Methamphetamine e sebetsana le mekhoa e mengata ea li-neuron tse laolang boitšoaro ba thobalano linthong tsa banna (2010)

Khopolo-taba. 2010 Mar 31; 166 (3): 771-84. doi: 10.1016 / j.neuroscience.2009.12.070. Epub 2010 Jan 4.

Frohmader KS, Wiskerke J, RA e bohlale, Lehman MN, Coolen LM.

mohloli o moholo

Lefapha la Anatomy le Biology ea Cell, Sekolo sa Meriana ea Bongaka le Bongaka ba Meriana, Univesithing ea Bophirimela Ontario, London, ON, Canada, N6A 5C1.

inahaneloang

Methamphetamine (Meth) ke ho tsuba haholo. Ho sebelisa tlhekefetso ea meth hangata ho amahanngoa le mokhoa oa ho etsa boitšoaro bo kotsi ba ho kopanela liphate le ho ata ha batho ba nang le HIV le Immetodeficiency Virus, ba tlaleha takatso ea ho kopanela liphate, ho tsosoa le ho thabela thobalano. Sepheo sa tlhaho bakeng sa nexus ena ea thobalano ha e tsejoe. Phuputso ea morao tjena e bonts'a hore tsamaiso ea Meth e litoeba tsa banna e etsa li-neurone libakeng tsa boko ba tsamaiso ea mahlo a maholo a amehang ho laola boitšoaro ba thobalano. Ka ho khetheha, lisele tsa mothe le tsa ho kopanya li-activate cell nucleus accumbens mongobo le shell, basolateral amygdala, le anterior cingulate cortex. Liphuputso tsena li bontša hore ho fapana le tumelo ea morao-rao lithethefatsi tsa tlhekefetso li ka etsa hore lisele tse tšoanang le ts'ebeliso ea tlhaho ea thobalano, e leng boitšoaro bo bobe ba thobalano, 'me e ka ba le tšusumetso ea boikhathollo bakeng sa moputso ona oa tlhaho.

Keywords: nucleus accumbens, basolateral amygdala, prefrontal cortex, tšebeliso e mpe ea lithethefatsi, ho ikatisa, ho lemala

Tšusumetso le moputso li laoloa ke mokhoa oa mesolimbic, khokahano e kopanetsoeng ea libaka tsa boko tse nang le sebaka sa ventral tegmental (VTA) nucleus accumbens (NAc), amolgallal amygdala, le mediater prefrontal cortex (mPFC) (Kelley, 2004, Kalivas le Volkow, 2005). Ho na le bopaki bo bongata ba hore tsamaiso ea mahlaseli ea motlakase e sebelisoa ho arabela litsing tse peli tsa tlhekefetso (Di Chiara le Imperato, 1988, Chang le al., 1997, Ranaldi et al., 1999) le mekhoa e metle ea boitšoaro e kang boitšoaro ba thobalano (Fiorino et al., 1997, Balfour et al., 2004). Boitšoaro bo bong bo hlephileng ba ho kopanela liphate, 'me ka ho khetheha ejaculation, bo khotsofatsa haholo ebile bo matlafatsa liphoofolo (Pfaus et al., 2001). Litoeba tsa banna li hlahisa sebaka se khethehileng sa sebaka sa tlhaho (CPP) ho kopana (Agmo le Berenfeld, 1990, Martinez le Paredes, 2001, Tenk, 2008), 'me o tla etsa mesebetsi e sebetsang ho fumana mosali ea amohelang thobalano (Everitt et al., 1987, Everitt le Stacey, 1987). Lithethefatsi tsa tlhekefetso li boetse li khotsofatsa le ho matlafatsa, 'me liphoofolo li tla ithuta ho itlhokomela ka ho hlekefetsa, ho akarelletsa li-opiates, nicotine, joala le psychostimulants (Bohlale, 1996, Pierce le Kumaresan, 2006, Feltenstein le See, 2008). Le hoja ho tsejoa hore lithethefatsi tse peli tsa tlhekefetso le boitšoaro ba ho kopanela liphate li etsa hore libaka tsa boko bo sebetse hantle, hona joale ha hoa utloahala hore na lithethefatsi tsa tlhekefetso li susumetsa li-neurons tse tšoanang tse kopanelang boitšoaro ba thobalano.

Liphuputso tsa elektrophysiological li bontšitse hore lijo le k'hok'heine li sebelisa li-neurons ho NAc. Leha ho le joalo, li-reinforcers tse peli ha li sebelise lisele tse tšoanang ho NAC (Carelli le al., 2000, Carelli le Wondolowski, 2003). Ho feta moo, lijo le ho hlahisa boipheliso ba tsona ha li bake liphetoho tse telele tsa motlakase oa elektrophysiological tse bakoang ke cocaine (Chen le al., 2008). Ka lehlakoreng le leng, pokello ea bopaki e fana ka maikutlo a hore boitšoaro ba banna ba ho kopanela liphate le lithethefatsi tsa tlhekefetso e ka 'na ea e-ba boemong bo tšoanang ba neurons mesolimbic. Li-Psychostimulants le opioids li fetola mokhoa oa ho kopanela liphate ka likhoto tsa banna (Mitchell le Stewart, 1990, Fiorino le Phillips, 1999a, Fiorino le Phillips, 1999b). Litaba tsa morao-rao tse tsoang laborateng tsa rona li bontšitse hore phihlelo ea thobalano e fetola boikarabello ho li-psychostimulants joalokaha ho pakoa ke likarabo tsa moahi ea khothatsang le ho lemoha ts'ebeliso ea moputso ho d-amphetamine liphoofolong tse nang le phihlelo (Pitchers et al., 2009). Karabo e tšoanang e 'nile ea bonoa hangata ka ho pepeseha ha amphetamine kapa lithethefatsi tse ling tsa tlhekefetso (Lett, 1989, Shippenberg le Heidbreder, 1995, Shippenberg et al., 1996, Vanderschuren le Kalivas, 2000). Ka kakaretso, lipatlisiso tsena li fana ka maikutlo a hore boitšoaro ba thobalano le likarabo ho lithethefatsi tsa tlhekefetso li kopanngoa ke neurons tse tšoanang tsamaisong ea mesolimbic. Ka lebaka lena, sepheo sa pele sa thuto ena ke ho etsa lipatlisiso tsa ho sebelisoa ha neural ea tsamaiso ea mesoli ka boitšoaro ba thobalano le tsamaiso ea lithethefatsi phoofolo e le 'ngoe. Ka ho khetheha, re ile ra leka khopolo-taba ea hore psychostimulant, methamphetamine (Meth), e sebetsa ka ho toba ho methapo e tloaelehileng e sebelisang thobalano.

Meth ke e 'ngoe ea lithethefatsi tse seng molaong tse hlekefelitsoeng ka ho fetisisa lefatšeng (NIDA, 2006, Ellkashef et al., 2008) a'me e' nile ea amahanngoa hangata le boitšoaro bo fetotsoeng ba thobalano. Ho thahasellisang ke hore basebelisi ba Meth ba phahamisa takatso ea ho kopanela liphate le ho tsosoa, hammoho le thabo e eketsehileng ea thobalano (Semple et al., 2002, Schilder et al., 2005). Ho feta moo, Tlhekefetso ea meth hangata e amana le boitšoaro bo boima ba ho kopanela liphate (Rawson et al., 2002). Hangata basebetsi ba tlaleha hore ba na le balekane ba bangata ba thobalano 'me ha ba na monyetla oa ho sebelisa tšireletso ho feta ba bang ba hlekefetsang lithethefatsi (Somlai et al., 2003, Springer et al., 2007). Ka bomalimabe, lipatlisiso tse bontšang hore Meth e sebelisa mokhoa oa ho beha likotsi tsa thobalano li lekane ha li itšetlehile ka litlaleho tsa boipheliso bo sa netefatsoang (Elifson et al., 2006). Ka lebaka lena, lipatlisiso ka metso ea lisele tsa liphetoho tse bakoang ke Meth ka boitšoaro bo bobe ba thobalano li hlokahalang bakeng sa ho utloisisa mohopolo ona o rarahaneng oa thobalano le thobalano.

Ka lebaka la bopaki bo hlalositsoeng ka holimo bo bontšang hore lithethefatsi tsa tlhekefetso, haholo-holo Meth, li ka sebetsana le li-neurons tse tloaelehileng tse amanang le ho kopanela boitšoarong ba thobalano, sepheo sa thuto ea hona joale e ne e le ho batlisisa ts'ebetso ea neural ka boitšoaro ba thobalano le tsamaiso ea psychostimulant Methe. Phuputso ena e sebelisitse mokhoa oa phekolo, ho sebelisa pono ea immunohistochemical ea liphatsa tsa lefutso tsa pele tsa Fos le Phosphorylated Mapaase (PERK) ho lemoha ho sebelisoa ha neural ka mokhoa oa ho kopanela liphate le Meth ka ho latellana. Fos e hlahisoa feela ka har'a motsoako oa lisele, e nang le metsotso e fapaneng ea polelo ea 30-90 ka mor'a hore ho sebelisoe neuron. Ho na le bopaki bo bongata ba hore ho kopanela liphate ho etsa hore Pos e bue ka bokong (Pfaus le Heeb, 1997, Veening le Coolen, 1998), ho akarelletsa le mesocorticolimbic system (Robertson et al., 1991, Balfour et al., 2004). Hape ho na le bopaki ba hore lithethefatsi tsa tlhekefetso li kenyelletsa polelo e hlahang ka har'a tsamaiso ea mesocorticolimbic (Valjent et al., 2000, Valjent et al., 2004, Valjent et al., 2005). Ho fapana le polelo ea Fos, phosphorylation ea ERK ke ts'ebetso e matla haholo 'me e hlaha feela metsotso ea 5-20 ka mor'a activation ea neuronal. Litlhaloso tse fapaneng tsa nakoana tsa Fos le pERK li etsa hore e be letšoao le letle la liketso tsa neuronal tse latelang ka likhopolo tse peli tse sa tšoaneng.

MELAO EA TŠEBELETSO

Lihlooho

Maqeba a banna ba baholo ba Sprague Dawley (210-225 g) a fumanoang ho Charles River Laboratories (Montreal, QC, Canada) ba ne ba lula ka makhetlo a mabeli ka cage ka mekhahlelo e tloaelehileng ea plexiglas (matloana a lehae). Kamore ea phoofolo e ne e bolokiloe ka 12 / 12 h ho potoloha ha leseli (khantša 10.00 h). Lijo le metsi li ne li fumaneha ad libitum. Tlhahlobo eohle e ile ea etsoa nakong ea halofo ea pele ea lefifi le lefifi tlas'a khanya e khubelu e khanyang. Li-sululus tse tšehali tse sebelisetsoang ho kopanela liphate li ne li e-na le mahlaseli a mabeli ka tlase ho anesthesia (13 mg / kg ketamine le 87 mg / kg xylazine) 'me e fumanoe ho kenngoa ha metso e nang le 5% estradiol benzoate (EB) le 95% k'holisolerole. Ho amoheloa ka thobalano ho ne ho bakoa ke tsamaiso ea subcutaneous (sc) ea 500 μg progesterone ka 0.1 ml sesame oli 4 h pele ho lekoa. Mekhoa eohle e ile ea amoheloa ke Komiti ea Tlhokomelo ea Liphoofolo Univesithing ea Western Ontario 'me e lumellana le tataiso e hlalositsoeng ke Canadian Council on Animal Care.

Litlhahiso tsa Liteko

Liteko tsa 1 le 2: Likoe tsa banna (n = 37) li lumelloa ho kopana le basali ba amohelehang ho ejaculation e (E) kapa bakeng sa 30 min, e kileng ea tla pele litlamong tse hloekileng tsa tlhahlobo (60 × 45 × 50 cm) ka makhetlo a mabeli habeli -e leng pele ho tlhahlobo ea ho kopanya liphate, ho fumana phihlelo ea thobalano. Nakong ea litekanyetso tse peli tsa ho qetela, litekanyetso tsohle tse tloaelehileng tsa ts'ebetso ea thobalano li ne li ngotsoe, ho kenyeletsa: mount latency (ML; nako ho tloha kenyelletsong ea basali ho fihlela holima pele), latency latency (IL; nako ho tloha kenyelletsong ea basali ho fihlela ha ho qala ho kenngoa ha motsoako oa botšehali oa mosali), latency ejaculation (EL; nako ho tloha pele ho e-ea ho ea pele ho ea pele), nako ea poso ea ho ejaculation (PEI; nako ho tloha ho ejaculation ho ea pele ho ea pele), palo ea likhahla (M), le palo ea li-intromissions (IM) (Agmo, 1997). Banna bohle ba amohetse ente ea letsatsi le letsatsi ea 1 ml / kg ea 0.9% NaCl (saline; sc) 3 matsatsi a latellanang pele ho letsatsi la teko, bakeng sa tloaelo ea ho sebetsana le liente. Ka letsatsi le leng pele ho letsatsi la teko, banna bohle ba ne ba lula ba le masoha. Ho banna ba nang le phihlelo, Fos e ka susumetsoa ke maemo a boemong ba boemo bo amanang le phihlelo ea pele ea thobalano (Balfour et al, 2004). Ka lebaka leo, bohle ba neng ba itšoara le ho laola litsela nakong ea liteko tsa ho qetela li ne li khannoa ka matlung a matlo (ho qoba ho qoba ho etsa joalo) ho thibela ho kenngoa ha maemo ho etsa hore ho be le tšusumetso ho banna ba sa laoleheng. Banna ba babeli ba ile ba ajoa ka lihlopha tse robeli tsa liteko tse neng li sa fapane ka mokhoa leha e le ofe oa ho kopanela liphate nakong ea likhetho tse peli tsa ho qetela (data e sa bontšoang). Nakong ea teko ea ho qetela, banna ba ne ba lumelloa ho kopanela matlong a bona a lehae ho fihlela ba bonts'a ho kopanela liphate (ho kopanela liphate) kapa ba sa amohele molekane oa basali (ho se thobalano). Banna bohle ba motona ba ne ba sebelisoa hampe ka metsotsoana ea 60 ka mor'a ho qala ho nyalana ho lumella ho hlahlobisoa ha polelo ea Fos e entsoeng ka ho kopanela liphate. Banna ba ile ba fuoa lengolo la 4 mg / kg Meth kapa 1 ml / kg saline (sc) (n = 4 ka mong), kapa 10 (teko ea 1) kapa 15 (teko ea 2) metsotso pele ho phallo, bakeng sa ho hlahloba phosphorylation e entsoeng ke lithethefatsi ea MAP kinase. Tekanyo le nako pele phallo e ne e thehiloe litlalehong tse fetileng (Choe et al., 2002, Choe le Wang, 2002, Chen le Chen, 2004, Mizoguchi le al., 2004, Ishikawa et al., 2006). Lihlopha tsa taolo li kenyelletsa banna ba sa kang ba nyalana, empa ba amohela Meth 10 (n = 7) kapa 15 (n = 5) metsana pele ho sehlabelo, kapa li-injection tsa saline 10 (n = 5) kapa 15 (n = 4) metsana pele ho sehlabelo . Ka mor'a ho etsa sehlabelo, boko ba ile ba sebelisoa bakeng sa immunohistochemistry.

Hlahloba 3: Kaha methe e phahameng ea Meth e ne e sebelisitsoe tekong ea 1 le 2, ho ile ha etsoa teko e eketsehileng ea phekolo ea meriana ho hlahloba hore na boitšoaro ba ho kopanela liphate le tekanyo e ka tlase ea Meth e baka mekhoa efe e itšetlehileng ka neural activation. Phuputso ena e entsoe ka mokhoa o ts'oanang le liteko tsa 1 le 2. Leha ho le joalo, tekong ea ho qetela, lihlopha tse nang le menyetla e mengata (n = 6 ka 'ngoe) li amohetse 1 mg / kg Meth (sc) 15 min pele ho sehlabelo.

Hlahloba 4: Ho hlahloba hore na neural activation e bakoang ke thobalano le Meth e totobetse bakeng sa Meth, tlhahlobo ena e ile ea batlisisa hore na mekhoa e tšoanang ea ho sebelisoa ha neural activation e ka bonoa ke psychostimulant d-amphetamine (Amph). Tlhahlobo ena e ile ea etsoa ka mokhoa o ts'oanang le liteko tsa 1 le 2. Leha ho le joalo, tekong ea ho qetela, banna ba ne ba fuoa Amph (5 mg / kg) kapa saline (1 mg / kg) (sc) 15 metsana pele ho sehlabelo (n = 5 ka mong). Ho laola banna ba sa mameleng ba amohetse saline kapa Amph 15 metsotso pele ho sehlabelo. Tlhaloso e akaretsang ea lihlopha tsa liteko tse sebelisitsoeng litsing tsa 1-4 li fanoe ka Lethathamo 1.

Lethathamo 1      

Kakaretso ea lihlopha tsa liteko tse kenyelletsong litsong tsa 1-4.

Boitokisetso ba Matlalo

Liphoofolo li ne li ts'oaetsoe ke pentobarbital (270 mg / kg; ip) mme li sebelisetsoa transcardially le 5 ml ea saline e lateloa ke 500 ml 4% paraformaldehyde ho 0.1 M phosphate buffer (PB). Bokooa bo ile ba tlosoa 'me ba kenngoa morao bakeng sa 1 h ka mocheso oa motsoako o tšoanang, ba kenngoa 20% sucrose le 0.01% Sodium Azide ho 0.1 M PB mme ba bolokoa 4 ° C. Likarolo tsa Coronal (35 μm) li ne li khethiloe ka microtome e bolileng (H400R, Micron, Jeremane), e bokelloa ka lihlopha tse 'nè tse tšoana le tharollo ea cryoprotectant (30% sucrose le 30% ethylene glycol ka 0.1 M PB) ebe e bolokiloe 20 ° C ho fihlela ho feta ho sebetsa.

Immunohistochemistry

Lesebelisoa tsohle li ne li etsoa ka mocheso oa motsoako o nang le tsitsipano e bonolo. Likarolo tse phaphametseng tsa mahala li ne li hlatsuoa haholo ka letsoai la 0.1 M Phosphate-buffered (PBS) pakeng tsa ho tsuba. Likarolo li ne li kenngoa ka 1% H2O2 bakeng sa minara ea 10, ebe e koetsoe ka tharollo ea motsoako (PBS e nang le 0.1% serum albumin le 0.4% Triton X-100) bakeng sa 1 h.

PERK / Fos

Li-tissue li ne li koaheloa bosiu bosiu ka poporo ea polyclonal ea mmutla khahlanong le p42 le mapolanka a popyclonal a nang le p44 le mapolanka a p1 (pERK; 2: tlhahlobo ea 1 400 lot 1; 19: tlhahlobo ea 1 4.000 le 2 lot 3; Cat Signaling Cat # 21;), e lateloa ke 9101 h ho kenyelletsa likokoanyana tse nang le likokoana-hloko IgG (1: 1; Jackson Immunoresearch Laboratories, West Grove, PA) le complex complex peroxidase complex (ABC Elite; 500: 1; Vector Laboratories, Burlingame, CA). Joale, lisele tsena li ne li kenngoa ka metsotsoana ea 1000 e nang le biraminylated tyramide (BT; 10: 1 ho PBS + 250% H2O2;; Setšoantšo sa Tyramid Signal Amplification, NEN Life Sciences, Boston, MA) le bakeng sa 30 min le Alexa 488 conjugated strepavidin (1: 100; Jackson Immunoresearch Laboratories, West Grove, PA). Ka mor'a moo, masiana a ne a koetlisoa ka lekhetlo le leng le le leng ka setlolo sa popula sa polyclonal sa mmutla khahlanong le c-Fos (1: 500; SC-52; Santa Cruz Biotechnology, Santa Cruz, CA), e lateloa ke 30 min ho kopanya le rabbit ea poli-goat Alexa 555 (1: 200; Jackson Immunoresearch Laboratories, West Grove, PA). Ka mor'a ho silafatsa, likarolo li ile tsa hlatsoa ka botlalo ho 0.1 M PB, tse phahamiselitsoeng li-slide tsa khalase le 0.3% gelatin ka ddH20 'me e koahetsoeng ka sekhahla se nang le metsi a mangata (Gelvatol) se nang le 1,4-diazabicyclo (2,2) octane (DABCO; 50 mg / ml, Sigma-Aldrich, St. Louis, MO). Li-controls tsa immunohistochemical li ne li akarelletsa ho se lumellane ha li-antibodies tse ka sehloohong kapa tse peli, e leng se etsang hore ho se ke ha e-ba le li-labeling ka bokahohleng bo nepahetseng.

Boitsebiso ba Lintlha

Boitšoaro ba thobalano

Bakeng sa liteko tsohle tse 'nè, litekanyo tse tloaelehileng tsa ts'ebetso ea thobalano li ile tsa tlalehoa joalo ka ho hlalositsoe ka holimo le ho hlahlojoa ha ho hlahlojoa sechabeng (ANOVA). Tlhahlobo ea lintlha tsa boitšoaro ba thobalano nakong ea tlhahlobo ea ho qetela ea letsatsi la teko ha ea ka ea bontša hore ho na le phapang e khōlō pakeng tsa lihlopha ho tse ling tsa likarolo tsa thobalano

pERK / Fos Cell Counts

Lisele tse se nang molekane le tse peli tse ngotsoeng bakeng sa Fos le pERK li ne li baloa maemong a caudal a NAC le lihlopha tsa lihlopha tsa shell, basolateral amygdala (BLA), posterodorsal medium amygdala (MEApd), central amygdala (CeA), nucleus ea pele-pele (MPN), posteromedial le Motheo oa bethe oa kamore ea pele ea stria terminalis (BNSTpm le BNSTpl), le sebaka se ka pele sa tlhaho (ACA), pele ho moo (PL), le libaka tse ling tsa infralimbic (IL) tsa mPFC. Litšoantšo li ile tsa nkoa ka k'hamera ea CCD e khutsitseng (Microfire, Optronics) e kopantsoeng le microscope ea Leica (DM500B, Leica Microsystems, Wetzlar, Jeremane) le software ea Neurolucida (MicroBrightfield Inc) e nang le likarolo tse tsitsitseng tsa likhamera bakeng sa lihlooho tsohle (ho sebelisa li-10x lipakane). Ho sebelisa software ea neurolucida, libaka tsa tlhahlobo li hlalositsoe ho latela mekhoa e metle (Swanson, 1998) e ikhethang bakeng sa sebaka ka seng sa boko (bona Setšoantšo sa 1). Libaka tse tloaelehileng tsa tlhahlobo li ne li sebelisoa libakeng tsohle ntle le NAC ea motheo le shell. Libakeng tse qetellang, polelo ea PERK le Fos e ne e sa tšoane 'me e hlahetsoe ka mekhoa e kang ea majoe. Ka hona, mokokotlo o moholo le sekhetla li ne li hlalositsoe ho latela likaroloana (lateral ventricle, boithabiso bo sa tloaelehang le lihlekehlekeng tsa Calleja). Libaka tsa tlhahlobo ha lia ka tsa fapana pakeng tsa lihlopha tsa liteko, 'me li ne li le 1.3 mm2 ho NAC ea motheo le shell. Libaka tse tloaelehileng tsa tlhahlobo bakeng sa libaka tse setseng li ne li le: 1.6 mm2 ho BLA, 2.5 le 2.25 mm2 ho MEApd le CeA ka ho latellana, 1.0 mm2 ho MPN, 1.25 mm2 metseng ea BNST le mPFC, le 3.15 mm2 ho VTA. Likarolo tse peli li ne li baloa ka lipalo tse peli bakeng sa sebaka ka seng sa boko ka liphoofolo, 'me palo ea lisele tse se nang molekane le tse peli tse ngotsoeng bakeng sa PERK le Fos hammoho le liphesente tsa lisele tse nang le lisele tse hlalosang letšoao la Fos li baliloe. Bakeng sa liteko 1, 2, le 4, lipalo tsa sehlopha li ne li bapisoa ka tsela e 'meli ea ANOVA (mabaka: ho kopanya le lithethefatsi) le Fisher's LSD bakeng sa post hoc litšoantšiso ka tekanyo ea bohlokoa ea 0.05. Bakeng sa liteko 3, likarolo tsa sehlopha li ne li bapisoa le ho sebelisa liteko tse sa sebetsanang le litlhahlobo tsa boemo ba 0.05.

Setšoantšo sa 1      

Litšoantšo le litšoantšo tse bontšang libaka tsa boko ba tlhahlobo. Libaka tsa ts'ebetso li bontšitsoe li thehiloe libakeng tse ikhethileng sebakeng se seng sa boko, se sa fapane pakeng tsa lihlopha tsa liteko, mme li ne li le 1.25 mm2 ho metse ea mPFC (a), 1.3 mm2 ka ...

Images

Litšoantšo tsa Dijithale tsa Setšoantšo sa 3 li ile tsa nkoa ka ho sebelisa CCD kamera (DFC 340FX, Leica) e kopantsoeng le microscope ea Leica (DM500B) 'me ea kenngoa ka Software ea Adobe Systemshop 9.0 (Adobe Systems, San Jose, CA). Litšoantšo ha lia ka tsa fetoloa ka tsela leha e le efe ntle le ho fetola khanya.

Setšoantšo sa 3      

Litšoantšo tsa litšoantšo tsa NAc li-immunostained bakeng sa Fos (khubelu; a, d, g, j) le pERK (tala; b, e, h, k) ea liphoofolo tsa sehlopha se seng le se seng sa liteko: Ha ho Sex + Sal (a, b, c) , Ho kopanela liphate + Sal (d, e, f), ha ho na thobalano + Meth (g, h, i), le Sex + Meth (j, k, l). Lipampiri tse nepahetseng ke ...

LIPOTSO

Neural e ts'ebetsong ea Lenaneo la Limbic ka boitšoaro ba thobalano le tsamaiso ea Meth

Hlahloba 1: Tlhahlobo ea lisele tse se nang molekane le tse peli tse ngotsoeng bakeng sa Fos le ho susumetsoa ke Meth ho banna ba amohetseng metsotso ea Meth 10 pele ho sehlabelo ba senola Fos e entsoeng ka mating ka MPN, BNSTpm, NAc core le shell, BLA, VTA, le li-subregions tsohle tsa mPFC, tse lumellanang le lithuto tsa pele tse bontšang polelo ea Fos e susumelitsoeng ho kopanela likarolong tsena (Baum le Everitt, 1992, Pfaus le Heeb, 1997, Veening le Coolen, 1998, Hull et al., 1999). Tsamaiso ea Meth 10 metsotso pele ho sehlabelo e etsa hore ho be le sebopeho sa NAc le khetla, BLA, MeApd, CeA, BNSTpl, le libaka tsa mPFC, tse lumellanang le ho etsa liphatsa tse susumelitsoeng ke tse ling tsa psychostimulants (Valjent et al., 2000, Valjent et al., 2004, Valjent et al., 2005).

Ho feta moo, mekhoa e meraro ea li-co-expression e sebelisoang ka neural ka boitšoaro ba ho kopanela liphate le Meth e ile ea hlokomeloa: Ntlha ea pele, libaka tsa bokooa li ile tsa tsejoa moo ho kopanela liphate le lithethefatsi li ntseng li lumelloa hore li se ke tsa kopanya li-neural populationLethathamo 2). Haholo-holo, ho CeA, MEApd, BNSTpl, le mPFC, keketseho e kholo ho PERK e bakoang ke lithethefatsi (F (1,16) = 7.39-48.8; p = 0.015- <0.001) le Fos e susumetsoang ke thobalano (F (1,16, 16.53) = 158.83-0.001; p <1,16) li ile tsa bonoa. Leha ho le joalo, libakeng tsena ho ne ho se na keketseho e kholo ho li-neuron tse peli tse ngotsoeng ho banna ba tšoaroang ke Meth. Mokhelo feela e ne e le MEApd, moo phello ea ho nyalanya lipalo tsa lisele tse nang le mabitso a mabeli li fumanoeng (F (9.991) = 0.006; p = XNUMX). Leha ho le joalo, ho ne ho se na phello e akaretsang ea kalafo ea lithethefatsi le ho ngola mabitso a mabeli lihlopheng tse tšoaroang ke Meth ho ne ho se holimo haholo ho feta ho lihlopha tse tšoaroang ka letsoai, ka hona ha hoa bakoa ke setlhareLethathamo 2). Ntlha ea bobeli, libaka tsa boko li ile tsa khetholloa moo ho sebelisoa ha neural ho susumetsoa feela ke ho nyalana (Lethathamo 3). Ka ho khetheha, MPN, BNSTpm, le VTA li ile tsa sebelisoa feela ka ho kopanya, 'me li na le keketseho e kholo ho Fos (F (1,16) = 14.99-248.99; p ≤ 0.001), empa ha ho na pERK e susumelitsoeng ke Meth.

Lethathamo 2      

Tlhaloso ea tlhaloso ea Fos le ea Meth e entsoeng ke Meth libakeng tsa bokooa moo ho kopanela liphate le lithethefatsi ho etsa hore ho se ke ha e-ba le batho ba bangata ba nang le melaetsa ea ho kopanela liphate.
Lethathamo 3      

Tlhaloso ea tlhaloso ea Fos le ea Meth e entsoeng ke Meth libakeng tsa bokooa moo ho sebelisoa ha neural ho susumelitsoe feela ke ho nyalana.

Qetellong, libaka tsa boko li ile tsa fumanoa moo ho kopanela liphate le lithethefatsi ho ileng ha lumella batho ba bangata ba nang le li-neuron (Setšoantšo sa 2 'me Le3) .3). Mokokotlong oa NAc le khetla, BLA, le ACA, ho bile le litlamorao tse akaretsang tsa ho nyalanya (F (1,16) = 7.87-48.43; p = 0.013- <0.001) le kalafo ea lithethefatsi (F (1,16) = 6.39– 52.68; p = 0.022- <0.001), hammoho le tšebelisano lipakeng tsa lintlha tsena tse peli (F (1,16) = 5.082-47.27; p = 0.04- <0.001; ha ho na tšebelisano e kholo ho ACA) lipalo tsa lisele tse hlalosang ka bobeli PERK e susumetsoang ke ho kopanya. Tlhahlobo ea Post hoc e senotse hore lipalo tsa li-neuron tse peli tse ngotsoeng li ne li phahame haholo ho banna ba kenngoeng ke Meth ba tšoeroeng ke 'mele ha ba bapisoa le kalafo e sa sebetsoang ea Meth (p = 0.027- <0.001), kapa ba tšoeroeng ka letsoai (p = 0.001- <0.001) banna (Setšoantšo sa 2 'me Le3) .3). Ha data e ne e hlahisoa e le liphesente tsa neurons tse sebelisoang ke lithethefatsi, 39.2 ± 5.3% mofuteng oa NAc, 39.2 ± 5.8% ka shell ea NAc, 40.9 ± 6.3% ho BLA, 'me 50.0 ± 5.3% ea ma-neurons a ACA a tsositsoe ke ho nyalana le Meth.

Setšoantšo sa 2      

Puo e hlalositsoeng ka ho kopanela liphate Fos le motsoako oa Meth ho NAC, BLA, le ACA neurons 10 min ka mor'a tsamaiso ea 4 mg / kg Meth. Palo e bolelang ± sem ea Fos (a, d, g, j), pERK (b, e, h, k), le tse peli (c, f, i, l) lisebelisoa tse ngotsoeng kahare ho NAC (a, ...

Tlhokomelo e sa lebelloang e ne e le hore boitšoaro ba thobalano bo amme pERK e bakoang ke Meth. Le hoja Meth e ile ea etsa hore lihlopha tse peli tse nang le methapo e nang le methapo e nang le methapo ea meth le e sa amoheloeng, ka NAC, BLA, le ACA, ho ngolisoa ha lipalo ho ne ho le tlaase haholo ho banna ba nang le meth e entsoeng ka methe ha e bapisoa le banna ba sa tšoaeng ke Meth. (Setšoantšo sa 2b, e, h, k; p = 0.017- <0.001). Tlhaloso ena e ka tsoela pele ho tšehetsa khopolo ea hore thobalano le lithethefatsi li sebetsana le li-neurons tse tšoanang, empa e ka 'na ea boela ea e-ba pontšo ea liphetoho tse bakoang ke ho kopanela liphate ho tlatseng lithethefatsi kapa metabolism eo ka lebaka la eona e fetotseng likarabo tsa methati ho Meth. Ho etsa lipatlisiso haeba boitšoaro bo bobe ba ho kopanela liphate bo baka mokhoa o fapaneng oa nako ea ts'ebeliso ea lithethefatsi, likarolo tsa NAc, BLA, le ACA li ne li silafalitsoe ke banna ba hlabelitsoeng ka nako e telele (15 min) ka mor'a tsamaiso ea lithethefatsi (teko ea 2).

Hlahloba 2: Ho hlahlojoa ha lisele tse nyenyane le tse peli tse ngotsoeng ka holimo li tiisitse liphuputso tse hlalositsoeng ka holimo hore boitšoaro ba ho kopanela liphate le ho pepesehela Meth 15 metsotso pele ho sehlabelo se entse hore ho eketseha ho hoholo ha Fos le pERK immunolabeling molaong oa NAc le shell, BLA, le ACA. Ho phaella moo, ho bonts'oa ha bohlokoa ho bonts'oa ha Fos le Meth-induced by PETK ho ile ha boela ha fumanoa libakeng tsena (Setšoantšo sa 4; Phello ea ho nyalana: F (1,12) = 15.93-76.62; p = 0.002- <0.001; phello ea lithethefatsi: F (1,12) = 14.11-54.41; p) = 0.003- <0.001). Palo ea li-neuron tse peli tse ngotsoeng mabitso a batona ba nang le meth Ha data e hlahisoa e le liperesente tsa li-neuron tse sebelisitsoeng ke lithethefatsi, 0.001 ± 0.001% (NAc core), 47.2 ± 5.4% (NAc shell), 42.7 ± 7.6% (BLA), le 36.7 ± 3.7% (ACA) ea li-neuron ka ho tlolelana ha liphoofolo le tsona li ile tsa sebelisoa ke Meth. Ho feta moo, pERK e bakoang ke lithethefatsi e ne e sa fapane pakeng tsa liphoofolo tse nyalaneng le tse sa emang (Setšoantšo sa 4b, e, h, k), libakeng tsohle ntle le ACA (p <0.001). Litaba tsena li bonts'a hore boits'oaro ba botona le botšehali bo hlile bo baka phetoho ea sebopeho sa nakoana sa Meth.

Setšoantšo sa 4      

Puo e hlalositsoeng ka ho kopanela liphate Fos le motsoako oa Meth ho NAC, BLA, le ACA neurons 15 min ka mor'a tsamaiso ea 4 mg / kg Meth. Palo e bolelang ± sem ea Fos (a, d, g, j), pERK (b, e, h, k), le tse peli (c, f, i, l) lisebelisoa tse ngotsoeng kahare ho NAC (a, ...

Neural Activation ho latela boitšoaro ba ho kopanela liphate le 1 mg / kg Meth

Ho fihlela joale litholoana li senola hore boitšoaro bo bobe ba ho kopanela liphate le 4 mg / kg Meth e sebelisitse batho ba bangata ba nang le li-neurone mofuteng oa NAC le shell, BLA, le ACA. T► Ho batlisisa tšusumetso ea litekanyetso tsa lithethefatsi tabeng ena ea ho sebetsa, mekhoa ea ts'ebetso ea neural e boetse e ithutiloe ka mokhoa o tlaase oa Meth. Motsoako oa NAC le khetla, BLA, le ACA li ile tsa hlahlojoa bakeng sa ts'ebetso e susumelitsoeng ke thobalano le Meth. Ha e le hantle, boitšoaro ba ho kopanela liphate le ho pepeseha ha Meth ho ile ha etsa hore ho be le keketseho e kholo ea Fos le pERK immunolabeling ho NAC le libaka tse ling tsa shell, BLA, hammoho le neurons sebakeng sa ACA sa mPFC (Setšoantšo sa 5). Ho thahasellisang, tekanyo e tlaase ea Meth e hlahisitse lipalo tse tšoanang tsa lipere tse nang le li-neurone tse kentsoeng ke 4 mg / kg Meth libakeng tse 'nè tsa boko bo hlahlojoa. Habohlokoa le ho feta, mohopolo oa NAC le shell, BLA, le ACA li bonts'e keketseho e kholo palo ea lisele tse peli tse ngotsoeng tse ngotsoeng (Setšoantšo sa 5c, f, i, l) ha e bapisoa le banna ba sa entsoang ba entsoang ke Meth (p = 0.003- <0.001). Ha data e hlahisoa e le liperesente tsa li-neuron tse sebelisitsoeng ke lithethefatsi, 21.1 ± 0.9% le 20.4 ± 1.8% ho konokono ea NAc le khetla ka ho latellana, 41.9 ± 3.9% ho BLA, le 49.8 ± 0.8% ea li-neuron tsa ACA li ile tsa ts'oaroa ka thobalano le Meth.

Setšoantšo sa 5      

Puo e hlalositsoeng ka ho kopanela liphate Fos le motsoako oa Meth ho NAC, BLA, le ACA neurons 15 min ka mor'a tsamaiso ea 1 mg / kg Meth. Palo e bolelang ± sem ea Fos (a, d, g, j), pERK (b, e, h, k), le tse peli (c, f, i, l) lisebelisoa tse ngotsoeng kahare ho NAC (a, ...

Neural Activation ho latela boitšoaro ba thobalano le tsamaiso ea d-Amphetamine

E le ho hlahloba hore na liphello tse ka holimo li ne li totobetse bakeng sa Meth, liteko tse ling li ile tsa etsoa ho ithuta ho sebelisana le 'mino oa neural-activated. Ho hlahlojoa ha lisele tse se nang molekane le tse peli tse ngotsoeng bakeng sa PERK le Fos li bontšitse hore boitšoaro ba ho kopanela liphate le ho pepeseha ha Amph ho hlahisitse keketseho e kholo ea Fos le pERK immunolabeling molaong oa NAc le shell le BLA (Setšoantšo sa 6; Phello ea ho nyalana: F (1,15) = 7.38-69.71; p = 0.016- <0.001; phello ea lithethefatsi: F (1,15) = 4.70-46.01; p = 0.047- <0.001). Ho feta moo, lipalo tsa li-neuron tse nang le mabitso a mabeli li ne li phahame haholo ho li-amph-treatment ha li bapisoa le tse sa sebetsoang tsa Amph (p = 0.009- <0.001), kapa tse ts'oaroang ka letsoai (p = 0.015- <0.001) banna (Setšoantšo sa 6c, f, i). Ha data e hlalosoa e le liphesente tsa li-neurons tse sebelisoang ke lithethefatsi, 25.7 ± 2.8% le 18.0 ± 3.2% ho NAC le shell ka ho latellana, 'me 31.4 ± 2.0% ea li-neurons tsa BLA li ile tsa ts'oaroa ka bobeli ba likhahla le Amph. Sebaka sa ACA sa mPFC se bontšitse maemong a bohlokoa a Fos (Setšoantšo sa 6j; F (1,15) = 168.51; P <0.001). Leha ho le joalo, ho fapana le Meth, Amph ha ea ka ea baka keketseho e kholo maemong a ts'ebeliso ea lithethefatsi ho ACA (Setšoantšo sa 6k) kapa linomoro tsa tse peli tse ngotsoeng ka neurons ho ACA (Setšoantšo sa 6l) ha e bapisoa le banna ba babeli ba nang le letsoai le ba sa hlajoeng ka letsoai.

Setšoantšo sa 6      

Tlhaloso ea Fos le ea Amph-e bakoang ke ho kopanela liphate, e hlalosang thobalano ka NAc, BLA, le ACA neurons 15 min ka mor'a tsamaiso ea 5 mg / kg Amph. Palo e bolelang ± sem ea Fos (a, d, g, j), pERK (b, e, h, k), le tse peli (c, f, i, l) lisebelisoa tse ngotsoeng kahare ho NAC (a, ...

TŠOHLOA

Phuputso ea morao tjena e bonts'a sekala sa cellular ho kopana pakeng tsa ho sebelisoa ha neural ka boitšoaro bo bobe ba ho kopanela liphate le tlhaho ea psychostimulant Meth. Ka hona, litlaleho tsena li bontša hore lithethefatsi ha li sebelise feela libakeng tse tšoanang tsa boko tse laolang moputso oa tlhaho, empa ha e le hantle, lithethefatsi li etsa lisele tse tšoanang tse amehang ho laola meputso ea tlhaho. Ha e le hantle, ho bontšitsoe mona hore boitšoaro ba thobalano le Meth li sebelisitse li-neuron tse ngata ho NAC ea motheo le shell, BLA, le ACA sebakeng sa mPFC, ho khetholla libaka tseo ho tsona Meth e ka susumetsang boitšoaro ba thobalano.

Tlhahiso ea morao-rao ea hore boitšoaro ba thobalano le tsamaiso ea Meth e sebelisang batho ba bangata ba nang le li-neuron tse nang le NAC, BLA, le ACA li fapane le liphuputso tse ling tse bontšang hore batho ba fapaneng ba Nac neurons ba khomarela moriana le moputso oa tlhaho.

Ka ho khetheha, lithuto tsa electrophysiological tse neng li bapisoa le ts'ebetso ea neural nakong ea ho itlhophisa ha litlhohonolofatso tsa tlhaho (lijo le metsi) le cocaine e entravenous e bontšitse hore k'hok'heine ea boipheliso e ile ea etsa hore ho be le batho ba sa tšoaneng ba neurone bao ho seng bonolo ho oela nakong ea ho arabela metsi le ho matlafatsa lijo (92%). Ke 8% feela ea li-neurons tse hlahelletseng tse bontšang ts'ebetso ka cocaine le moputso oa tlhaho (Carelli le al., 2000).

Ka lehlakoreng le leng, boholo ba (65%) ea sele ka NAC bo ile ba bontša ts'ebetsong ka meputso e fapaneng ea tlhaho (lijo le metsi), esita le haeba e le 'ngoe e neng e ka natefisa (sucrose) (Roop et al., 2002).

Ho ka 'na ha e-ba le mabaka a' maloa a tlatselitseng ho fapana le liphello tsa hona joale. Ntlha ea pele, mekhoa e fapaneng ea theknoloji e ne e sebelisetsoa ho batlisisa mesebetsi ea neural. Phuputso ea morao tjena e sebelisitse mokhoa oa ho boloka ho sebelisoa ha li-neural ka nako e le 'ngoe ka mekhoa e' meli e sa tšoaneng e sebelisang immunocytochemisty tse peli tsa fluorescencent bakeng sa Fos le pERK, e lumellang ho phenyekolla ho sebelisoa ha sele e le 'ngoe holim'a libaka tse kholo tsa libaka tsa boko. Ka lehlakoreng le leng, liphuputso tsa Carelli le basebetsi-'moho le tsona li sebelisitse lirekoto tsa electrophysiological tse behiloeng ho NAC ea liphoofolo tse itšoereng hantle ho rarolla hore na ho itlhophisa ha lithethefatsi tsa tlhekefetso ho etsa hore ho be le mechine e meng ea litšebeletso tsa mahlaseli e sebelisoang ke meputso ea tlhaho.

Ntlha ea bobeli, phuputso ea morao tjena e batlisitse moputso o fapaneng oa tlhaho, e leng boitšoaro ba thobalano ho bapisoa le lithuto tsa pele, tse sebelisang lijo le metsi linthong tse thibelitsoeng (Carelli, 2000). Lijo le metsi li ka 'na tsa e-ba le bohlokoa bo fokolang ho feta ho kopanela liphate. Boits'oaro ba botona kapa botšehali boa putsa haholo 'me likhoto li etsa hore CPP e sebetsane hantle (Agmo le Berenfeld, 1990, Martinez le Paredes, 2001, Tenk, 2008). Leha ho le joalo, litoeba tse fokolang lijo li theha CPP bakeng sa metsi (Agmo et al., 1993, Perks le Clifton, 1997) le lijo (Perks le Clifton, 1997), dMefuta e sa thibeloang ke likhoto li ja le ho theha CPP bakeng sa lijo tse ling tse nang le monate (Jarosz et al., 2006, Jarosz et al., 2007).

Ntlha ea boraro, lithuto tsa rona li ne li kenyelletsa lithethefatsi tse fapaneng tsa tlhekefetso ha li bapisoa le lithuto tsa pele, ho sebelisa methamphetamine le amphetamine ho e-na le cocaine. Liphello tsa hona joale li bontša hore Meth e khethehileng, le ho feta ntate ea amphetamine, e entse hore ho ts'oaroa ha li-neurone hape ho tsositsoe ke boitšoaro ba thobalano. Liphihlelo tsa lithethefatsi e ka 'na eaba li bile le karolo ho seo re se fumaneng. Lithuto tsa morao-rao li sebelisitse liphoofolo tse nang le phihlelo ea ho kopanela liphate, empa li-naïve tsa lithethefatsi. Ka lehlakoreng le leng, lithuto tsa electrophysiological tsa Carelli le basebetsi-'moho le tsona li sebelisitsoe "liphoofolo tse koetlisitsoeng hantle" tse ileng tsa fumanoa khafetsa ka cocaine.

Ka lebaka leo, ho ka etsahala hore ho ts'ebetswa ha Meth-metsoako ea li-neurone e susumelitsoeng ke boitšoaro ba thobalano ho fetoloa likarolong tse nang le phihlelo ea lithethefatsi. Leha ho le joalo, lipatlisiso tsa pele ho laborateng tsa rona li bontša hore ho ba le phihlelo ea lithethefatsi ha ho bonolo hore e be sesosa se seholo joaloka boitšoaro ba ho kopanela liphate le phekolo ea Meth ho banna ba phekoloang ka nako e telele le Meth likarolo tse tšoanang tsa li-neurons tse sebelisoang ke lithethefatsi tse tlalehiloeng thuputsong ea morao-rao (20.3 ± 2.5% ho NAC ea core le 27.8 ± 1.3% ho NAc shell; Frohmader le Coolen, litlhaloso tse sa hatisoang).

Qetellong, phuputso ea morao tjena e ile ea phenyekolla khato ea "ka kotloloho" ea lithethefatsi tse sebelisang tsamaiso ea boipheliso. Ka lebaka leo, tlhahlobo ea morao tjena ha e senole tlhahisoleseding e mabapi le lipotoloho tsa meriana tse kenang ho batla lithethefatsi kapa li-cues tse amanang le moputso oa lithethefatsi, empa ho e-na le hoo li senola mosebetsi oa meriana o bakoang ke ketso ea meriana ea lithethefatsi. Liphuputsong tse fetileng tsa electrophysiological, NAc neural activity e hlahang ka metsotsoana ea likarabo tse matlafatsang ha e bakoe ke mokhoa oa phekolo ea k'hok'heine, empa e itšetlehile haholo ka lintho tse amanang le lik'hemik'hale ka hare ho puso ea 'Carelli, 2000, Carelli, 2002). Ka ho khetheha, NAc neural activity e susumetsoa ke litlhaloso tse ikemetseng tsa likarabo tse amanang le ho fana ka li-cocaine tse nang le li-intravenous hammoho le lisebelisoa tsa lisebelisoa (ke hore, ho hatella ka lehlakoreng) ho na le karolo ea ponahalo ea boitšoaro (Carelli, 2000, Carelli le Ijames, 2001, Carelli, 2002, Carelli le Wightman, 2004). Ka bokhutšoanyane, liphihlelo tsa rona tsa ts'ebetsong ka moputso oa tlhaho le lithethefatsi li ka ba tse tobileng bakeng sa ts'ebetso ka thobalano le Meth le Amph.

Meth le thobalano li ile tsa thibela batho ba bangata ba nang le li-neuron tse nang le melumo ea NAC le shell ka mokhoa o itšetlehileng ka tekanyo ea tekano. Li-neurons tse sebeliselitsoeng li-NAC li ka buisana ka liphello tsa Meth ka litšobotsi tse susumetsang le tse putsang tsa boitšoaro ba thobalano ha litsi tsa NAc li senya boitšoaro ba thobalano (Liu et al., 1998, Kippin le al., 2004). Ho phaella moo, li-neuron tsena li ka 'na tsa e-ba locus bakeng sa liphello tsa lithethefatsi tse itšetlehileng ka lithethefatsi ha li kopane, kaha methane e tlaase ea Meth (1 mg / kg) e fokolitse palo ea lisele tse peli tse ngotsoeng ka 50% ha li bapisoa le tekanyo e phahameng ea Meth (4 mg / kg). Le hoja thuto ena e sa khetholle lik'hemik'hale tsa phenotype tsa co-activated, lipatlisiso tsa pele li bontšitse hore polelo e entsoeng ke lithethefatsi ea PERK le Fos ho NAc e itšetlehile ka bobeli ba dopamine (DA) le li-receptors tsa glutamate (Valjent et al., 2000, Ferguson et al., 2003, Valjent et al., 2005, Letsatsi le al., 2008). Le hoja ho sa hlaka hore na ho sebelisoa ha neural ho kenya letsoho ho NAC ho itšetlehile ka li-receptor tsena, sena se 'nile sa bontšoa libakeng tse ling tsa boko, haholo-holo sebakeng sa pele se ka pele ho moo (Lumley le Hull, 1999, Dominguez et al., 2007). THus, Meth e ka sebetsa ka li-neurone e boetse e sebelisoa nakong ea boitšoaro bo bobe ba ho kopanela liphate ka ho kenyelletsa dopamine le li-receptor tsa glutamate. Karolo ea NAC ea ho kopanela liphate ka mokhoa oa ho kopanela liphate ha e hlahe hantle, empa e thehiloe hantle hore DA e phetha karolo ea bohlokoa molemong oa boitšoaro ba thobalano (Hull et al., 2002, Hull et al., 2004, Pfaus, 2009). Liphuputso tsa Microdialysis li tlalehile ho eketseha ha metsi a NAC DA a ntse a e-na le tšusumetso nakong ea liketso tse mpe tsa ho kopanela liphate (Fiorino le Phillips, 1999a, Lorrain et al., 1999) 'me mahlaseli a mangata a DA a sebelisitsoe ho tsamaisa mokhoa oa ho qalisa le ho boloka boitšoaro ba thobalano (rat)Pfaus le Everitt, 1995). Ho feta moo, lipatlisiso tsa maqheka a DA li bontša hore bahanyetsi ba DA ba NAC ba thibela boitšoaro ba ho kopanela liphate, athe li-agonist li thusa ho qalisoa ha boitšoaro bo bobe ba ho kopanela liphater (Everitt et al., 1989, Pfaus le Phillips, 1989). Kahoo, Meth e ka ama tšusumetso ea boitšoaro bo bobe ba thobalano ka ho kenyelletsa li-receptors tsa DA.

Ho fapana le NAC, palo ea lisele tse peli tse ngotsoeng ka BLA le ACA li ile tsa sala li sa fetohe ho sa tsotellehe tekanyo ea Meth. BLA ke ea bohlokoa bakeng sa thuto e kopanetsoeng e hlophisitsoeng 'me e ameha ka matla ho tiisetsoeng ka boemo bo hlophisitsoeng le ho putsa tekanyetso nakong ea ho arabela lipapali (Everitt et al., 1999, Cardinal le al., 2002, Bona, 2002). BLA e hlakotsweng litoeba e bontša ho fokotseha ha sebete ho qobella mokhoa o tsitsitseng oa ho ja lijo (Everitt et al., 1989) kapa ho matlafatsa thobalano (Everitt et al., 1989, Everitt, 1990). Ka lehlakoreng le leng, ho qhekella hona ha ho ame karolo ea ho fepa le boitšoaro ba thobalano (Cardinal le al., 2002). BLA e boetse e phetha karolo ea bohlokoa mohopolong oa tšusumetso e tloaelehileng e amanang le tšitiso ea lithethefatsi (Grace le Rosenkranz, 2002, Laviolette le Grace, 2006). Likokoana-hloko kapa mekhoa ea phekolo ea meriana ea BLA e thibela ho fumana (Whitelaw et al., 1996) le polelo (Grimm le See, 2000) ho tsosolosoa ha cocaine e kentsoeng hantle, ha e sa ame mokhoa oa tsamaiso ea lithethefatsi. Ho feta moo, Amph e kentse ka ho toba ho BLA e hlahisang ts'ebeliso ea lithethefatsi e ka 'nang ea e-ba teng ka pel'a botumo ba litlamorao (Sheba le al., 2003). Ka lebaka leo, ho ka etsahala hore phetoho ea DA ea psychostimulant e ntlafetseng ka BLA e fella ka ho ba le boikutlo bo matla ba maikutlo le ho batla (Ledford et al., 2003) ea moputso oa ho kopanela liphate, ka tsela eo ho tlatsetsa ho matlafatsong ea thobalano le takatso e tlalehiloeng ke balekane ba Meth (Semple et al., 2002, Green le Halkitis, 2006).

A ACA, ts'ebetso ea neural ea li-neurons tse sebelisitsoeng ho kopanela liphate e ne e le e ikemetseng le e khethehileng bakeng sa Meth, kaha e ne e sa hlokomeloe le Amph. Le hoja Meth le Amph li na le mekhoa e tšoanang le ea metsoako ea meriana, Meth ke psychostimulant e matla haholo ho feta Amph e nang le nako e telele (NIDA, 2006). Liphuputso tsa Goodwin le al. o bontšitse hore Meth e hlahisa DNA e kholoanyane le e thibelang ho tlosoa ha DA sebakeng seo ka katleho ka katleho ea NAc ho feta Amph. Litšobotsi tsena li ka kenya letsoho ho matla a ho lemalla Meth ho bapisoa le Amph (Goodwin le al., 2009) 'me mohlomong ho se tšoane ha li-neural ho sebelisoa pakeng tsa lithethefatsi tse peli. Leha ho le joalo, ha ho hlake hore na liphetoho tse fapaneng tsa liphello li bakoa ke phapang ea katleho pakeng tsa lithethefatsi kapa lipotso tsa potency tse amanang le litekanyetso tse sebelisitsoeng le lipatlisiso tse ling li hlokahalang.

Tšebelisano-'moho le Meth le thobalano ha lia ka tsa hlokomeloa libakeng tse ling tsa mPFC (IL le PL). Hape, ACA e 'nile ea ithuta ka hohle ka mesebetsi e matlafatsang, e tšehetsa karolo ea lihlopha tse tsosang takatso ea li-stimulus-reinforcer (Everitt et al., 1999, Bona, 2002, Cardinal le al., 2003). Ho na le bopaki bo bongata ba hore mPFC e ameha litakatsong tsa lithethefatsi le ho khutlela mokhoeng oa ho batla lithethefatsi le ho sebelisa lithethefatsi ho batho le likhoto (Grant et al., 1996, Childress et al., 1999, Capriles et al., 2003, McLaughlin le See, 2003, Shaham le al., 2003, Kalivas le Volkow, 2005). KeHa ho joalo, ho 'nile ha etsoa tlhahiso ea hore mPFC e se ke ea sebetsoa ka lebaka la ho pepeseha lithethefatsi tsa tlhekefetso e ka ba le boikarabello ba ho fokotsa ho laola maikutlo le ho eketsa boitšoaro bo tsamaisoang ke lithethefatsi joalokaha ho boleloa ke batho ba bangata ba lemaletseng lithethefatsi (Jentsch le Taylor, 1999). Litaba tsa morao-rao tse tsoang laboratori ea rona li bontšitse hore mPFC lisosa phello ea ho tsoela pele ho batla boitšoaro ba thobalano ha sena se ne se amahanngoa le ts'oaetso e tsitsitseng (Davis et al., 2003). Le hoja thuto ena e sa ka ea batlisisa ACA, e tšehetsa khopolo ea hore mPFC (le ACA ka ho khetheha) li phelisana le liphello tsa Meth ka ho lahleheloa ke taolo ea ho thibela ho kopanela liphate joalokaha ho tlalehoa ke balekane ba Meth (Salo et al., 2007).

Qetellong, liphuputso tsena hammoho li theha mohato oa pele oa ho utloisisa hantle hore na lithethefatsi tsa tlhekefetso li etsa joang litseleng tsa neural tse tloaelehileng ho sebelisana le meputso ea tlhaho. Ho feta moo, liphuputso tsena li bontša hore ho fapana le tumelo ea morao-rao ea hore lithethefatsi tsa tlhekefetso ha li lumelle lisele tse ts'oanang le mahlaseli a tlhaho e le moputso oa tlhaho, Meth, le ka tlaase ho Amph, etsa lisele tse tšoanang le boitšoaro ba thobalano. Ka lehlakoreng le leng, li-neural activated-neural populations li ka susumetsa ho batla ka moputso oa tlhaho ka mor'a ho hlahisa lithethefatsi. Qetellong, liphello tsa thuto ena li ka kenya letsoho haholo kutlong ea rona ea ho lemala ka kakaretso. Litšoantšiso tsa ho tšoana le ho se tšoane, hammoho le liphetoho tsa ho sebelisoa ha neural ea tsamaiso ea mesoli e entsoeng ka boitšoaro ba ho kopanela liphate le lithethefatsi tsa tlhekefetso e ka lebisa kutloisisong e ntlafetseng ea lithethefatsi tse mpe le liphetoho tse amanang le moputso oa tlhaho.

lumela hore baa fokola

Phuputso ena e ne e tšehetsoa ke lichelete tse tsoang ho Mekhatlo ea Sechaba ea Bophelo ba R01 DA014591 le Mekhatlo ea Mokhatlo oa Bophelo ba Bophelo ea RN 014705 ho LMC.

BOPHELO

  • ABC
  • avidin-biotin-horseradish peroxidase complex
  • ACA
  • anterior cingulate sebakeng seo
  • Amph
  • d-amphetamine
  • BLA
  • basolateral amygdala
  • BNSTpl
  • setsi sa bolulo se ka morao-rao sa stria terminalalisalis
  • BNSTpm
  • mokokotlo oa bethe oa setho sa stria terminalis
  • BT
  • biotinylated tyramide
  • CeA
  • lekholo la li-amygdala
  • CPP
  • sebaka seo ho khetholloang sebaka ka sona
  • E
  • ho khaola
  • EL
  • latency latency
  • IF
  • infralimbic sebakeng seo
  • IL
  • latency latency
  • IM
  • ho kenya letsoho
  • M
  • thabeng
  • MAP Kinase
  • protein kinase e entsoeng ka metogen
  • MEApd
  • li-amygdala tsa morao-rao
  • Methi
  • methamphetamine
  • ML
  • thaba ea latency
  • mPFC
  • khetho ea lipere tsa libaka
  • MPN
  • mokokotlo oa mehleng ea boholo-holo
  • NAc
  • nucleus e kopane
  • PB
  • phosphate buffer
  • PBS
  • saline ea phosphate e nooang
  • PEI
  • nako ejaculatory post
  • PERK
  • MAP Kinase ea phosphorylated
  • PL
  • sebaka sa prelimbic
  • VTA
  • sebaka sa ventral tegmental

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.

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