Ts'ebeliso ea methapo ea methapo ea mokokotlo tsamaisong ea Mesolimbic e susumelitsoeng ke Moputso oa Tlhaho le Mopholosi oa Boipheliso. (2010)

LIPOTSO: Boithuto bo bonts'a liphetoho tse amanang le neuroplastic le boits'oaro ho potoloho ea moputso li ka hlaha liketsong tsa thobalano. Tsena li kenyelletsa kholo ea makala a neuron le karabelo e matla ea lithethefatsi. Joalo ka tloaelo, ba matlafatsang litlhare le lithethefatsi li na le litlamorao tse tšoanang bokong.

THUTO E TLAHANG

Pitchers KK, Balfour ME, Lehman MN, Richtand NM, Yu L, Coolen LM.

Psychology ea Biol. 2010 May 1; 67 (9): 872-9. Epub 2009 Dec 16.

Lefapha la Anatomy le Cell Biology, Sekolo sa Bongaka sa Schulich le Phekolo ea meno, Univesithi ea Western Ontario, London, Ontario, Canada.

HO HLOKA

LITLHAHISO: Moputso oa tlhaho le lithethefatsi tsa tlhekefetso li fetoha tsamaisong ea mesolimbic, moo lithethefatsi tsa tlhekefetso li etsang liphetoho tsa neuronal. Mona, re lekile polasetiki tsamaisong ena kamora moputso oa tlhaho le tšusumetso e latelang ea likarabo tsa lithethefatsi.

METSOALLE: Liphello tsa boiphihlelo ba botona le botšehali ho likhoto tsa banna mabapi le boits'oaro ba boitšoaro le khetho ea sebaka se amanang le d-amphetamine (AMPH) le li-dendrites tse tsamaeang le Golgi-impregnated le li-spine tsa li-nucleus accumbens (NAc) li ile tsa khethoa. Ho feta moo, tšusumetso ea ho ila boitšoaro ba thobalano ho banna ba nang le boiphihlelo litekanyetsong tsena e ile ea lekoa.

LIKOTSO: Taba ea pele, khafetsa boits'oaro ba thobalano bo hlohlelletsa karabelo ea maikutlo a popota ho AMPH ha e bapisoa le lithuto tsa taolo ea thobalano tse nang le thobalano tse hlokometseng 1, 7, le matsatsi a 28 kamora matsatsi a hoqetela. Taba ea bobeli, liphoofolo tse nang le thobalano li thehile mofuta o ikhethileng bakeng sa litekanyetso tse tlase tsa AMPH ho feta ba batona ba sa kopaneleng ho tsa thobalano, tse bonts'ang boleng bo ntlafalitsoeng ba moputso ba AMPH. Kamora nako, tlhahlobo ea Golgi-Cox e bonts'itse palo e eketsehang ea dendrites le masapo mokokotlong oa NAc le khetla e nang le boiphihlelo ba thobalano. Liphetoho tse peli tsa ho qetela li ne li its'etleha holima nako ea ho ila matsatsi a 7-10.

LITLHOKOMELISO: Boiphihlelo ba thobalano bo etsa hore ho be le liphetoho lipakeng tsa ts'ebetso ea mesolimbic e tšoanang le ho pepesetsoa khafetsa ho psychostimulants. Ho feta moo, ho ila boitšoaro ba thobalano kamora ho nyaloa khafetsa ho ne ho hlokahala bakeng sa moputso o eketsehileng oa lithethefatsi le li-arhente tsa dendritic tsa NAc neurons, ho fana ka maikutlo a hore tahlehelo ea moputso oa thobalano e kanna ea tlatsetsa le neuroplasticity ea mesolimbic system. Liphetho tsena li fana ka maikutlo a hore liphetoho tse ling tsamaisong ea mesolimbic li tloaelehile bakeng sa moputso oa tlhaho le oa lithethefatsi mme li ka bapala karolo ea matlafatso ka kakaretso.

Copyright 2010 Mokhatlo oa Biology Psychiatry. E phatlalalitsoe ke Elsevier Inc. Litokelo tsohle li sirelelitsoe.

Keywords: dopamine, nucleus accumbens, psychostimulant, boitšoaro ba thobalano, tlhekefetso ea lithethefatsi, lesapo la mokokotlo
Eya ho:

SELELEKELA

Sisteme ea mesolimbic dopamine (DA), e kenyelletsa li-neuropathy tsa dopaminergic sebakeng sa ventral tegmental (VTA) ka projeke ea li-nucleus accumbens (NAc) le medial prefrontal cortex (mPFC), e bapala karolo ea bohlokoa linthong tse susumetsang le tse khotsofatsang tsa boitšoaro bo kenyeletsang. mabifi (1), fepa (2-7), ho nwa (8), mating9-11) le tlamo ea botsoalle (12-13). Lithethefatsi tsa tlhekefetso li fetohela holim 'a mesolimbic DA system (14-15). Ho feta moo, taolo e pheta-phetoang ea lithethefatsi e ka baka liphetoho tsa methapo methapong ena, hore le eona e phethe karolo ea bohlokoa ho eketseng ts'ebeliso ea lithethefatsi hape, kapa phetohong ea ts'ebeliso ea lithethefatsi ho ea bokhobeng ba lithethefatsi (16-18). Litlamorao tsa boitšoaro ba rTsamaiso ea lithethefatsi epeated e kenyelletsa karabelo ea locomotor e khahlisang li-psychostimulants le opiates (19-21), moputso o ntlafalitsoeng oa lithethefatsi (22-24), AKe fumana likarabo tse sebetsang mabapi le likotsi tse amanang le tšebeliso ea lithethefatsi tsa pele (25). Ho feta moo, taolo e pheta-phetoang ea lithethefatsi e baka liphetoho tse tšoarellang morphology ea methapo le lesapo la mokokotlo ho potoloha mesolimbic circuit (16, 26-31), hape e etsa hore polelo ea gene e fetohe (32-35). Kamora nako, ts'ebetso ea lithethefatsi tse pheta-phetoang e fetola matla a li-synaptic nakong ea thabo le lithibelo tse thibelitsoeng ho li-neuron tsa midbrain dopamine (36-41), le li-neuron ho NAc (42-44). Hajoale ha ho tsejoe haeba liphetoho tse tšoanang tsamaisong ea mesolimbic li etsahala ka ho pepesetsoa khafetsa meputso ea tlhaho. Ho fumana hore na liphetoho tse joalo li tlatsana le kapa li ikhethile lithethefatsing tsa tlhekefetso ho ka lebisa kutloisisong e ntle ea methapo ea selula e bakoang ke phapang lipakeng tsa ho matlafatsoa ha moputso khahlano le ho batla moputso o itseng.

Ho ts'ehetsa hypothesis e susumetsang ntle le lithethefatsi ho ka baka liphetoho tsa neuronal tsamaisong ea mesolimbic ke lintho tse fumanoang tse susumetsang khatello ea ts'ebetso ea dopamine (khatello ea maikutlo le ts'usumetso ea dopamine).45-47), le ho etsa hore kelello e hlasimolohe ea psychomotor (21, 48-50) hape o khutlele mehlaleng ea ho itaola (51-54). Leha ho le joalo, ke liphuputso tse 'maloa tse entseng lipatlisiso tsa hore na boitšoaro bo nang le moputso oa tlhaho bo ka hlahisa liphetoho tsamaisong ea DA (6, 55-56). Ka hona, hypothesis e ile ea lekoa hore boiphihlelo ba banna ba botona le botšehali bo baka liphetoho tsa neuronal kahare ho sisteme ea mesolimbic DA ka tlhahlobo ea litlamorao tsa boiphihlelo ba botona ba botona le botšehali ho sensomization ea boemo bo botle, khetho ea sebaka se ikhethileng, le dendrite morphology ea NAc neurons. Ntle le moo, re fane ka maikutlo a hore nako ea ho ila thobalano (moputso oa thobalano) e bohlokoa bakeng sa liphetoho tsena, ho latela lipatlisiso tsa morao-rao tsa hore ho ila lithethefatsi ho bapala karolo ea kholo ho holiseng boteng ba neural bo amanang le ho pepesetsoa lithethefatsi khafetsa (40, 57-59).

Eya ho:

METHODA

Animals

Ho ile ha fumaneha likhoto tsa banna ba baholo tsa Sprague Dawley (ligrama tsa 210-250) ho Harlan Laboratories (Indianapolis, IN, USA) kapa Charles River Laboratories (Senneville, QC, Canada) mme ba bolokiloe matlong a Plexiglas a nang le lihubhu tsa kotopo. Ba batona ba ne ba kentsoe liaparo tsa bong bo tšoanang ho liteko tsohle (liteko tsa 2-5), ntle le tlhahlobo ea 1 eo ho eona banna ba neng ba lutse ba le bang qalong ea thuto. Kamore ea kolone e laoloang ke mocheso e ne e bolokiloe mochineng o bobebe oa 12 / 12 hr lefifi ka lijo le metsi tse fumanehang ad libitum ntle le nakong ea tlhahlobo ea boitšoaro. Li-femme tsa Stimulus (210-220 gram) bakeng sa litloaelo tsa bocha tsa ho ruruha li ne li etsoa ka mokhoa o kopaneng oa ovariectomate mme li fumane ho kenella ka boqhetseke tse nang le 5% estradiol benzoate le 95% cholesterol. Boitšoaro ba thobalano bo ile ba susumetsoa ke tsamaiso ea 500μg progesterone ho 0.1 ml sesame oli hoo e ka bang lihora tsa 4 pele ho liteko. Ts'ebetso tsohle li ananetsoe ke Likomiti tsa Tlhokomelo ea Liphoofolo le Ts'ebeliso ea Yunivesithi ea Cincinnati le Univesithi ea Western Ontario, 'me li lumellana le melaoana ea NIH le CCAC e kenyeletsang liphoofolo tse amanang le liphoofolo tse amanang le lefu lena.

Phekolo ea Lithethefatsi

D-Amphetamine (AMPH) sulfate (Sigma, St. Louis, MO) e ile ea qhibiliha ka letsoai la 0.9% saline (SAL). Liphoofolo li fumane litekanyetso tsa boima ba 'mele tsa XPHUM ho ea 0.5-5.0 mg / kg, tse lekantsoeng motheong oa mahala, molemong oa boima ba' mele ba 1mL / kg. Liphoofolo tse laolang li amohetse SAL. Liente tsohle li ile tsa fanoa hanyane ka hanyane nakong ea halofo ea khanya (lihora tsa 2-6 kamora khanya ea mabone), kapele pele li kenngoa ka har'a lisebelisoa tsa boits'oaro.

Teko ea Mosebetsi oa locomotor

Ts'ebetso ea locomotor e lekantsoe ho sebelisoa likamore tse etselitsoeng tloaelo ea li-locomotor (LACs), e etselitsoeng likamoreng tse entsoeng ke Segal le Kuczenski (60). Ts'ebetso ea locomotor e lekantsoe ho sebelisoa 16 x 16 arrbeam array (San Diego Instruments, San Diego, CA) mme e hlahisoa e le crossovers ka motsotso (s). Ho ne ho tlalehoa nako le nako ha phoofolo e kena ho eng kapa eng ea "sebaka se sebetsang" sa phaposi, e bonts'itsoeng joaloka libaka tse moriti ho Setšoantšo sa 1A (61).

Setšoantšo sa 1     

Karabelo ea locomotor ea liphoofolo tse nang le tsebo ea thobalano le naïve ho saline kapa amphetamine tsamaiso. A ke setšoantšo sa 'mapa oa' mapa o sebelisoang ho lekanya tšebetso ea sebaka. Ho tlaleha rekoto ea nako le nako ha phoofolo e kenella ho e ntso ...

Teko ea boitšoaro ba thobalano

Litekong tsohle, likhoto tsa banna ba sa kopaneleng ka thobalano li ne li arotsoe ka mokhoa o sa khetholloang ka lihlopha tse neng li fumana boiphihlelo ba thobalano kapa li sa lula le nave. Bakeng sa boiphihlelo, liteko tsohle tsa ho ruruha li ile tsa etsoa halofong ea pele ea mokhahlelo oa lefifi (lihora tsa 3-8 kamora hore mabone a tima) tlasa lebone le lefubelu. Liphoofolo tse ileng tsa sala li sa sebetse ka thobalano li ne li tšoaroa le ho bolokoa ka liphapusing tse le tse tona tse tona, kahoo ho pepesetsoa maemo a ts'oanang a ts'abo, tikoloho e ncha le monko oa basali ba hole joalo ka liphoofolo tse nang le boiphihlelo. Bakeng sa liteko tsohle, banna ba nang le tsebo ea thobalano ba ile ba bapisoa ka boiphihlelo ba thobalano (ba ipapisitse le lipalo tsa kemolo, le ho lutla le ho nyamela nakong ea ho qetela ea kemaro).

Leka 1

Liteko 1 le 2 li sebelisitse lipapatso tse fapaneng ho leka litlamorao tsa ho hloa mekoalaba le tikoloho. Litekong tsa 1, liphoofolo tse nang le lihlopha tsa batho ba nang le thobalano li amohetse matsatsi a 5 a arohaneng a 3-4 ka nako e le 'ngoe, ka nako eo ba neng ba hlekefetsoa malapeng a bona ka basali ba amohelang bakeng sa lihlooho tsa 3 tsa ho kopitsa (ho kenyeletsa le ho ntsoela) kapa metsotso ea 60, hore na ke efe e tlang pele. Liphoofolo tse finyeletseng lethathamo la litlatsetso tse fetang tse hlano li ne li nkuoa e le tsa bootsoa. Ka thobalano liphoofolo tsa naïve ha lia ka tsa amohela balekane ba basali. Bekeng e le 'ngoe kamora seboka sa ho emisa, liphoofolo tse nang le tsebo ea thobalano le tsa naïve li ile tsa aroloa ka lihlopha tse amohelang AMPH (0.5 mg / kg) kapa SAL bakeng sa lihlopha tse' ne (Naïve Amphetamine: NA; Amphetamine ea nang le boiphihlelo: EA; Naïve Saline: NS; le Saline e nang le boiphihlelo: ES; n = 6 e ngoe le e ngoe).

Leka 2

Teko ena e ne e fapane le liteko tsa 1 ka mekhoa e meraro: 1. Liphoofolo li tloaelane le kemiso e le 'ngoe ka matsatsi a latellanang; 2. Liphoofolo li qoaketsana ka har'a ntlo eane e tšoanang le eo li fumaneng ho eona AMPH (li-LACs); 3. Ketsahalo ea locomotor e latelang AMPH e ile ea hlahlojoa ka makhetlo a mararo a fapaneng ho latela boiphihlelo ba thobalano. Liphoofolo tse nang le thobalano li fumane 7 linako tse latellanang tsa ho kopanya letsatsi le letsatsi ho li-LACs le tšebetso ea locomotor e tlalehiloe nakong ea metsotso ea 15 pakeng tsa ho beoa ho LACs le ho kenngoa ha basali. Liphoofolo tsa naïve tsa thobalano li ile tsa beoa ka har'a li-LACs ka linako tse supileng tse latellanang ntle le ho tlolelana. Letsatsi le latelang karolo ea ho qetela ea mating (Letsatsi la 8 la tlhahlobo), liphoofolo li ile tsa beoa ka har'a LACs hang hang ka mor'a ho kenoa ka ente ea AMPH (0.5 mg / kg) kapa SAL (Naïve Amphetamine: NA; Amphetamine ea nang le boiphihlelo: EA; Naïve Saline: NS; Saline e nang le boiphihlelo: ES; n = 8-9 e ngoe le e ngoe) le liketsahalo tsa locomotor li ile tsa tlalehoa. Liphoofolo li ile tsa lekoa hape ho li-LAC hape bekeng e le 'ngoe ho latela seboka sa ho qetela sa ho tlolelana ha liphoofolo (Letsatsi la 14). Liphoofolo tse amohetseng AMPH ka Letsatsi 8 li amohetse SAL ka Letsatsi 14, mme liphoofolo tse fumaneng SAL ka Letsatsi 8 li amohetse AMPH ka Letsatsi la 14. Halofo ea liphoofolo tsa Naïve le tse nang le boiphihlelo li ile tsa etsoa sehlabelo letsatsi le le leng hamorao bakeng sa ho ntšoa RNA (data e sa kenyelletsoeng tlalehong ena). Khoeli e le 'ngoe kamora seboka sa ho qetela sa ho ruruha (Letsatsi la 35), halofo e setseng ea liphoofolo (Naïve, n = 8; Phihlelo, n = 9) e amohetse AMPH le mosebetsi oa locomotor o tlalehiloe.

Boitsebiso ba Lintlha

Ketsahalo ea locomotor

Lintlha li ile tsa bokelloa ka lilibeng tsa metsotso ea 3 bakeng sa metsotso ea 90 ka mor'a ente ea AMPH kapa SAL. Liphetho li bonts'oa joalo ka moelelo ± SEM ea sehlopha ka seng mme e hlahlojoe ho sebelisoa mekhoa e 'meli ea ANOVA (liteko 1, liteko tsa matsatsi a 2 8-14: lintlha: boiphihlelo ba thobalano, kalafo ea lithethefatsi), kapa ANOVA e le' ngoe (liteko tsa 2 tsa 35 le ts'ebetso pele ho nako ea ho nyaloa; ntlha: boiphihlelo ba thobalano). Post-hoc papiso e entsoe ka liteko tsa Fisher LSD ka boleng bo behiloeng ho p-value <0.05.

Teko ea Sebaka se Ikhethileng (CPP)

didirisiwa

CPP e ile ea etsoa ka har'a lisebelisoa tse kopaneng tsa mekato e meraro (Med Associates Inc., St. Albans, VT, USA) e neng e na le likamore tse peli tse kholo, tsa kantle (28 × 22 × 21cm) e khetholloang ke litšebeletso tse bonoang le tse litšila, e arotsoe ke bohareng bo nyane. komporo (13 × 12 × 21cm). Lisebelisoa li ne li entsoe ka maballo a lifoto bakeng sa ho itlhahloba ka boithuto ba ho lekola le ho lekanya mesebetsi ea locomotor.

Boemo le Teko

Boemo le tlhahlobo ea CPP li ile tsa etsoa nakong ea halofo ea pele ea nako ea khanya. Ho ile ha etsoa mano ho khetholla hore na phoofolo e 'ngoe le e' ngoe e rata eng pele. Ha ho liphapang tse kholo tse fumanoeng pakeng tsa linako tse sebelisitsoeng ka phapusing efe kapa efe. Letsatsing le hlahlamang, likhoto tsa banna li ne li ts'oareloa feela kamoreng e katiloeng ka AMPH kapa kamoreng e katiloeng ke SAL bakeng sa metsotso ea 30. Lits'ila li fumane kalafo e fapaneng ka tsatsi le hlahlamang ka tsela e hanyetsanang. Letšoao la morao-rao le neng le ts'oana le mokhoa o hlophisitsoeng hantle ho joalo le ile la etsoa ka letsatsi la ho qetela.

Leka 3

Liphoofolo tse lihlopheng tse nang le tsebo ea thobalano li amohetse li-5 ka tatellano letsatsi le leng le le leng ka nako ea ho rupela ka har'a koekoe ea liteko. Day 1 e ne e abetsoe letsatsi la pele la mating. Ba batona ba taolo ba ile ba lula ba le thobalano ka thobalano, empa ba ne ba beoa terakeng e hloekileng ea hora ea 1 letsatsi le leng le le leng bakeng sa matsatsi a 5 a latellanang. Liphoofolo li ne li arotsoe ka lihlopha tse amohelang tekanyetso e fapaneng ea AMPH (mg / kg; sc) (Naïve: N0.5, N1.0, N2.5 kapa N5.0, n = 7-8 e 'ngoe; Boiphihlelo: E0, E0.5, E1.0, E2.5 kapa E5.0, n = 6, n = 9, n = 14, n = 15 -16 ka 'ngoe). E ntle ka ho fetisisa e etsahetse ka letsatsi la 17, liteko tsa boemo ka matsatsi a 10 le XNUMX, le posttest ka letsatsi XNUMX. Kemiso ena e lumelletse matsatsi a XNUMX a ho ila boitšoaro ba thobalano pele ho maemo.

Leka 4

Ba batona ba nang le thobalano ba fumane boiphihlelo ba thobalano ka 5 ka matsatsi a latellanang a ho ts'oana le Teko ea 3. Phapang ea bohlokoa boitekong ba 4 e ne e le hore tlhahlobo ea CPP e etsahetse ha liphoofolo li ntse li fumana boiphihlelo ba thobalano, ka hona ho ne ho se na nako ea ho ila boitšoaro ba thobalano. Ho fapana le moo, liteko tsa maemo li ile tsa qala ho latela likarolo tsa pele tsa 3 tsa mating. Liphoofolo li ne li arotsoe ka lihlopha tse amohelang tekanyetso e fapaneng ea AMPH (mg / kg; sc) (Naïve: N0.5, N1.0, N2.5 kapa N5.0, n = 6-8 e 'ngoe; Boiphihlelo: E0, E0.5, E1.0, E2.5 kapa E5.0, n = 7, n = 11, n = XNUMX, n = XNUMX -XNUMX ka 'ngoe).

Boitsebiso ba Lintlha

Lipalo tsa CPP li ile tsa baloa bakeng sa e mong le e mong ea nang le 'mele joalo ka nako e sebelisitsoeng (sec) ka phapusing e kopaneng nakong ea posttest ho feta ea pele. Mekhoa ea sehlopha e baliloe mme e bapisoa le sehlopha se tšoaroang ke SAL (E0) ho sebelisoa liteko tse sa sebetsanang le liteko. Bakeng sa bohlokoa bohle ba liteko bo behiloe ho boleng ba p <0.05.

Teko ea Golgi

Leka 5

Tse tona lihlopheng tse nang le tsebo ea thobalano li ile tsa beoa ka mokotleng oa tlhahlobo le mosali ea amohelang 'me tsa lumelloa ho nyaloa ho fihlela emong e le' ngoe kapa metsotso ea 60, e hlahang pele, matsatsing a 7 a latellanang. Ba batona ba taolo ba ile ba lula ba le thobalano, empa ba nkuoa lapeng la bona 'me ba kenngoa ka terakeng e hloekileng ea metsotso e 30 letsatsi le leng le le leng ka matsatsi a supileng a latellanang. Lihlopheng tsa liphoofolo tse nang le boiphihlelo kapa tsa naïve li ne li etsoa sehlabelo ka letsatsi le le leng (N1; n = 5; E1; n = 7) kapa matsatsi a 7 (N7, E7; n = 5 e 'ngoe le e' ngoe ka mor'a kemiso ea ho qetela ea ho tlolelana kapa ho pepesetsoa teko ea teko. Lihlopha tse nang le bohlola li ne li sa fapana ka boiphihlelo.

Ho sebetsa ka lisele

Ka letsatsi le le leng kapa beke e le 'ngoe ka mor'a seboka sa ho emisa kapa ho pepesetsoa mofuta oa teko ea liphoofolo, liphoofolo li ile tsa fuoa overdose ea sodium pentobarbital (ip) mme ea tlotsoa ka 500 ml ea saline. Mekokotlo e ne e sebetsoa Golgi-Cox stain o sebelisa mokhoa o ikhethileng ho tsoa ho Pugh le Rossi (62). Bakeng sa lintlha tse ling bona Tlatsetsa 1.

Tlhahlobo ea lintlha

Litšoantšo tsa Camera Lucida li ne li entsoe ka li-neuron tsa 5-7 boteng ba caudal NAc le subregions tsa shell ho phoofolo ka 'ngoe. Ho ile ha khethoa lisele tse neng li bonahala hohle kapa boholo ba makala a dendritic ebile ho le bonolo ho a khetholla ho lisele tse haufi. Makala a hatisang a ne a hlakotsoe ka tatellano ea centrifugal (63) le litekanyetso tsa phoofolo ka seng li baliloe. Li-spendritic spine li ne li thathamisitsoe ka bolelele ba 40 μm ea li-dendrites tsa bobeli tsa tatellano ka seleng e le ngoe (lisele tsa 4-7 ka phoofolo e ngoe le e ngoe). Mekhoa ea sehlopha e tšoantšoa le ho sebelisa ANOVA ea mekhoa e 'meli (lintlha: boiphihlelo ba thobalano le nako ea thobalano) le liteko tsa Fisher LSD bakeng sa liteko tsa post hoc tlhahlobo.

Eya ho:

LIPOTSO

Leka 1

Morero oa Teko ea 1 e ne e le ho bona hore na boiphihlelo ba thobalano bo ama karabelo ea locomotor ho AMPH ka likhoto tsa banna. Ts'ebetso ea locomotor nakong ea metsotso ea 90 e ile ea lekanngoa litabeng tsa thobalano le lithupelo tsa Naïve tse latelang kalafo e nang le 0.5 mg / kg AMPH kapa SAL. Liphetho tse tsoang ho Teko ea 1 li bontšoa ka Setšoantšo sa 1. Boiphihlelo ba bobeli ba thobalano (F1,22= 15.88; p = 0.0006) le kalafo ea lithethefatsi (F1,22= 45.00; p <0.0001) e bile le litlamorao tse kholo mesebetsing ea locomotor mme ho sebelisana ka tsela tse peli lipakeng tsa boiphihlelo ba thobalano le kalafo ea lithethefatsi ho ile ha bonoa (F1,1,22= 14.27; p = 0.0010). Ka ho khetheha, liphoofolo tse naïve le tse nang le boiphihlelo ka botlalo li bontšitse karabelo e atolositsoeng ea locomotor ho AMPH ha e bapisoa le taolo e loketseng ea SAL. Ho feta moo, likhoto tse nang le thobalano li bonts'itse karabelo e kholo ea locomotor ho AMPH ha e bapisoa le liphoofolo tsa naïve. Likhoto tse nang le tsebo ea thobalano le tsa naveve li ne li sa fapana karabelong ea tsona ho SAL.

Tlhahlobo ea likarabo tsa locomotor ho AMPH ka nako e nyane ea metsotsoana ea 30 le metsotso ea 3 li bontšoa ho Setšoantšo sa 1, likonopo CF. Ba batona ba nang le thobalano ba bontšitse karabelo e eketsehang ea locomotor ho AMPH ha e bapisoa le likhoto tsa naïve nakong eohle ea tlhahlobo ea metsotso ea 90. Ho feta moo, litoeba tse nang le thobalano li bonts'itse karabelo e atolositsoeng ea locomotor ho AMPH ha e bapisoa le taolo ea SAL ho pholletsa le nako ea tlhahlobo ea metsotso ea 90, ha liphoofolo tsa Naïve li bonts'a karabelo e phahameng haholo nakong ea metsotso ea 30 ea ho qetela (Setšoantšo sa 1; li-p-boleng li thathamisitsoe ho legend ea lipalo).

Leka 2

Morero oa ho leka 2 e ne e le ho etsa liteko haeba ho ba le boiphihlelo ba thobalano ho hlahisa maikutlo a popelo ho liphoofolo tse ileng tsa ts'oaroa ka matsatsi a latellanang, le tikolohong e ts'oanang le eo li pepeselitsoeng AMPH. Ho pepesehela tikoloho e kopaneng le thobalano ho bakile tšebetso e eketsehang ea metsotso nakong ea metsotso ea 15 pele ho karolo e 'ngoe le e' ngoe ea ho ikatisa (Figure S1 ho Supplement 1), e bonts'a kamano e ithutileng pakeng tsa boitšoaro ba thobalano le tikoloho. Ntle le moo, liteko tsa 2 li fuputse sebopeho sa nakoana sa maikutlo a locomotor ho AMPH ka litoeba tsa banna ba nang le thobalano. Karabelo ea locomotor ho AMPH kapa SAL e ne e lekantsoe ka letsatsi le le leng (Letsatsi la 8), beke e le 'ngoe (Letsatsi la 14) le khoeli e le' ngoe (Letsatsi la 35) kamora seboka sa ho qetela sa mating. Joalo ka teko ea 1, litoeba tse nang le thobalano li bonts'itse karabelo e kholo ho AMPH ha e bapisoa le liphoofolo tsa naïve. Ho feta moo, phello ena e ne e bonahala ka matsatsi ohle a mararo a liteko. Setšoantšo sa 2 e bonts'a ts'ebetso ea locomotor nakong ea liteko tsa 60 tsa ho qetela tsa liteko tseo ho tsona ho ileng ha bonoa liphapang tse matla haholo, mme data ea metsotso ea 30 ea pele e bonts'oa ho Figure S2 (Tlatsetso ea 1). Liphoofolo tsa Naïve le tse nang le boiphihlelo li ne li sa tšoane karabelong ea tsona ho SAL ka matsatsi afe kapa afe a liteko, mme likhoto tse amohetseng AMPH li bonts'itse ts'ebetso e kholo ea locomotor ha e bapisoa le taolo ea SAL (Setšoantšo sa 2; li-p-boleng li thathamisitsoe ho legend ea lipalo).

Setšoantšo sa 2     

Karabelo ea locomotor ea liphoofolo tse nang le tsebo ea thobalano le naïve ho saline kapa amphetamine tse fanoeng ka letsatsi le le leng (Letsatsi la 8; A, B), beke e le 'ngoe (Letsatsi la 14; C, D) kapa khoeli e le' ngoe (Letsatsi la 35; E, F) kamora kemiso ea ho qetela ea ho tlolelana ha liphoofolo. . Bolela +/− SEM ea palo eohle ...

Leka 3

Teko 3 e fuputse phello ea boiphihlelo ba thobalano ho moputso oa AMPH o nang le maemo. AMPH CPP e ile ea lekoa ka banna le basali ba nang le boiphihlelo ba matsatsi a 10 kamora nako ea ho qetela ea ho tlolelana. Liphoofolo tse nang le bohlola li bontša moputso o ntlafalitsoeng oa AMPH. Ka ho khetheha, ba batona ba nang le thobalano ba thehile khetho e matla bakeng sa kamore e katiloeng ke AMPH ka litekanyetso tse tlase tsa 0.5 le 1.0 mg / kg empa eseng ka litekanyetso tse phahameng tsa 2.5 kapa 5.0 mg / kg. Ho fapana le moo, banna ba naïve ba ho etsa thobalano ba theha kamore e ratoang haholo ea AMPH ka lipilisi tse phahameng, 2.5 le 5.0 mg / kg, eseng litekanyetso tse tlase (Setšoantšo sa 3A; li-p-boleng li thathamisitsoe ho legend ea lipalo).

Setšoantšo sa 3     

Sebaka se khethiloeng sa liphoofolo tse nang le tsebo ea thobalano le tse sa tsotelleng ho arabela amphetamine ka matsatsi a 10 kamora (A) kapa nakong ea (B) linako tsa ho kopanya. Ho boleloa ka +/− SEM ea palo ea CPP, e hlalosoang e le nako e sebelisitsoeng ka kamoreng e katiloeng ka paqama ea AMPH ho ...

Leka 4

Teko 3 e bontšitse hore boiphihlelo ba thobalano bo lateloang ke nako ea thobalano bo ile ba fella ka moputso o ntlafalitsoeng oa boemo ba AMPH. Teko 4 e fuputse hore na phello ea boiphihlelo ba thobalano ho moputso oa AMPH e amanang le moputso e ne e its'etleha nakong ena ea bootsoa. Liphetho li bonts'a hore liphoofolo tse nang le thobalano ha li a bonts'a boleng bo eketsehileng ba moputso oa AMPH. Liphoofolo tse nang le tsebo ea botona le botšehali li bontšitse khetho e matla bakeng sa kamore e kolobelitsoeng ea AMPH e nang le tekanyetso e phahameng ea 2.5 le 5.0 mg / kg. Leha ho le joalo, ha ho na banna ba nang le thobalano kapa banna ba naïve ba bonts'itseng palo ea CPP e eketsehang ka litekanyetso tse tlase tsa 0.5 le 1.0 mg / kg tekanyo. Motsoako o tlase oa 0.5 mg / kg o bile oa baka karabelo, empa hona ho fihlela bohlokoa feela ho liphoofolo tse nang le tsebo ea thobalano bakeng sa kamore e kolobelitsoeng ea AMPH (Setšoantšo sa 3B; li-p-boleng li thathamisitsoe ho legend ea lipalo).

Leka 5

Morero oa Teko ea 5 e ne e le ho hlahloba liphetoho tse amanang le morphological tsamaisong ea mesolimbic, haholo-holo NAc, kamora boiphihlelo ba thobalano. Liphetoho tsa moralological li ile tsa totobala bekeng e le 'ngoe (Setšoantšo sa 4H, J le L; boleng ba p-lethathamo bo ngotsoe lethathamong la lipalo), empa ha ho letsatsi le le leng (Setšoantšo sa 4G, 'na le K), kamora seboka sa ho qetela sa ho emisa. Haholo-holo, keketseho e kholo ea lipalo tsa dendrites (letšoao la ho eketseha ha dendritic branching) e fumanoe ho mantlha ea NAc le khetla (Setšoantšo sa 4H le J). Ntle le moo, lipalo tsa methapo ea methapo ea dendritic li ile tsa eketseha haholo libakeng tsa maqhubu le a mantlha, bekeng e le 'ngoe, empa eseng ka letsatsi le le leng, kamora boiphihlelo ba thobalano (Setšoantšo sa 4L).

Setšoantšo sa 4     

Dendritic morphology ho NAc ea liphoofolo tse nang le bohlola le ba naveve. Boiphihlelo ba thobalano bo bakile keketseho ea lipalo tsa dendrites le dendritic spines, tse bontšitsoeng ke litšoantšo (A, B) le lits'oants'o tsa khamera ea lucida (C, D) ea moemeli oa NAc shell ...
Eya ho:

TŠOHLOA

Boithuto bona bo bonts'a hore boiphihlelo ba thobalano le boikoetliso kamora boiphihlelo ba botona kapa botšehali bo susumetsa liphetoho tse sebetsang le morphong tsamaisong ea mesolimbic ea likhoto tsa banna. Liphetoho tse sebetsang li ile tsa bonahala ka mokhoa oa karabelo ea sensomotor e amohelang le moputso o ntlafalitsoeng o nang le AMPH ka mor'a boiphihlelo ba thobalano.

Karabelo ea sensomisedor ea sensomised e ile ea bonoa joalo ka letsatsi la 1 mme e bolokiloe ho fihlela matsatsing a 28 kamora seboka sa ho qetela sa mathe. Ka lehlakoreng le leng, moputso o ntlafalitsoeng oa AMPH o ne o bonahala feela kamora nako ea ho ila thobalano. Liphetoho tsa morphological maemong a mantlha le likhetla tsa NAc li ile tsa bonoa matsatsi a 7, empa eseng letsatsi la 1, kamora seboka sa ho qetela sa ho ruruha ho liphoofolo tse nang le bohlola. Ka bobeli lintlha tsena li bonts'a hore boiphihlelo ba thobalano bo etsa hore polasetiki tsamaisong ea mesolimbic le hore nako ea thobalano e tlo bohlokoa ho nts'etsopele ea tse ling, empa ha se liphetoho tsohle tsa sisteme ea mesolimbic.

Ho tsebahala hore litloaelo tse khahlisang tsa tlhaho le lithethefatsi tsa tlhekefetso li sebetsa ka har'a litsela tse tšoanang tsa neural (64). Ka sebele, lithethefatsi tsa tlhekefetso li bontšitsoe li ama polelo ea boitšoaro bo khotsofatsang (65-67-67-70). Liphetoho tsa boits'oaro ba thobalano le sepheo se bakoang ke taolo e sa khaotseng ea lithethefatsi li itšetlehile ka nako ea ho tlohela kapa ho itlopa joala ho lithethefatsi, hammoho le tikoloho eo setheo se hlahisitsoeng ho sona. Phuputso ea morao-rao e bonts'itse hore ho pepesehela boitšoaro ba thobalano ho fetola karabelo ho lithethefatsi tsa tlhekefetso. Ho ile ha fihleloa hore litoeba tsa banna tse nang le thobalano li lemohuoa ka litlamorao tsa AMPH, le hore ketsahalo ena e nka nako e telele ebile e ikemetse ka nako ea thobalano ho tloha ho tlolelanoeng. Ntle le moo, karabelo ea locomotor e ne e sa ikemisetse kemiso ea mating kapa tikoloho ea mating mme e bonoa kamora linako tse latellanang kapa tse sa ts'oaneng tsa nako ea ho emisa tse etsahetseng tikolohong e le 'ngoe kapa e fapaneng e le tlhaiso ea lithethefatsi. Smaqheka a entsoeng ka hamsters ea basali a bonts'itse hore li-hamsters tsa basali tse nang le thobalano li bonts'a ho qaleha ka potlako ha karabelo ea locomotor ea AMPH bapisoa le taolo ea na sexuallyve ea thobalano (71). Leha ho le joalo, litoeba li fana ka likarabo tsa tlhekefetso ea thobalano ho li-psychostimulants (72-73). Kahoo, lithuto tsa hajoale li atolosa lipatlisiso ho li-hamsters tsa basali mme li bonts'a likhoto tsa banna, ho qala ka potlako le nako e telele ea likarabo tsa locomotor tse ntlafalitsoeng ho li-psychostimulants tse latelang boits'oaro ba thobalano.

Ha ho hlake ho tsoa lithutong tsa morao-rao hore na likarolo tsa boitšoaro ba thobalano li kenya letsoho molemong oa sensorization ea AMPH le hore na litšebelisano tsa sechaba li lekane. Liphoofolo tse tekong ea 2 tse ileng tsa hloleha ho fihlela maemo a boiphihlelo ba thobalano (tse bonts'itseng le ho kenella, empa li sa kopane ho 5 ejusionsations nakong ea nako ea ho ruruha) ha e a ka ea bontša karabelo e khahlisang (Figure S3 ho Supplement 1). Ka hona, ho ile ha etsoa tlhahlobo e 'ngoe eo ho eona banna ba ileng ba pepesetsoa mosali ea amohelang ntle le tšebelisano ea' mele, kapa ba bonts'a litheko le ho kenella, ho se letho le ileng la fella ka likarabelo tsa locomotor tsa AMPH (Figure S4 ho Supplement 1). Kahoo, litšebelisano tsa kahisano ha li bonahale li kenya letsoho ho litlamorao tsa boiphihlelo ba thobalano ho maikutlo a AMPH, empa ho e-na le hoo, ho kopitsoa ho kenyelletsa kemolo ho bonahala ho le bohlokoa bakeng sa mofuta ona oa polasetiki.

Ntle le karabelo e ntlafalitsoeng ea boitšoaro, boiphihlelo ba thobalano bo ntlafatsa boleng ba moputso ba AMPH, empa bo latela feela ho se thibele moputso oa thobalano. Mosebetsi oa nakong e fetileng o sebelisa CPP o bonts'a hore ho pepesetsoa khafetsa ho li-psychostimulants kapa ho hlahisa litlamorao tse hlahisang litheko tse tsamaisanang le lithethefatsi tumellanong le sensitization ea maikutlo a ts'ebeliso ea lithethefatsi (22-24). Tsamaiso e phetoa-phetoang bakeng sa matsatsi a 5 a cocaine (10 mg / kg), d- amphetamine (0.5 mg / kg) kapa morphine (5 mg / kg) e utloa litlamorao tse khahlisang tsa koae ha e lekoa matsatsi a 3 kamora ho felisoa ha kalafo ea kalafo ea lithethefatsi pele . Phello e ntlafalitsoeng e bonts'itsoe ka ho shebella khetho e nang le maemo le liteko tse fokolang tsa boemo (ho tloha 3 ho 2) le litekanyetso tse tlase tsa lithethefatsi ha li bapisoa le liphoofolo tse laoloang pele tsa SAL. Motsoako o bonts'itsoeng o hlahisoang ke koae e pheta-phetoang o fumanoe matsatsi a 7, empa eseng matsatsi a 14, kamora ho qhekella ho qetela ka koae (23). Phuputso e ts'oanang e sebelisang matsatsi a 5 ea morphine (5.0 mg / kg) e bonts'a karabelo ea moputso e sa fumaneng boemo ba morphine ha boemo bo qala 3, 10, kapa matsatsi a 21 kamora matsatsi a kalafo ea pele ho lithethefatsi. Karabo ena e matlafalitsoeng e ne e le sieo ka letsatsi la 1 ka mor'a kalafo ea morphine ea pele (24). SHo fumanoe ho fumanoe hore nako ea ho tlosoa ha lithethefatsi ea bonyane matsatsi a 3 e ea hlokahala bakeng sa moputso o ananeloang kapa o thehiloeng sefapanong bakeng sa psychostimulants ka bobeli le opiates. Sboiphihlelo ba nakong, joalo ka taolo ea lithethefatsi khafetsa, bo kanna ba eketsa neuroadaptations ho sisteme ea mesolimbic e ikarabellang bakeng sa karabelo ena ea lithethefatsi hang ha moputso o felisitsoe. Hajoale ha ho hlake haeba ho lahla meputso ho amahanngoa le khatello ea maikutlo 'me kahoo ho sebetsa e le khatello ea maikutlo e kenyang letsoho lipuisanong tse bonoang.

Ho hlakile hore ho na le kamano lipakeng tsa litlamorao tsa moputso oa tlhaho le oa lithethefatsi. Reward-sensitization e fana ka maikutlo a hore litlamorao tsa nako e telele tsa boitšoaro ba thobalano le lithethefatsi li tsamaisoa ke mekhoa e tloaelehileng ea sele kapa ea limolek'hule.. Ka hona, ho nahanoa hore liphetoho tse kopantsoeng ke boitšoaro ba thobalano li laola likarolo tse matlafatsang tsa boitšoaro ba thobalano ka hona e ka ba tsa bohlokoa bakeng sa ho matlafatsa boitšoaro bo botle ka kakaretso. Hmang kapa mang, ho itima monyetla oa ho khaotsa ho fumana moputso oa thobalano ho ka etsa hore motho a be le tjantjello ea ho batla moputso, kapa ho ba kotsing ea litlamorao tsa lintho tse lemalloang tse tšoanang le litlamorao tsa ho ila 'takatso ea litakatso tsa lithethefatsi' (25, 33, 74). Ka kakaretso, boitšoaro ba thobalano ka litoeba tsa banna ha bo bake ho batla thobalano, ho bonts'itsoeng ho sebelisa liteko tse amanang le tšusumetso ea mala75), leha tšusumetso ea ho ila e sa lekoa.

Dendritic morphology e se e hlahlobiloe ka botebo makaleng a ho ithuta le ho hopola (76-77) le bokhoba ba tahi (59, 78-79), mme o tsejoa ho susumetsoa ke tikoloho (80) le lintlha81-82). Kaha maiketsetso a synaptic a atile haholo ho li-dendrites kapa dendritic spine, ke tsona sepheo sa ts'ebetso sa li-neuroplasticity tse nang le boiphihlelo. (26, 83). Ho fokotseha ha tlhaho kapa tsamaiso ea lihormone tsa gonadal ho fumanoe ho baka liphetoho dendritic nakong ea lihora tse 'maloa (84-87). Also, litšila ho sistimi, khatello e joalo (88) kapa cocaine e sa foleng79), etsa hore liphetoho tse kopitsoang li ka bonoa nakong ea lihora tsa 24.

Mona, liphetoho ho dendritic morphology ea li-spiny neurons tse mahareng ka bobeli ba NAc konokono le khetla li ne li sa bonoe ka nako ea lihora tsa 24, mme ho fapana le moo ho ne ho hloka nako ea ho ila kamora boiphihlelo ba thobalano. Liphetoho tse hlophiloeng tse hlahisitsoeng ke boiphihlelo ba thobalano le ho ila boitšoaro bo ts'oanang li tšoana le tse bonoang khafetsa ho li-psychostimulants (16-17, 26, 30). Ka lehlakoreng le leng, ho fokola ha DA ho NAc ho fella ka palo e fokolang ea dendrites le ho rarahana ha khetla (18, 89). Kahoo liphetoho tse susumetsang takatso ea thobalano li kanna tsa its'etleha ketsong ea DA ho NAc. Leha ho le joalo, liphetoho tse amanang le morphological tse amanang le ho nyalisoa li ne li bonahala hantle feela ka matsatsi a 7 kamora seboka sa ho qetela sa ho kopanya le ho hokahana le moputso o ntlafalitsoeng oa AMPH ho liphoofolo tse nang le bohlola. Lintlha tsena li fana ka maikutlo a hore keketseho ena ea ho sisinyeha ha methapo le methapo ha e hlokehe bakeng sa ho hlahisa maikutlo a nakoana a locomotor ho AMPH, yet e ka bapala karolo ea tokiso le polelo ea nako e telele ea maikutlo. Boithuto ba pejana ba taolo e sa phetseng ea lithethefatsi bo hlokometse hape karohano lipakeng tsa maikutlo a nako e telele le liphetoho tsa morphological ho NAc (89-94). Ho ntse ho sa hlake hore na ts'ebetso e lumellanang le ea liphetoho tsa morphological ke efe, empa e ka bapala karolo ea phetoho ea nako e telele tšebetsong le polelo ea mofuta.

Ka bokhutšoanyane, lintlha tse hlahisitsoeng mona li bonts'a hore boitšoaro ba thobalano - khothalletso e nang le moputso oa tlhaho - e ka baka neuroadaptations ea nako e telele tsamaisong ea mesolimbic. Seo re se fumaneng se fana ka maikutlo a hore boits'oaro bo nang le boits'oaro, haholo-holo karabelo ea sensomotor, ke sephetho sa nako e telele le sa nako e telele sa boiphihlelo ba thobalano. Ntle le moo, nako ea ho itlopa bolutu e ka lumella hore neuroadaptations e be bohlokoa bakeng sa liphetoho tse bonoang moruong oa NAc le moputso o latelang oa lithethefatsi tse latelang. Ts'ebetso ena ea polasetiki e nang le boits'oaro le neural e latela mokhoa o ts'oanang, empa o sa tšoane, o hlahella joalo ka ha o bonoa liphoofolong tse lemosetsoeng lithethefatsi. Lintlha tsena li khahla haholo hobane re bonts'a hore ho ila meputso ea tlhaho ho etsa hore naha e be tlokotsing ea taolo ea lithethefatsi. Ho utloisisa hore na mekhoa ea tlhaho le lithethefatsi tsa tlhekefetso li ka tsamaisa lits'ebetso tsena tse bakang neuroadaptations ho ka re fa temohisiso e ntlafalitsoeng ea ho matlafatsa le moputso ka kakaretso, hape ho re fa temohisiso e eketsehileng ka mekhoa ea bokhoba ba lithethefatsi.

Eya ho:

Boitsebiso bo Eketsehileng

Eya ho:

lumela hore baa fokola

Ngaka Richtand o amohetse chelete ea lithuso ho NIH le Lefapha la Litšebeletso tsa Lipatlisiso tsa Bongaka la Veterans. Ngaka Richtand o tlaleha hore o sebelitse e le moeletsi ho tsa meriana ea Temo, Bristol-Meyers squibb, le Gerson Lehrman Group; setsing sa sebui sa Bristol Meyer's squibb le Schering-Plow Corporation; Lipehelo tsa Grand Round ho: Sanford School of Medicine ea Univesithi ea South Dakota le Scius, LLC; hape o amohetse tšehetso ea lithuso ho: Janssen Pharmaceutics Research Foundation le Astra Zeneca Pharmaceuticals (lithethefatsi tsa thuto feela). Bangoli bohle ba bang ha ba tlalehe lithahasello tsa lichelete tse sa lumellaneng kapa likhohlano tse ka bang teng tsa litheko, ntle le lithuso tse latelang ho ts'ehetsa patlisiso ena: Litsi tsa Naha tsa Bophelo (R01 DA014591), Likolo tsa Canada tsa Patlo ea Bophelo (RN 014705), le Lekhotla la Mahlale la Naha of Canada (NSERC) Discovery Grant (341710) ho Dr. Lique Coolen, le thuto ea PGS-M ho tloha NSERC (360696) ho Kyle Pitchers. Re leboha Mme Maureen 1 Fitzgerald ka thuso ea hae mabapi le ts'ebetso ea Golgi le Dr. Christine Tenk bakeng sa thuso ka liteko tsa tlatsetso 1.

Eya ho:

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.

Eya ho:

References

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