Ukulawulwa kwezenhlalakahle kwiinkwenkwekazi: i-dopamine receptor umsebenzi kunye nokuqiniswa kwe-cocaine (2013)

Ingqondo yebhayoloji. Umbhalo obhaliweyo ifumaneka kwi-PMC Sep 1, 2013.

Ishicilelwe kwifomu yokugqibela ehleliweyo njenge:

Ingqondo yebhayoloji. I-Sep 1, 2012; I-72 (5): 414-421.

Ipapashwe kwi-intanethi ye-Aprili 14, 2012. doi: I-10.1016 / j.biopsych.2012.03.002

PMCID: PMC3399959

I-NIHMSID: I-NIHMS363193

UMichael A. Nader,^1,² USusan H. Nader,¹ Paul W. Czoty,¹ UNatallia V. Riddick,¹ H. UDonald Gage,² URobert W. Gould,¹ UBrandi L. Blaylock,¹ UJay R. Kaplan,³ Pradeep K. Garg,² Huw ML Davies,⁴ UDaniel Morton,⁴ Sudha Garg,² kwaye UBeth A. Reboussin⁵

Ulwazi loMbhali ► Ulwazi lobunikazi kunye neelayisensi ►

Inguqulelo yokugqibela yomhleli yeli nqaku iyafumaneka apha Biol Psychiatry

Bona amanye amanqaku ku-PMC Wisdom nqaku epapashwe.

Abstract

imvelaphi

Ukuqiqisa ubuchopho kunye nezifundo zokuziphatha kucebisa ubudlelwane obunxaxhileyo phakathi kwe-dopamine (DA) D2 / D3 receptors kunye nokuba semngciphekweni wokuxhatshazwa yi-cocaine, nangona uninzi uphando sele lusebenzisile amadoda. Umzekelo, iinkawu ezingamadoda ezibalaseleyo kwiqela lentlalontle zinokuphakama okuphezulu kwi-D2 / D3 receptor kufumaneka kwaye akuthinteleki ekuqinisweni kwe-cocaine.

tindlela

Ukufunyanwa kwe-DA D2 / D3 receptor kwavavanywa kwiinkawu ze-cynomolgus zeenkosikazi (n = 16) zisebenzisa i-positron emission tomography (PET) ngelixa zigcinwa zodwa, i-3 iinyanga emva kweendlela ezizinzileyo zentlalo zaye zenziwa kwaye ziphinde zafunyanwa zodwa. Ukongeza, i-PET yayisetyenziselwa ukuvavanya utshintsho kwi-DA transporter (DAT) ukufumaneka emva kolawulo lobuchule bendawo. Emva kokuba izifundo zokwenza imaging zigqityiwe, iinkawu zafakelwa ii-catheter zangaphakathi kunye ne-cocaine eyenzelwe oko (i-0.001-0.1 mg / kg / inaliti) phantsi kweshedyuli yomiselo lwe30 emiselweyo. Ukufunyanwa kokuqiniswa kwecocaine kwenzeka xa amazinga okusabela ayephezulu kakhulu kunangexesha le-saline yayizilawula.

iziphumo

Nokuba i-DAT okanye i-D2 / D3 receptor ifumaneka kwi-caudate nucleus kwaye i-putamen yayixelwa kwangaphambili kwinqanaba lentlalontle, kodwa zombini zitshintshe kakhulu emva kokudalwa kwee-hierarchies zentlalo. Ukufumaneka kwe-D2 / D3 receptor kwanda kakhulu kwabasetyhini okuye kwaba negunya, ngelixa ukubakho kwe-DAT kuncipha kumabhinqa angaphantsi. Iinkawu zasekhaya zifumene ukuqiniswa kwecocaine kumazantsi aphantsi kakhulu kuneenkawu.

izigqibo

Ngokusekwe kwezi zinto zifunyanisiweyo, ubudlelwane phakathi kwe-D2 / D3 receptor ukufumaneka kunye nokuba semngciphekweni kokuqiniswa kwe-cocaine kuvela ngokuchaseneyo kwabasetyhini kunye nabesilisa. Ezi datha zibonisa ukuba imeko yezentlalo ichaphazela kakhulu inkqubo ye-DA, kodwa ikwenza oko ngendlela eyahlukileyo enefuthe elisebenzayo kubantu ababhinqileyo kunamadoda.

Internet: Ukuphinda ubeke emngciphekweni, ukuba sesichengeni, ukucinga ngePET, inqanaba lentlalontle, abafazi, ukwahluka kwezesondo

INTSHAYELELO

Ukusetyenziswa gwenxa kweziyobisi kuyaqhubeka nokuba yingxaki enkulu yezempilo yoluntu kwihlabathi liphela (1), malunga ne-1.6 yezigidi eziMelika eziqinisekisa ukusetyenziswa kwecocaine ngoku (2). Ngaphakathi kwi-European Union, i-56% yawo onke amazwe anika ingxelo ngeendlela zecocaine ezibhaliweyo (1). Nangona iindlela ezithile zinovelwano ziqwalaselwa, okwangoku akukho zonyango zivunyiweyo ze-FDA zotshintsho lwecocaine (3-4). Kukho ubungqina bokwehluka ngokwabelana ngesondo xa usengozini yokuxhatshazwa yi-cocaine (5), kunye nabasetyhini abaqala ukusebenzisa iziyobisi kwiminyaka yobudala engaphambili, bayiqhubela phambili ukuxhomekeka ngokukhawuleza kwaye babeke emngciphekweni omkhulu emzimbeni, engqondweni nasentlalweni.6-7). Nangona kunjalo, izifundo zababhinqileyo zabonakaliswa ngaphambili kuphando lokuqala kunye nonyango. Olu phononongo lwangoku lusebenzise iinkawu ze-cynomolgus yabasetyhini kwimodeli yezilwanyana ekhethekileyo ebandakanya indlela yokuziphatha kwezentlalo, ukucinga ngengqondo usebenzisa i-positron emission tomography (PET), kunye nokuzilawula kwe-cocaine kumzamo wokuphucula ukuqonda kwethu i-etiology yokusetyenziswa gwenxa kweziyobisi ngenjongo yokuphuhlisa iindlela zonyango zokunyanga. Injongo eyongeziweyo yesifundo esikhoyo yayikukunyusa umsebenzi wangaphambili kwimidlalo yezoluntu eyabelwe iimazi ezingamakhwenkwe.

I-dopamine ye-Brain dopamine (DA)8). Uphando lusebenzisa izifundo zesilisa (umntu, inkawu kunye nentonga) lubonisa ubudlelwane phakathi kwe-D2 ye-D3 / DXNUMX receptors kunye nokomqiniswa kwe-psychostimulant, ukuze umntu onamanyathelo asezantsi afumane ukuqiniswa okukhulu (8-11). Umzekelo, ukubakho kwe-D2 / D3 receptor kwavavanywa kwiinkawu ezingamadoda ngelixa zigcinwa ndlwini nganye kwaye kwakhona emva kweenyanga ze-3 kwizindlu zokuhlala (9). Ngelixa ukufumaneka kwe-D2 / D3 yokufunyanwa kwe-receptor yayingekokucingelwa isigxina sentlalo, yenyuka kakhulu nyani kwaye yaba negunya kwiqela lentlalontle. Ngokuhambelana noko kufunyanisiweyo kuxeliwe emadodeni, ukwanda kokufumaneka kwe-D2 / D3 receptor kwakudityaniswa namaxabiso asezantsi okuzilawula kwe-cocaine; Kukho, okwangoku, ubungqina obuncinci bolwalamano olunjalo kubantu basetyhini. Ezona njongo zintathu ziphambili zesifundo esikhoyo yayikuku: i-1) ukufumanisa ukuba ngaba oomama abaphambili, njengabafazi abangamadoda, bane-D2 / D3 receptors ephezulu kunye namaqondo ancitshisiweyo okuzilawula kwe-cocaine; I-2) ivavanye ukufumaneka kwe-DA (i-DAT) emva kokusekwa kweehierarchies ezilawulayo; kunye ne-3) kuvavanya utshintsho kwi-D2 / D3 receptorfumanekayo emva kokubuyisa ubudoda kwimeko yokuhlala yezindlu.

Kwimodeli yezilwanyana, imeko yezindlu, inqanaba lentlalontle, ukungafani komntu kunye neempawu zobuntu zinokuba nefuthe elinamandla lokuqiniswa kwecocaine (9,11-15). Saqonda ukuba iinkomo ezingamadoda ezibalaseleyo zazikhuselwe kukuqiniswa kwecocaine kuba zihlala kwindawo etyebileyo (2,16). Ngelixa amaqela esini esifanayo abandakanyeka kwi-macaques yabasetyhini nayo ikwakha ii-hierarchies ezisemgceni (17,18), iimazi ezibalaseleyo zibonakala zixinanisa ngokubhekisa kumakhonkco abo amakhulu kunokubona phakathi kwamadoda (19,20). Ke, iya kuhlala igqitywe ukuba ingaba kufunyanwe isikhundla esiphambili kwindawo yokuhlala phakathi kweenkawu zabasetyhini kuyafana nokunxulunyaniswa kwendalo kunye nokuhla kokuqiniswa kwecocaine xa kuthelekiswa neenkawu zesetyhini ezithi ziphantsi kweqela lentlalontle. Kuba i-estrogen inokuchaphazela amanqanaba e-DA (21,22) kunye nesigaba somjikelezo wokuya esikhathini kunokuphembelela ukubakho kwe-receptor ye-D2 / D3 (23), yonke imizobo ye-PET yenziwa kwinqanaba le-follicular apho ukufumaneka kwe-D2 / D3 receptor isezantsi ngokuthembekileyo kwisigaba se-luteal, esayithethayo sivumele ukunyusa okanye ukuncipha ngenxa yokwakheka kwenqanaba lentlalontle.

IMPAHLA NENKQUBO

I zifundo

Izifundo yayiyi-16 ngokuzama nge-na adultve yabantu abadala i-cynomolgus nyani (IMacaca fascicularis), engeniswe evela eIndonesia (Iziko uPertanian Bogor, Bogor, Indonesia), 8-18 iminyaka ubudala. Iinyani zazihlala kwizisele ezingasasebenziyo (0.71 × 1.73 × 1.83 m; Allentown Caging Equipment, Co, Allentown, NJ) ngeengcingo ezikhutshiweyo ezahlulahlula iinkawu zaba zii-quadrants (0.71 × 0.84 × 0.84 m). Ngexesha lezindlu zokuhlala, iinkawu zahlulwa zaza zaxhotyiswa umntu ngamnye nge1-2 hrs yonke imihla ukuze zondliwe. Inkawu enye ifile ngenxa yezendalo ngaphambi koqeqesho lomsebenzi ngokuzisa inani lezifundo kwi15. Inkawu nganye yayifakwe ikhola yealuminium (Imveliso yePrime, iDolophu yaseRedwood, CA) kwaye iqeqeshelwe ukuhlala ngokuzinzileyo kwisitulo esimiselweyo (Iimveliso zakwamva). Iinyani zazinzima iveki yonke kwaye zondla ukutya okwaneleyo mihla le (iPurina Monkey Chow kunye neziqhamo nemifuno emitsha) ukugcina ubunzima bomzimba phantse nge-95% yamanqanaba okondla asimahla. Amanzi ayekhona ad adum kwikhaya lasekhaya. Isigaba somjikelezo wokuya esikhathini saphononongwa ngoSuku lobufazi imihla ngemihla (18,23) kwaye yayimalunga neentsuku ezingama-28. Usuku lokuqala lokopha lwalubonisa ii-mens kwaye kwabalwa njengosuku lwe-1 lomjikelo. Sithathele ingqalelo iintsuku ze-2-10 zesigaba sokulandelwa kunye neentsuku ezingama-19 ukuya ku-28 zenqanaba lesigaba sokuya exesheni. Izifundo zokuziphatha zaqhutywa kuzo zombini izigaba zomjikelo wokuya exesheni, ngelixa izifundo zokucinga ze-PET zaziqhutywa kuphela kwinqanaba lokulandela; oku kwaqinisekiswa ngokulinganisa i-plasma progesterone concentrations (i-Biomarkers Core Laboratory, i-Yerkes National Primate Research Centre, e-Atlanta, GA). Amanqanaba eprogesterone <4 ng / ml ayebonisa isigaba sobunzima. Indlu yezilwanyana, ukuphathwa kunye nazo zonke iinkqubo zovavanyo zenziwa ngokungqinelana neBhunga loPhando kuZwelonke lika-2003 Izikhokelo zoKhathalelo kunye nokuSetyenziswa kweeMammals kwi-Neuroscience kunye noPhando lokuziphatha zaye zamkelwa yiKomiti yoKhathalelo lweZilwanyana kunye neKomiti yokuSebenza yeYunivesithi yaseWake Forest. Ukuphuculwa kwendalo esingqongileyo kwanikezelwa njengoko kuchaziwe kwisicwangciso sokuphuhlisa indalo esingqongileyo esingumntu kwiYunivesithi yaseWake Forest.

Ukuzimisela kwinqanaba lentlalontle

Ubume bezentlalo bugqitywe ngokusetyenziswa kwesiphumo sezinto eziqubayo (17). Ukusuka kwiiveki i-2-12 yezindlu zentlalo, abaqwalaseli babini baqhuba ngokwahlukeneyo i-3 / iveki ngepeni nganye, yokufumana iiseshoni zokujonga 34-36 ngepeni nganye (18). Abaphumelele kwimloba babethathwa njengabakhulu kunabo baphulukene noko; I hierarchies ezisemgceni kunye nezishukumayo zazikho kwipeni nganye. Iinkawu ezisibhozo zachongwa njengezinamandla (zibekwe #1 okanye #2) kwaye i-7 zaziphantsi (zibekwe #3 okanye #4), njengoko yayikhe yenziwa ngaphambili emadodeni (9). Amanqanaba obunzima bomzimba, ubudala kunye nenqanaba lentlalontle alizange lihambelane18).

Ukugxila kweCerebrospinal fluid (CSF)

Ukuvavanya ukugxininiswa kwe-DA ye-metabolite homovanillic acid (HVA), i-CSF yaqokelelwa sisibeleko kwisibeleko esivela kwi-12 nyani, kanye ngexesha lesigaba se-follicular kwaye kanye ngexesha lesigaba sokuhamba kokuya esikhathini ngelixa izilwanyana zazingafakwanga nge-10 mg / kg (im) ketamine (18). Iinkawu ezine zazingajikelezi rhoqo ngeli xesha, ngoko iisampulu ezimbini zithathwe kwiiveki ze-2 zahlukile. Xa kwagqitywa emva koko ukugxininiswa kwe-HVA kwahlukile kwisigaba sokujikeleza kokuya esikhathini (Ithebula leS1), idatha evela kwizampulu ezibini yalinganiswa kwimazi nganye, kubandakanya ezo zazingakhange ibhayisekile, kwaye zaqwalaselwa zodwa zigcinwe kwiziseko ze-CSF HVA (n = 16). Ukulandela ukwakhiwa kwezindlu, i-CSF yaqokelelwa kuzo zonke iinkawu ngexesha lesigaba se-follicular. Ngeenjongo zamanani, ukuxelwa kwangaphambili kwe-HVA ngaphambi kwezindlu zasemva kwendawo esetyenzisiweyo kusetyenziswa indlela ye-2 ephindaphindiweyo ye-ANOVA ngayo yonke indlela ezimbini zokuthelekisa uvavanyo lwe-hoc (uvavanyo lweTukey).

Ukucinga nge-PET

Isifundo se-magnetic resonance imaging (MRI) yesakhelo saqhutywa kwimazi nganye ephantsi kwecetamine (15-20 mg / kg, im) i-anesthesia ene-1.5-Tesla GE Signa NR scanner (GE Medical Systems). Imifanekiso yobunzima be-T1 enesisindo sonke yayisetyenziselwa ukuchaza imimandla eyindawo enomdla (i-ROIs), kubandakanya ilungelo kunye nekhohlo le-caudate nucleus (Cd), putamen (Pt), zombini kububanzi be-0.5 cm ububanzi kunye ne-cerebellum (Cb; 0.8 cm cm), Ubhaliso lwakwangoko ngemifanekiso yePET. Izifundo ze-PET zisebenzisa i-radioligand ye-DAT [¹⁸F] fluorobenzylchlorotropane (FCT) (24) kunye ne-D2 / D3 receptor radioligand [¹⁸F] i-fluoroclebopride (FCP), engafaniyo phakathi kwe-subtypes ye-D2-njenge-superfamily (okt, D₂, D₃ kunye noD₄ ii-receptors) (25). Monkey nganye yaskenwa kunye nababini beentaka ngexesha ngalinye lifakwe kwindlu kunye emva kweenyanga ze-3 kwizindlu zokuhlala. I # 1- kunye ne # 4 ezikudidi lweenkawu zahluzwa okwesithathu emva kokuba zibuyele kwizindlu. Kwisiqingatha seenkawu, izifundo ze-D2 / D3 PET zaziqhutywa ngaphambi kwe-DAT. Ubushushu bomzimba bugcinwe kwi-40 ° C kwaye iimpawu ezibalulekileyo zajongwa kuyo yonke inkqubo yokuskena (jonga 23). Izikena ze-PET zifunyenwe kusetyenziswa isitshixo seNokia / CTI Concorde Primate PPNUMX scanner eyilelwe ngokukodwa izilwanyana, malunga nokusonjululwa kwe-4 mm. Ukuqala kweskena, malunga ne-2 mCi ye [¹⁸F] I-FCP okanye [¹⁸I-F] i-FCT yajova, yalandelwa yi-3 ml yealine heparinised. Iithayile zexesha elisebenza ngexesha leetoni zenzelwa ukujoliswa kwe-radiotracer kwi-ROI nganye kunye nomyinge wokuhambisa umthamo (i-DVR) ye-Cd kunye ne-Pt zabalwa kusetyenziswa i-Cb njengommandla wokurekhoda.

Ukuhlinzwa

Inkawu nganye yayilungiswa ngohlobo olungapheliyo lwe-venous catheter kunye ne-portcutaneous vascular port (Ukufikelela kubuchwephesha, Skokie, IL) phantsi kweemeko zoqhaqho, njengoko kuchaziwe ngaphambili (26). Phambi kweseshoni nganye yokuzilawula iziyobisi, ngasemva kwesilwanyana kwakucocwa ngesisombululo se-chlorhexidine kunye ne-95% EtOH kwaye izibuko lixhunyiwe kwimpompo yokufakwa ebekwe ngaphandle kwegumbi nge22-gauge Huber Point Inaliti (iTekhnoloji yokuFikelela).

Ukuzilawula kwecocaine

Izixhobo ezazinegumbi elingena moya elingene ngaphakathi, elinesandi (i-1.5 × 0.74 × 0.76 m; I-Med Associates, i-East Fairfield, i-VT) eyilelwe ukuhlalisa isitulo esimileyo. Izitshixo ezibini zokuphendula (i-5 cm ububanzi) zazibekwe kwelinye icala yegumbi kunye nomqolo othe tyaba wezibane ezintathu zokuphakamisa i-14 cm ngaphezulu kweqhosha lokuphendula ngalinye kunye nendawo yokufumana indawo yokutya yayikhona phakathi kwezitshixo zokuphendula. Inkawu nganye yayiqeqeshelwe ukuphendula kwiqhosha lasekhohlo okanye lasekunene, phantsi kweshedyuli ye-30-reaction fixed ratio (FR 30) ishedyuli yokuqinisela. Ngaphantsi kwale meko, ipellet yokutya yathunyelwa emva kwe-30^th impendulo, elandelwa lixesha lokuphuma kwe10. Iiseshini ziphele emva kokuqiniswa kwe15 okanye i-60 min, okoko kwenzeka okokuqala. Ukukhanya ngaphezulu kwempendulo isitshixo esikhoyo sokufumaneka kokutya; Isitshixo esinye kuphela esasebenza ngexesha leseshoni.

Emva kokufakwa ngaphakathi kwe-catheter, ukugcinwa kokugcinwa kokutya kwamiswa kwakhona kwaye i-saline yatshintshwa i-pellets yokutya okungenani iiseshini ze-5 zilandelelana kwaye de kube ukuphendula kuthathwa kucinyiwe (oko kukuthi, isilinganiselo sokuphendula sincitshisiwe okungenani i-80% yokuphendula okuqinisiweyo kokutya kwe-3 Iiseshini ezilandelelanayo ngaphandle kweendlela zokuphendula). Emva kokumiselwa kwakhona kokuphendula kokugcinwa kokutya, iidosi ezahlukeneyo zeCocaine HCl (iZiko leSizwe kuSebenzisa gwenxa iziyobisi, iBethesda, MD, yanyibiliswa kwisalfa ye-0.9% yealine) zathathelwa indawo iipellets zokutya ngomyalelo osuka kwi-0.001 mg / kg / inaliti eyanda iziqingatha zezixhobo zokungena kwi-0.1 mg / kg / inaliti; idosi nganye yayikho kangangeeseshoni ze-5 ubuncinci kwaye ide iphendulwe ithathwa ukuba izinzile (umda wokuphendula uthetha ± I-20% ngaphandle kwemikhombandlela yeeseshini ezilandelanayo ze3). Iiseshini ziphele emva kwe-30 inaliti okanye i-60 min, nokuba yeyiphi eyenzeke okokuqala. Idosi nganye yayifumaneka imihla ye-2-10 (ekuqaleni ukuya phakathi) yesigaba se-follicular okungenani iiseshini ze-5 ezilandelelanayo. Impendulo egcinwe kukutya iphinde yenziwa ngokutsha ngexesha le-follicular yokugqibela ukuya kwisigaba sokuqala se-luteal (ngesiqhelo i-11-18). Ukuba i-cocaine ye-self-management ayifunyanwanga ngexesha lesigaba se-follicular yangaphambili, idosi efanayo ye-cocaine yenziwa yafumaneka ngexesha eliphakathi ukuya kwelokugqibela-leentsuku (ngeentsuku ze-19-26). Kude ke kufunyanwe izinto, iidosi ezintsha bezisoloko ziziswa kwinqanaba le-follicular. Kwakukho ukubuyela ekuphenduleni okugcinwa kokutya, ubuncinci iiseshini ze-3, phakathi kweedosi ezahlukeneyo ze-cocaine. Iyona dosi ye-cocaine iphantsi kakhulu apho amazinga okuphendula ebephezulu kakhulu kunokuphendula ekhokelela kwizitofu ze-saline ichazwe njengeyona ndlela yokufumana. Idosi ye-cocaine yacaciswa ngokusebenza njengokuqiniswa ngokusebenzisa ii-t -vavanyo ezimbini zomsila othelekisa i-3 yeentsuku zosuku zokuphendula intsingiselo yedosi enikwe i-cocaine yokuthetha amazinga okuphendula xa i-saline yayifumaneka.

Uhlalutyo lwesatisatisti

Ukuchonga ukuba ngaba kukho umahluko kwinqanaba lokufumana phakathi kweenkawu ezongamileyo nezingaphantsi, uhlalutyo lwelog ye-Kaplan-Meier curves curves yabalwa. Ukuvavanya yonke ijikaji yempendulo yedosi yecocaine, izinto eziphambili ezixhomekekileyo yayiyinqanaba lokuphendula (iimpendulo zizonke zahlulwe ngokobude beseshoni) kunye nokutya kwecocaine (iyonke ityiwa kumg / kg ngeseshoni). Amanqanaba empendulo agcinwe kukutya kunye neziqinisi (idatha eluhlaza) yahlalutywa ngeendlela ezahlukeneyo zovavanyo olunemisila emibini. Iimvavanyo ezimbini ezinomsila, ezibini, ngaphakathi kwinqanaba eliphambili nelingaphantsi, zenziwa kwinqanaba lokuphendula kunye namanyathelo okuthatha ukumisela ukuba ngaba kukho isiphumo sesigaba sokuya exesheni kwidosi nganye evavanyiweyo. Kuba kwakungekho ziphumo zibalulekileyo zesigaba somjikelo wokuya exesheni, i-avareji yazo zombini izigaba zedosi nganye yecocaine yamanqanaba okuphendula kunye nokungenisa kwahlaziywa kusetyenziswa iindlela ezi-2 eziphindaphindwayo zamanyathelo ohlalutyo lokwahluka (ANOVA), kwaza kwalandelwa uhlalutyo lwasemva kwe-hoc kusetyenziswa konke ukudibanisa Iinkqubo zokuthelekisa ezininzi (uvavanyo lukaTukey). Ukwenza i-2-way ANOVA, idatha eluhlaza yokungenisa yatshintshwa (log10) ngenxa yokungafani okungalinganiyo kunye neenkqubo zasemva kokuthelekisa ezininzi ezenziweyo (uvavanyo lukaTukey). Kuzo zonke iimeko, iyantlukwano yathathelwa ingqalelo ibalulekile ngokwe-p <0.05.

IINKCUKACHA

Iiprofayili zokuziphatha kunye ne-neurochemical yabasetyhini abagcinwe ekuhlaleni

Izilwanyana zahlaliswa ngokukodwa iinyanga ze-27, ngexesha apho iindlela ezahlukeneyo zokuziphatha kunye ne-neurotransmitter metabolite yavavanywa ukuba isetyenziswe kamva njengababenokubona kwangaphambili bezikhundla zentlalo (18). Emva kokufumana yonke imilinganiselo yesiseko esisiseko, iinkawu zabelwa ngokungafaniyo kumaqela entlalontle ye4 yeenkawu ngepeni. Inqanaba lentlalontle (F_1,31 = 5.94, P <0.05) ichaphazele amanyathelo e-CSF e-HVA. Xa zigcinwe zodwa, iinkawu ezingaphantsi kwexesha elizayo zazinokugxila okuphezulu kwisiseko xa kuthelekiswa neenkawu ezilawulayo zexesha elizayo ezijolise ekubalulekeni (t₁₄ = 2.06, P = 0.052). Umahluko kukugxininiswa kwe-HVA kwakubalulekile (t₁₄ = 2.29, P <0.05) zakuba zifikile ezi zigaba zentlalo (Umzobo 1A). Uvavanya eyona nyani (# 1-ekumgangatho) kunye nezona ziphantsi (# 4-zibekwe) nyani (Umzobo 1B) Iqinisekisile ukugxila kwe-HVA ephezulu kakhulu kwiinkawu ezingaphantsi (t₆ = 2.48, P <0.05).

A. Ukugxilwa kwe-CSF ye-CSF kwiinkawu ze-cynomolgus zabasetyhini njengomsebenzi wenqanaba lokugqibela loluntu ngelixa zibekwa zodwa kwaye zilandela ukwakhiwa kweqela elizinzileyo loluntu. Kule datha, i #1 kunye #2 ibekwe nyani (iivalo ezivulekileyo) zithathwa njengobalaseleyo ngelixa #3 kunye ...

Inqanaba lentlalontle kunye nomsebenzi we-dopamine receptor

Iskena se-PET senziwa ngaphambi kunye nokulandela iinyanga ze-3 zezindlu zentlalo. Zombini [¹⁸F] FCT kunye [¹⁸F] I-FCP, bekukho inqanaba eliphezulu lokuthathwa kwe-Cd kunye ne-Pt kunye namanqanaba asezantsi kwi-Cb. Ukufumaneka kwe-DAT kwi-Cd ne-Pt kuchatshazelwe ngokwahlukileyo kubume bezindlu, ngonxibelelwano olubalulekileyo phakathi kweSikhundla neZindlu (F_1,31 Ukuba ngu-4.67, P <0.05; F_1,31 = 4.97, P <0.05, ngokwahlukeneyo). Uvavanyo lwe-post-hoc lubonise ukuba xa iinkawu zahlaliswa ngokukodwa, ii-DVRs ze [¹⁸F] FCT (1 Tablekwi-Cd (t₁₄ = 0.54, P = 0.60) kunye ne-Pt (t₁₄ = 1.62, P = 0.12) khange ichaze kwangaphambili imeko yentlalo. Emva kwezindlu zokuhlala, iinkawu eziphantsi kwezantsi ziye zancipha kakhulu [¹⁸F] Ii-DVR ze-FCT kwi-Cd (t₇ = 2.79, P <0.05) nakwi-Pt (t₇ = 2.52, P <0.05); I-DAT DVRs ayitshintshanga kwiinkawu ezaye zaba namandla (1 Table, Ikhiwane. 2). Xa zigcinwe zodwa, kwabakho unxibelelwano olubalulekileyo phakathi kobudala kunye ne-DAT DVR kwi-Pt (r = -0.60, P <0.05); le mpembelelo ilahlekile emva kwezindlu zentlalo.

Umzobo 2

[¹⁸F] FCT (iphaneli ephezulu) kunye [¹⁸F] I-FCP (iphaneli ezantsi) i-ratio yomthamo wokusasazwa (i-DVRs) itshintsha njengomsebenzi wenqanaba lentlalontle kwi-caudate nucleus (iipaneli zasekhohlo) kunye ne-putamen (iipaneli zasekunene). Iiphaneli zibonisa ixabiso lexabiso le-DVR ye-prime (uluhlu #1 kunye #2) kunye ...

Dopamine Transporter Ukufumaneka kwiiNkawu zaBasetyhini

Iimeko zezindlu zichaphazele ukufumaneka kwe-D2 / D3 receptor kwi-Cd (F_1,31 = 5.87, P <0.05), kodwa hayi kwi-Pt [F_1,31 = 4.11, P = 0.06) (2 Table). Uvavanyo lwasemva kwe-hoc lubonisa ukuba xa iinkawu zigcinwa zodwa, ii-DVR ze [¹⁸F] I-FCP (2 Table) kwi-cd khange ichaze kwangaphambili inqanaba lentlalontle (t₁₄= 0.83, P = 0.42), kodwa ukuba DVRs yanda kakhulu kwiinkawu zaba negunya (t₇ = 2.54, P <0.05). Ukuthelekisa phakathi kwamaqela asekuhlaleni,¹⁸F] Ii-DVR ze-FCP kwi-Cd zaziphezulu kakhulu xa kuthelekiswa neenkawu ezingaphantsi (t₇ = 2.32, P <0.05; 2 Table kwaye Amakhiwane. 2 kwaye And3) .3). Zonke iinkawu zabuyiselwa kwizindlu ezizodwa kwiinyanga ze-3 kwaye ubume beplastikhi ye-D2 / D3 receptor yahlolwa ngophawu kwezona nyani ziphambili nezona ziphantsi. Ukufumaneka kwendlu nganye kwe-D2 / D3 receptor kwi-Cd bekungafani naphambi kokuhlala kwizindlu zasemva kokuhlala kwindawo ephakathi (t₃ = 2.18, P = 0.12) kunye nokuzithoba (t₃ = 0.85, P = 0.46) iinkawu (2 Table). Ngexesha lendlu nganye, kwakungekho lungelelwaniso lubalulekileyo phakathi kobudala kunye ne-D2 / D3 DVR kwi-Cd ne-Pt.

Umzobo 3

Amanyathelo e-dopamine D2 / D3 receptor ukufumaneka kokunyuka kweenkawu zesetyhini ezibalaseleyo. Imifanekiso eqhelekileyo, ebhalisiweyo ye-PET (ipesenti yenaliti nge-ml) ye [¹⁸F] Ukuzibophelela kwe-FCP kwi-midbrain (i-caudate nucleus kunye ne-putamen) yesikhundla esiphantsi kunye naphantsi ...

I-Dopamine D2 / D3 Receptor Ukufumaneka kwiiNkawu zaBasetyhini

Inqanaba lentlalo kunye nokuzilawula kwe-cocaine

Nje ukuba izikhundla ze-PET zigqityiwe iinkawu zibuyiselwe kumaqela abo okuqala entlalontle kwaye kuvavanywa kwiiseshini zokuziphatha apho kugcinwa khona i-lever phantsi kweshedyuli yeFR 30 yokuqiniswa kokutya. Kwakungekho mahluko kumanqanaba okusisiseko amaxabiso okuphendula phakathi kweenkawu ezinkulu nezingaphantsi (t₁₃ = 0.68, P = 0.51). Xa i-saline ithathelwe indawo yokutya, kwakungekho mahluko weqela kumanqanaba okuphelisa ukuphendula (3 Table). Ukunyuka kwedosi yecocaine kwathatyathwa ngokulandelelana endaweni yokutya kwinkawu nganye kwaye kwafunyanwa ukuqiniswa kwecocaine. Iinkawu ezilawulayo zabasetyhini zifumene ukomelezwa kwecocaine kwiidosi ezisezantsi zecocaine xa kuthelekiswa neenkawu ezingaphantsi (kuvavanyo lwenqanaba lokulingana kwee-curve zokuphila, χ2 = 5.63, P <0.05), ebonisa uvakalelo olukhulu kwiziphumo zokomelela kwecocaine (Ikhiwane. 4). Ukufunyanwa kwe-cocoaine kwenzeka kwisigaba se-follicular kwi-11 yeenkawu ze15. Kwiinkawu ezine eziye zafunyanwa kwinqanaba le-luteal, enye yayi- # 1-zibekwe, ezimbini zanikwa # 2-zibekwe kwaye enye yayingu- # 4-zibekwe. Ngenxa yokuba kwakungekho mahluko kumjikelo wokuya esikhathini, idatha yedosi nganye kwisigaba ngasinye iphindaphindwe (Ikhiwane. 5). Uvavanyo lweendlela eziphenduliweyo ze-cocaine i-curves zibonisa ukuba, kuzo zombini iinkawu eziphambili kwaye zingaphantsi, amazinga okusabela (F_5,84 = 4.22; P <0.005) kunye nokutya i-cocaine (F_4,69 = 53.18; P <0.001) yahluka kakhulu njengomsebenzi wedosi yecocaine (Ikhiwane. 5). Uvavanyo lwasemva kwe-hoc lubonakalise amaqondo aphakamileyo okuphendula (Umzobo 5A) kweenkawu ezibalaseleyo xa kuthelekiswa nezilwanyana ezisezantsi xa i-0.003 mg / kg cocaine yayikhona ukulungiselela ukuzilawula (t₁ = 2.89, P <0.05). Ukutya kwecocoaine kunyuke ngokuziphatha njengomsebenzi wedosi kuzo zonke iinkawu kwaye kwakungahlukanga kwiinkawu ezongamileyo nezingaphantsi (Umzobo 5B).

Umzobo 4

Iimazi zasekhaya ezomeleleyo zifumana ukuqiniswa kwecocaine kumadosi asezantsi kuneenkawu ezingaphantsi. Ipesenti yenani elikhulu (iisimboli ezivuliweyo) kunye neesimboli ezingaphantsi (ezivaliweyo) zefikelele kwiindlela zokufumana ukuzilawula kwe-cocaine kwiidosi ezahlukeneyo ...

Ukunyanzelwa kweziphumo zecocaine kukhulu kwiinkawu ezibalaseleyo zowesifazane xa kuthelekiswa nezilwanyana ezingaphantsi. A. Ithetha (± SEM) inqanaba lokuphendula (iimpendulo / sec) xa i-saline okanye iidosi ezahlukeneyo zecocaine zazifumaneka ngeseshoni nganye (uluhlu #1 ...

Amanqanaba okusabela kumanqanaba asezantsi kweenkawu zasetyhini ezihlalisiweyo.

UKUQALA

Iziphumo ezifumanekayo zandisa umsebenzi wangaphambili kwizifundo ezingamadoda (abantu, iinkawu kunye neentonga) kwiinkawu zabasetyhini ezibonisa indima enamandla kwindalo yendawo yokuhlala kunye notshintsho ngaphakathi kwenkqubo ye-DA, ngakumbi i-DAT kunye ne-D2 / D3 receptor ukubakho komngcipheko wokuqiniswa kwe-cocaine. Uphando lwangaphambili lubonakalisile ukuba iinkawu ezingamadoda ezibalaseleyo zibonakalisa ukwanda okukhulu kukufumaneka kwe-D2 / D3 receptor, okukhokelele kumanyathelo asezantsi okuqiniswa kwe-cocaine (9). Iziphumo eziphambili zophando olukhoyo ngoku kukuba iinkawu zesetyhini ezibalaseleyo zibonakalise ukwanda okukhulu kwi-D2 / D3 receptor ukutholakala ngokulandela isikhundla sentlalontle kodwa zisengozini ngakumbi yokuqiniswa kwecocaine. Ezi zinto zifunyenwe ngaphakathi zizinto zokuqala ezichaza ulawulo lwe-cocaine lwe-intravenous kwi-nyani egcinwe ngokwasetyhini kunye nokuchonga umahluko obonakalayo wesini kubudlelwane phakathi kwe-D2 / D3 ukubakho kwe-receptor kunye nokusetyenziswa kweziyobisi.

Amanyathelo angathanga ngqo omsetyenzana we-DA abonakalise ubudlelwane phakathi kwe-CSF HVA ekugxilwe kuyo kunye nenqanaba lentlalontle, kangangokuba iinkawu ezibalaseleyo zine-avareji ye-HVA ephantsi xa kuthelekiswa neenkawu ezingaphantsi. Ezi zinto zifunyanisiweyo ziyahambelana nezifundo ebantwini (27) Ukubonisa ukugxininisa okusezantsi kwe-CSF HVA kudityaniswa nobundilele obukulu kubasetyhini abaphambili. Nokuba ngaba i-akhawunti ye-CSF HVA yomahluko wesini ekuqiniseni i-cocaine iya kuhlala imisiwe; la manyathelo zange afunyanwe ngokukodwa okanye ngokwendoda kwindawo yokuhlala zenkawu (9). Isifundo esikhoyo sikwandisile nomsebenzi wangaphambili (28) ukuquka amanyathelo e-presynaptic e-DA ngokubonisa ukuba ukubakho kwe-DAT, ngelixa kungakhange kucingelwe kwisikhundla sentlalontle, kunciphe kakhulu kwiinkawu zesetyhini eziye zangaphantsi. Ezi ziphumo zibonisa ukuba ukuba phantsi koluntu akufani nokuhlala ndlwini nganye.

Ngokuhambelana nefuthe elibonwe kwiinkawu ezingamadoda, i-D2 / D3 ukutholakala kwesamkeli inyuke kakhulu kumabhinqa aba namandla. Olu nyuso lwayanyaniswa nendawo yokuhlala kuluntu, kuba ukubuyisa eyona (irenti #1) kunye neyona nyani # (N4) yeenkawu kwimeko yazo yezindlu nganye kubangele ukulingana kwe-D2 / D3 receptor. Ubudlelwane phakathi kwamanyathelo amathathu e-neurotransmission ye-DA ibonakala ngokulandelelana. Iinkawu ezingaphantsi kune-CSF ephezulu ye-HVA, ehambelana ne-extracellular ephezulu ye-DA xa kuthelekiswa nabasetyhini abaphambili; ukubakho kwe-DAT esezantsi kwiindawo ezingaphantsi kuyahambelana nelo hypothesis. Ukufumaneka kwe-D2 esezantsi / D3 ye-receptor esezantsi kweenkawu ezingaphantsi kunokubonakalisa ukugxininiswa okuphezulu kwe-DA, njengoko kwenziwe uvavanyo lweenkawu ezingaphantsi kwendoda (9, 16). Ngokuchasene noncwadi olunokuqwalaselwa kubesilisa abacebisa ubudlelwane obonakalayo phakathi kwe-D2 / D3 ukubakho kwesixokelelwano nokuxhaphazwa okunokubakho kwezivuseleli (8-11), iziphumo ezivela kwisifundo esikhoyo zibonisa ubudlelwane ngqo phakathi kwe-D2 / D3 yokufumaneka komntu kunye nokuqiniswa kwe-cocaine kwiinkawu zesetyhini. Oko kukuthi, abantu besetyhini abane-D2 / D3 ephezulu yokufunyanwa kwe-receptor babekuso sengozini yokuqiniswa kwe-cocaine kuneenkawu ezinomgangatho ophantsi we-D2 / D3 receptor.

Kwakukho ukwahlukahlukana kwenkqubo phakathi kwezifundo ezikhusela ngokuthe ngqo ukuthengisa ngokwesondo ngokwendlela yokuziphatha kunye nokucinga kwengqondo. Izifundo zokuzilawula ezikhoyo zenzelwe ukubonisa ukuba sesichengeni - ukumisela elona zantsi lethamo le-cocaine elisebenza njengendawo yokuqinisela. Ngelixa sifumene umahluko obonakalayo kumanqanaba okusabela, ngakumbi kumachiza asezantsi e-cocaine, asizange siqwalasele umohluko kwi-cocaine. Ngokwahlukileyo koko, iimfene ezingamadoda ezingaphantsi kwenduna zazinokutya okuphezulu kwe-cocaine xa kuthelekiswa neenkawu ezikhulu (9). Kumadoda, iidosi zavavanywa ngokulandelelana, endaweni yokunyuka ngokulandelelana njengangoku kufundo lwangoku, olunokuthi lubangele umahluko kukutya kwe-cocaine phakathi kwamadoda nabasetyhini (bona 29). Nangona kunjalo, isifundo esikhoyo sibonisa ngokucacileyo ukuba amabhinqa amakhulu abona bantu basemngciphekweni ngakumbi kukuqiniswa kwecocaine xa kuthelekiswa nabangaphantsi. Kubalulekile ukuba uqaphele ukuba, phantsi kweemeko apho kungekho mehluko khona kulawulo lwe-cocaine yolawulo phakathi kweenkawu ezibalaseleyo kunye nezingaphantsi, ukuphathwa gwenxa kwendalo kunokuvelisa iziphumo ezahlukileyo ngokuxhomekeke kwinqanaba lenkawu (30). Njengoko inxulumene nokufumaneka kwe-D2 / D3 receptor, iikhamera ezahlukeneyo zePET zazisetyenziswa kumadoda nabasetyhini. Kwindoda, ukulungiswa kwendawo ngelo xesha kwakungu-9 mm kuphela kunye ne-DVR yamadoda abalulekileyo kwi-basal ganglia yayiyi-3.04. Amaxabiso afunyenwe kwabasetyhini ayephezulu kakhulu (1 Table). Ngelixa bekuya kuba kufanelekile ukuvavanya isini sobabini ngaxeshanye, ubudlelwane phakathi kwe-D2 / D3 receptor ukufumaneka kunye nenqanaba lentlalontle kuyafana kwabesilisa nabasetyhini.

Ubudlelwane obunxaxhileyo phakathi kwe-D2 / D3 receptor ukufumaneka kunye nokuba semngciphekweni wokusetyenziswa gwenxa kweziyobisi kuthathwe njengento efanele ukuba inxulumene nokudakumba kwe-DA (8,31). Ugxininiso lwe-HVA lubonakalisiwe kumanyathelo ahambelana ne-DA kwisistriatum (32); Ke ngoko, i-HVA esezantsi yokugxila kweenkawu ezibalaseleyo, ezisengozini ngakumbi, xa kuthelekiswa nabangaphantsi, inika inkxaso kwinkqubo ye-hypodopaminergic. Nangona kunjalo, ubudlelwane ngqo phakathi kokufumaneka kwe-D2 / D3 receptor kunye nokuba semngciphekweni kwabasetyhini kuchasene nokuqaphelekileyo kumadoda kwaye kucebisa ukuba utshintsho lwe-D2 / D3 receptor kuphela alunako ukutshintsha imvakalelo yokuqiniswa kwe-cocaine. Umsebenzi wokuqala weenkawu zesilisa ubonise ukuba ukubonakaliswa okungapheliyo kwe-cocaine kunciphise amanyathelo e-D2 / D3 receptor (10,33,34) kunye nokunyuka kokuxinana kweentsuku zeenkawu (35) kunye nabantu (36). Yiyo ke into emadodeni, i-D2 / D3 ephezulu kunye nokufumaneka kwe-DAT kufuneka kukhokelele kubuthathaka obuncinci kunye neendlela zokwenza unyango eziphakamisa i-D2 / D3 yokufumaneka kwe-receptor kunye / okanye ukunciphisa ukubakho kwe-DAT kufanelekile. Nangona kunjalo, eli cebo alinakuba lulutho kubantu basetyhini, nangona uphando olongezelelekileyo kubantu ababhinqileyo luyafuneka ukuze baqonde ngcono umahluko wesini ngeendlela zokulwa ubungozi bokusetyenziswa gwenxa kweziyobisi (37).

Kukho ubungqina bobuhlobo obunxaxhileyo phakathi kwe-D2 / D3 receptor ekhoyo kunye neendlela ezininzi zokuziphatha, kubandakanya ukutyeba (38). Kwisifundo esikhoyo, iinkawu ezingaphantsi kwe-D2 / D3 receptor etholakalayo, ehambelana nolunye uphando olubonisa ukuba ii-macaques zangaphantsi zesetyhini zitya ukutya okunamafutha asezantsi kunye namafutha aphezulu kwaye zifumane ubunzima obungakumbi xa kuthelekiswa neenkawu ezinkulu zowesifazana (39,40). Nangona kunjalo, inyani yokuba iinkawu ezibalaseleyo zowesetyhini zazinolwazelelelo lokuqiniswa kwecocaine xa kuthelekiswa nabangaphantsi kunxamnye nomqondo wokuba zonke iindlela zokuziphatha zine-etiology efanayo.41,42). Enye into enokwenzeka kukuba ii-pellets ezinencasa yeebheli yayingumthombo oqinileyo wokuzimela kweenkawu xa kuthelekiswa nezilwanyana eziphambili kwaye ukufaka icocaine kwezi zinambuzane zinencasa ye-cocaine kubangela ukuba icocaine ibe yinto exhomekeke kubuthathaka benkawu engaphantsi, inkqubo ebizwa ngokuba ngumvuzo wokudambisa ixabiso (43,44). Nangona kunjalo, kwakungekho mahluko unxulumene nenqanaba ekuphenduleni okugcinwa kokutya. Okwesibini kunokwenzeka kukuba amaxabiso asezantsi e-cocaine azilawule ngokwenkawu engaphantsi kweenkawu abonisa amandla ombane “omeleleyo” wecocaine. Ukusetyenziswa kweeshedyuli ezibekiweyo zemilinganiselo emiselweyo akuvumeli ukuthelekiswa kwamandla okomeleza (45). Nangona kunjalo, uyilo lovavanyo lwavumela ukuvavanywa okungalinganiyo kokufunyanwa kokuqiniswa kwe-cocaine kwaye yachaza ukuba iinkawu ezihamba nazo zamabhinqa zisengozini yokuqiniswa kwe-cocaine. Izifundo zexesha elizayo ezibandakanya ukhetho lokutya kwe-cocaine ziya kuwujongisa umba wokuba amandla omeleko eecocaine ahlukile kubasetyhini abagcinwe ekuhlaleni.26).

Ngelixa siphawule umahluko wesini kwimfene yethu yokuhlala, asizange siqwalasele iimpembelelo ezibonakalayo zesigaba sokuya esikhathini sokuqiniswa kweecocaine. Oku kuyamangalisa xa kuthathelwa ingqalelo ubungqina botshintsho kwi-D2 / D3 receptor available in the phase of menstrualjikelezisa isigaba (23). Enye into enokwenzeka kukuba sasijolise ikakhulu ekubeni sesichengeni kokungafaniyo kunye nokuba umahluko wokuya esikhathini uye waphawulwa phantsi kwemeko yokufikelela ixesha elide kwi-cocaine (46). Kufunyenwe ngokwahluka ngokwesondo ekuqiniseni i-cocaine kumagundane (46,47), nyani (46,49) nabantu (50) kunye nophando lwakutshanje kubantu abatshayayo lubonakalise ukungafani kwesondo kwi-DA D2 / D3 receptor available in men vs. (51). Isifundo esikhoyo siqinisekisa ukubaluleka kwezinto zentlalo kunye nokusingqongileyo ekusebenzeni kwengqondo ye-receptor ye-DA nakwiziphumo zezi zinto zinobungozi ekuxhatshazweni yi-cocaine (52,53). Ukuthathela ingqalelo ukuba uninzi lophando ngokulutha lwecocaine luyenzeka emadodeni, ukuqatshelwa kokungafani ngokwesini kwiziphumo ze-neurobiological, kunye ne-etiology kunye neempawu zibonisa ukuba iindlela ezahlukeneyo zonyango ziyasebenza kubafazi xa kuthelekiswa namadoda kwaye nokomeleza ukubaluleka kokufunda ngamadoda nabasetyhini. Ngenjongo yokhetho olukhethiweyo kunyango.

Izinto ezongezelelweyo

01

Cofa apha ukujonga.^{(39K, pdf)}

Imibulelo

Sithanda ukubulela uCora Lee Wetherington ngamagqabantshintshi ngohlobo lwangaphambili lo mbhalo-mibhalo kunye noJennifer Sandridge, Michelle Icenhower, Susan Martelle, Whitney Wilson, Tonya Calhoun, Dewayne Cairnes, uKim Black, uHolly Smith noLi Wu ngoncedo lobuchwephesha. Iisampulu ze-CSF zahlaziywa nguGqirha John Mann kwiZiko leengqondo laseNew York. Olu phando luxhaswe liZiko leSizwe leSibonelelo sokuSetyenziswa gwenxa kweziyobisi i-DA 017763.

Imihlathi

IZIXHOBO ZEMALI

Akukho ziveliso zemali okanye ukungqubana kwenzala ukunika ingxelo kuye nawuphi na umbhali.

IZIXHOBO ZOKUTHENGA

Indoda, i-SHN, i-PWC kunye ne-NVR benze uvavanyo. I-NVR, i-RWG kunye ne-BLB zenze izifundo eziziphethe kakuhle, kubandakanya nokuqunjelwa ngaphakathi. I-HDG yahlalutya idatha ye-PET, i-JRK incedisa ekusetyenzisweni kwezindlu ekuhlaleni, i-PKG, i-HMLD, i-DM kunye ne-SG babandakanyeka ekuqulunqweni kokubini kwezixhobo ze-radiotracers kwaye u-BAR wayenoxanduva lokuphicothwa kweenkcukacha manani. Umbhalo obhaliweyo ubhalwe ngu-MAN ngoncedo oluvela kwi-SHN, PWC, RWG, BLB kunye ne-JRK

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.

Ucaphulo

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