I-Methamphetamine isebenza kwimigqaliselo ye-neurons elawula ukuziphatha ngokwesondo kwiisundu zamadoda (i-2010)

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

Frohmader KS, Wiskerke J, Ihlakaniphileyo RA, Lehman MN, Coolen LM.

imvelaphi

ISebe le-Anatomy kunye ne-Biology ye-Cell, iSchool School of Medicine kunye neDentistry, iYunivesithi yaseWestern Ontario, eLondon, ON, Canada, N6A 5C1.

Abstract

I-Methamphetamine (i-Meth) ivuselela kakhulu umlutha. Ukusetyenziswa kakubi kweMeth kudla ngokuqhelaniswa nokuziphatha komngcipheko wesondo kunye nokwanda kwe-Human immunodeficiency Virus kunye nabasebenzisi beMeth, banokuphakamisa umnqweno wesini, ukuvusa, nokuzonwabisa. Isiseko sezinto eziphilayo ze-sex nexus aziwa. Uphononongo lwangoku lubonisa ukuba ukuphathwa kweMeth kwinduna zamadoda kuvula i-neurons kwimimandla yengqondo ye-eyelimbic system echaphazelekayo ekulawuleni ukuziphatha ngokwesondo. Ngokukodwa, i-Meth kunye nokubambisana kusebenze iseli kwi-nucleus iqokelela i-core kunye ne-shell, i-amygdala ye-basolateral, kunye ne-cortex yangaphakathi. Ezi ziphumo zibonisa ukuba ngokuchasene nenkolelo yangoku iziyobisi zokusetyenziswa kakubi kweziyobisi zingenza iiseli ezifanayo njenge-reinforcer yemvelo, oko kukuziphatha ngokwesondo, kwaye kungakhokelela ekufuneni ukunyanzeliswa kwalo mvuzo wendalo.

Internet: i-nucleus accumbens, i-amygdala ye-basolateral, i-prefrontal cortex, ukusetyenziswa kakubi kweziyobisi, ukuzaliswa, umlutha

Iinjongo kunye nomvuzo zilawulwa yinkqubo ye-mesolimbic, inethiwekhi edibeneyo yeendawo zengqondo ezibandakanya indawo ye-ventral tegmental (VTA) i-nucleus accumbens (NAc), i-amygdala ye-basolateral kunye ne-corrox ye-preferenceal (mPFC).Kelley, 2004, IKalivas neVolkow, i-2005). Kukho ubungqina obuninzi bokuthi inkqubo ye-mesolimbic isebenziselwe ukuphendula kwizinto zombini zokusetyenziswa gadalala (I-Di Chiara kunye ne-Imperato, i-1988, Chang et al., 1997, Ranaldi et al., 1999) kunye nokuziphatha okuvuzayo ngokwemvelo njengokuziphatha ngokwesondo (Fiorino et al., 1997, Balfour et al., 2004). Indlela yokuziphatha ngokwesini, kwaye ngokukhethekileyo, i-ejaculation, ivuyisa kakhulu kwaye iqinisa kwiimpawu zezilwanyana (Pfaus et al., 2001). Amagundane angamadoda ahlakulela indawo ekhethiweyo (CPP) ekuqhubeni (Agmo noBerenfeld, 1990, UMartinez kunye neParedes, i-2001, Tenk, 2008), kwaye iya kwenza imisebenzi esebenzayo ukufumana ukufikelela kumntu wesini esamkelekileyo ngokwesini (Everitt et al., 1987, Everitt no Stacey, 1987). Iziyobisi zokusetyenziswa gadalala nazo zivuza kwaye ziqinisa, kwaye izilwanyana ziza kuzifunda izinto zokuziphatha kakubi, kuquka i-opiates, iicicin, i-alcohol, kunye neengqondo (Ubulumko, 1996, UPierce noKumaresan, i-2006, I-Feltenstein ne-See, i-2008). Nangona eyaziwa ukuba zombini iziyobisi zokusetyenziswa kakubi nokuziphatha kakubi ngokwesondo zivuselela iindawo zengqondo zengqondo, okwangoku akucaci ukuba iziyobisi zokusetyenziswa kakubi zichaphazela i-neurons efanayo ekudibaniseni ukuziphatha ngokwesondo.

Ucwaningo lwe-Electrophysiological lubonise ukuba ukutya kunye ne-cocaine zombini kusebenze i-neurons kwi-NAc. Nangona kunjalo, abaqinisekisi ababini abasebenzisi iiseli ezifanayo kwi-NAc (Carelli et al., 2000, Carelli noWondolowski, 2003). Ukongezelela, ukutya kunye ne-sucrose self-administration akubangeli ukuba utshintsho lwexesha elide lwezakhiwo ze-electrophysiological njengoko zibangelwa yi-cocaine (Chen et al., 2008). Ngokwahlukileyo, ukuqokelela ubungqina kubonisa ukuba ukuziphatha ngokwesini kunye neziyobisi zokusetyenziswa kakubi kuyenzeka ngokwenene kwi-nelions eyelimbic neurons. I-Psychostimulants kunye ne-opioids ziguqula indlela yokuziphatha ngokwesondo kwiinkizi zamadoda (UMitchell noStewart, i-1990, Fiorino kunye nePhillips, 1999a, Fiorino kunye nePhillips, 1999b). Idatha yakutshanje evela ebhodini lethu ibonise ukuba amava olwabelana ngesondo aguqula impendulo kwiingqondo eziphambili zengqondo njengoko kubonakaliswe iimpendulo ezenziwayo ezenziwayo kunye nombono wokufumana umvuzo kwi-d-amphetamine kwizilwanyana ezithandana ngesondo (Pitchers et al., 2009). Impendulo efana nayo iye yabonwa ngokuphindaphindiweyo kwi-amphetamine okanye ezinye iziyobisi zokusetyenziswa kakubi (Lett, 1989, Shippenberg kunye noHeidbreder, 1995, Shippenberg et al., 1996, Vanderschuren kunye neKalivas, i-2000). Ngokubambisana, ezi ziphumo zibonisa ukuba ukuziphatha ngokwesondo kunye nezimpendulo kwiziyobisi zokusetyenziswa gadalala zidibaniswa yi-neurons efanayo kwindlela ye-eyelimbic. Ngaloo ndlela, injongo yokuqala yokufunda kwangoku kukuphanda ukusebenza kwe-neural ye-eyelimbic system ngokuziphatha ngokwesondo kunye nokulawulwa kwezidakamizwa kwisilwanyana esifanayo. Ngokukodwa, savavanya ingcinga yokuba i-psychostimulant, i-methamphetamine (iMeth), yenza ngokuthe ngqo kwi-neurons ngokuqhelekileyo idibanisa indlela yokuziphatha ngokwesondo.

I-Meth yenye yezilwanyana ezingekho mthethweni kwiiNhlaba (i-NIDA, i-2006, Ellkashef et al., 2008) kwayekwaye bekuye rhoqo kudibaniswa nokuziphatha kwezesondo. Okuthakazelisayo kukuba, abasebenzisi beMeth bakhupha umnqweno wesini kunye nokuvusa, kunye nokunyaniseka kwezesondo (Semple et al., 2002, Schilder et al., 2005). Ngaphezu koko, Ukusetyenziswa kakubi kweMeth ngokuqhelekileyo kunxulumene nokuziphatha ngokunyanzela ngokwesondo (Rawson et al., 2002). Abasebenzisi bavame ukuchaza ukuba banamaqela amaninzi eentlobano zesini kwaye abanako ukuzisebenzisa ukukhusela kunabanye abaxhaphaza iziyobisi (Somlai et al., 2003, Springer et al., 2007). Ngelishwa, iziphumo ezibonisa ukuba iMeth zisebenzisa njengendlela yokuziphatha yengozi yezocwangco zikhawulelwe njengoko zixhomekeke kwiingxelo ezizimeleyo (Elifson et al., 2006). Ngako-ke, uphando olwenziwe kumaselula olutshintsho lwe-Meth ukutshintsha kwezenzo zesondo kwisimo semfuyo kuyadingeka ukuba uqondisise le ngxaki yokuxhatshazwa kwezidakamizwa zesini.

Ngenxa yolu bungqina obukhankanywe ngasentla lubonisa ukuba iziyobisi zokusetyenziswa kakubi, kunye ne-Methi, zisebenza kwi-neurons eziqhelekileyo ezibandakanyekayo ekujonganeni nokuziphatha ngokwesondo, injongo yolu cwaningo luyilo ukuphanda ukusebenza kwe-neural ngokuziphatha ngokwesondo kunye nokuphathwa kwe-psychostimulant Meth. Olu pho nonongo luqalise ubuchule be-neuroanatomical, esebenzisa ukubonakaliswa kwe-immunohistochemical ye-genes yokuqala ye-Fos kunye ne-Phosphorylated Imephu ye-Kinase (PERK) ukufumanisa ukusebenziselwa kwe-neural ngokusebenza ngokuziphatha ngokwesondo kunye neMeth ngokulandelanayo. I-Fos iboniswa kuphela kwi-nucleus yeeseli, enezinga eliphezulu lokubonisa i-30-90 imizuzu emva kokusebenza kwe-neuron. Kukho ubungqina obuninzi bokuthi izenzo zesondo zenza ukuba intetho ye-Fos ibe yingqondo (Pfaus noHeeb, 1997, Veening and Coolen, 1998), kubandakanywa ne-mesocorticolimbic system (URobertson et al., 1991, Balfour et al., 2004). Kukho ubungqina bokuba iziyobisi zokusetyenziswa gadalala zikhuthaza ukubonakalisa i-PERK ngaphakathi kwenkqubo ye-mesocorticolimbic (Valjent et al., 2000, Valjent et al., 2004, Valjent et al., 2005). Ngokuphambene nokubonakaliswa kweFos, i-phosphorylation ye-ERK yinkqubo enamandla kakhulu kwaye ivele emva kweminye imizuzu ye-5-20 emva kokusebenza kwe-neuronal. Iiprofayili zexesha eliqhelekileyo ze-Fos kunye ne-PERK zenza iisethi ezifanelekileyo zeemakishi ukwenzela ukusebenziselwa kwe-neuronal ngokulandelelana kwezimbini ezahlukeneyo.

IINKQUBO ZEMISEBENZI

I zifundo

Amadoda amadala Amagqabi aseDawley ama-Sprague (210-225 g) atholakala kwiCharles River Laboratories (eMontreal, QC, Canada) ayehlala ezimbini kwi-cage kwizicatshulwa ze-plexiglas (amakhaya asekhaya). Igumbi lesilwanyana laligcinwe kwi-12 / 12 h ejikelezayo umjikelezo wokukhanya (ukukhanyisa kwi-10.00 h). Ukutya kunye namanzi kwakhona ad adum. Zonke iilingo zenziwa kwinqanaba lokuqala lesigaba esimnyama phantsi kokukhanya okubomvu obomvu. Iistimulus zezilwanyana ezisetyenziselwa ukuziphatha ngokwesondo zaye zahlukunyezwa ngama-anesthesia (i-13 mg / kg ketamine kunye ne-87 mg / kg xylazine) kwaye yafumana impembelelo ene-5% estradiol benzoate (EB) kunye ne-95% ye-cholesterol. Ukumkelwa kwezesondo kuqhutywe ngulawulo olungaphantsi (sc) lolawulo lwe-500 μg progesterone kwi-0.1 ml ye-oil yesameki 4 ngaphambi kokuvavanya. Zonke iinkqubo zivunyiwe yiKomidi yokuNakekela iZilwanyana kwiYunivesithi yaseWestern Ontario kwaye iyavumelana nezikhokelo ezichazwe yiCanada Council malunga nokuNakekela kwezilwanyana.

IziCwangciso zoPhando

Iingcamango ze-1 kunye ne-2: Amakhwenkwe angamadoda (n = 37) avunyelwe ukudibana nomfazi okwamkelekileyo kwi-ejaculation enye (E) okanye kwi-30 min, eyayiqala kuqala kwiibhokisi zokuvavanya ezicocileyo (60 × 45 × 50 cm) kwixesha eliphindwe kabini -isiseshwankathelo sokuvavanya ngaphambi kokuvavanya, ukufumana amava ezesondo. Ngethuba leeseshoni ezimbini zokugqibela, zonke iiparameter eziqhelekileyo zentsebenzo yesondo zarekhodwa, kubandakanywa: i-latency ye-mount (ML; ixesha lokusuka kwintombi kuze kube yintaba yokuqala), i-latrom latency (IL; ukungena kwebhinqa), i-ejaculation latency (EL; ixesha ukusuka ekungeneni kokuqala ukuya ku-ejaculation), ixesha lokuthunyelwa kwe-ejaculation (i-PEI; ixesha ukusuka ekujongeni ukuya kutshatyalaliswa kokulandelayo), inani leentaba (M) kunye nenani le-intromissions (IM) (Agmo, 1997). Bonke abesilisa bafumana i-1 ml / kg engenayo yansuku zonke ye-0.9% NaCl (i-saline; sc) Iintsuku eziyi-3 ezilandelelana ngaphambi kovavanyo lomhla, ukuba ziqhube ukuphathwa kunye neenjini. Ngenye imini ngaphambi kovavanyo lomhla, bonke abesilisa babehlala bengatshatanga. Kwindoda enamava, iFos inokunyanzeliswa yimiqathango ehambelana nemeko ehambelana namava esondo sangaphambili (Balfour et al, 2004). Ngoko ke, zonke izixhobo zokulinganisa nokulawula ngexesha lokugqibela iimvavanyo zenziwa kwindlu yekhaya (ukuphepha kweengcambu ezicwangcisiweyo zokukhusela) ukukhusela i-cue-cue eyenziwe kusebenze kumadoda alawulwayo. Amadoda asasazwa kwiqela elinesibhozo zokuhlola ezingafaniyo nawuphi na umlinganiselo wesenzo sezesondo ngexesha leeseshoni zokugqibela zokugqibela (idatha engaboniswa). Ngethuba lokuvavanya kokugqibela, amadoda angavunyelwa ukuba athathane kwikhaya labo, ade adibanise (isondo) okanye angamkelanga iqabane lomfazi (akukho ngesondo). Bonke abesilisa abathandekayo baxhatshazwa imizuzu ye-60 emva kokuqalisa ukulinganisa ukuvumela uhlalutyo lwegama le-Fos-induced-induced. Amadoda athola umjovo we-4 mg / kg Meth okanye i-1 ml / kg i-saline (sc) (n = 4 nganye), okanye i-10 (uvavanyo lwe-1) okanye i-15 (uvavanyo lwe-2) min ngaphambi kokungcoliswa, ukuhlalutya kwe-phosphorylation MAP kinase. Isisombululo kunye nexesha ngaphambi kokuba kufakwe umonakalo kusekelwe kwiingxelo zangaphambili (Choe et al., 2002, Choe noWang, 2002, UKhen noKen, i-2004, Mizoguchi et al., 2004, Ishikawa et al., 2006). Amaqela okulawula aquka amadoda angakhange athathwe, kodwa wamkela i-Meth 10 (n = 7) okanye i-15 (n = 5) min ngaphambi kokubingelelwa, okanye i-injection saline 10 (n = 5) okanye i-15 (n = 4) . Ukulandela umnikelo, ubuchopho buye baqhutyelwa kwi-immunohistochemistry.

Uvavanyo lwe-3: Njengoko i-Meth ephezulu yayisetyenziselwa ukulinga i-1 kunye ne-2, kwenziwa uphando olongezelelweyo lwe-neuroanatomical ukuphanda ukuba ukuziphatha ngokwesondo kunye ne-dose ephantsi yeMet kwenza ukuba iipatheni zixhomekeke kwi-dose yokusebenzisa i-neural activation. Olu pho nonongo luqhutyelwe ngendlela efanayo nokuhlola kwe-1 ne-2. Nangona kunjalo, ekuvavanyeni kokugqibela, amaqela kunye namaqela angabonakaliyo (n = 6 nganye) athola i-1 mg / kg Meth (sc) 15 min ngaphambi kokubingelelwa.

Uvavanyo lwe-4: Ukuvavanya ukuba usebenziso lwe-neural olubangelwa ngokwesondo kunye neMeth lubhekiselele kwi-Meth, lo vavanyo luchengisise ukuba iipateni ezifanayo zokusebenzisa i-neural activation zingabonwa nge-psychostimulant d-amphetamine (Amph). Olu lwenziwa lwenziwa ngendlela efanayo nokuhlola kwe-1 ne-2. Nangona kunjalo, ekuhlolweni kokugqibela, amadoda alawulwa yi-Amph (5 mg / kg) okanye i-saline (1 mg / kg) (sc) 15 min ngaphambi kokubingelelwa (n = 5 nganye). Ukulawula abesilisa abangenasiphelo bafumana i-saline okanye i-Amph imizuzu ye-15 ngaphambi kokubingelelwa. Ukujonga ngokubanzi amaqela okulinga asetyenziswe kwizilingo 1-4 inikwe 1 Table.

1 Table      

Ubume ngokubanzi kwamaqela okulinga afakwe kwiimvavanyo 1-4.

Ukulungiselela Amathambo

Izilwanyana zazixhaswe nge-pentobarbital (270 mg / kg; ip) kwaye zenziwe nge-transcardially nge-5 ml ye-saline elandelwa ngu-500 ml 4% ipolformaldehyde kwi-0.1 M i-phosphate buffer (PB). Ubunjongo buyasuswa kwaye bubekwa bucala kwi-1 h kwiqondo lokushisa lokushisa kwi-fixation efanayo, kwaye zifakwe kwi-20% sucrose kunye ne-0.01% ye-Sodium Azide kwi-0.1 M PB kwaye igcinwe kwi-4 ° C. Iziqendu ze-Coronal (35 μm) zachithwa kwi-microtome ebandayo (i-H400R, iMicron, eJamani), iqokelelwe kwichungechunge emine ehambisanayo kwisisombululo se-cryoprotectant (30% sucrose kunye ne-30% ethylene glycol kwi-0.1 M PB) kwaye igcinwe kwi-20 ° C kude kube ku sebenza.

Immunohistochemistry

Zonke iifubation zaqhutyelwa kwiqondo lokushisa kwamagumbi kunye nokunyanzelisa. Iziqendu ezihambayo zamahhala zihlanjwe kakhulu kunye ne-0.1 M i-Phosphate-buffered saline (PBS) phakathi kokutsalwa. Amacandelo afakwe kwi-1% H2O2 i-10 min, kwaye ivalwe kwisisombululo sokuxubusha (i-PBS equkethe i-0.1% ye-serum albumin kunye ne-0.4% iTriton X-100) ye-1 h.

PERK / Fos

I-tissue yayibanjwe ngobusuku bobusuku kunye nomntu onogxobhozo we-polyclonal kunye ne-p42 kunye ne-p44 imephu ye-ERK1 kunye ne-ERK2 (pERK; 1: 400 uvavanyo 1 lot 19; 1: 4.000 uvavanyo 2 kunye ne-3 iqela le21; i-Cell Signaling Cat # 9101;), ilandelwa I-1 h incubation kunye ne-IgG (1: 500; i-Jackson Immunoresearch Laboratories, West Grove, PA) kunye ne-avidin-horseradish peroxidase complex (ABC Elite; 1: 1000; iVector Laboratories, Burlingame, CA). Emva koko, izicubu zazingeniswa kwi-10 min kunye ne-tyramide e-biotinylated (BT; 1: 250 kwi-PBS + 0.003% H2O2; I-Tyramid Signal Amplification Kit, i-NEN Life Sciences, i-Boston, MA) kunye ne-30 min kunye ne-Alexa 488 conjugated strepavidin (i-1: i-100; i-Jackson Immunoresearch Laboratories, i-West Grove, i-PA). Emva koko, izicubu zazingeniswa ngobusuku obunobunqunu obunobuthi be-polyclonal anti-cos (1: 500; i-SC-52; iSanta Cruz Biotechnology, iSanta Cruz, CA), ilandelwa yi-30 min incubation kunye neebhokhwe e-anti-rabbit Alexa 555 (1: 200; i-Jackson Immunoresearch Laboratories, iWest Grove, PA). Ukulandela udoti, amacandelo ahlambuliswa ngokupheleleyo kwi-0.1 M PB, ephakanyiswe kwiilayidi zeglasi kunye ne-0.3% ye-gelatin kwi-ddH2I-0 kwaye igxinwe nge-medium-mounting medium (Gelvatol) ene-anti-fading agent I-1,4-diazabicyclo (2,2) octane (iDABCO; 50 mg / ml, Sigma-Aldrich, St. Louis, MO). Ukulawulwa kwama-immunohistochemical kuquka ukushiywa kwezinto zombini okanye zombini izixhobo eziphambili, okubangelwa ukungabikho kwileyibhile kwi-longueur eyiyo.

Uhlalutyo lweenkcukacha

Ukuziphatha ngokwesondo

Kuzo zonke iimvavanyo ezine, iiparameter eziqhelekileyo zentsebenzo yesondo zabhalwa njengoko zichazwe ngasentla kwaye zihlaziywa ngokusebenzisa uhlalutyo lokuhluka (ANOVA). Ukuhlalutya kwedatha yokuziphatha ngokwesini ngexesha lokugqibela lokuvavanya akubonakali ukungafani okwakubonakala phakathi kwamacandelo nakweyiphi imimiselo yezenzo zesondo.

I-PERK / Fos Cell Counts

Amaseli angatshatanga kunye namabini adibeneyo kwi-Fos kunye ne-PERK babalwa kumanqanaba angqalileyo e-NAc kunye neengqungquthela ze-shell, i-amygdala ye-shelly (BLA), i-amygdala ye-posterodorsal (MEApd), i-amygdala ephakathi (CeA), i-nucleus yangaphambili (MPN), i-posteromedial kunye I-nucleus yebhedi yesikhombiso se-stria terminalis (i-BNSTpm kunye ne-BNSTpl), kunye neendawo zangaphambili ezicwangcisiweyo (ACA), i-prelimbic (PL), kunye ne-infralimbic (IL) kwiingingqi ze-mPFC. Imifanekiso ifakwe kwiComputer ye-CCD (Microfire, Optronics) ifakwe kwi-microscope yeLeica (i-DM500B, iLeica Microsystems, i-Wetzlar, eJamani) kunye ne-neurolucida software (MicroBrightfield Inc) kunye nezicwangciso zekhamera ezizimeleyo kuzo zonke izifundo (usebenzisa iinjongo ze-10x). Ukusebenzisa isofthiwe ye-neurolucida, iindawo zokuhlalutya zachazwa ngokusekelwe kwiimpawu zomhlaba (Swanson, 1998) ekhethekileyo kwingingqi nganye yengqondo (jonga Umzobo 1). Imimandla ephezulu yokuhlalutya isetyenziswe kuzo zonke iindawo ngaphandle kwe-NAc yengundoqo kunye negobolondo. Kwimimandla ekugqibela, ukubonakaliswa kwePER kunye neFos kwakungekho okufanayo kwaye kubonakala kwiipatheni ezinjenge-patch. Ngoko ke, yonke ingundoqo kunye negobolondo yachazwa ngokusekelwe kumanqaku omhlaba (i-ventricle lateral, ukuzonwabisa kwangaphambili, kunye neziqithi zaseCalleja). Imimandla yohlalutyo ayizange ihluke phakathi kwamaqela okulinga, kwaye yayingu-1.3 mm2 kwi core NAc kunye negobolondo. Imimandla ephezulu yokuhlalutya kwimimandla esele yile: 1.6 mm2 kwi-BLA, i-2.5 kunye ne-2.25 mm2 kwi-MEApd kunye neCeA ngokulandelanayo, i-1.0 mm2 kwi-MPN, 1.25 mm2 kwi-BNST ne-mPFC, kunye ne-3.15 mm2 kwiVTA. Amacandelo amabini ayebalwa ngokubaluleka kwendawo nganye yengqondo ngesilwanyana ngasinye, kunye nenani leelinye elilodwa kunye nelibini elibhalwe nge-PERK kunye ne-Fos kwakunye neepesenti zeeseli ze-PER ezichaze uphawu lweFos zibalwe. Kwimizamo ye-1, i-2, kunye ne-4, imilinganiselo yeqela yayiqhathaniswa isebenzisa iindlela ezimbini ze-ANOVA (izinto: ukulingana kunye neziyobisi) kunye ne-LSD ye-Fisher iposi ukuthelekisa kwinqanaba elibalulekileyo le0.05. Ukulinga kwe-3, imilinganiselo yeqela yayiqhathaniswa nokusebenzisa iimvavanyo ze-T ezingaphelelwanga kwinqanaba elibalulekileyo le-0.05.

Umzobo 1      

Imidwebo yeSikimu kunye nemifanekiso ebonisa indawo yengqondo yokuhlalutya. Iindawo zokuhlalutya ziboniswe zisekelwe kwiimpawu ezimpawu eziqhelekileyo kwingingqi nganye yengqondo, azizange zihluke phakathi kwamaqela okulinga, kwaye ziyi-1.25 mm2 kwimimandla ye-mPFC (a), 1.3 mm2 kwi ...

imifanekiso

Imifanekiso yeDigital Umzobo 3 zafakwa kwi-CCD ikhamera (DFC 340FX, Leica) ifakwe kwi-microscope yeLeica (DM500B) kwaye yangeniswa kwi-software ye-Adobe Photoshop 9.0 (i-Adobe Systems, iSan Jose, CA). Imifanekiso ayizange yatshintshwe nayiphi na indlela ngaphandle kohlengahlengiso.

Umzobo 3      

Imifanekiso engummeli we-NAc i-immunostained ye-Fos (obomvu; a, d, g, j) kunye ne-pERK (eluhlaza; b, e, h, k) yezilwanyana zeqela ngalinye lokulinga: Akukho isondo + Sal (a, b, c) , Sex + Sal (d, e, f), Akukho isondo + iMeth (g, h, i), kunye no-Sex + Meth (j, k, l). Iipaneli ezifanelekileyo ...

IINKCUKACHA

Ukusebenza kwe-Neural ye-Limbic System ngokuziphatha koSondo kunye noLawulo lweMeth

Uvavanyo lwe-1: Uhlalutyo lweeseli ezibhaliweyo kunye ezimbini ezibhaliweyo ze-Fos kunye ne-MET-induced proerk kumadoda athola imizuzu ye-Meth 10 ngaphambi kokubingelelwa ibonakalisa i-Fos enokubambisana kwi-MPN, i-BNSTpm, i-NAc kunye ne-shell, i-BLA, i-VTA, kunye nayo yonke imimandla ye-mPFC, ehambelana neengxelo zangaphambili ezibonisa ukuboniswa kwe-Fos yokuxubusha kule mimandla (Baum no-Everitt, i-1992, Pfaus noHeeb, 1997, Veening and Coolen, 1998, Hull et al., 1999). I-Meth yokulawula i-10 imizuzu ngaphambi kokuba idini lenze i-PERK kwi-NA core kunye ne-shell, i-BLA, MeApd, i-CeA, i-BNSTpl kunye nemimandla ye-mPFC, ehambelanayo neendlela zokusebenza ezibangelwa ezinye i-psychostimulants (Valjent et al., 2000, Valjent et al., 2004, Valjent et al., 2005).

Ngaphezu koko, iipatheni ezintathu zokubambisana kwe-neural ngokusebenzisa ukuziphatha ngokwesondo kunye neMeth zaqatshelwa: Okokuqala, iinkalo zengqondo zachongwa apho ubulili kunye neziyobisi zisebenzisana nabantu abangabambanga izibilini (2 Table). Ngokukodwa, kwi-CeA, MEApd, BNSTpl, kunye ne-mPFC, ukonyuka okubonakalayo kweziyobisi zibangelwa ziziyobisi (F (1,16) = 7.39-48.8; p = 0.015- <0.001) kunye neFos eyenzelwe isondo (F (1,16, 16.53) = 158.83-0.001; p <1,16) yabonwa. Nangona kunjalo, kule mimandla kwakungekho lonyuka lubalulekileyo kwii-neurons ezibhalwe amagama kumadoda aphathwa ngeMeth. Okukuphela kwento eyahlukileyo yayiyi-MEApd, apho kufunyenwe isiphumo sokudibana kwamanani eeseli ezinelebheli ezimbini (F (9.991) = 0.006; p = XNUMX). Nangona kunjalo, kwakungekho siphumo sipheleleyo sonyango lweziyobisi kunye neelebheli ezimbini kumaqela anyangiweyo eMeth zazingaphakamanga kangako kunamaqela anyangwe ngetyuwa, ngenxa yoko khange kubangelwe sisiyobisi (2 Table). Okwesibini, iingingqi zengqondo zachongwa apho ukusebenza kwe-neural kubangelwa kuphela ukulingana (3 Table). Ngokukodwa, i-MPN, i-BNSTpm, kunye ne-VTA yenziwa ngokucwangciswa kuphela, kwaye iqulethe ukwanda okwenziwe kwiFos (F (1,16) = 14.99-248.99; p ≤ 0.001), kodwa akukho mveliso eyenziwe nguMeth.

2 Table      

Ubume bemizekelo ye-Fos kunye ne-MTE-induced expression-expression in the brain in areas where the brain and drugs are activated.
3 Table      

Ubume bemizekelo ye-Fos kunye ne-MTE-induced expression in PERK kwiindawo zobuchopho apho kusebenziselwa i-neural ukusebenza kuphela ngokubambisana.

Ekugqibeleni, iingingqi zengqondo zafunyanwa apho ubulili kunye neziyobisi zisebenza ngokugqithisileyo kwabantu abaninzi.Umzobo 2 kwaye And3) .3). Kwisiseko se-NAc kunye negobolondo, i-BLA, kunye ne-ACA, bekukho iziphumo zokulingana (F (1,16) = 7.87-48.43; p = 0.013- <0.001) kunye nonyango lweziyobisi (F (1,16) = 6.39– 52.68; p = 0.022- <0.001), kunye nokunxibelelana phakathi kwezi zinto zimbini (F (1,16) = 5.082-47.27; p = 0.04- <0.001; akukho nxibelelwano lubalulekileyo kwi-ACA) kumanani eeseli ezibonisa zombini I-Fos kunye ne-Meth. I-post hoc uhlalutyo luveze ukuba amanani e-neuron abhalwe kabini ayephezulu kakhulu kumadoda afakwe kwiMeth xa kuthelekiswa nonyango olungafakwanga iMeth (p = 0.027- <0.001), okanye unyango lwe-saline (p = 0.001- <0.001) yamadoda (Umzobo 2 kwaye And3) .3). Xa idatha ibonakaliswe njengepesenti ye-neurons esebenze izidakamizwa, i-39.2 ± 5.3% kwi-NAC yengundoqo, i-39.2 ± 5.8% kwi-shell ye-NAc, i-40.9 ± 6.3% kwi-BLA, kwaye i-50.0 ± 5.3% ye-ACA neurons yavulwa bobabini kunye noMeth.

Umzobo 2      

I-Fos-eyenziweyo ye-Fos kunye ne-MET-induced proerk in expression kwi-NAc, BLA, kunye ne-ACA neurons 10 min emva kokulawulwa kwe-4 mg / kg Meth. Amanani amaninzi ± sem ka-Fos (a, d, g, j), pERK (b, e, h, k), kunye kunye (c, f, i, l) iiseli ezibhalwe kwi-NAc core (a, ...

Ukuqwalaselwa okungalindelekanga kukuba ukuziphatha ngokwesondo kuchaphazelekile ukusetyenziswa kwe-MET. Nangona i-Meth yenza kakhulu amanqanaba e-PERK kumaqela amabini kunye ne-MET-injected, kwi-NAc, BLA, ne-ACA, ukubhalwa kwee-label kwaye kwaphantsi kakhulu kwindoda ejoyiweyo iMeth xa kuthelekiswa namadoda angenayo iMeth-injected. (Umfanekiso 2b, e, h, k; p = 0.017- <0.001). Oku kufumaneka kukuxhasa ngakumbi i-hypothesis yokuba isondo kunye neziyobisi zisebenza kwi-neurons efanayo, kodwa kungabonakalisa ukuguqulwa kwamathambo kwisiphumo sokusetyenziswa kwezidakamizwa okanye imetabolism leyo eyenza iinguqu ze-neural ziphendukele kwiMeth. Ukuphanda ukuba ukuziphatha ngokwesini kubangela umzekelo wexesha eliqhelekileyo lokuqalisa ukusebenza kweziyobisi, amacandelo e-NAc, BLA, kunye ne-ACA athatyathwa ngamadoda atshiswayo kwixesha elide (15 min) emva kokulawulwa kweziyobisi (uvavanyo lwe-2).

Uvavanyo lwe-2: Ukuhlaziywa kwamaseli angatshatanga kunye namabini atyhiweyo aqinisekisile iziphumo ezichazwe apha ngasentla ukuba ukuziphatha ngokwesondo kunye nokungena kwiMeth 15 imizuzu ngaphambi kokubingelelwa kubangele ukwanda okwenziwe kweFos kunye ne-PERK immunolabeling kwi-NAc yengundoqo kunye ne-shell, i-BLA, ne-ACA. Ukongezelela, ibonakaliso ebalulekileyo yokubambisana kwe-Fos kunye ne-MET-induced proerk yafunyanwa kwakhona kule mimandla (Umzobo 4; Iziphumo zokulingana: F (1,12) = 15.93-76.62; p = 0.002- <0.001; Iziphumo zeziyobisi: F (1,12) = 14.11-54.41; p = 0.003- <0.001). Inani lee-neurons ezibhalwe amagama amabini kumadoda afakwe kwi-Meth ayephezulu kakhulu xa kuthelekiswa nonyango olunganyangekiyo lweMeth (p <0.001) okanye unyango lwetyuwa olunyuliweyo (p <0.001) eyindoda. Xa idatha ibonakalisiwe njengepesenti ye-neurons esebenzayo, i-47.2 ± 5.4% (i-NAc core), i-42.7 ± 7.6% (i-NAc shell), i-36.7 ± 3.7% (BLA), kunye ne-59.5 ± 5.1% (ACA) ye-neurons esebenzayo ngokudibanisa kwenziwa kwakhona nguMeth. Ngaphaya koko, i-pERK ebangelwa ziziyobisi ayizange yahluke phakathi kwezilwanyana ezinamaqabane kunye nezingafakwanga izilwanyana (Umfanekiso 4b, e, h, k), kuzo zonke iindawo ngaphandle kwe-ACA (p <0.001). Ezi datha zibonisa ukuba indlela yokuziphatha ngokwesondo ibangela ukuba kutshintshwe iphethini yexeshana yokungeniswa kweMER.

Umzobo 4      

I-Fos-eyenziweyo ye-Fos kunye ne-MET-induced proerk in expression kwi-NAc, BLA, kunye ne-ACA neurons 15 min emva kokulawulwa kwe-4 mg / kg Meth. Amanani amaninzi ± sem ka-Fos (a, d, g, j), pERK (b, e, h, k), kunye kunye (c, f, i, l) iiseli ezibhalwe kwi-NAc core (a, ...

Ukusebenza kwe-Neural emva kokuziphatha koSondo kunye ne-1 mg / kg Meth

Ngako oko iziphumo zibonakaliswe ukuba ukuziphatha ngokwesondo kunye ne-4 mg / kg Meth isebenze i-populations ye-neurons kwi-NAC kunye ne-shell, i-BLA kunye ne-ACA. To ukuphanda impembelelo ye-drug-dosage kule mpahla ekusebenziseni, iipatheni zokusebenza kwe-neural ziye zafundiswa ngokusebenzisa i-dose ephantsi yeMeth. Inqobo ye-NAc kunye negobolondo, i-BLA, kunye ne-ACA zahlaziywa ngenxa yokusebenziselwa ngokwesondo kunye neMeth. Enyanisweni, ukuziphatha ngokwesondo kunye nokungena kwiMeth kubangele ukunyuka okukhulu kweFos kunye ne-PERK immunolabeling kwinqanaba le-NAc kunye neengqungquthela ze-shell, i-BLA, kwakunye ne-neurons kwingingqi ye-ACA ye-mPFC (Umzobo 5). Kuyathakazelisa ukuba i-dose ephantsi yeMethi yabangela inani elifanayo le-PERK ebizwa nge-neurons njengoko yenziwe ngu-4 mg / kg Meth kwiindawo ezine zengqondo ezihlalutyiweyo. Okubaluleke ngakumbi, i-NAc yengundoqo kunye negobolondo, i-BLA, kunye ne-ACA ibonise ukwanda okwenene kwinani lamaseli adibeneyo amabini (Umfanekiso 5c, f, i, l) ngokuthelekiswa nokungafakwanga ngamadoda afakwe kwiMeth (p = 0.003- <0.001). Xa idatha ibonakalisiwe njengepesenti ye-neurons eyenziwe yiziyobisi, i-21.1 ± 0.9% kunye ne-20.4 ± 1.8% kwisiseko se-NAc kunye neqokobhe ngokwahlukeneyo, i-41.9 ± 3.9% kwi-BLA, kunye ne-49.8 ± 0.8% ye-ACA neurons yenziwe yasebenza ngesondo kunye neMeth.

Umzobo 5      

I-Fos-eyenziweyo ye-Fos kunye ne-MET-induced proerk in expression kwi-NAc, BLA, kunye ne-ACA neurons 15 min emva kokulawulwa kwe-1 mg / kg Meth. Amanani amaninzi ± sem ka-Fos (a, d, g, j), pERK (b, e, h, k), kunye kunye (c, f, i, l) iiseli ezibhalwe kwi-NAc core (a, ...

Ukusebenza kwe-Neural emva kokuziphatha ngokwesondo nokulawulwa kwe-d-Amphetamine

Ukuvavanya ukuba ngaba iziphumo ezingentla zizodwa malunga neMethi, kwenziwa ukuhlolwa okongeziweyo ukufundela ukusebenzisana kwe-neural ne-Amph-induced activation. Uhlalutyo lwamaseli angabini kunye namabini atyhiweyo e-PERK ne-Fos abonise ukuba ukuziphatha ngokwesondo kunye nokuchasana okulandelayo kwi-Amph kubangele ukwanda okwenziwe kwe-Fos kunye ne-PERK immunolabeling kwi-NAc yengundoqo kunye ne-shell kunye ne-BLA (Umzobo 6; Iziphumo zokulingana: F (1,15) = 7.38-69.71; p = 0.016- <0.001; Iziphumo zeziyobisi: F (1,15) = 4.70-46.01; p = 0.047- <0.001). Ngaphaya koko, amanani ee-neurons ezibhalwe amagama aphakame kakhulu kunyango lwe-Amph xa kuthelekiswa nokunganyangwa kwe-Amph (p = 0.009- <0.001), okanye unyango lwe-saline (p = 0.015- <0.001) yamadoda (Umzobo 6c, f, i). Xa idatha ibonakaliswe njengepesenti ye-neurons esebenze izidakamizwa, i-25.7 ± 2.8% kunye ne-18.0 ± 3.2% kwi-NAc yengundoqo kunye neqokebhe ngokulandelanayo, kwaye i-31.4 ± 2.0% ye-BLA neurons yavulwa ngokubambisana kunye ne-Amph. Ummandla we-ACA we-mPFC ubonise amanqanaba afanelekileyo eFos-induced-fos (Umfanekiso 6j; F (1,15) = 168.51; p <0.001). Nangona kunjalo, ngokungafani neMeth, i-Amph ayikhange ibangele ukonyuka okukhulu kumanqanaba e-PERK abangelwa ziziyobisi kwi-ACA (Umzobo 6k) okanye amanani amabini e-neurons abiziweyo kwi-ACA (Umzobo 6l) xa kuthelekiswa nakwindoda ejoyiweyo e-saline.

Umzobo 6      

I-Fos-induced Fos kunye ne-Amph-induced incerk expression in NAc, BLA, kunye ne-ACA neurons 15 min emva kokulawulwa kwe-5 mg / kg. Amanani amaninzi ± sem ka-Fos (a, d, g, j), pERK (b, e, h, k), kunye kunye (c, f, i, l) iiseli ezibhalwe kwi-NAc core (a, ...

UKUQALA

Uphononongo lwangoku lubonakalisa kumgangatho weselula ukuxhatshazwa phakathi kokusebenza kwe-neural ngokuziphatha kwezesondo zokumgangatho wesimo kunye neMeth psychostimulant. Ngoko ke, ezi nkcukacha zibonisa ukuba kungekhona kuphela izidakamizwa ezisebenza kwiindawo ezifanayo zengqondo ezilawula umvuzo wendalo, kodwa empeleni, iziyobisi zisebenzise iiseli ezifanayo ezibandakanyekayo ekulawuleni umvuzo wendalo. Ngokukodwa, kuboniswe apha ukuba indlela yokuziphatha ngokwesondo kunye neMeth yaqalisa ukusebenzisana nenani le-neurons kwi-NAc yengundoqo kunye ne-shell, i-BLA, kunye ne-ACA kwingingqi ye-mPFC, ukuchonga iziza ezinokwenzeka apho iMeth inokuchaphazela ukuziphatha ngokwesondo.

Ukufumana kwangoku ukuba ukuziphatha ngokwesondo kunye nokulawulwa kweMeth kusebenze ukugqithwa kwabantu be-neurons kwi-NAc, BLA, kunye ne-ACA kuhambelana nokufunyaniswa nezinye iifundo ezibonisa ukuba abantu abahlukeneyo be-NAc neurons badibanisa umvuzo kunye nemvelo.

Ngokukodwa, izifundo ze-electrophysiological eziqhathanisa ukusebenza kwe-neural ngexesha lokuzilawula ngokwasemzimbeni wemvelo (ukutya kunye namanzi) kunye ne-cocaine e-intravenous zibonise ukuba i-cocaine-self-administration yenze i-differential, i-coorine ye-self-administration eyenziwa ngokungafaniyo eyayingaphenduliyo ngexesha lokuphendula ngokusebenza kwamanzi kunye nokuqiniswa kokutya (92%). Kuphela i-8% ye-neurons ye-accumal neurons ibonise ukusebenza ngokubini kwe-cocaine nomvuzo wendalo (Carelli et al., 2000).

Ngokwahlukileyo, ininzi (i-65%) yeseli ku-NAc ibonise ukusebenzisiswa ngembuyekezo eyahlukileyo yemvelo (ukutya kunye namanzi), nangona ukuba omnye umfaki-mandla wayenomdla kakhulu (i-sucrose) (Roop et al., 2002).

Zininzi izinto ezinokubangela ukungafani neziphumo zangoku. Okokuqala, iindlela ezahlukahlukeneyo zobugcisa zazisetyenziselwa ukuphanda imisebenzi ye-neural. Ukufunda kwangoku kusetyenziswe indlela yokusebenzisa i-neuroanatomical yokufumana ukusetyenziswa kwe-neural ngokufanayo kunye nemifanekiso emibili ehlukeneyo usebenzisa i-immunocytochemisty ye-fluorescencent emibini ye-Fos kunye ne-PERK, evumela ukuphanda ukusetyenziswa kwamaseli omnye kwiindawo ezinkulu zeengqondo. Ngokwahlukileyo, izifundo zikaCarlli kunye nabasebenzi abasebenzisanayo basebenzisa i-electrophysiological recordings kuphela kwi-NAc yokuziphatha izilwanyana ukujongana nokuba ukulawulwa kwezilwanyana zokusetyenziswa kakubi kweziyobisi kusebenze isiphaluka esifanayo esisetyenziselwa imivuzo yemvelo.

Okwesibini, uphononongo lwangoku luphande umvuzo wendalo ohlukeneyo, oko kuthetha ukuziphatha ngokwesondo xa kuthelekiswa nezifundo zangaphambilini, ezisebenzisa ukutya kunye namanzi kwimizi (Carelli, 2000). Ukutya kunye namanzi kunokuba nexabiso elincinci elincinci kunokuba ukulingana. Ukuziphatha ngokwesondo kuvuyisa kakhulu kwaye iinkozi zenza i-CPP ngokukhawuleza ukuba iqhube (Agmo noBerenfeld, 1990, UMartinez kunye neParedes, i-2001, Tenk, 2008). Nangona, iiriti ezidityanisiweyo zokutya zenza i-CPP yamanzi (Agmo et al., 1993, Iipeksi kunye neClafton, i-1997) kunye nokutya (Iipeksi kunye neClafton, i-1997), dIingcingo ezingenakuvinjelwa zikhetha ukugqiba kwaye zenze iCPP yokutya okunomdla (Jarosz et al., 2006, Jarosz et al., 2007).

Okwesithathu, izifundo zethu zazibandakanya iziyobisi ezahlukileyo zoxhatshazo xa kuthelekiswa nezifundo zangaphambili, zisebenzisa i-methamphetamine kunye ne-amphetamine esikhundleni se-cocaine. Iziphumo ezikhoyo zibonisa ukuba iMeth ngokuthe ngqo, kunye ne-amphetamine encinci, yabangela ukuba kusebenze i-neurons nayo isebenze ngokuziphatha ngokwesondo. Amava eziyobisi angaba nawo adlala into ekufumaneni kwethu. Izifundo zangoku zizisetyenziswe izilwanyana ezazibandakanya ngokwesondo, kodwa i-drug naïve. Ngokwahlukileyo, izifundo ze-electrophysiological ze-Carelli kunye nabasebenzi abasebenzisana nabo basebenzisa "izilwanyana eziqeqeshwe kakuhle" ezifumene ngokuphindaphindiweyo kwi-cocaine.

Ngenxa yoko, kunokwenzeka ukuba ukusebenziselwa kweMeth ye-neurons eyenziwe yindlela yokuziphatha ngokwesondo kuguqulwa kwiirats ezizizonyango. Nangona kunjalo, izifundo zokuqala ezivela kubhanki bethu zibonisa ukuba amava eziyobisi ayinakwenzeka ukuba yinto ebalulekileyo njengendlela yokuziphatha ngokwesondo kunye nokuphathwa kweMeth kwindoda engapheliyo rhoqo ngeMeth esebenza ngokufanayo kunye neephesenti ezifanayo ze-neurons ezenziwe ngamachiza njengoko zichazwe kwisifundo esilandelayo (20.3 ± 2.5% kwi-NAc kunye ne-27.8 ± 1.3% kwi-shell ye-NAc; i-Frohmader ne-Coolen, ukunyatheliswa kokushicilelwa).

Ekugqibeleni, uphononongo lwangoku luphengulule isenzo "ngokuthe ngqo" seziyobisi esebenzisa ukuphathwa okungekhoyo. Ngoko ke, uhlalutyo lwangoku alubonakali ulwazi malunga nezijikelezo zeebrama ezibandakanya ukufunyanwa kwezidakamizwa okanye iingcamango ezinxulumene nomvuzo weziyobisi, kodwa kunoko kubonakalisa umsebenzi we-neural obangelwa isenzo se-pharmacological yesilwanyana. Kwizifundo zangaphambili ze-electrophysiological, umsebenzi we-NAc we-neural okwenzeka ngaphakathi kwemizuzwana yeempendulo eziqinisiweyo akuyiyo imbangela yesenzo se-pharmacological ye-cocaine, kodwa ixhomekeka kakhulu kwizinto ezinxulumene neparadigm (Carelli, 2000, Carelli, 2002). Ngokukodwa, imisebenzi ye-NAc ye-neural ithonywe yimbonakalo yodwa yokuziphendulela ezizimeleyo ze-cocaine ezithunyelwayo kunye neengxaki zokusebenza (oko kukuthi, ukucindezela kwe-lever) ehambelana nale mpahla yokuziphatha (Carelli, 2000, Carelli no-Ijames, i-2001, Carelli, 2002, Carelli kunye noWightman, 2004). Isishwankathelo, iziphumo zethu zokubambisana kunye nomvuzo wendalo kunye neziyobisi zingacaciswa ngokusebenza ngokuziphatha ngokwesondo kunye ne-Meth ne-Amph.

I-Meth kunye ne-sex activated populations of neurons kwi-NAC kunye negobolondo ngendlela exhomekeke kuyo. Ama-neurons asebenze ngokubambisana nawo kwi-NAc angahle adibanise iziphumo ezinokwenzeka zeMethi kwiimpawu ezikhuthazayo kunye nezivuzayo zokuziphatha ngokwesondo njengoko izilonda ze-NAc ziphazamisa ukuziphatha ngokwesini (Liu et al., 1998, Kippin et al., 2004). Ukongezelela, la ma-neuron ayenokuba yindawo yokuxhatshazwa kwezidakamizwa ekuxhaseni, ekubeni i-Meth dose ephantsi (i-1 mg / kg) inciphise inani leelitha ezimbini ezibhalwe nge-50% xa kuthelekiswa nomlinganiselo ophezulu weMeth (4 mg / ikg). Nangona esi sifundo asiqapheli i-phenotype yemichiza ye-neurons esebenzisanayo, uphando lwangaphambili lubonise ukuba ukubonakaliswa kwe-PERK kunye ne-Fos ibonakaliso kwi-NAc kuxhomekeke kwi-dopamine (DA) kunye ne-glutamate receptors (Valjent et al., 2000, Ferguson et al., 2003, Valjent et al., 2005, I-al et al., I-2008). Nangona akucaci ukuba ukusebenziselwa kwe-neural activation ku-NAc kuxhomekeke kulezi zifunyenwe, oku kuboniswe kwezinye iindawo zengqondo, ngokukodwa kwindawo yangaphambili yomhlaba (ULumley noHull, 1999, IDominguez et al., 2007). Tke, iMeth inokusebenza kwi-neurons nayo isebenze ngexesha lokuziphatha ngokwesondo ngokusebenzisa i-dopamine kunye ne-glutamate receptors. Indima ye-NAc igxininisa ekuziphatheni ngokwesondo okwamanje ayikho into ecacileyo, kodwa ichanekile ukuba i-DA inendima ebalulekileyo ekukhuthazeni ukuziphatha ngokwesondo (Hull et al., 2002, Hull et al., 2004, Pfaus, 2009). Ucwaningo lwe-Microdialysis luchaze ukunyuka kwe-NAc DA ye-efflux ngexesha lokunyanzelisa nokuqhelanisa nokuziphatha komntu wesini (Fiorino kunye nePhillips, 1999a, Lorrain et al., 1999) kunye ne-mesolimbic ye-DA ye-efflux iye yahambelana nokuququzelela ukuqaliswa nokugcinwa kokuziphatha ngokwesondo (rat)Pfaus no Ever Ever, 1995). Ukongezelela, izifundo ze-DA zonyango zibonisa abadlali be-DA kwi-NAc bavimbela ukuziphatha ngokwesondo, ngelixa i-agonists iququzelela ukuqaliswa kwesenzo sokuziphatha ngokwesondor (Everitt et al., 1989, Pfaus kunye nePhillips, i-1989). Ngaloo ndlela, iMeth inokuchaphazela ukukhuthazwa kokuziphatha ngokwesondo ngokusebenzisa ii-receptors ze-DA.

Ngokuphambene ne-NAc, inani lamaseli abulawe kabini kwi-BLA ne-ACA yahlala ingatshintshanga nantoni na i-Meth dose. I-BLA ibaluleke kakhulu ekufundeni okudibeneyo kunye nokubandakanya ngamandla ekuqinisekiseni umgangatho kunye nokuvuza umvuzo ngexesha lokuphendula kweengoma (Everitt et al., 1999, IKhadidi kunye no-., 2002, Yabona, 2002). I-BLA ikhonjiswe iirati ibonisa ukunciphisa i-lever yokunyanzelisa i-stimuli ehambelana nokutya (Everitt et al., 1989) okanye ukuqiniswa ngokwesini (Everitt et al., 1989, Everitt, 1990). Ngokwahlukileyo, oku kuphazamiseka akuchaphazeli isigaba sokugqibela sokutya nokuziphatha ngokwesondo (IKhadidi kunye no-., 2002). I-BLA nayo idlala indima ebalulekileyo kwimemori ye-stimuli echanekileyo ehambelana nesishumbiso seziyobisi (UGrace noRosenkranz, i-2002, ULaviolette noGrace, i-2006). Izilonda okanye ukuchithwa kwee-pharmacological kweBLA kuvimba ukufumana (I-Whitelaw et al., 1996) kunye ne ntetho (Grimm kwaye Jonga, 2000) ukubuyiswa kwe-cocaine yokupheliswa komzimba, ngaphandle kokuchaphazela inkqubo yokulawulwa kweziyobisi. Ngaphezu koko, I-Amph ingene ngqo kwiziphumo ze-BLA kwisigxina sokubuyisela iziyobisi phambi kweengxelo ezimiweyo (Bona kunye al., 2003). Ngoko ke, kunokwenzeka ukuba ukudluliselwa kwe-DA kwengqondo ye-psychostimulant kwi-BLA kubangelwa kukunyamekela kwengqondo kunye nokufuna (ULedford et al., 2003) umvuzo wesini, oko kuncedisa ekwenzeni ukuxhatshazwa ngokwesini kunye nomnqweno ochazwe ngabahlukumezi beMeth (Semple et al., 2002, Uhlaza kunye neHalkitis, i-2006).

Kwi-ACA, ukusebenziselwa kwe-neural ye-neurons esebenze ngesondo kwakuyi-self-dosage-self-specific and specific for Meth, njengoko yayingagcinwanga kunye ne-Amph. Nangona i-Meth ne-Amph zinempahla efana nesakhiwo kunye ne-pharmacy, i-Meth yinto engcono kakhulu ye-psychostimulant kune-Amph eneempembelelo ezingapheliyo (NIDA, 2006). Izifundo zikaGoodwin et al. wabonisa ukuba iMeth ivelisa i-DA enkulu ye-efflux kwaye inqanda ukukhutshwa kwe-DA esebenzayo ngokufanelekileyo kwi-rat NAc kune-Amph. Ezi zimpawu zinokuthi zenze igalelo kwiimpawu eziluthayo zeMeth ngokumalunga ne-Amph (Goodwin et al., 2009) kwaye mhlawumbi ulwahlulo lwentsebenziswano lwe-neural luboniswa phakathi kwezi zi yobisi. Nangona kunjalo, akucaci ukuba ngaba iipatheni ezahlukeneyo zeziphumo zibangelwa ukungafani kokusebenza phakathi kwamachiza okanye imicimbi enxulumene namayeza aqeshwe kwaye uphando oluthe lufunekayo.

Ukusebenza ngokubambisana nguMeth kunye nesondo akuzange kubonwe kwezinye iimimandla zeMPFC (IL kunye ne-PL). Kwi-rat, i-ACA iye yafundwa ngokubanzi ngokusetyenziswa kwemimiselo, ixhasa indima kwimibutho yokuvuselela (Everitt et al., 1999, Yabona, 2002, IKhadidi kunye no-., 2003). Kukho ubungqina obuninzi bokuthi i-mPFC ibandakanyeka ekufuneni izidakamizwa kwaye iphinde ibuyele ekusebenziseni izidakamizwa nokuziphatha kwezidakamizwa kubini kunye neerati (Isibonelelo kunye no-1996, Childress et al., 1999, Capriles et al., 2003, McLaughlin kunye ne-See, 2003, Shaham et al., 2003, IKalivas neVolkow, i-2005). MnaNgokumalunga nalokhu, kucetyiswa ukuba i-mPFC yokusebenza kakubi kubangelwa ukugqithiswa ngokuphindaphindiweyo kwimichiza yokusetyenziswa gadalala inokuba noxanduva lokulawulwa kokunyanzeliswa komfutho kunye nokuziphatha okunyanzelisiweyo kwezidakamizwa njengoko kubonwe kumlutha amaninzi (UJentsch noTylor, i-1999). Idatha yakutshanje evela kwibhubhoratri yethu ibonise ukuba izilonda ze-mPFC ziphumela ekufuneni ngokuqhubekayo ngokwesondo xa oku kuhambelana nokuvuselela (Davis et al., 2003). Nangona esi sifundo asizange siphenye i-ACA, sisekela ingcinga yokuba i-mPFC (kunye ne-ACA ngokukhethekileyo) idibanisa imiphumo ye-Meth ekulahlekelweni kokulawulwa kwe-inhibitory malunga nokuziphatha ngokwesondo njengoko kuchazwe ngabahlukumezi be-Meth (Salo et al., 2007).

Ekugqibeleni, ezi zifundo zenza isinyathelo sokuqala esona siphumelelo ekuqondeni kangcono indlela ukusetyenziswa kweziyobisi kakubi ngayo indlela yokuziphatha kakubi. Ngaphezu koko, ezi ziphumo zibonisa ukuba ngokuchasene nenkolelo yangoku yokuba iziyobisi zokusetyenziswa kakubi azisebenzisi iiseli ezifanayo kwi-eyelimbic system njengomvuzo wendalo, iMeth, kunye ne-Amph encinci, isebenzise iiseli ezifanayo njengendlela yokuziphatha ngokwesondo. Ngaloo ndlela, aba bantu basebenzisane ngokubambisana nabo bangabangela ukuba bafumane umvuzo wendalo emva kokungabikho kwezidakamizwa. Ekugqibeleni, iziphumo zolu pho nonongo zinganceda kakhulu ukuqonda kwethu isiseko somlutha ngokubanzi. Ukuthelekiswa kokufana kunye nokungafani, kunye nokuguqulwa kwindlela yokusebenzisa i-neural ukusebenza kwenkqubo ye-mesolimbic efunwa ngokwesenzo sokuziphatha ngokwesini kunye nokusetyenziswa kakubi kweziyobisi kunokukhokelela ekuqondeni okungcono ukusetyenziswa kakubi kweziyobisi kunye nokuguqulwa okuhambelana nomvuzo wendalo.

Imibulelo

Olu phando lwaxhaswa yimali evela kwiiNational Institutes of Health R01 DA014591 kunye namaziko aseKhanada oPhando lwezeMpilo RN 014705 ukuya kwiLMC.

AMABHUNGA

  • ABC
  • ubunzima be-pidxadase-biotin-horseradish complex
  • aca
  • indawo yangaphambili
  • Amph
  • d-amphetamine
  • BLA
  • amygdala
  • BNSTpl
  • I-nucleus yebhedi ye-posterolateral ye-stria terminalis
  • BNSTpm
  • I-nucleus yebhedi ye-posteromedial ye-stria terminalis
  • BT
  • tyramide
  • CeA
  • amygdala
  • CPP
  • indawo ekhethiweyo
  • E
  • ejaculation
  • EL
  • ejaculation latency
  • IF
  • indawo ye-infralimbic
  • IL
  • ukuhamba kwexesha lokuyeka
  • IM
  • ukungena
  • M
  • Ukunyuka
  • MAP Kinase
  • protein kinase esebenzayo
  • MEApd
  • i-amygdala yangaphakathi
  • IMeth
  • methamphetamine
  • ML
  • latency hill
  • mPFC
  • i-cortex yomda
  • MPN
  • nucleus yangaphambili
  • NAc
  • nucleus Accumbens
  • PB
  • i-phosphate buffer
  • PBS
  • i-phosphate i-saline ephuhliweyo
  • PEI
  • kwithuba lokuvala ixesha
  • PERK
  • IPhosphorylated MAP Kinase
  • PL
  • indawo yangaphambili
  • VTA
  • indawo yezentlalo

Imihlathi

Iphepha elichazayo ukuba awusenanto oyifunayo: Le fayili yeFayile yombhalo wesandla ongabhalwanga owamkelwe ukushicilelwa. Njengenkonzo kumakhasimende ethu sinika le ngcaciso yokuqala kwincwadi yesandla. Umbhalo wesandla uza kufumana ukukopishwa, ukufakela, nokuphonononga ubungqina obunokubakho ngaphambi kokuba kukhutshwe kwifomu yayo yokugqibela. Nceda uqaphele ukuba ngexesha lokuveliswa kweeprogram ezinokuthi zifumaneke ezinokuthi ziphazamise umxholo, kunye nazo zonke izisemthethweni ezichasayo ezisetyenziswa kwiphephancwadi.

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