I-Dopamine i-D2 receptors kunye nokutshatyalaliswa kwe-striatopallidal kwi-addiction kunye nokukhuluphala (2013)

Ukuphulukana nolawulo lokusetyenziswa kokutya kubantu abatyebileyo abasokolayo nabangakwaziyo ukulawula imizimba yabo kuyafana kwiimeko ezininzi kunyanzeliso lweziyobisi olubonwa kumakhoboka eziyobisi [1,2]. Ngokusekwe koku kufana, kuye kwaqinisekiswa ukuba iinkqubo ezinobuntu okanye ezenzelwa ekhaya zinokuthi zibe negalelo kwezi zinto ziziphetheyo [1,3-6]. Into ebangela umdla kukuba, izifundo zabantu abacinga ukuba zifumanise ukuba i-dopamine D2 receptor (D2R) ifumaneka ngokubanzi njengezantsi.7 ••, 8 ••, 9]. Intsilelo efanayo ekufumanekeni kwe-D2R ikwafunyanwa kwabo baphethwe gwenxa kweziyobisi [10-12]. Abantu ababambe i TaqIA A1 i-allele, ekhokelela kwi-~ 30-40% yokuncitshiswa kwe-striatal D2Rs ngokuthelekiswa naleyo ingathwaliyo i-allele [13-15], zimelwe ngaphezulu kwi-feta kunye nabantu abaxhomekeke kwiziyobisi [7 ••, 8 ••, 9, 16-18]. Yiyo loo nto iinguqu kwi-striatal D2Rs zinokuba negalelo elinokubakho kukutya okunyanzelekileyo kokutya okanye ukusetyenziswa kweziyobisi ngokutyeba kakhulu kunye neziyobisi, ngokulandelelana.

I-Dopamine D2 receptors kumlutha kunye nokukhuluphala

Kutshanje, siphande ukuba ingaba yindlela yokuziphatha engafunekiyo yokondla, njengoko kulinganiswa kukutya okungathandekiyo okuchasene nesohlwayo sokunyanzeliswa (okanye ii-cices ezixela kwangaphambili) ukuvela kwiigundane ngokufikelela okuthe kratya kokutya okumnandi okubangela i-hyperphagia kunye nokufumana ubunzima obukhulu. Sabanika amagundane phantse ukufikelela okungenamkhawulo kwemihla ngemihla kwindawo yokutya "yecafeteria" equka ukhetho lweemveliso zokutya ezinamandla kakhulu ezinentengiso ezithengiswayo kurhwebo olufumaneka kakhulu kwiivenkile zokutyela kunye nomatshini wokuthengisa ukuze usetyenziswe ngabantu, ofana ne-cheesecake kunye ne-bacon, ezivuselela ukukhuluphala kwiintonga kakhulu. njengeempuku zabo ezifanayo zabantu [19,20]. Njengoko la magundane efumana ubunzima, babonisa indlela yokutya engavisisaniyo neziphumo zoxinzelelo lwezinto ezibonakalayo ezixela kwangaphambili ukuqala kwexesha lokuphambukela [21 ••]. Ukutya okufana nokunyanzeliswa kufana nokubonwa kwiigunds kuphendulwa ukumiliselwa kwe-cocaine emva kwethuba elongezelelekileyo lokufikelela kwichiza [22,23 ••].

In ukongeza ekuthandeni kwabo ngokugqithisileyo kunye nokutya okunyanzelekileyo, iigundane zokutya kwecafeteria nazo zinciphile ukubonakaliswa kwe-D2Rs kwi-striatum [21 ••]. Sivavanye ke ukuba ngaba ukunqonqoza kwe-D2Rs ye-striatal kungakhawulezisa na ukuvela kokutya okunyanzeliswayo-kwirati yokutya kwecafeteria. Ukujonga ukuba i-lentivirus iphantsi kwamazinga aphantsi kakhulu okuhambisa, le ndlela iqinisekisa ukuba i-postynaptic D2Rs kwii-neurons ezikwi-striatum, hayi ezo zibekwe ngokongenelelo lokungeniswa kwe-dopamine, thina sibe nefuthe kolu manyano [21 ••]. I-Striatal D2R i-knockdown iyakhawulezisa ukuvela kokusetyenziswa okunganyanzelekanga njengokutya okune-calorical komethayo. Nangona kunjalo, ukwehla kwe-D2R ye-striatal akuzange kubangele ukuphendula okuqhelekileyo kwe-chow, iphakamisa ukuba izilwanyana zinamava endibaniselwano ye-D2R ye-knockdown kunye nokuvezwa okuncinci kokutya okuthandekayo ngaphambi kokuvela kokunyanzelwa [21 ••]. Okothusayo, iimpembelelo zokuphazamisa i-striatal D2R signaling kwiipateni ezinyanzelekileyo zokutya iziyobisi azikavavanywa.

Ukuhanjiswa kwe-Striatopallidal kunye nomvuzo weziyobisi

Iakhawunti eyintloko ye-neurN projektha yee-neurons ephakathi kwe-90-95% ye-neurons kwi-striatum. Ii-MSNs ngokubanzi zahlulwe zaba ziziqwenga ezibini ezingabonakaliyo, ezibizwa ngokuba zii-neurons zendlela ngqo nezingathanga ngqo, nangona olu phawu phantse lulula kakhulu lokudityaniswa kwe-MSNs; umzekelo, jonga ii-Ref. [24-26]. TUqondisa indlela ye-MSNs, ekwabizwa ngokuba yi-striatonigral neurons, avakalise i-dopamine D1 receptors (D1Rs) kunye neprojekhthi ngqo ukusuka striatum ukuya kwi -antiantia nigra pars reticulata (SNr) kunye necandelo langaphakathi le-globus pallidus (GPi). Indlela engathanga ngqo ye-MSNs, ekwabizwa ngokuba yi-striatopallidal neurons, ichaza ii-D2R kunye neprojekti ngokungangqalanga ukusuka kwi-striatum ukuya kwi-SNr / GPi ngokusebenzisa icandelo elingaphandle le-globus pallidus (GPe) kunye ne-subthalamic nucleus (STN).

Ukusebenza kwe-striatonigral neurons ngokubanzi kuqhubela phambili i-locomotor behaviouris, ngelixa ii-striatopallidal neurons zinefuthe eliphikisayo lokuthintela. Ukongeza kwi-striatopallidal neurons, i-cholinergic interneurons kwi-striatum ikwaveza ii-D2R [27, 28 ••, 29]. Le heterogeneity ye-D2R expression in striatum inezinzame ezinzima zokuqonda iindlela ii-D2Rs ezinokuthi zibe negalelo kuphuhliso lokunyanzelwa kwesiyobisi nokutya. Nangona kunjalo, ukuphuhliswa kweempuku ezibonisa i-Cre recombinase ngaphakathi kweendawo ezichaziweyo zee-neurons, kudibene nokuvela kweendlela zokuxhomekeka kohlobo lweCre zokulawula umsebenzi we-neur-expression neurons, njenge-optogenetics [I-30] kunye nee-Receptors zoMyili eziSebenzelwe ngokukhethekileyo kuMachiza aSebenzisa iziyobisi (DREADDs) [31,I-32], eqala ukuchaza igalelo labemi abathile beeseli zesistri kukutya iziyobisi kunye nokutya. Njengoko kushwankathelwe apha ngezantsi, ezi ndlela zinoveli zibonisa igalelo eliphambili le-D2-yokubonakalisa i-neurons kwi-striatum yokuchasana nepropathi evuselelayo kunye neyinzuzo yamachiza amakhoboka, kwaye nangokuchasene nokuvela kweepateni ezingenakulinganiswa, ezinyanzelekileyo ezifana nokutya okanye iziyobisi.

I-Striatopallidal neurons kodwa hayi ii-interneurons ze-cholinergic ziveza i-adenosine 2A receptors (A2AR). Ngokusekwe kule nyani, uDurieux kunye nabalingane basebenzise iimpuku ze-A2AR-Cre ukuqhuba ukuchaza i-diphtheria toxin receptor kwi (DTR) kwi-striatopallidal neurons, emva koko bafaka izilwanyana nge-diphtheria toxin ukuze bathathe izilonda ezikhethekileyo kwezi neurons [33 ••]. Obu buqhophololo babangela i-hyperlocomotion enzulu kunye nokwanda okuphawulweyo kwemvakalelo kwiziphumo ezinomvuzo ze-amphetamine [33 ••]. U-Lobo kunye nabalingane baye baxela ukuba kucinywe ukugxothwa kwe-Tropomyosin-kinase B (TrkB), i-receptor ye-brain-based neurotropic factor (BDNF), kwi-striatonigral yanciphisa iipropathi ezinomvuzo ze-cocaine, ngelixa i-TrkB iknkqenkqeza kwi-D2 echaza umvuzo we-cocaine [34 ••]. Ngapha koko, ukungqongqo kwe-TrkB kwi-D2-echaza i-MSNs kwandise ukugcoba kwabo, ngokunyusa kwe-optogenetic yalezi neurons ngokufanayo kunciphisa umvuzo wecocaine [34 ••]. Kutshanje, uNeumeier kunye nabalingane basebenzise ii-DREADDs ukubonisa ukuba ukuthintela i-striatonigral neurons kuvimbe ukuvela kweempendulo ze-locomotor ze-sensor kwi-amphetamine, ngelixa ukuthintela kwe-striatopallidal neurons kuphuculo lwento.I-35]. Ezi ziphumo zibonisa ukuba ukubonakaliswa kwe-striatopallidal kuphikisa iinkqubo ezinxulumene nomvuzo kwaye kungakhusela ngokuchasene ne-neuroplasticity ehambelana nesiyobisi.

Ukuhanjiswa kwe-striatopallidal kunye nokusetyenziswa okunyanzelekileyo kweziyobisi

Iziphumo zamva nje ziye zanefuthe ekubonakalisweni kwe-striatopallidal kwi-"bhetyebhetye" ukuphendula-amandla okuyeka ukuphendula xa uphikelela ekuziphatheni kunokubangela iziphumo ezibi-ukuphazamiseka apho kunokubangela ukuvela kokunyanzelwa. U-Kravitz kunye nabalingane bafumanise ukuba ukuvuselela kwe-optogenetic ye-striatopallidal neurons kukhokelele ekuphenduleni-okunjengempendulo kwizilwanyana, kubonakaliswa kuthintelo lokukhuthaza u-Optical [I-36]. Isebenzisa iselfowuni ebonakalisa ukuqina kwe-tetanus toxin ukuvimba ukukhutshwa kwe-neurotransmitter, uNakanishi kunye nabalingane bafumanise ukuba ukuphazamiseka kwendlela yokubonakalisa istriatopallidal kwabutshitshisa ubuchule bezilwanyana zokufunda indlela yokuthintela ukungathinteli (ukunqanda imeko apho uthunyelwa khona ii-footshocks zombane) [37 ••]. Isebenzisa le ndlela i-tetanus toxin esekwe kwindlela, i-Nakanishi kunye nabalingane bafumanise ukuba ukuphazamiseka kokuhanjiswa kwes striatopallidal kubaphembelele ekuziphatheni okungaphathekiyo okufana nokuziphatha kweempuku apho bangakwazanga ukuguqula indlela abaziphatha ngayo ngenxa yemisebenzi ebekiweyo.38]. Ezi zinto zifunyanisiweyo ziyahambelana nendima ye-striatopallidal neurons yokulawula ukuguquguquka kokuziphatha, indima ephambili enikezela ukutshintshwa phakathi kweendlela ezahlukeneyo zokuziphatha ukuze kwandiswe amathuba emvuzo [38]. Yiyo loo nto iplasitiki ebangelwa zezi ziyobisi kwi-striatopallidal neurons ekhokelela ekuphelisweni kwenkqubo yabo inokubangela ukuba iimeko zokwenza iziyobisi zingabi lula, zinganyanzelekanga. Ngokuhambelana nolu nokwenzeka, uAlvarez kunye nabasebenza kunye basandula ukubonakalisa ukuba ukuqiniswa kwe-synaptic kwi-D2-i-MSNs ebonakalayo kwi-nucleus accumbens yenzeka ngeempuku kunye nembali yokuzilawula kwe-cocaine ye-intravenous [39 ••]. Oku kuqiniswa kwe-synaptic kwahambelana nokunxulunyaniswa nokuvela kokuphendula okunganyanzelekanga-njengecocaine [39 ••]. Ngapha koko, i-DREADD-mediated inhibition, okanye ukukhuthaza kwamehlo, kwe-striatopallidal neurons yanda okanye yancipha, ngokulandelanayo, ngokunyanzelwa-njengokuphendula i-cocaine kumagundane [39 ••].

Ukuhanjiswa kwe-striatopallidal kunye nokutya okunyanzelekileyo

TIziphumo ezifumanekayo apha ngasentla zinika ubungqina ngqo bokuxhasa indima ephambili ye-D2- ukuchaza ii-MSNs ekuphenduleni kwe-cocaine. Oku kuphakamisa umbuzo obalulekileyo wokuba ingaba i-striatopallidal neurons iyabandakanyeka ekusetyenzisweni okunyanzelekileyo kokutya okuthandekayo ekutyebeni kakhulu. Kuyamangalisa ukuba, oku kunokwenzeka akukabikho kuphononongwa kwaye oku kufanekisa isikhewu esikhulu kulwazi. Nangona kunjalo, kukho iingcebiso ezinomdla ukuba oku kunokuba njalo kwimeko. Njengoko kuphawuliwe apha ngasentla, ii-A2ARs zichazwe ngokunzulu zi-striatopallidal neurons [40]. Ngokunjalo, iiarhente zekhemistiki eziguqula umsebenzi we-A2AR kulindeleke ukuba zibe nefuthe kukhuthazo lokuhambisa i-stonatopallidal i-agonists ye-A2AR, eyonyusa usuleleko lwe-striatopallidal, ukunciphisa ukusetyenziswa kokubini okuthandekayo kunye ne-chow esemgangathweni kwiigundane [41], kunye nokucutha uxinzelelo lwe-lever kwimivuzo yokutya [42]. Kwelinye icala, ibhlokondibolikheyibhem ye-A2A receptors yonyuse ukutya okuthandekayo xa ilawulwa yodwa, kwaye ukutya okuqinisiweyo kokutya okubangelwa lulawulo lwe-intra-drabens ye-µ-opioid receptor agonist (DAMGO) [43]. TIziphumo zophando ziyakhumbuza iimpembelelo zothintelo lwendlela engathanga ngqo kumvuzo wamachiza ochazwe apha ngasentla, kwaye bacebisa ukuba i-D2-echaza indlela engathanga indlela ye-MSNs inokulawula ukutya kakhulu ngendlela efanayo abalawula ngayo umvuzo wamachiza.

Iziphelo kunye nolawulo lwekamva

Ezi ziphumo zilapha ngasentla zixhasa isikhokelo somxholo apho ukusetyenziswa gwenxa kweziyobisi okanye ubunzima bufumana iimpendulo eziguqukayo kwi-striatopallidal neurons, kukhokelela kwiipatheni ezingaguqukiyo zokutya okuya kunyanzeleka ngokuthe ngcembe kwindalo. Ke, indawo enkulu yomsebenzi wexesha elizayo kuphando lokukhuluphala kunokwenzeka ukuba ichaze eyona ndima ichanekileyo ye-striatopallidal neurons ekumiseleni ukuvela kokutya okunyanzelekileyo. Kuya kufuneka kwakhona ukufumanisa ukuba ngaba oku kuzisa oluhlobo lokutya okungaguqukiyo kunokuba sisiseko sezicwangciso ezifanelekileyo zokufezekisa ukunciphisa umzimba ixesha elide. Enye indawo yophando enokubakho inomdla ekubonakaleni kuwo omabini la makhoboka otywala kunye nokukhuluphala kuya kuchazwa ngcono indima ye-D2 receptors ebekwe kwi-cholinergic interneurons. I-Optical inhibition ye-interneurons ye-cholinergic kwi-striatum ichitha iziphumo ezinomvuzo ze-cocaine [44]. Ii-receptors ze-D2 kwi-cholinergic interneurons zilawula imeko yokuqhekeza kweepateni zokudubula kwezi seli ngokuphendula kwisisithukuthezi sokunxibelelana ne-nicotinic acetylcholine receptors (i-NAChRs) ebekwe ngokungenasiphelo kwizitampu zedopamine [28]. Into enomdla kukuba, ukubakho kwe-NAChR kuthintela ukunyuka kokutya i-cocaine kumagundane ngokufikelela okude kwesiyobisi [45]. Ngenxa yoko, kuya kuba kubalulekile ukufumanisa ukuba i-D2 receptor signaling in interriuron cholinergic interneurons nayo inegalelo kunyanzeliso lokusetyenziswa kweziyobisi kunye nokuziphatha kokutya.

Imibulelo

Imihlathi

Izalathiso kunye nokufunda okucetyiswayo