Overexpression na DeltaFosB yana hade da hawan cocaine mai cikewa wanda ya haifar da maye gurbin saccharin ci a cikin mice. (2009)

FULL STUDY

Behav Neurosci. 2009 Apr; 123 (2): 397-407.

Freet CS, Steffen C, Nestler EJ, Grigson PS.

source

Ma'aikatar Neural da Kimiyyar Bahavioral, Jami'ar Kimiyya ta Jami'ar Pennsylvania State, Hershey, PA 17033, Amurka. [email kariya]

Abstract

Rodents hana maye saccharin lokacin da aka haɗa shi da miyagun ƙwayoyi na zalunci (Goudie, Dickins, & Thornton, 1978; Risinger & Boyce, 2002). Ta hanyar asusun mawallafi, wannan abin mamaki, wanda ake kira a matsayin kwatankwacin sakamako, ana zaton za a yi shiru ta hanyar jirage na kyawawan kaddarorin miyagun ƙwayoyi (PS Grigson, 1997; PS Grigson & CS Freet, 2000). Kodayake ba a fahimci wani abu mai yawa game da ladabi da jaraba ba, an san cewa rashin yin magana akan ΔFosB yana haɗuwa da haɓakawa da ƙwarewar miyagun ƙwayoyi. Idan aka ba wannan, marubuta sun yi la'akari da cewa maganganu na ΔFosB ya kamata kuma ya goyi bayan ƙaddamar da ƙimar ƙwayar cuta ta hanyar ladabi. Don jarraba wannan jumlar, NSE-tTA × TetOp-ΔFosB ƙuda (Chen et al., 1998) tare da na al'ada ko kuma ba'a bayyana ΔFosB a cikin striatum an ba su damar samun saccharin kuma sai injected da saline, 10 mg / kg cocaine, ko 20 mg / kg cocaine. Sabanin asalin asali, rashin nuna bambanci na ΔFosB an hade shi da maye gurbin ciwon hanta na saccharin. An yi tsammanin cewa tsayin daka na ΔFosB ba kawai yana ƙara yawan darajar magani ba, amma sakamakon ladaran saccharin.

keywords: sakamakon kwatankwacin, sakamakon ladabi, mice mai sutsi, CTA, ci

ΔFosB wani memba ne na iyalin Fos na abubuwan da ke rubuce-rubuce wanda ya karbi mai yawa da hankali kamar yadda za'a iya yin amfani da kwayoyin kwayoyin halitta don yin amfani da filastan neuronal mai tsawo a cikin maganin ƙwayoyi (McClung et al., 2004; Nestler, Barrot, & Kai, 2001; Nestler, Kelz, & Chen, 1999). ΔFosB zai iya yin homodimerize (Jorissen et al., 2007) ko heterodimerize tare da JunD (da kuma zuwa karami, JunB; Hiroi et al., 1998; Perez-Otano, Mandelzys, & Morgan, 1998) don samar da ƙwayoyin gina jiki-1-activator (Chen et al., 1995; Curran & Franza, 1988; Nestler et al., 2001). Magani mai gina jiki-1, to, yana ɗaure a tashar yarjejeniyar yarjejeniya-1-activator (TGAC / GTCA) don inganta ko kuma hana haɗin gwiwar kwayoyin daban-daban ciki har da, amma ba'a iyakance ga, dynorphin ba, mai karɓa na AMPA glutamate ƙarƙashin GluR2, 5 kinase na dogara cyclin , da kuma makaman nukiliya factor kappa B (Chen, Kelz, Hope, Nakabeppu, & Nestler, 1997; Dobrazanski et al., 1991; Nakabeppu & Nathans, 1991; Yen, Hikima, Tratner, & Verma, 1991). A cikin ƙananan yanayi, hawan ΔFosB ya hana kisa na dynorphin (McClung et al., 2004, amma gani Andersson, Westin, & Cenci, 2003) amma inganta ingantaccen rubutu na GluR2 (Kelz & Nestler, 2000), 5 kinase dangin cyclin-dependentMcClung & Nestler, 2003), da kuma makaman nukiliya factor kappa B (Ang et al., 2001). Hanyar da yawa daga cikin wadannan kwayoyin (da / ko samfurorinsu) an samo su don yin tasiri ga magunguna na zalunci. Alal misali, rashin fahimtar GluR2 ta hanyar amfani da kwayar cutar ta hanyar rigakafi ta hanyar ratsi, ko haɗuwa na dynorphin ta hanyar mai kwakwalwa mai kwakwalwa ko kuma na BNI a cikin ƙananan yara, yana ƙaruwa sakamakon sakamako na cocaine da morphine,Kelz et al., 1999; Zachariou et al., 2006).

Wasu dalilai da dama zasu iya bunkasa ΔFosB a cikin kwakwalwa, kuma tayarwa zai iya zama yanki musamman. Rikici na lokaci, magungunan antipsychotic, da magungunan zalunci duk suna tayar da ΔFosB a dorsal (caudate-putamen) da kuma ventral striatum (Atkins et al., 1999; Perrotti et al., 2004, 2008). A cikin kwakwalwa (watau tsakiya), duk da haka, kowane ɗayan waɗannan abubuwa sun bambanta ΔFosB a wasu nau'in tantanin halitta. Alal misali, damuwa na yau da kullum yana ɗauke da ΔFosB a cikin dynorphin + / abu P + da kuma enkephalin + raguwa na matsakaici na kwayoyin dopamine a cikin ventral striatum (Perrotti et al., 2004). Magungunan antipsychotic sun daukaka ΔFosB a cikin enkephalin + dopamine neurons a cikin ventral striatum (Atkins et al., 1999; Hiroi & Graybiel, 1996), da kuma magungunan ƙwayoyi suna daukaka ΔFosB a dynorphin + / abu P + dopamine neurons a cikin ventral striatum (Moratalla, Elibol, Vallejo, & Graybiel, 1996; Nye, Fata, Kelz, Iadarola, & Nestler, 1995; Perrotti et al., 2008). Wannan sifa na karshe na ΔFosB magana a cikin dorsal striatum da a cikin dynorphin + / abu P + dopamine neurons a cikin tsakiya accumbens cewa mun koma a matsayin "striatal" magana a cikin wannan labarin (sai dai idan ba a lura da shi) domin shi ne wannan hanyar nunawa cewa ya fi dacewa da sakamakon ladabi, magungunan zalunci, da jaraba (Colby, Whisler, Steffen, Nestler, & Kai, 2003; McClung et al., 2004; Olausson et al., 2006; Werme et al., 2002), kuma wannan nau'i ne na furucin da aka samo a cikin mice da ake amfani da su a cikin binciken mu (Kelz et al., 1999).

Abin sha'awa shine, tayar da ΔFosB ta hanyar maganin cin zarafi yana buƙatar na kullum maimakon ƙananan daukan hotuna (McClung et al., 2004; Nye et al., 1995; Nye & Nestler, 1996). Saboda haka, kodayake yawancin maganin da aka yi wa kwayoyi ya karu da yawa yawancin sunadaran Fos a cikin striatum, irin su C-Fos da FosB (Daunais & McGinty, 1994; B. Fata, Kosofsky, Hyman, & Nestler, 1992; Persico, Schindler, O'Hara, Brannock, & Uhl, 1993; Sheng & Greenberg, 1990), akwai ƙananan ƙarami a ΔFosB (Nestler, 2001a; Nestler et al., 1999). Duk da haka, da zarar an tsara shi, ΔFosB yana da kwanciyar hankali kuma yana da rabin rabi na rayuwa fiye da 1 da aka kwatanta da 10-12 Hr ga sauran Furo sunadarai (Chen et al., 1997). Wannan kwanciyar hankali na ba da izini don raguwa na ΔFosB tare da daukan hoto mai tsanani. Sauran sunadarai Fos, idan aka kwatanta, suna nuna amsawar da ba a rage ba a lokacin (Fata da al., 1992, 1994; Moratalla et al., 1996; Nye et al., 1995). Bayanan shan magani na yau da kullum, to, yana ba da damar ΔFosB don isa matakan da zai iya rinjayar layin jinsi kuma ya zama dacewa.

Akwai litattafan wallafe-wallafen masu girma da suka nuna cewa tayi girman ΔFosB yana ƙaruwa da fahimtar darajoji na magungunan ƙwayoyi. Alal misali, zaɓi ga wuraren da ake haɗar da miyagun ƙwayoyi, wanda aka tsara ta wurin sanyawa zaɓi, an ƙara shi a cikin ƙananan ƙira tare da girman ΔFosB a cikin striatum (Kelz et al., 1999). Samun da kuma kiyaye maganin magungunan miyagun ƙwayoyi, da kuma motsawa don yin amfani da miyagun ƙwayoyi, an ninka haka a cikin ƙananan yara tare da mai girma ΔFosB (Colby et al., 2003). Ko da yake an ci gaba da fahimtar sakamakon ΔFosB a yawancin fannonin maganin miyagun ƙwayoyi, wani yanki wanda ba'a bincikar shi ba ne sakamakon ΔFosB kan ragewar farashi na dabi'a. A cikin 'yan adam, wannan alamar yana bayyana a dalilin ragewa ga aikin, abokai, iyali, da kuma kuɗin kuɗi (misali, Goldstein et al., 2006, 2008; Jones, Casswell, & Zhang, 1995; Nair et al., 1997; Santolaria-Fernandez et al., 1995).

Bayananmu suna nuna cewa wannan mummunan sakamako na jaraba a cikin mutane za a iya tsara su a cikin rodents ta yin amfani da alal misali kwatanta (Grigson & Twining, 2002). A cikin wannan yanayin, samun damar yin amfani da wani maganin saccharin mai sauƙi wanda aka biyo baya ya bi ta hanyar amfani da miyagun ƙwayoyi, kamar morphine ko cocaine. A karkashin waɗannan yanayi, berayen da ƙuda zasu zo ne don kaucewa cin abinci na dandano a cikin tsammanin gudanar da magani (Grigson, 1997; Grigson & Twining, 2002; Risinger & Boyce, 2002). Bisa ga kwatancin kwatancin da aka kwatanta da ita, ana kauce wa cin hanci da rashawa bayan an yi amfani da miyagun ƙwayoyi na zalunci, a kalla farko (duba Wheeler et al., 2008), saboda darajan gustatory stimulus yayi da aka kwatanta da yiwuwar sakamako masu arziki na miyagun ƙwayoyi (Grigson, 1997). Wannan ra'ayi ya bambanta da asusun da ake dasu mai dorewa (CTA) na bayanai-wato, ra'ayi ya bambanta da shawara cewa ratsaye kauce wa cin abinci na dandano domin yana tsinkaye magungunan miyagun ƙwayoyi (Nachman, Lester, & Le Magnen, 1970; Riley & Tuck, 1985).

Idan kwatancin kwatancin kwatancin daidai ne, duk wani yanayin ko yanayin da ya haɓaka ƙimar da aka yi la'akari da sakamako na miyagun ƙwayoyi ya kamata ya daina yin la'akari da ƙananan saccharin. Daidai ne, ragowar Lewis masu shan ƙwayar cuta suna nuna mafi girma daina yin saccharin bayan saccharin-cocaine pairings fiye da ratsan Fischer mai da hankali (Grigson & Freet, 2000). Rabaran Sprague-Dawley kuma suna nuna mafi girma daga wani dandano mai haɗi tare da cocaine ko sucrose bayan bayanan tarihin jiyya na jiki (Grigson, Wheeler, Wheeler, & Ballard, 2001). Abin sha'awa shine, ratsan Lewis da na Sprague-Dawley masu guje-guje da tarihin maganin jiyya na yau da kullum sun haɓaka ΔFosB a cikin ƙananan mahaifa (Haile, Hiroi, Nestler, & Kosten, 2001; Nye & Nestler, 1996). Binciken 1 ya fi dacewa nazarin muhimmancin ΔFosB a cikin maye gurbin shan magani wanda ya shawo kan ciwon sharaɗi (CS) ta hanyar nazarin maganin maganin maganin cocaine da ake amfani da shi na saccharin cue a cikin ƙananan yara wanda ya tabbatar da hakan a cikin striatum.

Experiment 1

Binciken da ya gabata ya nuna cewa ƙwayoyi suna hana cin abincin ɗanɗanar lokacin da aka haɗa su tare da miyagun ƙwayoyi na zalunci a hanyar da ya dace da abin da aka gani a cikin berayen (Risinger & Boyce, 2002; Schroy, 2006). Mafi yawan binciken da ya shafi kwari, waɗannan nazarin sun yi amfani da ƙuntatawa ga ruwa da kuma hanyar 0.15% saccharin da aka fi sani da CS (Bachmanov, Tordoff, & Beauchamp, 2001; Tordoff & Bachmanov, 2003). A cikin wadannan gwaje-gwajen, an kawar da ciwo na saccharin lokacin da inuwa na 10 mg / kg cocaine (in DBA / 2 mice) ko 20 mg / kg cocaine (a cikin DBA / 2 da C57BL / 6 mice ) cocaine (Risinger & Boyce, 2002; Schroy, 2006). Saboda haka, gwajin 1 yayi la'akari da maye gurbin amfani da 0.15% saccharin lokacin da aka haɗa shi da saline, 10 mg / kg cocaine, ko 20 MG / kg cocaine a cikin NSE-TTA × TetOp-ΔFosB Line A ƙusa. Wadannan ƙananan ƙananan ƙwayoyin halitta (SJL × C57BL / 6 baya) suna nuna nuna rashin amincewarsu na ΔFosB a cikin striatum kan kawar da doxycycline daga ruwa (Chen et al., 1998). Bisa ga bayanan da aka samo a cikin berayen, munyi tsammanin karuwar ΔFosB a cikin wadannan ƙananan za su kara yawan sakamakon da miyagun ƙwayoyi suke ciki sannan kuma su taimakawa magance maganin saccharin da ya shafi ΔFosB na sarrafawa na al'ada.

Hanyar

batutuwa

Wadannan batutuwa sune 60 namiji NSE-TTA × TetOp-ΔFosB Line A bitransgenic mice. Kwanan nan an gina su ne daga Cibiyar Magunguna na Jami'ar Texas ta Kuduwestern Medical Center a Dallas, Texas, kuma suna kiyaye 100 μg doxycycline / ml a cikin ruwan sha. Wannan tsarin yana cike da cikakken rikici na bayyanar ΔFosB maganganu kuma hakan yana ba da dama don ci gaban al'ada (kamar yadda aka bayyana a cikin Chen et al., 1998). An kuma aika ƙugiya zuwa ga kayan dabba a Pennsylvania College of Medicine a Hershey, Pennsylvania, kuma an tsare shi don watanni 2 (dukkanin ƙwayoyin da aka kiyaye a kan doxycycline a lokacin sufuri da kuma lokacin cinyewa). A saki daga keɓe masu ciwo, rabin rami (n = 30) an cire cire nauyin doxycycline, kuma an yarda da ΔFosB aukuwa don 8 makonni kafin gwajin, lokacin da ake buƙata don aikin ΔFosB mafi girma (McClung & Nestler, 2003). Sauran ƙuda (n = 30) ya kasance a kan doxycycline don tsawon lokacin karatu. Mice da aka auna a tsakanin 31.2 g da 45.0 g a farkon gwajin kuma an sanya su a kowane ɗigon a cikin daidaitattun kwakwalwan filafin filastik a cikin kulawar dabba mai sarrafawa (21 ° C) da 12-hr haske-dark cycle (hasken wuta akan a 7: 00 am). Dukkanin gwajin gwaji an gudanar da 2 hr (9: 00 am) da kuma 7 hr (2: 00 a cikin watsi). An kiyaye ƙudaje ta hanyar samun damar shiga kayan abinci (W) 8604 da ruwa, har sai idan ba a lura ba.

inji

Dukkanin gwajin gwaji an gudanar da su a cikin gida. An yi amfani da pipettes na Mohr da aka kammala don samar dH2O kuma hanyar saccharin. Kungiyar Pipettes ta canza zuwa gilashin ruwan tabarau ta hanyar kawar da ƙarancin tafe. An rufe wani katako na caba tare da kayan jikin bakin karfe wanda aka sanya ta cikin cibiyar sannan a sanya shi a cikin kasa na Silinda, da kuma irin gado na katako (ƙananan nauyin) ya rufe saman Silinda. Ciyar da dH2An rubuta sa da kuma saccharin a cikin 1 / 10 ml.

hanya

Dukkanin batutuwa sun kasance sau ɗaya kowace rana a cikin binciken. Bayan saki daga keɓe masu ciwo, kuma kamar yadda aka bayyana, ƴan ΔFosB musexpression mice (n = 30) an cire su daga 100 μg / ml doxycycline. Wadannan mice sun karbi dH ba tare da dadewa ba2Ya ga sauran sauraren binciken, da sauran rabi na mice (n = 30), ƙungiyoyin ΔFosB na al'ada, sun ci gaba a kan doxycycline. Bayan makonni na 8 na ΔFosB overexpression, an yi la'akari da yawan ruwa mai tsabta. Don ma'aunin ma'auni, an sanya dukkan ƙwayoyi a kan raƙuman ruwa wanda ya ƙunshi dH2O (tare da ko ba tare da doxycycline dangane da ƙungiyar kulawa) don 1 hr farawa a 9: 00 am kuma na 2 hr farawa a 2: 00 pm Ana amfani da baseline abinci da nauyin jiki don 1 mako. A lokacin gwajin, duk ƙwayoyin da aka samu 1 Hr zuwa 0.15% saccharin da safe sun biyo baya ta hanyar injection intanetitoneal saline (n = 10 / cell), 10 mg / kg cocaine (n = 10 / cell), ko 20 mg / kg cocaine (n = 10 / cell). Maganin ƙwaƙwalwar magani ya faru a kowace 48 hr don gwaji biyar. Don kula da hydration, dukkanin batutuwa sun karbi 2 Hr damar shiga dH2O ko 100 μg / ml doxycycline kowace rana da 1 hr shiga dH2O ko 100 μg / ml doxycycline kowace safiya tsakanin gwajin gwajin gwaje-gwajen, kamar yadda aka ƙayyade ta aiki ta rukuni. An samo Saccharin daga kamfanin Sigma Chemical Company, St. Louis, MO, da kuma HCl na cocaine ta Cibiyar Nazarin Kasuwanci ta Drug. An gabatar da maganin saccharin a cikin ɗakin da zafin jiki.

Sakamako da Tattaunawa

Adireshin CS

An yi nazari da amfani da jikin jiki ta hanyar amfani da 2 × 3 × 5 nazarin magungunan da ake yi akan bambancin (ANOVAs) da magungunan magani (salula, da rashin maganin ΔFosB), miyagun ƙwayoyi (saline, 10 mg / kg cocaine, ko 20 mg / kg cocaine), da kuma gwaji (1-5). An gudanar da gwaje-gwaje masu gwaje-gwajen, idan ya dace, ta yin amfani da gwajin Neuman-Keuls tare da haruffan na .05. Binciken Figure 1 yana nuna cewa rashin nuna bambanci na ΔFosB a cikin striatum yana haɗuwa da raguwa maimakon haɓaka rage maye gurbin hawan cocaine na amfani da saccharin.

Figure 1 

Ma'anar (± SEM) abinci (ml / 1 hr) na 0.15% saccharin bayan biyar pairings tare da allurar saline na intanetitoneal, 10 mg / kg cocaine, ko 20 mg / kg cocaine a NSE-tTA × TetOp-ΔFosB Line A mice da al'ada (bangaren hagu) ko girman ...

Taimako don wannan ra'ayi an samo shi ta hanyar binciken ƙarshe na wani magani mai mahimmanci × Drug × Jarabawar hulɗa, F(8, 212) = 2.08, p <.04. Musamman, sakamakon gwajin Newman-Keuls ya nuna cewa kodayake kashi 10 mg / kg na hodar iblis ba shi da tasiri wajen rage cin CS a cikin ƙungiyoyin kulawa biyu (p > .05), nauyin 20 MG / kg bai da tasiri a cikin ƙananan yara tare da haɓakar ΔFosB (duba Figure 1, kuskuren kwamitin). Wato, ko da yake jiyya tare da nauyin hawan gwiwar MG / kg na 20 ya rage yawan haɗin saccharin zumunta ga kowane nau'in sarrafa saline a cikin gwaji 2-5 (ps <.05), beraye tare da madaukakiyar magana ta ΔFosB sun cinye mafi yawan alamun saccharin wanda aka haɗu tare da 20 mg / kg hodar Iblis fiye da yadda al'ada ke bayyana iko. Wannan tsarin halayyar ya kasance mai mahimmanci a kan gwaji 3-5 ( ps <.05).

Nauyin jiki

Babu bayyanar ΔFosB a cikin striatum ko magungunan miyagun ƙwayoyi yana da muhimmanci canza jiki. Wannan mahimmanci ya goyi bayan wani sakamako mai ban mamaki na magani, F <1, ko magani, F(2, 53) = 1.07, p = .35. Babban sakamako na gwaji yana da muhimmanci, F(5, 265) = 10.54, p <.0001, wanda ke nuna cewa nauyin jiki ya canza akan gwaji masu zuwa. A ƙarshe, kodayake matakan 2 × 3 × 6 da aka maimaita ANOVA sun bayyana mahimmin magani × Drug × Gwajin gwaji, F(10, 265) = 4.35, p <.01, sakamakon gwaje-gwajen bayanan da ba a san su ba.

Amfanin ruwa

Amfani da dh na dH2O (ml / h) a kwanakin da ke tsakanin gwajin gwaji (tushen, W1-W4 gwaji) an gabatar da su Figure 2 (hagu na hagu da dama).

Figure 2 

Ma'ana (± SEM) amfani dH2A cikin safiya (ml / 1 hr, kwanuka na sama) da kuma maraice (launin ml / 2 hr da kasa) a cikin NSE-tTA × TetOp-ΔFosB Line A ƙugiya tare da al'ada (hagu na hagu) ko matakan haɓaka (dama) na ΔFosB a cikin striatum ...

Wani 2 × 3 × 5 haɗin gwaninta na ANOVA ya nuna cewa babu wani maganganu na ΔFosB a cikin striatum ko magungunan miyagun ƙwayoyi yana da muhimmanci canza dH2Abinci kamar yadda Nasiji mara kyau ya nuna • Drug × Jarabawar hulɗa (F <1). Bugu da kari, ba babban tasirin magani ba, F <1, ko magani, F(2, 53) = 2.55, p = .09, ko magani na Drug hulɗa, F(8, 212) = 1.57, p = .14, ya kasance muhimmiyar mahimmanci.

Hawan ruwan zafi

Ciyar da dH2O don lokacin shiga 2-hr a cikin rana don dukkan gwaje-gwaje an gabatar da shi Figure 2 (ƙananan hagu da dama). Babban sakamako na jiyya ba muhimmi (F <1), yana ba da shawarar cewa yawan bayyana ΔFosB bai shafi maraice dH ba2Ya ci gaba. Babban magungunan miyagun ƙwayoyi, duk da haka, bai kai ga mahimmanci ba, F(2, 53) = 7.95, p <.001, kamar yadda aka yi maganin × Drug intera Gwajin gwaji, F(18, 477) = 2.12, p <.005. Gwajin gwaji na wannan hanyar uku ANOVA ya bayyana a wannan yammacin dH2Rashin shiga a cikin ƙungiyar cocaine 10 mg / kg ba ta da bambanci sosai daga abin da aka yi na saline (ps> .05). Koyaya, la'asar dH2An ci gaba da samun ci gaba a cikin ƙungiyoyi na 20 mg / kg idan aka kwatanta da haɓin saline, kuma wannan tasiri yana da muhimmanci wajen shawo kan gwaje-gwaje inda ƙudaje suka guje wa abincin saccharin da safe (watau Trials 3, 4, da 5 a cikin yara tare da al'ada ΔFosB da gwaje-gwaje 4 da 5 a cikin ƙananan mata tare da mai girma ΔFosB, ps <.05).

Experiment 2

Sakamakon da aka samu a cikin gwajin 1 ba daidai ba ne ga wadanda aka annabta akan bayanan da aka buga. Mice tare da kalma mai girma na ΔFosB ya nuna karami, maimakon mafi girma, kauce wa wani saccharin bayan bin maimaita saccharin-cocaine. Akwai wasu bayanai masu yiwuwa don waɗannan bayanai. Mafi bayyane, wanda aka ba wallafe-wallafen, shine cewa wannan tsari yana da damuwa ga juyawa, maimakon mahimmanci, dukiyar likitanci (Nachman et al., 1970; Riley Tuck, 1985). Sakamakon ΔFosB, to, ƙila ba kawai ƙara karɓar amsawa ga magungunan miyagun ƙwayoyi ba, amma zai iya rage karɓar amsawa ga magungunan miyagun ƙwayoyi. Idan wannan lamari ne, to ana iya tsammanin cewa ƴan ΔFosB mai girma yana iya nuna ƙaramin CTA fiye da ƙwayoyin CI fiye da mice tare da maganganu na ΔFosB. Don gwada wannan tsinkayyar, ana amfani da irin wannan nau'in a cikin yanayin kwalliya wanda ya karbi 1 Hr zuwa wani labari na 0.1 M naCl, sannan, nan da nan, an yi masa inji tare da saline, 0.018 M LiCl, ko 0.036 M LiCl.

Hanyar

batutuwa

Wadannan batutuwa sune 58 (29 da aka nuna ΔFosB da 29 na al'ada ΔFosB) namiji NSE-tTA × TetOp-ΔFosB Line A ƙwayoyin da aka yi amfani da ita a gwaji 1. Mice ba su da kyau don rarraba saccharin-saline ko saccharin-cocaine cikin kungiyoyin. A lokacin jaraba, ƙuda a cikin rukuni na gwaji sunyi maganganu na ΔFosB a cikin striatum na kimanin makonni 17, kuma dukkan ƙwayoyin da aka auna tsakanin 31.7 da 50.2 a farkon gwajin. An kafa su a kowane ɗayan kuma suna kiyaye kamar yadda aka bayyana a sama.

inji

Jirgin ya kasance daidai da kwatancin gwajin 1.

hanya

Dukkanin batutuwa sun kasance sau ɗaya kowace rana a cikin binciken. Don ma'aunin ma'auni, an sanya dukkan ƙananan ƙwayoyi a kan tsarin raƙuman ruwa wanda aka bayyana a sama (1 hr am da 2 x), tare da ko ba tare da doxycycline ba a matsayin aiki na kowane. An rubuta jigon layin layi da nauyin jiki don 1 mako. A lokacin gwaji, duk ƙwayoyin da aka samu 1 Hr zuwa 0.1 M NaCl da safe sun biyo baya ta hanyar injection intanetitoneal saline (n = 9 / cell), 0.018 M LiCl (n = 10 / cell), ko 0.036 M LiCl (n = 10 / cell). A cikin berayen, sakamakon maye gurbin nauyin 0.009 M na LiCl an daidaita shi da nauyin 10 mg / kg na cocaine (Grigson, 1997). Duk da haka, an ba da kwarewar kwarewa a cikin gwaji 1 da kuma shaidar da ke nuna cewa irin wannan kwarewa ta baya zai iya jinkirta ci gaba da / ko bayyana wani ƙarfafawa na CS-unconditioned (US) ƙungiyar (Twining et al., 2005), mun yi amfani da ƙwayoyin LiCl da yawa (0.018 M da 0.036 M). Maganin ƙwaƙwalwar magani ya faru a kowace 48 hr don gwaji biyar. Dukkanin batutuwa sun karbi 2 Hr zuwa dH2O ko 100 μg / ml doxycycline kowace rana da 1 hr shiga dH2O ko 100 μg / ml doxycycline kowace safiya tsakanin gwajin gwaji. An samo NaCl daga Fisher Chemical, Pittsburgh, PA; An samo LiCl daga Sigma Chemical Company, St. Louis, MO. An gabatar da bayani na NaCl a cikin dakin da zafin jiki.

Sakamako da Tattaunawa

Adireshin CS

An yi nazarin amfani tare da amfani da 2 × 3 × 5 mai mahimmanci na ANOVA (magani na yau da kullum) da miyagun ƙwayoyi (saline, 0.018 M LiCl, ko 0.036 M LiCl), da gwaji (1-5). An gudanar da gwaje-gwaje masu gwaje-gwajen, idan ya dace, ta yin amfani da gwajin Neuman-Keuls tare da haruffan na .05. Ana nuna alamar ΔFosB a kan ilimin LiCl CTA a cikin Figure 3.

Figure 3 

Ma'anar (± SEM) (ml / 1 hr) na 0.1 M NaCl bayan bayanan biyar tare da allurar saline na intanetitoneal, 0.018 M LiCl, ko 0.036 M LiCl a cikin NSE-tTA × TetOp-ΔFosB Line A mice tare da al'ada (bangaren hagu ) ko ɗagawa (madaidaiciyar panel) ...

Sakamakon ANOVA ya nuna mahimmanci Drug × Trials gwagwarmaya, F(8, 204) = 5.08, p <.001, yana nuna cewa duk beraye, ba tare da la'akari da bayanin ΔFosB ba, ya guji karɓar NaCl CS wanda aka haɗu tare da wakilin LiCl mai haifar da rashin lafiya dangane da batutuwa da aka kula da su. Ba kamar bayanan cocaine da aka bayyana a sama ba, hanya uku ANOVA ba ta kusanci ƙididdigar lissafi ba (F <1). Bugu da kari, babu wani muhimmin sakamako na jiyya (watau doxy ko ruwa; F <1), Jiyya ction Hulɗar gwaji (F <1), ko Jiyya × Maganin ƙwayoyi (F <1). Duk da haka, lura da bayanan da aka nuna a ciki Figure 3 ya nuna cewa sakamakon maye gurbin LiCl, irin su cocaine, na iya kasancewa karami a cikin ƙananan ΔFosB. Ta haka ne, mun sake nazarin sassa daban-daban na jiyya ta hanyar amfani da 3 × 5 wanda ke dauke da kwayoyi da gwaji. Sakamakon waɗannan ANOVAs sun tabbatar da wani ƙwararren kwayoyi na Drug × gwaji na al'ada, F(8, 100) = 3.48, p <.001, da abin da ya wuce gona da iri, F(8, 108) = 2.19, p <.033, mFosB beraye Gwaje-gwajen bayan fage sun nuna raguwa mai yawa a cikin cin CS ta mafi girman adadin LiCl akan Gwaji na 3-5 don ƙananan beraye na yau da kullun da kuma akan gwaji 3 da 4 don ƙananan beraye (ps <.05).

Duk da yawan samfurin samfurin, samfurin LiCl ya fi muni fiye da bayanan cocaine a cikin gwajin 1. A canji da aka nuna a Figure 3 mai yiwuwa dangantaka da tarihin salin ko cocaine magani a gwaji 1. A kokarin ƙoƙarin gwada wannan tsinkaya, mun sake sake bayani game da bayanan CTA da aka yi amfani da 2 × 2 × 3 × 5 na ANNUX wanda ya bambanta tarihin (Saline vs Cocaine), magani (al'ada da kuma rashin maganin ΔFosB), magani (saline, 0.018 M LiCl, ko 0.036 M LiCl), da gwaji (1-5). Don kare kanka da sauƙi, tarihin cocaine ya nuna yawancin bayanai daga ƙananan yara tare da tarihin kwarewa tare da 10 mg / kg da 20 mg / kg na cocaine. Hakazalika da sakamakon binciken farko, hanyar hulɗar hanya guda hudu ta kasa cimma muhimmancin mahimmanci, F(8, 180) = 1.34, p = .22. Tarihin saccharin-saline ko saccharin-cocaine pairings, to, yana iya taimakawa wajen canzawa cikin bayanan, amma tasiri ba uniform ba ne, kuma hada da tarihin tarihin bai taimakawa wajen nuna bambancin bambance-bambance a cikin girman LiCl- Cdu tsakanin CTA tsakanin ƙwayoyin ΔFosB na al'ada da mice tare da nuna rashin jin dadi na ΔFosB. A takaice dai, LiCl ya shafe amfani da NaCl CS, kuma ko da yake akwai nau'i na sauƙin haɓakawa a cikin ƙwayoyin ΔFosB mai tsanani, bambancin tsakanin kungiyoyin kulawa bai kusanci muhimmancin kididdiga ba.

A haɗuwa tare, sakamakon daga gwaje-gwaje 1 da 2 sun nuna cewa ƙuda da mai girma ΔFosB suna cinyewa mafi mahimmanci daga sabobin CS bayan saccharin-cocaine pairings kuma sukan cinye fiye da NaCl CS bayan NaCL-LiCl pairings. Halin da ake yi na cinye mafi yawan CSs masu dangantaka da miyagun ƙwayoyi (musamman a gwaji 1) na iya haifar da karuwa a hankali ga dukiyar da aka samu na saccharin da / ko NaCl CS saboda matakan girman ΔFosB suna da dangantaka da wani karuwa a karɓa ga sauran ladaran dabi'a irin su gurasar abinci (Olausson et al., 2006) da kuma motar motar (Werme et al. 2002). Gwajin 3 na gwaje-gwaje ko waɗannan ƙwayoyin da ƙananan matakan girman ΔFosB sunyi karɓuwa ga dukiyar da aka samu na jinsin sukari da gishiri a cikin gwaje-gwajen kwalba guda biyu tare da ruwa.

Experiment 3

An kirkiro 3 gwaji don nazarin zaton cewa rageccen maye na samun CS ta hanyar ƙananan ΔFosB a gwajin 1 shine sakamakon karuwar farashin sakamako ba kawai da miyagun ƙwayoyi ba, amma sakamakon saccharin na hakika. Don kimanta wannan tsinkaya, mun yi amfani da gwaje-gwaje guda daya da na kwalban guda biyu don nazarin sakamakon rashin maganin ΔFosB a kan amfani da wani abu na cigaba (sucrose). Bugu da kari, an ba da halin wa annan ƙananan su don ɗaukar NaCl CS bayan NaCl-LiCl a cikin gwaji 2, mun kuma yi amfani da gwaje-gwaje guda biyu da kwalban kwalba don bincika tasiri mai girma ΔFosB game da amfani da kewayon yawan more "tsaka tsaki" NaCl mafita. An yi nazari na uku na NaCl (0.03 M, 0.1 M, da 0.3 M) da kuma saroon (0.01 M, 0.1 M, da 1.0 M). An yi tsammanin cewa idan hawan ΔFosB ya haɓaka tamanin lada mai ladabi, cin abinci na sucrose ya zama mafi girma a cikin gwajin gwaji idan aka kwatanta da sarrafawa.

Hanyar

batutuwa

Wadannan batutuwa sune 28 (14 da aka nuna ΔFosB da 14 na al'ada ΔFosB) namiji NSE-tTA × TetOp-ΔFosB Line A ƙwayoyin da aka yi amfani da ita a gwaji 1. A lokacin jaraba, ƙuda a cikin rukuni na gwaji sunyi maganganu na ΔFosB a cikin striatum don kimanin makonni 25. Bugu da ƙari, ƙananan ƙwaƙwalwa sun taɓa yin amfani da saccharin-sucrose a cikin gwajin gwajin da ba a yi nasara ba (matakan da ke tallafawa bambanci a cikin ƙananan yara har yanzu suna binciken). Mice da aka auna tsakanin 31.5 da 54.5 g a farkon gwajin. An zauna su kuma suna kiyaye kamar yadda aka bayyana a baya.

inji

Jirgin ya kasance kamar yadda aka bayyana a cikin gwaji 1.

hanya

Dukkanin batutuwa sun kasance sau ɗaya kowace rana. A ranar 4 kwanan rana, kowane linzamin kwamfuta ya karbi 1 hr zuwa dH2O da safe da 2 hr shiga cikin rana. A cikin gwaji, mice tare da mai girma ΔFosB (n = 14) ya karbi dH2Ya sake rehydrate kowace rana, da kuma mice tare da al'ada ΔFosB (n = 14) sun karbi 100 μg / ml doxycycline. Sauran nau'o'in NaCl (0.03 M, 0.1 M, da 0.3 M) da kuma sucrose (0.01 M, 0.1 M, da kuma 1.0 M) an yi amfani dashi azaman dandano. An gabatar da kowane maida hankali ga mice a lokacin safiya na 1-hr na 3 a jere. Kwanan 2 na farko sune gabatarwa guda daya na dandano kuma ranar 3rd ya kunshi gabatarwa biyu na dandalin dandalin da dH2O. Matsayin kwalabe ya zama abin ƙyama, hagu da dama, a cikin kungiyoyi da kuma a yayin taron gwajin kwalban. An gabatar da mafita a cikin tsari mai girma, kuma an yi amfani da NaCl a gaban sukari. DH biyu2An yi gwajin gwaji kawai tsakanin NaCl da gwajin sukari. An kiyasta yawancin rana kowace rana zuwa mafi kusa 1 / 10 ml.

data analysis

Ana nazarin bayanan ta amfani da su t gwaje-gwaje tare da haruffan na .05.

Sakamako da Tattaunawa

Bayanan da aka samu daga jarrabawar kwalbar guda biyu sun fi dacewa kuma, saboda haka, an gabatar da su a nan (duba Figure 4). Ana nuna alamar ruwan kwalban kwalba guda ɗaya a matsayin ma'ana.

Figure 4 

Ma'anar (± SEM) (ml / 1 hr) na kewayon na NaCl (saman kwanuka) da kuma sucrose (ƙananan bangarori) dH2O a cikin NSE-TTA × TetOp-ΔFosB Line A mice tare da al'ada (hagu na bangarori) ko girman (matakai na dama) na ΔFosB ...

NaCl zaɓi

Bugu da ƙari, tarihin CTA koyon ilimin 0.1 M na NaCl bayan maganganu tare da ƙananan ƙwayar LiCl ba su hana maganganun ayyukan da suka fi so ba don ƙara yawan karfin NaCl lokacin da aka gwada su cikin gwaji. A cikin ƙananan ƙwayar jiki tare da al'ada ΔFosB (hagu na hagu), cin abinci na biyu mafi ƙasƙanci na NaCl (0.03 M da 0.1 M) ba su bambanta daga amfani dH2Ya a cikin jarrabawar kwalba guda biyu (ps> .05). Matsayi mafi girma na NaCl (0.3 M), duk da haka, ya kasance mafi ƙarancin fifiko fiye da dH2O (p <.0001), daidai da yanayin ƙyamar wannan maida hankali (Bachmanov, Beauchamp, & Tordoff, 2002). A cikin mice tare da girman ΔFosB (hagu na dama), irin wannan tsari ya bayyana tare da nazarin 0.3 M na NaCl (p <.01), yana nuna cewa haɓakar ΔFosB ba ta canza mahimmancin martani ga wannan motsawar ba. Wani samfurin daban, yadda koyaushe, ya faru tare da ƙananan ƙananan NaCl. Musamman, beraye tare da ɗimbin magana na ΔFosB sun nuna fifiko don ƙananan ƙananan 0.03 M da 0.1 M na NaCl dangane da dH2Ya a cikin jarrabawar kwalba guda biyu (ps <.03). Hawan ΔFosB, sabili da haka, na iya canza fifiko don ƙananan ƙananan NaCl daga tsaka tsaki zuwa zaɓi.

Sucrose zaɓi

Yin amfani da zane-zane t gwaje-gwaje don samfurori masu dogara sun nuna cewa a cikin ƙananan yara tare da ΔFosB na al'ada, cin abinci mafi yawan ƙasƙanci na sucrose (0.01 M) ba ya bambanta da dH ba2O (p = .82). Sabanin haka, 0.1 M da 1.0 M surori da yawa sun fi son dH2O (ps <.0001). A cikin ƙananan yara tare da ΔFosB mai girma, an fifita sucrose da fifiko dH2Ya a fadin dukkanin gwaji da aka gwada (ps <.02). Wannan binciken yana ba da goyan baya don ƙaddara cewa ɗaga ΔFosB yana ƙaruwa da fifiko don ladaran ƙasa.

Janar Tattaunawa

Bayanin da ke cikin wannan labarin ya nuna cewa hawan ΔFosB a cikin striatum an hade shi da maye gurbin abincin saccharin. Wannan binciken ya saba da asalinmu na asali cewa irin wannan halayen ya kamata a sauƙaƙe sakamakon cutar cocaine. Musamman, hawan ΔFosB yana ƙaruwa da magungunan ƙwayoyi na zalunci (Colby et al., 2003; Kelz et al. 1999), da dabbobin da ke da jaraba-samfurin phenotype ko tare da tarihin magani tare da mummunan cututtuka (duka biyu suna samar da hawan ΔFosB) ya nuna mummunar maganin saccharin abincin da ke da alaka da sarrafawa (Grigson & Freet, 2000; Grigson et al., 2001). Yana da muhimmanci a lura da cewa, batutuwa a cikin gwaje-gwajen da suka gabata ba su da girman kawai ΔFosB, amma har da sababbin hanyoyi masu yawa wanda ya haifar da yuwuwa zuwa kwayoyi masu cin zarafin ko tsangwama-samfurin phenotype (Nestler, 1995, 2001b; Nestler & Aghajanian, 1997). Wadannan ƙarin gyare-gyare sun ba da gudummawar halayyar da kuma gabatar da yiwuwar rikice lokacin ƙoƙarin fassara fasalin ΔFosB, ta hanyar, a cikin maye gurbin miyagun ƙwayoyi na shigar CS. Wannan rikicewa an sarrafa shi a cikin wadannan gwaje-gwajen (watau, dukkanin batutuwa sun kasance daidai ba tare da galibi ba a ΔFosB), suna ba da damar fassara fassarar tasirin ΔFosB a cikin sabon abu. Kamar yadda aka bayyana a sama, bayanai na yanzu sun nuna cewa maye gurbin hawan cocaine na abincin saccharin yana faruwa ne a gaban girman ΔFosB, amma an rage sakamako akan dangantaka. Hawan ΔFosB a cikin striatum, to, ya rage don ragewa maimakon inganta haɓakar cocaine ta maye gurbin saccharin.

Akwai fassarori da yawa game da sakamako wanda aka rage wanda za'a iya cire shi da sauri. Na farko, yana yiwuwa adadin da ke cikin ΔFosB ya rage darajar cocaine. Wannan yana nuna bayanin da ba a iya ba da shi ba don wallafe-wallafen wallafe-wallafe da aka haɗaka ΔFosB zuwa karuwa a cikin ƙididdigar farashin cocaine da sauran magunguna na zalunci (Colby et al., 2003; Kelz et al., 1999; McClung & Nestler, 2003; McClung et al., 2004; Nestler et al., 2001, 1999). Na biyu, haɓakawa zai iya nuna bambancin jinsin a cikin maye gurbin miyagun ƙwayoyi da kuma halin halayen ΔFosB. Bugu da ƙari, wallafe-wallafe ba su goyi bayan wannan yiwuwar ba saboda ƙudaje da ƙuda suna nuna irin wannan yanayin a cikin maye gurbin maganin CS (Grigson, 1997; Grigson & Twining, 2002; Risinger & Boyce, 2002) da kuma haɓaka halayyar hali ta ΔFosB (Kelz et al., 1999; Olausson et al., 2006; Werme et al., 2002; Zachariou et al., 2006). A ƙarshe, yana yiwuwa adadin ΔFosB zai iya haifar da raguwa ta tarayya wanda zai iya rage rage cin abinci na cocaine da ke saccharin. Wannan yiwuwar kuma, ya bayyana ba zai iya yiwuwa ba saboda rashin fahimtar wannan yanayin ba a ganin koyo ko aiki na halayyar mai aiki ba (Colby et al., 2003), da kuma sayen CTA mai ƙaddamar da LiCl ba ya bambanta, muhimmi, a matsayin aikin ΔFosB a gwaji 2. Hakanan ΔFosB yana nuna halayen al'ada a cikin Morris ruwa da kuma a cikin yanayin da aka sanya dashi (Kelz et al., 1999).

Wata mahimmancin yiwuwar tasowa ta hanyar CTA fassarar bayanai a cikin gwaji 1. Wato, idan an kawar da maganin saccharin ta hanyar cocaine na amfani da kayan magungunan magani, to, wanda zai yanke cewa ΔFosB mai girmanta ya rage, a kalla a wani ɓangare, tasirin waɗannan magungunan miyagun ƙwayoyi. A gaskiya ma, akwai shaidar cewa magunguna na cin zarafi suna da dukiya. An nuna Cocaine a cikin tsoro kamar yiwuwar amsa jirgin (Blanchard, Kaawaloa, Hebert, & Blanchard, 1999) da kuma halayen tsaro (Blanchard & Blanchard, 1999) a cikin mice. Duk da haka, yawancin shaidu sun nuna cewa magungunan ƙwayoyi suna hana adadin CS ta hanyar amfani da magunguna masu kyauta (Grigson & Twining, 2002; Grigson, Twining, Freet, Wheeler, & Geddes, 2008). Misali, raunuka na gustatory thalamus (Grigson, Lyuboslavsky, & Tanase, 2000; Reilly & Pritchard, 1996; Scalera, Grigson, & Norgren, 1997; Schroy et al., 2005), gustatory thalamocorticol madauki (Geddes, Han, & Grigson, 2007), da kuma ƙwayoyin cuta (Geddes, Han, Baldwin, Norgren, & Grigson, 2008; Mackey, Keller, & van der Kooy, 1986) rushe tsoma bakin saccharin da sucrose da magunguna na zalunci, amma ba ta LiCl ba. Hakazalika, raƙuman ragu na zafin jiki na nuna bambancin daban-daban ga miyagun ƙwayoyi na zalunci ko sautin Amurka, amma ba don LiCl Amurka ba (Glowa, Shaw, & Riley, 1994; Grigson & Freet, 2000). An nuna irin wannan rashin daidaituwa tare da mantawa da rashin cin hanci (Grigson, Lyuboslavsky, Tanase, & Wheeler, 1999) kuma a cikin berayen da tarihin morphine na yau da kullum (Grigson et al., 2001). Bugu da ƙari, a cikin gwaje-gwajen 3 da 2, girman tarin ΔFosB ba shi da tasiri a kan ko dai ba tare da kariya ba ko mayar da martani ga yanayin da ya haifar, kamar haka. Saboda haka, zumunta da ƙwayar miki, ƙuda da hawan ΔFosB da aka haɓaka ya nuna irin wannan ƙyama ga yiwuwar 0.3 M NaCl bayani a cikin gwajin 3 da gwagwarmaya kamar yadda ya dace da CS na haɗin LiCl a cikin gwaji 2.

Wannan hujja ta nuna, a cikin binciken da aka yi kwanan nan, mun sami shaida cewa an kawar da cututtukan cocaine da ake amfani da shi na saccharin cue tare da farawa na jihar da aka yi wa kwalliya (Wheeler et al., 2008). Mun yi tsammanin cewa gwamnati ta yi watsi da shi, a wani ɓangare na musamman, ta hanyar ci gaba da janyewa daga ɓoye (Grigson et al., 2008; Wheeler et al., 2008). Da yiwuwar, to, za a iya la'akari da cewa karuwa a ΔFosB a cikin striatum yana kaiwa ga rashin guje wa maganganun miyagun ƙwayoyi saboda magani yana taimaka wa cigaba da raguwa. Ko da yake zai yiwu, wannan mahimmanci ma yana da wuyar karɓar saboda a cikin berayen, mafi yawan ƙyama ga CS (kamar yadda aka ƙaddara ta hanyar haɓaka a halayyar halayyar amsawa) yana haɗuwa da karuwa a karɓa ga miyagun ƙwayoyi (Wheeler et al., 2008). Sabili da haka, ta yin amfani da wannan mahimmanci, za mu tilasta maimaita cewa ƙuda da koli mai girma ΔFosB sun fi dacewa da dukiyar da ake amfani da ita na miyagun ƙwayoyi, kamar yadda aka nuna, amma kuma ya nuna sha'awar da ba'a samu ko janyewa. Wannan ba alama ba ne.

Ƙarin bayani game da sakamako mai zurfi a bayanan yanzu shine cewa kodayake girman da ΔFosB ya ƙaru sakamakon sakamako na hawan coca a cikin waɗannan ƙananan ƙwayoyi, haka kuma ya kara yawan kimar saccharin. Idan ΔFosB ta karu da cikakken sakamako na saccharin da cocaine, kamar yadda ka'idar Weber ta bayyana (watau mahimmanci ga sauyawar da muka yi a hankali ya dogara ne akan ƙarfin ƙarfin abubuwan da suka faru. ; Weber, 1846). Irin wannan karuwa a zumuncin CS ɗin zai iya rage bambancin zumunci tsakanin lada kuma ya rage sakamako na sakamako (Flaherty Rowan, 1986; Flaherty, Turovsky, & Krauss, 1994). Wannan fassarar ta kara tallafawa da wallafe-wallafen da ke nuna cewa tada girman ΔFosB yana ƙaruwa don amsawa ga sakamakon ladabi. Alal misali, anara tana gudana (Werme et al., 2002) da kuma dalili don abinci na abinci (Olausson et al., 2006) dukansu suna karuwa tare da hawan ΔFosB. Bugu da ƙari, bayanan da aka samu a gwajin 3 ya nuna cewa karuwar ΔFosB yana ƙaruwa don zabar sucrose (0.03 M, 0.1 M, da 0.3 M) da kuma ƙananan ƙananan na NaCl (0.01 da 0.1 M) a cikin gwajin kwalba biyu tare da ruwa.

Manufar wannan gwaji shine don kimanta sakamakon sakamako mai girma ΔFosB a cikin sakamako wanda aka kwatanta da shi, hanyar da ta yi la'akari da kwatancen ƙimar ƙwayar cuta ta hanyar ladabi ta 'yan adam (addicts)Grigson, 1997, 2000, 2002; Grigson & Twining, 2002; Grigson et al., 2008). Addini yana da siffar halayyar kirkira mai rikitarwa, kuma wasu dalilai da dama suna cikin cikin labarun hali na buri. Duk da haka, bisa ga wallafe-wallafe na yanzu, girman da ΔFosB ya haifarwa ta hanyar daukan lalacewa ga magungunan ƙwayoyi yana nuna rawar da ya taka wajen fahimtar sakamakon sakamako na miyagun kwayoyi (Colby et al., 2003; Kelz et al., 1999) da kuma ƙara karɓar amsawa ga sakamakon ladabi (Olausson et al., 2006; Werme et al. 2002). Wannan labarin ya nuna haske game da sakamakon ΔFosB a cikin hulɗar waɗannan sakamako. Yunƙurin ΔFosB ba ya bayyana wajibi ne don ƙaddamarwa da miyagun ƙwayoyi game da saccharin. A hakikanin gaskiya, sarrafa ƙwayoyi suna hana cin abinci na saccharin da kyau. Maimakon haka, bayanan mu na nuna cewa tarin girman ΔFosB a striatum na iya tsayayya da wannan abu ta hanyar rage bambancin ra'ayi tsakanin darajar ladabi tsakanin ladabi da magungunan zalunci. A yin haka, ƙwayar miki tare da wannan samfurin na iya zama mafi alhẽri daga kare shi daga miyagun ƙwayoyi lokacin da aka gabatar da kyakkyawan sakamako mai kyau. A goyan baya, samun dama ga saccharin yana da ƙwayar ƙwayar ƙwayar cuta don amsawa zuwa kwayar farko na morphine a cikin ratsan Sprague-Dawley (Grigson & Hajnal, 2007) da kuma taƙaitaccen damar yin amfani da shi a yau da kullum zuwa ga ratsi mai ladabi na 'yan ratsi' 'shirye-shiryen yin aiki don maganin cocaine a farkon saye'Twining, 2007) Saboda haka, kodayake hawan ΔFosB na iya raya ratsi da hauka zuwa halayen miyagun ƙwayoyi idan ba tare da wani sakamako ba, zai iya kare batun daga yanayin shan magani a gaban wata hanya mai mahimmanci madaidaicin halitta.

Acknowledgments

Wannan bincike ya goyan bayan taimakon Sashen Lafiya na Jama'a da DA09815 da DA024519 da kuma Asusun Kula da Taimako na Jihar PA 2006-07.

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