IMIBUZO: Ukufundwa kubonisa izinguquko ze-neuroplastic and behavioral in circuit circuit kungaba nokuvela emsebenzini wezocansi. Lokhu kuhlanganisa ukukhula kwamagatsha e-neuron nokuphendula okunamandla kwezidakamizwa. Njengenjwayelo, iziqinisi zemvelo nezidakamizwa zinemiphumela efanayo ebuchosheni.
Pitchers KK, Balfour ME, Lehman MN, Richtand NM, Yu L, Coolen LM.
I-Biol Psychiatry. 2010 May 1; 67 (9): 872-9. I-Epub 2009 Dec 16.
Umnyango we-Anatomy ne-Cell Biology, iSchool School of Medicine kanye namaDentistry, eNyuvesi yaseWestern Ontario, eLondon, e-Ontario, eCanada.
UKUQALA
UMLANDO: Umvuzo wemvelo kanye nezidakamizwa zokuhlukunyezwa ziguqulela ohlelweni lwe-mesolimbic, lapho izidakamizwa zokuhlukunyezwa zidala ukuguqulwa kwe-neuronal. Lapha, sihlolwe i-plasticity kule nqubo emva komvuzo wemvelo kanye nomthelela olandelayo kwizimpendulo zezidakamizwa.
IZINDAWO: Imiphumela yezocansi emantwini abesilisa ekukhuthazeni ukuziphatha nokuhlelwa kwendawo ehlotshaniswa ne-d-amphetamine (AMPH) kanye ne-Golgi-impregnated dendrites nezinsimba zamaseli we-nucleus accumbens (NAc) anqunywe. Ngaphezu kwalokho, umthelela wokuzigwema ekuziphatheni ngokobulili kubantu besilisa abanolwazi kulezi zimingcele kwahlolwa.
IZIPHUMA: Okokuqala, ukuziphatha ngokocansi okuphindaphindiwe kwenzé impendulo yokuvakasha ezwelayo kuya ku-AMPH uma kuqhathaniswa nezihloko zokulawula ukuhlukunyezwa ngokobulili zibheke i-1, i-7, nezinsuku ze-28 ngemuva kokugcina kokuhlangana kokugcina. Okwesibili, izilwane ezitholakale ngokobulili zakha indawo ehlelwe yindawo ehlelwe yindawo ehlelwe ngayo ye-AMPH kunamadoda angama-sexuality, okukhombisa ukuphakama kwenzuzo ye-AMPH. Okokugcina, ukuhlaziywa kweGolgi-Cox kubonise izinyuka ezikhudlwana zama-dendrites kanye nezimpande kwi-NAc core kanye negobolondo ngesipiliyoni socansi. Izinguquko ezimbili zokugcina zixhomeke esikhathini sokuziqeda kwezinsuku ze-7-10.
IMIBUZO: Ukuhlangenwe nakho ngokocansi kudala ukuguqulwa okusebenzayo nokuziphatha komzimba we-mesolimbic kufana nokuchayeka ngokuphindaphindiwe kuma-psychostimulants. Ngaphezu kwalokho, ukuziyeka ekuziphatheni ngokocansi ngemuva kokubambisana ngokuphindaphindiwe kwakudingeka ukuze kukhule umuthi wezidakamizwa kanye namadwala e-NAc, okuphakamisa ukuthi ukulahlekelwa umvuzo wezocansi kungase kube negalelo le-eyelimbic system. Le miphumela iphakamisa ukuthi ezinye izinguquko ohlelweni lwe-mesolimbic zivame umvuzo wemvelo kanye nezidakamizwa futhi zingase zidlale indima ekuqiniseni jikelele.
I-copyright 2010 Society of Biological Psychiatry. Ishicilelwe ngu-Elsevier Inc. Wonke amalungelo agodliwe.
ISINGENISO
Uhlelo lwe-mesolimbic dopamine (DA), olunezinkanyezi ze-dopaminergic endaweni ye-ventral tegmental (VTA) enezilinganiso ze-nucleus accumbens (NAc) kanye ne-prefrontal cortex (i-mPFC) ephakathi, idlala indima ebalulekile ezicikweni ezikhuthazayo nezivuza zokuziphatha kuhlanganise ulaka (1), ukudla (2-7), ukuphuza (8), ukulinganisa (9-11) nokuhlanganiswa komphakathi (12-13). Izidakamizwa zokuhlukunyezwa ziguqukela ohlelweni lwe-DA lwe-mesolimbic (14-15). Ngaphezu kwalokho, ukuphathwa kwezidakamizwa okuphindaphindiwe kungaholela ekuguqulweni kwe-neuronal kulezi zindlela, okuphinde kudlale indima yokufaka ekwenzeni ukwandisa ukutholakala kwezidakamizwa, noma ekushintsheni kokusetshenziswa kwezidakamizwa ukuya ekulutha izidakamizwa (16-18). Imiphumela yokuziphatha ka-rUkuphathwa kwezidakamizwa ezithintekayo kuhlanganisa impendulo yokuvakasha ezwelayo kuma-psychostimulants nama-opiates (19-21), umvuzo wezidakamizwa othuthukisiwe (22-24), aNgiye ngandisa izimpendulo ezisebenzayo zokubamba izidakamizwa ezihambisana nokudla kwangaphambili kwezidakamizwa (25). Ngaphezu kwalokho, ukuphathwa kwezidakamizwa okuphindaphindiwe kuholela ekushintsheni okuhlala njalo ku-dendritic morphology kanye nomswakama womgogodla kulo lonke i-circui ye-mesolimbict (16, 26-31), futhi kudala izinguquko zesimo sezakhi zofuzo (32-35). Okokugcina, ukuphathwa kwezidakamizwa okuphindaphindiwe kuguqula amandla e-synaptic kuma-syapses angenayo futhi evimbelayo phakathi kwe-midbrain i-dopamine neurons (36-41), ne-neurons ku-NAc (42-44). Okwamanje akucaci ukuthi izinguquko ezifanayo ohlelweni lwe-mesolimbic zenzeka ngokuchayeka ngokuphindaphindiwe kumvuzo wemvelo. Ukunquma ukuthi ukuguqulwa okunjalo noma okungafani nezidakamizwa zokuhlukunyezwa kungaholela ekuqondeni kangcono amasistimu weselula ephazamisa umehluko phakathi kokufunwa komvuzo okujwayelekile noma ukufuna ukuphoqelela umvuzo othile.
Ukusekela inkolelo yokuthi izinyathelo ezingaphezu kwezidakamizwa zingabangela ukuguqulwa kwe-neuronal ohlelweni lwe-mesolimbic kukhona okutholakele okucindezelayo ukuvuselela izinhlelo ze-dopamine (45-47), futhi kubangele ukukhushulwa kwe-psychomotor ukuvuselela okukhuthazayo (21, 48-50) futhi abuyele emibonisweni yokuzibusa (51-54). Kodwa-ke, izifundo ezimbalwa ziye zaphenya ukuthi ukuziphatha kwemvelo okuvuzayo kungabuye kuveze izinguquko ezisebenzayo ohlelweni lwe-DA (6, 55-56). Ngakho-ke, i-hypothesis ihlolwe ukuthi isipiliyoni sobulili besilisa senza ushintsho lwe-neuronal ngaphakathi kwesistimu ye-DA ye-mesolimbic ngokuhlaziywa kwemiphumela yesimo socansi ekuqinisekiseni ukukhiqiza, ukukhetha indawo okwakhiwe, kanye ne-dendrite morphology ye-NAc neurons. Ngaphezu kwalokho, sasizicabangela ukuthi isikhathi sokuziqeda ekuziphatheni ngokobulili (umvuzo wezocansi) kubalulekile ekuqaleni kwalezi zinguquko, ngokususelwa ekuqapheliseni kwamuva ukuthi ukuqeda izidakamizwa kudlala indima ebalulekile ekwakhiweni kweplastiki ye-neural ehambisana nokutholakala kwezidakamizwa eziphindaphindiwe (40, 57-59).
IZINDLELA
Izilwane
Amantombazane amadala aseSprague Dawley (ama-210-250 amagremu) atholakala eHarlan Laboratories (Indianapolis, IN, USA) noma iCharles River Laboratories (eSenneville, QC, Canada) futhi ahlala emagumbini e-Plexiglas ngamatayipi emigwaqo. Abesilisa babehlala ngamabili obulili bobulili obufanayo phakathi kokuhlolwa (ukuhlolwa kwe-2-5), ngaphandle kokuhlola i-1 lapho amadoda angashadile ayehlala khona lapho kuqala ukutadisha. Igumbi lokushisa elisezingeni lokushisa ligcinwe ku-12 / 12 hr umjikelezo omnyama omnyama nokudla namanzi atholakalayo isikhangiso ngaphandle kokuhlolwa kokuziphatha. Ama-stimulus females (ama-210-220 amagremu) wokuzibandakanya kokuzibandakanya ayenziwe ngama-ovariectomized futhi athola isitshalo esincane esine-5% estradiol benzoate ne-95% ye-cholesterol. Ukwamukelwa ngokocansi kwenzelwa ukuphathwa kwe-progesterone ye-500μg ku-0.1 ml i-sesame yamafutha cishe amahora angu-4 ngaphambi kokuhlolwa. Yonke inqubo yamukelwa yi-Animal Care kanye namakomidi asetshenziswayo eNyuvesi yaseCincinnati naseYunivesithi yaseWestern Ontario, futhi iyahambisana nemikhombandlela ye-NIH kanye ne-CCAC ehilela izilwane ze-vertebrate ekucwaningweni.
Ukuphathwa kwezidakamizwa
I-D-Amphetamine (AMPH) i-sulfate (Sigma, iSt. Louis, MO) yachithwa ngo-strick 0.9% saline (SAL). Izilwane zithole imithi ye-AMPH ephakathi kwe-0.5-5.0 mg / kg isisindo somzimba, ibalwa ngokusekelwe esiteshini samahhala, ngevolumu ye-1mL / kg isisindo somzimba. Ukulawula izilwane zithole SAL. Yonke imijovo yanikezelwa ngaphansi kwesigamu sokuqala kwesigaba sokukhanya (amahora angu-2-6 ngemva kokukhanyisa), ngokushesha ngaphambi kokufakwa kumadivaysi okuziphatha.
Ukuhlola Ukusebenza Kwendawo
Umsebenzi wokwenza indawo ulinganisiwe usebenzisa amakamelo okusebenza okwakhiwa ngokwezifiso (LACs), okuhlongozwa ekamelweni elakhiwe nguSegal no-Kuczenski (60). Umsebenzi we-locomotor walinganiswa usebenzisa uhlu lwe-16 × 16 le-photobeam (i-San Diego Instruments, i-San Diego, CA) futhi waboniswa njengama-crossovers ngeminithi. I-crossover ibhaliwe isikhathi ngasinye lapho isilwane singena noma yikuphi "izingxenye ezisebenzayo" ekamelweni, ezikhonjiswe njengezindawo ezinomthunzi Umfanekiso 1A (61).
Ukuhlolwa kokuziphatha ngokocansi
Kuzo zonke izivivinyo, amagundane angamadoda ahlukunyezwa ngokobulili ahlukaniswe ngamaqembu abe ngamaqembu angaba nesipiliyoni socansi noma ahlale engenzi lutho. Ukuze uthole okuhlangenwe nakho, zonke izivivinyo zokulinganisa zenziwa phakathi nengxenye yokuqala yesigaba somnyama (amahora angu-3-8 ngemva kokukhanya okukhanyisiwe) ngaphansi kokukhanya okubomvu obomvu. Izilwane ezahlala ziphila ngokocansi zaphathwa futhi zahlala emakamelweni afanayo njengamadoda abesilisa ngokobulili, ngakho-ke zivezwe emazingeni afanayo okuphazanyiswa, izakhiwo zemvelo kanye neziphunga ezikude zezilwane njengezilwane ezinolwazi. Kuzo zonke izivivinyo, amaqembu abesifazane abesilisa ocansini ahlotshaniswa nesipiliyoni socansi (ngokusekelwe ezinombolweni ze-ejaculations, kanye nama-latencies ekujuleni nasekunciphiseni ngesikhathi sokugcina ukuhlangana).
Zama i-1
Ukuhlolwa kwe-1 no-2 basebenzisa ama-paradigms ahlukene ukuze bahlole imiphumela yokulingana okuphakathi kanye nemvelo. Ekuvivinyweni kwe-1, izilwane kumaqembu ahlangene ngocansi zithola ama-5 amaseshini wokulinganisa okuphakathi kwesikhathi ahlukaniswe nezinsuku ze-3-4, lapho zihlala khona emakamelweni abo ngamadoda atholakele ngochungechunge lwe-3 (kufaka phakathi i-ejaculation) noma imizuzu ye-60, noma yikuphi okufika kuqala. Izilwane ezaqedela uchungechunge olwengeziwe lwezinhlamvu eziphindwe ezinhlanu zazibhekwa njengezicansi. Izilwane ezingenayo ucansi azizange zithole abalingani besifazane. Ngesonto elilodwa emva kweseshini yokugcina yokubeletha, izilwane ezitholakalayo ngokobulili nezizimele zahlukaniswa ngamaqembu athola ama-AMPH (0.5 mg / kg) noma i-SAL yamaqembu amane (i-Naïve Amphetamine: NA; i-Amphetamine ene-Experienced: EA; Naïve Saline: NS; I-saline enobuchwepheshe: ES; n = 6 ngayinye).
Zama i-2
Lokhu kuhlolwa kuhluke ekuhlolweni kwe-1 ngezindlela ezintathu: 1. Izilwane zihambisana nokukhipha okulodwa ngesikhathi sezinsuku ezilandelanayo; I-2. Izilwane zihlala emgodini ofanayo lapho zithola khona i-AMPH (kuma-LACs); I-3. Umsebenzi wokwenza indawo olandelayo ngemuva kwe-AMPH uhlaziye ngezikhathi ezintathu ezilandelelanayo kulandela isipiliyoni socansi. Izilwane ezitholakale ngokobulili zithola izixuku ze-7 ezilandelanayo zemihla ngemihla emisebenzini ye-LAC kanye nomsebenzi wokuvakasha wabhalwa phakathi nemizuzu ye-15 phakathi kokubekwa kuma-LAC nokufakwa kwesifazane. Izilwane ezizibandakanya ngokobulili zafakwa kuma-LACs ngezikhathi eziyisikhombisa ezilandelanayo ngaphandle kokulingana. Ngosuku olulandelayo iseshini yokugcina ukuhlangana (usuku lwe-8 lokulingwa), izilwane zafakwa kuma-LACs ngokushesha ngemva kokujova kwe-AMPH (0.5 mg / kg) noma i-SAL (i-Naïve Amphetamine: NA; i-Amphetamine ene-Experienced: EA; Naïve Saline: NS; kanye no-Saline abanolwazi: ES; n = 8-9 ngayinye) nomsebenzi wokuqasha wabhalwa. Izilwane zahlolwa ku-LACs ngesonto elilodwa ngemuva kweseshini yokugcina ukuhlangana (Usuku 14). Izilwane ezithola i-AMPH ngosuku lwe-8 zithole i-SAL ngosuku lwe-14, kanti izilwane ezathola i-SAL ngosuku lwe-8 zithole i-AMPH ngosuku lwe-14. Ingxenye yezilwane ezizizwayo nezizibonela zahlatshwa usuku olulandelayo ngenxa yesikhumba se-RNA (idatha engekho kulo mbiko). Inyanga eyodwa elandela iseshini sokugcina yokuhlangana (usuku lwe-35), ingxenye engezansi yezilwane (i-Naïve, n = 8; Okuhlangenwe nakho, n = 9) ithola umsebenzi we-AMPH no-locomotor obhalwe phansi.
Ukuhlaziya Data
Umsebenzi wokuqapha
Idatha iqoqwe kumabhontshi angu-3 amaminithi we-90 ngemuva kwe-AMPH noma i-SAL injection. Imiphumela iboniswa njenge-mean ± SEM eqenjini ngalinye futhi lihlaziywa besebenzisa i-ANOVA emibili (ukuhlolwa kwe-1, izinsuku ze-2 zokuhlola 8-14: izici: ubulili, isipiliyoni semithi), noma indlela eyodwa-ANOVA (usuku lokuhlola lwe-2 35 nomsebenzi ngaphambi kwesisindo sokuhlangana; isici: isipiliyoni socansi). I-Post-hoc ukuqhathanisa kwenziwa kusetshenziswa izivivinyo ze-Fisher LSD ngokubaluleka okusethwe ku-p-value <0.05.
Ukuhlolwa Kwendawo Yokwenziwe (CPP) Ukuhlola
Iinsetjenziswa
I-CPP yenziwa emaphaketheni amathathu (i-Med Associates Inc., iSt Albans, i-VT, eU.SA) eyayinamakamelo amabili amakhulu, angaphandle (28 × 22 × 21cm) ehlukaniswa yizici ezibukwayo nezibucayi, ehlukaniswe ngendawo encane igumbi (13 × 12 × 21cm). I-apparatus yayinemibhoshongo yesithombe sokuhlaziywa okuzenzekelayo kokulandelela nokusebenza kokulinganisa umsebenzi.
Ukubeka isimo nokuhlola
Ukulungiswa kwe-CPP nokuhlolwa kwenziwa ngesikhathi sokuqala kwesikhathi sokukhanya. Ukuziqhenya kwakwenziwe ukucacisa okukhethwa kuqala kwesilwane ngasinye. Akukho ukungafani okuphawulekayo okutholwe phakathi kwezikhathi ezithathwe kunoma iyiphi ikamelo. Ngosuku olulandelayo, ama-rats angamadoda ayehlanganiswe ekamelweni elihlangene le-AMPH noma ekamelweni elihlangene le-SAL lamaminithi we-30. Amagundane athola ukwelashwa okuphambene ngosuku olulandelayo ngendlela engalingani. I-posttest eyayiyinkambinkimbi efana neyengqayizivele yayiqhutshwa ngosuku lokugcina.
Zama i-3
Izilwane emaqembu ahlangene ngokobulili athola izixuku ze-5 ezilandelanayo ezilandelanayo nsuku zonke ezinqolobaneni zokuhlola. Usuku lwe-1 lunikezwe usuku lokuthoma lokuqala. Ukulawulwa kwamadoda kwahlala ku-naïve ngokocansi, kodwa kwafakwa endaweni yokuhlola ehlanzekile yehora le-1 ngosuku ngosuku lwezinsuku ezingu-5 ezilandelanayo. Izilwane zahlukaniswa ngamaqembu athola amanani ahlukene we-AMPH (mg / kg; sc) (i-Naïve: N0.5, N1.0, N2.5 noma i-N5.0, n = 7-8 ngayinye; Ulwazi: E0, E0.5, E1.0, E2.5 noma E5.0, n = 6 -9 ngayinye). Ukukhishwa kwangaphambili kwenzeka ngosuku 14, ukuhlolwa kwesimo sezinsuku ezinsukwini ezingu-15 no-16, nokuthunyelwe ngosuku 17. Lesi simiso sivunyelwe izinsuku ezingu-10 zokuzigwema ekuziphatheni ngokocansi ngaphambi kokumiswa.
Zama i-4
Amadoda abesilisa ngokobulili athole ulwazi lwezocansi ngezinsuku ezingu-5 zokulandelana ezifanayo nokuhlolwa kwe-3. Umehluko oyinhloko nokuhlolwa kwe-4 kwaba ukuthi ukuhlolwa kwe-CPP kwenzeka ngesikhathi izilwane zithola ulwazi lwezocansi, ngakho-ke kwakungenaso isikhathi sokuziyeka ekuziphatheni ngokobulili. Esikhundleni salokho, ukuhlolwa kwesimo sokuqala kwaqala ukulandela izikhathi zokuqala zokuxhuma ze-3. Izilwane zahlukaniswa ngamaqembu athola amanani ahlukene we-AMPH (mg / kg; sc) (i-Naïve: N0.5, N1.0, N2.5 noma i-N5.0, n = 6-8 ngayinye; Ulwazi: E0, E0.5, E1.0, E2.5 noma E5.0, n = 7 -11 ngayinye).
Ukuhlaziya Data
Izikolo ze-CPP zabalwa i-imal ngayinye njengesikhathi esichithwe (isekhondi) egumbini lokubhanqa ngesikhathi se-posttest kukhishwa ukuzenzisa. Izindlela zeqembu zabalwa futhi zaqhathaniswa neqembu eliphethwe i-SAL (E0) kusetshenziswa izivivinyo ezingakhokhelwa. Kukho konke ukubaluleka kokuhlolwa kusethwe ku-p-value <0.05.
Isivivinyo se-Golgi
Zama i-5
Amadoda kumaqembu ahlangene ngokocansi abekwe emgodini wokuhlola newesifazane owamukelayo futhi avunyelwe ukushada kuze kube yilapho ejaculation noma imizuzu ye-60, noma yikuphi okwenzeka kuqala, phakathi nezinsuku ezingu-7 ezilandelanayo. Ukulawula abesilisa babelokhu bengenayo ngokocansi, kodwa bathathwa emgodini wabo wasekhaya bafakwa emgodini wokuhlola ohlanzekile emaminithini we-30 usuku ngalunye ngezinsuku eziyisikhombisa ezilandelanayo. Amaqembu wezilwane ezinolwazi noma ezama-naïve ahlatshelwe usuku olulodwa (N1; n = 5; E1; n = 7) noma izinsuku ze-7 (N7, E7; n = 5 ngayinye) emva kweseshini yokugcina ukuxhuma noma ukuvezwa kwenkathi yokuhlola. Amaqembu ahlangene ngokobulili ahluke ngokuhlangenwe nakho.
Ukucubungula kwezicubu
Ngolunye usuku noma ngesonto elilodwa ngemuva kweseshini yokugcina ukuvuthwa noma ukuvezwa kokuhlolwa kwezilwane, izilwane zanikezwa ngokweqile kwe-sodium pentobarbital (ip) futhi zenziwa nge-500 mL ye-saline. Ubuchopho buqhutshwa ukugcoba i-Golgi-Cox ngokusebenzisa indlela eguqulelwe kuPugh noRossi (62). Ukuze uthole imininingwane eyengeziwe bheka Ukwengeza i-1.
ukuhlaziywa kolwazi
Imidwebo yekhamera Lucida yenziwe nge-5-7 neurons ku-NAC core kanye ne-shells subregions kwisilwane ngasinye. Amaseli akhethwe kuwo wonke ama-dendritic amagatsha noma ayeningi futhi alula ukuhlukanisa namaseli angomakhelwane. Amagatsha e-Dendritic ayebalwa nge-centrifugal order (63) kanye nesilinganiso semfuyo ngayinye kubalwa. Izimpande ze-Dendritic zazinqunywa ku-40 μm ubude be-dendrites amabili yesibili ngomakhalekhukhwini ngamunye (amaselula we-4-7 ngesilwane ngasinye). Izindlela zeqembu ziqhathaniswa zisebenzisa i-ANOVA emibili (izici: isipiliyoni socansi nokuziqeda) kanye nokuhlolwa kwe-Fisher LSD i-post hoc ukuhlaziywa.
IZIPHUMA
Zama i-1
Umgomo Wokuhlola i-1 kwakuwukunquma ukuthi ukuhlangabezana nesimo socansi kuthinta impendulo yokuvakasha ku-AMPH kwamagundane angamadoda. Umsebenzi wokwenza indawo phakathi nesikhathi seminithi ye-90 kulinganiswe namagundane anesifo socansi kanye nama-naïve ngemuva kokwelashwa nge-0.5 mg / kg AMPH noma i-SAL. Imiphumela evela ku-Uhlolo lwe-1 iboniswe ku Umfanekiso we-1. Kokubili nesimo socansi (F1,22= 15.88; p = 0.0006) nokuphathwa kwezidakamizwa (F1,22= 45.00; p <0.0001) kube nemiphumela ebalulekile emsebenzini we-locomotor kanye nokuxhumana kwezindlela ezimbili phakathi kokuhlangenwe nakho kocansi nokwelashwa kwezidakamizwa kwabonwa (F1,1,22= 14.27; p = i-0.0010). Ngokucacile, izilwane zombili ezizizwayo nezizibonela zibonise impendulo yokwandisa kakhulu i-AMPH uma kuqhathaniswa nezilawuli ezifanele ze-SAL. Ngaphezu kwalokho, amagundane awaziwa ngokobulili abonisa ukuphendula okwenyuka kwe-AMPH uma kuqhathaniswa nezilwane ezingenayo. Amagundane awaziwa ngokocansi kanye nama-naïve awazange ahluke ekuphenduleni kwawo ku-SAL.
Ukuhlaziywa kwezimpendulo zokungena ku-AMPH ngezikhathi ezincane zamaminithi we-30 nemizuzu ye-3 iboniswe ku- Umfanekiso we-1, ama-panels CF. Amadoda abesilisa ngokobulili abonisa ukuphendula okwenyuka kwe-AMPH uma kuqhathaniswa namagundane ama-naïve phakathi nesikhathi sokuhlola samaminithi angu-90. Ngaphezu kwalokho, amagundane akwazi ukuhlukunyezwa ngokobulili abonise ukuphendula okwenyuka kwe-AMPH uma kuqhathaniswa nokulawulwa kwabo kwe-SAL kuwo wonke umzuzu wokuhlola wamaminithi we-90, kanti izilwane ezingenayo zibonisa kuphela impendulo ephakeme kakhulu yokuphumula ngesikhathi sokugcina isikhashana se-30 (Umfanekiso we-1; Ama-p-amanani afakwe kuhlu lomlando).
Zama i-2
Umgomo wokuhlola i-2 kwakuwukuhlola uma isipiliyoni socansi siholela ekutheni sikwazi ukukhuthaza izilwane ezithintekayo phakathi nezinsuku ezilandelanayo, nasendaweni efanayo lapho zivezwa khona ku-AMPH. Ukuvezwa kwendawo yokubambisana ngobulili kubangele umsebenzi owenziwe ukwandisa phakathi nemizuzu ye-15 ngaphambi kweseshini ngasinye sokuhlangana (Umfanekiso weS1 ku-Supplement 1), ebonisa ubudlelwane obufundiwe phakathi kokuziphatha ngokobulili nemvelo. Ngaphezu kwalokho, ukuhlolwa kwe-2 kuphinde kuhlolwe umdwebo wesikhashana wokukhuthaza ukuvakasha ku-AMPH kuma-rats angamadoda avela ocansini. Impendulo yomthengisi ku-AMPH noma i-SAL ilinganiswa ngelinye ilanga (Usuku 8), ngesonto elilodwa (Usuku 14) nenyanga eyodwa (Usuku 35) ngemuva kweseshini yokugcina yokuhlangana. Njengokuhlolwa kwe-1, amagundane awaziwa ngokocansi abonisa impendulo enkulu yokuvakashela i-AMPH uma kuqhathaniswa nezilwane ze-naïve. Ngaphezu kwalokho, lo mphumela wabonakala kuzo zonke izinsuku ezintathu zokuhlolwa. Umfanekiso we-2 ibonisa umsebenzi wokuthutha phakathi nemizuzu yokugcina ye-60 yokuhlolwa lapho ukungafani okuqinile kunakekelwa khona, futhi idatha yemizuzu yokuqala ye-30 iboniswa Umfanekiso weS2 (Supplement 1). Izilwane ezingamaNavive nezingaziwayo azifani uma zisabela ku-SAL kunoma yikuphi kwezinsuku zokuhlola, futhi ama-rats athola i-AMPH abonise umsebenzi wokwenza umsebenzi wokukhula uma kuqhathaniswa nokulawulwa kwabo kwe-SAL (Umfanekiso we-2; Ama-p-amanani afakwe kuhlu lomlando).
Zama i-3
Uhlolo lwe-3 luhlolile isipiliyoni socansi lomphumela kumvuzo we-AMPH esimweni. I-AMPH CPP ihlolwe kuma-sex naïve abanamava kanye nezinsizwa ezinsukwini ezingu-10 ngemuva kweseshini yokuqeda ukugcina. Izilwane ezitholakale ngokobulili zibonisa ukulungiswa okuthuthukisiwe kwe-AMPH. Ngokuqondile, abesilisa abathandana nabo ngokocansi babeka ukukhetha okunamandla ekamelweni elihlangene le-AMPH ngamanani aphansi ka-0.5 no-1.0 mg / kg kodwa hhayi ngamazinga aphezulu 2.5 noma i-5.0 mg / kg. Ngokuphambene nalokho, abesilisa abathandana nabo ngokocansi baqala ukwakheka okunamandla ekamelweni elihlangene le-AMPH ngamanani aphezulu, i-2.5 ne-5.0 mg / kg, hhayi amazinga aphansi (Umfanekiso 3A; Ama-p-amanani afakwe kuhlu lomlando).
Zama i-4
Isivivinyo i-3 yabonisa ukuthi isipiliyoni socansi esilandelwa yisikhathi sokuzigcina siphumelele kuholela ekutholeni okungcono kwe-AMPH. Ukuhlola i-4 iphenye ukuthi ngabe imiphumela yezocansi ngesipiliyoni se-AMPH esimisiwe sincike kule nkathi yokuzigwema. Imiphumela ibonise ukuthi izilwane ezitholakale ngokobulili azizange zibonise inani lokuvuza elimisiwe le-AMPH. Izilwane ezitholakale ngokobulili nezizimele zibonisa ukukhetha okunamandla ekamelweni elihlangene le-AMPH namazinga aphezulu we-2.5 no-5.0 mg / kg. Kodwa-ke, abesilisa abathandana nabo ngokocansi noma abama-naïve babonisa amaphuzu we-CPP okwenyuka ngamanani aphansi we-0.5 no-1.0 mg / kg umthamo. Isilinganiso esincane kunazo zonke se-0.5 mg / kg kwaze kwaba nomphumela wokuphendulela, kodwa lokhu kwafinyelela ekubalukeni kuphela ezilwaneni ezihlangene ngokobulili ekamelweni elihlangene le-AMPH (Umfanekiso we-3B; Ama-p-amanani afakwe kuhlu lomlando).
Zama i-5
Inhloso Yokuzama i-5 kwakuwukuhlola ukushintsha kwe-morphological ohlelweni lwe-mesolimbic, ngokukhethekile i-NAc, elandela isipiliyoni socansi. Ukuguqulwa kwemiqondo kwaba nesonto elilodwa (Umfanekiso 4H, J noL; Ama-p-amanani afakwe kuhlu legend), kodwa hhayi usuku olulodwa (Umfanekiso 4G, mina no-K), ngokulandela iseshini yokugcina yokuhlangana. Ngokuyinhloko, ukwanda okukhulu kwezibalo zama-dendrites (okubonisa ukukhula kwe-dendritic) kutholakale ku-NAc core kanye negobolondo (Umfanekiso 4H noJ). Ngaphezu kwalokho, izinombolo zezinhlamba ze-dendritic zanda kakhulu kuzo zombili igobolondo nezindawo eziyinhloko, ngesonto elilodwa, kodwa hhayi ngosuku olulodwa, emva kobulili (Umfanekiso 4L).
UKUKHULUMA
Lolu cwaningo lubonisa ukuthi isipiliyoni socansi kanye nokuzivocavoca okulandelwayo ekuziphatheni ngokocansi kwenza ukuguqulwa okusebenzayo nokuhleleka komzimba kuhlelo lwe-mesolimbic lwamagundane angamadoda. Izinguquko ezisebenzayo zabonakala ngendlela yokuphendula komuntu oyisisusa kanye nomvuzo okwenziwe ngcono nge-AMPH kulandela okuhlangenwe nakho kocansi.
Impendulo yokuvakasha ezwelayo ihlonziwe ngesikhathi se-1 futhi igcinwe izinsuku ezingu-28 ngemuva kokugcina kokuhlangana kokugcina. Ngokuphambene nalokho, ukubuyiswa kwe-AMPH okwenziwe ngcono kubonakala ngokulandela isikhathi sokuziqeda ekuziphatheni ngokocansi. Ukuguqulwa kwemiqondo emibili emikhakheni esemqoka kanye negobolondo ye-NAc yaqaphelwa izinsuku ezingu-7, kodwa hhayi usuku lwe-1, ngemuva kweseshini yokugcina ukuhlangana emfuyweni. Ngokubili le datha ibonisa ukuthi isipiliyoni socansi senza i-plasticity ohlelweni lwe-mesolimbic nokuthi isikhathi sokuziqeda ngokubambisana kubalulekile ekuthuthukiseni ezinye, kodwa hhayi zonke izinguquko zesimiso se-eyelimbic.
Kuyaqaphela kahle ukuthi ukuziphatha okuvuzayo kwemvelo kanye nezidakamizwa zokuhlukumeza kwenziwa ngezindlela ezifanayo ze-neural (64). Ngempela, izidakamizwa zokuhlukumeza ziye zaboniswa ukuthi zithinte inkulumo yokuziphatha okuvuza (65-67), kufaka phakathi ukuziphatha kobulili besilisa (67-70). Ukuguquka kokuziphatha ngokocansi kanye nokugqugquzela okubangelwa ukuphathwa kwezidakamizwa eziphindaphindiwe kuxhomeke ekuhoxisweni noma esikhathini sokuzigwema kwezidakamizwa, kanye nemvelo lapho isidakamizwa sinikezwa khona. Ucwaningo lwamanje lubonise ukuthi ukuchayeka kokuziphatha ngokocansi kushintsha ukuphendula kwezidakamizwa zokuhlukunyezwa. Kwakuhloswe ukuthi izimpumputhe zamadoda ezithandana nocansi ziyakhuthazwa emiphumeleni ye-AMPH, nokuthi lesi simo sihlala isikhathi eside futhi sizimele ngesikhathi sokuziqeda kusuka ekuhlanganiseni. Ngaphezu kwalokho, impendulo yokuvakasha ezwelayo yayizimele ngokwemigomo yokulinganisa noma imvelo yokulinganisa futhi yabonwa ngemva kokuhlanganyela okulandelanayo okulandelanayo noma okuphakathi kwesikhathi okwenzeka endaweni efanayo noma ehlukile njengokungabonakali kwezidakamizwa. SUkukhishwa kwama-hamsters wesifazane kubonisa ukuthi i-hamster yabesifazane abathintekayo ngokobulili ibonisa ukuqala okusheshayo kokuphendula kwe-AMPH-okubangelwa abantu uma kuqhathaniswa nokulawulwa kocansi (71). Noma kunjalo, ama-rodents abonisa izimpendulo zobulili zesimo se-psychostimulants (72-73). Ngakho-ke, izifundo zamanje zikhulisa lokho okufundwayo kuma-hamsters wesifazane futhi kuboniswa ngamagundane angamadoda, ukuqala okusheshayo kanye nobude obude bezimpendulo ezithuthukisiwe ezithuthukisayo kuma-psychostimulants ngemuva kokuziphatha ngokocansi.
Akucacile kusuka ezifundweni zanamuhla ukuthi yiziphi izakhi zokuziphatha ngokocansi ezifaka isandla ekukhulumeni kwe-AMPH ukukhuthaza futhi uma ukuxhumana komphakathi kuwanele. Izilwane ezisetshenziselwa i-2 ezingaphumeleli ukuhlangabezana nesimo sohlelo lwezocansi (ama-mounts abonisiwe nama-intromissions, kodwa awazange alandele ku-5 ejaculations ngesikhathi sesisindo sokuhlangana) akazange abonise impendulo ezwelayo (Umfanekiso weS3 ku-Supplement 1). Ngakho-ke, ukuhlolwa okwenziwe kwenziwa ngesikhathi abesilisa bezitholwa kumuntu otholayo ngaphandle kokuxhumana ngokomzimba, noma ukukhonjiswa kwezintaba nokuphazamiseka okungahambisani naso, futhi akuzange kube nomphumela wokuphendula izimpendulo ezithintekayo ku-AMPH (Umfanekiso weS4 ku-Supplement 1). Ngakho-ke, ukusebenzisana kwezenhlalo akubonakali kubangele imiphumela yezocansi ku-AMPH ukukhuthaza, kepha ukukopisha kufaka phakathi ukujula kubonakala kubalulekile kule fomu ye-plasticity.
Ngaphezu kokuphendula okuziphatha okuqinisekisiwe, isipiliyoni socansi sithuthukisa inani lomvuzo we-AMPH, kodwa kuphela ukulandela ukuyeka ukuzibophezela ngokocansi. Umsebenzi wangaphambilini usebenzisa i-CPP uye wabonisa ukuthi ukuchayeka okuphindaphindiwe kuma-psychostimulants noma ama-opiates kwandisa imiphumela evuzayo yezidakamizwa ngokuhambisana nokukhuthazwa kwezivakashi ezibangelwa izidakamizwa (22-24). Ukuphathwa okuphindaphindiwe kwezinsuku ze-5 ze-cocaine (i-10 mg / kg), i-d- amphetamine (i-0.5 mg / kg) noma i-morphine (i-5 mg / kg) iqinisekisa imiphumela emihle ye-cocaine uma ihlolwe izinsuku ezingu-3 ngemva kokuphela kwesandulela ngculaza . Umthelela ozwakalayo waboniswa ngokubheka ukukhetha okufakiwe ngokunciphisa izivivinyo zesimo (kusukela ku-3 kuya ku-2) nangamazinga aphansi okudakamizwa uma kuqhathaniswa nezilwane zokulawula ezilashwa ngaphambilini. Umvuzo oqinisekisiwe owenziwe yi-cocaine ophindaphindiwe wathola izinsuku ezingu-7, kodwa hhayi izinsuku ezingu-14, ngemuva kokuqothulwa kokugcina kwe-cocaine (23). Ucwaningo olufanayo olusetshenziswa ngezinsuku ze-5 ze-morphine (5.0 mg / kg) lubonisa impendulo engaphenduliwe yomvuzo ku-morphine lapho isimo siqala i-3, i-10, noma izinsuku ezingu-21 ngemuva kokulashwa kwezidakamizwa. Le mpendulo eyongeziwe yayingekho ngosuku lwe-1 elandela ukwelashwa ngaphambi kwe-morphine (24). SUkuthola okuphambene nakho kubonisa ukuthi isikhathi sokuhoxiswa kwezidakamizwa okungenani izinsuku ezingu-3 siyadingeka ukuze kutholakale umvuzo oqinisekisiwe noma owenziwe ngezindlela zomzimba zombili we-psychostimulants kanye ne-opiates. SOkuhlangenwe nakho okuhlangenwe nakho, njengokuphathwa kwezidakamizwa eziphindaphindiwe, kungase kube nokufaka ama-neuroadaptations afanayo ohlelweni lwe-mesolimbic elibhekene nalokhu ukuphendula kwezidakamizwa ezizwelayo uma umvuzo ususiwe. Okwamanje akucaci ukuthi ukuyeka ukuzibamba kuhlotshaniswa nokucindezeleka futhi ngaleyo ndlela kuthatha ukucindezeleka kwengqondo okubangela ukuguqulwa okuphawuliwe.
Ngokusobala, kukhona ukusebenzisana phakathi kwemiphumela yomvuzo wemvelo nemithi. Umvuzo wokunciphisa ukuphazamiseka ukuphakamisa ukuthi imiphumela ehlala njalo yendlela yokuziphatha ngokocansi kanye nezidakamizwa ixhunyaniswe yizinhlelo ezivamile zamaselula noma izinqubo zamangqamuzana. Ngakho-ke, kuthathwa ngokuthi ukuziphatha kobulili-okubangelwa ukuguqulwa kwezinto eziphathelene nobulili kugunyaza izingxenye zokuqinisa ukuziphatha ngokobulili ngakho-ke kungase kubaluleke kakhulu ekuqinisekiseni ukuziphatha okuvuzayo ngokugcwele. HKodwa-ke, ukuziyeka okulandelayo okuvela emcimbini wobulili kungaholela esimweni sokufuna umvuzo okhulayo, noma ukulimala emiphumeleni yezidakamizwa ezifana nemiphumela yokuzilahla 'ukuthuthwa kwezidakamizwa' (25, 33, 74). Ngokuvamile, ukuziphatha ngokobulili kumagundane wesilisa akubangeli ukufuna ukuphoqeleka ngokobulili, kuboniswe ngokusebenzisa ukuhlolwa kwe-copulation-malaise (associative conditioning tests)75), nakuba ithonya lokuziqeda lingakahlolwa.
I-morphology ye-Dendritic iye yahlolwa ngokujulile emkhakheni wokufunda nokukhumbula (76-77) nokulutha (59, 78-79), futhi uyaziwa ukuthi uyathonywa yizemvelo (80) nezici ze-hormonal (81-82). Njengoba izimpendulo ze-synaptic ziningi kakhulu kuma-dendrites noma izinsiza ze-dendritic, yilokho okuhloswe kakhulu kwe-neuroplasticity eyenziwe yi-experience (26, 83). Ukushintshwa kwemvelo noma ukuphathwa kwamahomoni e-gonadal kuye kwatholakala ukudala ushintsho lwe-dendritic emahoreni amaningana (84-87). Also, ukuphazamiseka ohlelweni, ukucindezeleka okunjalo (88) noma i-cocaine engapheli (79), bangela ushintsho lwe-dendritic olutholakala phakathi kwamahora we-24.
Lapha, izinguquko ku-dendritic morphology ye-neurons ephakathi kwe-NAc kanye negobolondo azizange zigcinwe ngaphakathi kwamahora angu-24, futhi esikhundleni salokho zifuna isikhathi sokuzilahla ngemva kokuhlangenwe nakho kobulili. Ukuguqulwa kwesakhiwo okubangelwa isipiliyoni socansi nokuziqhenya okulandelayo kufana nalabo abonwa ngokulandela ukuvezwa okuphindaphindiwe kuma-psychostimulants (16-17, 26, 30). Ngokuphambene nalokho, ukuchithwa kwe-DA ku-NAc kubangela inani elinciphile lama-dendrites nobunzima kwi-shell (18, 89). Ngakho-ke izinguquko ezenzelwe ukwenziwa kocansi zingase zithembeke kwisenzo se-DA esingapheli ku-NAc. Kodwa-ke, ukuguqulwa kwe-morphological okufakwe ekuhlanganyeleni kubonakala kuphela izinsuku ezingu-7 emva kweseshini yokugcina yokuhlangana futhi zihambelana nokuvuselelwa okwenziwe ngcono kwe-AMPH ezilwaneni ezibhekene nocansi. Le datha ibonisa ukuthi lokhu kwanda ku-dendritic ukuhlaziywa kanye nezinsipho akudingeki ukuba kubonakale ukuzwela kwe-short-term ukukhuthaza ku-AMPH, yfuthi ingadlala indima ekugcineni kanye nokubonakaliswa kwesikhathi eside kwesikhuthazo. Ucwaningo lwangaphambili lokulawulwa kwezidakamizwa eziphindaphindiwe luye lwaphawula ukuxhuma phakathi kokuqwashisa isikhathi eside kanye nokuguqulwa kwemvelo e-NAc (89-94). Akukacaci ukuthi ukusebenza okusebenzayo kungukushintsha kokuziphatha, kodwa kungase kudlale indima ekuguqulweni kwesikhathi eside ekusebenzeni nasekukhulumeni kwegenesheni.
Ngokufingqiwe, idatha evezwe lapha ibonisa ukuthi ukuziphatha ngokocansi - ukuvuselela okuvuzayo kwemvelo - kungenza ukuthi kube neuroadaptations ehlala njalo esimisweni se-mesolimbic. Okutholakele kwethu kusikisela ukuthi ipulasitiki yokuziphatha, ikakhulukazi impendulo yokuvakasha ehlonzwe, iyisiphumo esisheshayo kanye nesikhathi eside socansi. Ngaphezu kwalokho, isikhathi sokuziqeda singavumela ukuthi izinkinga ze-neuroadaptations zibucayi ngenxa yokuguqulwa kwezinguquko ze-morphological ku-NAc kanye nomvuzo owenziwe ngcono wezidakamizwa. Le-plasticity ye-behavioral neural isilandela iphrofayili efanayo, kodwa engafani, njengoba iboniswa ezilwaneni ezikhuthazwa izidakamizwa. Lezi zindaba zinesithakazelo esikhethekile ngoba sibonisa ukuthi ukuyeka ukuzihlaziya kwemvelo kudonsela isimo esiphephile ekulawulweni kwezidakamizwa. Ukuqonda ukuthi indlela yokuziphatha engokwemvelo kanye nezidakamizwa zokuhlukunyezwa kusebenze ngayo lezi zinqubo ezibangela izinkinga ezingasetshenzisiwe zingasinika ukuqonda kangcono kokuqiniswa nokuvuza ngokujwayelekile, futhi sihlinzeke ngokuqondisisa okwengeziwe izindlela zokulutha izidakamizwa.
Ukuvuma
UDkt. Richtand uthola imali evela ku-NIH kanye noMnyango Wezandla Zomsebenzi Wezokwelapha Zezokwelapha. UDkt. Richtand ubika ukuthi ube ngumxhumanisi we-Forest Pharmaceuticals, uBristol-Meyers Squibb, noGerson Lehrman Group; kwi-bureau ye-Bretol Meyer sika-Squibb ne-Schering-Plow Corporation; Ama-Grand Rounds I-Presentations ku: iSanford School of Medicine yase-University of South Dakota neScius, LLC; futhi uthola ukwesekwa kwesibonelelo kusuka ku: Janssen Pharmaceutics Research Foundation kanye ne-Astra Zeneca Pharmaceuticals (ukuhlola izidakamizwa kuphela). Bonke abanye abalobi ababiki izimfuno zezimali eziphilayo noma izingxabano ezingase zibe khona, ngaphandle kwezibonelelo ezilandelayo zokusekela lolu cwaningo: Izikhungo Zempilo Zikazwelonke (R01 DA014591), ama-Institutes of Health Research (i-RN 014705) yaseCanada, kanye ne-National Sciences and Engineering Research Council waseCanada (NSERC) Ukutholakala Kwezimali (341710) kuDkt. Lique Coolen, kanye nokufundiswa kwe-PGS-M kusuka ku-NSERC (360696) ku-Kyle Pitchers. Siyabonga uNksz Maureen 1 Fitzgerald ngokusiza kwakhe ngeGolgi ukucubungula kanye noDkt. Christine Tenk usizo ukuhlolwa okungeziwe 1.
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.
Okubhekwayo
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