I-Methamphetamine yenza izinto ezincane ze-neurons ezilawula ukuziphatha kobulili kumagundane wesilisa (2010)

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

Frohmader KS, Wiskerke J, I-RA ehlakaniphile, Lehman MN, Coolen LM.

Umthombo

Umnyango we-Anatomy ne-Cell Biology, iScluch School of Medicine kanye namaDentistry, iNyuvesi yaseWestern Ontario, eLondon, ON, Canada, N6A 5C1.

abstract

I-Methamphetamine (i-Meth) ishukumisa kakhulu umlutha. Ukuhlukunyezwa kwe-Meth kuvame ukuhlotshaniswa nomkhuba wokuziphatha ngengozi ngokocansi kanye nokukhula kwesibalo se-Human Immunodeficiency Virus kanye nabasebenzisi be-Meth kubika isifiso sobulili, ukuvusa kanye nokuzijabulisa kocansi. Isisekelo sezinto eziphilayo zalesi sidakamizwa sobulili ocansini asiziwa. Ukutadisha kwamanje kubonisa ukuthi ukuphathwa kweMeth kumagundane abesilisa kusebenza ama-neurons ezindaweni ezibucayi zesistimu ye-mesolimbic ehilelekile ekulawuleni ukuziphatha ngokobulili. Ngokuqondile, i-Meth nokuxhuma kusebenze amaseli ku-core nucleus accumbens core kanye negobolondo, amolgala e-basolateral, ne-anterior cingulate cortex. Lokhu kutholakala kubonisa ukuthi ngokungafani nenkolelo yamanje izidakamizwa zokuhlukunyezwa kungenza kusebenze amaseli afana nokuqinisa imvelo, lokho kuziphatha ngokocansi, futhi kungase kuthonye ukufuna okuphoqelekile kwalokhu umvuzo wemvelo.

Amagama angukhiye: i-nucleus accumbens, i-amygdala ye-basolateral, i-prefrontal cortex, ukusetshenziswa kabi kwezidakamizwa, ukukhiqiza, ukulutha umlutha

Ukugqugquzela kanye nomvuzo kulawulwa uhlelo lwe-mesolimbic, inethiwekhi ehlangene yezindawo zobuchopho ezakhiwe endaweni ye-ventral tegmental (VTA) nucleus accumbens (NAc), i-basolateral amygdala, kanye ne-prefrontal cortex (mPFC) yangaphakathiKelley, 2004, Kalivas noVolkow, i-2005). Kukhona ubufakazi obuningi bokuthi uhlelo lwe-mesolimbic lusetshenziswa ekuphenduleni kokubili izinto zokuhlukunyezwa (I-Di Chiara ne-Imperato, i-1988, Chang et al., 1997, I-Ranaldi et al., I-1999) nokuziphatha okuvuzayo ngokwemvelo njengokuziphatha kocansi (Fiorino et al., 1997, I-Balfour et al., I-2004). Ukuziphatha ngokobulili ngokobulili, futhi ikakhulukazi ukujula, kuvuzisa kakhulu futhi kuqiniswe ezithombeni zezilwane (I-Pfaus et al., I-2001). Amagundane angamadoda ahlakulela indawo yokuhlala (conditional place preference) (CPP) yokubhekana nayo (I-Agmo no-Berenfeld, i-1990, U-Martinez no-Paredes, i-2001, I-Tenk, i-2008), futhi uzokwenza umsebenzi osebenzayo ukuze uthole ukufinyelela kwesifazane wesifazane othola ucansi (Everitt et al., 1987, Everitt no-Stacey, i-1987). Izidakamizwa zokuhlukumeza zibuye zizuzise futhi ziqinise, futhi izilwane zizofunda ukuzitholela izinto zokuhlukunyezwa, okubandakanya ama-opiates, i-nicotine, u-alcohol, nama-psychostimulants (Ohlakaniphile, 1996, Pierce noKumaresan, i-2006, I-Feltenstein ne-See, i- 2008). Nakuba kwaziwa ukuthi kokubili izidakamizwa zokuhlukunyezwa nokuziphatha ngokocansi kuvuselela izindawo zengqondo zobuchopho, okwamanje akucaci ukuthi izidakamizwa zokuhlukunyezwa zithinta izinkanyezi ezifanayo ezixhumanisa ukuziphatha ngokobulili.

Ucwaningo lwe-electrophysiological lubonise ukuthi ukudla kanye ne-cocaine kokubili kusebenze i-neurons ku-NAc. Kodwa-ke, lezi ziqinisi ezimbili azivuli amaseli afanayo ngaphakathi kwe-NAc (I-Carelli et al., 2000, U-Carelli no-Wondolowski, i-2003). Ngaphezu kwalokho, ukudla nokunciphisa ukuzilawula akubangeli ukuguqulwa kwesikhathi eside kwemishini ye-electrophysiological njengoba kubangelwa i-cocaine (Chen et al., 2008). Ngokuphambene nalokho, ukuqoqwa kobufakazi kubonisa ukuthi ukuziphatha ngokobulili wesilisa kanye nezidakamizwa zokuhlukunyezwa kungase kwenzeke ngempela kwi-neurons efanayo ye-mesolimbic. Ama-Psychostimulants nama-opioid ashintsha indlela yokuziphatha ngokobulili kumagundane angamadoda (UMitchell noStewart, i-1990, I-Fiorino no-Phillips, i-1999a, I-Fiorino no-Phillips, i-1999b). Idatha yakamuva evela ebhodini lethu yabonisa ukuthi isipiliyoni sezocansi sishintsha ukuphendula kuma-psychostimulants njengoba kuboniswa izimpendulo ezithintekayo zokuvakasha kanye nokuqonda okuvezwe umvuzo ku-d-amphetamine ezilwaneni ezibhekene nocansi (Pitchers et al., 2009). Impendulo efanayo iye yaboniswa ngaphambilini ngokuchayeka ngokuphindaphindiwe kwe-amphetamine noma ezinye izidakamizwa zokuhlukunyezwa (I-Lett, i-1989, U-Shippenberg no-Heidbreder, i-1995, Shippenberg et al., 1996, I-Vanderschuren ne-Kalivas, i-2000). Ngokubodwa, lezi zithole ziphakamisa ukuthi ukuziphatha ngokocansi kanye nezimpendulo ezidakamizwa zokuhlukunyezwa zihanjiswa yi-neurons efanayo ohlelweni lwe-mesolimbic. Ngakho-ke, inhloso yokuqala yesifundo samanje ukuphenya ukusebenza kwe-neural ye-eyelimbic system ngokuziphatha ngokocansi nokuphathwa kwezidakamizwa esilwaneni esifanayo. Ngokuyinhloko, sivivinye ukucabanga ukuthi i-psychostimulant, i-methamphetamine (i-Meth), yenza ngokuqondile kwi-neurons evame ukuxhumanisa ukuziphatha ngokocansi.

I-Meth ingenye yezidakamizwa ezingekho emthethweni kakhulu emhlabeni (i-NIDA, i-2006, i- U-Ellkashef et al., 2008) futhiNgiye njalo ihlotshaniswa nokuziphatha kocansi okushintshiwe. Ngokuthakazelisayo, abasebenzisi beMeth babika isifiso sobulili ephakeme futhi bavusa, kanye nokuthokozisa ngokocansi okuthuthukisiwe (Semple et al., 2002, Schilder et al., 2005). Ngaphezu kwalokho, Ukuhlukunyezwa kwe-Meth kuvame ukuhlotshaniswa nokuziphatha kocansi (Rawson et al., 2002). Abasebenzisi bavame ukubika ukuthi banabalingani abaningi bezocansi futhi bancane amathuba okusebenzisa ukuvikelwa kunabanye abahlukumeza izidakamizwa (Somlai et al., 2003, Springer et al., 2007). Ngeshwa, ukuhlola okubonisa ukuthi i-Meth isebenzisa njengendlela yokuziphatha engozini ngokobulili inqunyelwe njengoba incike ekuzikeleni kwemibiko engaqinisekisiwe (U-Elifson et al., 2006). Ngakho-ke, uphenyo olusungulwa ngamaselula lwezinguquko ezenziwa nguMeth ekuziphatheni ngokocansi ngesimo semfuyo kuyadingeka ukuze uqondisise le nkinga yokuxilonga izidakamizwa zocansi.

Ngenxa yalokho okushiwo ngenhla okubonisa ukuthi izidakamizwa zokuhlukunyezwa, ikakhulukazi i-Meth, zingase zisebenze nge-neurons evame ukuhileleka ekuxhumaniseni ukuziphatha ngokocansi, inhloso yesifundo samanje kwakuwukuphenya ukusebenza kwe-neural ngokuziphatha kobulili nokuphathwa kwe-psychostimulant Meth. Lolu cwaningo luqalise uhlelo lwe-neuroanatomical, lusetshenziselwa ukuboniswa kwe-immunohistochemical yezinhlobo zokuqala zezinhlobo ze-Fos ne-Phosphorylated Map Kinase (pERK) ukuze kutholakale ukusebenza kwe-neural ngokuvumelana nokuziphatha kocansi kanye ne-Meth ngokulandelanayo. I-Fos iboniswa kuphela ngaphakathi kwe-nucleus yamaseli, enezinga eliphezulu lokuveza izinga elingu-30-90 ngemva kokusebenza kwe-neuron. Kunobufakazi obuningi bokuthi izenzo zocansi zenza ukukhulunywa kwe-Fos ebuchosheni (U-Pfaus no-Heeb, i-1997, I-Veening ne-Coolen, i-1998), kuhlanganise uhlelo lwe-mesocorticolimbic (URobertson et al., I-1991, I-Balfour et al., I-2004). Kukhona nobufakazi bokuthi izidakamizwa zokuhlukumeza zenza ukukhulumisana kwe-PERK ngaphakathi kwesistimu ye-mesocorticolimbic (U-Valjent et al., 2000, U-Valjent et al., 2004, U-Valjent et al., 2005). Ngokungafani nenkulumo ye-Fos, i-phosphorylation ye-ERK iyinqubo eguquguqukayo kakhulu futhi ivele ngemva kwemizuzu engu-5-20 ngemuva kokusebenza kwe-neuronal. Amaphrofayli aphansi we-Fos ne-PERK abenza kube isethi ekahle yamakaki okwenziwa kusebenze nge-neuronal ngezinqubo ezimbili ezahlukene.

IMISEBENZI YOKUPHAKATHI

Tifundvo letifundvwa

Amantombazane amadala aseSprague Dawley (i-210-225 g) atholakala kuCharles River Laboratories (Montreal, QC, Canada) ayehlala emizileni emibili ngamakamelo ajwayelekile e-plexiglas cage (amakheji asekhaya). Igumbi lesilwane lagcinwa ku-12 / 12 h umjikelezo wokukhanya ovuliwe (ukhanyisa ku-10.00 h). Ukudla namanzi kwakutholakala isikhangiso. Konke ukuhlolwa kwenziwa ngesikhathi sokuqala kwesigaba somnyama ngaphansi kokukhanya okubomvu okubomvu. Ama-stimulus females asetshenziselwa ukuziphatha ngokocansi ayenziwa ngama-ovariectomized ngaphansi kwe-anesthesia ejulile (i-13 mg / kg ketamine ne-87 mg / kg xylazine) futhi athola ukufakelwa okungaphansi kwe-5% estradiol benzoate (EB) ne-95% ye-cholesterol. Ukwamukelwa ngokocansi kwabangelwa ukuphathwa okungaphansi kwe-500 μg progesterone ku-0.1 ml i-sesame oil 4 h ngaphambi kokuhlolwa. Yonke inqubo yamukelwa yiKomiti Yezokulondwa Kwezilwane eNyuvesi yaseWestern Ontario futhi iyavumelana neziqondiso ezichazwe yiCanada Council on Animal Care.

Imiklamo yokuhlola

Ukuhlolwa kwe-1 ne-2: Amagundane angamadoda (n = 37) avunyelwe ukuba abambisane nowesifazane obamukelekayo ku-ejaculation eyodwa (E) noma i-30 min, eyake yafika kuqala emaceleni okuhlola ahlanzekile (60 × 45 × 50 cm) phakathi kwamahlanu kabili -ukuhlola ngaphambi kokuhlola ukulinganisa, ukuthola okuhlangenwe nakho kocansi. Phakathi nezikhathi ezimbili zokugcina, yonke imingcele ejwayelekile yokusebenza ngokocansi ibhalwe phansi, kufaka phakathi: ukuphakama kwe-latency (i-ML; isikhathi kusukela kokusungulwa kwesifazane kuze kube sekuthomeni kokuqala), i-latency intromission (i-IL; isikhathi kusukela kokusungulwa kwesifazane kuze kufike kuqala ukungena kwesisu), i-ejaculation latency (i-EL; isikhathi kusukela ekungeneni kokuqala ukuya ekujuleni), isikhathi sokuthunyelwa kwe-ejaculation (i-PEI; isikhathi esivela ejaculation kuya kokungeniswa kokuqala okulandelayo), inani lezintaba (M), nenombolo ye-intromissions (IM) (I-Agmo, i-1997). Bonke abesilisa bathola injection yansuku zonke ye-1 ml / kg ye-0.9% NaCl (usawoti; sc) Izinsuku ezingu-3 ezilandelanayo ngaphambi kosuku lokuhlola, ukujwayela ukuphatha nokujova. Ngolunye usuku ngaphambi kosuku lokuhlolwa, bonke abesilisa babehlala bengashadile. Emadodeni abanolwazi, i-Fos ingaxoshwa ngemibono ehambisana nesimo esithintekayo ehlangene nesipiliyoni sangaphambi kocansi (I-Balfour et al, i-2004). Ngakho-ke, konke ukulingana nokulawula ukuphathwa ngesikhathi sokuhlolwa kokugcina kwenziwa enkampanini yasekhaya (gwema izinhlamvu ezibikezelayo) ukuvimbela ukukhishwa okufakwe emgodini ekusebenziseni ekusebenzeni kwamadoda angabonakali. Amadoda asatshalaliswa emaqenjini ayisishiyagalombili okuhlola awazange ahluke kunoma yiliphi isilinganiso sokusebenza kocansi ngesikhathi sokugcina kokubili kokulinganisa (idatha engaboniswa). Phakathi novivinyo lokugcina, abesilisa babevunyelwe ukuba bahlanganyele emakhayeni abo ekhaya kuze kube yilapho bebonisa ukukhipha (ubulili) noma bangatholi umlingani wesifazane (akukho ocansini). Bonke abesilisa abathintekayo baphuthumiswe imizuzu ye-60 ngemuva kokuqala kokulinganisa ukuze kuvumele ukuhlaziywa kwe-Fos-inkulumo ekhonjisiwe. Amadoda athola umjovo we-4 mg / kg Meth noma i-1 ml / kg saline (sc) (n = 4 ngayinye), noma i-10 (ukuhlolwa kwe-1) noma i-15 (ukuhlolwa kwe-2) iminithi ngaphambi kokukhipha, ukuhlaziywa kwe-phosphorylation eyenziwe yizidakamizwa of MAP kinase. Isilinganiso nesikhathi ngaphambi kokukhishwa kwamandla kusekelwe emibikweni yangaphambilini (Choe et al., 2002, Choe no-Wang, i-2002, U-Chen no-Chen, i-2004, Mizoguchi et al., 2004, Ishikawa et al., 2006). Amaqembu wokulawula afaka abesilisa abangazange baxoxe, kodwa bathola i-Meth 10 (n = 7) noma i-15 (n = 5) iminithi ngaphambi kokunikela, noma ama-saline injection 10 (n = 5) noma i-15 (n = 4) min ngaphambi komhlatshelo . Ukulandela umhlatshelo, ubuchopho babucubungula nge-immunohistochemistry.

Ukuzama i-3: Njengoba isilinganiso seMeth esasetshenziselwa ukuhlola i-1 ne-2, kwenziwa ukuhlolwa okwenziwe nge-neuroanatomical ukuhlola ukuthi ukuziphatha ngokobulili nomthamo we-Meth ophansi kwenza yini amaphethini axhomeke kumthamo we-activation neural activation. Lolu cwaningo lwenziwe ngendlela efanayo nokuhlolwa kwe-1 ne-2. Kodwa-ke, ekuhlolweni kokugcina, amaqembu aphikisiwe kanye nama-nonmated (n = 6 ngamunye) athola i-1 mg / kg Meth (sc) i-15 min ngaphambi kokunikela.

Ukuhlola i-4: Ukuze uhlole ukuthi ukusebenza kwe-neural okubangelwa ubulili kanye ne-Meth kubhekisela ngqo ku-Meth, lolu cwaningo lucwaningo ukuthi ngabe amaphethini afanayo we-activated neural activation angabonwa yini ne-psychostimulant d-amphetamine (Amph). Lokhu kuhlolwa kwenziwa ngendlela efanayo nokuhlolwa kwe-1 ne-2. Kodwa-ke, ekuvivinyweni kokugcina, abesilisa babephathwa ngokuthi i-Amph (5 mg / kg) noma i-saline (1 mg / kg) (sc) i-15 min ngaphambi komhlatshelo (n = 5 ngamunye). Lawula abesilisa abangenalutho abathola ama-saline noma amaminithi angu-Amph 15 ngaphambi komhlatshelo. Ukubuka kabanzi kwamaqembu okuhlola asetshenziselwa ukuhlola i-1-4 inikeziwe Ithebula 1.

Ithebula 1      

Uhlolojikelele kwamaqembu okuhlola afakiwe ezivivinyweni 1-4.

Ukulungiselela izicubu

Izilwane zazixoshwa nge-pentobarbital (270 mg / kg; ip) futhi zenziwe kabi nge-transcardially ne-5 ml ye-saline zilandelwa yi-500 ml 4% ye-paraformaldehyde ku-0.1 M phosphate buffer (PB). Ama-Brains asusiwe futhi alondolozwe kabusha ku-1 h ekamelweni lokushisa endaweni efanayo, bese efakwe ku-20% sucrose no-0.01% Sodium Azide ku-0.1 M PB futhi agcinwe ku-4 ° C. Izigaba ze-Coronal (35 μm) zazinqunywa ezincane ze-microtome (i-H400R, i-Micron, eJalimane), iqoqwe ngochungechunge olunezinhlangothi ezine eziyisixazululo se-cryoprotectant (30% sucrose ne-30% ethylene glycol ku-0.1 M PB) futhi igcinwe ku-20 ° C kuze kube yilapho ukucubungula.

Immunohistochemistry

Zonke izifubhu zenziwa ngaphakathi ekamelweni lokushisa nge-agitation. Izigaba ezihambayo zamahhala zahlanzwa kakhulu nge-0.1 M Phosphate-buffered-saline (PBS) emkhatsini wokukhulelwa. Izigaba zafakwa ngaphakathi ku-1% H2O2 ye-10 min, bese ivinjelwe kwisisombululo sokufakwa ngaphakathi (i-PBS equkethe i-0.1% ye-serum albin ne-0.4% Triton X-100) ye-1 h.

pERK / Fos

I-tissue yayisetshenziswe ngobusuku obunamaphilisi we-polyclonal onogwaja ngokumelene ne-p42 ne-p44 imephu ye-kinases ERK1 no-ERK2 (pERK; 1: 400 ukuhlolwa kwe-1 lot 19; 1: ukuhlolwa kwe-4.000 2 ne-3 lot 21; I-Cat Signaling Cat # 9101;), ilandelwa I-1 h incubations ne-IgG anti-rabbit IgG (1: 500; i-Jackson Immunoresearch Laboratories, i-West Grove, i-PA) kanye ne-avidin-horseradish i-peroxidase complex (i-ABC Elite; i-1: i-1000; i-Vector Laboratories, i-Burlingame, i-CA). Khona-ke, izicubu zafakwa emaminini angu-10 nge-tyramide e-biotinylated (BT; 1: 250 ku-PBS + 0.003% H2O2; I-Tyramid Signal Amplification Kit, i-NEN Life Sciences, i-Boston, MA) kanye ne-30 min nge-Alexa 488 conjugated strepavidin (i-1: i-100; i-Jackson Immunoresearch Laboratories, i-West Grove, i-PA). Okulandelayo, izicubu zakhiwe ngobusuku obuseduze nomuntu onogwaja we-rabbit polyclonal ngokumelene ne-c-Fos (i-1: i-500; i-SC-52; i-Santa Cruz Biotechnology, i-Santa Cruz, i-CA), ilandelwa i-30 min incubation nembuzi elwa no-rabbit Alexa 555 (1: 200; Jackson Immunoresearch Laboratories, West Grove, PA). Ukulandela ukubola, izigaba zahlanzwa kahle ku-0.1 M PB, zifakwe kuma-slides e-glass nge-0.3% gelatin ku-ddH2I-0 futhi ihlanganiswe nge-aqueous mounting medium (Gelvatol) ene-anti-fading agent i-1,4-diazabicyclo (2,2) octane (i-DABCO; i-50 mg / ml, i-Sigma-Aldrich, iSt. Louis, MO). Ukulawulwa kwama-immunohistochemical kufaka phakathi ukungabikho kokubili kwamagciwane okuqala noma okubili okuholela ekungabikho kwe-labeling ku-wevelength efanelekile.

Ukuhlaziya Data

Ukuziphatha ngokocansi

Kuzo zonke izivivinyo ezine, imingcele ejwayelekile yokusebenza kocansi ibhalwe njengoba ichazwe ngenhla futhi ihlaziywe ngokusebenzisa ukuhlaziywa kokuhluka (ANOVA). Ukuhlaziywa kwedatha kokuziphatha ngokocansi ngesikhathi sokuhlolwa kokugcina akuvezwanga umehluko omkhulu phakathi kwamaqembu kunoma imiphi imingcele yokusebenza ngokocansi.

I-PERK / Fos Cell Counts

Amangqamuzana angabodwa namabhulogi aqoshiwe we-Fos ne-PERK abalwa emazingeni e-caudal we-NAc core kanye ne-sub-regions, i-basolateral amygdala (i-BLA), i-amygdala ye-posterodorsal yomphakathi (MEApd), i-amygdala emaphakathi (CeA), i-nucleus yangaphakathi emaphakathi (i-MPN), i-posteromedial i-nucleus ye-bedraolateral ye-stria terminalis (i-BNSTpm ne-BNSTpl), ne-anterior cingulated area (ACA), i-prelimbic (PL), ne-infralimbic (IL) ezingaphansi kwe-mPFC. Izithombe zithunjiswe ngokusebenzisa ikhamera yeCCD ehlile (Microfire, Optronics) exhunywe kwi-microscope yeLeica (DM500B, Leica Microsystems, Wetzlar, eJalimane) kanye ne-Neurolucida software (MicroBrightfield Inc) ngezilungiselelo ezihambile zekhamera kuzo zonke izifundo (usebenzisa izinhloso ze-10x). Ukusebenzisa isofthiwe ye-neurolucida, izindawo zokuhlaziywa zachazwa ngokusekelwe emigqumeni (U-Swanson, i-1998) esiyingqayizivele esifundeni ngasinye sobuchopho (bheka Umfanekiso we-1). Izindawo ezijwayelekile zokuhlaziywa zazisetshenziswa kuzo zonke izindawo ngaphandle kwe-NAc core kanye negobolondo. Kulezi zindawo zokugcina, ukukhuluma kwe-PERK ne-Fos kwakungavumelani futhi kuvele kumaphethini afana nama-patch. Ngakho-ke, wonke umgogodla kanye negobolondo baboniswe ngokusekelwe emigqumeni yezimpawu (i-ventricle lateral, ukuzijabulisa kwangaphakathi, neziqhingi zaseCalleja). Izindawo zokuhlaziya azifani phakathi kwamaqembu okuhlola, futhi zaziyi-1.3 mm2 ku-NAc core kanye negobolondo. Izindawo ezijwayelekile zokuhlaziywa kwezindawo ezisele ziyi: 1.6 mm2 ku-BLA, i-2.5 ne-2.25 mm2 ku-MEApd ne-CeA ngokulandelana, i-1.0 mm2 ku-MPN, i-1.25 mm2 ema-subregion we-BNST ne-MPFC, no-3.15 mm2 ku-VTA. Izigaba ezimbili zabalwa ngokubambisana endaweni yesiguli ngasinye ngesilwane ngasinye, futhi inani lamangqamuzana angashadile namabili aqoshiwe we-PERK ne-Fos kanye namaphesenti ama-PERK amangqamuzana aveza umaka we-Fos ayebalwa. Ukuhlolwa kwe-1, i-2, ne-4, izilinganiso zeqembu zaziqhathaniswa zisebenzisa izindlela ezimbili ze-ANOVA (izici: ukulingana nomuthi) kanye ne-Fisher's LSD i-post hoc ukuqhathanisa ezingeni elibalulekile le-0.05. Ukuhlolwa kwe-3, izilinganiso zeqembu zaziqhathaniswa zisebenzisa ukuhlola okungapheli kahle kwezinga le-0.05.

Umfanekiso we-1      

Imidwebo yesimiso nemifanekiso ekhombisa izindawo zobuchopho zokuhlaziywa. Izindawo zokuhlaziywa zikhonjisiwe zisekelwe emigqumeni yezindawo eziyingqayizivele esifundeni ngasinye sobuchopho, azifani phakathi kwamaqembu okuhlola, futhi zaziyi-1.25 mm2 ema-subregions (a), i-1.3 mm2 ku ...

Izithombe

Izithombe zedijithali Umfanekiso we-3 bathunjwa besebenzisa ikhamera ye-CCD (i-DFC 340FX, i-Leica) enamatheksikidi ye-Leica (DM500B) futhi yangeniswa kwi-Adobe Photoshop 9.0 software (Adobe Systems, San Jose, CA). Izithombe azishintshe nganoma iyiphi indlela ngaphandle kokulungiswa kokukhanya.

Umfanekiso we-3      

Izithombe ezimele ze-NAc ezingenayo i-Fos (red, a, d, g, j) kanye ne-PERK (eluhlaza; b, e, h, k) yezilwane zeqembu ngalinye lokuhlola: Akukho Sex + Sal (a, b, c) , Sex + Sal (d, e, f), Awukho ucansi + Meth (g, h, i), no-Sex + Meth (j, k, l). Amapaneli angakwesokudla ...

IZIPHUMA

Ukusebenza kwe-Neural ye-Limbic System ngokuziphatha kocansi nokuphathwa kwe-Meth

Isivivinyo i-1: Ukuhlaziywa kwamaseli angashadile aqoshiwe abanjwe amaFos ne-Meth-induced pERK kumadoda athola imizuzu ye-Meth 10 ngaphambi komhlatshelo wembula i-Fos eyenziwe ngokulinganayo ku-MPN, BNSTpm, NAc core kanye negobolondo, i-BLA, i-VTA, kanye nayo yonke imibuso ye-mPFC, ehambisana nezifundo zangaphambili ezibonisa ukuboniswa kwe-Fos okufakwe ekuhlanganyeleni kulezi zindawo (I-Baum no-Everitt, i-1992, U-Pfaus no-Heeb, i-1997, I-Veening ne-Coolen, i-1998, Hull et al., 1999). Ukuphatha i-Meth imizuzu engu-10 ngaphambi kokunikela ngomhlatshelo e-NAc core kanye negobolondo, i-BLA, MeApd, i-CeA, i-BNSTpl, kanye nezifunda ze-mPFC, ehambisana namaphethini wokusebenza eyenziwe amanye ama-psychostimulants (U-Valjent et al., 2000, U-Valjent et al., 2004, U-Valjent et al., 2005).

Ngaphezu kwalokho, amaphethini amathathu okubambisana kwe-neural ngokusebenzisa ukuziphatha ngokocansi kanye ne-Meth yaqaphela: Okokuqala, izindawo zengqondo zahlonishwa lapho ubulili nezidakamizwa zisebenzisana nabantu abangahlanganisi izidakamizwa ze-neural (Ithebula 2). Ngokuqondile, ku-CeA, MEApd, BNSTpl, ne-mPFC, ukwanda okuphawulekayo kuzo zombili izidakamizwa ezenziwe ngomuthi (F (1,16) = 7.39-48.8; p = 0.015- <0.001) kanye ne-Fos eyenziwe ngocansi (F (1,16, 16.53) = 158.83-0.001; p <1,16) kubonwe. Kodwa-ke, kulezi zifunda bekungekho ukunyuka okuphawulekayo kuma-neuron amabili afakwe ilebula emadodeni aphethwe yi-Meth. Okuwukuphela kokuhlukile kwakuyi-MEApd, lapho kutholakala umphumela wokuqhathanisa ezinombolweni zamaseli amabili anelebula (F (9.991) = 0.006; p = XNUMX). Kodwa-ke, bekungekho mphumela ophelele wokwelashwa kwezidakamizwa kanye nokulebula okubili emaqenjini aphethwe yi-Meth bekungekho phezulu kakhulu kunakwamaqembu aphathwa ngosawoti, ngakho-ke akubangekanga ngenxa yesidakamizwa (Ithebula 2). Okwesibili, izindawo zobuchopho zikhonjiswe lapho ukusebenza kwe-neural kungenziwa kuphela ngokulingana (Ithebula 3). Ngokucacile, i-MPN, i-BNSTpm, ne-VTA yenziwe ngokuvuthwa kuphela, futhi iqukethe ukunyuka okuphawulekayo ku-Fos eyenziwe ngokulinganisa (F (1,16) = 14.99-248.99; p ≤ 0.001), kodwa akukho meth-induced pERK.

Ithebula 2      

Uhlolojikelele lwe-Fos ne-Meth-induced expression expression in izingxenye zobuchopho lapho ubulili nezidakamizwa kusebenze khona abantu abangahlangene ne-neural.
Ithebula 3      

Uhlolojikelele lwe-Fos ne-Meth-induced expression pERK ezindaweni ezibucayi lapho ukusebenza kwe-neural kukhishwe kuphela ngokulingana.

Ekugcineni, izindawo zobuchopho zitholakala lapho ubulili nezidakamizwa zisebenzisela khona izixuku ze-neurons (Umfanekiso we-2 futhi Ne -3) .3). Kumgogodla we-NAc negobolondo, i-BLA, ne-ACA, kube nemiphumela ephelele yokuhlangana (F (1,16) = 7.87-48.43; p = 0.013- <0.001) kanye nokwelashwa kwezidakamizwa (F (1,16) = 6.39– 52.68; p = 0.022- <0.001), kanye nokuxhumana phakathi kwalezi zinto ezimbili (F (1,16) = 5.082-47.27; p = 0.04- <0.001; akukho ukuxhumana okuphawulekayo ku-ACA) ezinombolweni zamaseli aveza zombili I-FOS ne-Meth eyenziwe nge-Mat. Ukuhlaziywa kwe-Post hoc kuveze ukuthi izinombolo zama-neuron amabili afakwe ilebula ayephakeme kakhulu emadodeni ajovwe ngeMeth uma kuqhathaniswa nokwelashwa kweMeth (p = 0.027- <0.001), noma okwenziwe ngosawoti (p = 0.001- <0.001) abesilisa (Umfanekiso we-2 futhi Ne -3) .3). Lapho idatha iboniswa njengephesenti ye-neurons esebenze izidakamizwa, i-39.2 ± 5.3% kwinhloko ye-NAc, i-39.2 ± 5.8% kugobolondo le-NAc, i-40.9 ± 6.3% ku-BLA, futhi i-50.0 ± 5.3% ye-ACA neurons yavulwa kokubili ukulingana noMeth.

Umfanekiso we-2      

I-Fos eyenziwe ngocansi kanye nokukhulunywa kwe-MER-induced pERK ku-NAc, BLA, ne-ACA neurons i-10 min ngemuva kokuphathwa kwe-4 mg / kg Meth. Izinombolo zamagama ± sem we-Fos (a, d, g, j), i-pERK (b, e, h, k), kanye nambili (c, f, i, l) amaseli abhalwe nge-NAc (a, ...

Ukubhekwa okungalindelekile ukuthi ukuziphatha ngokobulili kuthinte i-PERK eyenziwe nge-Meth. Nakuba i-Meth yenza kakhulu amazinga we-PERK emaqenjini ama-Meth-injected ama-mated futhi angenakulinganiswa, ku-NAc, BLA, ne-ACA, ukubhaliswa kwe-PERK kwakunciphile kakhulu kuma-meth-injected abesilisa uma kuqhathaniswa namadoda angenayo i-Meth-injected (Umfanekiso 2b, e, h, k; p = 0.017- <0.001). Lokhu kutholakala kungase kusekele phambili ukucabanga ukuthi ubulili nezidakamizwa zisebenza nge-neurons efanayo, kodwa kungase kube nokukhombisa ukuguqulwa okubangelwa ukulinganisa ekufakweni kwezidakamizwa noma ekusetshenzisweni kwezidakamizwa okubangelwa ukuthi kuguqulwe izimpendulo ze-neural kuMeth. Ukuze uphenye uma ukuziphatha ngokocansi kubangela iphethini ehlukile yesimiso sokuqalisa ukusebenza kwezidakamizwa, izingxenye ze-NAc, BLA, ne-ACA zenzelwe abesilisa abahlatshelwe umnikelo esikhathini esizayo (15 min) okulandelayo ukuphathwa kwezidakamizwa (ukuhlolwa kwe-2).

Ukuhlolwa kwe-2: Ukuhlaziywa kwamaseli angamakhebuli angashadile namabili aqinisekisile okutholakala ngenhla ukuthi ukuziphatha ngokocansi nokuchayeka okulandelayo emaminithini kaMeth 15 ngaphambi komhlatshelo kubangele ukunyuka okuphawulekayo kwe-Fos kanye ne-PERK immunolabeling ku-NAc core kanye ne-shell, i-BLA, ne-ACA. Ngokungeziwe, ukubonisana okuphawulekayo kokubambisana kwe-Fos kanye ne-MET-induced pERK kutholakala futhi kulezi zindawo (Umfanekiso we-4; umphumela wokulinganisa: F (1,12) = 15.93-76.62; p = 0.002 - <0.001; umphumela wezidakamizwa: F (1,12) = 14.11-54.41; p = 0.003- <0.001). Inombolo yama-neuron amabili afakwe ilebula emadodeni ajovwe ngeMeth ayephakeme kakhulu uma kuqhathaniswa nabaphethwe yiMeth (p <0.001) noma abesilisa abaphathwa ngosawoti (p <0.001). Ngenkathi idatha ivezwa njengamaphesenti ama-neurons asebenza ngezidakamizwa, i-47.2 ± 5.4% (i-NAc core), i-42.7 ± 7.6% (i-NAc shell), i-36.7 ± 3.7% (BLA), ne-59.5 ± 5.1% (ACA) ye-neurons eyenziwe yasebenza ukukhwelana nakho kusebenze nguMeth. Ngaphezu kwalokho, i-PERK eyenziwe yizidakamizwa ayizange yehluke phakathi kwezilwane ezihlanganisiwe nezingashayiwe (Umfanekiso 4b, e, h, k), kuzo zonke izindawo ngaphandle kwe-ACA (p <0.001). Le datha ikhombisa ukuthi ukuziphatha ngokocansi empeleni kubangela ukuguqulwa kwephethini yesikhashana yokwenziwa kweMER.

Umfanekiso we-4      

I-Fos eyenziwe ngocansi kanye nokukhulunywa kwe-MER-induced pERK ku-NAc, BLA, ne-ACA neurons i-15 min ngemuva kokuphathwa kwe-4 mg / kg Meth. Izinombolo zamagama ± sem we-Fos (a, d, g, j), i-pERK (b, e, h, k), kanye nambili (c, f, i, l) amaseli abhalwe nge-NAc (a, ...

Ukusebenza kwe-Neural kulandela ukuziphatha kocansi kanye ne-1 mg / kg Meth

Imiphumela imanje ibonisa ukuthi ukuziphatha ngokobulili kanye ne-4 mg / kg Meth kusebenze iziqhumane ezithintekayo ze-neurons ku-NAc core kanye negobolondo, i-BLA, ne-ACA. To ukuphenya ithonya lemithi yezidakamizwa kulokhu kuqhutshwa ekusebenzeni, amaphethini wokusebenza kwe-neural abuye afundwe esebenzisa umthamo ophansi weMeth. I-NAc core kanye negobolondo, i-BLA, ne-ACA yahlaziywa ngenxa yokusebenza okubangelwa ubulili ne-Meth. Ngempela, ukuziphatha ngokocansi nokuchayeka okulandelayo kuMeth kubangele ukunyuka okuphawulekayo kwe-Fos kanye ne-PERK immunolabeling ezingxenyeni ze-NAc nama-shell, i-BLA, kanye ne-neurons esifundeni se-ACA se-mPFC (Umfanekiso we-5). Ngokuthakazelisayo, umthamo ophansi weMeth waba nezinombolo ezifanayo ze-PERK ezibhalwe nge-neurons njengoba zenzelwe i-4 mg / kg Meth ezindaweni ezine zobuchopho ezihlaziywe. Okubaluleke kakhulu, i-NAc core kanye negobolondo, i-BLA, ne-ACA ibonise ukwenyuka okuphawulekayo kwinani lamaseli amabili aqoshiwe (Umfanekiso 5c, f, i, l) uma kuqhathaniswa nabesilisa abangenalutho be-Meth-injected (p = 0.003- <0.001). Ngenkathi idatha ivezwa njengamaphesenti ama-neurons asebenza ngezidakamizwa, i-21.1 ± 0.9% ne-20.4 ± 1.8% kumgogodla we-NAc negobolondo ngokulandelana, i-41.9 ± 3.9% ku-BLA, ne-49.8 ± 0.8% ye-ACA neurons yenziwe yasebenza ngocansi kanye neMeth.

Umfanekiso we-5      

I-Fos eyenziwe ngocansi kanye nokukhulunywa kwe-MER-induced pERK ku-NAc, BLA, ne-ACA neurons i-15 min ngemuva kokuphathwa kwe-1 mg / kg Meth. Izinombolo zamagama ± sem we-Fos (a, d, g, j), i-pERK (b, e, h, k), kanye nambili (c, f, i, l) amaseli abhalwe nge-NAc (a, ...

Ukusebenza kwe-Neural ngokulandela ukuziphatha ngokobulili nokuphathwa kwe-d-Amphetamine

Ukuhlola ukuthi ngabe imiphumela engenhla yayisetshenziselwe yini i-Methi, ukuhlolwa okwenziwe kwenziwa ukutadisha ukusebenziselwa kwe-neural kanye ne-Amph. Ukuhlaziywa kwamangqamuzana angabodwa kanye amabili aqoshiwe we-PERK no-Fos abonise ukuthi ukuziphatha ngokobulili nokuchayeka okulandelayo ku-Amph kubangele ukunyuka okuphawulekayo kwe-Fos kanye ne-PERK immunolabeling ku-NAc core kanye ne-shell (BLA)Umfanekiso we-6; umphumela wokulinganisa: F (1,15) = 7.38-69.71; p = 0.016- <0.001; umphumela wezidakamizwa: F (1,15) = 4.70-46.01; p = 0.047- <0.001). Ngaphezu kwalokho, izinombolo zama-neurons abhalwe ngamagama amabili zaziphakeme kakhulu ekuphathweni kwe-Amph uma kuqhathaniswa nokwelashwa okungafakwanga kwe-Amph (p = 0.009- <0.001), noma ukuphathwa ngosawoti (p = 0.015- <0.001) abesilisa (Umfanekiso 6c, f, i). Lapho idatha iboniswa njengamaphesenti we-neurons esebenze izidakamizwa, i-25.7 ± 2.8% ne-18.0 ± 3.2% ku-NAc core kanye negobolondo ngokulandelana, futhi i-31.4 ± 2.0% ye-BN neurons yenziwa ngokubili kokulingana no-Amph. Isifunda se-ACA se-mPFC sibonise amazinga abalulekile we-Fos eyenziwe ngokulingana (Umfanekiso 6j; F (1,15) = 168.51; p <0.001). Kodwa-ke, ngokungafani neMeth, i-Amph ayizange ibangele ukwanda okukhulu kwamazinga we-PERK abangelwa izidakamizwa ku-ACA (Umfanekiso 6k) noma izinombolo ze-neurons ezimbili ezibhalwe nge-ACA (Umfanekiso 6l) uma kuqhathaniswa namadoda omabili abanjwe ngobuningi futhi angenayo.

Umfanekiso we-6      

I-Fos ne-Amph-eyenziwe ngo-sex inkulumo e-NAc, BLA, ne-ACA neurons i-15 min ngemva kokuphathwa kwe-5 mg / kg Amph. Izinombolo zamagama ± sem we-Fos (a, d, g, j), i-pERK (b, e, h, k), kanye nambili (c, f, i, l) amaseli abhalwe nge-NAc (a, ...

UKUKHULUMA

Ucwaningo lwamanje lubonisa ezingeni lamaselula ukuqubuzana phakathi kokusebenza kwe-neural ngokuziphatha komzimba ngokobuciko kanye nemeththi ye-psychostimulant. Ngakho-ke, le datha ibonisa ukuthi izidakamizwa azisebenzi nje ezindaweni ezibucayi ezilawula umvuzo wemvelo, kodwa empeleni, izidakamizwa zivuselela amaseli afanayo ahilelekile ekulawuleni umvuzo wemvelo. Ngokucacile, kuboniswe lapha ukuthi ukuziphatha ngokobulili kanye ne-Meth kusebenze inqwaba ye-neurons ku-NAc core kanye negobolondo, i-BLA, ne-ACA esifundeni se-mPFC, ukukhomba izindawo ezingenzeka lapho iMeth ingathonya ukuziphatha ngokocansi.

Ukutholakala kwamanje ukuthi ukuziphatha ngokocansi nokuphathwa kweMeth kusebenze izidakamizwa ze-neurons e-NAc, BLA, ne-ACA ngokuphambene nokuthola okuvela kwezinye izifundo ezibonisa ukuthi abantu abahlukahlukene be-NAc neurons bahlanganisa umuthi nomvuzo wemvelo.

Ngokuqondile, izifundo ze-electrophysiological eziqhathanisa ukusebenza kwe-neural ngenkathi ukuzibusa kwemiklomelo yemvelo (ukudla namanzi) kanye ne-cocaine engaphakathi kwegciwane kubonise ukuthi i-cocaine self-administration yenze i-coconine self-administration yenze umehluko, inqwaba yabantu abangenawo ama-neurons okwakungaphenduli ngesikhathi sokuphendula ngokusebenza kwamanzi nokuqiniswa kokudla (92%). Kuphela i-8% ye-neurons engavamile ibonise ukusebenza ngokubili kwe-cocaine nomvuzo wemvelo (I-Carelli et al., 2000).

Ngokuphambene nalokho, iningi (i-65%) yeseli ku-NAc ibonise ukuvuselelwa ngemiphumela ehlukahlukene yemvelo (ukudla namanzi), noma ngabe enye i-reinforcer iyathandeka kakhulu (i-sucrose) (Roop et al., 2002).

Izici eziningana kungenzeka ukuthi zenze umphumela wokungafani nemiphumela yamanje. Okokuqala, izindlela ezihlukahlukene zobuchwepheshe zisetshenziselwa ukuphenya imisebenzi ye-neural. Ucwaningo lwamanje lusetshenziselwa indlela ye-neuroanatomical yokuthola ukusebenziselwa kwe-neural ngokufanayo ngezinyathelo ezimbili ezahlukene ngokusebenzisa i-immunocytochemisty ye-fluorescencent yombili ye-Fos ne-PERK, okuvumela ukuphenywa kokusebenza kwamaseli okukodwa ngaphezulu kwezindawo ezinkulu zobuchopho. Ngokuphambene, izifundo zikaCallili kanye nabasebenzi basebenzisane basebenzisa ukuqoshwa kwe-electrophysiological kuphela ku-NAc yokuziphatha izilwane ukuze zibheke ukuthi ukuzitholela izidakamizwa zokuhlukunyezwa kuvuselela izifunda ezifanayo ze-neural ezisetshenziselwa imivuzo yemvelo.

Okwesibili, isifundo samanje siphenye umvuzo ohlukile wemvelo njengokuziphatha kobulili uma kuqhathaniswa nezifundo zangaphambilini, ezisetshenziselwa ukudla namanzi ezimantwini ezivinjelwe (I-Carelli, i-2000). Ukudla namanzi kungase kube nenani elincane elivuza ngaphezu kokulingana. Ukuziphatha ngokocansi kuvuzisa kakhulu futhi amagundane akwenza kalula i-CPP yokubhekana (I-Agmo no-Berenfeld, i-1990, U-Martinez no-Paredes, i-2001, I-Tenk, i-2008). Nakuba, amagundane okuvimbela ukudla enza ifomu le-CPP yamanzi (I-Agmo et al., I-1993, Ama-Perks no-Clifton, i-1997) nokudla (Ama-Perks no-Clifton, i-1997), dUkubeka amagundane angavinjelwe kahle ukudla nokufaka i-CPP yokudla okunomsoco (Jarosz et al., 2006, Jarosz et al., 2007).

Okwesithathu, izifundo zethu zazibandakanya izidakamizwa ezihlukumezayo zokuhlukunyezwa uma kuqhathaniswa nezifundo zangaphambilini, zisebenzisa i-methamphetamine ne-amphetamine endaweni ye-cocaine. Imiphumela yamanje ibonisa ukuthi iMeth ngokuqondile, futhi kancane kancane i-amphetamine, iholele ekusebenzeni kwe-neurons futhi kusebenze ngokuziphatha kocansi. Ukwaziswa kwezidakamizwa kungenzeka ukuthi kwadlala nesici ekutholeni kwethu. Izifundo zamanje zasebenzisa izilwane ezazibonela ngokocansi, kepha izidakamizwa ziyizidakamizwa. Ngokuphambene nalokho, izifundo ze-electrophysiological ze-Carelli kanye nabasebenzi abasebenza nabo basebenzisa "izilwane eziqeqeshwe kahle" ezithola ukuvezwa ngokuphindaphindiwe kwe-cocaine.

Ngakho-ke, kungenzeka ukuthi ukusetshenziselwa kwe-Meth-induced activation of neurons okusetshenziselwa ukuziphatha ngokocansi kuguqulwa kumagundane anezimboni. Kodwa-ke, izifundo zokuqala ezivela ebhodini lethu zisikisela ukuthi isipiliyoni sezidakamizwa cishe akuyona into ebalulekile njengokuziphatha kocansi nokuphathwa kweMeth kubantu abesilisa abangaphenduliwe ngama-Meth amaphesenti afanayo afanayo ne-neurons asetshenziselwa izidakamizwa njengoba kubikiwe esifundweni samanje (20.3 ± 2.5% ku-NAc core kanye ne-27.8 ± 1.3% kugobolondo le-NAc; i-Frohmader ne-Coolen, ukubonwa okungashicilelwe).

Okokugcina, isifundo samanje siphumelele isenzo "sokuqondisa" semithi esebenzisa ukuphathwa okungahleliwe. Ngakho-ke, ukuhlaziywa kwamanje akudalula ulwazi olumayelana nezifunda ze-neural ezihilelekile ekufuneni izidakamizwa noma iziqu ezihlobene nomvuzo wezidakamizwa, kodwa kunalokho kubonisa umsebenzi we-neural obangelwa isenzo semithi yesidakamizwa. Ezifundweni zangaphambilini ze-electrophysiological, umsebenzi we-NAc we-neural owenziwa ngaphakathi kwemizuzwana yezimpendulo eziqinisekisiwe akuwona umphumela wezenzo zokwelapha ze-cocaine, kodwa kuxhomeke kakhulu ezintweni ezihlangene ngaphakathi kwesikhangiso sokuphatha (I-Carelli, i-2000, I-Carelli, i-2002). Ngokucacile, umsebenzi we-NAc we-neural uthonywe yizethulo ezizimele zokuziphendulela zezinto ezihambisana nokuthengiswa kwe-cocaine kanye nezinsimbi zomculo (okungukuthi, ukucindezela kwe-lever) kulesi sigaba sokuziphatha (I-Carelli, i-2000, U-Carelli no-Ijames, i-2001, I-Carelli, i-2002, U-Carelli no-Wightman, i-2004). Ngokufingqa, ukutholakala kwethu kokusebenzisana ngomvuzo wemvelo kanye nezidakamizwa kungase kube ngokucacile ekusebenziseni ukuziphatha ngokobulili kanye ne-Meth ne-Amph.

I-Meth ne-sex activated the populations of neurons in the core NAc kanye negobolondo ngendlela exhomeke emthamo. I-neur esebenzisana ngokuhlanganyela e-NAc ingase ixoxisane nemiphumela emihle ye-Meth ezakhiweni ezikhuthazayo nezokuvuza zokuziphatha ngokocansi njengoba izilonda ze-NAc ziphazamisa ukuziphatha ngokobulili (Liu et al., 1998, I-Kippin et al., 2004). Ukwengeza, lawa ma-neurons angase abe locus imiphumela emixhomeke emithini yezidakamizwa ekukhuliseni, njengoba i-Meth dose ephansi (1 mg / kg) inciphise inani lamaseli amabili abiziwe ngamagama angu-50% uma kuqhathaniswa nesilinganiso esiphakeme seMeth (4 mg / kg). Nakuba lolu cwaningo alubonakali i-phenotype yamakhemikhali ye-neurons esebenzisana ngokuhlanganyela, izifundo zangaphambilini zibonise ukuthi ukuboniswa kwe-PERK ne-Fos okudakamizwa ku-NAc kuncike kokubili i-dopamine (i-DA) ne-glutamate receptors (U-Valjent et al., 2000, I-Ferguson et al., I-2003, U-Valjent et al., 2005, I-al et al., I-2008). Nakuba kungacacile uma ukusebenza kwe-neural eyenziwe nge-nec ku-NAc kuncike kulezi zamukeli, lokhu kuye kwaboniswa kwezinye izifunda zobuchopho, ikakhulukazi endaweni yangaphambili ye-preoptic (ULumley noHull, i-1999, I-Dominguez et al., 2007). Ti-Meth ingasebenzisa ama-neurons futhi asebenze ngesikhathi sokuziphatha ngokobulili ngokusebenzisa ukusebenza kwe-dopamine ne-glutamate receptors. Indima ye-NAc igxile ekuziphatheni ngokocansi okwamanje ayikho into ecacile, kodwa kuqinisekiswe ukuthi i-DA idlala indima ebalulekile ekugqugquzelweni kobulili (Hull et al., 2002, Hull et al., 2004, I-Pfaus, i-2009). Ucwaningo lwe-Microdialysis lwabike ukwanda kwe-NAc DA efflux ngesikhathi sokucindezela nokuqeda ukuziphatha kobulili wesilisa (I-Fiorino no-Phillips, i-1999a, Lorrain et al., 1999) futhi i-mesolimbic ye-DA efflux iye yahlanganiswa ukuze kusetshenziswe ukuqaliswa nokugcinwa kokuziphatha ngokocansi (rat)U-Pfaus no-Everitt, i-1995). Ngaphezu kwalokho, izifundo zokuxhaphaza i-DA zibonisa ukuthi abaphikisi be-DA e-NAc bavimbela ukuziphatha ngokocansi, kuyilapho ama-agonists enza ukuqala kokuziphatha ngokocansir (Everitt et al., 1989, U-Pfaus no-Phillips, i-1989). Ngakho, i-Meth ingathinta isisusa sokuziphatha ngokocansi nge-activation ye-DA receptors.

Ngokuphambene ne-NAc, inani lamaseli amabili aqoshwayo e-BLA ne-ACA ahlala angenakushintshwa kungakhathaliseki ukuthi i-Meth dose. I-BLA iqakathekile ekufundeni okuhlanganisako okuqakathekileko begodu ibandakanyeke khulu ekuqinisekiseni okuqinisekisiweko nokuhlaziya ukuhlola ngesikhathi sokuphendula ngeengoma (Everitt et al., 1999, Ikhadineli no-al., 2002, Bheka, i-2002). Amagundane ahlaselwe yi-BLA abonisa ukwehla kwe-lever ngokucindezela kwesimiso esinesimiso esinezinhlobo zokudla (Everitt et al., 1989) noma ukuqiniswa ngokocansi (Everitt et al., 1989, Everitt, 1990). Ngokuphambene nalokhu, ukuxhaphaza akuthinti isigaba sokuphela sokudla nokuziphatha ngokobulili (Ikhadineli no-al., 2002). I-BLA nayo idlala indima ebalulekile ekukhunjweni kwesimiso esivumelana nesimo esithinta izidakamizwa (UGrace noRosenkranz, i-2002, Laviolette noGrace, i-2006). Izilonda noma ukungasebenzi kwemithi ye-BLA kuvimbela ukuthengwa (I-Whitelaw et al., I-1996) kanye nenkulumo (I-Grimm ne-See, i- 2000) ukubuyiswa kabusha kwe-cocaine okuphethwe, okungahambisani nenqubo yokuphathwa kwezidakamizwa. Ngaphezu kwalokho, I-Amph ingene ngqo kwimiphumela ye-BLA endaweni yokubuyiswa kwezidakamizwa okungenzeka kube khona phambi kwamakhodi afakiwe (Bheka futhi isib., 2003). Ngakho-ke, kungenzeka ukuthi ukuhanjiswa kwe-DA okugxilwe kwengqondo ye-psychostimulant ku-BLA kubangelwa ukukhathazeka okungokomzwelo futhi kufuneke (Ledford et al., 2003) yomvuzo wezocansi, ngaleyo ndlela kunomthelela ekuthuthukiseni ucansi olufisayo nesifiso esibikwe abahlukumezi beMeth (Semple et al., 2002, I-Green ne-Halkitis, i-2006).

Ku-ACA, ukusebenza kwe-neural ye-neurons esebenziwe ngokobulili kwakuyizilinganiso ezizimele futhi eziqondile ze-Meth, njengoba kwakungabonwa nge-Amph. Nakuba i-Meth ne-Amph inezakhiwo ezifanayo nezakhiwo zemithi, i-Meth ingumqondo onamandla kakhulu kune-Amph nemiphumela engapheli (NIDA, 2006). Izifundo zikaGoodwin et al. wabonisa ukuthi i-Meth ikhiqiza i-DA enkulu ye-efflux futhi igwema ukuvulwa kwe-DA esebenziwe endaweni ephumelelayo ku-NAC ye-Rat kunamaph. Lezi zici zingaba nomthelela ezakhiweni zokulutha zikaMeth uma kuqhathaniswa no-Amph (I-Goodwin et al., I-2009) futhi mhlawumbe umehluko we-neural activation umehluko phakathi kwezidakamizwa ezimbili. Kodwa-ke, akucaci ukuthi amaphethini ahlukene emiphumela angenxa yokuhlukana okuphumelelayo phakathi kwezidakamizwa noma izimpikiswano ze-potency ezihlobene namanani asetshenziselwe futhi uphenyo oluqhubekayo liyadingeka.

Ukusebenza ngokubambisana yi-Meth nocansi akuzange kubonwe kwezinye izifundazwe ze-mPFC (i-IL ne-PL). Esikhathini, i-ACA iye yafundwa ngokubanzi ngemisebenzi yokuncintisana, isekela indima ezinhlanganweni zokuvuselela (reinforcer-associations)Everitt et al., 1999, Bheka, i-2002, Ikhadineli no-al., 2003). Kunobufakazi obuningi bokuthi i-mPFC ihilelekile ekufiseni izidakamizwa futhi iphinde ibuyele ekuziphatheni izidakamizwa nokuthatha izidakamizwa kokubili abantu namagundane (U-Grant et al., I-1996, I-Childress et al., I-1999, I-Capriles et al., I-2003, McLaughlin no-See, i-2003, Shaham et al., 2003, Kalivas noVolkow, i-2005). IN line nalokhu, kuphakanyisiwe ukuthi ukuhlukunyezwa kwe-mPFC okubangelwa ukuchayeka ngokuphindaphindiwe kwezidakamizwa zokuhlukumeza kungase kube nomthwalo wokulawula ukunciphisa ukucindezeleka nokuziphatha okunyanyisiwe kwezidakamizwa njengoba kubonwe kumlutha amaningi (UJentsch no-Taylor, i-1999). Idatha yakamuva evela esibhedlela sethu yabonisa ukuthi izilonda ze-mPFC ziholela ekuqhubekeni okuqhubekayo kokuziphatha ngokocansi uma lokhu kuhlotshaniswa nesishu (UDavis et al., 2003). Ngisho noma lolu cwaningo aluzange luphenye i-ACA, lusekela ukuthi i-mPFC (ne-ACA ngokuqondile) iqondana nemiphumela yeMet ekulahlekelweni kokulawulwa okungavimbela ukuziphatha ngokocansi njengoba kubikwa abahlukumezi beMeth (Salo et al., 2007).

Ekuphetheni, ndawonye lezi zifundo zakha isinyathelo sokuqala esibucayi ekuqondeni kangcono ukuthi izidakamizwa zokuhlukumeza zisebenza kanjani ezindleleni ze-neural ezivame ukusebenzisana nemivuzo yemvelo. Ngaphezu kwalokho, lokhu okutholakele kubonisa ukuthi ngokungafani nenkolelo yamanje yokuthi izidakamizwa zokuhlukunyezwa azisebenzisi amaseli afanayo ohlelweni lwe-mesolimbic njengomvuzo wemvelo, iMeth, nangaphansi kwe-Amph, kusebenze amaseli afanayo nokuziphatha ngokobulili. Ngalokhu, lezi zinhlangano ezisebenza ngokuhlanganyela ezithintekayo zingathonya ukufuna umvuzo wemvelo emva kokutholakala kwezidakamizwa. Okokugcina, imiphumela yalolu cwaningo ingaba negalelo elikhulu ekuqondeni kwethu ngesisekelo somlutha ngokujwayelekile. Ukuqhathaniswa kokufana nokuhlukana, kanye nokuguqulwa kokusebenza kwe-neural kwendlela ye-mesolimbic eyenziwe ukuziphatha ngokobulili ngokuhambisana nezidakamizwa zokuhlukunyezwa kungaholela ekuqondeni kangcono ukusetshenziswa kabi kwezidakamizwa kanye nokushintshaniswa okuhambisana nomvuzo wemvelo.

Ukuvuma

Lolu cwaningo lusekelwe yizibonelelo ezivela eNational Institutes of Health R01 DA014591 naseCanada Institutes of Health Research RN 014705 kuya kuLMC.

IZIMBUZO

  • ABC
  • i-avidin-biotin-horseradish i-peroxidase eyinkimbinkimbi
  • ACA
  • indawo yangaphakathi ye-cingulate
  • Amph
  • d-amphetamine
  • BLA
  • i-basolateral amygdala
  • BNSTpl
  • i-nucleus ye-bedraolateral ye-stria terminalis
  • BNSTpm
  • I-nucleus ye-bedridomedial ye-stria terminalis
  • BT
  • i-tyramide ye-biotinylated
  • CeA
  • i-amygdala engamakhulu
  • I-CPP
  • okwenziwe endaweni ehleliwe
  • E
  • ukujula
  • EL
  • i-latency latency
  • IF
  • indawo ye-infralimbic
  • IL
  • i-latency latency
  • IM
  • ukungahambi kahle
  • M
  • khuphuka
  • MAP Kinase
  • i-protein kinase esebenzayo ye-mitogen
  • MEApd
  • i-amygdala yomphakathi yangemva kwesikhathi
  • I-Meth
  • methamphetamine
  • ML
  • khuphula i-latency
  • mPFC
  • i-prefrontal cortex yangaphakathi
  • MPN
  • i-nucleus yangaphambili yangaphakathi
  • I-NAc
  • i-nucleus Accumbens
  • PB
  • i-phosphate buffer
  • PBS
  • i-phosphate i-saline ephuziziwe
  • I-PEI
  • ukuvala isikhashana ejaculatory
  • PERK
  • I-MAP Kinase i-phosphorylated
  • PL
  • indawo yangaphambili
  • I-VTA
  • indawo ye-ventral tegmental

Imibhalo yaphansi

Ukuzikhulula komshicileli: Leli fayili le-PDF yesandla esingenakubalwa esamukelwe ukuze sishicilelwe. Njengenkonzo kumakhasimende ethu sinikeza le nguqulo yokuqala yombhalo wesandla. Umbhalo wesandla uzothola ukukopisha, ukufaka izinhlobo, nokubukeza ubufakazi obulandelayo ngaphambi kokuba ushicilelwe efomini layo lokugcina. Uyacelwa ukuthi uqaphele ukuthi ngesikhathi sezinqubo zokukhiqiza kungenzeka ukuthi zitholakale ezingahle zithinte okuqukethwe, nazo zonke izinqamulajuqu ezisemthethweni ezisebenza kulo magazini.

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