source
Cibiyar Wagoner don Alcoholism da Addiction Bincike, Cibiyar Nazarin Neuroscience, Jami'ar Texas a Austin, Austin, TX, 78712, Amurka. [email kariya].
Abstract
ABDRACT:
BACKGROUND:
Rashin iyawa don ragewa ko kuma yin amfani da shan barasa shine alamar alamar maganin cuta. Bincike a kan fasalin fasali da kwayoyin halittu na kwarewa-sauye-sauye a cikin shan giya zai kara fahimtar ilimin rikitarwa na barasa. An lura da irin yadda ake amfani da halayen shan giya a lokacin da aka kwatanta nauyin ƙwayoyin miki biyu na F1: C57BL / 6J x NZB / B1NJ (BxN) nuna rageccen zabi na giya bayan da kwarewa da yawan giya da lokutan abstinence yayin da C57BL / 6J x FVB / NJ (BxF) ya nuna ci gaba da barasa. Wadannan samfurori suna da ban sha'awa saboda wadannan samfurori sun nuna abin da ya faru na karuwa da kwayoyin halitta (BxN) da kuma rashin rinjaye (BxF) a cikin yalwar da ke ciki a cikin kwarewa.
Musamman, BxF yana nuna goyon baya ga barasa da BxN yana nuna rage yawan abincin giya a bayan kwarewa tare da babban darajar ethanol; duk da haka, kwarewa tare da ƙananan ƙarfin ethanol samar da ci barasa zabi ga duka hybrids.
A cikin binciken yanzu, mun gwada zaton cewa waɗannan samfurori suna wakiltar samarda nau'i na nau'in sakonnin ƙaddamarwa, ΔFosB, a cikin sakamako, ƙyama, da yankuna masu kwakwalwa masu dangantaka.
Sakamakon:
Canje-canje na filastan neuronal (kamar yadda aka auna ta ΔFosB matakan) sun sami kwakwalwa, kazalika da kwakwalwa yankin da kuma genotype takamaiman, kara tallafawa da kewayon neuronal underlies motsa jiki al'amurran da ethanol amfani.
Mice BxN dake nuna rage yawan abincin giya yana da ƙananan matakan ΔFosB a tsakiya na Edinger-Westphal fiye da mice da ke nuna ci gaba da shan barasa, kuma ya kara yawan matakan ΔFosB a tsakiyar amygdala na tsakiya kamar idan aka kwatanta da mice.
Mice BxN da ke nuna ci gaba da shan giya ya nuna mafi girma ΔFosB matakan a cikin yanki na kwakwalwa, Edinger-Westphal tsakiya, da kuma amygdala (tsakiya da kuma na tsakiya).
Bugu da ƙari, a Matakan BxN ΔFosB a cikin yankin Edinger-Westphal da kuma yankuna masu kwakwalwa na kwakwalwa an danganta da haɓaka da zaɓi na ethanol da ci. Bugu da ƙari, bincike-binciken ƙididdigar mahimmanci ya nuna cewa yawancin ƙananan éthanol-nau'i da ƙananan ƙananan ΔFosB suna cikin ɓoye, yayin da yawancin ƙuda da ke nuna ci gaba da shan barasa tare da dukkanin matakan ΔFosB masu girma suna cikin gungu tare.
TAMBAYOYI:
Ta hanyar kwatanta da kuma bambanta kwayoyi guda biyu, wannan binciken ya nuna cewa ladaran da aka ba da sakamako da kuma damuwa (ciki har da mahadar Edinger-Westphal, yanki mai kwakwalwa, amygdala) yana da karfin filasta wanda ya nuna yadda za a rage ruwan inabi.
Tarihi
Akwai sanannun abubuwa masu illa, muhalli da kwayoyin halitta, wadanda ke hade da cin zarafi da maye gurbi. Rashin iya shan giya mai yawa ba tare da ɗanɗanar mutum ba shine bayyanar farko ta alama a yawancin giya, yana nuna cewa matakin ƙananan amsawa ga barasa shine muhimmiyar mawuyacin factor a ci gaba da maye gurbin [1,2]. Ƙayyade abubuwa masu ilimin kwayoyin halitta da ke taimakawa wajen yin amfani da barasa zai taimaka mana fahimtar yin amfani da barasa da kuma zalunci, kuma yana da tasiri mai mahimmanci wajen bunkasa ingantattun maganin jiyya ga mutanen da aka bincikar su tare da maganin matsalar barasa. Yin amfani da tsarin kwalliya don yin koyi da cutar ɗan adam ya zama kayan aiki mai karfi wajen ci gaba da fahimtar wannan cuta da inganta lafiyar. Akwai hanyoyi daban-daban na yin nazari game da cin zarafi da maye gurbi, duk da haka babu wani abu mai maye gurbin baki daya. Matsayin da linzamin kwamfuta zai yi wa jagorancin yaduwar maganganu na yaduwar maganin da ke cikin yanayin yanayin yanayi kamar yadda ya kamata ya dogara da burbushin halittu [3].
Kwanan nan, mun gano cewa C57BL / 6JxFVB / NJ (BxF) da FVB / NJxC57BL / 6J (FVBxB6) F1 nau'i na matasan matasan sunyi jagorancin barazanar shan barasa a lokacin jarrabawar zabi guda biyu (matan suna cin 20-35 g / kg / rana da maza maza 7-25 g / kg / rana, dangane da ƙaddarawa da tsari) [4]. Wannan sababbin samfurori na da amfani mai mahimmanci idan aka kwatanta da matsalolin da ke ciki, ciki har da hujjoji game da samfurin mamba da kuma shan giya ga matakan hawan jini [4]. Bugu da ƙari, ana amfani da ƙananan ethanol amfani da ƙwayoyin BxF a ƙarin ƙarin ƙarancin éthanol guda biyu (sha a cikin duhu da kuma karɓar éthanol a yayin da aka samu damar shiga ruwa)4]. Daga nan sai muka lura da irin yadda ake amfani da halayen gine-gine mai nauyin shawo kan F1: C57BL / 6J x NZB / B1NJ (BxN) ya nuna rage yawan abincin giya bayan da kwarewa da yawan giya da lokutan abstinence da BxF ya nuna ci gaba da zafin giya [5]. Yin amfani da baturi na gwaje-gwaje na hali, mun nuna cewa BxN sun fi hankali fiye da ƙwayar BxF zuwa ƙyama da ƙwaƙwalwa, amma ba kyauta ba, sakamakon tasirin [6].
Bincike na asali game da tsarin halayyar halayen shan giya mai mahimmanci da kwarewa a cikin shan giya zai kara fahimtar ilimin shan barasa da shan barasa. Abun da ake bukata na ɗanɗanar barasa mai ban sha'awa shine mai ban sha'awa saboda ƙwayoyin BxN da farko sun nuna babban zaɓi ga mafitacin ethanol. Kodayake yanayin motsa jiki na rage cin abincin barasa bayan da ya sami kwarewa mai yawa da kuma abstinence ba a san shi ba, ana iya kwatanta ƙwayar BxN ga masu shan giya masu tsada a cikin abin da suke ci gaba da cin ganyayyakin yaduwa amma a matakin ƙananan, mai yiwuwa ne saboda kwarewa.
Abubuwan da ake son ci gaba da shan barasa yana da ban sha'awa, kamar yadda ƙwayoyin BxF suna cike da ƙananan matakan yaduwa ba tare da kwarewar da suka gabata ba. Taimakawa da rage yawan abincin giya zai iya zama alaƙa da mummunan sakamako na barasa, wani abu ne inda dabbobi ke nuna muhimmanci ƙara yawan amfani da barasa bayan an tilasta abstinence [7]. Hanyoyin barazanar maye gurbin abu ne da ke amfani da shi wajen nazarin yawan shan barasa. Kodayake gwajin gwajin da aka sani don haifar da mummunan sakamako na shan barasa ya bambanta da jadawalin da aka yi amfani da shi a nan, kwatanta ci gaba da rage yawan abincin giya zuwa wani tasiri na maye gurbi ya danganta abubuwa daban-daban da aka tattauna a nan zuwa wani muhimmin abu a cikin tsarin bincike na barasa. Yawancin zafin giya zai zama akasin maye gurbin shan barasa da kuma ci gaba da zafin abincin giya zai iya bayyana shi a matsayin rashin barazanar shan barasa. Yin amfani da nau'o'in nau'in dabba, irin su BxF da BxN, na taimakawa wajen ci gaban filin tun lokacin da ake amfani da cututtukan shan barasa daga haɗayyar dangantaka tsakanin halittu da muhalli. Gano ma'anar bambancin jigilar hanzari na wadannan samfurori ya ba da hankali a cikin kwakwalwa yana da mahimmanci ga dukiyar da aka ba da kyauta.
Anyi nazarin Ethanol da sauran kwayoyin da ke dauke da kwayar cutar a cikin takamaiman nau'i na mai amfani da alamomin kwayoyin ne na neuronal filastity da / ko aiki [8-15]. Adana da aka gudanar da kuma éthanol mai gudanarwa ba ya haifar da taswirar kwakwalwa na kwakwalwa daidai, wanda ya bada shawara cewa ƙayyadaddun ƙwayoyin lantarki suna amfani da ilimin ƙarfin ƙarfin ethanol [8,9].
Ɗaya daga cikin maɓallin mahimmanci, duk da haka an bincika shi a cikin binciken bincike na barasa, shine jarrabawar ci gaba da kuma rage yawan abubuwan da ake son haɓaka da ruwan inabi da kuma ganewa da hanyoyin da ke tattare da su a lokacin waɗannan halayyar. Manufar wannan gwaji shine don gane yankunan kwakwalwa da suka ci gaba da ci gaba da rage maye. Saboda ana nuna alamun barazanar shan barasa (tare da sauran magunguna) don haifar da bambance-bambance a cikin sassan kwakwalwa a matakan ΔFosB, mun gwada zaton cewa wadannan siffofin halayen suna wakiltar samarda nau'in nauyin sakonnin inbacible, ΔFosB, a yankuna masu kwakwalwa da aka sani kasancewa cikin lada, raguwa, da damuwa [10].
Bayanin lokaci na haifar da bambance-bambance a cikin yanayi na ΔFosB sun hada da magungunan zalunci (barasa, cocaine, amphetamine, nicotine, morphine, and antipsychotics), matsanancin danniya (damun damuwa, damuwa marar tabbas,11]. A matsayinsu mai matsakanci mai dacewa na ƙwaƙwalwar lokaci a cikin kwakwalwa, gano ainihin bambancin FosB (FosB ko ΔFosB) saboda amsa maganin ilimin éthanol na yau da kullum shine muhimmin bambanci.
Akwai nazarin da yawa da suka auna FosB da ΔFosB bayan matsalolin da suka faru wanda ba a tabbatar da shi ba cewa ΔFosB shine mamba mafi rinjaye (kamar wadanda aka bayyana a kasa). Duk da haka, akwai tabbaci mai karfi cewa ΔFosB, ba FosB ba ne, shi ne muhimmiyar gwagwarmaya bayan matsalolin da ke ciwo [10-12]. Wani binciken da Ryabinin da Wang (1998) suka yi sun gano cewa a cikin ƙananan ƙananan giya da ke fi son tsuntsaye na DBA / 2J, kwanaki hudu na ci gaba da yaduwa na éthanol ya haifar da ƙaruwa a cikin fosB maganganun a cikin kwakwalwa masu kwakwalwa: tsakiya na amygdaloid na tsakiya, na tsakiya septum ventrale, tsakiya amygdala , amygdala na lakabi, hypothalamus a gefe, tsakiya yana kara kwaskwarima, ginshiƙan launi na stria finalis, da tsakiya na tsakiya na thalamus [13]. Sakamakon su ya gano wani neurocircuit mai yalwacin. Bayanan FosB an kuma auna shi a cikin babban giya da ya fi son C57BL / 6J linzamin lokacin da yake saye da kuma kiyaye kula da kai na ethanol a cikin iyakokin iyakacin iyaka. Babu canje-canje a cikin matakan FosB yayin sayen mulkin kai [14]. Duk da haka, bayan makonni biyu na iyakokin sararin samaniya na sararin samaniya, an ƙarfafa matakan FosB a tsakiya na tsakiya na tsakiya na amygdala da Edinger-Westphal [15]. Bugu da ƙari, rahotanni sun nuna yankuna na yankuna da suke aiki a kan mulkin gwamnati, kuma suna da tasiri ga hanyar da ake kira mesocorticolimbic kuma suna kara amygdala [16]. Duk da haka, yana da mahimmanci a lura cewa canje-canje a cikin matakan ΔFosB sun dogara ne akan hanyar hanyar gudanar da mulkin ethanol, kashi, da kuma tsawon lokacin da aka nuna zuwa wani magani ko tsarawa [13-15].
Hakan da aka yi amfani da shi a cikin wannan binciken yana samar da matakai mai ban sha'awa don kwatanta ci gaba da rage yawan zafin giya da kuma ginshiƙan da ke da alhakin waɗannan maganganun barasa. Wannan binciken yana nuna cewa ƙwayar mice da ke nuna rage yawan abubuwan shan giya yana nuna muhimmancin filastik a cikin ladabi da kuma jigilar kayan haɗari (ciki har da tsakiya na Edinger-Westphal, yankin ƙananan kwakwalwa, amygdala, ƙananan ƙari, da cingulation cortex).
results
Sakamakon yawan giya da kuma lokacin abstinence a kan mulkin kai a cikin BxF da ƙananan BxN
Don nuna cewa sauye-sauyen yaduwar ethanol da / ko abstinence lokaci ya canza amfani da ethanol, zamu shirya jigilar lokaci hudu (kungiyoyi) don auna amfani da ethanol (Figure (Figure1a, b).1a, b). Akwai ƙungiyoyi masu gwaji hudu na kowanne matasan: Ƙananan Hawan Kasuwanci, Ƙananan Haɗuwa da Tsarin Abstinence, Low Concentrations, da Ƙananan Ƙasashen tare da Tsarin Abstinence Periods. Cikakken bayanai don zaɓi na ethanol (Figure (Figure2)2) da kuma amfani (Hoto (Figure3)3) bayanai (ga dukan kungiyoyi da duka jinsin) an gabatar su don tunani. Don kafa da kuma nuna misalin siffofin ci gaba da rage yawan abincin giya, zaɓi na 9% ethanol da kuma amfani da bayanan amfani a cikin siffofin Figures44 da kuma da kuma 5.5. Wadannan siffofi na al'ada suna dogara akan kwatanta nauyin 9% da ethanol da kuma amfani daga na farko, na biyu, na uku, da na huɗu a cikin ƙungiyoyi masu tasowa masu tsayi da kwanakin gwaji masu dacewa ga ƙungiyoyi masu ƙananan Ƙananan. Hanyar guda biyu ANOVA (gwanin gizon x) na 9% zaɓi da kuma amfani da ethanol. Ga Ƙungiyar Ƙungiyoyi masu Mahimmanci, zaɓi na ethanol (Figure (Figure4a)4a) da kuma amfani (Figure (Figure5a)5a) sun kasance mafi girma ga BxF fiye da BxN, kuma BxF sun nuna fifikon giya da ci yayin da BxN ke nuna rage fifiko da amfani da giya (ITANOL PREFERENCE - interaction F (3,54) = 4.83, P <0. 01, genotype F (1,54, 24.10) = 0.001, P <3,54, lokaci F (9.92) = 0.0001, P <1,54; ITANOL CIGABA - hulɗar N / S, genotype F (50.73) = 0.0001, P <3,54, lokaci F (11.68, 0.0001) = XNUMX, P <XNUMX). Ga groupungiyar Babban Taro tare da abstinence, fifita ethanol (Hoto (Figure4b)4b) da kuma amfani (Hoto (Figure5b)5b) sun kasance mafi girma ga BxF fiye da BxN, kuma BxF sun nuna fifikon giya da ci yayin da BxN ya nuna rage fifiko da amfani da giya (ETHANOL PREFERENCE - interaction F (3,132) = 15.89, P <0.0001, genotype F (1,132) = 250.43, P <0.0001, lokaci F (3,132) = 27.48, P <0.0001; CIGABA DA ITA - hulɗa F (3,132) = 11.35, P <0.0001, genotype F (1,132) = 510.88, P <0.0001, lokaci F (3,132) = 22.42, P <0.0001). Don theungiyar Conananan centididdiga, fifikon ethanol (Hoto (Figure4c)4c) da kuma amfani (Hoto (Figure5c)5c) sun kasance mafi girma ga BxF fiye da BxN, kuma duka matasan sun nuna fifikon giya da ci (ETHANOL PREFERENCE - interaction N / S, genotype F (1,54) = 12.2, P <0.01, time N / S; ITANOL CONSUMPTION - interaction N / S, jinsin F (1,54) = 74.83, P <0.0001, lokaci N / S). Don Conungiyar Lowananan withididdiga tare da abstinence, fifita ethanol (Hoto (Figure4d)4d) da kuma amfani (Hoto (Figure5d)5d) sun kasance mafi girma ga BxF fiye da BxN, kuma duka matasan sun nuna ragi matsakaici a cikin fifikon giya da amfani (ETHANOL PREFERENCE - interaction N / S, genotype F (1,132) = 166.58, P <0.0001, time N / S; ITANOL CONSUMPTION - interaction F (3,132) = 3.61, P <0.05, genotype F (1,132) = 480.64, P <0.0001, lokaci F (3,132) = 7.87, P <0.0001). A taƙaice, a cikin Highungiyoyin Babban Taro (ba tare da kamewa ba), BxF sun nuna fifikon giya yayin BxN ya nuna rage fifikon barasa kuma a cikin inungiyoyin Conananan (ananan (ba tare da kamewa ba), duka BxF da B6xN sun nuna fifiko mai maye. Tunda abubuwanda ake sha'awa sune mafi kyawun kamawa cikin ƙungiyoyi ba tare da kamewa ba, sune mahimmancin saura na binciken.
ΔFosB Levels
ΔFosB ƙayyadewa da bincike sun kasance ana amfani dasu don gano raunin neurocircuitry da aka kunna a lokacin da aka ci gaba da rage yawan abincin giya. Akwai ƙungiyoyi masu gwaji guda uku ga kowane samfurori: Tsakanin Ƙasa, Ƙananan Ƙirƙirar, da Ruwa (Gudanarwa). Bayanan ΔFosB an gabatar dashi a cikin kashi ΔFosB masu amfani da kwayoyin halitta [[# of ΔFosB masu amfani da magunguna) / (# na ΔFosB masu amfani da ƙwayoyin cuta + # na Nissl masu amfani ne)] (Table (Table1).1). Ayyukan baya sun nuna cewa ilimin éthanol zai iya haifar da neurodegeneration [17]. Saboda haka, mun bincika lambobi ne a cikin wannan binciken kuma ba muyi rahoton bambanci ba dangane da jinsin ko rukuni na yankuna masu kwakwalwa wanda aka tsara a wannan binciken. An gwada fasali uku na bayanan ΔFosB: 1) hanyoyi guda uku ANOVA (ƙungiyar genotype x tsarin kwakwalwa), 2) hanyoyi guda biyu ANOVA (ƙwaƙwalwar rukuni na yanki) ga kowane jinsin, da kuma 3) an haɗu da matakan haɗin kai don tsara tasiri cibiyoyin sadarwa.
Maimaita maimaita hanyoyi uku ANOVA (genotype x rukuni x kwakwalwa yankin) ya bayyana hulɗar yankin kwakwalwar jini [F (15,375) = 2.01, P <.05], hulɗar yankin x kwakwalwa yankin [F (15.375) = 1.99, P <0.01], kuma babban tasirin yankin kwakwalwa [F (15,375) = 43.36, P <.000]. Maimaita matakai guda biyu ANOVA (yankin yanki x rukuni) na kowane nau'in halitta ya nuna cewa akwai babban tasirin rukuni da yankin kwakwalwa ga duka BxF da BxN [BxF - F (2,374) = 11.79, P <.0001, babban tasirin rukuni; F (15,374) = 25.64, P <.0001, babban tasirin yankin kwakwalwa; BxN - F (2,360) = 43.38, P <.0001, babban tasirin rukuni; F (15,360) = 23.73, P <.0001, babban tasirin genotype]. Binciken bayan-lokaci ya nuna manyan bambance-bambance shida na BxN (Hoto (Figure6A-c).6ac). Kashi ΔFosB matakan sun fi girma a ƙasashen Low Concentrations fiye da Rukunin ruwa a La, CeC / CeL, EW, da kuma VTA. Kashi ΔFosB ya fi girma a cikin ƙungiyoyi masu tasowa mafi girma a cikin Rukunin ruwa a CeMPV. Kashi ΔFosB ya fi girma a cikin Ƙananan Ƙungiyoyi fiye da Ƙungiyar Ƙungiyoyi masu ƙarfi a EW. Bayanin ΔFosB ga dukan sauran ƙananan ƙwaƙwalwar da aka ƙayyade aka gabatar a cikin Table Table1.1. An yi amfani da bincike na alaƙa na Pearson don ƙayyade idan% na ΔFosB ƙananan ƙwayoyin cuta a cikin yankin ƙwaƙwalwar da aka bayar yana da alaƙa da amfani da ethanol ko fifiko. Amfani da Ethanol da fifikonsu sun nuna muhimmiyar ma'amala mai kyau tare da% ΔFosB a cikin EW da VTA na berayen BxN (ITANOL CONSUMPTION - EW r = 0.85; VTA r = 0.85; ETHANOL PREFERENCE - EW r = 0.83, VTA r = 0.88; p <0.05 ga duka).
An haɗu da dangantaka mai mahimmanci tsakanin bayanin ΔFosB, genotype, yankin kwakwalwa, da kuma amfani da ethanol ta yin amfani da bincike na kayan aiki da kuma ɗaukar hoto. Babban mahimman bayanai sun nuna cewa mafi yawancin canji (~ 80%) a cikin bayanan sune 5 aka wakilta. Ƙungiyoyin ɗakunan da ba a kula da su ba (waɗanda mutane da ƙananan kwakwalwa suka ƙunsa) an yi su kuma an umarce su ta yin amfani da matakan farko (Figure (Figure7).7). Ƙarƙashin mutum ya nuna karfi, amma ba cikakke ba, alamu na haɗuwa dangane da amfani da ethanol, komai bambancin kwayar. Mutane da yawa daga cikin 'yan ƙananan ethanol-naïve sun haɗu tare da nuna yawan ΔFosB gaba ɗaya fiye da ma'anar da yawa daga cikin ƙananan da suka nuna ci gaba da abincin shan giya sun haɗa tare kuma suna nuna mafi yawan ΔFosB fiye da ma'anar. Wadannan gungu guda biyu sun kasance mafi banbanci. Ƙididdigar uku a tsakanin suna wakiltar fiye da, žasa, da kuma ma'anar tasirin ΔFosB da kuma samfurori na éthanol.
tattaunawa
An lura da halin da ake ciki na shan barasa a yayin da aka kwatanta nauyin F1 guda biyu na mice: BxN ya nuna rage yawan zafin giya bayan da ya sami kwarewa da yawan giya da lokutan abstinence yayin da BxF ya nuna ci gaba da zafin giya. Hanyar BxF, yawan amfani (ci gaba da shan giya) da kuma BxN masu shaye-shaye masu tsada (rageccen giya). Kwanancin neuronal (ko aiki, kamar yadda aka auna ta ΔFosB matakan) ya bambanta dangane da ilimin éthanol, ya cigaba da tallafawa muhimmiyar rawar da ke tattare da ƙirar ƙirar da aka ƙulla da kuma rage yawan abincin giya.
Domin babban barasa mai cinyewa, C57BL / 6, zaɓi da kuma amfani da ethanol suna dogara ne akan ƙaddamar farko na ethanol, tsawon abstinence, da sub-strain (C57BL / 6Cr ko C57BL / 6J) [7,18]. Mun gano cewa zaɓi ethanol da aka gani a cikin ƙwayoyin BxF sun kasance mafi girma (kuma sun fi zaman lafiya fiye da BxN) a cikin jigilar jigilar hudu da aka gwada. Ana son ci gaba da yin amfani da anhan a cikin BxN tare da lakabi na yau da kullum (Low Concentrations ba tare da abstinence) ba, yayin da ragewa a zabi da kuma amfani da aka kiyaye tare da duk sauran lokuta na sha da aka gwada. BxN ta rage yawan abincin giya yana ba da samfurin dabba wanda ya sabawa (zane-zane na tanthanol bayan kwarewa tare da ƙananan samshan tayi da / ko wasu gajeren lokaci na abstinence) ya karu da karfin mayar da martani ga wani jigilar hankalin éthanol da aka fi so.
Adana da aka gudanar da kuma yayinda ake gudanarwa a cikin gwaji ya samar da taswirar kwakwalwa daban-daban na kwakwalwa, yana bayar da shawara cewa ƙayyadaddun kundin tsarin mulki suna amfani da illolin ƙarfin ƙarfin ethanol [8,9]. Mun gwada tsammanin cewa ci gaba da rage yawan abubuwan da ake bukata na barasa suna nunawa ta hanyar samar da nau'in sakonnin ƙaddamarwa, ΔFosB, a wurare masu kwakwalwa da aka sani da zasu shiga cikin lada, da ƙyama, da kuma danniya. ΔFosB wani nau'i ne na ƙididdiga tare da kwanciyar hankali na dogon lokaci kuma ba ya ragewa ga cigaba kamar yadda C-Fos ya yi, maimakon haka ya tara a lokacin jiyya. Ƙarawa a ΔFosB saboda yawan ƙananan aikin neuronal kuma ana zaton suyi nuni da kasancewa mai tsabta neuronal. Mun gano cewa kashi dari na samfurin ΔFosB masu ƙarfi a yankuna na kwakwalwa sun dogara ne da genotype (BxF da BxN) da kuma rukuni (Gudanar ruwa, Ƙananan Ƙungiyoyin, da Ƙananan Haɗuwa).
Fko BxN, bayanan bayanan bayanan da aka gabatar ya nuna cewa amfani da yashan din da ake amfani da ita ya haifar da karuwar ΔFosB a tsakiya na EW, VTA, da kuma amygdala: yana nuna karin ƙwarewar neuronal a cikin ƙwayoyin kwakwalwa da aka sani cewa zasu shiga cikin ethanol, sakamako, da kuma matakan damuwa. Maganin BxN a cikin ƙungiyoyi masu tasowa (rageccen buƙataccen giya) sun rage nauyin hawan neuronal a cikin EW, suna nuna cewa wadannan masu amfani da su sunyi amfani da abin shan barasa tare da nauyin da suka shafi kwarewa. A cikin Ƙananan Ƙungiyoyi (wanda aka nuna ci gaba da shan giya), nauyin haɗin gwiwar neuronal a cikin EW ya fi girma a cikin Ƙunƙolin Ƙungiyoyi da Rukunin ruwa. Kodayake ana gudanar da su ta hanyar amfani da misalin misalin dafanol da nau'o'in jigilar kwayoyin halitta, bincikenmu a cikin EW na BxN mice ya yarda tare da nazarin nazarin amfani da yaduran da aka yi amfani da su na baya-bayan nan [14,15]. Ba a daɗewa an bayyana wadanda ba a yi amfani da su ba tun da farko kamar yadda ake dauke da mai dauke da perioklomotor urocortin (Ucn)19]. Ucn1 wani nau'in ƙaddamar da corticotropin (CRF) -like peptide wanda ke ɗaukar masu karɓar CRF1 da CRF2. Nazarin baya da aka yi ta amfani da kwayoyin halitta, kwarewa, da kuma layi sun nuna cewa Ucn1 yana da hannu wajen sarrafa shan barasa [19-22]. Ta nan ne sanannun kwayoyin predisposition ga babban barasa shiga cikin rodents da aka hade tare da mafi girma matakan matakan Ucn1 a EW da LSi [23]. Saboda haka, rashin mahimmancin muhimmancin da muka lura a cikin EW ga babban giya da ake son da amfani da ƙwayar BxF shine ba tsammani ba. Wataƙila wannan shi ne saboda ƙananan ƙimar ΔFosB a cikin rukuni na BxF kamar yadda aka kwatanta da kungiyar BxN. Lallai, matakan ΔFosB cikin dari ga dukan ƙwayoyin da ke nuna ci gaba da shan giya (BxF High Concentrations group, BxF Low Concentrations group, da BxN Low Concentrations group) sun kasance kamar kama.
Don BxN, amfani da ethanol a cikin Ƙananan Ƙungiyar Ƙungiyar ta ƙara ƙananan sunaye a cikin VTA (mafi girma a cikin Ƙananan Ƙungiyoyi da Kungiyoyin Ruwa na Ruwa). Ƙaunar Ethanol da kuma amfani sun kasance mafi girma ga ƙungiyar Low Concentrations. Rashin muhimmancin muhimmancin da muka lura a cikin VTA don babban giya da ake son da kuma cinyewa maras kyau BxF wani abu ne mai tsammanin kuma yana iya kasancewa saboda ƙananan ƙananan matakan ΔFosB a cikin ƙungiyar kula da ruwa. Kashi ΔFosB matakan da aka haɓaka a cikin ƙananan ruwa na BxF kamar yadda aka kwatanta da rukuni na BxN, yayin da kashi ΔFosB kashi ya kasance daidai da dukkan ƙananan yara masu nuna ciwon giya (BxF High Concentrations group, BxF Low Concentrations group, da BxN Low Concentrations group) . Shirin VTA dopamine yana taka muhimmiyar rawa wajen watsa labarun ƙarfafa ilimin ethanol kuma ya shiga cikin abubuwa da dama da ke da alaka da ma'anar ethanol da halayen sakamako [24-26]. Bugu da ƙari, ayyukan VTA na amygdala da EW nu. An nuna rutunansu ga direbobi masu ba da umurni kai tsaye a cikin VTA [27]. Har ila yau, yaduwar éthanol yana kara yawan ƙananan ƙwayoyin cuta a cikin VTA [28,29]. Za a iya haɓaka yawan ƙwayar kamfanonin da aka shigar da ΔFosB a cikin VTA wanda muka lura bayan bin tsarin mulkin yaduwar jin dadi a BxN.
Harkokin giya yana haifar da neuroadaptations na dogon lokaci, wanda ya haifar da mummunar jiha; wata mahimmanci a cikin ƙarfin ƙarfafawa shi ne corticotropin-releasing factor (CRF) alama a cikin amygdala [30]. Magungunan samfurin nema a cikin CeA sun yi niyya ga GABA, CRF, opioid, serotonin, dynorphin, da masu karɓa na norepinephrine [25,31-34]. GABA masu adawa da juna, da magunguna na CRF, rage yawan amfani da ethanol [32,33,35]. Abun layi na CeA suna karuwa sosai don amfani da yalwar da ake amfani dasu [36]. Abubuwan da muka samu sun kara goyon baya ga CeA a cikin ka'idojin shan giya. Ƙirƙirar ƙwayoyin cuta a cikin tsakiyar amygdala sun samar da yawan mutanen da ke da alaƙa da alaka da abin da suke ciki na peptide. Wadannan takamarorin GABAergic sun haɗa da aikin samarwa na CeA. Kamar yadda aka duba a [Mu da Koob (2010]), syawancin karatun sun gano muhimmancin dynorphin da kappa opioid masu karɓa a cikin kiyayewa da kuma karuwa daga ƙarancin ethanole [37]. Kwanan nan, Walker et al ya nuna cewa mai amfani da mai kwakwalwa na ky-opioid, ko binaltorphimine, a cikin amygdala mai zurfi ya rage gwargwadon ikon da ake yi na ethanol a cikin dabbobi masu karewa [38]. Kappa opioid siginar sigina ya kasance babban abin sha'awa na bincike a intersection na damuwa, sakamako, da kuma sokewa. Har ila yau an nuna cewa tsarin kula da kai da ethanol mai saurin ƙarfin ya zama mai jarrabawa ta hanyar siginar mai karɓa na opioid [39]. Za a iya rarraba cibiyar CeA ta tsakiya a cikin labaran da ke ciki (CeL / CeC) da kuma kwakwalwa na tsakiya. Ƙananan matakan da ke CeL / CeC suna karɓar abubuwan da suka dace daga VTA; kamar yadda aka gani, ana amfani da waɗannan nau'ikan bayan babban mulki na ethanol kuma ya nuna yawan ƙarar ΔFosB da ke nuna ci gaba da barasa. Har ila yau, ga Mc [Bride (2002]) don kyakkyawan nazari kan CeA da sakamakon maye [40]. A cikin bincikenmu, ƙwararrun BxN tare da ci gaba da ciwon giya (Ƙananan ƙungiyoyi masu zaman kansu) sun nuna karuwar ƙananan neuronal a cikin CeC / CeL da kuma La da BxN mice tare da zabi mai ƙananan giya (Ƙungiyar Haɗin Kasuwanci) suna nuna ƙarar ƙirar neuronal a cikin CeMPV. Wadannan sakamakon sun nuna cewa kwarewar ilimin éthanol ya shafi filasta a cikin GABAergic neurons a amygdala. Tare da wannan bayanan, tare da canje-canje masu dacewa a cikin nauyin lantarki a cikin VTA da EW, muna ba da shawara cewa wannan tafarki yana karɓar filastik a karkashin yanayin da ake son shan giya.
Binciken da ya gabata ya nuna cewa C57BL / 6J yara za su iya samun matakan giya mai girma ta hanyar zabi guda biyu, amma duk da haka waɗannan nauyin barazanar jini ba a ci gaba ba kuma sau da yawa ruwan sha ba ya dace da ka'idoji na dalili na Pharmacological da Dole da Gentry (1984)41,42]. Maganin BxN da ke nuna rage yawan abincin da ake amfani da su na ruwan inabi ya rage fiye da za a iya sa ran daga C57BL / 6J linzamin kwamfuta na jiki [1]. Saboda haka, ko da yake ba mu ɗauki samfurorin barasa na jini ba, bazai yiwu ba cewa ƙwayar BxN ta rage yawan abincin giya don samun ciwon haɗarin barasa na jini, wanda ya bada shawara cewa yawan giya na barasa bazai buƙatar ya haifar da filastik a cikin wadannan kwakwalwa ba. Yana da mahimmanci a lura cewa wani tasiri mai mahimmanci na rukuni yana samuwa a cikin BxF, ko da yake sakamakon ƙarshe (gyare-gyare don kwatankwacin jimillar) ga yankunan ƙwaƙwalwar BxF ba su nuna canje-canje mai yawa a cikin kashi ΔFosB masu amfani da ƙwayoyin cuta ga kowane yanki ba bayan mai amfani da ethanol na yau da kullum tare da waɗannan jadawalin jadawalin.
Don ganin hangen nesa tsakanin maɗauran hade-haɗe mai mahimmanci. Tasirin zafi na binciken da aka samar ya nuna yanayin yaudara tsakanin matakan ΔFosB da kuma amfani da ethanol ko da kuwa genotype. Mafi girma ΔFosB matakan da aka hade da ƙananan ruwan sha da ƙananan ΔFosB matakan da aka haɗa da dabbobi masu kulawa; duk da haka, ƙarfin haɗin da bai isa ya yi daidai ba da hangen nesa da shan samfurori da aka dogara kawai akan matakan ΔFosB.
karshe
An lura da halin da ake ciki na shan barasa tare da nauyin nau'i na mice guda biyu na F1: BxN ya nuna rage zabiicin giya bayan jin dadi tare da cikewar barasa yayin da BxF ya nuna ci gaba da zafin giya. Hanyar BxF, yawan amfani (ci gaba da shan giya) da kuma BxN masu shaye-shaye masu tsada (rageccen giya). Canje-canje a cikin nauyin ƙananan neuronal (kamar yadda aka auna ta ΔFosB matakan) sun dogara ne da kwarewa, da kuma kwakwalwa na yankin- da kuma genotype-musamman, kara bayyana ma'anar neuronal circles motsa jiki al'amurran da amfani da ethanol. Wadannan sakamakon sun nuna cewa sauyawa na ɗaya iyaye a cikin ƙananan ƙwayoyi suna haifar da canje-canje a cikin alamu na amfani da barasa kuma suna nuna canje-canje a cikin sifofin ΔFosB maganganu, suna nuna cewa cibiyoyin kwakwalwa dabam dabam suna cikin waɗannan nau'ikan ƙwayoyi.
Hanyar
Ethics
An gudanar da wannan binciken a cikakke daidai da shawarwari a cikin Jagora don Kulawa da Amfani da Dabbobin Laboratory na Cibiyar Kula da Lafiya ta kasa. Kwamitin kula da kula da dabbobi da amfani na Jami'ar Texas a Austin (AUP 2010-00028) ya yarda da yarjejeniyar. An yi dukkan tiyata a karkashin sodium pentobarbital anesthesia, kuma duk kokarin da aka yi don rage girman wahala.
Animals
An gudanar da nazarin ta hanyar amfani da ƙwayoyin mace na F1 na mace wanda aka samo daga C57BL / 6J kuma ko dai FVB / NJ ko NZB / B1NJ mice (BxF F1 da BxN F1, nau'in nau'ikan xin tsofaffin mahaifa). C57BL / 6J, FVB / NJ, da kuma NZB / B1NJ masu sayarwa da aka saya daga Laboratory Jackson (Bar Harbor, ME) kuma sun yi a cikin 7-8 makonni. An yaye yaron a cikin kungiyoyi masu banƙyama na kowane jinsin (BxF F1, BxN F1). Mun jarraba kawai ƙwayoyin mata don sauƙaƙa kwatanta da bayanan da aka tattara [1,5,6]. Mice sun kasance a cikin gida mai kyau tare da abinci da ruwan da aka ba su ad libitum. Ƙungiyar mallaka da ɗakin gwaji sun kasance a kan haske na 12: 12 h juyayi (hasken wuta a 07: 00).
Biyu gwajin zaɓi na zafin zabi guda biyu
Anyi amfani da hanyar zabi guda biyu don sanin tsarin dabi'u na ƙa'idar tahanol a cikin mata BxF da BxN mice [1,6]. F1 nau'in mice mace (shekarun 63) an saka su a ɗayan ɗayan su a cikin ɗakunan ajiya yayin da suke ci gaba da kasancewa a cikin mako daya zuwa kwalabe tare da tubunan sipper dauke da ruwa kafin gabatar da wani bayani na ethanol. Bayan haɓakawa, ƙwayoyi sun sami dama ga kwalabe guda biyu: daya dauke da ruwa da sauran dauke da wani bayani na ethanol. An canza matsayi na wutan yau da kullum don sarrafawa don zaɓin wuri. Don lissafin yiwuwar fitarwa da kuma evaporation, an rage nauyin nauyin nau'i daga shambura a cikin cages mai kulawa ba tare da mice ba daga mutum mai sha dabi'u kowace rana. An auna nau'in kowane nau'in 4 a cikin gwajin. Dukkanin amfani da ruwa ya kasance a kullum cikin gwaji. An kiyasta yawan adhan da aka yi amfani da su da kuma anhanol don kowane linzamin kwamfuta, kuma waɗannan dabi'un suna da yawa ga kowane maida hankalin ethanol. Ana nuna alamun barasa da lokacin abstinence a kan mulkin kai a BxF da ƙananan BxN ta hanyar kirkiro ƙungiyar gwaji tare da samun dama ga Ƙananan Ƙungiyoyin (ƙaddara samun damar shiga 3-35% ethanol mafita, sannan 3 maimaitawa ta 9, 18, da kuma 27% ethanol, ta ƙare tare da gabatarwar 9% ethanol na karshe) kuma wani rukuni tare da Low Concentrations (ƙaddara samun dama ga 3-9% ethanol, tare da sauran gwajin da aka yi tare da damar shiga 9% ethanol). Kowace ƙungiyar ta ƙunshi rukuni guda ɗaya wanda ya yi ko bai taɓa yin kwana uku na mako ɗaya na abstinence ba. Mice masu sarrafawa sun fuskanci irin wannan yanayi a lokaci ɗaya kamar ƙwayar gwaji, amma an ba da kwalban ruwa kawai.
A cikin duka, akwai rukunoni guda biyar ga kowane matasan: Ruwa (n = 14-16), Ƙananan Haɗuwa (n = 10), Ƙananan Haɗuwa tare da Tsarin Tsarin Abstinence (n = 20), Ƙananan Hakan (n = 10), da Low Concentrations tare da Abstinence Periods (n = 20). Duba Hoto Figure11 don cikakkun jerin jinsin kungiyoyi guda biyu.
ΔFosB Immunohistochemistry da kimantawa
MeasuredFosB immunohistochemistry (IHC) an auna shi a cikin yankuna 16 na kwakwalwa daga beraye da suka sami kwana 72 na ci gaba da samun dama ko dai ruwa (Sarrafawa) ko ruwa & giya [Babban Taro da Lowananan Taro]. Tasirin Babban Maida hankali akan fifiko da amfani da ethanol ya fi tasirin ƙauracewa; Sabili da haka, ƙungiyoyin da suka ɗanɗana lokacin ƙauracewa ba a haɗa su cikin matakan ΔFosB IHC ba. Bugu da ari, an gudanar da gwajin fiye da farkon bayyanar ci gaba ko rage fifikon barasa don nuna dabi'un halayyar suna da karko tare da sake zagayowar sauyawar saurin yaduwar ethanol don bincika tasirin shan ethanol na yau da kullun. Awanni hudu zuwa takwas bayan cire giya a ranar 73 na gwajin, ɓeraye sun kamu sosai (175 mg / kg sodium pentobarbital) kuma sun shanye cikin intracardially tare da 20 ml na 0.01 M phosphate sunadarin gishiri (PBS), sannan 100 ml na 4% paraformaldehyde a cikin PBS. An cire kwakwalwa, an gyara su a cikin 4% paraformaldehyde a 4 ° C, an saka su a cikin 3% agarose, an rarraba (50 um, coronal) a kan vibratome, an sanya su a cikin kwayar cuta (30% sucrose, 30% ethylene glycol, da 0.1% polyvinyl pyrrolidone a cikin PBS) na dare a 4 ° C, kuma an adana shi a -20 ° C har sai an sarrafa shi don IHC. An wanke sassan da aka narke tare da PBS, an bi da su da 0.3% H2O2, kuma an saka su na awa ɗaya a cikin 3% na maganin akuya na al'ada don rage takamaiman lakabin. Daga nan aka sanya sassan nama a cikin 4 ° C a cikin 3% na ƙwayar akuya da anti-FosB (SC-48, 1: dilution dillan, Santa Cruz Biotechnology, Santa Cruz, CA). An wanke sassan, an sanya su a cikin halittar anti-zomo ta biotinylated (5000: 1 dilution, Vector Laboratories, Burlingame, CA) na awa daya, a wanke, kuma a sanya su cikin hadadden avidin-biotin (200: 1 dilution, Elite kit-Vector Laboratories) . An nuna aikin peroxidase ta hanyar aiki tare da 200% diaminobenzidine (dauke da 0.05% H2O2). Sassan sassa na Nissl sun yi amfani da su (ta amfani da methylene blue / azure II). An tsara zane-zane don ƙidaya makafi. ΔFosB-IR sunadarai an ƙidaya su akan girman 50X (man fetur) ta hanyar amfani da siginar fractionator kuma StereoInvestigator software. Samfurin bayani na asali: tsarin ƙididdiga (50um x 50um x 10um) daidai yake ga dukan yankunan da aka kimanta; duk da haka, an ƙaddamar da girman grid ga kowane ɓangaren ƙwaƙwalwar ajiya don tabbatar da cewa yawan ƙididdigar kwayoyin halitta daidai yake da 100-300 don cimma daidaitattun bambancin kasa da 0.1. An kiyasta bayanai a matsayin kashi dari na ΔFosB tabbatacce nuclei (adadin ΔFosB tabbatacce nuclei / yawan tarabobi) ga kowane yanki.
An yi amfani da cutar ta Fosba a wannan binciken (SC-48, Santa Cruz Biotechnology, Santa Cruz, CA) a kan wani yanki na FosB kuma ya gane duka FosB da ΔFosB. Kodayake wannan mutum yana gane duka FosB da ΔFosB, ƙananan jigilar kwayoyin halitta da aka tsara a cikin wannan binciken za a kira su samfurin ΔFosB ne a yayin da aka nuna cewa kwayoyi masu cin zarafi, ciki har da barasa, musamman sun jawo ΔFosB, ba FosB, a cikin takardun kuɗi. Perrotti et al. ([2008]) auna ΔFosB shigarwa (a cikin mayar da martani ga tsarin ci gaba da maganin magunguna, ciki har da barasa) ta yin amfani da kwayoyi guda biyu: daya wanda ya gane FosB da ΔFosB (SC-48) kuma wanda ya zaɓa domin ΔFosB (ba a kasuwanci ba) kuma ya gano cewa ga dukkan kwayoyi nazarin, aikin da aka yi amfani da shi ta hanyar amfani da kwayar FosB (SC-48) shi ne saboda ΔFosB, tun da ba su gano dukkanin igiyoyin da ba su da kariya ba tare da amfani da wani antibody zabi don FosB mai cikakke ba [10]. Bugu da ƙari, an san ΔFosB a cikin ƙwayar kwakwalwa- da kuma nau'in ƙwayoyin salula, ta hanyar magunguna na yau da kullum da kuma kyakkyawan sake dubawa akan wannan batu suna samuwa [11,43,44].
Abbreviations da wurare na neuroanatomical Tsarin
Il - infralimbic bawo (+1.70 mm); Cg1 - cingulate bawo 1 (+1.1 mm); Cg2 - cingulation bawo 1 (+1.10 mm); NAcc core - ginshiƙan mahimmin ƙarfi (+1.10 mm); NAcc shell - ƙananan ƙwayoyin harshe (+ 1.10 mm); LSi - matsakaiciyar tsaka-tsalle (+1.10 mm); La - amygdala a kaikaice (-1.22 mm); Bla - amygdala na asali (-1.22 mm); CeC / CeL - tsakiya da tsakiyar amygdala (−1.22 mm); CeMPV - tsakiya na tsakiya na tsakiya na amygdala (-1.22 mm); PAG - launin toka mai ƙwanƙwasa (−3.64 mm); EW - Edinger-Westphal tsakiya (−3.64 mm); VTA - yankin ƙananan kwakwalwa (−3.64 mm); DR - dorsal raphe (- 4.60 mm); PBN - tsakiya na parabrachial (-5.2 mm); NTS - ƙananan ƙwayoyin cuta (sol6.96 mm). Brain Mouse a Cikakken Stereotaxic[45] an yi amfani da shi don daidaita batun daya zuwa kashi uku don tantancewa ga kowane ƙwaƙwalwa.
Hanyar lissafi
Ana bayar da bayanai a matsayin ma'anar ± SEM, sai dai idan ba a lura ba. An rarraba bayanai da yawa. An yi amfani da bayanan statistical 6 (StatSoft, Tulsa, Ok, Amurka) da kuma GraphPad Prism version 4.00 (GraphPad Software, San Diego, CA, Amurka). An aiwatar da hanyoyi guda biyu na ANOVA don amfani da ethanol da kuma abubuwan da suka fi so don tantance bambancin tsakanin kungiyoyi. An yi ANOVA guda biyu da uku don bayanai na ΔFosB don tantance haɗin kai da kuma babban mahimmanci ga ƙungiyoyi (Ƙunƙolin Kasuwanci, Ƙananan Ƙungiyoyin, da Ruwa), yankin ƙwaƙwalwa, da kuma genotype. An yi gyaran gyaran Bonferroni don kwatancen da yawa da kuma bayanan Bonferroni a lokacin da ya dace. Musamman, mun yi tsammanin cewa jituwa da ladaran da aka samu zai kara FosB a cikin ƙwayar mice wanda ya nuna rage yawan abincin giya. Ga kowane gicciye na matasan, an yi amfani da Pearson ta riko don gano muhimmancin haɓaka tsakanin matakan ΔFosB da kuma zaɓi na ethanol da kuma amfani da ƙwayar ƙarancin ethanol.
An gudanar da rikici na haɗin gwiwar domin ya hango yadda mahaɗin bayanai ya bambanta da kuma tantance yadda ƙungiyar bayanai ta haɗa. Matsayin dabi'u da aka lalata ya maye gurbin bayanan ΔFosB wanda ba ya ciki ba, wanda bai wuce 15% na bayanai ba. Ko da yake akwai mafi girma da rashin tabbas fiye da idan an lura da dabi'un da ake kididdiga, bincike na ƙididdigar ɗigon ƙididdiga yana buƙatar cikakken memba ko sharewa cikakke don kwatanta hukunci. An yi amfani da rukuni na haɓaka ta hanyar amfani da hanyar Ward da kuma jigilar da aka samo asali daga cikin ɓangaren farko na bangaren bincike na musamman (JMP®, Shafin 8, SAS Institute Inc., Cary, NC). Ga ƙungiyoyin ruwa da kunshe da tarin hankalin éthanol, bayanan ΔFosB ga kowane ɓangaren ƙwaƙwalwar ajiya an zartar da z-score kuma an gudanar da bincike na musamman don gano ƙididdigar gungu. Bayanin bayanan ya ƙunshi bayanan ƙwaƙwalwar ƙwaƙwalwa da kuma mutane ta yin amfani da bincike na ƙididdigar kulawa.
Takardun masu aiki
ARO, YAB, RAH, TAJ sun ba da gudummawa wajen tsara wannan binciken. ARO ya sami bayanai. ARO, IP, RDM ta tantance bayanan. ARO, RDM, IP, TAJ, YAB, da kuma RAH sun shiga cikin rubutun da kuma sake duba rubutun. Duk marubuta sun karanta kuma sun yarda da rubutun ƙarshe.
Godiya
Muna son gode Drs. Jody Mayfield da Colleen McClung don tattaunawar tattaunawa tare da Marni Martinez, Jennifer Stokes, Michelle Foshat, Jose Cienfuegos, Jamie Seymour, da Darshan Pandya don tallafawa fasaha. Wannan bincike ya goyan bayan Cibiyar Neuroscience Initiative akan Alcoholism Consortium Grant AA13520, da Ƙungiyar Ƙasa ta Cibiyar Hanyoyin Maganin Alka da Alcoholism AA06399-S da AA16424.
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