Proc Natl Acad Sci US A. 2007 Mar 20;104(12):5181-6. Epub 2007 Mar 9.
Ventura R, Morrone C, Puglisi-Allegra S.
imvelaphi
I-Santa Lucia Foundation, iZiko laseYurophu loPhando lweBrain (CERC), Via del Fosso di Fiorano 65, 00143 eRoma, eItali. [imeyile ikhuselwe]
Abstract
Ubungqina bamva nje bubonisa ukuba i-stimuli enomvuzo kunye ne-aversive ichaphazela iindawo zobuchopho ezifanayo, kubandakanya ne-medial prefrontal cortex kunye ne-nucleus accumbens. Nangona i-nucleus accumbens yaziwa ngokuphendula kwisivuseleli esinamandla, nokuba ithini na i-hedonic valence, ngokunyuswa kokunyuswa kwe-dopamine, kuncinci okwaziwayo malunga nendima ye-prefrontal cortex kumvuzo- kunye nenkuthazo enxulumene ne-aversion okanye malunga ne-neurotransmitters ebandakanyekayo. Apha sifumanisa ukuba ukuncipha kwe-norepinephrine ekhethiweyo kwi-medial prefrontal cortex yeempuku kuphelise ukonyuka kokukhutshwa kwe-norepinephrine nge-prefrontal cortex kunye ne-dopamine yi-nucleus accumbens ebangelwa kukutya, i-cocaine, okanye i-lithium chloride kwaye yonakalise indawo yendawo ebangelwa yi-lithium zombini. i-chloride (ukucaphuka) kunye nokutya okanye i-cocaine (ekhethwayo). Obu bubungqina bokuba i-prefrontal cortical norepinephrine transmission iyimfuneko kwi-motivation salience kubalulwe kuzo zombini izivuseleli ezinxulumene nomvuzo-kunye nenzondo ngokumodareyitha i-dopamine kwi-nucleus accumbens, indawo yobuchopho ebandakanyeka kuzo zonke iindlela zokuziphatha ezikhuthazayo.
Izilwanyana kwakunye nabantu batyekele ekufuneni imivuzo nokuphepha ukohlwaywa. Oku kuziqhelanisa ngokucacileyo nokuziphatha kubandakanya ukukwazi ukumela ixabiso lokuvuza kunye nokohlwaya, ukuseka uqikelelo malunga nabo, kwaye usebenzise ezi ziqikelelo ukukhokela indlela yokuziphatha (1). Ngokumalunga neemvakalelo zinokuchazwa “njengamazwe afunwa ngabaqinisekisi (imivuzo kunye nabohlwaywa)” (2), ukuqonda iindawo zobuchopho ezibandakanyekayo ekusetyenzweni okuvuzayo okuvuzayo okanye izivuseleli ezikhuthazayo kunokubaluleka ekuqondeni ukusilela kweemvakalelo okuninzi ebantwini.
Idatha yamva nje ibonisa ukuba i-nucleus accumbens (NAc) kunye ne-prefrontal cortex (pFC) zenza i-substrate eqhelekileyo yokusetyenzwa kokubini okuvuzayo kunye ne-aversive stimu (3-7). I-Ventral striatum (okanye i-NAc) ibandakanyeka ekuqhubeni ulwazi oluphantsi kolawulo olukhuthazayo lokuziphatha okujoliswe kuko, kwaye izifundo zabantu kunye nezilwanyana zixhasa indima ngokubanzi kule ndawo yobuchopho ekuqhubekiseni zombini izivuseleli ezinomvuzo kunye ne-aversive, kungakhathaliseki ukuba yintoni i-valence (3-8) ).
Ngaphezu koko, ubungqina obuninzi bubonisa ukuba i-pFC ibandakanyeka ngokuthe ngqo kwindlela yokuziphatha ejoliswe kwiinjongo kunye nakwindlela yokusebenza echaphazelekayo (1, 9). Nangona kunjalo, nangona ukuhanjiswa kwe-dopamine kwi-NAc kucetywayo ukuba kulamle inkqubo "ekhuthazayo" ekwabelwana ngayo kwi-valence elungileyo nengalunganga (3, 6), indima ye-pFC kule nkqubo kunye ne-neurochemical substrate ebandakanyekayo ayaziwa.
Ukudluliselwa kwe-Norepinephrine kwi-pFC kuqhutywe yi-aversive stimuli (10, 11) kunye ne-aversive and conditioned appetitive stimuli (12, 13). Ngaphaya koko, i-norepinephrine kwi-medial pFC (mpFC) isandula kuboniswa ukuba ibandakanyeka kwiziphumo ezinomvuzo zezinye iziyobisi ezixhaphakileyo ngesenzo sayo sokumodareyitha ukukhutshwa kwe-dopamine kwi-NAc (14, 15). Oku kuphakamisa ukuba i-prefrontal cortical norepinephrine transmission ibandakanya i-accumbal dopamine ukuze kuqhutywe isivuseleli esikhuthazayo.
Apha, sisebenzisa iimpuku, sizimisele ukuvavanya ukuba ingaba inkqubo ye-prefrontal cortical norepinephrine/mesoaccumbens dopamine yinto eqhelekileyo ye-neural substrate ebandakanyekayo ekusetyenzweni kwe-affectively positive and negative stimuli. Ngokukodwa, siphande ukuba ingaba i-norepinephrine kwi-mpFC, ngesenzo sayo sokulungelelanisa kwinkqubo ye-dopaminergic ye-mesolimbic, iyimfuneko ukuze kubonakaliswe ukunyanzeliswa kwenkuthazo kumvuzo- kunye nesenzo esinxulumene nokuchasa.
Kuba amava esona sigqibo siphambili sempembelelo yenkuthazo yalo naluphi na uvuselelo olunikiweyo (7), siye savavanya iziphumo zokuvezwa okokuqala kokuvuzwa kwendalo (ukutya okunencasa, itshokolethi yobisi) kunye ne-pharmacological (cocaine) isivuseleli kunye nesivuseleli se-pharmacological [lithium chloride]. (LiCl)] kwi-prefrontal cortical norepinephrine kunye ne-accumbal dopamine ukukhululwa nge-intracerebral microdialysis. Ukongeza, ukufumanisa ukuba ngaba i-norepinephrine prefrontal transmission ilawula i-accumbal dopamine outflow ebangelwa kukuvezwa okokuqala kwezi zivuseleli zikhuthazayo, siye savavanya iziphumo zokuphela kwe-norepinephrine kwi-mpFC ekukhutshweni kwe-dopamine kwi-NAc kunye nokukhululwa kwe-norepinephrine kwi-mpFC ebangelwa kukuvezwa kokuqala. kwezi zivuseleli.
Okokugqibela, siphande iziphumo zokuncitshiswa kwe-noradrenergic prefrontal ekhethiweyo kwindawo emiselweyo (CPP) eyenziwe yitshokholethi kunye ne-cocaine kunye ne-conditioned place aversion (CPA) eyenziwe yi-LiCl. Inkqubo yokumisela indawo yakhethwa kolu phononongo kuba ivumele ukuvavanywa kokufunyanwa kwemeko enokuthamba kunye nepropathi ephikisayo ukuba ivuselele idityaniswe nemivuzo ephambili kunye neziganeko ezichaseneyo kwaye ngenxa yokuba uninzi lobungqina bubonisa ukuba ngumlinganiselo othembekileyo weenkqubo ezisisiseko. i-motivational salience attribution to stimuli (3, 16).
IINKCUKACHA
Zama 1.
Ukuvavanya ukuba ingaba ukuvezwa kokuqala kokubini okuvuzayo kunye nokuvuselelayo kuchaphazela i-norepinephrine yangaphambili kunye ne-accumbal dopamine outflow, siye savavanya, nge-intracerebral microdialysis, iziphumo ze-systemic cocaine okanye i-LiCl kunye nokusetyenziswa kwetshokolethi ekukhutshweni kwe-norepinephrine kwi-mpFC kunye nokuphuma kwe-dopamine kwi-NAc. Ngaphaya koko, ukuze siqinisekise ukuba ukuhanjiswa kwe-cortical noradrenergic kuyafuneka na kwi-accumbal dopamine outflow eyenziwe kukuvezwa okokuqala kwezi zivuseleli zikhuthazayo, siye savavanya iziphumo zokuphela kwe-noradrenergic ekhethiweyo kwimpendulo ye-accumbal dopamine eyenziwe yi-cocaine, itshokolethi, kunye ne-LiCl. I-Cocaine, itshokolethi, kunye ne-LiCl zivelise ukunyuka okuxhomekeke kwixesha lokuphuma kwe-norepinephrine kwi-mpFC yamaqela aphathwe nge-sham, ukufikelela ekunyukeni okuphezulu kwe-≈200% kwi-40 min, ≈70% kwi-120 min, kunye ≈100% kwi-60 min, ngokulandelelanayo (Umfanekiso 1a). Nangona ukwanda kokukhutshwa kwe-norepinephrine kwi-pFC ekuphenduleni i-cocaine kuye kwaxelwa ngokubanzi, kulwazi lwethu le ngxelo yokuqala yokunyuka kokuphuma kwe-norepinephrine okubangelwa kukuvezwa okokuqala kwetshokolethi okanye i-LiCl yenkqubo ngaphakathi mpFC. Ezi zivuseleli ziphinde zavelisa ukunyuka okuhambelana nexesha elihambelanayo lokuphuma kwe-dopamine kwi-NAc yezilwanyana eziphathwe nge-sham (umzobo 1b), ngokuvumelana nombono wokuba le ndawo idlala indima enkulu ekuqhutyweni kwe-stimuli ephawulekayo kungakhathaliseki ukuba i-valence yabo (3) , 6). Iziphumo zolu kuncipha ekukhululweni kwe-norepinephrine kwi-mpFC nazo zavavanywa. Ukuncipha kwe-norepinephrine yangaphambili kwafunyanwa ngokuchithwa kwe-neurotoxic ekhethiweyo ye-prefrontal cortical norepinephrine afferents (amaqela aphelelwe yi-norepinephrine) kwi-mpFC emva kokukhuselwa kwe-dopamine ngesithinteli sokuthatha esikhethiweyo. Le ndlela ivelise ukuncipha okunzulu kwamanqanaba ezicubu ze-norepinephrine (≈90%), okushiya amanqanaba ezicubu ze-dopamine phantse angachaphazeleki. Izilwanyana zokulawula (amaqela aphethwe yi-sham) ziphantsi konyango olufanayo njenge-norepinephrine-depleted mice kodwa zifumana isithuthi se-intracerebral. (Amanqanaba e-norepinephrine tissue alandelayo: iqela eliphathwe nge-sham, i-698 ± 26 ng / g izicubu ezimanzi; iqela elichithwe yi-norepinephrine, i-63 ± 17 ng / g izicubu ezimanzi. Amanqanaba e-Dopamine alandelayo alandelayo: iqela eliphathwe nge-sham, i-203 ± I-18 ng / g izicubu ezimanzi; iqela eliphelelwe yi-norepinephrine, i-189 ± 16 ng / g izicubu ezimanzi.)
Umzobo 1.
Ukuncipha kwe-norepinephrine ye-cortical yangaphambili kwi-norepinephrine ye-extracellular kwi-mpFC kunye ne-dopamine kwi-NAc. I-Extracellular norepinephrine (NE) kwi-mpFC (a) kunye ne-dopamine (DA) kwi-NAc (b) yezilwanyana eziphathwe nge-sham okanye i-norepinephrine-ephelelweyo etofwe nge-saline, (ngaphezulu ...)
Ukuchithwa kwe-norepinephrine ekhethiweyo kwi-mpFC yonakalisa ukwanda kwe-accumbal dopamine kunye ne-prefrontal cortical norepinephrine ukukhululwa okubangelwa zombini iziyobisi kunye netshokolethi (Umfanekiso 1), nangona ayizange ichaphazele kakhulu i-basal extracellular dopamine kwi-NAc (iqela eliphathwa nge-sham, i-1.35 ± 0.15 pg nganye I-20 μl; iqela eliphelelwe yi-norepinephrine, 1.29 ± 0.18 pg nge-20 μl) okanye i-basal extracellular norepinephrine kwi-mpFC (iqela eliphathwa nge-sham, 1.31 ± 0.18 pg nge-20 μl; iqela eliphelelwe yi-norepinephrine-1.26 μ0.17 μ20 ± 20 μ3 ± XNUMX. Amaxabiso asezantsi e-basel ye-dopamine kwi-NAc kunye ne-norepinephrine kwi-mpFC kwiqela ngalinye [i-saline, i-cocaine (XNUMX mg/kg), i-LiCl (i-XNUMX meq/kg), kunye netshokholethi] ayizange yahluke kakhulu.
Iziphumo zethu zibonisa ukuba ukuhanjiswa kwe-noradrenergic ngaphakathi kwe-mpFC yimeko eyimfuneko yovuselelo lokukhutshwa kwe-dopamine okubangelwa kokubini okuvuzayo kunye nokuvuselelayo ngaphakathi kwe-NAc, ngaloo ndlela icebisa ngamandla indima yayo enkulu ekukhuthazeni.
Zama 2.
Ukuphanda ukuba ngaba i-norepinephrine prefrontal transmission iyimfuneko ekufumaneni i-conditioned appetitive and aversive properties to stimuli edityaniswe nemivuzo ephambili kunye neziganeko eziphazamisayo, sivavanye imiphumo yokuchithwa kwe-norepinephrine yangaphambili kwi-prefrontal kwindawo.
I-prefrontal noradrenergic depletion yabhangisa zombini i-cocaine- kunye ne-chocolate-induced CPP kunye ne-CPA eyenziwe yi-LiCl. Ngaloo ndlela, nangona izilwanyana eziphathwa nge-sham zibonisa ukhetho olubalulekileyo lwe-cocaine- okanye i-chocolate-paired compartment kunye nokuphazamiseka okuphawulekayo kwi-LiCl-paired compartment (Fig. 2a), izilwanyana ezichithwayo ze-norepinephrine azizange zibonise ukukhetha nokuba yiyiphi i-compartment (Fig. 2b). ).
Umzobo 2.
Ukuncipha kwe-norepinephrine ye-cortical yangaphambili kwindawo yokulungiswa kwendawo. Iziphumo zokusetyenziswa kokutya (1 g yetshokholethi yobisi; iqela eliphathwe nge-sham, n = 8; iqela le-norepinephrine-depleted, n = 8) kunye ne-systemic injection (ip) ye-saline (Sal) (iqela eliphathwe nge-sham, (ngaphezulu ...)
Qaphela ukuba kwiimvavanyo zangaphambili siye saqaphela ukuba zombini i-CPP kunye ne-CPA yezilwanyana eziphathwe nge-sham zazingabonakali kwizilwanyana ze-naïve. Izilwanyana eziye zafumana i-saline pairing kumacandelo omabini azizange zibonise ukukhetha nokuba yiyiphi i-compartment kungakhathaliseki ukuba imeko ye-lesion (i-sham iphathwa okanye i-norepinephrine iphelile). Ukuziphatha kwezilwanyana ezigqithisiweyo ze-norepinephrine eziphathwa nge-cocaine, itshokolethi, okanye i-LiCl yayifana nezilwanyana ezifumana isisombululo sesithuthi kuphela ngexesha loqeqesho; okt, ababonisanga kukhetha nakweliphi na igumbi.
UKUQALA
Apha sinikela ingxelo yobungqina bokuba ukuhanjiswa kwe-cortical norepinephrine yangaphambili, ngokumodareyitha i-dopamine kwi-NAc, yimeko eyimfuneko yonikezelo lwenkuthazo yenkuthazo kuzo zombini ezi zinto zihambelana nomvuzo- kunye nenzondo.
Okokuqala, ngenxa yokuba amava angaphambili esona sigqibo siphambili sempembelelo yenkuthazo yalo naluphi na uvuselelo olunikiweyo (7), siye savavanya, nge-intracerebral microdialysis, iziphumo zokuvezwa okokuqala kwi-systemic cocaine okanye i-LiCl kunye neziphumo zokusetyenziswa kwetshokholethi kwi-norepinephrine okanye i-dopamine. ukukhululwa kwi-mpFC kunye ne-NAc, ngokulandelanayo. I-Cocaine, itshokolethi, kunye ne-LiCl zivelise ukunyuka okuxhomekeke kwixesha kwi-accumbal dopamine kunye nokuphuma kwangaphambili kwe-norepinephrine yamaqela aphethwe yi-sham. Ukunyuka okubonakalayo kokuphuphuma kwe-norepinephrine kwabonakala kwi-mpFC yezilwanyana eziphathwe nge-sham ngaphakathi kwe-20 min yokufumana i-tshokoleta; Ukuphuphumala okuthe emva koko kwabuyela kumanqanaba esiseko kwaye kwalandelwa kukwanda okuzinzileyo okukhulu. Nangona olu nyuso lwe-biphasic lwetshokholeti lwe-norepinephrine kwi-mpFC aluzange luhambelane nokonyuka kwe-dopamine kwi-NAc kuyo yonke indawo, ukonyuka kokuqala kwakunokunxulumana nefuthe lokutya okunencasa kunye nokwanda kwe-dopamine kwi-NAc. Kwelinye icala, ukonyuka kwesibini okukhulu kunokumela i-neurochemical correlate ye-cortical arousal efunekayo ekusetyenzweni kolwazi lwendawo enxulumene nokukhangela kunye nokufumana umvuzo wokutya (17). Enyanisweni, kuye kwacetyiswa ukuba ukunyuka kwe-norepinephrine outflow kunceda ukubonakalisa ubukho be-stimuli kunye ne-salience ephezulu yokukhuthaza (17). Ke, oku kunyuka kokuphuma kwe-norepinephrine kunokuvumela ingqwalasela ekhethiweyo efunekayo ekufuneni ukutya okongeziweyo okunencasa kwaye inokunceda ekufumaneni iipropathi ezinomdla ezibekwe kwimeko yokukhuthaza ukudibanisa nokutya. Nangona kunjalo, imiphumo ye-postingestive yokutya kwi-norepinephrine ayinakukhutshelwa ngaphandle.
Nangona ukonyuka kokukhutshwa kwe-dopamine kwi-NAc ebangelwe kukuvuza okanye ukuvuselela amandla kunye nokwanda kokukhululwa kwe-norepinephrine kwi-pFC ekuphenduleni i-cocaine kuye kwaxelwa ngokubanzi, kulwazi lwethu le ngxelo yokuqala yokunyuka kokuphuma kwe-norepinephrine okubangelwa kukuvezwa kwetshokholethi okanye i-LiCl ngaphakathi kwe-mpFC. Okona kubaluleke kakhulu, sibonisa apha ukuba i-prefrontal cortical noradrenergic transmission iyimfuneko kwi-accumbal dopamine outflow ebangelwa kukuvezwa kokuqala kwezi zivuseleli zikhuthazayo. Ngapha koko, akukho lwando lubalulekileyo kuzo zombini i-norepinephrine yangaphambili kunye ne-accumbal dopamine outflow, ebangelwa zezi zivuseleli, kwabonakala kwiimpuku eziphelelwe yi-norepinephrine. I-Norepinephrine kwi-mpFC inokuvula ukukhutshwa kwe-mesoaccumbens ye-dopamine ngokusebenzisa i-excitatory prefrontal cortical projection ukuya kwi-ventral tegmental area cell dopamine (18, 19) kunye/okanye ngoqikelelo lwe-corticoaccumbal glutamatergic (20). Ngapha koko, indima yoqikelelo lwe-pFC kwi-locus coeruleus ekusebenziseni impembelelo ekhuthazayo inokucingelwa kuba le nucleus ibonakaliswe ukuba isebenze i-ventral tegmental area dopamine neurons (21-23), enokukhokelela ekonyukeni kokukhululwa kwe-dopamine kwi-NAc.
Ke, iziphumo zethu, ngokuvumelana neengxelo zangaphambili, zibonisa ukuba zombini izivuseleli ezingavuzwanga kunye ne-aversive zinyusa ukuphuma kwe-norepinephrine kwi-mpFC (10-15) kunye nokukhululwa kwe-dopamine kwi-NAc (3, 24). Okona kubaluleke kakhulu, nangona kunjalo, babonisa ukuba ukuhanjiswa kwe-noradrenergic ngaphakathi kwe-mpFC yimeko eyimfuneko yovuselelo lokukhutshwa kwe-dopamine okubangelwa kokubini okuvuzayo kunye nokuvuselela i-pharmacological kunye nendalo ngaphakathi kwe-NAc. Ngoko ke, babhekisela kwi-norepinephrine yangaphambili kunye nokuhanjiswa kwe-accumbal dopamine njengenkqubo ye-neural esebenzayo ngokuvuza okungafunekiyo kunye ne-aversive stimuli kusenokwenzeka ukuba sisisitshixo senkuthazo. Lo mbono uxhaswa ziziphumo zovavanyo lokuziphatha kwiziphumo ze-prefrontal norepinephrine depletion kwi-cocaine-, itshokolethi-, okanye i-LiCl-induced place conditioning.
Ke, isiphumo sesibini esibalulekileyo solu phononongo kukuba ukuncipha kwe-cortical norepinephrine yangaphambili kuyonakalisa zombini i-CPP eyenziwe yi-cocaine okanye ukutya kunye ne-CPA eyenziwe yi-LiCl. Nangona izilwanyana eziphathwe nge-sham zibonise ukhetho olubalulekileyo lwe-cocaine- okanye i-chocolate-paired compartment kunye nokucaphuka okuphawulekayo kwi-LiCl-paired compartment, izilwanyana eziphelelwe yi-norepinephrine azibonakali kukhetha naliphi na igumbi, ngaloo ndlela zibonisa ukuba ukuhanjiswa kwe-norepinephrine ye-cortical iyimfuneko. ekufumaneni iipropathi ezinemeko yokuvuselela ezidityaniswe nemivuzo ephambili okanye iziganeko ezichaseneyo kwinkqubo yokubeka indawo.
Iziphumo zangoku zibonisa ukuba, kwi-prefrontal cortical norepinephrine-epheleyo iimpuku, ukungabikho kokukhululwa kwe-norepinephrine okubangelwa kukuvezwa komvuzo kunye ne-aversive stimuli (i-cocaine, ukutya, okanye i-LiCl, i-stimulus engaguqukiyo) ithintele impembelelo ekhuthazayo kwi-stimulus enemeko (ipateni yendawo) iiseshini zokubhanqa. Kwakhona, qaphela ukuba i-prefrontal ye-norepinephrine depletion ayizange iphazamise okanye i-asociative okanye iinkqubo ze-mnemonic kuba, njengoko kubonisiwe ngaphambili, izilwanyana eziphelelwe yi-norepinephrine zibonakalise ukuba ziyakwazi ukufunda umsebenzi wokuphepha (15) kunye nokudibanisa umxholo kunye nemiphumo yeziyobisi (14). Nangona kunjalo, uphando olongezelelweyo luyimfuneko ukuqonda uhlobo oluchanekileyo lokukhubazeka kwezilwanyana ze-prefrontal cortical norepinephrine-depleted.
Usasazo lwe-Dopaminergic ngaphakathi kwe-NAc kuthathwa njengokulamla impembelelo ye-hedonic yomvuzo okanye imiba ethile yokufunda ngomvuzo (jonga iref. 25 ukuze uphonononge). Iziphumo zethu, ngokuvumelana nombono owahlukileyo (3), zibonisa ukuba ukuhanjiswa kwe-dopamine kwi-NAc kudlala indima kuzo zombini iindlela zokuziphatha ezikhuthazayo nezikhuthazayo; okona kubaluleke kakhulu, nangona kunjalo, babonisa ukuba le nkqubo yokukhuthaza ilawulwa yi-prefrontal cortical norepinephrine. Ngapha koko, i-prefrontal ekhethiweyo yokuchithwa kwe-norepinephrine ivelisa ibhloko yazo zombini i-cocaine- okanye i-CPP eyenziwe ngetshokholethi kunye ne-LiCl-induced CPA kunye nokuphazamiseka kokukhutshwa kwe-dopamine kwi-NAc ebangelwa zezi zivuseleli zinamandla kulawulo lweempuku, ngaloo ndlela ibonisa ukuba ukuhanjiswa kwangaphambili kwe-noradrenergic, ngokumodareyitha. Ukukhutshwa kwe-dopamine ngaphakathi kwe-NAc, yimeko eyimfuneko yokusetyenzwa kwenkuthazo yomibini yomvuzo- kunye nesivuseleli esinxulumene nokucaphukela.
Kuthatyathwe kunye, iziphumo zangoku ezivela kuvavanyo lokuziphatha kunye ne-microdialysis zibonisa ukuba ukuhanjiswa kwe-norepinephrine kwangaphambili akupheleli nje ekulamleni iipropathi ezinomvuzo zeziyobisi ezixhatshazwayo, njengoko kucetyisiwe kwizifundo zangaphambili (14, 15), kodwa iyimfuneko kwimpembelelo ekhuthazayo yokunika amandla kuwo omabini umvuzo- kunye no. Isivuseleli esinxulumene nokuchasa, ebonisa ngakumbi ukuba iziyobisi ezikhobokisayo, kunye ne-aversive pharmacological stimuli, zisebenzisa indlela efanayo ye-neurobiological njenge-stimuli yendalo.
Ukuqukumbela, idatha yethu yandisa iziphumo zangaphambili ezikhomba kwinkqubo ye-mesolimbic dopaminergic njenge "nkqubo yesalience" ebandakanyeka kuzo zonke iindlela zokuziphatha ezikhuthazayo (3, 6, 26). Bakwabonisa ukuba le nkqubo iphantsi kolawulo lwe-norepinephrine prefrontal cortical, ngaloo ndlela ixhasa umbono wokuba i-stimuli evuzayo kunye ne-aversive ichaphazela iindlela ezifanayo kwi-CNS (7).
Iziphumo zethu zibonelela ngengqiqo malunga ne-neurobiology yomvuzo kunye nenzondo kuba zibonisa ukuba ukusetyenzwa kokubini okuvuzayo kunye nokuphazamiseka okumangalisayo kubandakanya iindawo zobuchopho ezifanayo; oko kukuthi, bakhomba kwi-prefrontal noradrenergic kunye ne-accumbal dopaminergic transmission njengendlela eqhelekileyo ye-neural system. Ukuqonda iinkqubo ze-neurotransmitter ezivuzwe ngokuchukumisayo okanye ezivuselelayo kunye neendlela zabo zeemolekyuli ziya kunceda ukubonelela ngesiseko sokucacisa ukusebenza kweenkqubo ze-neural ezibandakanyekayo kwiimvakalelo ezintle kunye nezibi..
IMPAHLA NENKQUBO
Izilwanyana.
Iigundane zamadoda ze-C57BL / 6JIco inbred inbred (iCharles River Laboratories, Wilmington, MA), ezisetyenziswa ngokuqhelekileyo kwi-neurobehavioral phenotyping, iiveki ze-8-9 ubudala ngexesha lovavanyo, zigcinwe njengoko zichazwe ngaphambili (14, 15). Iqela ngalinye lovavanyo laliquka izilwanyana ezintandathu ukuya kwezisibhozo. Zonke iimvavanyo zenziwa ngokungqinelana nomthetho wesizwe waseItali (Decreto Legislative no. 116, 1992) olawula ukusetyenziswa kwezilwanyana kuphando.
Iziyobisi.
I-Chloral hydrate, i-6-hydroxydopamine (6-OHDA), i-GBR 12909, i-cocaine hydrochloride, kunye ne-LiCl zathengwa kwi-Sigma–Aldrich (St. Louis, MO). I-Cocaine (20 mg / kg), i-LiCl (3.0 meq / kg), i-chloral hydrate (350-450 mg / kg), kunye ne-GBR 12909 (15 mg / kg) yachithwa kwi-saline (0.9% NaCl) kunye ne-ip injected in a umthamo we-10 ml / kg. I-6-OHDA yachithwa kwi-saline equkethe i-sodium metabisulfite (0.1 M). Kuvavanyo lokutya, umvuzo yitshokholethi yobisi (1 g; uNestlé, Vevey, Switzerland).
Unyango.
Izilwanyana zifakwe i-anesthetized nge-chloral hydrate (450 mg / kg), ifakwe kwifreyimu ye-stereotaxic (uDavid Kopf Instruments, iTujunga, CA) exhotywe nge-adapter ye-mouse, kwaye ifakwe unilaterally kunye ne-cannula yesikhokelo (insimbi engenasici, i-shaft yangaphandle ububanzi be-0.38 mm ;Metalant AB, Stockholm, Sweden) kwi mpFC okanye kwi-NAc (14, 15). Ubude be-cannula yesikhokelo be-1 mm ye-mpFC kunye ne-4.5 mm ye-NAc. I-cannula yesikhokelo yalungiswa nge-epoxy glue, kunye ne-samente yamazinyo yongezwa ukuze kuqiniswe ngakumbi. Ulungelelaniso oluvela kwi-bregma [elinganiswe ngokweendlela zikaFranklin kunye nePaxinos (27)] zezi zilandelayo: + 2.52 anteroposterior kunye ne-0.6 lateral ye-mpFC kunye + 1.60 i-anteroposterior kunye ne-0.6 lateral ye-NAc [ikakhulukazi iquka ulwahlulo lwegobolondo (27)]. I-probe (i-dialysis membrane ubude be-2 mm ye-mpFC kunye ne-1 mm ye-NAc kunye nobubanzi obungaphandle be-0.24 mm, i-MAB 4 ye-cuprophane microdialysis probe; i-Metalant AB) yaziswa nge-24 h ngaphambi kovavanyo lwe-microdialysis. Izilwanyana zazincinci i-anesthetized nge-chloral hydrate (350 mg / kg) ukuququzelela ukufakwa ngesandla kwe-microdialysis probe kwi-cannula yesikhokelo. Izilwanyana zazibuyiselwa kwiindlwana zazo. Ityhubhu ye-outlet kunye ne-inlet probe ikhuselwe yiParafilm esetyenziswa ekuhlaleni. Iimbrane zavavanywa kwi-vitro recovery ye-dopamine kunye ne-norepinephrine (ukubuyiswa kwesihlobo kwaba ngolu hlobo lulandelayo: i-dopamine, i-10.7 ± 0.82%; i-norepinephrine, i-12.2 ± 0.75%; n = 20) ngosuku ngaphambi kokusetyenziswa ukuqinisekisa ukubuyiswa.
I-microdialysis probe ixhunywe kwipompo ye-CMA / 100 (iCarnegie Medicine, i-Stockholm, eSweden) nge-PE 20 tubing (i-Metalant AB) kunye ne-ultralow torque ye-dual-channel liquid swivel (imodeli 375 / D / 22QM; I-Instech Laboratories, iNtlanganiso ye-Plymouth, PA) ukuvumela ukuhamba ngokukhululekileyo. Ulwelo lwe-cerebrospinal eyenziweyo (i-147 mM NaCl/1 mM MgCL/1.2 mM CaCl2/4 mM KCl) yapompa ngeprobe ye-dialysis kwireyithi yokuhamba rhoqo ye-2 μl/min. Iimvavanyo zenziwa kwiiyure ezingama-22-24 emva kokubekwa kweprobe. Isilwanyana ngasinye safakwa kwikheji ejikelezayo ebonelelwe ngezixhobo ze-microdialysis (Instech Laboratories) kunye nebhedi yekheji yasekhaya phantsi. I-dialysis perfusion yaqalwa kwi-1 h kamva. Emva kokuqala kwe-dialysis perfusion, iigundane zashiywa zingaphazanyiswa kwi-≈2 h ngaphambi kokuqokelela iisampulu zesiseko. Ukugxininiswa okulinganiselwe kweesampuli ezintathu eziqokelelwe ngokukhawuleza ngaphambi kokuba unyango (<10% ukuhluka) luthathwe njenge-basal concentration. Phambi kokuba kuqale uvavanyo lwe-microdialysis, iimpuku zabelwa kolunye lonyango olwahlukileyo (i-saline, i-cocaine, itshokolethi, okanye i-LiCl) ngaphakathi kweqela ngalinye (i-sham iphathwa okanye i-norepinephrine iphelile). Kuvavanyo lokutya, izilwanyana zabekwa kwishedyuli yokuncitshiswa kokutya (28) kwiintsuku ze-4 ngaphambi kokuba kuqaliswe uvavanyo.
I-Dialysate yaqokelelwa yonke i-20 min kwi-120 (ye-cocaine kunye namaqela e-LiCl) okanye i-160 (yamaqela okutya) min. Kuphela yidatha evela kwiimpuku ezine-cannula ebekwe ngokuchanekileyo echazwe. Ukubekwa kwagwetywa nge-methylene blue staining. I-microliters ezingamashumi amabini zeesampulu ze-dialysate zahlalutywa yi-HPLC. I-20 μl eseleyo yagcinelwa uhlalutyo olunokwenzeka olulandelayo. Ugxininiso (pg nge-20 μl) aluzange lulungiswe ukuze kubuyiswe kwakhona. Inkqubo ye-HPLC yayinenkqubo ye-Alliance HPLC (Amanzi, i-Milford, MA) kunye ne-coulometric detector (imodeli 5200A; i-Coulochem II, i-ESA, i-Chelmsford, i-MA) ebonelelwa nge-cell conditioning (M 5021) kunye ne-analytical cell (M 5011) . I-cell conditioning yamiselwa kwi-400 mV, i-electrode 1 yamiselwa kwi-200 mV, kwaye i-electrode 2 yamiselwa ku--250 mV. Ikholamu yeNova-Pack C18 (3.9 × 150 mm; Amanzi) egcinwe kwi-33 ° C isetyenziswe. Umlinganiselo wokuhamba wawuyi-1.1 ml / min. Isigaba esihambahambayo sasichazwe ngaphambili (14, 15). Umda wokufumanisa ukuvavanya wawuyi-0.1 pg.
I-Norepinephrine Depletion kwi-mpFC.
I-Anesthesia kunye nesethi yotyando ichazwe ngasentla. Izilwanyana zafakwa nge-GBR 12909 (15 mg / kg) i-30 min ngaphambi kwe-6-OHDA microinjection ukukhusela i-neurons ye-dopaminergic. Inaliti yamazwe amabini ye-6-OHDA (i-1.5 μg nge-0.1 μl ye-2 min kwicala ngalinye) yenziwe kwi-mpFC [ulungelelwaniso lwaluyi +2.52 anteroposterior, ± 0.6 lateral, kunye -2.0 ne-ventral malunga ne-bregma (27)] ngentsimbi engenasici. i-cannula (i-diameter yangaphandle ye-0.15 mm; i-Unimed, i-Lausanne, i-Switzerland) ixhunywe kwi-syringe ye-1-μl nge-polyethylene ityhubhu kwaye iqhutywe yimpompo ye-CMA / 100. I-cannula ishiywe kwindawo yokongeza i-2 min emva kokuphela kokungena. Izilwanyana eziphathwe nge-Sham zaziphantsi konyango olufanayo kodwa zafumana isithuthi se-intracerebral. Izilwanyana zazisetyenziselwa i-microdialysis okanye iimvavanyo zokuziphatha kwiintsuku ze-7 emva kokuhlinzwa.
I-Norepinephrine kunye ne-dopamine tissue amanqanaba kwi-mpFC ahlolwe njengoko kuchaziwe ngaphambili (14, 15) ukuvavanya ubungakanani bokuphela.
Ukulungiswa kwendawo.
Iimvavanyo zokuziphatha zenziwa ngokusebenzisa izixhobo zokubeka indawo (14, 15, 29). I-apparatus yayiquka amagumbi amabini e-Plexiglas angwevu (15 × 15 × 20 cm) kunye ne-alley ephakathi (15 × 5 × 20 cm). Iingcango ezimbini ze-sliding (4 × 20 cm) zidibanise i-alley kumagumbi. Kwigumbi ngalinye i-parallelepipeds ezimbini ze-triangular (5 × 5 × 20 cm) ezenziwe nge-Plexiglas ezimnyama kwaye zicwangciswe ngeendlela ezahlukeneyo (ezihlala zigubungele ubuso obufanayo begumbi) zisetyenziswe njenge-stimuli ene-conditioned. Izilwanyana zazisetyenziselwa iimvavanyo zokuziphatha emva kweentsuku ezi-7 emva kokuhlinzwa. Phambi kokubekwa kwimeko, iimpuku zabelwa kolunye lonyango olwahlukileyo (i-saline, i-cocaine, itshokolethi, okanye i-LiCl) ngaphakathi kweqela ngalinye (i-sham iphathwa okanye i-norepinephrine iphelile).
Inkqubo yoqeqesho yokulungiswa kwendawo ichazwe ngaphambili (14, 15). Ngokufutshane, ngomhla we-1 (ukuhlolwa kwangaphambili), iigundane zazikhululekile ukuba zihlolisise zonke izixhobo ze-20 min. Ngethuba leentsuku ze-8 ezilandelayo (isigaba sokulungelelanisa), iigundane zazivalelwe imihla ngemihla kwi-40 min ngokutshintshana kwelinye lamagumbi amabini. Ukulungiswa kwendawo kunye ne-pharmacological stimuli, enye yeepateni yayihlala idityaniswe ne-saline kwaye enye ne-cocaine (20 mg/kg ip, CPP) okanye i-LiCl (3.0 meq/kg ip, CPA) ngexesha lesigaba sokumisela. La mayeza akhethwe ngesiseko sezifundo zangaphambili ezibonisa ukuba iimpuku ze-C57BL/6JIco zibonisa i-CPP eyomeleleyo kwidosi ye-cocaine ye-20 mg/kg (30, 31) kunye nomkhwa wokuchasa kuvavanyo lwe-CPA kwidosi ye-LiCl ye-3.0 meq/ kg (32). Kwizilwanyana kwiqela lolawulo, omabini amagumbi adityaniswe ne-saline. Kwi-CPP kunye nokutya, enye yeepatheni yayidityaniswe ngokuqhubekayo kunye nokutya okusemgangathweni (i-1 g ye-mouse standard diet) kunye nezinye ngokutya okunencasa (1 g yetshokolethi yobisi). Izilwanyana zafakwa kwishedyuli yothintelo lokutya (28) iintsuku ezi-4 phambi kokuba kuqaliswe ukulungiswa. Olu cwangciso lwahlala kulo lonke uhlengahlengiso.
Kuwo onke amalinge okulungisa indawo, ukudityaniswa kwalungelelaniswa ukuze kwisiqingatha seqela ngalinye lovavanyo isivuseleli esingaguqukiyo (i-cocaine, itshokolethi, okanye i-LiCl) yadityaniswa nenye yeepateni ezimbini; kwesinye isiqingatha seqela ngalinye, isivuseleli esingenamqathango sidityaniswe nenye ipateni. Uvavanyo lwenkcazo ye-CPP okanye i-CPA lwaqhutywa ngomhla we-10 ngokusebenzisa inkqubo yovavanyo lwangaphambili. Idatha yokuziphatha yaqokelelwa kwaye yahlalutywa yi-EthoVision inkqubo yokulandelela ividiyo ezenzekelayo ngokupheleleyo (Noldus, Wageningen, The Netherlands). Ngokufutshane, inkqubo yovavanyo irekhodwa yikhamera yevidiyo yeCCD. Umqondiso ke ufakwe kwidijithali (ngesixhobo se-hardware esibizwa ngokuba yi-frame grabber) kwaye idluliselwe kwimemori yekhompyutha. Kamva, idatha yedijithali ihlalutywa ngokusebenzisa i-software ye-EthoVision ukufumana "ixesha elichithwe" (ngemizuzwana), elisetyenziswa njengedatha ekrwada kumanqaku akhethwayo kwicandelo ngalinye le-apparatus ngesifundo ngasinye.
Izibalo.
Ukulungiswa kwendawo.
Kwiimvavanyo zokubeka indawo, uhlalutyo lweenkcukacha-manani lwenziwa ngokubala ixesha (ngemizuzwana) elichithwe kwiziko (Iziko), iziyobisi / i-chocolate-paired (I-Paired), kunye ne-saline / i-standard-paired food-pair (Unpaired) amagumbi ngosuku lovavanyo. Kwimeko yezilwanyana ezifumana ityuwa edityaniswe netyuwa kuwo omabini amacandelo, indawo eManyeneyo ichongwe njengeyokuqala eziye zachazelwa kuyo.
Iziphumo zokuchithwa kwe-prefrontal cortical norepinephrine kwindawo yokulungiswa kwendawo.
Idatha evela kwiimvavanyo zokubeka indawo yahlaziywa ngokusebenzisa i-ANOVA yokuphindaphinda kunye neyodwa phakathi kwezinto (unyango lwangaphambili, amanqanaba amabini: i-sham iphathwa kunye ne-norepinephrine depleted) kunye neyodwa ngaphakathi kwento (ukubhanqa, amanqanaba amathathu: Iziko, i-Paired, kunye ne-Unpaired) kunyango ngalunye [ saline/saline, saline/cocaine (20 mg/kg), saline/LiCl (3 meq/kg), kunye nokutya okuqhelekileyo/chocolate]. Ngenxa yokuba uthelekiso olubalulekileyo luphakathi kwee-Paired and Unpaired compartments, kuthetha ukuthelekiswa kwexesha elichithwe kula magumbi kwenziwa ngokusebenzisa imilinganiselo ephindaphindiweyo ye-ANOVA ngaphakathi kweqela ngalinye.
Iindlela ezimbini ze-ANOVA zibonakalise ukunyangwa kwangaphambili okubalulekileyo × ukusebenzisana kwe-cocaine [F (2, 28) = 3.47; P <0.05], LiCl [F (2, 28) = 4.55; P <0.05], kunye netshokolethi [F (2, 28) = 3.5; P <0.05].
Imilinganiselo ephindaphindiweyo ye-ANOVA ngaphakathi kweqela ngalinye ibonise umphumo obalulekileyo we-pairing factor kuphela kwizilwanyana eziphathwe nge-sham ezitofwe nge-cocaine [F (1, 14) = 24.3; P <0.0005], LiCl [F (1, 14) = 10.3; P <0.01], okanye itshokolethi [F (1, 14) = 7.31; P <0.05].
Ukuncipha kwe-Norepinephrine kwi-mpFC.
Iziphumo zokuncipha kwe-norepinephrine yangaphambili kumanqanaba ezicubu ze-dopamine kunye ne-norepinephrine kwi-mpFC zahlalutywa ngeendlela ezimbini ze-ANOVA. Imiba yayimi ngolu hlobo lulandelayo: i-lesion (amanqanaba amabini: i-sham iphathwa kwaye i-norepinephrine iphelile) kunye novavanyo (amanqanaba amabini: uvavanyo lokuziphatha kunye novavanyo lwe-microdialysis). Uthelekiso lomntu ngamnye phakathi kwamaqela lwenziwa xa kufanelekile ngovavanyo lwe-post hoc, uvavanyo lukaDuncan loluhlu olubanzi. Uhlalutyo lweenkcukacha-manani lwenziwa kwidatha evela kwiimvavanyo zokuziphatha kunye ne-microdialysis. I-ANOVA yeendlela ezimbini kwimiphumo ye-prefrontal ye-norepinephrine yokunciphisa i-dopamine kunye ne-norepinephrine ye-tissue amanqanaba kwi-mpFC ibonise umphumo obalulekileyo we-lesion we-norepinephrine kuphela [F (1, 188) = 2.02; P <0.0005], kodwa akukho ziphumo zovavanyo.
Unyango.
Uhlalutyo lweenkcukacha-manani lwenziwa kwidatha ekrwada (ugxininiso lwe-pg nge-20 μl). Iziphumo zokuncipha kwe-norepinephrine yangaphambili ekukhutshweni kwe-norepinephrine kwi-mpFC okanye ekuphumeni kwe-dopamine kwi-NAc yezilwanyana ezinomngeni nge-cocaine (20 mg / kg) okanye i-LiCl (i-3 meq / kg) zahlalutywa ngamanyathelo aphindaphindiweyo i-ANOVA kunye nezinto ezimbini phakathi kwezinto (unyango lwangaphambili, amanqanaba amabini, unyango lwe-sham kunye ne-norepinephrine luphelile; kunye nonyango, amanqanaba amathathu, i-saline, i-cocaine, kunye ne-LiCl) kunye neyodwa ngaphakathi kwento (ixesha, amanqanaba asixhenxe, 0, 20, 40, 60, 80, 100, kunye ne-120). Iziphumo zokuncipha kwe-norepinephrine yangaphambili ekukhutshweni kwe-norepinephrine kwi-mpFC okanye kwi-dopamine ephumayo kwi-NAc yezilwanyana ezivezwe kwitshokholethi zahlalutywa ngamanyathelo aphindaphindiweyo i-ANOVA kunye nenye phakathi kwento (unyango lwangaphambili, amanqanaba amabini, ukunyangwa kwe-sham kunye ne-norepinephrine ephelile) kunye nenye ngaphakathi kwento ( ixesha, amanqanaba alithoba, 0, 20, 40, 60, 80, 100, 120, 140, kunye ne-160). Iziphumo ezilula zavavanywa yindlela enye ye-ANOVA kwixesha ngalinye. Ukuthelekiswa komntu ngamnye phakathi kweqela kuye kwenziwa xa kufanelekile ngovavanyo lwe-post hoc, uvavanyo lwe-multiple-range lukaDuncan.
Uhlalutyo lwamanani malunga nemiphumo ye-pharmacological stimuli kwi-prefrontal norepinephrine outflow ibonakalise ukunyamekelwa okubalulekileyo × unyango × ukusebenzisana kwexesha [F (12, 180) = 4.98; P <0.005]. Uhlalutyo lwezibalo malunga nemiphumo yokusetyenziswa kwetshokolethi ekukhululweni kwe-norepinephrine kutyhile ukunyangwa kwangaphambili × ukusebenzisana kwexesha [F (8, 80) = 7.77; P <0.005]. Uhlalutyo olulula lwesiphumo luveze isiphumo esibalulekileyo sexesha kuphela kwiqela eliphathwe nge-sham kunye nomahluko omkhulu phakathi kwamaqela aphathwe nge-sham kunye ne-norepinephrine-ephelelweyo emva kwenaliti ye-cocaine okanye ye-LiCl kunye nasemva kokusetyenziswa kwetshokolethi.
Uhlalutyo lwamanani malunga neziphumo ze-pharmacological stimuli kwi-accumbal dopamine outflow ibonakalise ukunyangwa okubalulekileyo × unyango × ukusebenzisana kwexesha [F (12, 180) = 10.02; P <0.0005]. Uhlalutyo lwamanani lwedatha yetshokolethi lubonakalise ukunyanzelwa kwangaphambili okubalulekileyo × ukusebenzisana kwexesha [F (8, 80) = 2.12; P <0.05]. Uhlalutyo olulula lwesiphumo luveze isiphumo esibalulekileyo sexesha kuphela kumaqela aphathwe nge-sham kunye nomahluko omkhulu phakathi kwamaqela aphethwe yi-sham kunye ne-norepinephrine-ephelelweyo emva kwesitofu (i-cocaine okanye i-LiCl) kunye nasemva kokusetyenziswa kwetshokolethi.
AMAKHODI
Sibulela uGqr E. Catalfamo ngoncedo olunobuchule. Olu phando luxhaswe nguMinistero della Ricerca Scientifica e Tecnologica (PRIN 2005), Università "La Sapienza" Ateneo (2004/2005), kunye noMinistero della Salute (Progetto Finalizzato RF03.182P).
AMABHUNGA
I-NAc nucleus accumbens
pFC prefrontal cortex
mpFC medial pFC
Indawo ekhethwayo ye-CPP
CPA conditioned indawo inzondo
I-6-OHDA i-6-hydroxydopamine.
AMANQAKU
Ababhali bavakalisa ukuba akukho mpikiswano.
Eli nqaku kukungeniswa ngqo PNAS.
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