Ngwá Ọrụ Na-ahụ Maka Ọrịa na Ọgwụ Na-eme Omume na Ihe Ndị Na-emepụta Ngwá Ọrụ Na-emekarị Ihe na ΔFosB dịka Onye Mgbasa Ozi Dị Ukwuu (2013)

Ọmụmụ ihe a nyochare mmetụta nke ụgwọ ọrụ mmekọahụ na DeltaFosB na nsonaazụ DeltaFosB na omume mmekọahụ na ụgwọ ọrụ. Achọpụtara na mgbanwe mgbanwe molekụla a maara na-eme na ị addictionụ ọgwụ ọjọọ bụ otu ihe ahụ na-eme na mmekọahụ. N'ikwu ya n'ụzọ ọzọ, DeltaFosB ghọrọ usoro maka inwe mmekọahụ, mana ọgwụ na-apụnara otu usoro a. Nke a mechiri arụmụka ahụ banyere otu ị addicụ ọgwụ ọjọọ si dị iche na ị addicụ ọgwụ ọjọọ, na otú ị addicụ ọgwụ ọjọọ si bụrụ nanị mmanye (ihe ọ bụla ọ pụtara). Otu sekit, otu usoro, otu mgbanwe cellular, otu omume metụtara ya-na obere esemokwu.

J Neurosci. 2013 Feb 20;33(8):3434-3442.

Ntụziaka dị mma

Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM.

Source

Ngalaba Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Mahadum Western Ontario, London, Ontario N6A 3K7, Canada, Ngalaba Molecular & Integrative Physiology, Mahadum nke Michigan, Ann Arbor, Michigan 48109, Fishberg Ngalaba Neuroscience na Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, na Ngalaba nke Neurobiology na Anatomical Sciences na Physiology na Biophysics, Mahadum nke Mississippi Medical Center, Jackson, Mississippi 39216.

nkịtị

Iji ọgwụ ọjọọ eme ihe na-ebute neuroplasticity na ụzọ ugwo ugwo, n'ụzọ doro anya na oghere ahụ (NAc), si otú a na-eme ka mmepe na nkwupụta mmegbu ahụ. Ihe ngosi nke oge a na-enye echiche na ụgwọ ọrụ anụ ahụ nwere ike ime mgbanwe dị otú ahụ na NAc, na-atụ aro na ọgwụ ọjọọ nwere ike ịmegharị usoro nke plastik na-ekere òkè na ụgwọ ọrụ nkịtị, na ikwe ka ọhụụ dị iche n'etiti ọdịdị na ọgwụgwọ.

N'ọmụmụ ihe a, anyị na-egosi na ahụmahụ mmekọahụ na oke ụmụ nwoke ma ọ bụ ogologo oge nke ụgwọ ọrụ ego na-eme ka ụgwọ ọrụ amphetamine mepụtara, nke a na-egosi site na ọnọdụ dị ala maka 0.5 mg / kg amphetamine. Ọzọkwa, mmalite, ma ọ bụghị okwu ogologo oge, nke ụgwọ amphetamine mepere emezi jikọtara ya na mmụba na-aga n'ihu na nkwụsị dendritic na NAc. Ọzọ, arụ ọrụ dị oke mkpa maka ihe odide translators ΔFosB n'inweta mmekọahụ - mepụtara uru amphetamine mepụtara na mmụba ndị a na-ejikọta na ntinye nke dendritic na akara NDC guzobere site n'iji ọgwụ nje viral nyefee nke onye na-ejide onwe ya na-akwadoghị ya bụ ΔJunD. Ọzọkwa, e gosipụtara na ahụmahụ mmekọahụ na-ebute ụgwọ ọgwụ ọjọọ, ΔFosB, na spinogenesis na-adabere na activation dopamine D1 ntinye ọrụ na NAc. Mgbochi ọgwụ nke D1, ma ọ bụghị onye na-anabata D2, na NAc mgbe omume mmekọahụ dọrọ ΔFosB eleba anya ma gbochie spinogenesis dị ukwuu ma nweta ụgwọ ọrụ amphetamine.

TNchoputa a na-egosi na iji ọgwụ ọjọọ eme ihe na mmeghachi omume nke okike na-arụ ọrụ na ihe ndị na-eme ka ọgwụ ọjọọ bụrụ ihe na-adịghị mfe, nakwa na ọ bụ ΔFosB na mgbasa ozi ederede ya.

Okwu Mmalite

Ụkpụrụ nkwụghachi nke okike na ụgwọ ọgwụ ọjọọ na-agbakọta na ụzọ ntangọ nkịtị, usoro nchịkọta nke mesolimbic dopamine (DA), nke ụbụrụ ahụ na-ebute (NAc) na-arụ ọrụ dị mkpa (Kelley, 2004). Iji ọgwụ ọjọọ eme ihe na-ebute neuroplasticity na usoro mesolimbic, nke na-arụ ọrụ dị mkpa na ntụgharị site na ọgwụ ọjọọ iji ọgwụ ọjọọ eme ihe (Hyman et al., 2006; Kauer na Malenka, 2007; Kalivas, 2009; Chen et al., 2010; Koob na Volkow, 2010; Wolf, 2010a; Mamel na Luscher, 2011). E kwuwo na ọgwụ ọjọọ na ụgwọ ọrụ nkịtị anaghị eme ka otu ihe ahụ dị na usoro mesolimbic, ma si otú a na ọgwụ ọjọọ na-emegharị ma gbanwee circuit a. (Cameron na Carelli, 2012). Otú ọ dị, ọ na-aghọwanye nke doro anya na ụgwọ ọrụ nke anụ ahụ na ọgwụ ọjọọ na-emetụta usoro nke mesolimbic na ụzọ ndị dị iche na ụzọ dị iche iche nke na-enye ohere maka ịmekọrịta n'etiti ụgwọ ọrụ nkịtị, kpọmkwem ụgwọ ọrụ mmekọahụ, na mmetụta nke ọgwụ ọjọọ eme ihe (Frohmader et al., 2010a; Pitchers et al., 2010a; Olsen, 2011).

Mmekọahụ na-akwụ ụgwọ dị ukwuu (Tenk et al., 2009),

Nchọpụta ndị a na-egosi na ahụmahụ ọgwụgwọ anụ ahụ na ọgwụgwọ na-ejikọta usoro ndị nkịtị nke plasticity, nke nke a na-emetụta ọbịbịa nke iji ọgwụ ọjọọ eme ihe.

Ihe mgbaru ọsọ nke ọmụmụ ihe ugbu a bụ iji chọpụta ụdị usoro mgbasa ozi nke na-ekwusara mmekọrịta nwoke na nwanyị na-emetụta plasticity, nke na-eme ka ụgwọ ọgwụ ọjọọ mejupụtara. N'ụzọ doro anya, a na-enyocha ọrụ nke ihe odide translators ΔFosB n'ihi na ọ na-emetụta mmetụta nke ma nke ọma na ọgwụgwọ ọgwụ (Nestler et al., 2001; Werme et al., 2002; Olausson et al., 2006; Wallace et al., 2008; Hedges et al., 2009; Pitchers et al., 2010b). Tụkwasị na nke ahụ, a na-enyocha ọrụ nke dopamin D1 na-anabata (D1R) maka ahụmịhe mmekọahụ na-emetụta plasticity nke anụ ahụ n'ihi na Nc ΔFosB induction na mmụba spine nke ukwuu mgbe e gosipụtara ochichi psychostimulant na D1R-nwere neurons (Lee et al., 2006; Kim et al., 2009) na dabere na D1R mmalite (Zhang et al., 2002).

N'ebe a, anyị na-eji okwu mgbasa ozi nke nje ndị na-anaghị adịgide adịgide maka ΔFosB, labeling diOlistic, na manipulation nke ọgwụ na-eme ka nwalee echiche bụ na mmetụta ndị na-emetụta ndị ọzọ na-enwe mmetụta mmekọahụ na-esite na nkwụnye ụgwọ ụgwọ na nkwụghachi Amph a na-agbado D1R dabeere na ntinye nke ΔFosB na NAc na mmụba nke ụbụrụ NAc. Otu ihe, nchoputa na-enye ihe akaebe na ụgwọ ọrụ na ọgwụgwọ na-ejikọta usoro ndị nkịtị nke plasticity, na ΔFosB dịka onye ogbugbo dị egwu.

Akụrụngwa na ụzọ

Ụmụ anụmanụ.

Di na okenye (225-250 g on arrival) na nwanyị (210-220 g) Sprague Dawley rata (Charles River Laboratories) nọ na Plexiglas cages n'otu ụzọ abụọ nwoke na nwanyị, n'oge okpomọkụ na iru mmiri na 12 / 12 h Mmiri / ọchịchịrị gbara na nri na mmiri n'enweghị ihe ọ bụla. A na - azụ ụmụ nwanyị ndị na - ahụ maka mmekọ ahụ na ntanye na natara nkwụnye anụ ndị nwere 5% estradiol benzoate (Sigma-Aldrich) na injections nke 500 μg nke progesterone (na 0.1 ml nke mmanụ samema) Sigma-Aldrich) 4 h tupu ule. Usoro nhazi nile kwadoro usoro niile nke Ụlọ Akwụkwọ Mahadum Western Ontario na Mahadum Michigan ma soro Kansụl Kanada maka Nlekọta Ụmụ anụmanụ na National Institute of Health na-agụnye ụmụ anụmanụ na-eme nchọpụta.

Mmekọahụ.

Oge mmemme mere n'oge mbido oge (n'etiti 2 na 6 h mgbe mmalite nke oge gbara ọchịchịrị) n'okpuru nhie ọkụ na-acha ọbara ọbara, na ule nyocha dị ọcha (60 × 45 × 50 cm). Ụmụ oke ụmụ nwoke na-ejikọta na ejaculation n'oge 4 ma ọ bụ 5 kwa ụbọchị. A họọrọ oge ise n'ihi na anyị egosiwo na mbụ na ihe a na - eme ka ọ bụrụ na ị na -Pitchers et al., 2010b), ntụgharị uche na-eme ka ọrụ Amph locomotor (Pitchers et al., 2010a), na ụgwọ ọrụ (Pitchers et al., 2010a). A họọrọ nnwere onwe dị ka njedebe nke oge ọ bụla mwepụtara n'ihi na anyị gosiri na mbụ na ọ dị mkpa maka mmetụta nke inwe mmekọahụ na Amph locomotor sensitization (Pitchers et al., 2010a), nke na-emeghị mgbe a na-ahapụ ụmụ anụmanụ ka ha na ndị nwanyị nwee mmekọ na-enweghị ngosi nke ejaculation. Mmekọahụ na-enwe mmekọahụ (ya bụ, mgbaghara n'ugwu mbụ, intromission na ejaculation, na ọnụ ọgụgụ nke ndọda na mberede) e dekọrọ dị ka akọwapụtara na mbụ (Pitchers et al., 2010b). Maka nnwale niile, ndị otu nwoke na nwanyị nwere mmekọahụ na-ejikọta maka omume nwoke na nwanyị (ọnụ ọgụgụ niile nke ejaculations na njigide na ejaculation n'oge ọ bụla na-emekọ ntụrụndụ). Mgbe oge nke ise gasịrị, ụmụ nwoke nọ na-enwe otu nwoke ma ọ bụ nwanyị ibe ha ma ghara ikwe ka ha lụọ n'oge oge abstinence mmekọahụ nke 1, 7, ma ọ bụ 28 d. A na-elekọta ụmụ anụmanụ nọgidere na-enwe mmekọahụ rụrụ arụ ma nọrọ n'otu ọnụ ụlọ dị ka ụmụ nwoke nwere mmekọahụ. Tụkwasị na nke ahụ, a na-etinye nchịkwa dị nro n'igwe nyocha dị ọcha maka otu awa n'oge 5 ụbọchị ndị na-esoghị, na-enweghị ohere maka nwanyi na-anabata ya.

Okwu ΔFosB.

Ụmụ anụmanụ na - ejikarị anesthetized (sodium pentobarbital; 390 mg / kg; ip) na 50 ml nke 0.9% saline, tinyere 500 ml nke 4% paraformaldehyde (Sigma-Aldrich) na 0.1 m phosphate buffer (PB) maka oge ahụ isi na DR na-enyocha ya. E wepụrụ ụbụrụ na postfixed maka 1 h na ọnụ ụlọ okpomọkụ n'otu ihe ahụ, wee debe ya na 4 Celsius C na 20% sucrose na 0.01% sodium azide na 0.1 m PB. Maka nchọpụta DR na-eme, e wepụrụ ụbụrụ ma wepụ ya n'akụkụ oghere ahụ. E debere ọkara n'ime PB ma jiri ya maka DiOlistics, ma edozie nke ọzọ maka ΔFosB. Ejila microtome na-egbuke egbuke (35 μm) na microtome na-egbuke egbuke (Microm H400R), nke anakọtara na usoro anọ yiri otu na solution cryoprotectant (30% sucrose na 30% ethylene glycol na 0.1 m PB) na echekwara na -20 Celsius C. Achachasịrị akụkụ ndị na-ese n'elu mmiri na 0.1 m PBS, pH 7.35, n'etiti incubations, na nzọụkwụ niile nọ na okpomọkụ. E gosipụtara akụkụ nke 1% H2O2 (10 min) na nghazi ngwakọta (1 h; PBS nwere 0.1% BSA, Fisher; na 0.4% Triton X-100, Sigma-Aldrich). Mgbe ahụ, a na-emegharị akụkụ ahụ na pan-FosB rabbit polyclonal antibody (1: 5K; sc-48 Santa Cruz Biotechnology), nke a kwadoro na mbụ (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). A na-ebilite onye na-eme ihe pan-FosB megide mpaghara dị n'ime nke FosB na ΔFosB kekọrịta, na e gosipụtaburu ya iji lee anya sel ΔFosB na oge ejiri mee ihe na nyocha a (> 1 d mgbe ihe mkpali) (Perrotti et al., 2004, 2008; Pitchers et al., 2010b). Na - esote, a na - etinye ọkụ na IgG (1 h; 1: 500 na PBS +; Laboratories Vector), avidin-biotin-horseradish peroxidase (1 h; ABC elite; 1: 1000 na PBS; Laboratories Vector) , na 0.02% 3,3'-diaminobenzidine tetrahydrochloride (10 min; Sigma-Aldrich) na 0.02% nickel sulfate na 0.1 na PB na hydrogen peroxide (0.015%). E tinyere ihe ndị ahụ n'elu Superfrost tinyere ihe ngosi iko (Fisher) ma kpuchie xtthalate dibutyl phthalate.

Ọnụ ọgụgụ nke mkpụrụ ndụ ΔFosB-IR bụ gọọmenti NAc na isi n'ime usoro ntụle nke nyocha (400 × 600 μm) dị ka akọwapụtara n'oge gara aga (Pitchers et al., 2010b). A gụrụ akụkụ abụọ maka nchịkwa NAc, ọnụọgụgụ nke anụmanụ. N'ime oge nyocha, ọnụ ọgụgụ nke mkpụrụ ndụ ΔFosB-IR gosipụtara dị ka mgbanwe ngbanwe nke ìgwè nchịkwa ndị na-adịghị mma n'oge oge kwesịrị ekwesị ma jiri ya tụnyere n'etiti ìgwè ndị nwere ahụmahụ na ndị na-amaghị ihe maka mpaghara mpaghara ọ bụla na oge ọ bụla site n'iji unpaired t nyocha na ọkwa dị mkpa nke p <0.05. N'ime nnwale nke ΔJunD-AAV na DR, ụzọ abụọ ma ọ bụ otu ụzọ ANOVA, na usoro Holm-Sidak. Tụkwasị na nke ahụ, a gụrụ mkpụrụ ndụ ΔFosB-IR na dorsal striatum (mpaghara nyocha: 200 × 600 μm), na-aga ozugbo na NAc na n'akụkụ akụkụ ventral, na ụmụ anụmanụ niile nọ na nnwale DR antagonist. One-way ANOVA na t a na-eji nyocha iji tụnyere ndị otu.

DiOlistics.

Maka oge na ΔJunD na-achọpụta nje virus, a na-esi na 50 ml saline (0.9%) na-esi na 500% kwadoro ya, na 2 ml nke 0.1% paraformaldehyde na 100 m PB. A na-eji eriri akpụkpọ anụ (0.1 μm coronal) jiri vibratome (Microm) na ngalaba echekwara na 0.01 m PB na 4% sodium azide na 1.3 ° C. Ihe nkedo tungsten (1,1 μm dayameta, Bio-Rad) na lipophilic carbocyanine dye DiI (3,3,3'-dioctadecyl-3'XNUMX'-tetramethylindocarbocyanine perchlorate; Invitrogen) mere dika edere na mbu (Forlano na Woolley, 2010). A na-esi na 160-180 psi wepụta ihe ndị dị na DiN na-eji Helios Gene Gun system (Bio-Rad) site na nza na 3.0 μm pore size (BD Biosciences) ma kwe ka ọ na-agbasa site na membranes neuronal na 0.1 m PB maka 24 h mgbe nchekwa na 4 Celsius C. Na - esote, a na - etinye mkpụrụ osisi na 4% paraformaldehyde na PB maka 3 h na ọnụ ụlọ okpomọkụ, saa na PB, ma tinyekwa ya n'ime ụlọ ndị e kpuchiri etiti (Bio-Rad) na gelvatol nwere 1,4-diazabicyclo (2,2) octane ( 50 mg / ml, Sigma-Aldrich) (Lennette, 1978).

A na-eji ejiji na-akpọ Diu na-eji Zeiss LSM 510 m microscope confocal (Carl Zeiss) na helium / neon 543 nm laser. Maka anụmanụ ọ bụla, 2-5 neurons na mpaghara NC ọ bụla, ma ọ bụ n'ime shea (dabere na ọnọdụ dịka akara aka, gụnyere ngọngọ ventricle na ngosipụta ihu igwe) na ΔJunD-AAV na nchọpụta nke anwale nke DR, ejiri iji chọta mpaghara nke mmasị na nke abụọ iji dendrite maka ịkọpụta ihe. Maka onye ọ bụla neuron, a na-enyocha ndị Dendrite 2-4 iji tụọ 40-100 μm n'ogo dendritic ogologo. E weghaara ngalaba Dendritic site na iji 40 × ebumnuche mmiri-emikpu na 0.25 μm n'etiti oge z-axis, ma mechie ihe ngosi 3D (Zeiss) ma jiri deconvolution (Ndagharị X, Media Cybernetics) na-eji ntinye aka (ndị ìsì) na nkwupụta PSF dịka ọkachamara kwadoro. Ejila njupụta spine mee ihe site n'iji ngwugwu Filament nke Imaris software software (mbipụta 7.0, Bitplane). Ọnụ ọgụgụ nke mkpụrụ osisi dendritic ka e gosipụtara site na 10 μm, ọhụụ nke ọ bụla na-ahụ maka anụ ahụ ọ bụla. E kpebiri esemokwu nchịkọta akụkọ site na iji ANOVA ụzọ abụọ na-eme nchọpụta usoro oge n'etiti ụmụ anụmanụ na ụmụ anụmanụ nwere ahụmahụ n'oge ọ bụla (ihe kpatara: ahụmahụ mmekọahụ na subregion NAc) nakwa na nnwale ΔJunD (ihe: ahụmahụ mmekọahụ na vela viral), na otu - ANOVA na nchọpụta nke antagonist DR. A na-atụnyere otu ụzọ na ụzọ Holm-Sidak si dị mkpa p <0.05.

Nhọrọ ebe a chọrọ.

Usoro nyocha nke CPP bụ otu ihe dịka akọwapụtara n'oge gara aga (Pitchers et al., 2010a), na-eji ngwaọrụ atọ na-enweghị mmasị na (Med Associates), na-enweghị atụ, na-enwe otu ugwo ikpe na-adabere na d-Amph sulfate (Amph; Sigma-Aldrich; 0.5 mg / ml / kg sc na-agbakwasị ụkwụ na isi ala) ke okpukpu abụọ na saline na ụlọ a na-akwụghị ụgwọ n'oge ụbọchị ọzọ, ma rụọ ọrụ n'oge ọkara nke ọhụụ. Ụmụ anụmanụ na-achịkwa natara saline n'ime ụlọ abụọ ahụ.

A na-agụta ọtụtụ CPP maka anụmanụ ọ bụla dị ka oge eji (na sekọnd) n'ime ụlọ a jikọtara ọnụ mgbe a na-anwale ule na-emeghị ka pretest. Otu ANOVAs na ụzọ Holm-Sidak na-eji ya atụnyere ìgwè dị iche iche na oge nyocha. Enpaired t ule na ihe dị mkpa na p Ejiri 0.05 tụnyere Naive-Sal na Naive Amph n'ime oge ọ bụla oge na nyocha oge, yana n'ime ọgwụgwọ ọgwụgwọ ọrịa ọ bụla na nnwale ΔJunD. Na nnwale oge, ejiri otu ụzọ ANOVAs na usoro Holm – Sidak iji tụnyere otu ndị nwere mmekọrịta nwoke na nwanyị (Exp-Sal, 7 d Exp Amph na 28 d Exp Amph), na enweghị akwụ ụgwọ t E jiri ule mee ihe iji tụnyere otu ìgwè 2. Eji ụzọ ANOVA na ụzọ Holm-Sidak mee ihe iji tụnyere ndị niile nọ na nchọpụta nke antagonist DR. Abụọ ndị a na-akwụ ụgwọ t a na-eji nyocha nke Naive-Sal na Naive Amph dị iche iche na ọnọdụ ọgwụgwọ ọhụụ nke ọ bụla (GFP ma ọ bụ ΔJunD), ebe data dị oke mgbanwe na ìgwè ΔJunD ka o kwe ka nyocha ANOVA. Ejiri ọkwa dị mkpa p <0.05.

Nchọpụta veranda nke Viral.

A na-ejiri ketamine (87 mg / ml / kg; ip) na xylazine (13 mg / ml / kg ip), tinye ya n'ime ihe ndị dị na Kopf, ma nata microinjections nke ndị ọzọ na-ejikọta adeno na-agbanwe agbanwe. GFP naanị (protein fluorescent green), ma ọ bụ ΔJunD (onye kachasị mma na-ejikọta ibe ya nke ΔFosB) na GFP, n'ime NAc (nchịkọta: AP + 1.5, ML ± 1.2 si bregma, DV -7.6 si okpokoro isi), na olu nke 1.5 μl / gburugburu ebe 7 min na-eji eriri Hamilton (Harvard Apratus). ΔJunD na-ebelata nsụgharị nke ΔFosB site na ịsọpụrụ heterodimerizing na ΔFosB ma si otú a gbochie njigide nke ΔFosB ka mpaghara AP-1 n'ime mpaghara nkwalite nke mkpụrụ ndụ ihe nketa (Winstanley et al., 2007; Pitchers et al., 2010b). Ọ bụ ezie na ΔJunD na-ejikọta ịdị elu na ΔFosB, ọ ga-ekwe omume na ụfọdụ n'ime ihe ndị a chọpụtara site na ΔJunD nwere ike ịgbasa site n'itinye ndị na-edozi AP-1 ndị ọzọ aka. Otú ọ dị, o yiri ka ΔFosB bụ protin AP-1 kachasị na-egosipụta n'okpuru ọnọdụ a nwalere (Pitchers et al., 2010b). N'etiti n'agbata 3 na 4 izu ole na ole, ụmụ anụmanụ natara ahụmahụ mmekọahụ n'oge 4 na-esote ntụrụndụ ma ọ bụ nọgidere na-edozi iji mepụta òtù 4: GFP na-enwe mmekọahụ, GFP nwere mmekọahụ, akpaghị anya ΔJunD, na ahụmahụ ΔJunD. Mmekọahụ na-agụnye nsonye 4 kwa ụbọchị. A nwalere anụmanụ maka CPP na diOlistics. Emere nkwenye nke saịtị ịgba ọgwụ dị ka akọwapụtara na mbụ (Pitchers et al., 2010b). A na-edozi akụkụ ndị na-achịkwa (CCNUMX μm) maka GFP (100: 1, antibody GFP antibody; Invitrogen). Ọfụma na-agbasa kpamkpam na akụkụ ahụ nke NAC, na-agbakwunye na-agbasa.

D1R / D2R antagonists.

A na-ejide ụmụ irighiri ihe ndị na-ejiri intraperitoneal (0.1 ml / kg) nke ketamine (87 mg / ml) na xylazine (13 mg / ml), ma tinye ya n'ime ngwá ọrụ kopf. A na-eme ka nchịkwa 21 na-eduzi ndị mmadụ abụọ (Plastics One) dị na NAc na AP + 1.7, ML ± 1.2 si na bregma; -6.4 DV site na okpokoro isi ma chekwaa ya na eze anwụrụ, na-etinye aka na nkedo atọ esiri na okpokoro isi. A na-edozi ụmụ anụmanụ kwa ụbọchị ka ha wee nwee ike ịbanye na usoro infusion n'oge oge mgbake izu 2. Nkeji iri na ise tupu mmalite nke ọ bụla nke 4 kwa ụbọchị site na ịmebata ụmụ nwanyị na-anabata ihe, ụmụ nwoke na-anata microinjections nke D1R antagonist R (+) SCH-23390 hydrochloride (Sigma-Aldrich), onye na-anabata D2 (D2R) onye na- -) eticlopride hydrochloride (Sigma-Aldrich) gbasaa n'ime saline saline (0.9%, nke ọ bụla na 10 μg na 1 μl site na mkpịsị uhie, gbasasịrị na 0.9% saline), ma ọ bụ saline (1.0 μl per hemisphere), na ọnụego 1.0 μl / min n'elu oge minit 1 wee soro 1 min na-ejikọta eriri ogwu ahụ maka ebe a na-ekesa ọgwụ. Olu nke ọgwụ a ga-enye ma isi ma shea, dịka ihe ntanyere nke 0.5 μl na-ejikarị shea ma ọ bụ isi ike (Laviolette et al., 2008). Ntugharị ndị ahụ dabeere na nchọpụta ndị gara aga na-egosi na ndị a ma ọ bụ ndị dị ala na-emetụta ọgwụ ọjọọ ma ọ bụ ụgwọ ọrụ nke anụ ahụ (Laviolette et al., 2008; Roberts et al., 2012). Ndị ikom na-achịkwa ndị ikom nọgidere na-enwe mmekọahụ na-abaghị uru kama natara salite NAC na ntinye tupu ha etinye aka na ntinye ule efu, n'oge 4 kwa ụbọchị. Otu izu mgbe emechara ntụrụndụ ma ọ bụ njedebe ikpeazụ, a nwalere ụmụ nwoke maka Amph CPP, na spine na nchọpụta ΔFosB. A na-ahọrọ iji nnọkọ anọ, karịa sessions ise dị ka ndị ọzọ na-enyocha, iji kpochapụ ihe dị ukwuu nke NAC kpatara site na nkwụsịghachi ugboro ugboro ma si otú a nye ohere maka nchapụta na nchọpụta ΔFosB. N'ezie, mmebi ahụ apụtaghị ìhè, nyochaa nke spine na ΔFosB na NAc nke ụmụ anụmanụ na-azụ saline gosipụtara data yiri nke ahụ dịka ndị na-abụghị ndị na-esite na nchịkọta ndị gara aga. Ụzọ ANOVA na Holm-Sidak ụzọ abụọ dị mkpa p <Ejiri 0.05 iji chọpụta mmekorita nwoke na nwanyị na-enwe mmekorita nke mmekọahụ.

Results

Mmekọahụ enwere ike ịmalite ΔFosB upregulation dị ogologo

Nke mbụ, a na-edozi mmekọrịta dị n'etiti nwoke na nwanyị na-enwe mgbanwe n'ime okwu ΔFosB, ederede dendritic na NAc, na Amph-CPP, kpọmkwem mgbe oge dị mkpirikpi na ogologo oge abstinence si ụgwọ ọrụ mmekọahụ (7 ma ọ bụ 28 d). Na mbụ, e gosipụtara na ahụmahụ mmekọahụ nke usoro 5 kwa ụbọchị na-eme ka otu ΔFosB gbasaa n'usoro usoro mesolimbic, dịka NAC (Wallace et al., 2008; Pitchers et al., 2010b). N'ime nnyocha ndị gara aga, a tụrụ ụta ΔFosB n'ime 1 d mgbe enwere mmekọahụ, ọ dịghị ama ma mmelite ΔFosB nọgidere na-adịgide mgbe ogologo oge ị ga-enweta ụgwọ ọrụ abstinence. Ụmụ nwoke na-enwe mmekọahụ na-ejikarị 1, 7, ma ọ bụ 28 d mgbe njedebe nke 5 kwa ụbọchị na-agakọ, mgbe ndị nwoke na-etinyere otu ejaculation. A na-eme ka ndị na-eme ihe na-adịghị mma na-enwe mmekọahụ na-esite n'otu oge mgbe ikpeazụ nke 5 na-emezi oge. Ọnụ ọgụgụ nke mkpụrụ ndụ ΔFosB-IR na kọlụm NAc na isi dị elu karia nchịkwa nwoke na nwanyị na-enwekarị mmekọahụ na mgbe niile (Fig. 1A, shea; 1 d, p = 0.022; 7 d, p = 0.015; Fig. 1B: isi; 1 d, p = 0.024; 7 d, p <0.001; 28 d, p <0.001), belụsọ na NAc sheka mgbe 28 d abstinence (p = 0.280). Ya mere, nchịkwa nke ΔFosB na-adịgide mgbe ọ na-abstinence mgbe ahụmahụ mmekọahụ maka oge ọ dịkarịa ala 28 d.

Nyocha 1.      

Lelee nsụgharị buru ibu:      

Nyocha 1.      

Ahụmahụ mmekọahụ na-eme ka ọnụ ọgụgụ dị nta nke mkpụrụ ndụ ΔFosB-IR na-arịwanye elu n'oge na-aga n'ihu. Mgbanwe ngbanwe nke ọnụ ọgụgụ mkpụrụ ndụ ΔFosB-IR na akpụkpọ NAc (A) na isi (B) na ụmụ anụmanụ na-enwe mmekọahụ (ụmụ) ma e jiri ya tụnyere njikwa na-acha ọcha (ndị ọcha)n = 4 kwa otu). Data bu otu bu ± SEM. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa aghụghọ. Nnochite anya ihe oyiyi nke Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), na Exp 28 d (F). ac, Akara mma. Ogwe mmanya, 100 μm.

Mmekọahụ nke nwere mmụba na-enwe mmụba na spendendic spines bụ transient

Pitchers et al. (2010a) ekwuputala na-eji usoro gọọmenti golgi na-eme ka ahụmahụ 7 d, ma ọ bụghị 1 d, nke nkwụnye ụgwọ abstinence mere ka ụba bendritic branching na ọnụ ọgụgụ nke dendritic spines na NAc shell and core neurons (Pitchers et al., 2010a). N'ebe a, spinogenesis na ụmụ nwoke na-amaghị nwoke na ụmụ nwoke nwere ahụmahụ na-enyocha ma ọ bụ 7 d ma ọ bụ 28 d mgbe oge mgbakọ ikpeazụ. Nchọpụta ndị dị ugbu a site na iji usoro labeling diOlistics kwenyere na ahụmahụ mmekọahụ na-esote oge 7 dast abstinence oge mụbara ọnụọgụ nke mkpụrụ osisi dendritic (F(1,8) = 9.616, p = 0.015; Fig. 2A-C). N'ụzọ doro anya, ọnụọgụ nke mkpụrụ osisi dendritic dị na ụba nke ukwuu na kọlụm NAc na isi (Fig. 2A: shei, p = 0.011; isi, p = 0.044). Otú ọ dị, mmụba a na-agbanye n'ọkpụkpụ a na-agafe agafe, ọ dịghịkwa achọpụta mgbe a na-enwe oge abstinence nke 28 d na ma na mpaghara NAc (Fig. 2B).

Nyocha 2.      

Lelee nsụgharị buru ibu:      

Nyocha 2.     

Ahụmahụ mmekọahụ na-eme ka ọnụ ọgụgụ nke nrịba dendritic na-arịwanye elu na NAc ma matapụta ụgwọ ọrụ Amph. A, B, Ọnụ ọgụgụ nke dendritic spines na NAc shell na isi nke 7 d (A) ma ọ bụ 28 d (DB nke na-acha ọcha na-enwe mmekọahụ na anụ ọhịa [ụmụ]; n = 4 ma ọ bụ 5). Data bu otu bu ± SEM. #p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa aghụghọ. C, Ngalaba Dendritic na-anọchite anya ndị si na 7 d na Exp 7 d otu dị iche iche na-ejikọta ịdị na-ese spine. Ogwe mmanya, 3 μm. D, Ogologo oge a nọrọ n'ime ụlọ abụọ (Amph ma ọ bụ saline) n'oge ule nyocha a na-eme ka pretest (CPP score) maka ụmụ nwoke na-acha ọcha (ndị ọcha) ma ọ bụ ụmụ anụmanụ (anụ ọhịa) a nwalere ma ọ bụ 7 d ma ọ bụ 28 d mgbe emesịrị maọbụ nhazi oge: Nri-Sal (7 d mgbe ejizi; n = 8), Naive Amph (7 d mgbe ejizi; n = 9), Na-eme njem (gụnyere otu anụmanụ nke anwale ma ọ bụ 7 d ma ọ bụ 28 d mgbe nwatakịrị; n = 7), 7 d Exp Amph (7 d mgbe mating; n = 9), na 28 d Exp Amph (28 d mgbe mating; n = 11). Sal ndị otu natara Sal abụọ na ụlọ abụọ ahụ. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa nnu saline nwere mmekọahụ.

Mmekọahụ enwere ike ịmalite ịmalite ụgwọ ọrụ ụgwọ ọrụ ugo dị ogologo

Anyị gosipụtarala na ahụmahụ mmekọahụ na-esote 7-10 d nke abstinence rụpụtara uru Amph (Pitchers et al., 2010a). N'ụzọ doro anya, ụmụ anụmanụ na-ahụ maka mmekọahụ na-emepụta ohere dị mma (CPP) maka obere Amph (0.5 ma ọ bụ 1.0 mg / kg) nke na-adịghị emetụta CPP na njikwa ejidere mmekọahụ. Ọmụmụ ihe ugbu a kwadoro ma gosipụta ihe ndị a gara aga site na igosipụta mmụba Amph ụgwọ na ụmụ anụmanụ nwere mmekọahụ ma mgbe 7 d yana 28 d mmekọahụ abstinence oge (Fig. 2D; F(2,24) = 4.971, p = 0.016). N'ụzọ doro anya, ụmụ anụmanụ na-enwe mmekọahụ nwere ma ọ bụ 7 ma ọ bụ 28 d abstinence oge jiri nnọọ oge ka ukwuu na ụlọ Amph-paired n'oge ule nyocha ma e jiri ya tụnyere ndị na-ahụmahụ ọjọọ njikwa na natara Saline na ụlọ abụọ (Fig. 2D: Na-enyere anyị aka 7 d Exp AMPH, p = 0.032; vs 28 d Exp AMPH, p = 0.021). N'igosiputa nchọpụta gara aga, ụmụ anụmanụ na-adịghị mma na-enwe mmekọahụ na-etinyeghị oge karịa na ụlọ Amph-paired mgbe a na-enyocha ha, ha adịghịkwa iche na mmasị site na otu nchịkwa saline nke na-enwe mmekọahụ (Fig. 2D) (Pitchers et al., 2010a).

Ọrụ "FosB" dị oke egwu maka inwe mmekọahụ na-eme ka a ghọta ihe nrite

Nsonaazụ ya gosipụtara na ahụmahụ mmekọahụ na-eme ka ụba na-adịte aka nke Î "FosB na mkpụrụ ndụ NAc jikọtara ya na ụgwọ ọrụ Amph. Iji chọpụta ma ibuwanye ọrụ "FosB" dị oke egwu maka ụgwọ ọrụ Amph, "JunD, onye na-ejide onwe ya nke kachasị mma nke" FosB "nke na-ehichapụ" Nkọwapụta FosB "Winstanley et al., 2007), e gosipụtara ya site na ntinye mkpụrụ ndụ nke nje na-echekwa na NAc (Fig. 3A,B). Nsonaazụ nke nyocha Amph CPP gosiri na nkwụsịtụ nke "Ọrụ FosB site n'igosipụta Î" JunD na NAc gbochiri mmetụta nke ahụmahụ mmekọahụ na 7 d sex reward abstinence na mmelite ụgwọ. Mmekọahụ ahụmahụ "JunD ụmụ anụmanụ anaghị etolite a ịrịba CPP maka Amph na adịghị iche na mmekọahụ naive" JunD anụmanụ (Fig. 3B). N'adịghị iche, GFP nwere mmekọahụ na-achịkwa ụmụ anụmanụ guzobere CPP maka Amph dị ka egosiputa ọkwa CPP dị oke njọ ma e jiri ya tụnyere njikwa GFP gbasara mmekọahụ.Fig. 3B, p = 0.018).

Nyocha 3.     

Lelee nsụgharị buru ibu:     

Nyocha 3.     

Icheta Î "Ọrụ FosB na NAC egbochilarị ụgwọ ọrụ AMPH ma mụbaa ọnụ ọgụgụ ndị NAc na-agba na anụmanụ ndị nwere mmekọahụ. A, Ihe nnọchiteanya nke GFP okwu na ụmụ anụmanụ atọ na-enweta ọgwụ ogwu na-ejikarị adeno-adọrọ na-ejikarị adeno-Î "JunD eduzi na nucleus accumbens, na-egosipụta obere (aka ekpe), n'etiti (n'etiti), na nnukwu (aka nri) saịtị ogwu. ac; LV, mpụta ventricle. Ogwe mmanya, 250 μm. B, Ihe atụ nke atụmatụ kachasị ama na usoro nke mgbasa nke nje. N'ime anụmanụ niile, a hụrụ GFP na shea, ma gbasaa na isi ya gbanwere. C, Ogologo oge ejirila na-arụ ọrụ na-eme ka ndị na-eme ka a na-eme ka a na-eme ka ha ghara ịchọta GFP control vector (Naive, n = 9; Na-akọwa, n = 10) ma ọ bụ "JunD vector" (Naive, n = 9; Na-akọwa, n = 9). D, Ihe nnọchiteanya ndị nnọchiteanya nke akụkụ dendritic sitere na GFP na Î "JunD" na-enwe mmekọahụ ka ha na-atụle njupụta spine. Ogwe mmanya, 3 μm. E, Ọnụ ọgụgụ nke dendritic na-akụ na NAc nke ụmụ nwanyị na-adịghị ọcha (na-acha ọcha) na ụmụ anụmanụ nwere ahụmahụ (nwa) nke na-anata ọgwụ GFP akara vector ma ọ bụ "JunD vector. Data na-akpalite otu  ± SEM. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa aghụghọ. #p <0.05, ọdịiche dị ịrịba ama sitere na GFP nwere njikwa njikwa.

Mmetụta ndị na-emetụtaghị ihe ndị na-emepụta na JunD overexpression abụghị n'ihi mmetọ nke omume mmekọahụ mgbe ị nwetara ahụmahụ mmekọahụ. E gosipụtara nkwupụta nke "JunD na NAc" na mbụ iji gbochie mmemme nke omume mmekọahụ mgbe ahụmahụ mmekọahụ (Pitchers et al., 2010b). N'ezie, a gosipụtara nke a na nnwale ahụ ugbu a. GFP na-achịkwa ụmụ anụmanụ gosipụtara ụkọ nta karịa ugwu, intromission, na ejaculation, na nkwụsịtụ ole na ole na njedebe n'oge nke anọ nke na-esote ule ntanye, ma e jiri ya tụnyere ụbọchị mbụ nke mating (Isiokwu 1). N'aka nke ozo, umu mmadu umu mmadu n'ime umu mmadu adighi adighi gosiputa umuaka umuaka di elu karia elu ma obu mgbochi ma obu n 'onu ogugu nke ubochi nke ubochi nke ugbo ma o bu nke mbu. N'ihi ya, "JunD na-emetụta n'ime NAc ahụ na-emetụta mmetụta nke ahụmahụ mmekọahụ. Otú ọ dị, enweghi ọdịiche dịgasị iche na nke ọ bụla n'ime njikwa alụlụlụ n'etiti njikwa GFP na "JunD-infused groups during any of the test mating, na-egosi na mmetụta nke Î" JunD infusions na ahụmahụ mmekọahụ-induced sensitization nke Amph CPP abụghị n'ihi nsogbu dị iche iche na ahụmahụ mating kwa se (Isiokwu 1).

Lelee okpokoro a:      

Ntọala 1.     

Na njedebe nke omume mmekọahụ mgbe ị na-enweta ahụmahụ mmekọahụ na ìgwè dị iche iche nke natara akara NAc nke GFP- ma ọ bụ "JunD-na-egosipụta vectors viral vectorsa

Î "FosB dị oké mkpa maka mmụba nke mmekọahụ na-ebuli elu na nchịkwa Dendritic NAc

A na-achọkwa ọrụ FosB maka mmụba nrịba nke azụ nke mkpụrụ ndụ NAc mgbe enwere mmekọahụ na 7 d sex reward abstinence (Fig. 3C,D). Maka nyocha nke ihe nkedo na NAc nke ụmụ anụmanụ ndị a kọwara n'elu maka CPP, ụzọ abụọ ANOVA gosipụtara mmetụta dị ịrịba ama nke ahụmahụ mmekọahụ (F(1,34) = 31.768, p <0.001) na ịgwọ ọrịa ọgwụgwọ ọrịa (F(1,34) = 14.969, p = 0.001), yana mmekọrịta (F(1,34) = 10.651, p = 0.005). N'ụzọ doro anya, GFP inwe mmekọahụ na-achịkwa ụmụ anụmanụ nwere ọnụ ọgụgụ ka ukwuu nke ọkpụkpụ NAc ma e jiri ya tụnyere njikwa GFP na-enwe mmekọahụ rụrụ arụ (Fig. 3D: p <0.001), na-akwado nyocha anyị gara aga (Pitchers et al., 2010a). N'adịghị iche, ụmụ nwanyị JunD enweghi mmekọahụ dị iche iche dị iche iche na ìgwè ndị JunD, ma dị ntakịrị karị ma e jiri ya tụnyere GFP nwere mmekọahụ na-achịkwa ụmụ anụmanụ (Fig. 3D: p <0.001). Ya mere, okwu ΔJunD na NAc gbochiri mmetụta nke inwe mmekọahụ na ịkwụ ụgwọ abstinence na NAc spinogenesis.

D1R antagonist blocks sex experience-induced Î "FosB upregulation

Iji chọpụta ma ọ bụ D1R ma ọ bụ D2R ịmalite na NAc n'oge aging chọrọ maka inwe mmekọahụ na-emetụta Î "FosB upregulation ma ghọta Amph CPP, ụmụ anụmanụ natara mmerụ mpaghara nke ma ọ bụ D1R ma ọ bụ D2R antagonist (ma ọ bụ saline) n'ime NAc 15 min tupu onye ọbụla nke 4 kwa ụbọchị. N'ụzọ dị oke mkpa, ọ bụghị D1R ma ọ bụ D2R onye na-emegide ya na-abanye n'ime ntinye nke NAc ma ọ bụ igosipụta omume mmekọahụ n'oge ọ bụla nke oge mmekọ ahụ (Fig. 4N 'F). N'otu aka ahụ, DTNUMXR ma ọ bụ D1R antagonism adịghị egbochi mmetụta mmemme nke ahụmahụ mmekọahụ na mmekorita, dịka otu dị iche iche gosipụtara mmemme nke mmekorita nwoke, nke egosiri na umuaka ejaculation mkpirikpi n '4 nke oge a tụnyere 1 XNUMX (Fig. 4F) (F(1,40) = 37.113, p <0.001; Sal, p = 0.004; D1R Ant, p = 0.007; D2R Ant, p <0.001).

Nyocha 4.     

Lelee nsụgharị buru ibu:     

Nyocha 4.     

Onye na-anabata ọrịa nke Dopamine na-etinye n'ime NAc emetụtaghị mmekọahụ. Coronal NAc ngalaba (A, + 2.2; B, + 1.7; C, + 1.2 si bregma) na-egosi saịtị intra-NAc maka ụmụ anụmanụ niile. Ndị na-akpọ Cannula bụ ndị na-emekọrịta ihe ma ha na-anọchite anya ya iji mee ka ụmụ anụmanụ niile nwee ike ịdị na-ahụ (Naive-Sal, white, n = 7; Na-enye Saline; ọchịchịrị gbara ọchịchịrị, n = 9; Jiri D1R Ant, isi awọ, n = 9; Jiri D2R Ant, nwa, n = 8). ac; LV, mpụga ventricle; CPu, caudate-putamen. Ugwu ugwu (D), njedebe intromission (E), na ụkọ ejaculation (F) maka ndị ọ bụla nwere mmekọahụ (Saline, white; D1R Ant, gray; D2R Ant, black). Nchịkọta data pụtara  ± SEM. *p <0.05, ọdịiche dị ịrịba ama dị n'etiti ụbọchị 1 na ụbọchị 4 n'ime ọgwụgwọ.

Nchoputa nke ọnụ ọgụgụ mkpụrụ ndụ ΔFosB-IR na NAc 7 d mgbe ikpeazụ NAc ikpeazụ na ntinye ma ọ bụ nhazi oge gosipụtara ọdịiche dị iche n'etiti otu dị iche iche ma na klas NAc (F(3,29) = 18.070, p <0.001) na isi (F(3,29) = 10.017, p <0.001). Nke mbụ, ahụmịhe metụtara mmekọrịta nwoke na nwanyị na-achịkwa saline kpatara ezigbo ndozi nke ΔFosB ma e jiri ya tụnyere njikwa aghụghọ mmekọahụ (Fig. 5A, shea p <0.001; Fig. 5B: isi, p <0.001), na-akwado nsonaazụ dị n'elu. Mmegide nke D1R, mana ọ bụghị D2R, gbochiri ma ọ bụ mebie iwu a nke ΔFosB. N'ime okwute NAc, onye na-emegide D1R na-emeso ụmụ nwoke nwere mmekọahụ nwere mmụba adịghị na mkpụrụ ndụ ΔFosB-IR ma e jiri ya tụnyere njikwa aghụghọ mmekọahụ (Fig. 5A: p = 0.110), na okwu ΔFosB dị ntakịrị ma e jiri ya tụnyere ụmụ nwoke saline nwere mmekọahụ (Fig. 5A: p = 0.002). Na isi NAc, antagonism nke D1R nwere mmetụta dị nfe: ΔFosB ka ụba mụbaa na ụmụ nwoke na-emeso ndị na-eme ihe na-emegide ọrịa D1R ma e jiri ya tụnyere njikwa saline naive (Fig. 5B: p = 0.031), mana iweghachị a dị ntakịrị ma e jiri ya tụnyere ụmụ nwoke na-emeso saline nwere mmekọahụ (Fig. 5B: p = 0.012). Ngwọta nke ọrịa D2R adịghị emetụta ntinye nke ΔFosB dị ka ụmụ nwoke na-enwe mmekọahụ na-anata onye na-agba mbọ na D2R nwere ọnụ ọgụgụ ka ukwuu nke mkpụrụ ndụ ΔFosB-IR dị ka njiri saline naive (Fig. 5A: shei, p <0.001; Fig. 5B: isi, p <0.001) na D1R ndị na-emegide ndị mmadụ (Fig. 5A: shei, p <0.001; Fig. 5B: isi, p = 0.013), ma dị iche na ụmụ nwoke saline nwere mmekọahụ.

Nyocha 5.      

Lelee nsụgharị buru ibu:      

Nyocha 5.      

Ịkwụsị D1R na NAc na-eme ka ọnụọgụ nke mkpụrụ ndụ ΔFosB-IR dị na NAc nke ụmụ anụmanụ nwere ahụmahụ. Mgbanwe ngbanwe nke ọnụ ọgụgụ mkpụrụ ndụ ΔFosB-IR na akpụkpọ NAc (A) na isi (B) na ụmụ anụmanụ na-enwe mmekọahụ (nwa) ma e jiri ya tụnyere njikwa na-acha ọcha (ọcha) (Naive-Sal, n = 6; Na-eme saline, n = 7; Jiri D1R Ant, n = 9; Jiri D2R Ant, n = 8). Data bu otu bu ± SEM. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa aghụghọ. #p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere saline na D2R Ant ụmụ anụmanụ nwere ahụmahụ. Onye nnọchi anya ihe oyiyi nke Naive Sal (C), Exp Sal ​​(D), Exp D1R Ant (E), na Exp D2R Ant (F). ac, Akara mma. Ogwe mmanya, 100 μm.

Iji chịkwaa maka mgbasa ozi nke D1R ma ọ bụ D2R na-agbanye n'ime striatum dorsal, a na-enyocha okwu ΔFosB n'otu mpaghara ozugbo na na NAc na n'akụkụ n'akụkụ ventricle, dị ka ntinye nke ΔFosB na dorsal striatum site na psychostimulants na opiates dabere na D1R ọrụ (Zhang et al., 2002; Muller na Unterwald, 2005). Ahụmahụ mmekọahụ na-amụba ọnụ ọgụgụ nke mkpụrụ ndụ ΔFosB-ir na striatum dorsal na ụmụ nwoke na-agwọ saline (Naive-Sal: 35.6 ± 4.8 vs Exp-Sal: 82.9 ± 5.1; p <0.001), na-akwado akụkọ anyị gara aga (Pitchers et al., 2010b). Ọzọkwa, ọ bụghị D1R ma ọ bụ onye D2R na-abanye na NAc metụtara ahụmahụ nke mmekọahụ na-adaba ΔFosB na dorsal striatum (Exp-D1R: 82.75 ± 2.64 ir cells; Exp-D2R: 83.9 ± 4.4 ir cells; p <0.001 jiri ya tụnyere njikwa Naive-Sal). Nchọpụta ndị a na-egosi na mgbasa nke infusions antagonist bụ ọkachasị na NAc.

D1R antagonist na NAc blocks sensitized utịp ugwo

D1R igbochi na NAc n'oge mating na-egbochi mmekọahụ-enweta mmelite mepụtara mmh ụgwọ, nwalere 7 d mgbe ikpeazụ NAc infusion na ule nyocha (F(3,29) = 2.956, p = 0.049). Ụmụ anụmanụ ndị nwere mmekọahụ na-enweta saline na NAc mgbe ha nọ na-emekọ ihe na-etinye oge dị ukwuu na ụlọ Amph-paired ma e jiri ya tụnyere ụmụ nwoke na -Fig. 6A, p = 0.025), ihe na-egosi na n'elu. N'ụzọ dị iche, ụmụ anụmanụ na-ahụ maka mmekọahụ nke natara onye na-abanye na NAC D1R n'oge aging anaghị emepụta CPP maka Amph. Ha adịghị iche na njide na-enweghị isi na-enwe mmekọahụ, ha ejiri oge dị ntakịrị karịa na ụlọ Amph-paired tụnyere saline (Fig. 6A: p = 0.049) ma ọ bụ D2R antagonist (Fig. 6A: p = 0.038) nyere ụmụ nwoke nwere mmekọahụ. D2R antagonist infusions adịghị emetụta mmụba Amph ụgwọ dị ka ụmụ anụmanụ na-ahụmahụ anụmanụ na NAc D2R antagonist infusions guzobere ịrịba Amph-CPP tụnyere nchịkwa saline njikwa (Fig. 6A: p = 0.040) na D1R antagonist nwere ahụmahụ anụmanụ (Fig. 6A: p = 0.038), ma dị iche na ụmụ nwoke saline nwere mmekọahụ.

Nyocha 6.      

Lelee nsụgharị buru ibu:      

Nyocha 6.      

Idochi ndị na-anabata D1 na NAc na-ewepụ mmetụta dị iche iche Ngwaputa ntinye na ụba dendritic na-arịwanye elu na ụmụ anụmanụ nwere ahụmahụ. A, Ogologo oge a na-etinye na ụlọ Amph-paired mgbe a na-esiteghị na-eme ka pretest (CPP score, sekọnd) maka ịghọ onye na - n = 6) na ụmụ anụmanụ nwere ahụmahụ (nwa) nke natara saline (n = 7), D1R antagonist (n = 9), ma ọ bụ D2R antagonist (n = 8). Data bu otu bu ± SEM. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa nnu saline. #p <0.05, ọdịiche dị ịrịba ama sitere na D1R Ant anumanu nwere ahụmahụ. B, Ọnụ ọgụgụ nke mkpụrụ osisi dendritic (kwa 10 μm) maka ịbịaru nwoke na nwanyị (na-acha ọcha, n = 7) na ụmụ anụmanụ nwere ahụmahụ (nwa) nke natara saline (n = 8), D1R antagonist (n = 8), ma ọ bụ D2R antagonist (n = 8). Data bu otu bu ± SEM. *p <0.05, ọdịiche dị ịrịba ama ma e jiri ya tụnyere njikwa nnu saline. #p <0.05, ọdịiche dị mkpa site na njikwa nnu nnu nwere ahụmahụ.

D1R na-egbochi onye na-eme ihe gbasara mmekọahụ na-eme ka NAc spinogenesis

Nchoputa nke uzo ogwu di na NAc nke umu anumanu ndi a gosiputara na ichoputa D1R n'oge aging choro ka enwere otutu nchoputa nke NAc mgbe enwere mmekorita na 7 d nke mmekorita nke nwanyi na abstinence (Fig. 6B; F(3,26) = 41.558, p <0.001). Kpọmkwem, njikwa nnu na-enwe mmekọahụ na ụmụ anụmanụ na-eme ka D2R nwere ọnụ ọgụgụ ka ukwuu nke spines ma e jiri ya tụnyere njikwa nnu saline (Fig. 6B: p <0.001) na-akwado nyocha anyị gara aga (Pitchers et al., 2010a) na nchọta na GFP na-achịkwa vectors velocities kọwara n'elu. N'ụzọ dị iche, ndị na-ahụ maka ụdị mmekọahụ D1R na-enwe mmekọahụ na-ejupụta na ụmụ anụmanụ adịghị iche na nnu saline nke na-enwe mmekọahụ -Fig. 6B). Enwere mmetụta dị omimi nke ngwongwo nke D2R dịka D2R nyere ụmụ anụmanụ gosiri na ọ dị ntakịrị ala na-eme ka ọkpụkpụ nsị karịa nchịkwa saline nwere mmekọahụ (Fig. 6B: p = 0.02), ma ọnụ ọgụgụ dị elu nke ọkpụkpụ na-atụle ya na njiko saline na ndị okenye D1R na -p <0.001; Fig. 6B). Ya mere, D1R na-egbochi na NAc n'oge na-achọ ịlụ na-egbochi mmetụta nke ahụmahụ mmekọahụ na ụgwọ ọrụ abstinence na NAc spinogenesis.

Nkwurịta

N'ọmụmụ ihe ugbu a, anyị gosipụtara mgbakwasị ụkwụ n'etiti ọdịdị anụ ahụ na ọgwụgwọ, mgbe ụgwọ ọrụ nke oge na-esote oge nke ịghara ịba uru. N'ụzọ doro anya, anyị gosiri na ahụmahụ na omume mmekọahụ, nke 7 ma ọ bụ 28 d nke abstinence na-esote, na - eme ka ụgwọ ọrụ Amph. Nchọpụta ndị a nwere ihe ndị yiri ya na ọrụ dị oke mkpa nke oge abstinence site na iji ọgwụ ọjọọ eme ihe n'ụzọ na - ezighị ezi na -Lu et al., 2005; Thomas et al., 2008; Wolf, 2010b, 2012; Xue et al., 2012). Ọzọkwa, nkwụghachi ụgwọ a na-ahụ anya ΔFosB na NAc dị oké mkpa maka nkwụnyeghachi mkpụrụ ndụ nke abughi na nchịkwa psychostimulant, nke nwere ike site na spinogenesis na NAc n'oge a na-akwụ ụgwọ abstinence. Anyị gosipụtara na mmịpụta ΔFosB na NAc mgbe ahụmahụ mmekọahụ ga-adịte aka ma dabere na ọrụ NAc D1R n'oge ịlụ. N'aka nke a, a kwadoro usoro a nke D1R nke a na-etinye nchịkwa ΔFosB na NAc dị oke egwu maka ụgwọ ọrụ dị mma maka Amph na mmụba spin na-arịwanye elu na NAc, ọ bụ ezie na ihe ndị a na-akpata inwe mmekọahụ ga-adabere na oge nke ịhapụ ụgwọ ọrụ mmekọahụ (Pitchers et al., 2010a). N'ikpeazụ, anyị gosipụtara na NAc spinogenesis nwere ike inye aka na mmalite mmepe nke okwu dị mkpirikpi nke a ghọtara ụgwọ ọrụ Amash ma ọ bụghị ihe dị oké egwu maka ịnọgide na-egosipụta ngwongwo ọgwụgwọ bara uru, dị ka mmụba spine na NAc dị na-agagharị ma hụ mgbe 7 d, mana ọ bụghị 28 d, oge abstinence.

Ọ dịwo anya a mara na a na-ewepụta dopamine na NAc n'oge a na-akwụghachi ụgwọ omume, gụnyere omume mmekọahụ. N'elu mmeghe nke nwanyi na-anabata ihe, extracellular dopamine na NAc na-amụba ma na-ebuli elu mgbe ọ na -Fiorino et al., 1997). Nnyocha a na-amụ ugbu a gosiri na ịme onye na-eme ka onye na-ahụ maka dopamine banye na NAc n'oge enweghi mgbakọ enweghi mmetụta na mmalite ma ọ bụ ịrụ ọrụ nke omume mmekọahụ, nke kwekọrọ n'echiche bụ na dopamine adịghị etinye aka n'egosipụta ụgwọ ọrụ ọ bụla, ma kama n'ihi na omume nke mmesi obi ike nke ihe gbasara mmekọahụ (Berridge na Robinson, 1998). N'ezie, ịkọ ọdịnihu maka ụgwọ ọrụ mmekọahụ na-eme ka a na-arụ ọrụ nke neurons n'ime usoro nlekota oru dopamine, nke gụnyere dopaminergic sel na ventral area na iche ha, NA (Balfour et al., 2004). Omume ime omume ugboro ugboro na-adọta ΔFosB na NAc, nke n'aka nke ya na-etinye aka na nkwalite mmekorita nke inwe mmekọahụ (Pitchers et al., 2010b). Nsonaazụ ugbu a na-egosi na nkwụsịtụ nke ΔFosB bụ, n'ezie, dabere na mmalite D1R na NAc mgbe ị na-ahụ mating. Nchọta a kwekọrọ na nchọpụta ndị gara aga na-egosi na nchịkwa psychostimulant ugboro ugboro na-arịwanye elu ΔFosB na NAc spiny neurons na-akọwa D1R (Lee et al., 2006; Kim et al., 2009) nakwa na ihe dị otú ahụ ΔFosB upregulation dabeere na D1R ịrụ ọrụ (Zhang et al., 2002). Tụkwasị na nke ahụ, enwere ike ịmata azịza ọgwụ ọjọọ, nke a na-ahụkarị na anụ ọgwụ nwere ọgwụ, nwere ike ịmepụta na enweghị ọgwụ ọhụụ na-apụta site na ikwubiga okwu ókè nke ΔFosB na D1R na-ekwupụta neurons na striatum (Kelz et al., 1999). Tdi na nwunye, ma ugwo nke oma ma obu ugwo oria na-eme ka ΔFosB di na NAc site na usoro D1R iji kwado omume oma.

Ọzọkwa, nchọpụta ndị dị ugbu a na-egosi na ΔFosB bụ onye nkwekọrịta dị oke egwu nke ntụgharị uche n'etiti ọdịiche ahụike na ụgwọ ọrụ psychostimulant. Dị ka e kwuru, ọrụ a na-emepụta ΔFosB na NAc n'oge mbụ a na-azaghachi azịza ọgwụ, dị ka ΔFosB overexpression na NAc na-achọpụta na ịmalite ikpo ọkụ na cocaine mgbe ọ na-esetịbeghị ma ọ bụ ugboro ugboro (Kelz et al., 1999), na-enwekwu mmetụta maka cocaine na morphine CPP (Kelz et al., 1999; Zachariou et al., 2006), na-eme ka nchịkwa onwe onye nke cocaine dị ala (Colby et al., 2003). Ihe omumu nke di ugbu a gosiri na nchichi nke D1R ma obu ΔFosB oru na NAc n'oge di na nwunye wezuga inwe ihe omumu nke nwoke na nwanyi n'enye ihe omuma.

Nnyocha a na-amụ ugbu a gosipụtara na oge abstinence site na ụgwọ ọrụ mmekọahụ chọrọ maka ịmara nke ụgwọ Amph na NAc spinogenesis. Anyị na-eche na ΔFosB n'oge a na-abstinence na-emetụta ọrụ neuronal site n'ịgbanwe ntụgharị okwu nke ala ala iji malite spinogenesis ma gbanwee ike synaptic. N'ezie, igbochi ntinye nke ΔFosB na NAc mgbe ị na-aga na-egbochi mmụba nkwụsị na nke NAc ka a chọpụtara mgbe ọ kwụsịrị ụgwọ ọrụ. Ọzọkwa, nsị nke onye na-eme ka D1R banye na NAc tupu oge ọ bụla ejikọta ya na-egbochi inwe mmịba ahụmahụ nke mmekọahụ na ΔFosB na mmụba spine na-amụba.

ΔFosB bu ihe edeputara nke nwere ike ime dika onye na-eme ka o bu onye ozo na-emeghari ma o bu onye ozo iji megharia okwu nke otutu mmadu nke nwere ike ime ka mmuta ihe otutu na ike synaptic na NAc (Nestler, 2008). Karịsịa kpọmkwem, ΔFosB na-eme ka mkpụrụ ndụ-cyclic-dependence-5 rụọ ọrụ (Bibb et al., 2001; Kumar et al., 2005), nuclear factor k B (NF-κB) (Russo et al., 2009b), na ihe GluA2 nke onye na-anabata AMPA (Vialou et al., 2010) na rederede akwukwo ozi nke usoro mbu c-fos (Pitchers et al., 2010b) na monemltransferase G9 histone methyltransferase (Maze et al., 2010). Cezumike nke na-ahụ maka ya-5 na-achịkwa ndị na-edozi sistem na ntanetị n'ahụ (Taylor et al., 2007). Ọzọkwa, ịkwalite NF-κB na-amụba ọnụ ọgụgụ nke dendritic spines na NAc, ebe mgbochi nke NF-κB belata obere dendritic basal ma gbanwee mmụba cocaine na-ebunye ya na spines (Russo et al., 2009b). N'ihi ya, ụgwọ ọrụ mmekọahụ na-eme ka ΔFosB dị na NAc, nke nwere ike ịgbanwe akara nchịkwa NAc site na ọtụtụ lekwasịrị anya (ntụgharị, kinase-cyclic-kinase-5, NF-κB) nakwa na a na-ahụkarị ụgwọ ọrụ ọgwụgwọ, dị ka e kwuru Russo et al. (2009a) maka omume cocaine ugboro ugboro.

Nchọpụta a na-atụghị anya ya na nchọpụta a na-amụ ugbu a bụ na mmụba spin na-arịwanye elu na NAc bụ ihe na-agafe agafe, a dịghịkwa achọpụta ya na 28 d mgbe ahụmahụ mmekọahụ. N'ihi ya, a na - ejikọta njupụta nke azụ azụ na nmalite nke ụgwọ ntinye aka mepụtara ma nwee ike inye aka na mmalite mmepe ma ọ bụ okwu dị mkpirikpi nke ihe nzaghachi Amph. Otú ọ dị, ọ dịghị mkpa ịmalite ịdị na-agbapụta azụ maka nkwụsi ike nke ihe mmetuta Ngwaputa Amash mgbe oge abstinence dị ogologo. Anyị egosiwo na mbụ na ahụmahụ mmekọahụ na-eweta oge dị mkpirikpi (7, ma ọ bụghị 28, ụbọchị mgbe ikpeazụ ngwongwo) nke ntanye NMDA nọ n'okpuru NR-1 na NAc, bụ nke weghachitere na ọkwa ọkwa mgbe oge ogologo oge nke ụgwọ ọrụ abstinence (Pitchers et al., 2012). Nke a na-eme ka okwu ntinye nke NMDA buru ibu bu ihe e mere ka o doo anya na enwere mmekorita nwoke na nwanyi na-eme ka synapses (Huang et al., 2009; Brown et al., 2011; Pitchers et al., 2012), na-atụ aro na o nwere ike ịmalite inwe mmekọahụ na-emetụta ọganihu spine na-adabere na arụmọrụ NMDA nhazi (Hamilton et al., 2012).

N'ikpeazụ, nchọpụta a na-eme ugbu a na-eme ka a ghọta na ịgwọ ọgwụgwọ site na ụgwọ ọrụ (mmekọahụ) na ndabere ya na oge ịkwụsị ụgwọ ọrụ. Ọzọkwa, ΔFosB na-eme ka plasticity a na-akpa àgwà site na arụ ọrụ D1R na NAc. Ya mere, data na-atụ aro na nkwụsị nke ụgwọ ọrụ zuru oke mgbe ahụmahụ nkwụghachi ụgwọ nwere ike ime ka ndị mmadụ ghara ịdaba na mmepe nke ịṅụ ọgwụ ọjọọ nakwa na otu onye ogbugbo nke nsogbu a na-arịwanye elu bụ ΔFosB na nyochaa ederede ọdịda ya.

Ihe odide ala

  • Enwetara October 16, 2012.
  • Ntụle nwetara December 12, 2012.
  • Enwere December 23, 2012.

  • Ọrụ a bụ Ụlọ Ọrụ Na-ahụ Maka Ahụ Ike Canada (LMC), National Institute of Healthental Mental Health (EJN), na Kansụl na Nkà Na-ahụ Maka Nkà na Injinia nke Canada (KKP na LMC). Anyị na-ekele Dr. Catherine Woolley (Northwestern University) maka enyemaka na usoro ndebanye aha ndị mmadụ.

  • Ndị na-ede akwụkwọ ekwupụtaghị ihe gbasara ego.

  • Ekwesịrị inye Dr. Lique M. Coolen, Ngalaba Na-ahụ Maka Ahụike na Biophysics, Mahadum Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. [email protected]

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