Lenaneo la li-opioid li-mediate prefrontal cortex li kopana le ho ja (2013)

Ho lemalla Moferefere. 2013 Jan 24. doi: 10.1111 / adb.12033.

Blasio A, Steardo L, Sabino V, Cottone P.

mohloli o moholo

Laboraro la lemalla Lits'oaetso, Mafapha a Pharmacology le Psychiatry, Sekolo sa Bongaka sa Boston, Boston, MA, USA.

inahaneloang

Ho itlopa lijo ke bothata ba ho ja lemalla ntho-e kang bokuli bo khetholloang ke ho fetella lijo tšebeliso ka nako ea discrete ea nako.

Phuputso ena e ne e reretsoe ho utloisisa karolo ea sistimi ea opioid kahare ho "methapo ea methapo ea methapo" ea mantlha mabapi le lijo tse matlafatsang le tse khothatsang. Bakeng sa morero ona, re koetlisitse likhoto tsa banna ho fumana lijo tse tsoekere, tse fumanehang habonolo kapa litheko tsa Chow bakeng sa hora ea 1.

Joale re tla ea lekola litlamorao tsa mohanyetsi oa opioid receptor antagonist, naltrexone, ea fuoeng ka tatellano kapa saete-ka kotloloho ho li-nucleus accumbens (NAcc) kapa mPFC ka karo-karolelano ea 1 (FR1) le lenane la maemo a ntlafatso a ntlafatso ea lijo.

Kamora nako, re ile ra lekola polelo ea mofuta oa proopiomelanocortin (POMC), pro-dynorphin (PDyn) le pro-enkephalin (PEnk), re ngola likhakanyo tsa li-peptide tsa opioids ho NAcc le mPFC ka lihlopha tsena ka bobeli.

Likhoto tse monate li ile tsa potlakisa ho ja ha tsona ka makhetlo a mane. Naltrexone, ha e tsamaisoa ka mokhoa o hlophisehileng le ho NAcc, e fokotsitse FR1 e arabelang lijo le tšusumetso ea ho ja tlasa tekanyo e tsoelang pele litlamong ka bobeli tsa Chow le Palatable; ka lehlakoreng le leng, ha e nehelloa ka har'a mPFC, litlamorao e ne e le tsona tse ikhethileng bakeng sa ho itlopa lijo tsa litoeba. Ho feta moo, re fumane keketseho e habeli ho POMC le phokotso ea ∼50% ho polelo ea mofuta oa PDyn ho mPFC ea likhoto tse ntle, ha e bapisoa le likhoto tsa taolo; leha ho le joalo, ha ho liphetoho tse ileng tsa bonoa ho NAcc.

Lintlha tsa rona li fana ka maikutlo a hore neuroadaptations ea opioid ea ts'ebetsong ea mPFC e etsahala ka mora ho fihlella ha nako le nako hore e fumanehe habonolo lijo, e ka ikarabellang tlhabollong ea ho ja ho ja joalo ka.

Selelekela

Boloetse ba ho ja bo tšoaetsoa ke ts'ebeliso e ngata ea lijo tse sa laoleheng ka nako e khutšoane (Avena, Rada le Hoebel, 2008; Corwin, 2006; Cottone et al a, 2012). Litaba tse jang le ho ja ho feta tekano li e hlalosa e le tahlehelo ea taolo nakong ea ts'ebeliso e ngata ea lijo, e lebisang ho se pheleng ho phethahetseng le maikutlo a tebileng a ho nyahama le lihlong (Stein et al a, 2007). Ho ba le bothata ba ho ja hangata ho hlaha le ho hlaseloa ke mafu a mangata a kang botenya, lefu la tsoekere, mafu a pelo le mafu a mang a kelello (Javaras et al a, 2008; Wilfley et al a, 2011).

Ho entsoe boiteko bo matla ba ho leka ho qolla lintho tse tlatsetsang ho holiseng ho itlopa lijo tse hlabosang (Cottone et al a, 2008b; Hagan le Moss, 1997). Khopolo-taba e amoheloang hohle lithutong tsa ho ja ho tlatselletsoa ho latela phetiso ea boleng ba lijo. Ho joalo, thibelo ea ho ja lijo tse bobebe tse "fumanehang" tse sireletsehileng, tseo hangata li tsamaisoang ke litloaelo tsa setso kapa bophelo bo bobe, li ka etsa hore motho a lakatse lijo tse matlafatsang mme a khothaletsa ho ja ho feta tekano. Ho feto-fetoha ha linako kemisong ea maemo a boreleli, ka hona, ho fella ka ho itšunya-tšunya hoa tšebeliso e mpe ea mokhoa oa ho itlopa lijo / lithibelo.Ho lahla et al a, 1989; Polivy le Herman, 1985), e phahamisa potso ea hore na bothata ba ho ja ho ja boits'oaro bo ka nkuoa e le tlhekefetso e kang "ho tšoana le"Corwin le Grigson, 2009; Cottone, Sabino, Steardo et al a, 2008b; Cottone, Wang, Park et al a, 2012; Epstein le Shaham, 2010).

Ha ho na litheko tsa litlhare tse sebetsang bakeng sa bothata ba ho ja tse seng li ntse li fumaneha hona joale, leha ho ntse ho reriloe merero e fapaneng ea liteko (Cottone, Sabino, Steardo et al a, 2008b; Cottone, Wang, Park et al a, 2012). Sistimi ea opioid e 'nile ea nkuoa e le e' ngoe ea sepheo sa mantlha sa kalafo ea mathata a ho ja ho tloha li-1970s, ka lebaka la tlhokomeliso ea pejana ea hore bahanyetsi ba opioid ba kang naltrexone le naloxone ba khonne ho fokotsa tšebeliso ea lijo (Holtzman, 1974). Bopaki ba morao-rao bo bonts'itse hore sistimi ea opioid e ne e kentse letsoho molemong oa phetisetso ea boitšoaro bo fepa, ha e fuoa bokhoni ba morphine ho eketsa takatso ea lijo lijong le lijo tse sa hlotsoeng letho (Sanger le McCarthy, 1980). Ho tloha liphatlalatsong tsena tsa pele, karolo e hlahelletseng ea sistimi ea opioid ea ho loants'a lijo li hlalositsoe 'me bopaki bo bongata bo bonts'itse hore li-nucleus accumbens (NAcc) li emela sebaka sa bohlokoa se loantšang litlamorao tsena (Le Merrer et al a, 2009). Boithuto ba morao-rao bo supile hore phetoho ea opioid phetisetso ea tšebeliso ea lijo tsa hedonic ho NAcc ke karolo ea marang-rang a rarahaneng, a kenyelletsang likarolo tse 'maloa tsa boko ho kenyeletsa libaka tsa preronto-cortical (Mena, Sadeghian le Baldo, 2011).

Le ha lipatlisiso tse ngata li hatisa karolo ea mantlha ea ts'ebetso ea opioid phetohelong ea maemo a boreleli le ho fepa ka hedonic, sebaka se ikhethileng sa boko moo tsamaiso ea opioid e sebelisang ho ja joaloka ho ja sejo se ntse se sa tsejoe.

Ka hona, sepheo sa thuto ena e ne e le ho bona hore na optolone ea antagonist naltrexone, e laoloang ka mokhoa o hlophisehileng, o khonne ho thibela ts'ebeliso le tšusumetso ea ho fumana lijo tse monate haholo ka mokhoa oa ho ja o jang joalo ka rat. Bakeng sa morero ona, re sebelisitse mofuta oa ts'ebetso o sa tsoa qaptjoa moo likhoto li iketsetsang lijo tse matlafatsoang, tse tsoekere ka tlasa maemo a fokolang a ho fihlella (1 h / day), ho etsisa likarolo tse khothatsang le tse khothatsang tse bonoang bothateng ba ho ja ka tsela e sa tloaelehang (Cottone, Wang, Park et al a, 2012). Ka mor'a moo re ile ra tsoela pele ho fumana hore na ke karolo efe ea boko e ikarabellang bakeng sa litlamorao tsa naltrexone tsamaisong ea khatello ea ts'ebeliso le tšusumetso ea ho fumana lijo tse tsoekere, tse monate haholo. Bakeng sa morero ona, sebaka sa rona sa microinfuse ka ho khetheha ke mohanyetsi oa opioid ho khetla ea NAcc le mPFC. Kamora nako, re ile ra lekola polelo ea mofuta oa li-preOpioMelanoCortin (POMC), Pro-Dynorphin (PDyn), le Pro-Enkephalin (PEnk), re ngola likhakanyo tsa li-peptide tsa opioids ho NAcc le mPFC kamora pale ea ho ja joaloka ho ja.

Litaba le Mekhoa

Lihlooho

Lipoe tsa banna ba Wistar (n= 70), matsatsi a 41-47 a fihlile ha a fihla (Charles River, Wilmington, MA) a ne a kentsoe mohala o holimo-limo, mekotla e tloaelehileng ea polasetiki ka 12: 12 h reverse lightjikele (mabone a 10: 00 h), ka mongobo- (60%) le vivarium e laoloang ke mocheso (22 ° C). Ha a fihla, likhoto li ne li na le phihlello ea lijo tse thehiloeng holim'a poone (Harlan Teklad LM-485 Diet 7012 (65% (kcal) carbohydrate, 13% mafura, 21% protheine, 341 cal / 100 g); Harlan, Indianapolis, IN) le metsi ad libitum ka linako tsohle. Mekhahlelo e khanneloa ho Litheo tsa Naha tsa Bophelo Tataiso bakeng sa tlhokomelo le tšebeliso ea liphoofolo tsa liphoofolo (NIH phatlalatso ea 85-23, 1996 e ntlafalitsoeng) le Melao-motheo ea Tlhokomelo ea liphoofolo (http://www.nap.edu/readingroom/bookslabrats), mme e amohetsoe ke Komiti ea Tlhokomelo ea liphoofolo le Ts'ebetso ea Univesithi ea Boston (IACUC). Lits'ebetso tsa liteko li ne li sa kenyeletse thibelo ea lijo kapa thipa ea metsi, ntle le haeba ho boletsoe ka tsela e 'ngoe.

lithethefatsi

Naltrexone, (5α) -17- (Cyclopropylmethyl) -4,5-epoxy-3,14-dihydromorphinan-6-hydrochloride e le 'ngoe, e rekiloe ho Abcam (Cambridge, MA). Naltrexone e ile ea qhibiliha ka mokhoa o sa tsoakoang ka letsoai la isotonic e tlhotliloeng (0.9%) ka letsatsi la liteko. Naltrexone e ne e tsamaisoa ka mokhoa o sa tsamaisaneng (0, 0.03, 0.1 le 0.3 mg / kg, 1 ml / kg) Metsotso ea 30 pele ho seboka le saete-ka kotloloho mokokotlong oa NAcc le mPFC (0, 5 le 25 ug / lehlakore, bilatal) hang pele seboka. Litekanyetso le linako tsa ho ikhopola li ne li thehiloe mangolong (Bodnar et al a, 1995; MacDonald, Billington le Levine, 2003; Williams le Broadbridge, 2009).

Tsamaiso e jang ea ho jella joaloka ho ja

Baithuto ba ne ba koetliselitsoe ho iketsetsa lijo le metsi ka phapusing ea liteko tsa motho ka mong tse hlalositsoeng ka lintlha ho (Blasio et al a, 2012; Cottone, Wang, Park et al a, 2012). Bakeng sa lintlha tse ling, bona Lisebelisoa tse tlatsetsang le mekhoa.

koetliso ea

Mochini o jang oa lijo tse kang oa ho itlopa lijo o entsoe joalokaha ho hlalositsoe pele (Cottone, Wang, Park et al a, 2012). Likhoto (n= 70) ba ile ba feptjoa lijo tse tloaelehileng tsa Harlan Teklad ka har'a ntlo eabo. Kamora nako ea ho akofisa, lijo li ile tsa nkeloa sebaka ke sejo se thehiloeng ho AIN-76A, kamora moo se bitsoang 'Chow A / I' (Lijo tsa 5TUM li entsoe ka li-pellets tsa 4-5 g, li-65.5% (kcal) carbohydrate, mafura a 10.4% , Proteni ea 24.1%, 330 cal / 100 g; TestDiet, Richmond, IN). Likhoto li ile tsa koetlisetsoa ho itaola ka mokhoa o ikemetseng bakeng sa lijo (li-pellets tsa lijo tsa 45-mg ka ho nepahala (Chow A / I) le metsi (100 µl) tlasa kemiso e tsitsitseng ea 1 ea kemiso (Cottone et al a, 2009). Dispenser e ile ea fana ka 45-mg e nepahetseng hantle pellet e ts'oanang le khese ea lapeng ~ 5g lijo tse fetotsoeng, e le ho etsa bonnete ba hore Chow lijo tsa likhoto li ne li tsamaisoa feela ke litlhoko tsa homeostatic (Cottone, Sabino, Roberto et al a, 2009; Cottone et al a, 2008a). Likopano tsa letsatsi le letsatsi li ne li etsoa pele ho potoloho e lefifi 'me e ne e le 1 h nakong ea nako.

Testing

Kamora ts'ebetso e tsitsitseng ea motheo mananeong a 1 h ea ho itaola, ts'ebetso ea liteko e ile ea qalisoa. Likhoto, tse bapisoang le boima ba 'mele, ho ja lijo tsa letsatsi le letsatsi, ho fepa ka mokhoa o nepahetseng, hammoho le metsi le lijo tse arabelang ka boeona, li abetsoe "Chow"Sehlopha sa taolo, se mabokoseng a sebetsang se amohetse li-pellets tse tšoanang tsa 45-mg chow tse fanoang sethaleng sa thupelo, kapa"E khoneha”Sehlopha, se amohetseng lijo tse nang le phepo e nepahetseng, tse nang le chokolete e nang le phepo e ntle (50% kcal) Lijo tse thehiloeng ho AIN-76A, tse bapisoang le sebopeho sa macronutrient le boima ba matla le lijo tsa chow. (Foromo e nang le chokolete e nang le chokolete e 5UL ] lik'habohaedreite, mafura a 66.7%, protheine ea 12.7%, matla a metabolism 20.6 cal / 344g; e entsoe e le li-pellets tsa lijo tsa 100 mg ka nepo; TestDiet, Richmond, IN). Lijo tsena tse nang le tatso ea chokolete li khethoa ka matla ke likhoto tsohle (Cottone, Sabino, Steardo et al a, 2008a, b). Mananeo a ne a etsoa letsatsi le letsatsi.

Lenaneo la tsoelo-pele la ntlafatso ea lijo

Kamora ho tsitsisoa ha mokhoa oa ho ja oa ho ja joalo ka likhoto, likhoto (n= 53) ba ile ba koetlisoa ka tekanyo e tsoelang pele ea li-supplement tsa lijo (45-mg chow-usahihi pellets bakeng sa Chow sehlopha le 45-mg tsokolate e nang le chisi, pellet e phahameng ea tlhahlobo e nepahetseng bakeng sa E khoneha sehlopha). Lenane la tsoelo-pele la ntlafatso ea lijo le entsoe joalo ka ha ho hlalositsoe pele (Cottone, Sabino, Roberto et al a, 2009; Cottone, Sabino, Steardo et al a, 2008a; Sabino et al a, 2011). Bakeng sa lintlha tse ling, bona Lisebelisoa tse tlatsetsang le mekhoa. Qetellong ea karolo e 'ngoe le e' ngoe, lithuto li ne li khutlisetsoa ntlong ea bona ea malapeng moo Chow A / ke neng ke lula ke le teng ad libitum; mananeo a ne a etsoa letsatsi le letsatsi.

Opereishene ea Intracranial le ts'ebetso ea microinfusion

Opereishene ea Intracranial

Kamora ho tiisoa ha tšebeliso ea lijo lithutong tsa opereishene, likhoto li ne li kentsoe ka cannulas ea intracranial. Lingaka tse buoang li ile tsa etsoa joalokaha ho hlalositsoe pele (Cottone et al a, 2007; Iemolo et al a, 2012; Sabino et al a, 2007). Bakeng sa lintlha tse ling, bona Lisebelisoa tse tlatsetsang le mekhoa. Lihokela tsa li-cannula tse sebelisitsoeng bakeng sa khetla ea NAcc le mPFC e ne e le A / P +1.06 mm, M / L ± 0.75 mm, D / V −6.0 mm le A / P +3.2 mm, M / L ± 0.65 mm, D / V −3.5 mm, ka ho latellana. Mokoallo oa lithuso o ne o behiloe ka lehata le bataletseng (mokokotlo / ventral: bregma = lambda); likhokahano li ne li ipapisitse le atlelase ea Paxinos & Watson (Paxinos, 1986). Sesebelisoa sa dummy setaele sa tšepe (Plastics One, Inc., Roanoke, VA, USA) se ile sa boloka semmuso. Kamora ho buuoa, likhoto li ile tsa lumelloa ho hlaphoheloa ts'ebetsong ea ho buoa bakeng sa beke ea 1 pele ts'ebetso ea liteko e qala.

Ts'ebetso ea Microinfusion

Bakeng sa microinfusion ea naltrexone, setaele sa dummy se tlositsoe ho cannula ea tataiso mme sa nkeloa sebaka ka jekete ea tšepe e se nang tšepe e hlahisang 1.0 mm bakeng sa polokeho ea NAcc le 1.5 mm bakeng sa mPFC ka nqane ho ntlha ea "cannula" ea tataiso; injector e ne e hokahantsoe ka sefuba sa PE 20 ho ea microsyringe ea Hamilton e tsamaisoang ke pompo ea microinfusion (Kd Saense / Meetso ea Lintho Tse Phelang, Holliston, MA, USA). Microinfusions e hlahisitse bophahamo ba 0.5 µl ka holim'a metsotso ea 2; Ho ne ho setse li-ente tsa motsotso o mong bakeng sa ho fokotsa mokokotlo oa mokokotlo. Kalafo e ile ea fanoa ka meralo e felletseng ea sekwere sa Latin, ha 1-3 e kenella matsatsi a liteko tsa mahala tsa kalafo, tseo ho tsona lijo li neng li khutlela maemong a motheo. Likhoto li ile tsa fuoa matsatsi a 3 a ho eketsa liente tsa sham letsatsi le letsatsi, pele ho qaleho ea kalafo ea lithethefatsi. Sebakeng sa Cannula (Feie. 4) e netefalitsoe qetellong ea liteko tsohle ka microinfusing India Ink (0.5 µl holim'a metsotso ea 2). Li -lices tsa 40 µm li ile tsa bokelloa ho sebelisoa li-cryostat mme lipehelo tsa tsona tsa netefatsoa tlasa microscope. Ho likhoto tsa 68 tse sebelisitsoeng lithutong tsa microinfusion, 3 ha ea ka ea qheleloa ka mabaka a ts'ebetso, a kenyelletsang tahlehelo kapa tlhahiso ea cannulae, kapa ho sitoa ho boloka ts'ebetso e tsitsitseng. Ho 14 ea likhoto tsa 65 tse setseng, boemo ba cannula bo ne bo le ka ntle ho sebaka sa sepheo.

Setšoantšo sa 4

Setšoantšo sa 4

Setšoantšo sa methapo ea boko ea likhoto. Metsu e emetse libaka tsa ente ho (A) NAcc khetla le (B) mPFC e kenyellelitsoe tlhahlobisong ea data.

Kakaretso ea Nako ea 'Nete ea PCR

Sehlopha se le seng sa Chow 'me E khoneha likhoto (n= 15) e sebelisitsoe bakeng sa karabelo ea POMC, PDyn, le PEnk peptides mRNA. Liphoofolo li ile tsa etsoa sehlabelo 24 h kamora seboka sa ho qetela sa ho itlopa lijo joaloka letsatsi le letsatsi. Li-punches tsa medial prefrontal cortex li kenyeletsa libaka tsa prelimbic le infralimbic. Li-punches tsa li-nucleus tsa li-nucleus li kenyelletsa libaka tsa khetla le tsa motheo. Mekhoa e entsoe joalo ka ha ho hlalositsoe pele (Sabino et al a, 2009). Bakeng sa lintlha, bona Lisebelisoa tse tlatsetsang le mekhoa.

Tlhahlobo ea Litekanyetso

Litlamorao tsa naltrexone litekanyetsong tsa lijo, tšebeliso ea metsi, le sebaka se arohaneng li ile tsa hlahlojoa ho sebelisoa meralo e kopantsoeng ea li-ANOVA tse peli, tse nang le nalane ea Diet e le taba e pakeng tsa lithuto le kalafo e le taba e ka hare-hare, e lateloang ke mehato e phetoang ea ANOVA e le 'ngoe. Litlamorao tsa nalane ea phepo e nepahetseng maemong a mRNA li ile tsa hlahlojoa ho sebelisoa liithuti tse sa lefelloang tLiteko. Lintho tse sa atleheng tlhahlobo ea maemo li ile tsa hlahlobisisoa joalo ka maemo (Akritas, 1990). Liphutheloana tsa lipalo tse sebelisitsoeng e ne e le Instat 3.0 (GraphPad, San Diego, CA) le Systat 11.0 (SPSS, Chicago, IL).

Results

Litlamorao tsa tsamaiso ea methapo ea ts'oaetso ea opioid antagonist naltrexone ho ja ho jellang joaloka ho ja

Tsamaiso ea systemic ea naltrexone dose-e theotsoe ka kotloloho FR1 e arabelang lijo ka bobeli Chow 'me E khoneha lihlopha (Setšoantšo sa 1A; Phekolo: F(3,54) = 25.00, p<0.001; Nalane ea Lijo X Phekolo: F(3,54) = 0.64, ns) Li-ANOVA tsa tsela e le 'ngoe li tiisitse phello ea kalafo ea lithethefatsi ho tsona ka bobeli Chow (Phekolo: F(3,27) = 7.62, p<0.0008) le E khoneha likhoto (kalafo: F(3,27) = 16.78 p<0.0001). Tlhahlobo ea Post hoc e senotse hore, ha tekanyetso ea 0.03 mg / kg e ne e sa sebetse, bobeli ba litekanyetso tsa 0.1 le 0.3 mg / kg li fokotsitse boitaolo ba lijo lihlopheng tsena tse peli, ha li bapisoa le boemo ba koloi. Ho feta moo, ho noa metsi ho ile ha angoa ke kalafo (Lethathamo 1; Phekolo: F(3,54) = 8.46, p<0.0001; Nalane ea Lijo X Phekolo: F(3,54) = 0.76, ns). ANOVA ea tsela e le 'ngoe e tiisitse phello ea kalafo ea lithethefatsi ho tsona ka bobeli Chow (Phekolo: F(3,27) = 4.97, p<0.007) le E khoneha (Phekolo: F(3,27) = 3.76, p<0.022) likhoto. Tlhahlobo ea Post hoc e senotse phokotso e kholo ea phepelo ea metsi kamora ho tsamaisoa ha tekanyetso ea 0.1 le 0.3 mg / kg ho Chow likhoto le lethal dose ea 0.3 mg / kg ho E khoneha likhoto, ha li bapisoa le boemo ba koloi.

Setšoantšo sa 1

Liphetho tsa kalafo e hlophisitsoeng ka naltrexone (0, 0.03, 0.1, 0.3 mg / kg, subcutaneously) ho (A) boitlhokomelo ba lijon= 20) le (B) karohano lenaneong le tsoelang pele la karolelano ea khothatso (n= 19) ho likhoto tsa Wistar tsa banna. Liphanele li emela M± SEM. ...

Litlamorao tsa tsamaiso ea naltrexone ka tšebeliso ea metsi

Litlamorao tsa tsamaiso ea li-systemic antagonist naltrexone lenaneong le tsoelang pele la karolelano ea lijo le matlafatso ea lijo.

Naltrexone, e tsamaisoang ka mokhoa o hlophisehileng, litekanyetso li ile tsa fokotsa ho phatloha ka bobeli Chow 'me E khoneha likhoto (Setšoantšo sa 1B; Phekolo: F(3,51) = 41.31, p<0.0001; Nalane ea Lijo X Phekolo: F(3,51) = 1.96, ns). Ho latela phello ea bohlokoa ea kalafo (Chow sehlopha; Phekolo: F(3,27) = 5.99, p<0.003; E khoneha sehlopha; Phekolo: F(3,24) = 6.87, p<0.002), tlhahlobo ea post hoc e senotse hore lethal dose ea 0.3 mg / kg e fokolitse khefu haholo lihlopheng ka bobeli.

Litlamorao tsa naltrexone microinfusion ka har'a khetla ea NAcc mabapi le ho ja joalo ka phepelo

Naltrexone microinfusion ka har'a lethalinyana la NAcc-e fokotsehile ka ho arabela lijo bakeng sa bobeli ba Chow 'me E khoneha sehlopha (Setšoantšo sa 2A; Phekolo: F(2,32) = 10.76, p<0.0001; Nalane ea Lijo X Phekolo: F(2,32) = 4.36, p<0.02). Li-ANOVA tsa tsela e le 'ngoe li senotse phello ea kalafo ea lithethefatsi ka bobeli Chow (Phekolo: F(2,18) = 5.72, p<0.01) le E khoneha likhoto (kalafo: F(2,18) = 5.344, p<0.02) ka ho latellana. Ntle le moo, tlhahlobo ea poso ho senotsoe phokotso e kholo ea boitaolo ba lijo kamora kalafo e nang le lethal dose (25 µg) ka bobeli Chow 'me E khoneha lihlopha. Tšebeliso ea metsi ha ea ka ea angoa ke kalafo ea lithethefatsi (Lethathamo 1; Phekolo: F(2,32) = 2.48, ns; Phekolo ea Lijo X F(2,32) = 0.65, ns).

Setšoantšo sa 2

Kameho ea microinfusion ka naltrexone (0, 5, 25 µg / side) ho NAcc shell on (A) boitlhokomelo ba lijon= 18) le (B) karohano lenaneong le tsoelang pele la karolelano ea khothatso (n= 17) ho likhoto tsa Wistar tsa banna. Panel e emetse M± SEM. Matšoao ...

Litlamorao tsa naltrexone microinfusion ka har'a khetla ea NAcc lenaneong le ntlafalitsoeng la keketso ea lijo.

Ha naltrexone e ne e le sitein ka ho khetheha microinfuse ho NAcc, phokotso ea bohlokoa ka kakaretso Chow 'me E khoneha sehlopha se bonoe (Setšoantšo sa 2B; Phekolo: F(2,30) = 16.72, p<0.0001; Nalane ea Lijo X Phekolo: F(2,30) = 5.22, p<0.01). Sephetho sena se netefalitsoe ke tsela e le 'ngoe eo li-ANOVA li sebelitseng ka bonngoe sehlopheng ka seng sa tse peli (Chow sehlopha; Phekolo: F(2,16) = 6.11, p<0.01; E khoneha sehlopha; Phekolo: F(2,14) = 10.62, p<0.001). Tlhahlobo ea Post-hoc e senotse phokotso e kholo ea "breakpoint" lihlopheng ka bobeli ha litekanyo tsa 5 le 25 XNUMXg li ne li sebelisoa ka bongata. Phokotso ea "breakpoint" e ne e ts'oana le boholo lipakeng tsa Chow 'me E khoneha likhoto (50.8% le 53.2%, ha li bapisoa le maemo a koloi, ka tatellano).

Litlamorao tsa naltrexone microinfusion ho mPFC ho ja ho jellang joaloka ho ja

Sebaka sa Naltrexone - haholo-holo li-microinfuse ho MPFC li amme ka mokhoa o fapaneng lijo tse arabelang kahare Chow 'me E khoneha likhoto, joalo ka ha ho senotsoe ke tšebelisano ea bohlokoa (Setšoantšo sa 3A; Phekolo: F(2,30) = 4.77, p<0.02; Nalane ea Lijo X Phekolo: F(2,30) = 5.08, p<0.01). Ho joalo, ha naltrexone e sa ame ho arabela chow in Chow likhoto (kalafo: F(2,12) = 0.68, ns), e fokotsa - ho itšepa lijo ka mokhoa o ts'epahalang E khoneha likhoto (kalafo: F(2,18) = 9.25, p<0.002), ka tlhahlobo ea post hoc e bonts'a phokotso e kholo ho latela 25 µg dose, ha e bapisoa le boemo ba koloi. Ka hona, naltrexone, e kenngoe ka har'a mPFC, e amme lijo tse kang ho itlopa joala ka mokhoa o ikhethileng E khoneha likhoto, ntle le ho ama ho fepa ho likhoto tsa taolo. Ntle le moo, naltrexone e ne e se na phello ea tšebeliso ea metsi (Lethathamo 1; Phekolo: F(2,30) = 1.89, ns; Phekolo ea Lijo X F(2,30) = 0.69, ns).

Setšoantšo sa 3

Phello ea microinfusion ka naltrexone (0, 5, 25 µg / side) ho mPFC on (A) boitlhokomelo ba lijon= 17) le (B) karohano lenanengn= 17) ho likhoto tsa Wistar tsa banna. Panel e emetse M± SEM. Matšoao a bontša: ...

Litholoana tsa naltrexone microinfusion ka har'a mPFC lenaneong le tsoelang pele la karo ea lijo le matlafatso ea lijo.

ANOVA ea mekhahlelo e 'meli e sebelisitsoeng mohopolong oa Chow 'me E khoneha likhoto tse latelang microinfusion ea naltrexone ho mPFC e hlahisitse phello e kholo ea kalafo ea lithethefatsi (Setšoantšo sa 3B; Phekolo: F(2,30) = 9.057, p<0.001; Nalane ea Lijo X Phekolo: F (2,30) = 1.84, ns). Leha ho le joalo, leha tlhahlobo e le 'ngoe ea ANOVA e senotse phello ea kalafo ea lithethefatsi ho Chow sehlopha (Phekolo: F(2,18) = 4.43, p<0.027), kamora tlhahlobo ea kamora 'hoc kapa 5 µg kapa 25 µg dose ha e fapane haholo le boemo ba koloi. Mohlomong, phello ea bohlokoa ea kalafo e bonts'itsoeng ke ANOVA e ne e khannoa ke mokhoa o lebisang sebakeng se eketsehileng sa khefu ho latela tekanyetso ea 5 µg, ha e bapisoa le boemo ba koloi. Ka lehlakoreng le leng, ho E khoneha Sehlopha se ka ama melemo ea kalafo ea lithethefatsi (kalafo: F(2,12) = 5.31, p<0.02), mme lethal dose e phahameng ka ho fetisisa e kenngoeng ka mPFC e fokolitse khefu haholo, ha e bapisoa le boemo ba koloi.

Kakaretso ea Nako ea 'Nete ea PCR

PCR ea 'nete ea nako ea bohlokoa e bontšitse hore, 24 h kamora seboka sa ho qetela sa ho itlhoma lijo, ha ho phapang e kholo PPC, PDyn, le polelo ea PEnk lipakeng Chow 'me E khoneha likhoto li ile tsa bonoa ho NAcc (Litšoantšo 5A, 5B, le 5C). Leha ho le joalo, maemo a POMC mRNA a ne a phahame haholo ho PFC ea E khoneha likhoto, ha li bapisoa le Chow likhoto (keketseho ea 117.9%); Setšoantšo sa 5D). Ntle le moo, maemo a polelo a PDyn ho PFC ea E khoneha likhoto li ne li le tlase haholo ha li bapisoa le Chow likhoto (Phokotso ea 49.3%; Setšoantšo sa 5E). Ha ho na phapang pakeng tsa lihlopha tsena tse peli e ileng ea bonoa maemong a PEnk mRNA ho PFC (Setšoantšo sa 5F).

Setšoantšo sa 5

Setšoantšo sa 5

POMC, PDyn, le polelo ea PEnk mRNA ho NAcc (A, B 'me C) le ho mPFC (D, E 'me F) ea likhoto tsa Wistar tse tona. Libaka tsa methapo e ile ea bokelloa 24 h kamora kopano ea ho qetela ea ho itlopa lijo letsatsi le letsatsi. Moemeli oa data M± SEM e hlahisitsoeng e le liperesente tsa Chow sehlopha; ...

Puisano

Thutong ena re bonts'a hore opioid antagonist naltrexone, e laetsoeng ka mokhoa o hlophisehileng, e sa fokotse ts'ebeliso le tšusumetso ea ho fumana lijo, hape e fokotse tšebeliso ea metsi mebeleng ka bobeli e iphekisang lijo tse tloaelehileng le litoeba tse jang ho otla ka nako. Lijo tse monate haholo. Habohlokoa le ha litla-morao tsa lijo tsa 'nete le tse fumanehang habonolo li ile tsa bolokoa ha naltrexone e ts'oaetsoa leseling la NAcc, mohanyetsi oa opioid ka boomo o ile a fokotsa ts'ebeliso le tšusumetso ea ho fumana lijo tse fumanehang habonolo, empa eseng kamehla, ha microinfuse ho MPFC. Ntle le moo, ho netefatsa khethollo ea litlamorao tsa boits'oaro bo bonoang kamora ho buoa ha manttrexone ka har'a mPFC, polelo ea mRNA ea POMC le PDyn e ne e theotsoe mPFC, empa eseng ho NAcc, ea ho itlopa litoeba ho ja likhoto. Ha ho na tšusumetso e ileng ea bonoa ponong ea mofuta oa PEnk sebakeng ka bobeli.

Ka tloaelo, naltrexone e laetsoeng ka mokhoa o hlophisehileng E khoneha 'me Chow likhoto. Phekolo ea lithethefatsi e hlophisitsoeng e boetse e fokotsitse tšusumetso ea ho sebetsa, e le ho fumana lijo le lijo tse matlafatsoang ka tatellano ea karolelano ea tšehetso, paradigm e tiisitsoeng ea boitšoaro e sebelisitsoeng ho lekola matla a susumetsang a ho fumana li -forforcers (Cottone, Sabino, Roberto et al a, 2009; Cottone, Sabino, Steardo et al a, 2008a). Kamora ho tsamaisoa ha subcutaneous ho lethal e phahameng ka ho fetisisa naltrexone, boholo ba litlamorao tse kholo phokotsong ea karabelo ea FR1 le tšitiso ea kemiso e tsoelang pele ea tefello ea ts'ebetso e ne e ts'oana le lihlopheng tsena tse peli (FR1: 58.2% le 54.0%; ratio e tsoetseng pele: 40.5 % le 43.3%, ha e bapisoa le maemo a koloi ho Chow 'me E khoneha likhoto, ka ho latellana). Ka hona, litlamorao tsa naltrexone ea tsamaiso ea lijo tse nang le phepo e kanna ea kenyelletsa khatello ea boitšoaro ba homeostatic le hedonic (Le Merrer, Becker, Befort et al a, 2009). Ho khahlisang, litlamorao tsa tsamaiso e potolohileng ea naltrexone li ne li sa khethoe bakeng sa lijo, hobane kalafo ea lithethefatsi e ne e boetse e fokotse tšebeliso ea metsi taolong le litlamong tsa ho ja likhoto. Ka kakaretso, liphuputso tsena tsa pele li ne li fana ka maikutlo a ho hatella ka kakaretso boits'oaro ba ho ingestive, ho latela tsamaiso ea methati le mohanyetsi oa opioid (Frenk le Rogers, 1979).

Phuputsong ena re ne re batla ho tseba hore na li-opioid receptors tse ka har'a khetla ea Nacc li arolelana likarolo tsa phepelo le tse khothatsang tsa ho ja joaloka ho itlopa lijo. Ho joalo, sistimi ea opioid sebakeng sena e khothalelitsoe ho kenya letsoho ho fetoleng thepa ea monehelo oa lijo (Carlezon, Devine le Wise, 1995). Mona re bonts'a hore naltrexone microinfuse ka mokokotlong oa NAcc ha ea fokotseha feela ho ja-ja lijo tse matlafatsang haholo, empa le tšebeliso ea kamehla ea chow. Sephetho se ts'oanang se fumanoe ha re ne re leka litlamorao tsa naltrexone microinfusion ka mokokotlong oa NAcc pheletsong ea kemiso e tsoelang pele ea matlafatso ea lijo. Ha e le hantle, kalafo ea lithethefatsi e sa khethe, e ile ea fokotsa tšusumetso ea ho fumana lijo lijong le ho laola likhoto. Liphumano tsena li fana ka maikutlo a hore li-opioid receptors ka har'a khetla ea Nacc li fana ka phetoho e akaretsang ea boitšoaro ba ho fepa le ho tiisa lijo ka mokhoa o ikhethileng, ntle le mofuta kapa ts'usumetso ea lijo. Ho ts'ehetsa hypothesis ena, Kelley le basebetsi-mmoho ba bonts'itse hore blockade ea li-receptor tsa μ-opioid kahare ho NAcc e fokotsa tšebeliso ea lijo tse tloaelehileng tsa chow chow le tharollo ea sucrose (Kelley, Hlooho le Swanson, 1996). Ho fapana le seo re se boneng ho latela tsamaiso ea naltrexone e latelang, leqheka la microcfusion la lithethefatsi ha le amme ho ja metsi, ho fana ka maikutlo a hore li-receptor tsa opioid sebakeng sena sa boko li ameha ka ho khetheha phetolelong ea boitšoaro ba ho fepa, ho fapana le ka kakaretso boitsholong ba ho ingestive, kapa hore tekanyetso e phahameng ea hlokahala ho hatella tšebeliso ea metsi.

Re boetse ra etsa lipatlisiso hore na tsamaiso ea opioid ka har'a mPFC e bohlokoa hakae ho aroleng lijo tse matlafatsang joaloka ho ja lijo tse matlafatsang. Thutong ea rona, mPFC microinfusion ea mohanyetsi oa opioid ka mokhoa o ikhethileng le litekanyetso li fokotse ts'ebeliso le tšusumetso ea ho fumana lijo tse matlafatsang haholo litlamong tsa ho ja li-rats, ntle le ho ama ho ja khafetsa khafetsa ho ratseng. Tšebeliso ea metsi ha ea ka ea angoa ke kalafo ea lithethefatsi sehlopheng sena ka seng, ho fana ka maikutlo a hore litlamorao li ikhethile bakeng sa boits'oaro. Libaka tsa boko ba Fronto-cortical li bile le tšusumetso phapang ea boitšoaro ba ho fepaMoran le Westerterp-Plantenga, 2012). Tlaleho ea morao-rao e boetse e bonts'itse hore li-receptors tsa op-opioid kahare ho mPFC li bapala karolo ea bohlokoa ho khanna tšebeliso e feteletseng (Mena, Sadeghian le Baldo, 2011).

Ho bohlokoa ho tšohla mofetoleli o mong hore litlamorao tsa naltrexone li ka hlaha ka lebaka la ho kenella kapele ho bokong le pherekanong, ka tloaelo ho bahanyetsi ba bang ba li-quaternary derivatives opiate antagonists (Vaccarino, Bloom le Koob, 1985; Vaccarino et al a, 1985) tse nang le sekhahla se tlase sa phapang (Schroeder et al a, 1991). Khahlano le tlhaloso ena ho na le bopaki ba hore, phuputsong ena, naltrexone microinfuse libakeng tse peli tse fapaneng tsa boko (NAcc le PFC) ho Chow likhoto li bile le litlamorao tse sa tšoaneng. Ntle le moo, tlhahlobo ea nako ea thuto mabapi le karabelo ea lijo e bontšitse hore naltrexone e kentsoe MPFC e fokotsa ho arabela ha lijo E khoneha likhoto ka mor'a metsotso e 6 feela kamora microinfusion (M± SEM: 84.3 ± 7.5. 75.3 ± 6.6, veh vs. 25 µg / lehlakoreng, ka ho latellana, p<0.05). Ka lebaka la nako e khuts'oane, moelelo o mong oa hore phello e ka bonoang e ka tsoa ho CNS-wide kapa peripheral blockade ea li-opioid receptors ha ho bonolo. Ntle le moo, ho ts'ehetsa bonnete ba tlhaiso-leseling e fumanoeng thutong ena, lingoliloeng li tlaleha haholo litlamorao tsa naltrexone microinfused libakeng tse itseng tsa boko (Bodnar et al a, 2005). Leha ho le joalo, tšibeliso ea hore matla a naltrexone e kanna ea boela ea itšetleha ka ho kenella hanyane libakeng tsa boko tse amanang le Nacc shell kapa PFC, e ke ke ea qheleloa ka thoko.

Tlhaloso e 'ngoe ea ho haella ha litlamorao ho lijo tse tlang ka mor'a naltrexone microinfusion ho cortex ea pele Chow likhoto ke hore phello e bonoang e ka hlaha ho kopane ho kopaneng ha li-mu le kappa opioid receptors. Leha lits'ebetso tsena tse peli li bonts'itsoe ho fana ka litlamorao tse fapaneng tsa modulatory lits'ebetsong tse fapaneng ho kenyelletsa moputso, ba bontšitsoe hore ba fetole phepelo ea lapeng (joalo ka lijo tse fumanehang ho Chow liphoofolo tsa thuto ena) ka mokhoa o ts'oanang. Ka bobeli activation activation mu le kappa opioid li bontšitse ho eketsa takatso ea lijo, athe li-blockade tsa tsona li bontšitsoe hore li fana ka litlamorao (anorectic) (Cooper, Jackson le Kirkham, 1985; Gosnell, Levine le Morley, 1986) Ka hona, seo re se fumaneng se fana ka maikutlo a karolo e fapaneng phapusing ea boitšoaro ba ho ja e hlahisoang ke tsamaiso ea opioid ho NAcc le mPFC; ha li-receptor tsa NAcc opioid li bonahala li kenella mochineng o fapaneng oa phepelo, ntle le mofuta oa lijo tse kentsoeng (Kelley, Hlooho le Swanson, 1996), sistimi ea opoid ea mPFC e bonahala e hloa feela ka mor'a nalane ea phihlello ea lijo tse tsoekere, tse monate, ha likhoto li sa laole taolo ea lijo. Khopolo-taba ena e tsamaisana le ts'ebetso e phahameng ea kelello le taolo e rarahaneng ea tlhahlobo ea moputso e hlahisitsoeng ke mPFC.

Khopolo-taba ea karolo e akaretsang, e seng lijo tse ikhethang tsa li-receptor tsa NAcc opioid mokheng oa boitšoaro ba ho fepa, 'me ho hira mPFC ka mokhoa o ikhethileng ho tšehelitsoe ke tlhahlobo ea polelo ea gene ea POMC, PDyn, le PEnk. Ha ho phapang e kholo ponong ea mefuta e meraro e boneng ho NAcc, ha ho bapisoa ho ja le ho ja likhoto. Ka lehlakoreng le leng, ho mPFC, likhoto tse jang lijo tse ngata li bontšitse keketseho e fetang makhetlo a mabeli ea maemo a POMC mRNA, e tsamaisana le phokotso ea ~ 50% maemong a mRNA a PDyn, ha a bapisoa le litoeba tsa chow.

Mefuta ea POMC le PDyn e bontšitsoe hore e hlahisitsoe likarolong tsena ka bobeli tsa boko (Leriche, Cote-Velez le Mendez, 2007; Taqi et al a, 2011; Ziolkowska et al a, 2006). (Leha ho le joalo, bopaki bo bontša hore li-peptide tsa opioid tse lokollotsoeng ho mPFC le tsona li ka tsoa mehlolong ea lisele tse tsoang libakeng tse fapaneng tsa boko (ke hore sebaka sa likarolo tse sa sebetseng (ventral tegmental (Garzon le Pickel, 2004)), e hlahisang monyetla oa hore litlamorao tse bonoang thutong ena kamora naltrexone microinfusion kahare ho mPFC li ka se kopane le phapang ea polelo ea POMC le Pdyn sebakeng seo sa boko. POMC ke sethala sa li-endorphin tse khethang μ (empa hape le δ) li-receptor tsa opioid (Mansour et al a, 1995), ha PDyn e le eona e hlahelletseng ea li-dynorphin tse khethollang li-receptor tsa κ-opioid (Day et al a, 1998). Bopaki bo pharaletseng bo hlahisitse karolo e hanyetsanang ea li-receptor tsa μ- le κ-opioid phetolelong ea lits'ebetso tse fapaneng bokong ho kenyeletsa analgesia, mamello, mekhoa ea ho hopola, le moputso (Pan, 1998; Woolley et al a, 2007). Haholo-holo ebile e lumellana le khopolo ena, li-receptors tsa μ-opioid li netefalitsoe haholo hore li arolelana thepa ea moputso ea lijo le lithethefatsi tse ling tsa tlhekefetso (Zhang le Kelley, 2000); ka lehlakoreng le leng, li-receptor tsa κ-opioid li bonts'itsoe ho thusa ho phetola litlamorao le ho hlaseloa ke dysphoric, 'me ho hlahisitsoe joalo ka karolo ea "anti-moputso" sistimi (Koob le Le Moal, 2001). Habohlokoa le ho feta, maemong a thutong ena, ts'ebetso ea lithethefatsi tsa "receptor" tsa motsoako oa within- kapa κ-opioid kahare ho cortex ea pele li bontšitsoe hore li fana ka litlamorao tse hanyetsang: li-microinfusions tsa khetho ea μ-opioid receptor agonist e khetha sebaka, athe micinfusions of κ-opioid receptor agonist e hlahisa sebaka se nyatsehang (Bals-Kubik et al a, 1993).

Ntlha ea bohlokoa ea moqoqo ke hore na liphetoho lipuisanong tsa mRNA tse bonoang thutong ena li its'etleha ka ho fapana ha ho fokotseha hoa caloric kapa boima ba 'mele lipakeng Chow 'me E khoneha likhoto. Le ha lijo le boima ba 'mele li ne li sa ngolisoe ka har'a sehlopha sa liphoofolo tse sebelisoang bakeng sa PCR ea nakoana, re kile ra supa hore mokhoa o jang oa ho ja o sebelisoang mona ha o na tšusumetso ea lijo tse matlafatsang kapa boima ba' mele. Ho ja, likhoto tse jang tse ngata li bontša ho ja haholo nakong ea phihlello ea 1h lijong tse matlafatsang, empa ho tla buseletsoa nakong ea lihora tse setseng tsa 23 ka ho hlakola lijo tse tloaelehileng tsa chow.Cottone, Wang, Park et al a, 2012). Mokhoa ona o fetelletsang oa ho ja ka hona ha o felle ka hore ho fokotsehe takatso ea lijo tsa 'mele kapa ho fokotsa boima ba' mele lipakeng tsa ho ja ka thata le likhoto tse laoloang (Cottone, Wang, Park et al a, 2012).

Leha ho kopantsoe ho tšoana pakeng tsa mokhoa oa ho ja ho feta tekano / thibelo litabeng tsa ho itlopa lijo le ho tahoa kapa mokhoa oa ho khaotsa ho sebelisa lithethefatsi (Epstein le Shaham, 2010), hore na mofuta oa phoofolo e sebelisitsoeng thutong ena e ka ba molemo ho boithuto ba matšoao a fosahetseng a amanang le ho khaotsa lijo tse fumanehang habonolo ha a tsejoe. Polelo e ntseng e eketseha ea POMC ("pro-moputso" sistimi) le polelo e fokotsehileng ea Pdyn ("anti-moputso" sistimi) e bonoang mona kamora ho tloheloa ha 24h lijong tse matlafatso li bontša hore liphoofolo li ka se be le boemo bo bobe ba maikutlo. Leha ho le joalo, ho sebetsana le karolo ena ea bohlokoa ea ho palama libaesekele, liphuputso tse ling tse lekolang maikutlo le ho ba le seabo molemong oa khatello ea maikutlo (mohlala, corticotropin-releasing factor) li tla hlokahala. Ka hona, liphetoho tse fapaneng tlhahisong ea mofuta oa POMC le Pdyn e hlokometsoeng ho mPFC li ka hlalosoa e le tšebeliso e akaretsang ea thepa e tlatsetsang ea lijo tse fumanehang habonolo, tseo e ka bang sephetho sa kapa tsa tsamaisa ho ja ho hongata lithutong tsena.

Ka kakaretso, liphetho tsa thuto ena li ts'ehetsa maikutlo a hore tsamaiso ea opioid libakeng tse bokong tsa bongoana e kentse letsoho taolong ea boitšoaro ba phepo le ho e holisa ho latela mohopolo oa tšebeliso e mpe ea lijo tse matlafatsoang tse bonoang ho ba jang lijong tse ngata. (Mena, Sadeghian le Baldo, 2011). Libaka tsa boko ba Fronto-cortical li bapala karolo e kholo ho tekolo ea moputso le ho etsa liqeto (Clark et al a, 2008); lingoliloeng tse ngata li bonts'a hore lithuto tse nang le bothata ba ho lemalla le ho itlopa lijo tse litšila li bontša ho se sebetse hantle mPFC, e amanang le tlhahlobo ea moputso o fetotsoeng (Boeka le Lokken, 2011). Boitšoaro ba rona ba boits'oaro, meriana, le molek'hule, ka hona, re ts'ehetsa maikutlo a hore sistimi ea opioid ke mosireletsi oa bohlokoa oa phepo ea hedonic (Nathan le Bullmore, 2009) le ho fana ka tlhahiso ea hore li-neuroadaptations tsa opioid system ho mPFC li ka ikarabella bakeng sa tlhahlobo ea maikutlo ea lijo tse matlafatsang haholo, tse lebisang ho tahlehelo ea taolo ea ho ja.

Boitsebiso bo Eketsehileng

Phepelo

Tobetsa mona ho sheba.^{(35K, doc)}

lumela hore baa fokola

Re leboha Stephen St. Cyr, Aditi R. Narayan, Vamsee Neerukonda, Noah Kelley, Jin Won Park, Anoop Ravilla, le Sishir Yeety bakeng sa thuso ea mahlale, hammoho le Tamara Zeric bakeng sa thuso ea bongoli. Sengoliloeng sena se entsoe hore se khonehe ka linomoro tsa lithuso DA023680, DA030425, MH091945, MH093650A1, le AA016731 ho tsoa Setsing sa Naha sa Tlhekefetso ea Lithethefatsi (NIDA), Setsi sa Naha sa Bophelo bo Botle ba Kelello (NIMH) le Setsi sa Naha sa Tlhekefetso ea Joala le Tahi (NIAAA) , ke Peter Paul Career Development Professorship (PC) le Lenaneo la Patlisiso ea Baithuti ba Sekolo se Phahameng sa Boston University (UROP). Litaba tsa eona ke boikarabello ba bangoli ebile ha li bolele maikutlo a semmuso a Mekhatlo ea Naha ea Bophelo.

Mongolo o botlaaseng ba leqephe

Tlatsetso ea lingoli

AB, PC le VS ba ne ba ikarabella mohopolo oa thuto le moralo. AB, PC le VS ba ile ba etsa liteko tsa boitšoaro le tsa limolek'hule. AB le PC ba ile ba etsa tlhahlobo ea data. PC, VS le LS li thusitsoe ke ho fetolela se fumanoeng. AB le PC ba ile ba ngola sengoloa sena. PC, VS le LS li fane ka ntlafatso e matla ea buka e ngotsoeng ka letsoho bakeng sa litaba tsa bohlokoa tsa mahlale. Bangoli bohle ba ile ba lekola ka hloko se ngotsoeng le ho amohela mofuta oa ho qetela oa phatlalatso.

References

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