LINTHO: E hlalosa phapang lipakeng tsa khatello ea maikutlo e kenyellelitsoeng ho deltafosb induction le deltafosb induction e utloisang bohloko bo bokellaneng
Biol Psychiatry. 2012 Jan 1; 71 (1): 44-50. Doi: 10.1016 / j.biopsych.2011.08.011. Epub 2011 Sep 29.
Muschamp JW, Nemeth CL, Robison AJ, Nestler EJ, Carlezon WA Jr.
mohloli o moholo
Lefapha la Psychiki, Sekolo sa Bongaka sa Harvard, Sepetlele sa McLean, Seterata sa 115 Mill, Belmont, MA 02478, USA.
inahaneloang
Background
Polelo e phahameng ea taba ea transcript factor ΔFosB e tsamaisana le ho pepesetsoa lithethefatsi tsa tlhekefetso, haholo libakeng tsa boko tse amanang le moputso le khothatso (mohlala, li-nucleus accumbens [NAc]). Litlamorao tse sa khaotseng tsa ΔFosB ho liphatsa tsa lefutso li ka bapala karolo ea bohlokoa katolosong le ponts'ong ea mekhoa ea boits'oaro e khethollang ho lemalla. Phuputso ena e hlahloba kamoo ΔFosB e susumetsang karabelo ea sistimi ea moputso oa boko ho lithethefatsi tse khahlisang le tse pharalletseng.
mekhoa
Re sebelisitse paradigm ea Intracranial ea boithati (ICSS) ho lekola litlamorao tsa koae ho litoeba tsa transgenic ka ho se utloisisehe ho fetelletseng ha osFosB libakeng tse fumanehang (ho kenyeletsoa NAc le dorsal striatum). Lice tse kentsoeng ka li-electrode tse susumetsang tsa hypothalamic tse koetlisitsoeng li ile tsa koetlisoa ho sebelisa mokhoa oa 'rate-frequency' bakeng sa ICSS ho bona hore na tshusumetso e ba moputso neng (phello).
Results
Tlhahlobo ea phello ea litla-morao tsa litlamorao tsa koae e bontšitse hore litla-morao tsa ΔFosB li bonts'a kutloelo-bohloko ea litlamorao tsa litlamorao tsa lithethefatsi, ha li bapisoa le taolo ea littermate. Ho khahlisang, limpho tse hlalosang ΔFosB le tsona li ne li sa amehe haholo ka litlamorao tsa ho phahamisa (ho phahamisa) U50488, kappa-opioid agonist e tsejoang ho susumetsa dysphoria le litlamorao tse kang khatello ea maikutlo literekeng.
Nahanisisa
Lintlha tsena li fana ka maikutlo a hore ho kenella ha ΔFosB libakeng tse nang le litlamorao tse peli tsa bohlokoa tsa boitshwaro - ho eketsa teboho ea moputso oa lithethefatsi le ho fokolisa kutloelo-bohloko ba ho qhekella — ho hlahisa mofuta o rarahaneng o bonts'ang matšoao a ho ba kotsing ea ho lemalla le ho tsitsisa khatello ea maikutlo.
Keywords: sepheo sa ho hatisa, li-bokellane tsa nucleus, moputso oa ts'usumetso ea boko, tšebeliso ea matla, ho mamella, khatello, mohlala, panya
SELELEKELA
Ho pepesehela lithethefatsi tsa tlhekefetso ho etsa hore polelo ea fos lintlha tse tsoang ho lelapa ka methapo ea methapo ea kutlo (NAc; 1), sebopeho se kenelletseng ho batleng lithethefatsi le boits'oarong bo bong bo susumetsang (2-5). Le ha liprotheine tse ngata tsa lelapa la Fos li hlahisoa butle-butle ka mor'a ho pepesetsoa lithethefatsi 'me sena se hlahisoa ka dosing e sa foleng, ΔFosB, mofuta oa splice o fapaneng. fosB gene, e hanela tšilafalo ebile e bokellana ka ho pepesetsoa lithethefatsi khafetsa (6, 7). Hona joale ho na le bopaki bo boholo ba hore maemo a phahameng a phahameng a hlalosang expressionFosB ka har'a dynorphin / ntho P-positive spiny neurons ea NAc ke neuroadaptation e lebisang tlhokomelong e eketsehileng ea lithethefatsi tsa tlhekefetso le ho ba kotsing ea ho ntlafatsa boits'oaro. (8, 9). Ka nnete, koae e theha litakatso tse maemong a tlase ho litekanyetso tse tlase ho litoeba tsa transgenic tse nang le ΔFosB e senotsoeng ka ho khetheha e amanang le ΔFosB methapong ena ea kutlo ho feta litoeba tse laoloang (10). Ho kenyelletsa moo, litoeba tsa ΔFosB-overexpressinging fumana litheko tse matla tsa koae ka tekanyetso e tlase le ho etsa boiteko bo matla (ke ho re, bonts'a li-breakpoints tse phahameng tsa "cocaine infusions" tse latelang11). Ka kopanelo, lintlha tsena li bonts'a hore ΔFosB e phahameng ho NAc e phahamisa kutloisiso litlamorao tse khahlisang tsa koae.
Mefuta e fapaneng ea khatello ea maikutlo e sa feleng, ho kenyelletsa khatello ea maikutlo ea ho itšireletsa khafetsa kapa khatello ea khatello ea maikutlo sechabeng, e boetse e susumetsa ΔFosB ho NAc le libakeng tse ling tsa boko (12-14). Ho kenella ho joalo ho bonoa ka mokhoa o batlang o lekana ho dynorphin / drug P- le enkephalin-expression e bohareng ea spiny neurons. Hobane maemo a phahameng a ΔFosB ho NAc le ona a matlafatsa kutloisiso ea moputso oa tlhaho (15-17), datha tsena li ka bonts'a karabelo e tlamang e ka felisang tse ling tsa litlamorao tsa (dysphoric) tsa khatello ea maikutlo e sa feleng. Monyetla ona o ts'ehetsoa ke liteko tseo ho tsona litoeba tsa naha li hatelletsoeng ke khatello ea khatello ea mantlha ea bophelo bo botle pakeng tsa maemo a ΔFosB ho NAc le tekanyo eo litoeba li bonts'ang karabelo ea boitšoaro bo bobe khatellong. Lintlha tsena li tlatselletsoa ke liteko moo mola o tšoanang oa litoeba tsa ΔFosB-overexpressing tse bonts'itseng karabelo e phahameng ea koae le tsona li bonts'a ho se ts'oenyehe ho hoholo hoa khatello ea kelello ea hloloheloang (14). Kahoo, polelo e ntlafalitsoeng ea ΔFosB ho NAc e bonahala e etsa hore ho be le khatello ea maikutlo ('Resilience').
Ho na le bopaki bo bokelletseng ba hore lits'ebetso tsa boko kappa-opioid receptor (KOR) li bapala karolo ea bohlokoa lithutong tsa khatello ea maikutlo. Tsamaiso ea li-agonists tsa KOR e hlahisa dysphoria ho batho (18, 19) le mefuta e fapaneng ea lits'oants'o tse sithabetsang joaloka litoeba (20-24). Habohlokoa, bakuli ba KOR ba ka etsisa likarolo tse ling tsa khatello (25-28). Mochine o mong oo sena se ka etsahalang ke ka ho sebelisana pakeng tsa khatello ea maikutlo peptide corticotropin releasing factor (CRF) le dynorphin, ligo ea endo native ligor tsa KORs (29): litla-morao tse sithabetsang tsa khatello ea maikutlo li hlaha ka lebaka la tšusumetso ea CRF receptor-Mediated ea ho lokolloa ha dynorphin le ts'usumetso e ileng ea latela ea KORs (30, 31). Ho ts'ehetsa mochine ona, bahanyetsi ba KOR ba thibela litlamorao tsa khatello ea maikutlo (20, 25, 32-35). Ka kopanelo, liphumano tsena li fana ka maikutlo a hore lithuto tsa bo-ramahlale ba KOR li ka fana ka temohisiso e kholo molemong oa ts'ebetso ea khatello ea maikutlo ho litoeba.
Lithuto tse teng li ne li etselitsoe ho lekola ka botlalo tsela eo polelo e phahameng ea ΔFosB e amang maikutlo le mehopolo e nyarosang ka ho sebelisa boitšoaro bo le bong bo ikarabellang ho tsena ka bobeli: parrigranial ea boithati (ICSS) paradigm. Thutong ena, litoeba li iphelisa ka ho hlohlelletsa ho susumetsa hoa motlakase ka li-elektrone tse kentsoeng ho hypothalamus ea morao. Lithethefatsi tsa tlhekefetso li fokotseha hoa tlhotlollo e tšehetsang karabelo ("likotlo"), ha kalafo e hlahisa anhedonia kapa dysphoria ho batho (mohlala, ho tlosoa hoa lithethefatsi, li-antipsychotic, anti-manic, anti-manic receptor [KOR] agonists, khatello) phahamisa litsotsi tsa ICSS, ho bonts'a hore lipalo tsa khothatso tse ileng tsa arajoa nakong e fetileng ha li sa sebetsa ka lebaka la kalafo (bakeng sa tlhahlobo, bona 36). Kahoo, ICSS e tsotella ho qhekella ho eketsang moputso, ho fokotsa moputso kapa ho eketsa ho nyonya. Ts'ebeliso ea mofuta o le mong oa boits'oaro ho lekola kutloisiso ea melemo ho khothaletsa le litheko tse khahlisang e na le molemo o moholo ho litoeba tsa transgenic hobane e thusa sete e lekanang ea maemo a liteko le litekanyetso, e fokotsa phapang lipakeng tsa litlhoko tsa karabelo le nalane ea kalafo e ka bakang karohano ea data. Re fumane hore litoeba tse nang le polelo e phahameng ea ΔFosB ho dynorphin / ntho P e bonts'a methapo e bohareng ea li-neurc tsa NAc le dorsal striatum li phahamisitse kutloisiso ea litlamorao tse thabisang tsa koae e tsamaeang le maikutlo a fokotsehileng a maikutlo a kang a (aversive) a litlamorao tsa KOR agonist U50488, e hlahisa mofuta oa phenotype o bonts'ang matšoao a tlokotsing ea ho lemalla empa ho eketsa ho itoanela ha khatello ea maikutlo.
LISEBELISOA LE MEKHOA
Animals
Kakaretso ea litoeba tsa banna tsa 23 tse sa sebetseng, tse sebetsang hantle tsa bitransgenic tse hlalosang osFosB (mola oa 11A) li hlahisitsoe ho sebelisoa mokhoa oa polelo oa mofuta oa tetracycline-regied37). Litoeba tse tona tse nkileng NSE-tTA le TetOP-ΔFosB li ile tsa phahamisoa metsing a nang le doxecycline (DOX, 100 µg / ml; Sigma, St. Louis MO). Liteko li qalile libeke tse robeli kamora ho tlosa litoeba tsa 13 ho DOX ho lumella keketseho e tsitsitseng ea 7-fold ea TetOp-Mediated ΔFosB transgene expression ka har'a dynorphin-positive neurons ea striatum (ΔFosB-ON; bona 10, 37, 38). Linta tse Eleven li ile tsa sala ho DOX nako eohle ea liteko 'me ea theha sehlopha sa taolo (Taolo). Malinyane e ne e le litterlings tse neng li khutliselitsoe morao molatong oa C57BL / 6 bakeng sa bonyane meloko ea 12, 'me li ne li bolokoa ka bonngoe ad libitum phihlello ea lijo le metsi mochineng oa 12 h khanya (7: 00 AM ho 7: 00 PM) potoloho. Ntle le moo, litoeba tsa 9 tse nkileng NSE-tTA transgene li ne li sebelisoa feela e le sehlopha sa bobeli sa taolo; ba holisitsoe holima DOX, ebe ba tlosoa ho DOX bakeng sa ~ 8 libeke pele ho liteko tse ling (OFF-DOX). Mekhoa e ile ea etsoa ho latela 1996 National Institutes of Health (NIH) Tataiso bakeng sa tlhokomelo le tšebeliso ea liphoofolo tsa liphoofolo le tumello ea Komiti ea Tlhokomelo ea Liphoofolo le Ts'ebeliso Setsing sa Lipetlele sa McLean.
Immunohistochemistry
Transgene overexpression e tiisitsoe ke immunuohistochemistry bakeng sa FosB (Feie. 1). Litoeba tsa Bitransgenic li ile tsa etsoa sehlabelo tsa ba tsa sebelisoa ka mokhoa o hlakileng ka tranelate ea 0.1 M phosphate-buffered saline le 4% paraformaldehyde. Ka nako eo, masapo a botlokotsebe a ne a tlosoa, a nkuoa morao, ebe a bonoa joalo ka ha ho hlalositsoe pele (14, 38). Tissue e ne e sengoe ka sefofaneng sa coronal ho likarolo tsa 30 mm, le likarolo tse koetsoeng li sebelisa antioxoshene ea FosB (SC-48, Santa Cruz Biotechnology, Santa Cruz, CA). Diaminobenzidine stain e ne e sebelisetsoa ho bona lisele tse ntle tsa FosB. Litšoantšo li ile tsa fumanoa li sebelisoa ka microscope ea setšoantšo sa Zeiss Imager 1 mme tsa nkuoa ka dijithale ho sebelisoa software ea Axiovison (Carl Zeiss USA, Peabody, MA).
Li-Micrographic tse emelang tse tsoang ho litoeba tsa bitransgenic tse bonts'ang ho fetelletseng ha ΔFosB. Lebitso la nyutlelie bakeng sa FosB le tlase ho litoeba tsa taolo tse bolokiloeng ho doxycycline (phanele ea leqeleng) ho feta tse sa fuoeng doxycycline (ka ho le letona). ac = khefu ea kantle; NAc ...
ICSS
Litoeba (25-28 g) li ne li sa sebetsoa ka ente ea intraperitoneal (IP) ea motsoako oa ketamine-xylazine (80-10 mg / kg; Sigma) mme li kentsoe li-electrode tse matlafatsang tse tsamaeang le methapo ea methapo ea methapo ea methapo e tataisang methapo ea methapo ea kutlo (MFB; mm. Mm). ho tsoa bregma, AP: −1.9, ML: −0.8, DV: −4.8 ka tlase ho dura, ho latela sethala sa Paxinos le Franklin, 2nd ed., 2001). Kamora nako ea beke e le 'ngoe, litoeba li ile tsa fuoa koetliso ea ho arabela bakeng sa ho khothatsa ha boko nakong ea thupelo ea hora e le' ngoe (39). Stimulation ea hajoale e ile ea fetoloa hore e be boleng bo tlase bo neng bo tla tšehetsa karabelo e tsitsitseng (60 ± 6 likarabo / min) bakeng sa matsatsi a 3 a latellanang. Boleng bona bo ne bo nkuoa e le "bo fokolang haholo", mme mokhoa ona o kile oa sebelisoa ho supa phapang e bakiloeng phetisong ea kutlo ea motheo le litlamorao tse khothatsang tsa ho susumetsa (40). Kamora hore panya e ngoe le e ngoe e lekantsoe hanyane, e ne e lula e ts'oaroa. Litoeba li ile tsa lumelloa ho arabela ho e 'ngoe ea maqhubu a susumetso a 15 a hlahisoang ka tatellano ea ho theoha (0.05 log10 mehato ea yuniti) nakong ea liteko tse leshome le metso e mehlano tsa 50 sec. Liteko li ile tsa etelloa pele ke hlooho ea bobeli ea 5 moo ho ileng ha fanoa ka maikutlo a ho se kopanyetsano, a lateloa ke nako ea 5 sec eo ho eona karabelo e sa matlafatsoang. Karolo e 'ngoe le e' ngoe ea liteko tsa 15 (kapa "pass ') e ile ea hlahisoa,' me ea araba nakong ea teko e 'ngoe le e' ngoe ea 50 sec e tlalehiloeng. Ho feta thupelong ea beke ea 3-4, mefuta ea maqhubu a sebelisitsoeng e ile ea fetoloa e le hore litoeba li arabele maqhubu a 6-7 a phahameng ka ho fetesisa a fetang 6 (90 min of koetliso). Hangata maqhubu a tlase haholo a neng a ts'ehetsa ho arabela (khubung ea ICSS, kapa 'theta-zero') ho ne ho kopitsoa ho sebelisoa mohala o monyane haholo oa tlhahlobo e nepahetseng (36, 41). Ha liphoofolo li ne li bonoa li e-na le mehato e tsitsitseng ea ICSS (± 10% ho feta matsatsi a 5 a latellanang), phello ea kalafo ea lithethefatsi monyako oa ICSS e ile ea lekanngoa.
Teko ea lithethefatsi
Cocaine HCl le (±) -trans-U50488 methanesulfanoate (Sigma) e ile ea qhibiliha ka saline ea 0.9% mme ea kenya IP ka bongata ba 10 ml / kg. Linta li arabetse ka 3 e feta kapele pele ho kalafo ea lithethefatsi le menyako ho tsoa la bobeli le la boraro ho kenyelletsoa ho fumana litekanyetso tsa (basekete le boholo ba karabelo). Joale mouse e 'ngoe le e' ngoe e ile ea amohela ente ea lithethefatsi kapa koloi 'me ea lekoa bakeng sa metsotso ea 15 hang hang ho latela liente. Litoeba tsa Bitransgenic li ile tsa fuoa litekanyetso tsa koae (0.625-10 mg / kg) kapa U50488 (0.03-5.5 mg / kg) ka tatellano. Litoeba tsa OFF-DOX li fumane koae feela. Phekolo e 'ngoe le e' ngoe ea lithethefatsi e ile ea latela teko le koloi ka letsatsi le fetileng ho netefatsa hore mouse e hlaphohile kalafong ea pele le ho fokotsa litlamorao tsa lithethefatsi. Nako ea libeke tse peli e ile ea fanoa pakeng tsa cocaine le U50488 liteko. Joalo ka holimo, liphoofolo tse neng li sitoa ho bonts'a karabo ea motheo ea botsitso li ile tsa behelloa ka thoko. Phapang ea lihlopha e ile ea hlahlojoa ho sebelisoa t-Test (bonyane tekanyetso ea hona joale), ANOVA (litlamorao tsa kalafo ea lithethefatsi monyako le sekhahla se phahameng); litlamorao tsa bohlokoa li ile tsa hlahlojoa ho sebelisoa hape post hoc liteko (Teko ea Dunnett). Sebakeng ka seng, lipapiso li ne li etsoa ho ipapisa le maikutlo a null a bolelang hore maemong a phekotsoeng ke lithethefatsi a ne a ke ke a fapana le se boleloang ke maemo a tšoeroeng ke koloi. Hobane koae e tsejoa e le litefiso tse tlase tsa moputso ho ICSS (42), ho bapisoa le koloi ho entsoe ho ipapisitse le khopolo ea hore cocaine e ne e tla fokotsa moputso oa meputso. Ka lehlakoreng le leng, hobane li-agonists tsa kappa li bontšitsoe ho phahamisa menyako ea moputso ho ICSS (23), lipapiso li entsoe koloi ho latela mohopolo oa hore U50488 ka mokhoa o ts'oanang e tla phahamisa linyatso tsa moputso. Ho behoa ha li-electrode ho netefalitsoe ke histology (Feie. 2).
Virograph e emelang e bontša ho kenngoa ha electrode bakeng sa ICSS (motsu). LHA = sebaka sa morao-rao sa hypothalamic; fx = fornix. Scale bar = 250 µm.
LIPOTSO
ΔFosB oxpxpression le maemo a tlase a hajoale
Malinyane kaofela a fumane boitšoaro ba ICSS ka potlako mme a arabela ka litheko tse phahameng bakeng sa ts'usumetso ea MFB. Ho ne ho se na liphapang tsa sehlopha maemong a fokolang pakeng tsa litoeba tse feteletseng tsa ΔFosB ka striatum le NAc (ΔFosB-ON) le tse bolokiloeng ho DOX (Taolo; t(22)= 0.26, eseng bohlokoa [ns]) (Feie. 3) Sena se bonts'a hore liphatsa tsa lefutso ka bolona ha li na phello ea kutloelo-bohloko ea ho susumetsoa ke phello e khothatsang ea moriti oa hypothalamic tlas'a maemo a motheo.
Index ea xpFosB e sa sebetseng ha e na phello bonyane ba hona joale bo hlokahalang ho ts'ehetsa ICSS. Lipontšo tsa Scatterplot li bolela bonyane (li-bar) tse hlokahalang ho ts'ehetsa boitšoaro bo matla ba ICSS (60 ± likarabo tsa 6 / min) ho litoeba ka bomong ...
ΔFosB oxpxpression le litlamorao tsa koae
Cocaine e fokotsehile ho bolela litokollo tsa ICSS lihlopheng tsohle tsa litoeba, e leng ho etsang hore litšebeletso tsa ICSS li se ke tsa fetoloa ka sekhahla.Feiga. 4A, B). MFosB-ON litoeba li ne li amehile haholo ka litlamorao tse khahlisang tsa koae: counine ea 2-e phetseng-phetisetso ea mekhoa ea ICSS mabapi le litekanyetso tsa ICSS tse senolang litlamorao tse kholo tsa lethal dose ea koaeF(5,65)= 11.20, P<0.01), le kalafo ea DOX (F(1,13)= 6.23, P<0.05), empa ha ho na tefoF(5,65)= 0.87, ns). Phapano e reriloeng pele (liteko tsa Dunnett) ka kalafo ea makoloi kahare ho sehlopha ka seng e senotse hore litoeba tsa ΔFosB-ONn= 8) e bonts'itse phokotso ea bohlokoa molemong oa ICSS ho litekanyetso tsa ≥1.25 mg / kg, athe tekanyetso ea 10 mg / kg e ne e hlokahala ho hlahisa litlamorao tse kholo ho litoeba tsa taolo ea (ON-DOX) (Setšoantšo sa 4C). Mehato e pheta-phetoang ea 2-ANOVA mabapi le litekanyetso tse phahameng tsa karabo e senotse phello e kholo ea lethal dose ea koae (F(5,65)= 3.89, P<0.05). Phapang e reriloeng esale pele le kalafo ea makoloi a letsoai sehlopheng ka seng e senotse hore koae e hlahisitse litlamorao tse eketsang sekhahla litekanyong ≥5 mg / kg ho litoeba tsa osBFosB-ON, ntle le tšusumetso ho litoeba tsa ControlSetšoantšo sa 4D). Ha ho na phello e ka sehloohong ea kalafo ea DOX (F(1,13)= 1.56, ns), leha e le hore ho ne ho sena ts'ebelisano xF(5,65)= 0.43, ns). Phekolo ea DOX feela e ne e se na phello ea ho araba lethal dose ea li-cocaine tse lekiloeng (10 mg / kg) ha lihlopha tsa Ts'ireletso le tsa OFF-DOX li sa bonts'e phapang litekanyetsong tsa moputso (Setšoantšo sa 4C, sethala; t(14)= 0.27, ns), kapa litefiso tse phahameng tsa ho arabela (Setšoantšo sa 4D, sethala; t(14)= 0.34, ns).
Phokotso ea 'nete ea ΔFosB e eketsang kutloisiso ea melemo litlamorao tse khahlisang tsa koae. (A, B) Mesebetsi ea maqhubu a litekanyo bakeng sa litoeba tsa boemeli ka bomong sehlopheng ka seng li bonts'a liphetoho tse tlohelang lihlopheng tse peli tse kholo ho ΔFosB-ON ...
ΔFosB oxpxpression le U50488 liphello
The KOR agonist U50488 keketseho e kholo ea likokoana-hloko tsa ICSS ho litoeba tsa taolo, li baka phetoho e nepahetseng mosebetsing oa sehlopha sena, athe litoeba tsa ΔFosB-ON li ne li sa ananele lithethefatsi (Feiga. 5A, B). ANOVA e pheta-pheta tsela ea 2 e mabapi le litekanyetso tse nang le ICSS e bonts'a litlamorao tse kholo tsa lethal dose ea lithethefatsi (F(6,60)= 3.45, P<0.01), kalafo ea DOX (F(1,10)= 18.73, P<0.01), le tekanyetso ea bohlokoa × DOX (F(6,60)= 2.95, P Post hoc liteko (Teko ea Dunnett) e bonts'a seo, ha se bapisoa le koloi ea saline, U50488 (5.5 mg / kg) e hlahisitse litheko tse kholo tsa likotlo tsa ICSS ho litoeba tsa taolo (n= 4) empa ha e na phello ho litoeba tsa ΔFosB-ONSetšoantšo sa 5C). Ntle le moo, ho bile le phapang e kholo lipakeng tsa lihlopha ka tekanyetso ena. ANOVA ea 2 e pheta-phetoang ka tekanyo e phahameng ea karabelo e senotse litlamorao tse kholo tsa lethal dose (F(6,60)= 1.95, ns) kapa kalafo ea DOX (F(1,10)= 4.66, ns [P= 0.06]), hape ho ne ho se na lethathamo la lipuisano x DOX (F(6,60)= 1.31, ns) (Setšoantšo sa 5D). Lintlha tsena li bontša seo U50488 ha ea ka ea ama ka ho teba ho arabela tlasa maemo a lekiloeng.
Phoso ea vereFosB e sa sebetseng e thibela litlamorao tsa U50488. (A, B) Mesebetsi e ikemetseng ea litoeba tsa baemeli ka bomong sehlopheng ka seng e bonts'a se nepahetseng ...
TŠOHLOA
Re bontša hore litoeba tse feteletseng tse sa sebetseng tsa ΔFosB ho NAc le libakeng tse ling tse nang le mathata li ameha haholo ho litlamorao tsa koae hape ha li amehe habonolo ka phello ea maikutlo a mofumahali oa KOR U50488 bapisoa le litoeba tse tloaelehileng.
Lintlha tsena li tsamaisana le lingoliloeng tse seng li ntse li le teng mabapi le karolo ea ΔFosB moputsong oa lithethefatsi le khatello ea maikutlo, 'me li e atolla ka litsela tse' maloa tsa bohlokoa. Mosebetsi oa nakong e fetileng le litlamorao tsa oFosB ho tlola tekano moputsong oa lithethefatsi o sebelisitse maemo a itseng kapa litataiso tsa taolo ea lithethefatsi (10, 11). Lintlha tse tsoang tlhahlobong ea ICSS li tlatsana le mosebetsi ona ka ho fana ka index ea 'nako ea' nete 'ea tšusumetso ea lithethefatsi ho sensitivity ea li-circry tsa moputso oa boko. Boithuto ho litoeba tsa mofuta o hlaha li bonts'itse hore manipulla ea meriana e ka eketseha (mohlala, cocaine) kapa ea fokotseha (mohlala, U50488) tšusumetso e khotsofatsang ea tšusumetso ea MFB (24); ICSS ka hona e fana ka mokhoa oa ho kopanya hedonic state ha phoofolo e le tlasa ts'usumetso ea kalafo ea lithethefatsi. Hobane lithethefatsi tse tsejoang hore li na le moputso kapa tse nyenyefatsang ho batho li hlahisa tse fapaneng (ho bolelang hore likhutlo tse tlase le tse phahameng, ka ho latellana) tlhahiso ea ICSS, paradigm e ka hlakola maemo ana ka mokhoa o hlakileng ho feta ts'ebeliso ea lithethefatsi, moo litekanyetso tse tlase tsa taolo e ka etsang bonts'a ho satiety kapa ho hlaha ha litla-morao tse nyarosang (36). Ntle le moo, ICSS e qoba likhohlano tse ka bang teng tseo kalafo ea lithethefatsi e ka bang le tsona holima nts'etsopele le polelo ea likarabo tse ithutoang maemong a khale a maemo a tloaelo a sebelisoang ho ithuta moputso oa lithethefatsi (joalo ka maemo a sebaka).
Lintlha tsa rona tsa phokotso ea ICSS li bontša ka ho hlaka hore ho kenya ΔFosB ho ntlafatsa litlamorao tsa koae, hobane lithethefatsi li hlahisa phokotso e kholo lithutong tsa ICSS ka tekanyetso e tlase ho feta litekong tsa littermate moo overexpression e neng e sa qobelloa. Taba ea hore litoeba tsa ΔFosB-ON li bonts'itse le ho eketseha ha tekanyo e phahameng ea ho ts'oara koae ho hlahisa monyetla oa hore phello ea ΔFosB e tebang ho feta litšitiso tsa ICSS ke mohopolo oa tšebetso e phahameng ea bokhoni ba ts'ebetso kapa bokhoni ba karabelo.43). Sena ha se na monyetla ka mabaka a 'maloa. Taba ea mantlha, mokhoa oa rona oa ho sekaseka theta-0 o sebelisa mohala oa mabatooa o lekaneng ho hakanya hore na ho tsosa ho ba le moputso hakae. Hobane algorithm ea regression e theola litekanyetso tse feteletseng, e na le botebo ho liphetoho tse tlisoang ke kalafo ho bokhoni ba karabelo; ka lehlakoreng le leng, liphetoho lipuisanong le karabelo li le mong li ka baka phetoho ea maqhubu ha likotlo ha ho sebelisoa M-50, mohato o lekanang ho ED-50 ho pharmacology (bona 36, 41, 44, 45). Taba ea bobeli, keketseho ea litheko tse phahameng tsa "cocaine" tse phahameng haholo e bonahala ho litekanyetso tse phahameng haholo tsa koae, e leng lipalo tsa ICSS tsa liphoofolo tsa ΔFosB-ON. Kamora nako, haeba litlamorao tsa ΔFosB lithuleng tsa ICSS li ne li bakoa ke litlamorao tse sa sebetseng hantle tsa phetoho, litoeba li kanna tsa lebelloa ho bonts'a kutloisiso e kholo mabapi le litlamorao tsa ho hlohlelletsoa ha MFB ka boyona, ho bonahatsoa joalo ka bonyane bo tlase ba maemo a tšehetso ea likarabo tsa 60 ± 6 likarabo / metsotso, kapa ka ho eketseha ha litekanyetso tse phahameng tsa karabo tse latelang ho latela kalafo ka koloi. Ha rea fumana bopaki ba letho la litlamorao tsena. Ka kopanelo, liphumano tsena li bonts'a hore ΔFosB overexpression e baka kutloisiso e phahameng ho litlamorao tse peli (ka tekanyo e tlase ho isa ho tse phahameng) le litlamorao (litekanyetso tse phahameng feela) litlamorao tsa cocaine. Mokhoa o tšoanang oa litlamorao o tlalehiloe pele ho litoeba ka phetoho e hlahisang matšoao a kang a mania (40).
Ho khahlisang, ΔFosB oxpxpression e felisitse litlamorao tse phahamisang, tse sithabetsang tsa U50488. kenasmuch joalo ka kalafo ea KOR agonist e ka etsisa litlamorao tse itseng tsa khatello ea maikutlo (25-28), ho fumana hona ke sesupo sa ho inehela; 'nete ea hore oFosB e tebelitsoe haholo le ho ts'oaroa ke lits'oants'o tse nyahamisang joalo ka khatello ea maikutlo e sa feleng ea khatello ea maikutlo bathong ba ratang ho ikemela le tšebelisanong ea sechaba. (14, 46).
Khatello ea maikutlo e phahamisa polelo ea dynorphin (47, 48), mme bahanyetsi ba KOR ba hlahisa litla-morao tse kang li-antidepressant-and-anti-khatello ea maikutlo joalo ka (20, 32, 47, 49). Ho feta moo, karolo e iphekolang ea ts'ebetso ea hypothalamic-pituitary-adrenal axis e tsamaeang le khatello ea maikutlo e tsamaisoa ke dynorphin, joalo ka ha mokhoa o khahlano le litheko tse amanang le khatello ea ho sesa kapa corticotrophin o lokollang o koetsoe ke bahanyetsi ba KOR kapa dynorphin gene knockout. (30). Litoeba tse sebelisitsoeng boitekong bona li bontša ΔFosB overexpression e ikhethileng ea li-dynorphin neurons tsa striatum. Sena le sona se fokotsa polelo ea dynorphin methapong ena ea kutlo (38), phello e ka lebelloang ho fokotsa ts'ebetso ea mantlha ea lits'ebetso tsa boko KOR. Ho feta moo, hobane ts'ebetso ea KOR e bonts'a tokollo ea dopamine (DA; 22, 50), morekisi o tsejoang ho bapala karolo ea bohlokoa ho ts'ehetsa ICSS (51-53), phello ena e ka boela ea hlalosa karolo ea hore na ke hobaneng ΔFosB e tebisang maikutlo ea litoeba e bonts'a kutloisiso e kholo ea moputso oa koae. Taba ea hore litoeba tsena li fumane molumo oa dynorphin hammoho le ho se ananele litlamorao tse joalo tsa "agorists" ea khale tsa KOR e hlahisa monyetla oa hore phetoho e hlahise li-neuroadaptatons tse pharalletseng tse khonang ho fokotsa lits'ebetso tsa 'anti-moputso' bokong (54).
Ho sa tsotelehe hore na ho susumetsoa ke ho pepesehela lithethefatsi tsa tlhekefetso kapa khatello ea maikutlo, ho kenella ha ΔFosB le dynorphin ho ka nkoa e le neuroadaptations e hanyetsanang. ΔFosB e bonahala e susumetsa maikutlo a hlasimolohileng meputsong e fapaneng ea meriana le ea tlholeho (10, 11, 15). Tsamaiso dynorphin-Kor Leha ho le joalo, ho bonahala eka susumelletsa re prodepressive-joaloka tse amang likarolo tsa anhedonia, dysphoria, le hloile ho batho le liphoofolo le laboratori eo (19, 21, 35, 55).
Tlas'a maemo ao e seng a tlhaho, liphetoho tsena li ka utloisana bohloko, tsa baka karabelo e kang ea lapeng e lekanang le tšusumetso ea kantle ho molumo oa hedonic. Ka leseli la bopaki ba hore thabo ea NAc e mahareng ea li-spiny neurons e fapana ka mokhoa o fapaneng le boemo ba moea (14, 56, 57), ΔFosB e ka fana ka litlamorao khahlano le khatello ea khatello ea dysphoria ka ho fokotsa thabo ea lisele tsena ka polelo e ntlafalitsoeng ea GluR2 (10), e ratang sebopeho sa li-receptor tsa AMPA tsa GluR2, e nang le calcium-impermeable 58).
Ka lehlakoreng le leng, dynorphin kapa KOR agonists e ka bona maemo a phahameng a DA a tsamaeang le tšebeliso ea lithethefatsi tsa tlhekefetso (59). Bokhoba ba khatello ea maikutlo le khatello ea maikutlo bathong hangata li khothatsoa ebile li tsamaisoa ke khatello ea bophelo (60-62). Ho fapana le moo, mofuta oa litoeba tsa ΔFosB tse fetang tekano ke o mong oa ho batla lithethefatsi empa o le matla hape litlamorao tse nyahamisang tsa khatello ea maikutlo. Mekhoa e bakileng karohano ena ha e hlake, empa e kanna ea ba ka lebaka la mokhoa o thibetsoeng oa ΔFosB overexpression o bonts'itsoeng ke litoeba tsena. Elevated striatal ΔFosB le ho fokotseha ho latelang ha dynorphin ke a mabeli feela a li-neuroadaptations tse tsamaeang le ho pepesetsoa ha lithethefatsi le khatello ea maikutlo (63, 64). Kahoo, ha ba na monyetla oa ho hlahisa ka botlalo liphetoho tse tlisoang ke matšoao a bono ba ho lemalla le khatello ea maikutlo.. Ho bohlokoa hape ho totobatsa hore lithuto tsena li sebetsana le litlamorao tsa ΔFosB feela, le hore maemong a tloaelehileng ho pepesetsoa lithethefatsi tsa tlhekefetso le khatello ea maikutlo ho baka keketseho e potlakileng ea polelo ea liprotheine tse ling tsa lelapa tsa Fos tse sa ithutoang mona, ho kenyeletsoa le FosB ea bolelele bo felletseng.9).
Ka kakaretso, re sebelisitse ICSS ho transgenic mice overexpressing ΔFosB ho bonts'a hore ts'ebeliso ea liphatsa tsa lefutso e ntlafatsa litlamorao tse khahlisang tsa koae. Re boetse ra fumana hore sena se hanana le litlamorao tsa ts'usumetso ea KOR ka U50588. Hobane sistor ea dynorphin-KOR ke mokena-lipakeng oa sephetho se amehang sa khatello ea maikutlo, datha tsena li lumellana le maikutlo a hore ΔFosB e ntlafatsa kutloisiso ea moputso ha ka nako e ts'oanang e fokotsa karabelo ho ba hatellehileng. Kahoo, tlhahiso ea ΔFosB e ntlafatsang maemong a mang e ka khothaletsa bofokoli.
LINTLHA TSA LITLHAHO
Boithuto bona bo tšehelitsoe ke National Institute on Drug Abuse and National Institute of Mental Health (DA026250 ho JWM, MH51399 le DA008227 ho EJN, le MH063266 ho WAC).
Mongolo o botlaaseng ba leqephe
Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.
TLHOKOMELISO / LITLHAKISO TSA BOTSOANG
Lilemong tse fetileng tsa 3, Dr. Carlezon o amohetse matšeliso ho HUYA Biosciences le Myneurolab.com. O tšoere li-patent tse ngata le lits'ebeliso tsa patent tse sa amaneng le mosebetsi o hlalositsoeng tlalehong ena. Ha ho na chelete ea hau ea lichelete e ka nkuoang e le pherekano ea phaello. Dr. Nestler ke moeletsi oa PsychoGenics le Merck Research Laboratories. Dr. Muschamp, Dr. Robison, le Mme Nemeth ha ba tlalehe hore ho na le phapang pakeng tsa lichelete kapa likhohlano tse ka bang teng.
LITLHAHISO
1. Tšepo B, Kosofsky B, Hyman SE, Nestler EJ. Taolo ea polelo ea pele ea liphatsa tsa lefutso le AP-1 e tlamang lenaneong la litekanyetso ke cocaine e sa foleng. Proc Natl Acad Sci US A. 1992; 89: 5764-5768. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
2. Mogenson GJ, Jones DL, Yim CY. Ho tloha ho tšusumetso ho ea ketsong: sebopeho se sebetsang pakeng tsa tsamaiso ea maoto le tsamaiso ea enjene. Prog Neurobiol. 1980; 14: 69-97. [E fetotsoe]
3. Carlezon WA, Jr, Thomas MJ. Likarolo tsa tlhaho tsa moputso le bokhoba: senotlolo se bokella tšebetso ea tšebetso. Neuropharmacology. 2009; 56 Suppl 1: 122-132. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
4. Pennartz CM, Groenewegen HJ, Lopes da Silva FH. Li-nucleus li bokellana e le ntho e rarahaneng ea li-envirles tse fapaneng tse sebetsang ka nepo: ho kopantsoe ha data ea boits'oaro, ea electrophysiological le anatomical. ProgNeurobiol. 1994; 42: 719-761. [E fetotsoe]
5. Pierce RC, Vanderschuren LJ. Ho raha tloaelo eo: motheo oa mekhoa ea boitšoaro e kenelletseng bokhobeng ba koae. Neurosci Biobehav Rev. 2010; 35: 212-219. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
6. Tšepo BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, et al. Tlhahiso ea motsoako oa AP-1 oa nako e telele o qapiloeng ke liprotheine tse kang Fos ka bokong ka cocaine e sa feleng le kalafo tse ling tse sa foleng. Neuron. 1994; 13: 1235-1244. [E fetotsoe]
7. Chen J, Nye HE, Kelz MB, Hiroi N, Nakabeppu Y, Tšepo BT, et al. Taolo ea li-protein tsa delta FosB le tsa FosB ka ho ts'oaroa ke motlakase le kalafo ea koae. Mol Pharmacol. 1995; 48: 880-889. [E fetotsoe]
8. McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ. ΔFosB: phetoho ea limolek'hule bakeng sa ho ikamahanya le maemo ka nako e telele bokong. Patlisiso ea Bolo ea Melemo 2004; 132: 146-154. [E fetotsoe]
9. Nestler EJ. Mekhoa e meng ea ho lemalla: karolo ea ΔFosB. Phetohelo ea Philosophical ea Royal Society B: Litsebi tsa Bioloji. 2008; 363: 3245-3255. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
10. Kelz MB, Chen J, Carlezon WA, Jr, Whisler K, Gilden L, Beckmann AM, et al. Khopolo ea "transaction factor deltaFosB" bokong e laola maikutlo a cocaine. Tlhaho. 1999; 401: 272-276. [E fetotsoe]
11. Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW. Striatal cell Type overexpression e khethehileng ea DeltaFosB e ntlafatsa ts'usumetso ea koae. J Neurosci. 2003; 23: 2488-2493. [E fetotsoe]
12. Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, et al. Ho hlahisoa ha deltaFosB ka likarolo tsa boko tse amanang le moputso kamora khatello ea maikutlo e sa feleng. J Neurosci. 2004; 24: 10594-10602. [E fetotsoe]
13. Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP., Jr Phetoho ea nako e telele meaho ea mesocorticolimbic kamora ho pheta-pheta khatello ea maikutlo sechabeng ka litoeba: nako ea mo-opioid receptor mRNA le FosB / DeltaFosB. Eur J Neurosci. 2008; 27: 2272-2284. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
14. Vialou V, Robison AJ, LaPlant QC, Covington HE, Dietz DM, Ohnishi YN, et al. ΔFosB maemong a moputso oa boko e thusa ho sebetsana le khatello ea maikutlo le likarabo tse khahlanong le khatello ea maikutlo. Neuroscience ea Tlhaho. 2010; 13: 745-752. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
15. Wallace DL, Vialou V, Rios L, Carle-Florence TL, Chakravarty S, Kumar A, et al. Tšusumetso ea FosB ho LiNumus Accumbens mabapi le Boitšoaro bo amanang le Moputso oa Tlhaho. Tlaleho ea Neuroscience. 2008; 28: 10272-10277. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
16. Hedges VL, Chakravarty S, Nestler EJ, Meisel RL. Delta FosB overexpression bokong ba nyutlelie e ntlafatsa moputso oa thobalano ho li-hamsters tsa basali tsa Syria. Brain Behav. 2009; 8: 442-449. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
17. Pitchers KK, Frohmader KS, Vialou V, Mouzon E, Nestler EJ, Lehman MN, et al. DeltaFosB bokong ba li-nucleus li bohlokoa bakeng sa ho matlafatsa litlamorao tsa moputso oa thobalano. Brain Behav. 2010; 9: 831-840. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
18. Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated ke kappa opiate receptors. Mahlale. 1986; 233: 774-776. [E fetotsoe]
19. Wadenberg ML. Tlhahlobo ea thepa ea spiradoline: agonist e matla le e khethiloeng ea kappa-opioid. CNS Drug Rev. 2003; 9: 187-198. [E fetotsoe]
20. Mague SD. Liphetoho tsa li-antidepressant-joalo ka li-kappa -Opioid Receptor antagonists litekong tse qobelloang tsa Swim ho Rats. Tlaleho ea Pharmacology le Therapeutics ea Tlhahlobo. 2003; 305: 323-330. [E fetotsoe]
21. Todtenkopf MS, Marcus JF, Portoghese PS, Carlezon WA., Jr Liphello tsa kappa-opioid receptor ligands ho intracranial ho ikhatholla ho likhoto. Psychopharmacology (Berl) 2004; 172: 463-470. [E fetotsoe]
22. Carlezon WA, Jr, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, et al. Litlamorao tse kang khatello ea maikutlo ea "kappa-opioid receptor agonist salvinorin A" mabapi le boitšoaro le methapo ea kutlo ho likhoto. J Theracol Exp Ther. 2006; 316: 440-447. [E fetotsoe]
23. Tomasiewicz H, Todtenkopf M, Chartoff E, Cohen B, Carlezonjr W. Kappa-Opioid Agonist U69,593 e Thibela Khokahano ea Khokahano ea Kholo ea Brain. Psychology. 2008; 64: 982-988. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
24. Dinieri JA, Nemeth CL, Parsegian A, Carle T, Gurevich VV, Gurevich E, et al. Kutloelo e fetotsoeng ea lithethefatsi tse fanang ka moputso le tse o thusang ho litoeba ka tšitiso e sa sebetseng ea karabo ea cAMP e arolang likarolo tsa protein. J Neurosci. 2009; 29: 1855-1859. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
25. McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid receptor antagonism le prodynorphin gene disrupt blockchain-ikiwalelo tsa karabelo tsa boitšoaro. J Neurosci. 2003; 23: 5674-5683. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
26. McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C. Pele ho ts'ebetso ea li-receptor tsa kappa opioid ke li-mimics tsa U50,488 tse pheta-phetoang li hatelletse khatello ea ho sesa bakeng sa ho rata maemo a cocaine. Neuropsychopharmacology. 2006; 31: 787-794. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
27. McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C. Likarabo tsa boitšoaro tse tlisoang ke khatello ea maikutlo tse susumetsoang ke sechaba li kopants'oa ke tsamaiso ea endiozala kappa opioid. Neuropsychopharmacology. 2006; 31: 1241-1248. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
28. Tlhokomelo AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP. Endo native kappa opioid activation e sebetsana le bofokoli bo susumetsoang ke ho ithuta le ho hopola. J Neurosci. 2009; 29: 4293-4300. [E fetotsoe]
29. Chavkin C, James IF, Goldstein A. Dynorphin ke lesapo le khethehileng la semmuso sa kappa opioid receptor. Mahlale. 1982; 215: 413-415. [E fetotsoe]
30. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C. Karolo ea khatello ea methapo e kopantsoe ke ts'ebetso ea sistimi ea dynorphin kappa-opioid. J Neurosci. 2008; 28: 407-414. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
31. Bruchas MR, Schindler AG, Shankar H, Messinger DI, Miyatake M, Land BB, et al. Ho tlosoa ha p38α MAPK ho serotonergic neurons ho hlahisa khatello ea maikutlo maemong a khatello ea maikutlo le bokhoba. Neuron. (Ka ho tobetsa) [Tlhahiso ea mahala ea PMC] [E fetotsoe]
32. Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA., Jr E fetotsoe karabelo ho koaeine le ho eketseha ho sa feleng tekong e qobelloang ea ho sesa e amanang le polelo e phahameng ea cAMP element-binding protein. J Neurosci. 2001; 21: 7397-7403. [E fetotsoe]
33. Beardsley PM, Howard JL, Shelton KL, Carroll FI. Litlamorao tse fapaneng tsa mohanyetsi oa kappa opioid receptor antagonist, JDTic, mabapi le ho khutlisetsoa ha k'hok'heine ea koae e ts'oaroang ke liphihlelo tsa koae le litlamorao tsa koae le litlamorao tse joalo tsa litla-morao. Psychopharmacology (Berl) 2005; 183: 118-126. [E fetotsoe]
34. Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA. Litlamorao tse kang Anxiolytic-Like Liphetoho tsa li-antagonists tsa κ-Opioid Receptor ka Mehlala ea Batho ba sa Rutang le Ba Ithutileng Tšabo literekeng. Tlaleho ea Pharmacology le Therapeutics ea Tlhahlobo. 2007; 323: 838-845. [E fetotsoe]
35. Knoll AT, Carlezon WA., Jr Dynorphin, khatello ea maikutlo le khatello ea maikutlo. Brain Res. 2010; 1314: 56-73. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
36. Carlezon WA, Chartoff EH. Intracranial self-stimulation (ICSS) ka litoeba ho ithuta neurobiology ea sepheo. Li-Protocol tsa Tlhaho. 2007; 2: 2987-2995. [E fetotsoe]
37. Chen J, Kelz MB, Zeng G, Sakai N, Steffen C, Shockett PE, et al. Liphoofolo tsa Transgenic tse nang le polelo e sa bonahaleng e lebisitsoeng ho mofuta oa bokong. Mol Pharmacol. 1998; 54: 495-503. [E fetotsoe]
38. Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, Kelz MB, et al. Karolo ea bohlokoa ea ΔFosB ho li-nucleus e bokellanang ketsong ea morphine. Neuroscience ea Tlhaho. 2006; 9: 205-211. [E fetotsoe]
39. Gilliss BCM, Pieper J, Carlezon W. Cocaine le SKF-82958 moputso oa tšusumetso ea kelello bokahaneng ba Swiss-Webster. Psychopharmacology. 2002; 163: 238-248. [E fetotsoe]
40. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Boitšoaro bo kang ba Mania bo susumetsoang ke tšitiso ea CLOCK. Proc Natl Acad Sci US A. 2007; 104: 6406-6411. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
41. Miliaressis E, Rompre PP, Durivage A. Psychophysical mokhoa oa ho etsa li-substrates tsa boits'oaro bo sebelisang li-electrode tse tsamaeang. Brain Res Bull. 1982; 8: 693-701. [E fetotsoe]
42. RA ea bohlale. Lithethefatsi tse tlatsetsang le moputso oa boko bo susumetsang. Annu Rev Neurosci. 1996; 19: 319-340. [E fetotsoe]
43. Liebman JM. Ho khetholla pakeng tsa moputso le ts'ebetso: tlhahlobo e bohloko ea mekhoa ea ho itlhasimolla e kenang. Neurosci Biobehav Rev. 1983; 7: 45-72. [E fetotsoe]
44. Miliaressis E, Rompre PP, Laviolette P, Philippe L, Coulombe D. The parveigt shift paradigm in self-incimulation. Physiol Behav. 1986; 37: 85-91. [E fetotsoe]
45. Rompre PP, RA ea Bohlale. Ho sebelisana ha opioid-neuroleptic ho ts'usumetso ea brainstem. Brain Res. 1989; 477: 144-151. [E fetotsoe]
46. Vialou V, Maze I, Renthal W, LaPlant QC, Watts EL, Mouzon E, et al. Ntho e arabelloang ke Serum e khothaletsa ho tiisetsa khatello ea maikutlo sechabeng ka ho kenyelletsa DeltaFosB. J Neurosci. 2010; 30: 14585-14592. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
47. Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS. Khatello ea maikutlo e eketsa ts'ebetso ea dynorphin libakeng tsa bokong ba litho tsa 'mele' me khatello ea kelello ea dynorphin e hlahisa litlamorao tse kang antidepressant. J Neurochem. 2004; 90: 1258-1268. [E fetotsoe]
48. Chartoff EH, Papadopoulou M, MacDonald ML, Parsegian A, Potter D, Konradi C, et al. Desipramine e fokotsa khatello ea maikutlo e hlahisang khatello ea maikutlo ea dynorphin le phosphorylation ea CREB liseleng tsa NAc. Mol Pharmacol. 2009; 75: 704-712. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
49. Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, et al. Ho thibela protheine ea cAMP e kopanyang karolo kapa "dynorphin" e bokellaneng ea nucleus ho hlahisa phello e kang antidepressant-like. J Neurosci. 2002; 22: 10883-10890. [E fetotsoe]
50. Spanagel R, Herz A, Shippenberg TS. Ho hanyetsana le li-system tsa endio native opioid tse sebetsang ka tsela e hlophisehileng li fetole tsela ea mesolimbic dopaminergic. Proc Natl Acad Sci US A. 1992; 89: 2046-2050. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
51. Hernandez G, Shizgal P. Liphetoho tsa molumo oa dopamine nakong ea boithati ba sebaka sa ho kenella hare ho likhoto. Patlisiso ea Bitso ea Boitšoaro. 2009; 198: 91-97. [E fetotsoe]
52. U ZB, Chen YQ, RA ea bohlale. Ho nthekeloa ha dopamine le glutamate ka har'a li-nucleus tse bokelletsoeng le sebaka sa likarolo tsa likarolo tsa pato ka mor'a ho ikhatholla. Neuroscience. 2001; 107: 629-639. [E fetotsoe]
53. Hernandez G, Haines E, Rajabi H, Stewart J, Arvanitogiannis A, Shizgal P. Meputso e sa lebelloang le e sa lebelloang e hlahisa liphetoho tse tšoanang modulong oa dopamine. Neuroscience ea Boitšoaro. 2007; 121: 887-895. [E fetotsoe]
54. Koob GF, Le Moal M. Tlatsetso le Brain Antireward System. Annu Rev Psychol. 2008; 59: 29-53. [E fetotsoe]
55. Walsh SL, Strain EC, Abreu ME, Bigelow GE. Enadoline, kappa opioid agonist e khethang: ho bapisoa le butorphanol le hydromorphone ho batho. Psychopharmacology (Berl) 2001; 157: 151-162. [E fetotsoe]
56. Dong Y, Green T, Saal D, Marie H, Neve R, Nestler EJ, et al. CREB e hlophisa thabo ea methapo ea kutlo ea li-nucleus e bokellanang. Nat Neurosci. 2006; 9: 475-477. [E fetotsoe]
57. Roitman MF, Wheeler RA, Tiesinga PH, Roitman JD, Carelli RM. Hedonic le li-nucleus li bokella likarabo tsa neural ho moputso oa tlhaho li laoloa ke maemo a morao. Ithute Mem. 2010; 17: 539-546. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
58. Derkach VA, Oh MC, Guire ES, Soderling TR. Mehato ea taolo ea li-receptor tsa AMPA ka har'a polasetiki ea synaptic. Nat Rev Neurosci. 2007; 8: 101-113. [E fetotsoe]
59. Shippenberg TS, Zapata A, Chefer VI. Dynorphin le pathophysiology ea lithethefatsi tsa lithethefatsi. Mofuta oa Pharmacol. 2007; 116: 306-321. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
60. Jacobsen LK, Southwick SM, Kosten TR. Mathata a tšebeliso ea lithethefatsi ho bakuli ba nang le khatello ea maikutlo ea posttraumatic: tlhahlobo ea lingoliloeng. Ke J Psychiatry. 2001; 158: 1184-1190. [E fetotsoe]
61. Swendsen J, Conway KP, Degenhardt L, Glantz M, Jin R, Merikangas KR, et al. Mathata a kelello e le lintho tse ka bang kotsi bakeng sa tšebeliso ea lithethefatsi, tlhekefetso le ts'ehetso: diphetho ho latela tlhahlobo ea selemo sa 10 sa Patlisiso ea Naha ea Comorbidity. Ho lemalla. 2010; 105: 1117-1128. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
62. Liu RT, Alloy LB. Ho hlahisa khatello ea maikutlo maemong a khatello: Tlhahlobo e hlophisitsoeng ea lingoliloeng tse khothatsang le likhothaletso tsa boithuto bo tlang. Clin Psychol Rev. 2010; 30: 582-593. [Tlhahiso ea mahala ea PMC] [E fetotsoe]
63. Hyman SE, Malenka RC, Nestler EJ. Mekgwa ya Neural ea bokhoba: karolo ea thuto e amanang le moputso le memori. Annu Rev Neurosci. 2006; 29: 565-598. [E fetotsoe]
64. McEwen BS, Gianaros PJ. Ho sithabela ha khatello ea maikutlo le allostasis. Annu Rev Med. 2011; 62: 431-445. [E fetotsoe]
;
