Umlwelwe wokutya okuxilisayo: Ukuthelekisa i-Neurobiology ye-Bulimia Nervosa ukuya kwi-Addict Addiction (2014)

UNatalie A. Hadad, MA kunye ULori A. Knackstedt, Ph.D.

Ulwazi loMbhali ► Ulwazi lobunikazi kunye neelayisensi ►

Ukwenza i-BN engacociyo

Imodeli "yokuthintelwa kokutya / ukuvinjwa" isebenzisa iigundane ukubuyisela uhlobo olungacociyo lwe-BN ngokubeka amaxesha okuthintelwa kokutya okanye ukuvinjwa kunye namaxesha okufikelela simahla kwi-chow okanye ukutya okunencasa (umz., UHagan kunye noMoss ngo-1991; 1997). Emva kwemijikelezo emithathu yokunqongophala kokutya ukuya kwi-75% yobunzima bomzimba obuqhelekileyo obulandelwa kukubuyisela kubunzima obuqhelekileyo, iigundane zibonisa ukutya okufana nokutya ngexesha leyure yokuqala ye-ad lib yokutya kwe-rat chow (UHagan kunye noMoss ngo-1991). Ngokufanayo, iigundane eziphantsi kweeveki ze-12 zeentsuku ze-4 zokunqandwa kokutya okulandelwa yi-2- ukuya kwii-4-ixesha leentsuku zokufikelela ngokukhululekileyo kwi-chow okanye ukutya okunencasa namava e-hyperphagia ngexesha lokufikelela ngokukhululekileyo (UHagan kunye noMoss ngo-1997). Ngokucacileyo, ezi mpuku zibonakalisa iipatheni zexesha elide zokutya eziphambukayo kwaye ziyaqhubeka nokubonisa indlela yokutya kakhulu nasemva kokubuyela kwishedyuli eqhelekileyo yokutya kunye nobunzima bomzimba, ngakumbi xa kunikezelwa ngokutya okunencasa.UHagan kunye noMoss ngo-1997).

Kwimodeli "yokuxilwa kweswekile", iigundane zinikwa ithuba lokungena kwisisombululo seswekile: iiyure ze-12-16 zokunqongophala kokutya zilandelwa ziiyure ze-8-12 zokufikelela kwi-10% sucrose okanye i-25% yeglucose kunye ne-chow kunye namanzi yonke imihla (umz., Avena et al. 2008a, b; Avena et al. 2006a; Colantuoni et al. 2002). Xa kuthelekiswa neempuku zokulawula, iimpuku ezinikwe ufikelelo ngethutyana kwi-sucrose zonyusa ukuthathwa kwe-sucrose kunye nokuziphatha okufana nokuzingxala, okuchazwa sisixa se-sucrose esetyenzisiweyo ngeyure yokuqala yexesha lofikelelo ngalinye.Avena et al. 2008a; Avena et al. 2006a; Colantuoni et al. 2002). Ngokucacileyo, iigundane ezinikwe ukufikelela okwethutyana kwisisombululo se-sucrose ngokuzithandela zitya kakhulu i-chow encinci eqhelekileyo kuneempuku ezinikwe ithuba lokungena okanye i-ad libitum ukufikelela kwi-chow (Avena et al. 2008a; Avena et al. 2006a). Le hypophagia iyafana neepateni zokutya ze-BN-abantu abadla ngokunqanda ukutya kwangaphambili kunye nokulandela ukuntywila (Umbutho i-American Psychiatric Association 2013). Iimpuku ezinikwe ithuba lokungena kwiswekile (kodwa hayi i-chow eqhelekileyo) zikwabonisa iimpawu zokurhoxa (umzekelo, ukuncokola kwamazinyo, ukungcangcazela kwentloko) emva kweeyure ezingama-24-36 zokuhluthwa. Lo mzekelo uvumela ukuhlolwa kweempawu ze-neurobiological ngexesha lokutya ngokutya kunye nokuthintelwa okulandelayo, okubonisa ngokuchanekileyo iimpawu eziphambili ze-BN engahlanjululwayo.

Ngokungafaniyo neemodeli ezichazwe ngasentla, imodeli "yokufikelela okulinganiselweyo" ayivezi iigundane ekuthinteleni ukutya okanye ukuvinjwa. Endaweni yoko, iigundane zinikwa i-ad libitum ukufikelela kwi-chow eqhelekileyo kunye namanzi, kunye nokufikelela okuphakathi kokutya okunencasa okuhlanganiswe ngamafutha, iswekile, okanye indibaniselwano yamafutha / iswekile kwiiyure ezi-1-2 (umz., Corwin kunye neWojnicki ngo-2006; Wong et al. 2009). Iigundane zinikwe ukufikelela okwethutyana kwi-100% yokunciphisa imifuno ngokutya ngamafutha kunye nokunciphisa ngokuzithandela ukusetyenziswa kwe-chow rhoqo (Corwin kunye neWojnicki ngo-2006). Oku kuncipha kokusetyenziswa kwe-chow okusemgangathweni kuyafana neempuku ezinikwe ufikelelo lwethutyana kwisisombululo se-sucrose ye-10% (umz., Avena et al. 2008a) kunye ne-hypophagia ebonwa kwi-BN-abantu ngabanye (Umbutho i-American Psychiatric Association 2013). Ke, imodeli "yokufikelela okulinganiselweyo" iphinda ihlaziye iipatheni zokutya zabantu abangahlanjululwanga be-BN ngokubamba isithintelo esizibekelweyo esidityaniswa nokuzintyintya.

Idityaniswe kunye, imodeli "yesithintelo sokutya / yokungabikho", imodeli "yokukhotyokiswa yiswekile", kunye nemodeli "yokufikelela okulinganiselweyo" zonke zibangela ukuba umntu atye kakhulu. Ngaphaya koko, ziphawulwa ngomfuniselo- okanye ukuzibekela umda. Njengoko kucacisiwe ngasentla, ukuzinkcinkca kunye nokuthintela zizinto ezimbini eziphambili ze-BN engacociyo. Ke, ngokutshintshiselana kwamaxesha okutya kunye nokuthintelwa kokutya kunye/okanye ukutya okunencasa, le mizekelo isebenza njengemizekelo yezilwanyana eyonelisayo ye-BN engacociyo.

Ukwenza imodeli yokucoca i-BN

Ukudala imodeli yezilwanyana zohlobo lokuhlanjululwa kwe-BN kuye kwaba nzima kuba iigundane azinayo i-anatomy ye-muscular ye-esophageal yokuhlanza. Ke, ukuze ubambe zombini ukuzintyintya kunye nokucoca indlela yokuziphatha kwimodeli yesilwanyana esinye, abaphandi baye badibanisa imodeli yegundane yokondla i-sham kunye nokutya kakhulu (umz., Avena et al. 2006b). Kwimodeli yegundane ye-sham-feeding, i-fistula ye-gastric ifakwe kwisisu segundane okanye i-esophagus, okubangela ukudibanisa okuncinci phakathi kokutya kunye ne-gastric yezilwanyana kunye ne-intestinal mucosa. Ngenxa yokuba i-gastric fistula ibangela ukuba ulwelo olutyiweyo luphume kwisisu sempuku, ukufunxwa kwekhalori kulinganiselwe (UCasper et al. 2008). Ngokuhamba ngebhayisekile iigundane ezondliwa ngebhayisikile ngexesha le-12 leyure yothintelo lokutya olulandelwa ziiyure ezili-12 zokufikelela simahla ekutyeni, iigundane zizitya ngokutya okuswiti kwaye zicocwe nge-fistula yesisu.Avena et al. 2006b). Le nkqubo isandula ukuqinisekiswa phakathi kwabantu be-BN (bona UKlein noSmith ngo-2013). Ngokukodwa, abasetyhini be-BN abondliwe-i-sham-bondliwe ngokuntywila kunye nokutshicela kwizisombululo zolwelo babandakanyeka kwi-hyperphagia ngelixa ulawulo oluqhelekileyo kunye nabasetyhini abane-Anorexia Nervosa bengenzi. Ke, nangona iimodeli zezilwanyana zingenako ukubamba ngokupheleleyo ubunzima bokuphazamiseka kokutya kwabantu (Avena kunye neBocarsly 2012), imodeli yeempuku ezondla i-sham edityaniswe nokutya kakhulu ibamba ngokuchanekileyo ukuhlanjululwa kwe-BN.

Iikhrayitheriya zokubandakanywa kuphononongo lwangoku

Iimodeli zezilwanyana ezichazwe ngasentla zibuyisela iimpawu eziphambili ze-BN. Ukulinganisa i-BN engacociyo, "ukuthintelwa kokutya / ukunqongophala," "ukukhotyokiswa yiswekile," kunye "nokufikelela okulinganiselweyo" iimodeli ezitshatileyo ezizintyintya ngomfuniselo-okanye ukuzibekela umda. Okubalulekileyo, ezi zimbini iimpawu eziphambili ze-non-purging BN (Umbutho i-American Psychiatric Association 2000). Ukubamba amacandelo amabini aphambili okucoca i-BN (Umbutho i-American Psychiatric Association 2000), imodeli ye-sham-feeding/bingeing recapitulates ukuzintyintya kunye nokuhlanjululwa. Kukho ezinye iimodeli ze-BN, ezinje ngemodeli yothintelo-loxinzelelo oludibanisa uthintelo lokutya kunye noxinzelelo (umz., UHagan et al. 2002; Inoue et al. 1998). Nangona kunjalo, ezi modeli azizange zisetyenziselwe ukuvavanya utshintsho lwe-neurobiological olubhekiswe kulo mbhalo-ngqangi kwaye, ngenxa yoko, aluyi kuxoxwa.

Uphononongo lwangoku lubandakanya iimodeli zezilwanyana ezichazwe ngasentla. Kuba uthintelo kunye nokuzintyintya ngawona macandelo aphambili e-BN (Umbutho i-American Psychiatric Association 2013), ikwaqukwe apha zizinto ezifunyenweyo kwizifundo ezibandakanya nokuba ukuzila ukutya okanye ukuzinkcinkca kwizilwanyana zaselabhoratri. Sithelekisa iziphumo zolo phando kwezo zifunyenwe kusetyenziswa iimodeli ezahlukeneyo zokukhotyokiswa ziziyobisi ethi nganye ibambe izinto ezibalulekileyo zokukhotyokiswa ngumntu: indawo ekhethwayo, ukuzilawula kweziyobisi, ukusela utywala ngomlomo, kunye nokubuyiselwa ekufuneni iziyobisi emva kokuphela kweziyobisi. impendulo yokufuna iziyobisi. Okubalulekileyo, ngokungafaniyo nophononongo lwamva nje oluthelekisa i-neurobiological underpinnings yokukhotyokiswa kunye nokutya kakhulu kwizilwanyana okukhokelela ekutyebeni (umz., DiLeone et al. 2012; Volkow et al. 2013), iziphumo ezivela kwizifundo zisebenzisa imodeli yezilwanyana zokutyeba azibandakanyi apha kuba abantu be-BN abaqhelekanga ukutyeba kakhulu (Umbutho i-American Psychiatric Association 2013).

I-Nucleus iqokelela i-dopamine

Ukukhuthazwa kwee-neurons ze-DA kwi-VTA kubangela ukuba i-DA ikhutshwe kwi-NAc kwaye ilawule ukuziphatha okukhuthazwayo kunye nokufumana ukuba likhoboka leziyobisi. I-Ethanol, i-nicotine, i-opiates, i-amphetamine, kunye ne-cocaine yonyusa amanqanaba e-DA kwi-NAc, kodwa iziyobisi ezingasetyenziswanga kakubi ngabantu aziwatshintshi amanqanaba e-DA kule ndawo. (UDi Chiara kunye ne-Imperato 1988). Ngaphaya koko, ngelixa ukukhutshwa kwe-DA kuzinzile kulandela ulawulo lweziyobisi oluphindaphindiweyo, isiphumo sokutya ekukhululweni kwe-DA siyehla ngokuhamba kwexesha ngaphandle kokuba ukufumaneka kokutya kuyinoveli okanye akuhambelani. (Ljungberg et al. 1992; UMirenowicz kunye noSchultz ngo-1994). Apha sixoxa ngedatha evela kwiimodeli zezilwanyana zokuhlanjululwa kunye nokungahlanjululwa kwe-BN ebonisa ukuba impendulo ye-NAc DA ekutyeni okunencasa iyahluka ukusuka kwi-chow eqhelekileyo.

Kufundo lwabo lweempuku ezitya i-sucrose sham-fed-sucrose-bingeing, I-Avena kunye noogxa (2006b) ivavanye ukukhutshwa kwe-NAc DA ekuphenduleni i-sucrose. Iigundane kumaqela abondliwa nge-sham abane-fistula yesisu evulekileyo ngexesha leyure yokuqala yokufikelela kokutya babonise ukuziphatha kokutya kwe-sucrose kwaye batya kakhulu i-sucrose ngeyure yokuqala yokufikelela kuzo zonke iintsuku zovavanyo (iintsuku 1, 2, kunye ne-21) ngokumalunga iimpuku ezondliwe ngokwenene ezine-fistula yesisu yahlala ivaliwe. Kwi-vivo microdialysis ibonakalise ukuba i-NAc extracellular DA yonyuke kakhulu kuzo zombini iigundane ezondliwa nge-sham kunye nezondliwa ngokwenene ekuphenduleni ukungcamla i-sucrose kuzo zonke iintsuku zovavanyo. Okubalulekileyo, nangona i-sucrose ifakwe ngexesha lokuqala lokuzinkcinkca yakhutshwa ngokukhawuleza kwizisu ze-sham-feed rats, impendulo ye-DA kwi-NAc yaqhubeka ibonwa ngosuku lwe-21. Iziphumo ezifanayo zifunyenwe kusetyenziswa ukuhluka kwemodeli "ye-sugar addiction". Ukuveza iigundane kwixesha le-12-iyure yokuthintela ukutya okulandelwa lixesha lokufikelela ngokukhululekile kwiswekile kubangela ukuxhamla kwishukela imihla ngemihla kunye nokuqhubeka kokukhululwa kwe-DA kwigobolondo le-NAc kwiintsuku ze-1, i-2, kunye ne-21 yokufikelela kwiswekile (Rada et al. 2005). Ngokwahlukileyo, iigundane zokulawula kunye ne-ad libitum yokufikelela kwi-chow okanye iswekile okanye i-ad libitum yokufikelela kwi-chow kunye nokufikelela kwi-sucrose kuphela iyure ye-1 ngeentsuku ezimbini azigxili kwiswekile, kwaye azibonisi ukukhutshwa kwe-DA egcinwe kwiqokobhe le-NAc. Kwesinye isifundo, iigundane zazinqatshelwe ukutya kwiiyure ze-16 ezilandelwa kukufikelela kwi-chow kwiiyure ze-8 kunye ne-10% isisombululo se-sucrose esifumaneka kwiiyure ezimbini zokuqala kwiintsuku ze-21, okubangelwa ukuxhamla iswekile kunye nokwanda okukhulu kwi-extracellular NAc DA ngosuku lwe-21. (Avena et al. 2008b). Ngomhla we-28, emva kweentsuku ze-7 zokunciphisa ukuya kwi-85% yobunzima bomzimba wabo bokuqala, iigundane ezisela i-sucrose zibonise ukwanda kwe-NAc DA eyayiphezulu kakhulu kunokukhutshwa kwe-NAc DA okubangelwa ukusela i-sucrose kubunzima bomzimba obuqhelekileyo ngosuku lwe-21.Avena et al. 2008b). Kolunye uphononongo, iigundane zokuhamba ngebhayisikile ngeentsuku ezingama-28 zeprotocol "yomlutha weswekile" elandelwa ziiyure ezingama-36 zokuzila ukutya kubangele ukuthoba kakhulu iqokobhe le-NAc yeDA ngokunxulumene neempuku ezinikwe ithuba lokungena okanye i-ad libitum ukufikelela kwi-chow.Avena et al. 2008a).

Ithatyathwe kunye, ngelixa uthintelo okanye ukondla nge-sham-kunye ne-sucrose-bingeing iziphumo kunyuso lwe-NAc ye-DA engaphandle engahlali ixesha elide (umz., Avena et al. 2008b; Avena et al. 2006b; Colantuoni et al. 2001; Rada et al. 2005), amanqanaba e-DA ayancipha kwiqokobhe le-NAc ngexesha lokuzila ukutya (umz., Avena et al. 2008a). Xa ukufikelela kweyure ye-2 kwi-sucrose kuphinda kuzuzwe emva kwexesha lokuzila ukutya, amanqanaba e-DAc e-extracellular e-DA adlula oko kubonwa kwizilwanyana zokulawula ezinikwe ukufikelela kwi-sucrose, ebonisa impendulo ye-DA ecacileyo (umz., Avena et al. 2008b). Ngokufanayo, iigundane ezivezwe kwi-cocaine, i-morphine, i-nicotine, i-tetrahydrocannabinol, kunye nomboniso we-heroin wonyuse i-extracellular NAc DA (umz., UDi Chiara kunye ne-Imperato 1988; Gaddnas et al. 2002; Pothos et al. 1991; UTanda et al. 1997), ngelixa ukuhoxiswa kwezi zinto kunciphisa i-NAc DA (Acquas kunye Di Chiara 1992; UBharaki, uCarnicella, uYowell, kunye noRon, ngo-2011; Gaddnas et al. 2002; Mateo, Lack, Morgan, Roberts, & Jones, 2005; Natividad et al. 2010; Pothos et al. 1991; Rada, Jensen, & Hoebel, 2001; Weiss et al. 1992; Zhang et al. 2012). Ngokufanayo, izinga lokudubula kwe-VTA DA neurons liyancipha kwi-morphine (UDiana et al. 1999) kunye ne-cannabinoid (UDiana et al. 1998) ukurhoxiswa. Ngokufana nomsebenzi weDA ekuphenduleni i-sucrose emva kwexesha lokuthintelwa (Avena et al. 2008b), Ugxininiso lwe-NAc DA luyanda xa iigundane ziphinda zibonakaliswe kwi-nicotine emva kwexesha le-1 okanye i-10 yeentsuku zokuhoxiswa kwi-4 okanye kwiiveki ze-12 zokulawula i-nicotine yomlomo (Zhang et al. 2012). Izinga lokudubula kwe-VTA DA neurons yonyuka kakhulu ekuphenduleni imorphine (UDiana et al. 1999) kunye ne-cannabinoid (UDiana et al. 1998) ulawulo emva kokurhoxa. Nangona kunjalo, inaliti yomceli mngeni we-cocaine emva kwe-1 okanye iintsuku ezi-7 zokurhoxisa ukufikelela okwandisiweyo kokuzilawula kusilele ekunyuseni i-NAc DA, ebonisa uphuhliso lonyamezelo kunye nokungevani (UMateyu et al., 2005). Ukulandela ukufikelela okufutshane kwe-nicotine ye-intravenous self-administration, umngeni we-nicotine emva kweeyure ze-24 zokurhoxiswa uvelisa ukuphakama kwe-NAc DA ephantsi kunezo zibonwa kwiigundane ze-drug-naïve, ezibonisa ukuphuhliswa kokunyamezela.Rahman, Zhang, Engleman, & Corrigall, 2004). Ngelixa ufikelelo olwandisiweyo lwe-methamphetamine ukuzilawula ngokwakho (Le Cozannet, Markou, & Kuczenski, 2013) ivelisa iziphumo ezifanayo URahman et al. (2004), umngeni we-methamphetamine iinaliti ezilandela ukungena kokungathintelekiyo kunye nokufikelela okufutshane kwi-methamphetamine yokuzilawula ngokwakho kukhokelela ekukhululweni kwe-DA ngokuhambelana nolawulo lwe-naïve (Lominac, Sacramento, Szumlinski, & Kippin, 2012).

Ngokomlinganiselo, ngelixa ukubuyiselwa kokutya okunencasa emva kwexesha lokuvinjwa kukhokelela ekukhululweni kwe-DA, isiphumo esifanayo sibonwa kuphela emva kokuhoxiswa kwi-nicotine yomlomo elawulwayo, i-methamphetamine yokufikelela okufutshane, kunye nolawulo olungenasiphelo lwe-cannabinoids, i-morphine, kunye ne-methamphetamine. Umsebenzi we-DAT uyancipha emva kwexesha lokuzila ukutya (Patterson et al., 1998), enokuthi ibe negalelo kwi-DA ephakamileyo ejongwe kulo mmandla wobuchopho ngexesha lokutyisa kwakhona. Isiphumo esifanayo sibonwa ngexesha lokurhoxa kwi-methamphetamine elawulwa ngumfuniselo (IsiJamani, uHanson, kunye noFleckenstein, ngo-2012).

I-Nucleus accumbens i-dopamine receptor expression

Iigundane ezivezwe kumjikelezo ophindaphindiweyo wokutya kunye nokufikelela kuzo zombini i-glucose kunye ne-chow kwiintsuku ze-31 ngokuqhubekayo ukwandisa ukungena kwe-glucose, kodwa kungekhona i-chow intake (Colantuoni et al. 2001). Ishumi elinesibini ukuya kwiiyure ze-15 emva kokuzinkcinkca, i-D1 receptor ebophelelayo kwigobolondo le-NAc kunye nengundoqo iphezulu kakhulu ekuthinteleni kokutya, iigundane ezitya i-glucose ngokuhambelana nokulawula.. Within 1.5 kwiiyure ze-2.5 emva kokutya i-sucrose, iigundane ezithintelweyo zokutya kwaye zinikwe ukufikelela okulinganiselweyo kwi-sucrose kunye ne-chow kwiintsuku ze-7 zibonisa ngokuphawulekayo okuphantsi kwe-D2 ebophelelayo kwi-NAc ngokumalunga neegundane ezinikwe ukufikelela okulinganiselweyo kwi-chow yodwa (UBello et al. 2002). Ngokubhekiselele kwizilwanyana ezilawulayo ezinikwe i-chow kuphela, iigundane ezinokufikelela okwethutyana kwi-sucrose kwiintsuku ze-21 ziba zixhomekeke kwi-sucrose kwaye zibonise ukunciphisa i-D2 mRNA kunye nokwandisa i-D3 mRNA kwi-NAc 1 iyure emva kokufumana ukufikelela kwi-sucrose kunye ne-chow. (Spangler et al. 2004).

Ukonyuka okufanayo kwi-NAc D1 yokubopha i-receptor kunye / okanye amanqanaba e-mRNA afunyenwe emva kokulawulwa okuphindaphindiweyo kwe-cocaine.Unterwald et al. 2001, i-nicotine (Bahk et al. 2002kunye ne-amphetamine (Umncinci et al. 2011). Nangona kunjalo, Le Foll et al. (2003) kufunyenwe kuphela ukunyuka kwe-D3 yokubopha kunye ne-mRNA kodwa akukho tshintsho kwi-D1 elandela i-nicotine engekho. Ngokufanayo, Metaxas et al. (2010) akafumananga tshintsho kwintetho ye-D1 emva kokuzilawula ngokwakho inikotini. Kokubini ukuzilawulela utywala ngokuqhubekayo kunye naphakathi (USari et al. 2006), kunye nokufikelela okwandisiweyo kulawulo lwe-cocaine (UBen-Shahar et al. 2007) ukwandisa i-D1 mRNA kunye nokubonakaliswa kwayo komphezulu (Conrad et al. 2010).

Ukunyuka kwentetho ye-D1 kunokwenzeka ukuba kukhokhelele kwimpendulo eyandisiweyo kwi-DA. Ukukhutshwa kwe-DA kunye novuselelo olulandelayo lwe-D1 receptors kwi-NAc eyenzekayo ekulawuleni iziyobisi ezikhobokisayo kuvelisa i-cascade yomqondiso equka ukonyuka kokubonakaliswa kwezinto ezikhutshelweyo ezifana ne-ΔFosB (ukuvavanya bona Nestler et al. 2001). Ukuthintela umsebenzi woshicilelo we-ΔFosB kunciphisa iziphumo ezinomvuzo zamachiza (UZachariou et al. 2006) kunye nokuchazwa ngokugqithisileyo konyusa umvuzo weziyobisi (Colby et al. 2003; UKelz et al. 1999; UZachariou et al. 2006). Ukuthintelwa kokutya kukwanyusa amanqanaba e-ΔFosB kwi-NAc yeempuku (Isitampu et al. 2008; UVialou et al. 2011), okwandisa inkuthazo yokufumana imbuyekezo yokutya okunencasa kakhulu, njengoko kungqinwa kukufumanisa ukuba i-viral vector-mediated overexpression ye-ΔFosB yonyusa ukusetyenziswa kokutya okunencasa.UVialou et al. 2011). Thus, kusenokwenzeka ukuba i-BN inyuse amanqanaba e-ΔFosB kwi-NAc ngendlela efana neziyobisi ezikhobokisayo, ngaloo ndlela inyusa ixabiso elinomvuzo lokuzinkcinkca.

Ukuzinkcinkca kukwakhokelela ekuncipheni kwe-D2 ebophelelayo kwi-NAc (umzekelo, UBello et al. 2002; Colantuoni et al. 2001; Spangler et al. 2004). Ngokucacileyo, i-Taq1A, i-polymorphism eqhelekileyo yemfuza efumaneka phakathi kwe-BN kunye nabantu abakhotyokiswe ziziyobisi (Berggren et al. 2006; Connor et al. 2008; UNisoli et al. 2007), inxulumene nokunciphisa i-D2 receptor density (Neville et al. 2004). Nangona i-cocaine inciphisa ukubonakaliswa kwe-D2 kwi-NAc (Conrad et al. 2010), inikotini elawulwa ngokuphindaphindiweyo (Bahk et al. 2002), i-amphetamine elawulwa ngumfuniselo (UMukda et al. 2009), kunye notywala obuzenzele (USari et al. 2006) ukwandisa ukubonakaliswa kwe-D2 phakathi kweempuku. Ukukhanya komsebenzi kunye namakhoboka eziyobisi abantu abonisa ukunciphisa kwi-D2 yokubopha (Volkow et al. 2001; Volkow et al. 1993), Kuyathakazelisa ukuba into efanayo ayibonwa emva kwe-nicotine, i-amphetamine, okanye ukubonakaliswa kotywala kwizilwanyana. Nangona kunjalo, ukuncipha kokubophelela kwe-D2 okubonwa ebantwini kunokwandulela ukuvezwa kweziyobisi, kwaye ke amanqanaba asezantsi e-D2 akanakujongwa emva kokuvezwa kwezilwanyana. Ukuncipha kwentetho ye-D2 kunokuvelisa ukwanda kwe-DA efflux enokuqhuba ukuzintyintya okanye ukufuna iziyobisi.

Isishwankathelo, ukuxinana kwe-sucrose kwiimodeli zezilwanyana ze-BN kubangela ukuphakama okuqhubekayo kwe-NAc DA, ukunyuka kwe-D1 receptor dinding kunye ne-D3 mRNA, kunye nokunciphisa i-D2 receptor dinding kunye ne-mRNA kwi-NAc. Ngelixa i-D1 kunye ne-D3 zitshintsha zihambelana nezo ziveliswa ngamachiza okulutha (ngaphandle kwe-nicotine enokwenzeka yokutshintsha kwe-D1), Ukuncipha kwe-D2 akubonwa kwizifundo ezininzi zezilwanyana zokukhotyokiswa ziziyobisi. Kungenzeka ukuba ngelixa i-D2 yokunciphisa ekhoyo ebantwini isebenzela ukuqhuba ukusetyenziswa kweziyobisi, oku kuncipha kwandulela ukusetyenziswa kweziyobisi kwaye akubangelwa yiyo.

I-Dopamine kwindawo ye-ventral tegmental

Iiseli ze-Dopaminergic kwiprojekthi ye-VTA ukuya kwi-PFC, i-hippocampus, i-amygdala kunye ne-NAc. Ukukhutshwa kwe-Somatodendritic ye-DA kwakhona kwenzeka kwi-VTA ekudubuleni kweeseli (Beckstead et al. 2004) kwaye inempembelelo ebalulekileyo kumsebenzi we-dopaminergic VTA neurons. Olu hlobo lokukhutshwa kwe-DA lusebenza kwi-autoreceptors yendawo ye-D2 (Cragg kunye neGreenfield ngo-1997), ngaloo ndlela inqanda ukudubula kweeseli zeDA kwiVTA (UBernardini et al. 1991; Wang 1981; White kunye noWang 1984) kunye nokukhululwa kwe-DA kwi-PFC kunye ne-NAc terminal fields (Kalivas kunye noDuffy 1991; Zhang et al. 1994). Ke ngoko, ukukhutshwa kwe-somatodendritic kwe-DA kwi-VTA kudlala indima ebalulekileyo kulawulo losasazo lwe-DA ecaleni koqikelelo lwe-mesocorticolimbic.

I-In vivo microdialysis isetyenziselwe ukuvavanya ukugxila kwe-VTA DA ngexesha lokutyisa kwakhona. Iigundane zazinqatshelwe ukutya kunye namanzi kwiiyure ze-36 ngaphambi kwexesha lokutya kwakhona apho kwenziwa i-microdialysis (UYoshida et al. 1992). Ukonyuka okubalulekileyo kokugxilwa kwe-VTA DA kwabonwa ngexesha lokutyisa kwakhona kunye nokusela ngokumalunga nesiseko. Amanqanaba e-VTA DA agcinwe kwi-20-40 imizuzu emva kokuphela kweeseshoni zokutya kunye nokusela. Ngokufanayo, inaliti ye-IP ye-ethanol iphumela ekunyukeni kwe-VTA ye-extracellular ngaphakathi kwemizuzu engama-20, ethi emva koko ifikelele kwimizuzu engama-40 emva kokutofa kwaye yehle kwisiseko.Kohl et al. 1998). Ngokufanayo, i-intravenous (IBradberry kunye neRoth 1989) kunye ne-IP (UReith et al. 1997; Zhang et al. 2001Ulawulo lwe-cocaine kunye neenaliti ezibukhali ze-IP ze-methamphetamine (Zhang et al. 2001) ukwandisa i-DA ye-extracellular kwi-VTA. Ngelixa iziphumo ze UYoshida et al. (1992) Uphononongo lucebisa indima ebalulekileyo ye-VTA DA ekuziphatheni kokutyisa, iigundane kuphononongo zazijikeleziswa kuphela ngexesha elinye lokuthintelwa kokutya kunye nokutyisa, kunye nokuziphatha kokutya kakhulu akuzange kuhlolwe. Ngaphezu koko, kwakungekho qela lokulawula kwisifundo, ngoko ke akwaziwa ukuba umphumo ofanayo uya kubonakala phakathi kweegundane ezingabonakali kwi-paradigm yokuhluthwa. Ngaloo ndlela, ukuqhuba uvavanyo olufanayo usebenzisa imodeli yezilwanyana ze-BN kuyimfuneko.

Ugqithiso ecaleni koqikelelo lwe-mesolimbic lukwamodareyithwa ngamanqanaba e-DAT mRNA. I-DAT mRNA yenziwe kwi-VTA kwaye ilawula ukuthathwa kwakhona kwe-DA ngaphakathi kwe-VTA. Iyathuthwa isiwe kwi-NAc ukulawula ukuphinda kuthathwe kwakhona kwe-DA. Ukuza kuthi ga ngoku, uphando olulodwa kuphela luye lwavavanya ukulungiswa kwe-DAT kwi-VTA isebenzisa imodeli yezilwanyana ze-BN (UBello et al. 2003). Kuphononongo, iigundane zazithintelwe kukutya okanye zinikwe i-ad libitum ukufikelela kwi-sucrose okanye i-chow eqhelekileyo, ilandelwa sisidlo sokuqala se-sucrose okanye i-chow eqhelekileyo. Iigundane ezithintelwe ekutyeni zinikwe ufikelelo olucwangcisiweyo kwi-sucrose zidliwe kakhulu i-chow ngaphezu kwalo naliphi na elinye iqela leempuku. Nangona kunjalo, ngokuchasene nophando lwangaphambili (umz., Avena et al. 2008a; Avena et al. 2006a; Colantuoni et al. 2002; Corwin kunye neWojnicki ngo-2006; UHagan kunye noMoss ngo-1997), ukungafani kweqela kwi-sucrose intake ayifumanekanga (UBello et al. 2003). Iziphumo eziphikisanayo zinokubangelwa kukuba uBello kunye noogxa bakhe bakhwele iimpuku ngebhayisekile kwiprotocol kanye kuphela kwaye banikezela ngeempuku ezinemizuzu engama-20 kuphela yokufikelela kwi-sucrose. Nangona kunjalo, iyantlukwano yeqela ekuthatheni i-sucrose ivela xa iimpuku zijikeleziswa ngokuvinjwa kunye nokufikelela amaxesha amaninzi kwaye zinikwe ukufikelela kwi-sucrose kwi-1 ukuya kwiiyure ze-12 (umz., Avena et al. 2008a; Avena et al. 2006a; Colantuoni et al. 2002; Corwin kunye neWojnicki ngo-2006; UHagan kunye noMoss ngo-1997). Nangona kunjalo, iigundane zafunyanwa ukuba zonyuse i-sucrose yazo ngokuphindwe kathathu ngexesha leentsuku ze-7 (UBello et al. 2003), ebonisa ukuziphatha okufana nokuzinkcinkca. Ngokunxulumene nolawulo kunye neempuku ezinikwe simahla- okanye ezicwangcisiweyo-ufikelelo kwi-chow, iimpuku zinikwe umda-ufikelelo kwi-sucrose ecwangcisiweyo ebonakaliswe kakhulu ngokubophelela kwe-DAT kunye namanqanaba e-mRNA kwi-VTA kunye ne-DAT ebophelelayo kwi-NAc (UBello et al. 2003). Njengoko kuxoxwe ngasentla, i-NAc DA yonyuka ekunikezelweni kokutya okunencasa, kwaye ukunyanzeliswa kwintetho ye-DAT kwi-NAc inokuthi yenzeke njengenzame yokubuyisela oku kwanda. Oku kuphakamisa ukuba i-BN engahlanjululwayo idityaniswe ne-sucrose-bingeing ivelisa iziphumo kwi-VTA DA eyahlukileyo kwezo ziveliswa ngokutya okungenancasa. Ukuboniswa okuphindaphindiweyo kwi-amphetamine (Lu kunye noWolf 1997; Shilling et al. 1997kunye nenikotini (Li et al. 2004) kwandisa i-VTA DAT mRNA. Ngokwahlukileyo, i-cocaine engathintelekiyo iyancipha (Cerruti et al. 1994), ngelixa zombini umda- kunye nokufikelela okwandisiweyo kulawulo lwe-cocaine alunasiphumo (UBen-Shahar et al. 2006), DAT mRNA intetho kwiVTA.

Uphando olusebenzisa iimodeli zezilwanyana zothintelo lokutya lucebisa ukuba i-dopaminergic VTA efferents inokulawula olu phawu luphambili lwe-BN engacociyo. Ngokubhekiselele ekulawuleni iigundane kunye nokufikelela simahla ekutyeni, iigundane eziphantsi kwesithintelo sokutya esingapheliyo kwandisa ukubonakaliswa kwe-VTA yee-enzymes ezimbini ezibandakanyekayo kwi-DA synthesis: i-tyrosine hydroxylase (TH) kunye ne-aromatic L-amino acid decarboxylase (AAAD) (Lindblom et al. 2006). Ke, ixesha lokuzila ukutya linokulungiselela i-VTA DA neurons ukukhulula inani elikhulu le-DA kwi-NAc ekunikezelweni kokutya okunencasa. Ukuthintelwa kokutya okungapheliyo kubangela ukwanda okukhulu kwintetho ye-DAT kwi-VTA (Lindblom et al. 2006). Nangona kunjalo, kubalulekile ukuqaphela ukuba uthintelo lokutya luphawu olulodwa kuphela lokungahlanjululwa kwe-BN. Ke ngoko, uphando lwexesha elizayo kufuneka luphonononge ukuba ukuzinkcinkca okudityaniswa nothintelo lokutya okanye ukucocwa kunefuthe elingakanani kwi-VTA TH, AAAD, kunye ne-DAT. I-cocaine engapheliyo kunye nolawulo lwe-morphine yonyusa kakhulu i-VTA TH immunoreactivity (UBeitner-Johnson kunye noNestler 1991), kodwa ulawulo lwe-methamphetamine alutshintshi kakhulu amanqanaba e-TH mRNA kwi-VTA (Shishido et al. 1997).

Ngamafutshane, iimodeli zezilwanyana ezilinganisa i-BN engahlanjululwayo kunye nezinye izinto eziphambili ze-BN, ezifana nokuthintelwa kokutya, zisetyenziselwe ukufumana i-DAT mRNA eyandisiweyo, ukubonakaliswa okuphakamileyo kwee-enzymes ezinxulumene ne-DA synthesis (TH kunye ne-AAAD), kunye nokwandisa ukugxila kwe-DA. kwiVTA. Ezi ziphumo zithelekiseka ne-neuroadaptations efunyenwe emva kokuvezwa okuphindaphindiweyo kwe-amphetamine, i-morphine, kunye ne-nicotine, kodwa ingquzulwano kunye nezo ziveliswa yi-cocaine engaxhomekekanga kunye nezilawulayo kunye nolawulo lwe-methamphetamine. Zithathiwe kunye, iziphumo zokuqala eziphononongiweyo kweli candelo zibonisa ukuba utshintsho lwe-VTA dopaminergic olukhoyo kwiimodeli zezilwanyana ze-BN ziyafana nezo zikhoyo emva kokuvezwa kwiziyobisi ezithile ezikhobokisayo.

Iziphumo zabachasi be-dopamine ekutyeni ngokugqithisileyo kunye nasekufuneni iziyobisi

Ngenxa yokuba ukukhutshwa kwe-DA kwenzeka kwi-NAc ngexesha lokuzinkcinkca, inani lezifundo liye lavavanya amandla olawulo lwenkqubo ye-D1 kunye ne-D2 receptor antagonists ukulungelelanisa le ndlela yokuziphatha. Ukusebenzisa iprotocol yofikelelo olulinganiselweyo kunye nemixube yamafutha / sucrose, Wong kunye noogxa (2009) yafumanisa ukuba i-D2 ephikisana ne-raclopride yenza ukunciphisa okuxhomekeke kwi-dose ekusebenziseni ngokugqithisileyo ukutya okunencasa kunye noxinzelelo oluthile lwe-sucrose. Kuphononongo lwazo, iimpuku zivunyelwe ukufikelela kumxube we-100% wokunciphisa kunye nokuba yi-3.2, 10, okanye i-32 % sucrose (w / w) ngeyure enye, kunye nokufikelela kwansuku zonke okanye okungapheliyo (MWF). Ziimpuku kuphela ezinikwe ufikelelo ngethutyana ekutyeni okunencasa okuqulathe i-3.2 okanye i-10% ye-sucrose efikelele kwiikhrayitheriya zokuzinkcinkca. Kwezi zilwanyana, i-0.1 mg / kg (IP) umthamo we-raclopride yanda ukuzintyintya ngelixa i-0.3 mg / kg (IP) idosi yehla ukusetyenziswa kokutya okunencasa kwiimpuku ezidla i-3.2% ye-sucrose. I-Raclopride ayizange ibe nefuthe ekuthatheni phakathi kweegundane ezinikwe imihla ngemihla- okanye i-intermittent-access to high (32%) i-sucrose concentration ye-fat / sucrose umxube kuyo nayiphi na idosi, kwaye ayizange ichaphazele ukusetyenziswa kwiigundane ezinikwe ukufikelela kwansuku zonke. Kuphononongo olufanayo lweqela elifanayo, iidosi ezifanayo ze-raclopride zavavanyelwa ukukwazi kwabo ukunciphisa ukusetyenziswa kakhulu kweziyobisi. nokuba ukutya okunamafutha (ukunciphisa) okanye okuqulathe i-sucrose (3.2, 10, kunye ne-32%) emva kokuba izilwanyana zinikwe ufikelelo lwemihla ngemihla okanye lwethutyana koku kutya.Corwin kunye neWojnicki ngo-2009). Iyafana neziphumo ze Wong et al. (2009) Uphononongo, i-0.1 mg / kg idosi ye-raclopride yandise kakhulu ukuncipha kokunciphisa phakathi kweegundane ezivezwe kwiprotocol yokufikelela okulinganiselwe kwaye inikwe ukufikelela kweeyure ze-1 kwi-100% yamafutha, kodwa ezi ziphumo azizange zibonwe phakathi kweegundane ezinikwe ukufikelela kwansuku zonke kumanqatha.Corwin kunye neWojnicki ngo-2009). Idosi ephezulu ye-raclopride (0.3 mg/kg) iyancipha ukusetyenziswa kwe-sucrose zonke iimeko zokuzintyintya nge-sucrose. Kwesinye isifundo, iigundane ziphathwe nge-0.3 mg / kg (IP) i-raclopride kwaye zinikwe ukufikelela kweeyure ze-4 kwi-56% ye-emulsion eqinileyo ye-fat emulsion okanye ukufikelela kwi-4-iyure yonke imihla ukuya kwi-18%, i-32%, okanye i-56% i-emulsions yamafutha aqinileyo yehla kakhulu. ukungena kwabo (URao et al. 2008). I-Raclopride ayitshintshi ukutya okuqhelekileyo kwe-chow (Corwin kunye neWojnicki ngo-2009; URao et al. 2008; Wong et al. 2009), ebonisa ukuba i-raclopride ichaphazela ngokukodwa ukusetyenziswa kokutya okunencasa kwaye ikwenza oko kuphela kwizilwanyana ezitya oku kutya.

Ngokunxulumene nokukhotyokiswa kweziyobisi, i-0.1 mg/kg i-raclopride ithoba umxholo wokubuyiselwa kwe-cocaine (UCrombag et al. 2002) kunye ne-0.25 mg/kg i-raclopride ithomalalisa ukuphinda kubuyele i-heroin (UShaham noStewart ngo-1996). Ukulawulwa kwemodareyitha (0.1 mg / kg) kunye nephezulu (0.3 mg / kg) iidosi ze-raclopride iintsuku ezintlanu ezilandelelanayo zithintela i-cannabinoid (WIN)-i-alcohol ebangelwa ukuphindaphinda (UAlen et al. 2008). Ukufakwa kwe-Intra-amygdala ye-raclopride kuvelisa isiphumo esixhomekeke kwidosi ekubuyiselweni kwe-cue-primed yokufuna i-cocaine efana neziphumo zayo ekutyeni ngokutya: idosi ephantsi ivuselela ukubuyiselwa ngelixa idosi ephezulu iyayithoba (Berglind et al. 2006). Ithatyathwe kunye, iidosi eziphezulu ze-raclopride ziyancipha, ngelixa iidosi eziphantsi zinyuka, ukusetyenziswa kwamafutha kunye ne-sucrose kwiigundane ezizonwabisayo, kodwa kungekhona kwiigundane ezingadliyo ezinikwe ukufikelela kwimihla ngemihla ekutyeni okunencasa. Ngokumalunga nokubuyiselwa kokufuna iziyobisi, iimpembelelo ze-raclopride kwi-sucrose bingeing zifana nezo ziveliswa yi-intra-amygdala infusions kodwa kungekhona i-systemic injection.

Umchasi we-D1 we-SCH 23390 unciphisa ukuzinkcinkca ngokutya okunencasa. Ukunyanga iigundane nge-0.1 okanye i-0.3 mg/kg (IP) SCH 23390 kunciphisa ukuthathwa kwe-3.2%, i-10%, kunye ne-32% yezisombululo ze-sucrose zolwelo kwiigundane ezinikwe ukufikelela okulinganiselweyo (iyure enye / ngosuku) ukuba i-sucrose yonke imihla okanye ngokukhawuleza, kunye nemiphumo engaphezulu. kubizwe iimpuku ezinikwe ufikelelo oluphakathi (Corwin kunye neWojnicki ngo-2009). Ngaphezu koko, i-dose ye-0.3 mg / kg SCH 23390 iyancipha kakhulu ukunciphisa ukuthathwa kweegundane ezinikezelwa imihla ngemihla kunye ne-intermittent 1-iyure ukufikelela kwi-fat ngelixa i-0.3 mg / kg idosi ayinayo umphumo. Ngokucacileyo, i-SCH 23390 ayichaphazeli ukuthathwa kwe-chow rhoqo (Corwin kunye neWojnicki ngo-2009; URao et al. 2008; Wong et al. 2009). Ngokufanayo, ukunyanga iigundane nge-SCH 23390 kunciphisa kakhulu ukuphendula kwabasebenzi ekufikeleleni kwi-cocaine ehambelana ne-cocaine, kodwa impendulo kwi-stimuli ehambelana ne-chow ayiphenjelelwa kuninzi lweedosi (Weissenborn et al. 1996). I-SCH 22390 ikwajongela phantsi uhlaziyo lokuzilawula kwe-cocaine eyenziwe nomxholo (UCrombag et al. 2002), ukuphinda kubuyele iheroin (UShaham noStewart ngo-1996), ukuphinda kwe-ethanol (ULiu & Weiss, ngo-2002) kunye nokubuyiselwa kwe-heroin encitshisiweyo ekutyeni (Tobin et al. 2009) kwiimpuku. I-SCH 22390 iyanciphisa ukuzilawula kwe-nicotine (USurge & Clarke, ngo-2009; Izinyuko, Neugebauer, & Bardo, 2010) kunye nokuzilawula kwe-cocaine (USurge & Clarke, ngo-2009). Ngelixa i-SCH 22390 igxininisa kakhulu ukufuna i-cocaine emva kwexesha lokurhoxa kubo bobabini abangamadoda nabasetyhini banikwe ukufikelela okufutshane ekulawuleni i-cocaine, esi siphumo siyancitshiswa kwizilwanyana ezinikwe ukufikelela okwandisiweyo (Ramoa, Doyle, Lycas, Chernau, & Lynch, 2013), ngokuhambelana nokuncitshiswa kokukhutshwa kwe-DA okwenzeka emva kokufikelela okwandisiweyo (kuxoxwe ngasentla). Isishwankathelo, umchasi we-D1 i-SCH 22390 inqanda ukusetyenziswa kokutya okunencasa kunye nokunciphisa ukubuyiselwa kokufuna iziyobisi.

Ngenxa yokuba ukukhutshwa kwe-DA okuphuculweyo kubonwa kwi-NAc ngexesha lokuzinkcinkca, kuyahenda ukucebisa ukuba iziphumo zenkqubo ye-D1 kunye ne-D2 yokuchasana ngokuzinkcinkca ilawulwa yi-NAc. Ukuvavanya amandla okufakwa okuthe ngqo kwe-agonists kunye nabachasayo kwi-NAc ukunciphisa ukuzintyintya kuyimfuneko. Umchasi we-D2 u-raclopride wenza umphumo we-biphasic ekusebenziseni ngokutya ukutya okunencasa; oku kunokuvela njengesiphumo sohlobo oluhlukeneyo lwabantu ababini be-D2 receptors (ngaphambi nangemva kwe-synaptic). Amanani aphantsi e-agonists akhuthaza ngokukhethekileyo i-autoreceptors ye-D2 yangaphambi kwe-synaptic, ngaloo ndlela inciphisa ukukhululwa kwe-DA (UHenry et al. 1998). Kunokucingelwa ukuba iidosi eziphantsi zomchasi we-raclopride nazo ziya kuba nefuthe elikhethekileyo kwi-autoreceptors, ngaloo ndlela inyusa i-DA efflux (umz., Bona et al. 1991) kunye nokuqhuba ukusetyenziswa kokutya okunencasa. Idosi ephezulu inokuthi ithintele i-post-synaptic receptors, ngaloo ndlela inciphisa ukusetyenziswa kokutya okunencasa. Ezi ziphumo zibonisa ukuba i-DA ikhupha kwaye ibophelela kwi-post-synaptic D1, kwaye mhlawumbi i-D2, i-receptors ivuselela ukutya ngokutya. Ukonyusa ukukhutshwa kwe-DA ngokuchasana kwee-autoreceptors ze-D2 nako konyusa ukuzintyintya. Ezi ziphumo zifunyanisiweyo ezifanayo zokubophelela kwe-D1 kunye nokunciphisa i-D2 ebophelelayo kwi-NAc kwiigundane ezinembali yokuzinkcinkca ngokutya okunencasa. Ithathiwe kunye, kusenokwenzeka ukuba ukuncipha kwentetho ye-NAc D2 kukhokelela ekukhulisweni kwe-DA ngexesha lokuzinkcinkca ngelixa i-D1 ephuculweyo ye-primes ye-post-synaptic neurons ukuphendula ngokunamandla ngakumbi kwi-DA ekhutshwe ngexesha lokuzinkcinkca.

I-Glutamatergic neurotransmission kwi-BN

Utshintsho ekubonakalisweni kwe-glutamate receptors kunye ne-receptor subunits ziye zavavanywa ngokubanzi emva kokuzilawula kweziyobisi ezikhobokisayo ngeempuku. I-Glutamate ineentlobo ezininzi ze-receptor ezibekwe ngaphambili kunye ne-post-synaptically. Apha sixoxa ngedatha efanelekileyo malunga nee-receptors ezintathu ze-post-synaptic ezaziwa ngokuba zi-neuroplasticity: i-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), i-N-methyl-d-aspartate (NMDA), kunye i-metabotropic glutamate receptor 5 (mGluR5).

Ukulandela ukuyeka ukufikelela okwandisiweyo kulawulo lwe-cocaine, kukho ukonyuka kwe-NAc yembonakalo yomphezulu we-GluA1 subunit ye-tetrameric AMPA receptor, kodwa akukho tshintsho kwintetho ye-GluA2 subunit (Conrad et al. 2008). Olu hlengahlengiso lukhokelela ekubonakalisweni okwandisiweyo kwe-calcium-permeable, i-GluA2-eswele i-AMPA receptors (CP-AMPA), ethi ikhulise ubumnandi be-post-synaptic neurons, ngaloo ndlela iqinisa uxhulumaniso lwe-synaptic. (Conrad et al. 2008). Ukunyuka kwe-CP-AMPAs kuye kwabonwa emva kwe-30, i-45, kunye neentsuku ze-70 zokurhoxiswa, kodwa kungekhona emva kosuku olunye lokurhoxiswa. (UConrad et al., 2008; UFerrario et al., 2011; Wolf & Tseng, 2012) okanye emva kokufikelela okufutshane kuphela kulawulo lwe-cocaine (Purgianto et al. 2013). Iigundane ezithintelwe ngokutya zibonisa ukonyuka okukhulu kwe-post-synaptic density expression ye-GluA1 kwi-NAc xa kuthelekiswa nolawulo ngelixa intetho ye-GluA2 ingatshintshi.Peng et al. 2011). Ke, kuyenzeka ukuba amaxesha okuthintelwa kokutya okwenzeka ngexesha le-BN kubangele ukufakwa kwe-CP-AMPAs ethi emva koko itshintshe ukuphendula kwe-neurons ye-post-synaptic kwi-NAc kwi-glutamate engenayo. Ukuzilawula ngokwakho kweziyobisi ezikhobokisayo kwakhona kubangela ukwanda kwe-glutamate ekhutshwe nge-synaptically kwi-NAc, eqhuba ukuphindaphinda emva kwexesha lokungenaso iziyobisi; olu lwando lubonakaliswe ukuba lwenzeka kwimeko yokubuyela etywaleni (Irhasi et al. 2011), icocaine (McFarland et al. 2003kunye ne heroin (LaLumiere and Kalivas 2008). Ukukhutshwa kwe-glutamate enokubakho kudityaniswe nemithambo-luvo ye-post-synaptic ene-CP-AMPAs iphumela kwisekethe elungiselelwe ukuqhuba indlela yokuziphatha yokufuna iziyobisi (ngoqikelelo lwe-NAc ukuya kwimimandla yemoto yobuchopho). Ukuza kuthi ga ngoku, akukho zifundo zisebenzisa iimodeli zezilwanyana ze-BN okanye ukutya ngokuzingxamela ziye zavavanya amanqanaba e-glutamate kwi-NAc okanye kweminye imimandla yobuchopho kulandela ukusetyenziswa kokutya okunencasa emva kwexesha lokuzila (uthintelo lokutya). Nangona kunjalo, ukuba olo nyuso lunokwenzeka, luya kuxhasa uluvo lokuba ukulahleka kolawulo lokutya okunencasa kunye neziyobisi ezikhobokisayo emva kwexesha lokuziyeka kuxhomekeke kwi-neurocircuitry efanayo.

Ukuxhasa i-hypothesis yokuba ukukhululwa kwe-glutamate kubandakanyeka kwi-BN, i-NMDA receptor antagonist memantine iyanciphisa ukusetyenziswa kwe-lard efana ne-binge-efana neempuku ezingathintekiyo kwaye ivelise ukunyuka okuhambelanayo kokusetyenziswa kwe-chow yebhubhoratri eqhelekileyo (UPopik et al. 2011). Uphononongo olufanayo lubonise ukuba i-MTEP (3- (2-Methyl-4-thiazolyl-ethynyl) pyridine), i-modulator engalungile ye-allosteric ye-mGluR5, ibangele umkhwa wokunciphisa ukusetyenziswa kwe-lard. Ukusebenzisa imodeli yemfene yokuphazamiseka kokutya kakhulu apho iimfene zanikwa ukufikelela okwethutyana kwiswekile kunye ne-ad libitum yokufikelela kwi-chow eqhelekileyo, Bisaga kunye noogxa (2008) ifumanise ukuba zombini i-memantine kunye ne-MTEP zinciphisa ukusetyenziswa kweswekile ngokuzingxala. Impembelelo efanayo ye-memantine kumaxesha amaninzi okutya ngokugqithisileyo yabonwa kulingo lwezonyango (UBrennan et al. 2008).

Ngelixa izifundo ze-glutamate microdialysis kusafuneka zenziwe kusetyenziswa imifuziselo yezilwanyana ze-BN, into yokuba i-glutamate receptor antagonists memantine kunye ne-MTEP yehlisa ukutya ngokutya ixhasa i-hypothesis yokuba ukutya kakhulu kubandakanya ukuhanjiswa kwe-glutamatergic, nangona kunokwenzeka kwingingqi yobuchopho ngaphandle kwe-NAc. Kwiimpuku, i-MTEP ibonakaliswe ngokuthembekileyo ekunciphiseni ukufuna i-cocaine (IBäckström kunye neHytiä 2006; Knackstedt et al. 2013; Kumaresan et al. 2009; UMartin-Fardon et al. 2009), UtywalaSidhpura et al. 2010), i-methamphetamine (Osborne kunye noMnquma 2008kunye nee-opioids (UBrown et al. 2012). Ulingo oluncinci lwezonyango oluncinci lufumene ukuba i-memantine iyayinciphisa imiphumo ye-nicotine.UJackson et al. 2009kunye ne heroin (Comer kunye noSullivan 2007) kwaye kunciphisa iimpawu zokurhoxisa kuzo zombini utywala (UKrupitsky et al. 2007kunye nee-opioids (Bisaga et al. 2001). Nangona kunjalo, uphando olukhudlwana, olulawulwa yi-placebo lubonise ukuba i-memantine ayinciphisi ukusela kwizigulana ezixhomekeke etywaleni.Evans et al. 2007). Okubangela umdla kukuba, kuphononongo lomqhubi weleyibhile oluvulelekileyo lwe-29, i-memantine yanciphisa ixesha elichithwe ungcakazo kunye nokwanda kokuguquguquka kwengqondo (Grant et al. 2010), ebonisa ukuba i-memantine inokusebenza kwizigulana ezinemikhwa yokuziphatha efana nokungcakaza nokutya kakhulu kodwa hayi kwiziyobisi. Ngamafutshane, nangona kukho ubuthathaka bophando olusebenzisa imizekelo yezilwanyana ze-BN ukuvavanya ukuguqulwa kwe-glutamate transmission, iziphumo zokuqala ezihlaziywe kweli candelo zibonisa ukuba ukulungelelaniswa okufanayo kwinkqubo ye-glutamate neurotransmitter kunokunciphisa i-BN kunye nokufuna iziyobisi.

Ukuphulukana nolawulo

Ukukhotyokiswa ziziyobisi kubandakanya inguqulelo ukusuka kwisibhengezo, kwimisebenzi yesigqeba ukuya kwindlela yokuziphatha kunye nokuphulukana nolawulo lokuthatha iziyobisi okubangelwa kukuphazamiseka komsebenzi wePFC (IKalivas kunye ne-O'Brien 2008; I-Koob kunye neLe Moal 2001). Njengoko kukhankanyiwe ngaphambili, enye yeempawu eziphambili ze-BN yimvakalelo yokulahlekelwa kulawulo lokutya, kunye nokungakwazi ukuyeka ukutya okanye ukulawula oko okanye kungakanani ukutya okutyayo (Umbutho i-American Psychiatric Association 2013). Izifundo ze-Functional magnetic resonance imaging (fMRI) zifumanise ukuba, xa kuthelekiswa nolawulo olusempilweni, abantu be-BN babonisa umsebenzi ophantsi kakhulu we-PFC ngexesha lolawulo lwemisebenzi yokuqonda efana nolawulo lokungxama (impulsivity control).Marsh et al. 2011; Marsh et al. 2009). Amanqanaba aphantsi omsebenzi kwiindlela ze-frontostriatal, kubandakanywa ne-PFC ekhohlo ekhohlo, inxulumene nokuphendula ngokukhawuleza (Marsh et al. 2009), ebonisa ukusebenza kakubi kwesigqeba phakathi kwabantu be-BN. Ngokumalunga nolawulo, abantu be-BN babonisa umsebenzi ophezulu kwi-PFC xa beboniswa imifanekiso yokutya (Uher et al. 2004), ephawulwe ngamagama amabi ngokuphathelele umfanekiso womzimba (UMiyake et al. 2010), okanye imizimba ebonisiweyo etyebileyo (Spangler kunye Allen 2012).

Ithatyathwe kunye, abantu be-BN babonisa i-hypofrontality xa beziswe ngeendlela ezingahambelaniyo nokutya kunye nomsebenzi ogqithisileyo xa zivezwa ngeendlela ezinxulumene nokuphazamiseka. Le pateni yomsebenzi ikwabonwa phakathi kwamakhoboka eziyobisi. Ngokukodwa, i-hypoactivity kwi-PFC ekuphenduleni imisebenzi yengqondo engahambelani neziyobisi ibonakala phakathi kwabasebenzisi abangapheliyo be-cocaine (Goldstein et al. 2007), i-methamphetamine (UKim et al. 2011; Nestor et al. 2011; Salo et al. 2009), kunye notywala (Crego et al. 2010; UMaurage et al. 2012). Ukubonisa abakhotyoki ngemifanekiso yezinto ezinxulumene neziyobisi kwandisa umsebenzi we-PFC phakathi kwabanxilisayo (UGeorge et al. 2001; UGrusser et al. 2004; Tapert et al. 2004), icocaine (UWilcox et al. 2011), kunye nabantu abaxhomekeke kwi-nicotie (U-Lee et al. 2005). Ke, abantu be-BN babonisa iipatheni ezigwenxa zomsebenzi we-PFC ezifana nabantu abakhotyokiswe ziziyobisi.

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