileng tsa norepinephrine empa li ile tsa fuoa koloi e kenang. (Tekanyo ea lithane tsa Norepinephrine e ne e le ka tsela e latelang: sehlopha se tšoeroeng ke sham, 698 ng 26 ng / g wet tiske; sehlopha sa norepinephrine-depleted, 63 ± 17 ng / g litekanyetso tsa metsi tsa dopamine li bile ka tsela e latelang: sehlopha se tšoeroeng ke sham, 203 ± 18 ng / g wet wet; sehlopha se felloang ke norepinephrine, 189 tissue 16 ng / g wet wet.)
Setšoantšo sa 1.
Prefrontal cortical norepinephrine depletions ho extracellular norepinephrine ho mpFC le dopamine ho NAc. Extracellular norepinephrine (NE) ho mpFC (a) le dopamine (DA) ho NAc (b) ea liphoofolo tse hlatsoitsoeng ka sham kapa tsa norepinephrine tse hlatsoitsoeng ka letsoai, (more…)
Khetho ea ho fokola ha norepinephrine ho mpFC e bakelitse keketseho ea dopamine e tlisoang ke pele le tokollo ea pele ea cortical norepinephrine e hlahisoang ke lithethefatsi ka bobeli le chokolete (sa feiga. 1), leha e ne e sa ame ka matla phapang ea basal extracellular dopamine ho NAc (sehlopha se tšoeroeng ke sham-1.35 ± 0.15 pg ka nng. 20 μl; sehlopha sa norepinephrine-depleted, 1.29 ± 0.18 pg ka 20 μl) kapa basal extracellular norepinephrine ho mpFC (sehlopha se tšoaroang ke sham, 1.31 ± 0.18 pg ka 20 μl; sehlopha sa norepinephrine-depleted, 1.26 ± 0.17 pg ka 20 μl. Litekanyetso tsa motheo tsa dopamine ho NAc le tsa norepinephrine ho mpFC bakeng sa sehlopha ka seng [saline, cocaine (20 mg / kg), LiCl (3 meq / kg), le chokolete] li ne li sa fapana haholo
Liphetho tsa rona li bonts'a hore phetisetso e matla ea "noradrenergic" ka har'a mpFC ke boemo bo hlokahalang bakeng sa ts'usumetso ea tokollo ea dopamine e susumetsoang ke khothaletso e monate le e makatsang kahare ho NAc, ka hona, e fana ka maikutlo a hore karolo ea eona e kholo ketsong ea ts'usumetso.
Leka 2.
Ho etsa lipatlisiso tsa hore na phetisetso ea pele ea norepinephrine e ea hlokahala bakeng sa ho fumana thepa e nang le takatso le lintho tse hanyetsanang le sepheo sa ho khothaletsa meputso ea mantlha le liketsahalo tse bohloko, re ile ra lekola litlamorao tsa ho felloa ke matla ha pele ho norepinephrine maemong a sebaka.
Pele ho fokotseha ho fokotsoa ha morafo oa "cocaine" le chokolete e hlahisang chokolete hammoho le CPA e hlahisitsoeng ke LiCl. Kahoo, le ha liphoofolo tse phekotsoeng ke sham li bontšitse khetho ea bohlokoa bakeng sa kamore ea koae-kapa e nang le chokolete le bohlokoa bo boholo ho komporo ea li-LiCl-paired (sa feiga. 2a), liphoofolo tse se nang letho tse haellang li ne li sa rate letho ka komporong (sa feiga. 2b ).
Setšoantšo sa 2.
Prefrontal cortical norepinephrine e fokotseha maemong a boemo ba sebaka. Litlamorao tsa ts'ebeliso ea lijo (1 g ea chokolete ea lebese; sehlopha se tšoaroang ke sham
Hlokomela hore litlhahlobong tsa pele re hlokometse hore bobeli ba CPP le CPA ea liphoofolo tse tšoaroang ka sham li ne li sa khetholloe ho tsa liphoofolo tse hlaha. Liphoofolo tse ileng tsa bona ho kopantsoe ha letsoai ka har'a likarolo tseo ka bobeli ha lia ka tsa khetha ho rata ntlo e fapaneng le e 'ngoe ka lebaka la lesion (sham e tšoeroe kapa norepinephrine e felile). Boitšoaro ba liphoofolo tse felletseng tsa norepinephrine tse tšoaroang ka koae, chokolete, kapa LiCl li ne li tšoana le tsa liphoofolo tse ileng tsa fumana tharollo ea koloi feela nakong ea thupelo; ka mantsoe a mang, ba ne ba sa bonts'a boikhethelo bakeng sa komporo ena.
TŠOHLOA
Mona re tlaleha bopaki ba hore phetisetso ea pele ea cortical norepinephrine, ka ho feto-fetoha ha dopamine ho NAc, ke boemo bo hlokahalang bakeng sa tšusumetso ea sepheo sa ho susumetsoa ke meputso e amanang le moputso le boikemisetso.
Taba ea pele, hobane boiphihlelo ba pele bo supa qeto ea tšusumetso ea khothalletso e fe kapa e fe e fuoeng (7), re se re lekotse, ka intracerebral micodialysis, litlamorao tsa ho pepesehela k'holeseterole kapa LiCl le litlamorao tsa tšebeliso ea chokolete ho norepinephrine kapa dopamine. lokolloa ho mpFC le NAc, ka ho latellana. Cocaine, chokolete, le LiCl li hlahisitse keketseho e itšetlehileng ka nako ea dopamine e anngoeng hammoho le ho hlahella hoa pele ho norepinephrine ho tsoa lihlopheng tse tšoaroang ke sham. Keketseho e kholo ea phallo ea norepinephrine e ile ea bonahala ho mpFC ea liphoofolo tse tšoaroang ke sham nakong ea metsotso ea 20 ea ho amohela chokolete; khaphatseha ka morao ho moo e ile ea khutlela mehatong ea motheo 'me ea lateloa ke kholo e kholo e ntseng e tsoela pele. Leha keketseho ena ea bumpasic ea chokolete e bakiloeng ke ho eketseha ha norepinephrine ho mpFC ha e tšoane le keketseho ea dopamine ho NAc hohle, keketseho ea pele e kanna ea amana le phello ea lijo tse fumanehang habonolo le keketseho ea dopamine ho NAc. Ka lehlakoreng le leng, keketseho e kholo ea bobeli e kanna ea emela "neurochemical correlate" ea cortical arousal e hlokahalang bakeng sa ho sebetsa lintlha tsa sepakapaka tse amanang le ho batla le ho fumana moputso oa lijo (17). Ebile, ho fanoe ka maikutlo a hore norepinephrine e tsoetseng ntle e sebeletsa ho supa boteng ba mehopolo e nang le ts'usumetso e phahameng (17). Kahoo, tlhahiso ena e eketsehang ea norepinephrine e ka lumella tlhokomeliso e hlokoang ho batla lijo tse fumanehang habonolo mme e ka thusa ho fumana thepa ea boemo bo loketseng ea tšusumetso ea lijo. Leha ho le joalo, litlamorao tse tlisoang ke ho ja lijo ka norepinephrine li ke ke tsa hlakoloa.
Leha keketseho ea dopamine ho NAc e susumetsoa ke ts'usumetso e ntle kapa e nyarosang le tlhahiso e eketsehang ea norepinephrine ho pFC ha karabelo ea koae e tlalehiloe haholo, ho tsebo ea rona ke tlaleho ea pele ea tlhahiso ea norepinephrine e hlahisoang ke tlhahiso ea chokolete kapa LiCl ka har'a mpFC. Habohlokoa le ho feta, re bonts'a mona hore phetisetso ea pele ea cortical noradrenergic e hlokahala bakeng sa phetisetso ea dopamine e tsoang ntle le ho pepesoa ke ts'usumetso ea pele ea lintho tsena tse susumetsang tse susumetsang. Ha e le hantle, ha ho na keketseho e kholo ho li-norepinephrine tsa pele le tse hlahisoang ke tšusumetso ea dopamine, tse hlahisitsoeng ke lintho tsena tse susumetsang, tse neng li bonahala ho litoeba tse felisang norepinephrine. Norepinephrine ho mpFC e kanna ea kenya tšebetsong tlhahisoaccrebens ea dopamine ka ho hlahisa likhakanyo tsa pele tsa cortical cortical ho lisele tsa dopamine tsa sebakeng sa dopamine (18, 19) le / kapa ka likhakanyo tsa corticoaccumbal glutamatergic (20). Ntle le moo, karolo ea lipehelo tsa pFC ho cousuleus ea locus ho hlahisa tšusumetso e thabisang e ka nahannoa hobane khubu ena e bontšitsoe ho kenya tšebetsong sebaka sa dopamine neurons (21 - 23), se ka lebisang ho nts'etsopele ea dopamine ho NAc.
Kahoo, liphetho tsa rona, tumellanong le litlaleho tse fetileng, li bonts'a hore mehopolo e sa lefelloeng le e nyarosang e eketsa tlhahiso ea norepinephrine ho mpFC (10 - 15) hammoho le tokiso ea dopamine ho NAc (3, 24). Habohlokoa le ho feta, li bonts'a hore phetisetso e matla ea "noradrenergic" ho fetisoa ke "phapang" ke boemo bo hlokahalang bakeng sa ts'usumetso ea tokollo ea dopamine e susumetsoang ke ts'usumetso e ntle le e matla ea bo-ralitaba le tlhaho ea tlhaho ea NAc. Ka hona, li supa ho norepinephrine ea pele le phetisetso ea dopamine e amohelang joalo ka sistimi ea neural eo ts'ebetso ea eona ka ts'usumetso e sa lefelloeng le e nyarosang e ka bang molelele oa ts'usumetso ea ts'usumetso. Pono ena e tšehetsoa ke liphetho tsa liteko tsa boitsoaro mabapi le litlamorao tsa ho theoha hoa norepinephrine depletion ho cocaine-, chokolete-, kapa LiCl.
Kahoo, tlhahlobo ea bobeli ea bohlokoa ea phuputso ena ke hore prePortal cortical norepinephrine depletion e sitisa CPP e susumetsoang ke koae kapa lijo le CPA e hlohlellelitsoeng ke LiCl. Leha liphoofolo tse phekotsoeng ke sham li bontšitse hore li rata komporo ea koae kapa e entsoe ka chokolete, hape e hloile karolo e kholo ea "LiCl-paired", liphoofolo tse se nang phepo li sa bonts'a khethollo bakeng sa kamore efe kapa efe, ka hona, ho bonts'a hore phetisetso ea pele ea cortical norepinephrine e ea hlokahala. bakeng sa ho fumana thepa e nang le maemo hore e hlohlelletsoe ka liketsahalo tsa meputso tse tlang pele kapa tse nyarosang.
Liphetho tsa hona joale li bonts'a hore, pele ho litoeba tsa pele tsa cortical norepinephrine-depleted, ho haella ha norepinephrine ho lokolloa ho hlahisoang ke tšusumetso e ntle le e khothalletsang (cocaine, lijo, kapa LiCl, tšusumetso e se nang boikemelo) e thibetse tšusumetso ea maikutlo a ho susumetsa ka tšusumetso e nang le tšusumetso (sekhahla sa moea) nakong ea linako tsa ho rala. Hape, hlokomela hore ho fokotsoa ha matla pele a norepinephrine ha hoa ka ha kena-kenana le mekhoa e amanang le eona kapa ea moralo hobane, joalo ka ha ho bontšitsoe pejana, liphoofolo tse felletseng ke norepinephrine li bontšitse hore li khona ho ithuta mosebetsi oa ho qoba (15) le ho hokahanya maemo le litlamorao tsa lithethefatsi (14). Leha ho le joalo, lipatlisiso tse eketsehileng li hlokahala ho utloisisa sebopeho se nepahetseng sa ho senyeha ha liphoofolo tse tlileng pele ho lefu la tlhaho.
Phetisetso ea Dopaminergic kahare ho NAc e nkoa e le ho kenyelletsa phello ea hedonic ea moputso kapa likarolo tse ling tsa thuto ea moputso (sheba Ref. 25 bakeng sa tlhahlobo). Liphetho tsa rona, tumellanong le pono e fapaneng (3), li bonts'a hore phetisetso ea dopamine ho NAc e bapala karolo ea boits'oaro bo khothatsang le bo khelohang; Habohlokoa le ho feta, li bonts'a hore ts'ebetso ena ea susumetso e laoloa ke preoreal cortical norepinephrine. Ha e le hantle, ho khetha pele ho pele norepinephrine depletion ho etsa hore ho be le lithibelo tse peli tsa koae kapa k'hok'heine e hlahisang chokolete le ts'ilafalo ea tokollo ea dopamine ho NAc e susumetsoang ke ts'usumetso ea lisosa tsa taolo ea litoeba, ka hona e bonts'a phetiso ea pele ea moferefere. Ho lokolloa ha dopamine kahare ho NAc, ke boemo bo hlokahalang bakeng sa ts'ebetso e susumetsang ea litheko tse amanang le moputso le maikutlo tse amanang le ho hlohlona.
Ho nkuoa hammoho, liphetho tsa hona joale ho tsoa tlhahlobong ea boits'oaro le mahlale a bonts'oa li bontša hore phetisetso ea pele ea norepinephrine ha e anele feela thepa e khahlisang ea lithethefatsi tse tloaelo e hlekefelitsoeng, joalo ka ha ho bontšitsoe ke lithuto tsa nakong e fetileng (14, 15), empa ho hlokahala bakeng sa tšusumetso ea sepheo sa ho susumetsa ka bobeli ho fumana moputso- le tšusumetso e amanang le ho kheloha, e bonts'ang le ho feta hore lithethefatsi tse lemalloang, hammoho le tšusumetso ea lithethefatsi tsa bongaka, li sebelisa mochine o le mong o amanang le methapo ea tlhaho joalo ka tšusumetso ea tlhaho.
Qetellong ea, datha ea rona e atolosa liphumano tse fetileng tse supang mesolimbic dopaminergic system e le "sisteme system" e kenyelletsang litloaelo tsohle tse susumetsoang (3, 6, 26). Li boetse li bonts'a hore sistimi ena e tlas'a taolo ea bokhoni ba norepinephrine, kahoo e ts'ehetsa maikutlo a hore mehopolo e nang le moputso le e nyarosang e ama tsela e joalo ho CNS (7).
Liphetho tsa rona li fana ka leseli mabapi le neurobiology ea moputso le ho hlohlona hobane li bontša hore ho sebetsana le sepheo sa boithabiso le sa boithatelo se kenyelletsa likarolo tse tšoanang tsa boko; ke ho re ba supa phetiso ea dopaminergic ea pele le ea dumbaminergic e le sistimi e tloaelehileng ea neural. Ho utloisisa lits'ebetso tsa "neurotransmitter" tse sebetsoang ka ts'usumetso e ntle kapa e susumetsang, le lits'ebetso tsa tsona tsa limolek'hule ho tla thusa ho fana ka lebaka la ho hlakisa tšebetso ea litsamaiso tsa neural tse amehang ho tse ntle le maikutlong a fosahetseng..
LISEBELISOA LE MEKHOA
Liphoofolo.
Litoeba tsa banna tsa mofuta oa inbred C57BL / 6JIco (Charles River Laboratories, Wilmington, MA), tse atisang ho sebelisoa ha ho etsoa li-phenotyping tsa libeke tse robeli ka nako ea liteko, li ne li bolokiloe joalo ka ha ho hlalositsoe pele (8, 9). Sehlopha ka seng sa liteko se ne se e-na le liphoofolo tse tšeletseng ho isa ho tse robeli. Liteko tsohle li entsoe ho latela molao oa naha oa Italy (Decreto Legislative no. 14, 15) o laolang tšebeliso ea liphoofolo bakeng sa lipatlisiso.
Lithethefatsi.
Chloral hydrate, 6-hydroxydopamine (6-OHDA), GBR 12909, cocaine hydrochloride, le LiCl li ile tsa rekoa ho Sigma-Aldrich (St. Louis, MO). Cocaine (20 mg / kg), LiCl (3.0 meq / kg), chloral hydrate (350-450 mg / kg), le GBR 12909 (15 mg / kg) di ile tsa qhibiliha ka saline (0.9% NaCl) mme tsa kenella ka ipineng. bophahamo ba 10 ml / kg. 6-OHDA e ile ea qhibiliha ka letsoai le nang le sodium metabisulfite (0.1 M). Bakeng sa liteko tsa lijo, moputso e ne e le chokolete ea lebese (1 g; Nestlé, Vevey, Switzerland).
Microdialysis.
Liphoofolo li ne li sa kopeloe ka chloral hydrate (450 mg / kg), e kentsoeng ka har'a mochini oa likopi (David Kopf Instrsets, Tujunga, CA) e nang le adaptara ea khanya, 'me ea kenngoa ka ntle ho naha ka setlamo sa cannula (tšepe e sa jeng, moqomo oa ka ntle oa limilimithara tse 0.38 ; Metalant AB, Stockholm, Sweden) ho mpFC kapa ho NAc (14, 15). Bolelele ba cannula ea tataiso e ne e le 1 mm bakeng sa mpFC le 4.5 mm bakeng sa NAc. Cannula ea tataiso e ne e entsoe ka sekhono sa epoxy, 'me ho kentsoe samente ea meno bakeng sa ho tsitsa. Litlhophiso tse tsoang ho bregma [tse lekantsoeng ho latela mekhoa ea Franklin le Paxinos (27)] e ne e le tse latelang: +2.52 anteroposterior le 0.6 tsa morao-rao bakeng sa mpFC le +1.60 anteroposterior le 0.6 tsa morao-rao bakeng sa NAc [hangata e kenyelletsa karohano ea karohano (27)]. Probe (dialysis membrane bolelele ba 2 mm bakeng sa mpFC le 1 mm bakeng sa NAc le bophara ba kantle ba 0.24 mm, MAB 4 cuprophane micodialysis probe; Metalant AB) e ile ea hlahisoa ka 24 h pele ho liteko tsa microdialysis. Liphoofolo li ne li sa kopantsoe hanyane ka chloral hydrate (350 mg / kg) ho kenya letsoho tlhahlobo ea tlhahlobo ea maqhubu ka har'a cannula ea tataiso. Liphoofolo li ile tsa khutlisetsoa malapeng a tsona. Sebaka sa polokelo ea kantle le se kenang se ne se sirelelitsoe ke Parafilm e sebelisoang moo. Li-membrane li ile tsa lekoa bakeng sa ho hlaphoheloa ha dopamine le norepinephrine (ho hlaphoheloa ka mokhoa o itseng ka mokhoa o latelang: dopamine, 10.7 ± 0.82%; norepinephrine, 12.2 ± 0.75%; n = 20) ka letsatsi pele ho tšebeliso ho netefatsa ho fola.
Probe ea microdialysis e ne e hokahantsoe le pompo ea CMA / 100 (Carnegie Medicine, Stockholm, Sweden) ka PE 20 tubing (Metalant AB) le torque ea ultralow ea li-channel-swivel ea metsi a 'mele (ea mohlala 375 / D / 22QM; Instech Laboratories, Seboka sa Plymouth, PA) ho lumella motsamao oa mahala. Mokelikeli oa maiketsetso oa cerebrospinal (147 mM NaCl / 1 mM MgCL / 1.2 mM CaCl2 / 4 mM KCl) e ile ea pompeloa ka sesebelisoa sa dialysis ka sekhahla sa phallo ea 2 μl / min. Liteko li ile tsa etsoa 22-24 h kamora ho beoa ha lipatlisiso. Phoofolo e 'ngoe le e' ngoe e ne e behiloe ka mokoting o chitja o fanoeng ka lisebelisoa tsa microdialysis (Instech Laboratories) le libethe tsa lapeng fatše. Pente ea Dialysis e qalile 1 h hamorao. Kamora ho qala ha perfusion ea dialysis, litoeba li ile tsa sala li sa sitisoe ke ≈2 h pele ho bokelloa lisampole tsa mantlha. Mefuta e meraro ea mehlala e bokelletsoeng hanghang pele ho kalafo (<10% variation) e nkuoe e le mohopolo oa basal. Pele liteko tsa microdialysis li qala, litoeba li ile tsa fuoa e 'ngoe ea liphekolo tse fapaneng (letsoai, k'hok'heine, chokolete kapa LiCl) sehlopheng ka seng (ho phekoloa ka sham kapa norepinephrine e felile). Bakeng sa liteko tsa lijo, liphoofolo li ile tsa beoa lenaneong la khaello ea lijo (28) matsatsi a 4 pele liteko li qala.
Dialysate e ne e bokelloa metsotso e meng le e meng e 20 bakeng sa ba 120 (bakeng sa lihlopha tsa cocaine le LiCl) kapa 160 (bakeng sa lihlopha tsa lijo) min. Ke data feela e tsoang litoeba e nang le cannula e behiloeng ka nepo e tlalehiloeng. Meetso e ile ea ahloloa ka methapo e putsoa ea methylene. Li-microliters tse mashome a mabeli tsa sampuli tsa dialysate li ile tsa hlahlojoa ke HPLC. Li-20 remainingl tse setseng li ne li bolokiloe e le hore li ka hlahlojoa hamorao. Litaba (pg ka 20 perl) ha lia ka tsa khalemeloa ho fola. Sistimi ea HPLC e ne e na le Sisteme ea Alliance HPLC (Waters, Milford, MA) le setsi sa coulometric detector (mohlala 5200A; Coulochem II, ESA, Chelmsford, MA) ba fuoe sele e nang le maemo (M 5021) le sele ea ho hlahloba (M 5011) . Seli ea maemo e ne e behiloe ho 400 mV, electrode 1 e behiloe ho 200 mV, mme electrode 2 e behiloe ho −250 mV. Kholomo ea Nova-Pack C18 (3.9 × 150 mm; Waters) e hlokometsoeng ka 33 ° C e ile ea sebelisoa. Sekhahla sa phallo e ne e le 1.1 ml / min. Mokhahlelo oa mobile o ne o le joalo ka ha o hlalositsoe pele (14, 15). Sekhahla sa ho bona lintho ka bongata e ne e le 0.1 pg.
Norepinephrine Depletion ho mpFC.
Anesthesia le sete ea bongaka e hlalositsoe ka holimo. Liphoofolo li ne li kenngoa ka GBR 12909 (15 mg / kg) metsotso e 30 pele ho 6-OHDA microinjection ho sireletsa dopaminergic neurons. Ente ea ligateral ea 6-OHDA (1.5 μg ka 0.1l forl bakeng sa lehlakore le leng le le leng) e entsoe ka mpFC [li-link tsa tsona e ne e le +2 anteroposterior, ± 2.52 lateral, le −0.6 ventral mabapi le bregma (2.0)] ka tšepe ea tšepe. cannula (bophara ba kantle ho 27 limilimithara; Ha e sa sebetsoa, Lausanne, Switzerland) e hokahantsoeng le syringe ea 0.15-μl ka phofo ea polyethylene mme e tsamaisoa ke pompo ea CMA / 1. Cannula e ile ea sala e le sebakeng sa metsotso e meng ea 100 kamora ho qeta ho kenella. Liphoofolo tse tšoaroang ka Sham li ne li tšoaroa ka mokhoa o tšoanang empa li ile tsa fuoa koloi e kenang. Liphoofolo li ile tsa sebelisetsoa liteko tsa maiketsetso kapa liteko tsa boitšoaro matsatsing a 2 ka mor'a ho buuoa.
Maemo a tishu ea Norepinephrine le dopamine ho mpFC a ile a hlahlojoa joalo ka ha ho hlalositsoe pele (14, 15) ho lekola boholo ba depletion.
Sebaka sa Boemo.
Liteko tsa boitšoaro bo entsoe ka ho sebelisa lisebelisoa tsa boemo ba sebaka (14, 15, 29). Lisebelisoa li ne li e-na le likamore tse peli tse putsoa tsa Plexiglas (15 × 15 × 20 cm) le alley e bohareng (15 × 5 × 20 cm). Menyako e 'meli e thellelisang (4 × 20 cm) e hokahantse bolele le likamore. Ka phapusing e 'ngoe le e' ngoe likarata tse peli tsa 'mala o kopaneng (5 x 5 × 20 cm) tse entsoeng ka Plexiglas e ntšo hape li hlophisitsoe ka lipaterone tse fapaneng (ka linako tsohle li koahela bokaholimo bo lekanang ba kamore) li ne li sebelisoa joalo ka tšusumetso. Liphoofolo li ile tsa sebelisetsoa liteko tsa boitšoaro matsatsing a 7 ka mor'a ho buuoa. Pele ho maemo, litoeba li ne li fuoa e 'ngoe ea kalafo e fapaneng (saline, cocaine, chokolete, kapa LiCl) kahare ho sehlopha ka seng (sham e tšoeroe kapa e norepinephrine e felile).
Ts'ebetso ea koetliso bakeng sa maemo a sebaka e hlalositsoe pele (14, 15). Ka bokhutšoanyane, ka letsatsi la 1 (mokhabo-puo), litoeba li ne li lokolohile ho hlahloba lisebelisoa tsohle tse 20 min. Matsatsing a 8 a latelang (karolo ea maemo), litoeba li ne li ts'oaroa letsatsi le leng le le leng bakeng sa 40 min alternally ho e 'ngoe ea likamore tse peli. Bakeng sa maemo a sebaka ka tšusumetso ea pharmacological, e 'ngoe ea lipaterone e ne e kopantsoe khafetsa ka saline ebe e ngoe e na le koae (20 mg / kg ip, CPP) kapa LiCl (3.0 meq / kg ip, CPA) nakong ea maemo a maemo. Motsoako ona o ile oa khethoa motheong oa lithuto tse fetileng tse bonts'ang hore litoeba tsa C57BL / 6JIco li bonts'a CPP e matla ho lethal dose ea koae ea 20 mg / kg (30, 31) le mokhoa oa ho fetohela tekong ea CPA ka tekanyo ea LiCl ea 3.0 meq / kg (32). Bakeng sa liphoofolo tse sehlopha se laolang, likamore ka bobeli li ne li pentiloe ka letsoai. Bakeng sa CPP ka lijo, e 'ngoe ea lipampiri li ne li kopantsoe le lijo tse tloaelehileng (1 g ea lijo tse tloaelehileng tsa panya) e' ngoe ka lijo tse fumanehang habonolo (1 g ea chisi ea lebese). Liphoofolo li ile tsa beoa lenaneong la thibelo ea lijo (28) matsatsi a 4 pele boemo bo qala. Kemiso ena e ile ea tšoarella maemong ohle.
Bakeng sa liteko tsohle tsa maemo a boemo ba sebaka, lipara li ne li leka-lekane hoo halofo ea sehlopha ka seng sa liteko liteko tse sa lumellaneng (k'hok'heine, chokolete kapa LiCl) li neng li kopantsoe le o mong oa mekhoa e 'meli; bakeng sa halofo e 'ngoe ea sehlopha ka seng, tšusumetso e se nang maemo e ne e kopantsoe le paterone e' ngoe. Ho lekoa polelo ea CPP kapa CPA ho entsoe ka letsatsi la 10 ka ho sebelisa mokhoa oa boiketsetso. Lintlha tsa boits'oaro li ile tsa bokelloa tsa ba tsa hlahlojoa ke EthoVision sistimi e ikemetseng ea ho latela livideo (Noldus, Wageningen, Netherlands). Ka bokhutšoanyane, sistimi ea liteko e tlalehiloe ke kh'amera ea video ea CCD. Letšoao le ntan'o fetoloa ka digitally (ka sesebelisoa sa lisebelisoa se bitsoang frame frame) ebe le fetisetsoa mohopolong oa komporo. Hamorao, tlhaiso-leseling ea dijithale e sebelisoa ke software ea EthoVision ho fumana "nako e sebelisitsoeng" (ka metsotsoana), e sebelisoang e le data e tala bakeng sa likhetho tse khethiloeng lekaleng ka leng la lisebelisoa ka sehlooho ka seng.
Lipalopalo.
Sebaka sa boemo.
Bakeng sa liteko tsa maemo a sebaka, tlhahlobo ea lipalo e entsoe ka ho bala nako (ka metsotsoana) e sebelisitsoeng bohareng (Center), lithethefatsi / chocolate-paired (Paired), le li-compartments tsa saline / standard-paired (Unpaired) ka letsatsi la liteko. Sebakeng sa liphoofolo tse fumanang maratsoana a letsoai ka likarolo tse peli, phaposi ea Paired e ile ea tsebahala e le ea pele eo ba ileng ba e pepesetsoa.
Litholoana tsa ho ikhetholla ho fokola ha cortical norepinephrine kapa ho theoha ha boemo ba sebaka.
Lintlha tse tsoang litekong tsa maemo a sebaka li ile tsa hlahlojoa ka ho sebelisa mehato ea khafetsa ANOVA e nang le lipakeng tsa ntlha (boits'oaro, mekhahlelo e 'meli: sham e tšoeroe le norepinephrinedepleted) le ngoe ka har'a lebaka (ho tsamaisa, mekhahlelo e meraro: Setsi, se Paired, le se sa lefelloang) bakeng sa kalafo ka' ngoe [ saline / saline, saline / cocaine (20 mg / kg), saline / LiCl (3 meq / kg), le lijo tse tloaelehileng / chokolete. Hobane lipapiso tsa bohlokoa ke tseo lipakeng tsa lipapatso tsa Paired le tse sa lefelloang, ho bolelang hore papiso ea nako e sebelisitsoeng likamoreng tsena e entsoe ka mehato e phetoang ANOVA ka har'a sehlopha ka seng.
ANOVA ea mekhoa e 'meli e senotse tšebelisano-'moho ea bohlokoa pele ho ts'ebeliso ea "coc" [F (2, 28) = 3.47; P <0.05], LiCl [F (2, 28) = 4.55; P <0.05], le chokolete [F (2, 28) = 3.5; P <0.05].
Mehato e phetoang ANOVA sehlopheng ka seng e senotse phello e kholo ea ho beha lintho bakeng sa liphoofolo tse tšoaroang ke lihlong tse entšitsoeng ka cocaine [F (1, 14) = 24.3; P <0.0005], LiCl [F (1, 14) = 10.3; P <0.01], kapa chokolete [F (1, 14) = 7.31; P <0.05].
Tlokotsi ea Norepinephrine ho mpFC.
Litlamorao tsa ho felloa ke matla ha norepinephrine maemong a lisele tsa dopamine le norepinephrine ho mpFC li ile tsa hlahlojoa ke ANOVA ea litsela tse peli. Lintlha li ne li le ka tsela e latelang: leqeba (maemo a mabeli: kalafo ea sham le norepinephrine e felile) le teko (litekanyetso tse peli: liteko tsa boits'oaro le liteko tsa microdialysis). Papiso ea motho ka mong lipakeng tsa-lihlopha e ne e etsoa ha ho hlokahala ka tlhahlobo ea poso, liteko tsa Duncan tse fapaneng. Liphuputso tsa lipalo-palo li ile tsa etsoa ho tsoa litekong tsa boits'oaro le tsa microdialysis. ANOVA ea litsela tse peli bakeng sa litlamorao tsa ho felloa ke matla ha norepinephrine ho li-dopamine le li-norepinephrine lisele tsa mpFC li bontšitse phello e kholo ea lesion bakeng sa norepinephrine feela [F (1, 188) = 2.02; P <0.0005], empa ha ho na litlamorao tsa liteko.
Microdialysis.
Liphuputso tsa lipalo-palo li entsoe ka data e sa tsoakoang (likhakanyo tsa pg ka 20 μl). Litholoana tsa ho felloa ke matla ha norepinephrine ha ho lokolloa norepinephrine ho mpFC kapa ho tsoa ha dopamine ho NAc ea liphoofolo tse phephetsoeng ke cocaine (20 mg / kg) kapa LiCl (3 meq / kg) li ile tsa hlahlojoa ka mehato e phetoang ANOVA e nang le lintho tse peli lipakeng (kalafo ea kalafo, maemo a mabeli, kalafo ea sham le norepinephrine e felile; le kalafo, litekanyetso tse tharo, saline, cocaine, le LiCl) le e le 'ngoe ka nako (nako, litekanyetso tse supileng, 0, 20, 40, 60, 80, 100, le 120). Litholoana tsa ho felloa ke matla ha norepinephrine ho tsoa norepinephrine ho lokolloa ka mpFC kapa ho tsoa ha dopamine ho NAc ea liphoofolo tse pepeselitsoeng chokolete li ile tsa hlahlojoa ka mehato e phetoang ea ANOVA ka e le 'ngoe pakeng tsa factor (prereatment, maemo a mabeli, kalafo ea sham le norepinephrine e felileng) le e' ngoe ka hare ho factor ( Nako, mekhahlelo e robong, 0, 20, 40, 60, 80, 100, 120, 140 le 160). Liphetho tse bonolo li ile tsa hlahlojoa ka tsela e le 'ngoe ea ANOVA bakeng sa nako ka' ngoe. Papiso ea motho ka mong pakeng tsa sehlopha e ne e etsoa ha ho hlokahala ka tlhahlobo ea poso, liteko tsa Duncan tse fapaneng.
Liphuputso tsa lipalo-palo bakeng sa litlamorao tsa tšusumetso ea meriana ho tsoa pele ho norepinephrine outflow li senotse kalafo ea pele ea kalafo × kalafo × tšebelisano ea nako [F (12, 180) = 4.98; P <0.005]. Liphuputso tsa lipalo-palo bakeng sa litlamorao tsa ts'ebeliso ea chokolete ts'ebetsong ea norepinephrine li senotse ts'ebelisano pele ho nako x tšebelisano [F (8, 80) = 7.77; P <0.005]. Liphuputso tse bonolo tsa litlamorao li senotse phello ea bohlokoa ea nako bakeng sa sehlopha se tšoaroang ke lihlong le phapang e kholo lipakeng tsa lihlopha tse phekotsoeng ka sham le norepinephrine kamora ente ea cocaine kapa LiCl le kamora ts'ebeliso ea chokolete.
Liphuputso tsa lipalo-palo bakeng sa litlamorao tsa ts'oaetso ea meriana ho phallo ea accumbal dopamine li senotse ts'oaetso e kholo ea kalafo × kalafo × ho sebelisana ha nako [F (12, 180) = 10.02; P <0.0005]. Liphuputso tsa lipalo-palo tsa data ea chokolete li senotse tšebelisano-'moho ea bohlokoa pele ho ts'ebetso ea nako [F (8, 80) = 2.12; P <0.05]. Liphuputso tse bonolo tsa litlamorao li senotse phello e kholo ea nako feela bakeng sa lihlopha tse tšoaroang ke lihlong le phapang e kholo lipakeng tsa lihlopha tse phekotsoeng ka sham le norepinephrine kamora ho entoa ka lithethefatsi (cocaine kapa LiCl) le kamora ts'ebeliso ea chokolete.
LINTLHA TSA LITLHAHO
Re leboha Dr. E. Catalfamo bakeng sa thuso e bohlale. Patlisiso ena e ne e tšehelitsoe ke Ministero della Ricerca Sciectica e Tecnologica (PRIN 2005), Università "La Sapienza" Ateneo (2004/2005), le Ministero della Salute (Progetto Finalizzato RF03.182P).
BOPHELO
Nac li-bokella
PortCort ea pele
MPFC e bohareng ea mpFC
Khetho ea sebaka sa CPP
CPA e nang le maemo a hlobaetsang a sebaka
6-OHDA 6-hydroxydopamine.
LITŠOANTŠISO
Bangoli ba phatlalatsa hore ha ho na likhohlano tsa thahasello.
Sengoloa sena ke tlhahiso e ikhethileng ea PNAS.
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