Cudurka dareeraha 'opioid' ee loo yaqaan 'neuroplasticity' ee dopaminergic neurons ee ku yaala barmaamijka xayawaanka ayaa saameyn ku yeeshay abaalmarinta dabiiciga ah (opiate) (2014)

Faallooyin: The Daraasaadka DeltaFOSB Waxaan inta badan diirada saarnaa dhammaan diiradda saaran nukleus awday (xarunta abaalmarinta), oo waxay ogaatay in jinsigu si qurux badan u safro isla farsamooyinka maskaxda sida meth & cocaine. Laga soo bilaabo daraasadda taariikhiga ah ee isla cilmi-baaraha (Sharciga Abaalmarinta Dabiiciga ah ee Daroogada iyo Daroogada ee Nidaamka Nuugyada Soodhaweynta Nafaqada ee leh ΔFosB oo ah dhexdhexaadiye Muhiim (2013)):

Sidaa darteed, abaalmarinta dabiiciga ah iyo daroogada kaliya kuma xirna waddo isku mid ah neerfaha, waxay isugu yimaadaan isla dhexdhexaadiyeyaasha molikaliska, waxayna u badan tahay isla nuuroonnada Nucleus Accumbens, inay saameyn ku yeeshaan dhiirrigelinta dhiirrigelinta iyo "doonista" labada nooc ee abaalmarinta

Qaadashada: meth, kokain, iyo jinsi kastaa waxay sameeyaan waxyaabo asaasi ah oo isku mid ah unugyada dareemayaasha ee isku midka ah ee xarunta abaalmarinta (nucleus accumbens), wax kasta oo ay samayn karaan si ka duwan meelo kale oo maskaxda ah. Tani waxay burburisay meesha caadiga ah ee hadalka ah ee ah in abaalmarinta dabiiciga ah iyo daawooyinka ay ku kala duwan yihiin hababka iyo saameynta.

Daraasaddan cusub ayaa baartay waxa galmada ku sameyso VTA. VTA waa halka ay unugyada dareemayaasha ee soosaara dopamine ay ka bilaabmaan - waxayna laamo u yihiin nukleus accumens, kiliyaha hore, iyo amygdala. Asal ahaan VTA waa isha (isha) inta badan dawadeena 'dopamine'. Eeg kuwan 2 sawir ee wareegga abaalmarinta: Pic1, Pic2

Cilmi baadhayaashu waxay ogaadeen in galmada (duufaanta) ay keenayso meydka unugyada VTA si ku meelgaar ah (ragga). Maydhayaasha unugyada iyo dentiitigooda wuxuu ka kooban yahay miisaanka maskaxda. Tani waa xaqiiqda ah waxa loo yaqaan 'heroin' ee loo yaqaan 'VTA' (Ma ahan mar keliya isticmaalka hirowiin, laakiin isticmaalka heroin raagay). Ogsoonow in isku dhejintaas ka mid ah jirka unugyada VTA waxay ku dhacdaa dadka qaata heroin.

Iskuduwidda unugyada galmada ku-dhaco waxay socotaa ugu yaraan 7 maalmood. Isbeddelka ku yimid jinsiga ayaa ku soo noqdey caadi ahaan maalmaha 30, laakiin cilmi-baarayaashu waxay qiimeeyeen maalmo 1, 7, iyo 30.

Yaraanshaha jirka unugyada ku jira qabatinka hirowiinka ayaa keenaya dopamine hoose oo ku dhaca ku soo boodka - ama waxa aan ugu yeerno Maqnaanshaha. Cilmi baarayaashu waxay siiyeen morphine jiirka si ay u qiimeeyaan jawaabtooda (galmada kadib), laakiin waxba ma dhicin. Caadi ahaan jiirka ayaa aad u jecel morphine-ka, laakiin halkan si ku-meel-gaadh ah ayaa looga quustey. Marka la soo koobo, jiirka abaal-marinta 'post-ejaculatory' abaalmarinta wareegga ayaa ahaa mid aan ka jawaabin heerka hoose ee hirowiin. Cilmi-baadhayaashu waxay qiyaaseen in qiyaaso badan loo baahan yahay si loo helo falcelin jiir "caadi ah".

Si loo soo koobo - Jinsi (si ku meelgaar ah) wuxuu ku sameeyaa wax la mid ah VTA sidoo kale qabatinka hirowiinku: yaraanshaha dopamine ee soo saara jirka unugyada dareemayaasha. Tani waxay keenaysaa hoos u dhigista dopamine ee xarunta abaalmarinta, iyo ka jawaab celinta yar ee mukhaadaraadka - waxayna qaadataa ugu yaraan 7 maalmood maskaxda jiirka inay kasoo kabato.

 

J Neurosci. 2014 Jun 25;34(26):8825-36. doi: 10.1523 / JNEUROSCI.0133-14.2014.

Pitchers KK1, Coppens CM2, Xumaan LN3, Fuller J2, Van S2, Frohmader KS2, Laviolette SR2, Lehman MN4, Coolen LM5.

aan la taaban karin

Abaalgudka dabiiciga ah iyo daroogooyinka xadgudubka ah waxay kudhex yihiin wadada meeshan ee loo yaqaan 'mesolimbic pathway' waxayna kiciyaan habka caadiga ah ee naqshadaha nuuraliga ah ee ku jira sumadaha nucleus. Calaamadaha daba dheeraadka ah ee ka yimaada opiates ayaa soo jiidanaya balaastigga dopaminergic neurons ee degaanka ventral tegmental (VTA), kaas oo xakameynaya dulqaadka morfinka.

Halkan, waxaynu tijaabinaynaa sharraxaadyada in maadada loo yaqaan 'mating-induced opioids' ee loo yaqaan 'opioids' ee VTA ay keento isbeddel maskaxeed oo ah unugyada VTA dopamine ee jiirka jinsiga, kuwaas oo si toos ah u xakamaynaya muujinta muddada-dheer ee khibrad-xoojinta xoojinta dhaqanka galmada.

Marka hore, waayo-aragnimada galmada waxay hoos u dhacdey VTA dopamine soma xNUMX iyo 1, laakiin maaha maalmo 7 ka dib fadhigii ugu dambeeyey. Saameyntan waxaa la xakameeyey naloxoon kahor xili kasta oo la isku daro; Sidaa daraadeed, balaastiga unugyada VTA-du waxay ku xiran tahay tallaabo ka dhan ah opioids endogen.

Taas bedelkeeda, baqda VTA waxaa lagu xidhiidhiyay abaalmarin la badelay, iyada oo raggu u arkeen ragga oo aan ku haboonayn inay door bidaan booska 0.5 mg / kg morphine.

Marka xigta, waxaa la go'aamiyay in tallaabo-qaadis dhammaystiran oo dhexdhexaad ah oo dhexdhexaad ah abaalmarinta jinsiga iyo xusuusta jinsiyada labka ah ee lagu daaweeyo naloxoon inta lagu jiro khibradda maadinta, ama nidaam ahaan ama intra-VTA. Naloxone uma aysan horjoogsanin fududeynta asaasiga ah ee habdhaqanka jinsiga ah ee ku saabsan kulanno soo noqnoqonaya, ama booska la rabo in la isku daro. Si kastaba ha noqotee, daaweynta naloxoontu waxay soo jiitay muujinta muddada dheer ee fududeynta waayo-aragnimada kufsiga ee habdhaqanka jinsiga iyo firfircoonaanta neerfaha ee goobaha mesolimbic oo ay sababtay nacaybka la xiiro.

Wadajir ahaan, xogtaasi waxay muujinayaan in opioids endogen opioidada inta lagu guda jiro laysku daro saqafka neuralada ee VTA dopamine neurons kuwaasoo u muuqda kuwo muhiim u ah abaalmarinta morphine iyo xasuusta muddada dheer ee habdhaqanka dabeeciga dabiiciga ah.

 

Hordhac

Dabeecadaha abaalgudka dabiiciga ah waxaa dhexdhexaad ah nidaamka nidaaminta maskaxda (Meisel iyo Mullins, 2006; Hoebel et al., 2009; Frohmader et al., 2010a; Pitchers et al., 2010a; Young iyo al., 2011; Blum et al., 2012). Daroogooyinka xadgudubka waxay keenaan isbeddel xagga nukliyeerka ah ee nidaamkan, taas oo gacan ka geysata horumarinta iyo muujinta isticmaalka maandooriyaha (Hyman et al., 2006; Nestler, 2012). Waxaan hore u go'aaminay in khibrada dabeecadda dabiiciga ah, ie, waayo-aragnimada jinsiga ee jinsiga labka ah, ayaa sidoo kale keena nuucyada nuural ee numbarka xajmiga (NAc), oo ay ka mid yihiin xayawaanka dendritic (Pitchers et al., 2010a) iyo deltaFosB (Pitchers et al., 2013). Taas bedelkeeda, baqshaddaan jinsiga ku salaysan ayaa muhiim u ah saameynta khibradda jinsiga ee xiriirka dambe, oo lagu muujiyey fududeynta bilaabista iyo waxqabadka galmada (Pitchers et al., 2010b, 2012, 2013). Waxaa intaa dheer, waayo-aragnimada galmada waxay bedbaadinaysaa jawaab-celinta maskaxda, oo ay ku jirto dareen-celinta dhaqdhaqaaqa firfircoonida iyo abaalmarinta la xoojiyay (Frohmader et al., 2010a; Pitchers et al., 2010a, 2013).

NAc waa mid ka mid ah bartilmaameedka hoose ee dareenka dopaminergic ee degaanka ventral tegmental (VTA). Venter dopamine neurons waa la kiciyaa inta lagu jiro isku darka iyo ka dib soo-gaadhista shuruudaha xaaladaha cayiman ee abaalmarinta jinsiga (Balfour et al., 2004; Frohmader et al., 2010a), iyada oo loo marayo endio opioid peptide (EOP) -waxay ku xiran tahay xayaysiinta μ-opioid (MORs; Matthews iyo Jarmal, 1984; Johnson iyo Waqooyiga, 1992; Klitenick et al., 1992; Ikemoto et al., 1997; Balfour et al., 2004). Sidaa awgeed, soo-bandhigista xaaladaha xaaladaha ah ee saadaalinta dabeecada galmada waxay sababtaa sii-deynta EOP iyo VTA-dopamine-cell activation, taas oo fududaynaysa dhiirrigelin galmo (Mitchell iyo Stewart, 1990; van Furth et al., 1995; van Furth iyo van Ree, 1996) iyo dopamine sii daaya NAc (Fiorino et al., 1997).

Ku celcelinta soo noqnoqoshada cuncunka dibedda ah ayaa keena isbeddel maskaxeed ee VTA (Mazei-Robison et al., 2011; Mazei-Robison iyo Nestler, 2012), waxay hoos u dhacdey qiyaasta xaddiga qanjidhada VTA dopamine (Sklair-Tavron et al., 1996; Spiga iyo al., 2003; Chu et al., 2007; Russo et al., 2007; Mazei-Robison et al., 2011), heerarka hoos u dhaca ee borotiinka neurofilament (Beitner-Johnson et al., 1992), kor u kac waynaanta unugyada dopamine, iyo gaadiidka loo yaqaan 'axoplasmic' iyo 'dopamine' oo loo yareeyo NAc (Beitner-Johnson et al., 1992; Mazei-Robison et al., 2011). Dareerayaasha buuggan ee VTA-da waxay isbedbeddelayaan dulqaad mug leh oo miyir-beel ah, waxayna noqdaan kuwo ku-meel-gaadhsiis ah marka ay ku dhex wareegaan bil gudaheed daroogada (Russo et al., 2007). Waqti xaadirkan ma cadda in balastigga ah dareenka nukliyarka VTA uu yahay mid gaar ah ficillada opiates ama haddii ay sidoo kale soo saaraan sii deynta EOP inta lagu jiro dabeecadaha dabiiciga ah ee dabiiciga ah.

Halkan, waxaan ku tijaabinaynaa aragtida ah in waayo-aragnimada abaalmarinta dabiiciga ah ay sabab u tahay neuroplasticity oo la mid ah kuwa ay sababeen opiates, sidaas awgeed, kuwa ka soo horjeeda waxay kudhisan yihiin nidaam adag oo ku habboon dabeecadda dabeeciga dabiiciga ah iyo abaalmarinta xusuusta. Waxaan tijaabineynaa in khibradda galmada ee jiirka labka ah ay hoos u dhigayaan tirada qaddarka ee naasaha VTA dopamine iyada oo loo marayo habka ku xiran ficilka EOP ee VTA. Intaas waxaa dheer, in aan baarno haddii wax laga beddelo EOP-ku-beddelidda dareemayaasha dopamine ee VTA ay la xiriirto xoojinta dabeecadda dabiiciga ah ee dabiiciga ah iyo ku-saleysiga dhiirigelinta dhiirigelinta oo la xidhiidha abaalmarinta dabiiciga ah, iyada oo keenaysa is-dulqaadasho dulqaadka morfinka.

Qalabka iyo Dariiqooyinka

Xayawaanka

(200-225 g) ayaa laga helay juunyarka Charles River waxayna ku jiraan laba qolood oo qolal nadiif ah oo ku yaala 12 h wareegsan / mugdi ah oo mugdi ah dhammaan tijaabooyinka (nalalka off at 10: 00 AM marka laga reebo tijaabada dulqaadashada morphine , waxay iftiimaysaa xNUMX: 5 PM). Cuntada iyo biyaha ayaa la heli karaa ad libitum marka laga reebo inta lagu jiro baaritaanka habdhaqanka. Dumarka Stimulus ayaa la isku qurxiyey oo la geliyay si hoose oo leh 5% 17-β-estradiol benzoate Kaabayaasha SILASTIC (1.98 mm dhexroor gudaha ah, dhererka 0.5, Dow-Corning). Cirbadaha progesterone (subcutaneous, 500 μg ee 0.1 ml saliidda sisinta) waxaa la sameeyay 3-6 h ka hor inta aan la baarin si loo yareeyo galmada. Dhammaan nidaamyada waxaa ansixiyay Jaamacada Western Ontario iyo Jaamacadda Michigan ee Xannaanada Carruurta, waxayna u hoggaansamaan Golaha Kanada ee Daryeelka Xayawaanka iyo Hay'adaha Qaranka ee Caafimaadka ee ku lug leh xayawaannada xayawaanka ee cilmi baarista.

Waqtiga jimicsiga ee VTA dopamine soma isbedel

Kulanno maaliyadeed oo maalinle ah.

Si aad u baratid kooraska waqtiga ee isbeddelka dopamine neuron soma ee ku yaala VTA, xayawaanka ku nool khibrad iyo xayawaan badan ayaa lagu dilay 1, 7, ama 31 dn = 5-8 koox kasta) ka dib maalinta ugu dambeysa ee maadinta (khibrad leh) ama wax qabad (nadiif). Kooxaha jinsi ahaaneed ee loo yaqaan 'Sexual Orientation' ayaa loo geystay habdhaqan galmo inta lagu guda jiro munaasabada ugu dambeeya, iyo sidoo kale tirada guud ee shahwada shanta sano (celceliska 5 ee koox kasta), mana kala duwaneyn wax kasta oo ah habdhaqanka galmada.

Kalfadhiyada wadista.

Labada nin ee galmada ku jira ayaa loo qoondeeyey mid ka mid ah laba xaaladood oo tijaabo ah: galmo kufsi ah ama galmo ahaan khibrad leh. Xayawaannada jinsiga ah ayaa loo ogolaaday inay shan jeer isku darsadaan maalmo isku xigta oo ay ku jiraan dumarka aqbaliqsan baqshiinka tijaabada ah (60 × 45 × 50 cm) ilaa laga soo saaro shahwad ama ilaa 1 h (hadba kii hore). Baqshiinka waxaa si fiican loo nadiifiyey 70% xalal ethanol iyo gogol cusub ayaa lagu daray inta u dhaxaysa kulamada moodada. Habdhaqanka galmada waxaa la sameeyey intii lagu jiray marxaladda mugdiga (2-6 h ka dib bilawga madow). Kaliya xayawaanka la nuugay intii lagu jiray ugu yaraan afar ka mid ah shanta mater-ka ayaa loo tixgeliyey in ay yihiin khibrad galmo oo ay ku jiraan tijaabooyinka. Dhammaan kulannadii materiga ayaa la arkay oo dhaqanka galmada la duubay. Tirada miisaannada (M) (IM), latency mount (ML, wakhtiga laga bilaabo gogol haweenka ilaa koowaad), latency intrusion (IL; waqtiga laga bilaabo haweenka ilaa horraantii), iyo waaraajinta ejaculation (EL; Waqtiga ugu horreyn ee laga soo dhoofiyay xajmiga) ayaa la duubay (Agmo, 1997). Xayawaannada dumarka ah ayaa lagu dhajiyay qalab baadhitaan nadiif ah oo loogu talagalay 1 h oo si joogta ah ula socda ragga galmoodka ah ee kufilan qolka isku midka ah, sida ay u soo gaadheen urka haweenka ee fog, iyo heerarka isku midka ah ee khalkhalka iyo bay'ada deegaanka sida ragga.

Immunofluorescence labeling.

Xayawaanka ayaa si qoto dheer u suuxiyay iyada oo la isticmaalayo sodyum pentobarbital (270 mg / kg, ip) iyo xajmiga xannibaadaha 50 ee 0.9% saline, waxaa ku xiga 500 ml 4% paraformaldehyde ee 0.1 m sodium phosphate buffer (PB). Xanuunada ayaa laga saaray oo dib loogu soo celiyay 1 h heerkulka qolka (RT) ee isku midka ah, ka dibna wuxuu ku dhuftay 20% sukrose iyo 0.01% sodium azide ee 0.1 m PB loogu keydiyo 4 ° C. Qaybaha halbeegyada ayaa laga jaray 35 μm oo ku jira barafow microtome (H400R, Microm) waxaana lagu soo ururiyey afar taxan oo isku mid ah oo loo yaqaan 'cryoprotectant solution' (30% sukrose, 30% ethylene glycol in 0.1 m PB) kadibna lagu kaydiyey 20 ° C. Dhammaan kulubka waxaa lagu sameeyey RT iyaga oo si tartiib ah u dhaqdhaqaaqa iyo xakamaynta adag ee 0.1 m PBS, pH 7.35, inta u dhaxaysa burinta. Qeybaha waxaa loo soo gudbiyey 1% H2O2 10 min si loo baabiiyo peroxidase endogenous peroxidase, ka dibna waxay xannibaysaa 1 h ee xalka (inkabadan) (PBS +: PBS oo ka kooban 0.4% Triton X-100; Sigma-Aldrich) iyo 0.1% Sumamka Serum albumin (Jackson Immuno Research Laboratories). Xiga, qaybaha ayaa lagu daboolay habeenkii RT ee ku yaal tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Ka dib markii la isku daro antibody-ka, qaybaha waxaa lagu faafiyay AlexaFluor 555-isku-dhafan unugug (anti-mouse) anti-mouse (1; 100; Invitrogen, Eugene, AM) ee 30 min. Ugu dambeyntii, qaybaha waxaa lagu maydhay 0.1 m PB, oo lagu rakibay bogagga Superfrost Plus ee galaaska, oo la qalajiyey, iyo lakabiyey gelvatol oo ay ku jirto wakiil ka hortagis ah 1,4-diazabicyclo (2,2) octane (DABCO; 50 mg / ml, Sigma-Aldrich; Lennette, 1978).

Falanqaynta xogta: qiyaasta neuron soma.

Sawirrada sawirada nukliyarrada ah ee IR-da (VT) ee VTA ayaa lagu qaaday xNUMX × xajmiga seddex rostral si heerar kala duwan (Balfour et al., 2004). Ma jiraan wax ismaandhaaf ah oo lagu ogaanayo unugyada heerarka kala duwan. Qiyaasta Soma ee neer-mareenka ayaa la falanqeeyay iyadoo adeegsanaysa ImageJ (National Institutes of Health). Aagga celceliska, wareegga, iyo wareegga ayaa lagu qiyaasay sida lagu sharraxay Sklair-Tavron et al. (1996). Celcelis ahaan unugyada 25 kasta oo xayawaan ah (oo lagu daray dhammaan heerarka 3 VTA) ayaa la falanqeeyay oo unugyo kali ah oo leh muuqaal nucleus oo muuqda ayaa lagu daray. Xayawaan kasta, celceliska celceliska, wareegga, iyo wareegga ayaa la xisaabiyey. Falanqaynta tirakoobka ayaa loo isticmaalay labo nooc oo ANOVA ah (isirrada: waayo-aragnimada jinsiga (khibrad galmo ama jinsiga) iyo waqtiga (1, 7, ama 31 d) hose ah isbarbardhigyada iyadoo la adeegsanayo qaabka Holm-Sidak oo leh heer muhiim ah oo 0.05 ah.

Isbeddelada VTA-da dopamine

Kulammada labajibbaaranaha labadaba.

Si aad u tijaabiso in khibrad galmo inta lagu jiro kalfadhiyada maalinlaha ah ee loo baahan yahay hoos u dhac ku yimaada tirada TH-IR neuron soma, VTA dopamine neurons oo xayawaan ah oo isku duba ridey muddadii shan jeer oo isku dhafan ayaa la falanqeeyay. Kalfadhiyada mating ayaa sida kor lagu sharxay, laakiin muddo ka badan toddobaadyadii 2.5. Maskaxda waxaa la ururiyey 7 d kadib markii la isku daro ama la qabsado.

Calaamadaha Immunoperoxidase.

Waxaa intaa dheer, waxaa la baaray in isticmaalka farsamooyinka macdanta leh ee la adeegsanayo immunoperoxidase iyo baaritaanka chromogen, ay sidoo kale u oggolaan lahayd in muuqaal ahaanshaha xaddiga TH-IR soma isbedelo. Dhaqdhaqaaqa maskaxda iyo habka unugyada ayaa ahaa dhaqanka sida kor ku xusan. Kadib daaweynta 1% H2O2 iyo PBS +, qaybaha waxaa lagu kululeyn jiray habeenkii RT-ga oo ku jira mashiinka loo yaqaan 'tyrosine hydroxylase tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Ka dib markii kuleylka asaasiga ah ee asaasiga ah, qaybaha waxaa lagu kululeeyay roodhiga biotin-isku-dhafan ee kaabiga ah ee IgG (1 h, 1: 500 ee PBS +; Shaybaarada Wareegga), avidin-biotin-horseradish peroxidase (1 h, ABC elite; 1: 1 000 ee PBS ; 3,3'-diaminobenzidine tetrahydrochloride (10 min, 0.02%, DAB; Sigma-Aldrich) oo lagu daray nikkel sulfate (0.02% 0.1 m PB) oo leh hydrogen peroxide (0.015%). Qeybaha waxaa lagu dhaqay si buuxda 0.1 m PB si loo joojiyo dareen-celinta oo lagu rakibay midka lagu magacaabo "Supercrost" oo lagu daray xargaha dhalooyinka (Fisher) oo leh 0.3% gelatin ddH2O. Ka dib marka fuuqbaxa, dhammaan xayndaabyada waxaa lagu xakameeyey barxadda DPX (kiniiniga dibudhiga ah dibudhiga; Sigma-Aldrich).

Falanqaynta xogta: qiyaasta neuron soma.

Unugyada TH-IR waxaa lagu falanqeeyay bedka, wareega, iyo wareegga sida kor lagu sharaxay. Intaa waxaa sii dheer, unugyada TH-IR ee substantia nigra (SN), ee isla qaybaha loo adeegsaday falanqaynta unugyada VTA TH-IR, ayaa la falanqeeyay. Ugu dambeyntiina, ka dib falanqaynta la xiriirta unugyada VTA iyo SN TH-IR, qeybaha waxaa lagu falanqeeyey iyadoo la adeegsanayo unugyada loo yaqaan 'cresyl violet' iyo unugyada non-TH-IR waxaa lagu falanqeeyay iyadoo la adeegsanayo isla qaababka kor lagu soo sheegay. Farqiga u dhexeeya kooxaha caqliga iyo khibradda leh ayaa la barbardhigayaa iyadoo la adeegsanayo laba-ardaal oo Arday ah t imtixaannada leh heer muhiim ah ee 0.05.

Saameynta naloxoonta ee dopamine-ka dhiman ee khibrad u leh

Si loo go'aamiyo in MORs ay door ka qaadatay isbeddelka waayo-aragnimada jinsiga-isbeddelka ku dhaca qiyaasta dopamine neuron soma, MOR waxaa la xannibay intii lagu jiray falalka galmada. Kala badh xayawaanku waxay heleen khibrad jinsi ah, halka qeybtii kale ee la maareynayay laakin ay sii waday jinsi ahaan. Xayawaannada jinsiga ah ayaa loo ogolyahay in ay ku biiraan 5 maalmo isku xigta. Gudaha galmada iyo khatarta ah ee xayawaannada, xayawaanka waxaa lagu daaweeyaa lakulanka MOR antagonist naloxone (10 mg / kg, scan, Sigma-Aldrich, loona burburiyey 0.9% saline) ama saline 30 ka hor intaan la hirgelin haweenka (khibrad) ama ka hor (naag); Sidaa daraadeed waxay abuuri kartaa afar kooxood oo tijaabo ah: salineeska galmada (Naive Sal), galmada naloxone (Naive NLX), salineed khibrad u leh (Sal Sal), iyo Naloxone khibrad galmo ah (Exp NLX; n = 5-8 koox kasta). Daaweynta Naloxone ma aysan yeelin saameyn isireed oo muhiim ah oo ku aaddan wax kasta oo ka mid ah habdhaqanka galmada, mid kasta oo ka mid ah 5, iyo naloxone- iyo saline-daweynta la midka ah ayaa la mid ah khibradaha galmada. Dhamaan xayawaannada ayaa lagu dilay iyada oo loo marayo naqshadeynta xajmiga 7 d ka dib fadhiga ugu dambeeyay. Qeybinta, immunohistochemistry, iyo falanqaynta xogta (laba dhinac oo ANOVA; arimaha: khibradda galmada iyo daaweynta mukhaadaraadka) ee qiyaasta dopamine soma ayaa lagu sameeyey sida kor ku xusan.

Morphine oo leh xaalad doorasho ah

Naqshad tijaabo ah.

Hadda ka hor, Russo et al. (2007) waxay muujiyeen morfin daba-dheeraaday oo u dulqaadanaya abaalmarinta morphine. Maaddaama waayo-aragnimada jinsiga iyo morphine raagis ay keento hoos u dhac yar oo ka mid ah qiyaasta dopamine neurons ee VTA, isbedelka farsameynta ee isbeddelka miyuufaha ku salaysan jinsiga ayaa lagu tijaabiyay abaalmarinta morphine. Xayawaannada khibrada leh ee jinsiga ah iyo kuwa khatarta ah ayaa loo qaybiyay lix kooxood oo tijaabo ah (n = 9-13 koox kasta) oo ku salaysan dabeecada galmada (galmada kudhaca ama khibrad leh) iyo qiyaasta morphine (0.5, 5.0, ama 10.0 mg / kg, ip) waxaana lagu baari jirey mudnaanta booska xaaladaha morphine-sababtoo ah (CPP).

Morphine-CPP.

Xaaladda ayaa ka dhacday 1 d ka dib markii kulankoodii ugu dambeeya ee mawduucyada iyo kooxuhu ay udhigmeen waxqabadka galmada inta lagu jiro fadhigii ugu danbeeyay. Muuqaalka CPP-ka ee loo adeegsaday wuxuu ka kooban yahay maareyn, maalmo kicin, iyo imtixaan kadib, qalabkuna wuxuu ku salaysan yahay Tenk et al. (2009). Si kooban, qalabka CPP (MED Associates) wuxuu ka koobnaa saddex qol oo kala duwan. Inta udhaxeysa kulan kasta, qalabka waxaa si fiican loogu nadiifiyey 70% xalka ethanol si loo yareeyo tilmaamaha udugga ah ee raagaya. Si loo go'aamiyo dookhyada shaqsiyeed, tijaabo hore ayaa la qaaday intii lagu jiray xayawaanka si bilaash ah loo siiyay dhammaan qalabka 15 daqiiqo. Koox ahaan, xayawaanku ma muujin doorbid muhiim ah qol gaar ah, laakiin xayawaan kasta wuxuu lahaa doorbid yar oo bilow ah. Jiirka muujiyey doorbid la taaban karo oo ka mid ah qolalka (> 200 s farqiga u dhexeeya waqtiga lagu qaatay qolal kasta; <5% xoolaha) intii lagu jiray tijaabada ayaa laga reebay daraasadda. Intii lagu gudajiray qaboojinta, daroogada waxaa lagu lamideeyay mid markii horaba la doorbiday ama aan la doorbidin iyadoo la adeegsanayo qaab aan eex lahayn (Tzschentke, 2007) iyo xayawaanka ayaa lagu xayiray qolalka 30 min. Xayawaanka ayaa lagu duray saline (IP) subaxdii (9: 00: 12 AM illaa 00: 1 PM) waxayna kuxirantahay qolka saline-paired (control). Galabtii (00: 4: 00-0.5: 5.0: 10.0 PM), xayawaanka waxaa lagu duray morphine (IP, 0.9 mg / kg, 3 mg / kg ama XNUMX mg / kg, morphine sulfate oo lagu kala diro XNUMX% saline, Johnson Matthey) ilaa qolka morphine-paired. Xayawaanada waxaa lagu soo rogay laba maalmood oo cabitaan ah. Maalinta ku xigta (XNUMX d ka dib maalinta ugu dambeysa ee materka) ka dib, baaritaan dambe, hab nidaam ahaan la mid ah tan ugu horreeya, ayaa la sameeyey. Falanqaynta tirakoobka, waqtiga lagu qaatay qolka morphine-paired inta lagu guda jiro baaritaanka ka dib ayaa la barbardhigay wakhtigii lagu kharash gareeyey qolka saline-paired inta lagu guda jiro imtixaanka ka dib galmada ama ragga khibradda leh qiyaas kasta oo la isticmaalayo t imtixaan. p <0.05 waxaa loo tixgeliyey inay tirakoob ahaan muhiim tahay Kooxaha xakamaynta ee dheeraadka ah ee xayawaanka galmada iyo xayawaanka khibrada leh waxay ka heleen cusbada labada qol ee lammaanaha iyo kuwa aan loo baahnayn inay u noqdaan kontaroolo diidmo ah. Wax farqi ah oo udhaxeeya waqtiga udhaxeeyay qolalka looma ogaanin labada koox midkoodna.

Saameynta Naloxone nidaamsan oo ku saabsan fududeynta habdhaqanka galmada ee khibrad u leh

Naqshad tijaabo ah.

Khibrada galmada waxay fududeyneysaa fududaynta habdhaqanka jinsiga ah ee lagu hayo ugu yaraan 1 bisha (Pitchers et al., 2012). Si loo falanqeeyo saameynta joojinta MOR ee fududaynta habdhaqanka jinsiga ah, xayawaanka la xariira jinsiga ayaa helay naloxoon ama saline ka hor shanta kalfadal oo isku xig-xigxiga ah (n = 12 mid kasta) sida kor lagu sharaxay. Toddobaadkii kaddib marka la isku daro mishiinka ugu dambeeya, waxaa la sameeyey baaris rasmi ah oo lagu sameeyay xayawaankii oo dhan oo loo oggolaaday inay la midoobaan ilaa hal xayiraad ama ilaa 1 h. Lama daaweynin daaweynta naloxone ama daaweynta salineed ka hor inta aanad ku maareyn maalinta maalinta ugu dambeysa. Qodobbada isku dhafan ayaa la barbardhigay in la ogaado haddii naloxunku uu saameyn ku yeeshay khibrad jinsi ah oo la xidhiidha fududeynta isku-darka maadada (maalinta 1 iyo maalinta 5) ama dayactirka fududeynta (maalinti 5 vs imtixaanka) iyada oo la adeegsanayo labo hab oo ANOVA ah (isir-barar: daaweyn (saline-ka naloxone ) iyo maalinta (maalinta 1, maalinta 5, ama imtixaanka)] iyo Habka Holm-Sidak ee hose ah Isbarbardhigga. Dhammaan imtixaannada tirakoobka, p <0.05 waxaa loo tixgeliyey inuu yahay mid tirakoob ahaan muhiim ah.

Tijaabo dheeri ah oo dheeri ah

Naloxonka Naloxone ee maalinta imtixaanka.

Si loo muujiyo in dhaqanka galmada la bedelay maalinta ugu dambeeya ee tijaabada lagu sameeyey aysan ahayn sabab la'aanta maqnaanshaha naloxone, waxaannu maamulnay naloxone ama saline maalinta ugu dambeeya ee tijaabada ee xayawaanka lagu helay mary lala la socdo naloxoon inta ay heleen khibrad jinsi. Gaar ahaan, dhammaan xayawaanka ayaa la siiyay duritaanka naloxone (10 mg / kg, sc) 30 min ka hor inta aan la isku darin hal shahwo inta lagu jiro 5 maalmo isku xigta. Maalinta imtixaanka 7 kadib, qiyaastii kala badh xayawaanka ayaa qaatay cirbadeynta naloxone (10 mg / kg, n = 7) ama saline (n = 6) 30 ka hor inta aan la hirgelin haweenka qabta. Dhaqanka galmada ayaa la arkay oo la duubay. Qodobbada isku dhafan ayaa la barbardhigay in la ogaado haddii naloxunku uu saameyn ku yeeshay khibrad jinsi ah oo la xidhiidha fududeynta isku-darka maadada (maalinta 1 iyo maalinta 5) ama dayactirka fududeynta (maalinti 5 vs imtixaanka) iyada oo la adeegsanayo labo hab oo ANOVA ah (isir-barar: daaweyn (saline-ka naloxone ) iyo maalinta (maalinta 1, maalinta 5, ama imtixaanka)] iyo Habka Holm-Sidak ee hose ah Isbarbardhigga. Dhammaan imtixaannada tirakoobka, p <5% waxaa loo tixgeliyey inay tirakoob ahaan muhiim tahay.

Saameynta naloxoon ku saabsan muujinta gaaban ee dabeecadaha galmada ee fudud.

Saameynta naloxone (10 mg / kg, sc) daaweynta inta lagu jiro mareeynta ayaa lagu tijaabiyay dabeecad kale oo galmo ah inta lagu jiro tijaabada ugu dambeeya ee tijaabinta, taas oo la sameeyay keliya 1 d kadib marka la isku daro mishiinka (saline, n = 5; Naloxone, n = 4).

Qalabaynta Naloxone Systemic.

Si loo go'aamiyo in daaweynta Naloxone ee soo noqnoqda oo keliya ay keento cillad jinsi ah 7 d daaweynta ugu dambeysa, xayawaannada jinsiga ah waxay heleen shan maalin naloxone ah (10 mg / kg, sc) ama duri durbadiiba maalmo isku xigta kahor intaan la isku deyin in la baaro 7 d ka dambeeya naloxone ama cirbadeynta salineed. Maalinta tijaabada ee ugu dambaysa, xayawaanka lama helin wax cirbad ah. Akhlaaqda galmada ayaa la arkay oo la duubay sida kor lagu sharaxay. Qodobbada isku dhafan ayaa la barbardhigay kooxaha u adeegsanaya kuwa aan loo adeegsan t imtixaannada. Dhammaan imtixaannada tirakoobka, p <5% waxaa loo tixgeliyey inay tirakoob ahaan muhiim tahay.

Naloxone nidaamsan iyo abaalmarinta galmada.

Mid ka mid ah suurtagalnimada saamaynta naloxone ee soo-if-qaadidda muujinta dayactirka hab-dhaqanka fududaynta galmada ayaa ah in naloxone ay xannibayso saameynta abaalmarinta ah ee dabeecadda galmada. Si loo tijaabiyo suurtagalka, qaab baarista 'CPP' waxaa loo qabtay habdhaqanka galmada isla marka lagu daro naloxone ama duritaanka cusbada ee labka ah oo aan lahayn qibrad galmo hore. Habka CPP wuxuu la mid yahay kan kor lagu sharaxay morphine-CPP, oo ay kujiraan kahor, maalmaha sharuudaha, iyo baaritaanka-kadib.

Habdhaqanka jinsiga ayaa la isku duubay qolkii hore ee aan loo baahneyn. Si isku mid ah, xayawaan kasta wuxuu helay cirbadda naloxone (n = 12) ama saline (n = 11) 30 min ka hor inta aanad helin gogol gaban. Muddada celceliska muddada kulanku waa mawduucii "~ 13 min. Hal daqiiqo ka dib markii la naqdiyay, xayawaanka ayaa lagu meeleeyay qolka labiska ee 30 min. Xaaladda kale ee qaboojinta, xayawaanka ayaa la siiyay cirbadeynta naloxone ama saline (hadba inta ay ka heleen ka hor intaysan dhadin), waxaana la geliyay qolka aan la garin ee 30 min. Marka xigta, baaritaan dambe ayaa la sameeyay, oo la mid ah tan ugu horreeya. Si loo go'aamiyo doorbididda aqalka odhaahda, wakhtiga lagu kharash gareeyo qolka labiska inta lagu jiro baaritaanka hore iyo baaritaanka kadib. Falanqaynta tirakoobka, ayaa la isku daray t imtixaannada ayaa loo isticmaalay inay isbarbardhigaan kala doorashada iyo farqiga u dhaxeeya, iyo waqtiga qolka labiska inta lagu jiro baaritaanka hore iyo baaritaanka ka dib si loo go'aamiyo bal in CPP weyn loo sameeyay habdhaqanka galmada. p <0.05 waxaa loo arkaa mid muhiim ah.

Saameynaha naloxone-ka-gudubka-VTA-da oo ku saabsan fududeynta habdhaqanka jinsiga

Naqshad tijaabo ah.

Si loo go'aamiyo in ficilka EOP ee gaar ahaan VTA, uu mas'uul ka ahaa saamaynta isbeddelka ku yimid isbeddelka ku salaysan jinsiga, xayawaanka ayaa hoos u dhacay faleebo naloxoon ah ama saliinada VTA ka hor inta aan la shaacin shan cashar oo maalmo ah. Muuqaalka dabeecadda wuxuu la mid yahay tijaabada nalalka naloxoonta. Xayawaannada jinsiga ah ayaa loo ogolyahay in ay uuraystaan ​​inta lagu jiro 5 maalmaha isku xigga illaa hal aburka ama ilaa 1 h. Shan iyo toban daqiiqo kahor intaan la soo saarin haweeney soo dhaweyneysa, ragga labka ah waxay heleen faleebo labadaba naloxone labadaba (10 μg / μl halkii mitir, mugga xNUMX μl, kala diri 0.5% saline) ama saline (0.9 μl halkii mitir). Microinjectings-ka labada dhinac ayaa lagu maamuley xaddiga socodka 0.5 μl / min oo ka sarreeya 0.5 min interval waxaana ku xiga 1 dheeri oo dheeri ah oo leh cannula oo lagu duray meeshii loogu tala galay. Cannula duritaanka ayaa markaa la beddelay cannula caarada iyo boodhka. Hal toddobaad ka dib maalinta ugu dambeysa ee la isku daro (maalinta imtixaanka), dhammaan xayawaanku waxay mar kale ku dhufteen ejaculation aan lahayn faleebo naloxone ama saline. Jaantuska 3A waxay tilmaamaysaa naqshada tijaabada ah. Falanqaynta xogta waxaa lagu fuliyay sida lagu sharaxay tijaabooyinka nidaamka naloxoonta.

Qalliinka qaansiirka.

Jiirka labka ah ayaa la suuxiyay iyada oo la isku duro oo la isku duro (0.1 ml / kg) oo ketamiin ah (0.87 mg / ml) iyo xylazine (0.13 mg / ml), oo lagu rakibay qalab qalafsan (Kopf Instruments). Tilmaamaha 21-tilmaamaha cannulas (Plastics One) ayaa hoos loogu dhuftay godadka yar yar ee maskaxda ee maskaxda maskaxda ku haysa VTA at -4.8 mm AP, ± 0.75 mm ML laga bilaabo bregma iyo -7.8 mm DV oo kor ka sarreeya Paxinos iyo Watson (2013). Cannulas waxaa lagu xaqiijiyey in uu ku jiro akrilik ilkaha ah kaas oo u hoggaansamay saddex xayiraad oo la dhigay dharka. Xayawaanka waxaa la siiyay xilliga dayactirada 2, waxaana loo qabtay maalin kasta si loogu saxo habka loo isticmaalo hababka tallaalka loo isticmaalo inta lagu jiro baaritaanka dabeecadda.

Caddaynta meelaynta ee loo yaqaan 'kannula'.

Goobta cannulas waxaa la baaray iyada oo la adeegsanayo TH-immunosing si loo xaqiijiyo VTA in si sax ah loo beegsaday. Kaliya xayawaan leh meeleyn habboon ayaa lagu daray falanqaynta (tirada koobabka ugu dambeeya: salineed khibrad leh n = 8; Naloxone khibrad leh n = 6). Saddex xayawaan oo dheeri ah oo laga helay irbadaha naloxone intra-VTA-ga ee lagu faray meel ka baxsan VTA ayaa isku wada jira iyagoo koox wadaaga ah oo "la seegay". Kooxda la waayay waxay si gooni ah u falanqeeyeen si ay ugu adeegaan kantaroolka anatomical iyo Mann-Whitney U baaris ayaa loo isticmaalay in lagu barbardhigo dabeecada maalinta imtixaanka ee ugu dambeeya iyada oo la adeegsanayo naloxone iyo saline-lagu daaweeyo ragga.

Cunto-ku-xirxirid sharraxaad ah oo la xidhiidha erayga "PERK"

Naqshad tijaabo ah.

Ku dhajinta qafiska ee ragga ay heleen waayo-aragnimada maadinta ayaa loo muujiyay in ay sababaan firfircoonaanta MOR ee VTA iyo hawlaha neural ee VTA iyo NAc (Balfour et al., 2004). Sidaa daraadeed, jawiga mala-awaalku wuxu u adeegaa sida soo socota ee lagu sharxi karo abaalmarinta jinsiga. Daraasaddan imtixaanka ah ayaa lagu tijaabiyay in waxqabadka MOR ee hawsha xiliga jinsiga loo baahan yahay marka loo baahdo sii-deynta kicinta curyaanka. Naloxone ama saline waxaa la siiyay nidaam ahaan (IP) 30 min ka hor inta aan lagu meeleynin arena mareegga iyo soo bandhigida haweeney soo dhaweyneysa (maadi ah), ama ka hor intaan xukunka lagu xakameynin kuwaas oo ka kooban meelaynta kafateerinta gacanta iyada oo aan la soo bandhigin haween (dhexdhexaad ah) deegaanka; Sidaa darteed, afar kooxood oo tijaabo ah ayaa la sameeyay: Naive Sal, Naive NLX, Exp Sal, iyo Exp NLX. Hal todobaad ka dib markii uu dhammaadey kulamadii ugu danbeeyay, qeybaha kala duwan ee xayawaanka ee koox kasta waxay la kulmeen qafiska foorjeerka ah (ragga ragga ah: calaamadaha jinsiga ku xiran) ama qabashada kafateer (ragga labka ah: calaamadaha aan caadiga ahayn / dhexdhexaad ah), halka qeybta kale aaney u muuqan wax kasta oo loo baahan yahay iyo halkii ay ku sii jiri lahaayeen baqashada guriga (si loo go'aamiyo astaamaha asaaska ah). Nidaamkan tijaabada ah wuxuu soo saaray kooxo 8: Naive Sal-No Cue, Naive Sal + Cue, Naive NLX-Maya Cue, Naive NLX + Cue, Cun Sali No, Cun Sal + Cue, Cun NLX-Cue, Exp NLX + Cue (n = 4 kasta oo ka baxsan Naive NLX-No Cue, n = 3). Xayawaanku waxay ahaayeen kuwo buuxa 10-15 min kaddib markii la soo gaadhay cirifka. Xakamaynta xayawaanka ayaa laga saaray baqashooda guriga waxayna si siman ufilan yihiin.

Immunohistochemistry.

Qeybinta iyo immunohistochemistry ayaa lagu qabtay sida kor ku xusan. Halkan, waxaan isticmaalnay antibio bakteeriyada bakteeriyada ah bakteeriyada p42 iyo p44 MAP Kansarrada ERK1 iyo ERK2 (FOOD; 1: 4 000; Technology Technology Sign Signaling). Diidmada koowaad ee asaasiga ah ayaa si baaxad leh loogu sharaxay suugaanta (Roux iyo Blenis, 2004; Murphy iyo Blenis, 2006; Frohmader et al., 2010b). Waxaa intaa dheer, ka-reebista asaasiga ah ee asaasiga ah ayaa ka hortagay dhammaan tallaal-celinta iyo falanqaynta reer galbeed ee nudaha maskaxda ee loo yaqaan 'fungi' ayaa muujiyay laba kooxood oo miisaankooda ku habboon.

Falanqaynta xogta.

Unugyada difaaca jirka (-H) ayaa lagu tiriyay gobollo badan oo maskaxeed iyagoo isticmaalaya tube sawir gacmeed oo ku xiran a Leica DMRD mikroskop: NAc [core (C) iyo qolof (S); 400 600 μm; Kortex celcelis ahaan sax; mPFC; aagga barmaamyada hore (ACA); Kortel prelimbic (PL); qaboojiyaha infralimbic (IL); 600 × 800 μm kasta, caudate-putamen (CP; 800 800 μm), iyo amygdala basal (BLA; 900 1200 μm; Balfour et al., 2004; Frohmader et al., 2010b; Pitchers et al., 2010b). Laba qaybood ayaa lagu tiriyay gobolka maskaxda iyo tirooyinka unugyada ee goobaha caadiga ah ee falanqaynta ayaa markaa lagu xisaabinayaa tirada unugyada bil kasta2. Labada xisaab ayaa la isu geeyaa xayawaan si loo xisaabiyo kooxda. Celcelis kooxeedyada ku dhex jira kooxaha galmada ku jira ama kuwa khatarta ah ayaa la barbar dhigey iyadoo la isticmaalayo laba dhinac oo ANOVA ah [arrimaha: daaweynta daroogada (NLX ama Sal) iyo cue (cue ama no cue) hose ah isbarbardhigyada iyadoo la isticmaalayo Holm-Sidak ama Mann-Whitney oo ah sumado munaasib ah oo ku haboon heerkulka muhiimka ah p <0.05. Naqshadda NAc ee xayawaanka khibrad u leh galmada, waxaa jiray isbeddel xoog leh oo ku aaddan muhiimadda arrimaha iyo sidaas darteed, isbarbardhigyo isbarbar dhig ah ayaa loo sameeyay si loo barbardhigo cusbada (Sal-No Cue) iyo kooxda cusbada (Sal + Cue) oo keliya.

Sawirro.

Sawirada dijital ah waxaa lagu qabtay kamarad CCD (Macrofire, Optronics) oo ku xiran a Leica mikroskoob (DM5000B) leh goobaha kamaradaha go'an. Sawirrada waxaa lagu soo wareejiyey barnaamijka Adobe Photoshop 9.0. Sawirada laguma bedelin haba yaraatee marka laga reebo beddinta iftiinka iyo kala duwanaanta.

Natiijooyinka

Isbeddelka waayo-aragnimada galmada ee isbeddelka unugyada dopamine VTA

Khibradda galmada waxay sababtay hoos u dhac ku yimid tirada dopamine soma (Berdihii. 1A-C). Dhibaatooyinka galmada si weyn ayaa loo yareeyey aagga iyo wareega Soma ee unugyada VTA TH-IR (aag: F(1,31) = 23.068, p <0.001; wareega, F(1,31) = 18.225, p <0.001). Waxaa sidoo kale jiray saameyn weyn oo muhiim ah waqtiga (aagga: F(2,31) = 6.377, p = 0.005; wareega, F(2,31) = 4.389, p = 0.021) iyo isdhexgalka weyn ee u dhaxeeya waayo-aragnimada iyo waqtiga (aagga: F(2,31) = 5.284, p = 0.011; wareega, F(2,31) = 4.347, p = 0.022). Isbarbardhiga sawir-qaadista ayaa shaaca ka qaaday in aagga iyo wareegga unugyada TH-IR-yada ay aad u yareeyeen 1 iyo 7 ka dib maalinta ugu dambaysa ee dabeecada galmada ee xayawaanka la-yaabka ah ee la xariira marka la barbardhigo kantaroolka jinsiga ah [Berdihii. 1B, aagga: p = 0.002 (1 d), p <0.001 (7 d); C, wareega: p = 0.009 (1 d), p <0.001 (7 d)]. Saamaynta habdhaqanka galmada ayaa faafay markii ay ku xigtay muddadii abaalmarinta ka-dhaafitaanka iyada oo cabbirka soma ee TH-IR neur-mareennada uu dib ugu noqday gundhigga 31 d ka dib kal-fadhigii ugu dambeeyay (Berdihii. 1B, aagga: p = 0.798; C, wareega: p = 0.785). Isbedelka waayo-aragnimada jinsiga ayaa aan lagu ogaan karin xayndaabka mid kasta oo ka mid ah dhibcaha waqtiga (Berdihii. 1D). Isugeynta hoos u dhac ku yimaada VTA dopamine ma ahayn mid ku xiran fadhiyada moodooyinka maalinlaha ah, maaddaama waayo-aragnimo la isku mari la'yahay intii lagu jiray kalfadhi shan jeer oo isku dhafan ayaa sidoo kale waxay soo saareen cabirka dunta ee VTA dopamine soma (Berdihii. 2A,B, E-H, aagga: p = 0.004; wareega: p <0.001). Taa bedelkeeda, waayo-aragnimada jinsiga ma saameynin cabbirka TH-IR soma ee ku jira maaddada ()Berdihii. 2C, I-J, aagga: p = 0.13; wareega: p = 0.16) ama isbeddelka miisaanka Soma ee ku dhow xaafada VTA non-TH-IR neurons (Berdihii. 2D, E-H, aagga: p = 0.46; wareega: p = 0.45).

Jaantus 1. 

Isbedelada siyaadada ah ee opioid-ku-soo-baxa ee Soma-ku-is-beddelka ah ee isdifaaca nollooyinka VTA. A, Sawirrada wakiilada ee VTA dopamine neurons oo ka soo jeeda galmada iyo xayawaan khibrad leh oo muujinaya hoos u dhaca qadarka Soma X ee ka dambeeya koontoroolka finanku. Miiska barafka, 7 μm. Macluumaad macaash ah oo muujinaya in khibrad jinsi ah (Cun, baarar madow) ayaa sababay hoos u dhac weyn oo aagga ah (B; ee kudhow2) iyo wareega (C; ee μm) ee unugyada dopamine VTA, 1 d (Naive, Exp; n = 6) iyo 7 d (Naive, n = 5; Walaac, n = 6), laakiin maaha 31 d (Naive, n = 6; Walaac, n = 8) kaddib marka la isku daro mishiinka kama dambaysta ah, marka la barbardhigo kontoroolka jinsiga ah ee jinsiga (Naive, baraha cad). Aagga waxaa loo yareeyey 84% ee ragga khibrad leh marka loo eego kantaroolada khatarta ee 1 ama 7 d. Xuddunta ayaa loo yareeyay 91.6 iyo 90% kooxo khibrad leh marka la barbardhigo xakamaynta 1 iyo 7. Wax saameyn ah kuma yeelanin wareega (D). Xayawaanka unugyada ee dopamine ee aagga (E) iyo wareega (F) waxaa looga hortagey naloxoon (NLX, n = 8), laakiin ma salineed (Sal, n = 7) daaweeynta inta lagu jiro isku darka, 7 d ka dib markii la isku daro kalfadhiga ugu dambeeya ee lagu qiyaaso kontroolka jinsiga ah (Sal, n = 5; NLX, n = 6). Xogta waxay u taagan tahay SEM; * waxay muujinaysaa farqi weyn marka la barbar dhigo koontaroolka jinsiga ah ee isla maalintaas (B, C) ama marka la barbardhigo kantaroolka galmada ee lagu daaweeyo saline-daawaynta iyo naloxoon-la-daaweeyey raga (oo ah rag qibrad leh)E, F).

Jaantus 2. 

Khibrada galmada waxba kama yareeynin cabbirka sooman ee miisaanka nikra dopamine neurons ama Virka nondopamine neurons. VTA TH-IR neuron soma (A; ee kudhow2) iyo wareega (B; ee kudhow) jinsi ahaan jilicsan (cadaan) iyo xayawaan qibrad leh (madow) kuwaas oo helay khibrad adoo laba jeer isugeynaya toddobaadkii halkii maalmo isku xigta. Substantia nigra TH-IR Soma (C) iyo VTA non-TH-IR Soma (D) jinsi ahaan jilicsan (cadaan) iyo xayawaan khibrad leh (madow). Xogta waxay u taagan tahay SEM; * waxay muujinaysaa farqi weyn marka la barbar dhigo kantaroolka jinsiga. Sawirada wakiilada oo muujinaya TH-IR (brown) neur-mareenada VTA-ka ee jinsiga ah (E), iyo khibrad u leh (F) ragga. G, H, Sawir sare oo sareeya ee neuron tilmaamaya fallaadhaha E iyo F siday u kala horreeyaan. Calaamadaha maskaxda ayaa lagu muujiyaa buluugyada nuddaha leh. Sawirrada wakiilada oo muujinaya naqshadaha TH-IR ee SN ee jinsiga galmada ah (I) iyo khibrad (J) ragga. Rugta calaamadsan: E-J, 20 μm.

Waayo-aragnimada jinsiga-yar ee hoos u dhaca tirada dhimashada ee VTA dopamine waxay ku xiran tahay firfircoonida loo yaqaan 'opioid receptor activation'

Yaraynta VTA dopamine neuron soma oo ay sababtay khibrad galmo ayaa xannibay maadada Nortonone ee MOR antagonist, ka hor inta aan la isku darin kulankan. Daaweynta Naloxone ka hor inta aan la isku darin fadhiyada waxay saameyn weyn ku yeelatay degaanka (F(1,22) = 4.738, p = 0.041) oo u muuqday inay saameyn weyn ku leedahay wareega wareegga (F(1,22) = 2.892, p = 0.052). Is-dhexgalka weyn ee u dhaxeeya waayo-aragnimada iyo daaweynta naloxoonta ayaa laga helay degaanka (F(1,22) = 5.578, p = 0.027) iyo wareega (F(1,22) = 8.167, p = 0.009). Isbarbardhigga kala duwan ayaa muujiyay in waayo-aragnimada jinsiga ee xayawaanka lagu daweeyay ay si aad ah u yareeyeen aagga iyo wareega dareenka naqshadaha VTA dopamine 7 ka dib markii la isku daro kulankan ugu dambeeya ee lala yeeshay ragga iyo dumarka uurka lehBerdihii. 1E, aagga: p = 0.018; F, wareega: p = 0.007). Taa bedelkeeda, xayawaanka naloxoon-la-macaamilay oo la-macaamilay oo aan ka duwaneyn ragga naloxoon-la daweeyey (Berdihii. 1E, aagga: p = 0.483; F, wareega: p = 0.330). Intaas waxaa dheer, tirada sooman ee khibrada leh ee dabiiciga ah ayaa si aad ah hoos ugu dhacay marka la barbar dhigo xoolaha khibrada leh ee naloxone (Berdihii. 1E, aagga: p = 0.002; F, wareega: p = 0.002). Saameyntii Naloxone waxay ahayd mid gaar ah oo ku saabsan waayo-aragnimada galmada, maadaama ay daaweynta naloxoon kaliya aysan saameyneynin tirada unugyada TH-IR ee soomaliga ah ee kufsiga galmada naloxone-la-daweeyey marka la barbar dhigo kontoroolka saline-daaweynta (Berdihii. 1E,F). Waxaa intaa dheer, saameynta Naloxone-ga ee hoos u dhac ku yimid qiyaasta Soma ee khibrad la'aanta ah maaha sababo saameyn ku yeeshay naloxoon ku saabsan dabeecada galmada, maadaama dabeecada laysku daro si aan kala duwaneyn u dhexeysa naloxone-iyo saline-la daweeyey, marka laga reebo wakhti dheer oo lagu bilaabi karo mishiinka kadib marka la naqdiyo (isbeddelka dib u dhiska) ee ragga naloxoon-la daweeyo inta lagu guda jiro fadhiga koowaad iyo shanaad ee wada xaajoodka (p = 0.03 iyo p = 0.004, siday u kala horreeyaan). Labada nin ee saline-iyo naloxone-la daweeyey labadooduba waxay daraasad ku sameeyeen shahwad marka lagu guda jiro mid kasta oo ka mid ah shanta xisaab ee mawduucyada.

Dhiirrigelinta abaalmarinta jimicsiga ee mira dhalada

Saameynta dhibaatada galmada ee kudhaca qaybta VTA dopamine ee qiyaas ahaan tallaabada EOP ee VTA waxay la mid tahay kuwa lagu soo tabiyey wariyayaashii dibadda ahaa (Sklair-Tavron et al., 1996; Russo et al., 2007). Sidaa daraadeed, waxaa la baaray in bacriminta unugyada VTA-da ee abaalmarinta dabiiciga ah ay saameyn ku yeeshaan abaal-marinta morphine opiate. Runtii, waayo-aragnimada galmada waxay sababtay dulqaad miidhanka moorfiilka ah, oo la mid ah saamaynta ay ku yeesheen dadka dabiiciga ah (Russo et al., 2007). Ragga u dhashey jinsiga ayaa ku fashilmay in ay hormariyaan CPP xmmeX mg / kg morfin; halka, raga iyo dumarka uur-jiifka ah waxay sameysteen CPP qadarkan, sida lagu muujiyay iyadoo la isticmaalayo wakhti ka badan waqtiga qolka morphine-paired marka la barbar dhigo qolka saline-paired inta lagu guda jiro tijaabada kadib (Berdihii. 3; p = 0.039). Labada kooxood ee jinsiga ah iyo kuwa qibradaha leh waxay waqti badan ku qaadeen qolka morphine-paired marka la barbardhigo qolka saline-paired oo leh qiyaaso miisaan oo sare: 5.0 mg / kg (Berdihii. 3; Naïve: p = 0.029; Walaac: p = 0.012) iyo 10.0 mg / kg (Berdihii. 3; Naïve: p <0.001; Exp: p = 0.002).

Jaantus 3. 

Saameynta dhibaatooyinka galmada ee ku saabsan abaalmarinta morphine. Waqtiga lagu qaato saline- (Sal) ama morphine-paired (Mor; 0.5, 5 ama 10 mg / kg) oo qiyaasta baaritaanka ka dib galmada (Naive, n = 10-13) ama khibrad leh (Exp, n = 9-13) ragga. Xogta la soo bandhigay oo loo yaqaan "SEM"; * waxay muujinaysaa farqi weyn marka la barbar dhigo qolka Sal-paired ee xayawaanka isku midka ah. NS, Aan muhiim ahayn.

Dhibaatada waayo-aragnimada jinsiga-fududaynta dabeecadda mawqifka waxay ku xiran tahay firfircoonida gardarrada ee opioid

Natiijooyinka helitaanka illaa hadda waxay muujinayaan in EOP ku shaqeynayaan VTA inta lagu jiro 5 fadhiyada maalinlaha ee gaaban ee sababa kulannada naafonimada Venter dopamine neurons oo la mid ah saameynta morphine ama heroin-self-administration (Russo et al., 2007; Mazei-Robison et al., 2011). Waxaannu ku fekereynay in hoos u dhac weyn ee VTA dopamine uu yahay mid muhiim u ah barashada abaal-marinta iyo gaar ahaan khibradaha galmada-ku-sahlanaanta hab-dhaqanka jinsiga marka loo eego dhiirigelinta iyo waxqabadka. Tilmaamahan waxaa lagu baaray iyada oo la joojinayo isticmaalka naloxone inta lagu guda jiro mulkiilaha iyo baaritaanka saameynta fududeynta jinsiga galmada ee kufsaday jimicsiga galmada inta lagu guda jiro shanta kalfan oo maalmo ah. Xogta ayaa lagu soo bandhigay Jaantuska 4 oo ah fadhiyada ugu horreeya iyo shanaad oo kaliya, sida kuwani waa xogta ugu wanaagsan ee muujinaysa fududeynta khibrad u leh dabeecada mawqifka. Waxaa intaa dheer, saameynta muddada dheer ee daweynta naloxoon inta lagu jiro kalfadhiyada isku dhafan ayaa lagu tijaabiyaa dayactirka waayo-aragnimada ku-siman ee dabeecada maadada, inta lagu jiro tijaabada ugu dambeeya 1 kaddib. Jaantuska 4A waxay muujinaysaa naqshada tijaabada ah. Waxaa jirey saameyn weyn oo muhiim ah oo ku saabsan isku duba ridida dhammaan xuduudaha dabeecadaha jinsiga ah (qarsoodi: F(2,55) = 11.286, p <0.001; daahitaan la'aanta intromission: F(2,55) = 8.767, p <0.001; daahitaanka biyo baxa: F(2,55) = 10.368, p <0.001) iyo daaweynta naloxoon ee latencies si kor loogu qaado (F(1,55) = 6.585, p = 0.013) iyo isdhexgalka (F(1,55) = 7.863, p = 0.007). Isbarbardhigga kala duwan ayaa muujiyay in daweynta naloxoontu ay saameeysay habdhaqanka galmada inta lagu guda jiray munaasabada koowaad ee mawduucyada sababta oo ah xayawaanka naloxone ayaa si qoto dheer uga faaiidaystey si ay ugu horeeyaan (p = 0.002) iyo isdhexgalka (p = 0.002) marka la barbar dhigo xakamaynta saliida maalinta ugu horaysa ee mate. Saameyntan naloxooneed ee ku saabsan dabeecadda jinsiga hore ayaa lagu xakumay waaya-aragnimada jinsiga oo aan la ogaan intii lagu jiray mid ka mid ah kulammada muteShaxda 1). Intaa waxaa dheer, maamulka naloxoon ka hor mid kasta oo ka mid ah shan kulan oo mawaadiic ah ma aysan hor istaageynin fududeynta astaamaha galmada ee khibradda galmada. Iyadoo la tixgelinayo saameynta sii xoojinta khibradaha galmada, ragga qaba daawooyinka saline-ku-daweynta ah waxay muujiyeen hoos u dhigista latens si ay u dhistaan ​​(Berdihii. 4B; p = 0.032) Diidmada (Berdihii. 4C; p = 0.033) iyo dheecaan (Berdihii. 4D; p <0.001) inta lagu gudajiray kal fadhigii shanaad marka la barbardhigo kalfadhigii ugu horeeyey ee isku darka, kaas oo muujiyey fududeynta dhaqanka galmada. Sidoo kale, ragga la daweeyay naloxoon waxay soo bandhigeen daahitaanno aad u gaagaaban si ay u koraan (Berdihii. 4B; p <0.001), soo-galitaanka (Berdihii. 4C; p <0.001), iyo biyo baxa (Berdihii. 4D; p = 0.017) shanaad marka loo eego maalinta koowaad. Waxaa intaa dheer, ragga naloxoon-la daweeyey ma aysan ka duwanayn xakamaynta shubanka ee mid ka mid ah latans inta lagu jiro fadhiga shanaad ee mergedka.

Jaantus 4. 

Opioids endogen ophiid ah ayaa door muhiim ah ka ciyaara fududeynta habdhaqanka galmada ee khibrad u leh. A, Naqshad tijaabo ah. B-D, Xeerarka habdhaqanka galmada ee loogu talagalay raga la daweeyey cusbada (Sal, cadad cad, n = 11) ama naloxone (NLX; baararka madow, n = 12) oo leh nidaam nidaamsan. Xogta la muujiyay ayaa ah inay hoos u dhacaan (B; seken), galmo (C; ilbiriqsi), iyo dheecaan (D; ilbiriqsi) maalmaha 1 iyo 5 oo ah shan maalmood oo isku xigta oo lab ah. Intaas waxaa sii dheer, xogta ayaa lagu muujiyay imtixaanka ugu dambeeya ee maadada, 7 d ka dib fadhiga shanaad ee mating. Xogta waxaa lagu soo bandhigaa celcelis ahaan SEM; + wuxuu muujinayaa faraqa u dhaxeeya maalmaha 1 iyo 5 ee daaweynta; * waxay muujinaysaa faraqa u dhaxeeya maalinta iyo maalinta 5 ee daaweynta; # waxay muujinaysaa faraqa u dhaxeeya kooxaha naloxoon iyo saliinaha maalintii.

Eeg miiskaan: 

Jadwalka 1. 

Maamulka Naloxone ka hor inta aan la isku dardarin latencies kordhinta qulqulka iyo galmada oo kaliya maalinta ugu horeysa ee mate

Taa beddelkeeda, daaweynta naloxoon inta lagu guda jiro fadhiga khibradda galmada ayaa carqaladeeyey dayactirka waayo-aragnimada kufsiga ee habdhaqanka jinsiga ee maalinta dhammaadka tijaabada. Maalinta imtixaanka waxaa la qabtey 7 kadib kaddib fadeexadii ugu danbeysay ee mawduuca maqnaanshaha duritaanka naloxoon. Xakamaynta salineed ee daaweynta ragga ayaa soo bandhigay waayo-aragnimadii la filayay oo ay keentay fududeynta habdhaqanka galmada. Gaar ahaan, latencies si ay u fuushaan, roonaanta, iyo shahwad la'aanta lagama maarmaanka u dhaxaysa fadhiga shanaad ee mawduuca iyo maalinta imtixaanka ugu dambeeya (Berdihii. 4B-D). Halka, ragga naloxoon-la-daweeyey waxay muujiyeen koror weyn oo ku yimid latencies si ay u fuushaan (Berdihii. 4B; p = 0.033), galmo (Berdihii. 4C; p = 0.036) iyo dheecaan (Berdihii. 4D; p = 0.049) maalinta maalinta imtixaanka lagu barbardhigayo fadhiga shanaad ee mawqifka. Sidoo kale, maalmaha tijaabada naloxone naloxone ayaa lagu ogaadey inay aad u hooseyso marka loo eego ragga sida loo daaweeyo ee saline-ka lagu daaweeyo iyadoo lagu soo bandhigay dariiqa dheeriga ah ee cirifka (Berdihii. 4B; p = 0.017) iyo isdhexgalka (Berdihii. 4C; p = 0.043). Sidaa daraadeed, daaweynta naloxoontu waxay xannibaysaa dayactirka, laakiin ma ahan bilawga, horumarinta khibrad-u-sahlanaanta habdhaqanka galmada. Natiijooyinkaas waxay muujinayaan kaalin muhiim ah oo ku wajahan barta dopamine NOP-ta ee EOP-ku-daba-marinta dareenka muddada-dheer ee xoojinta dabeecadda dabiiciga ah ee dabiiciga ah.

Dhawr tijaabo oo dheeri ah ayaa la sameeyay si loo go'aamiyo saameynta astaamihii loo yaqaan 'opioid' ka horjoogsanaya in lumiyo xoojinta dhaqanka galmada mudo dheer oo ka timi la'aanta maamulka naloxoon la'aanta maalinta ugu dambeeya ee tijaabada ah (Berdihii. 5A,B), waxay ahaayeen kuwo si gaar ah u lumiya muddada fog, laakiin ma ahan daryeel waqti gaaban oo fudfudud ah (Berdihii. 5E,F), ma aysan keenin marxalad kasta oo la taabto naloxone oo kali ah (Berdihii. 5C,D), oo aan sababin luminta abaalmarinta jinsiga ee naloxoon-la-daweeyey ragga (Berdihii. 5G,H). Marka hore, si aad u muujisid dhaqanka isbeddelka ee isbeddelka ah ee tijaabada kama dambaysta ah ee maaddada naloxone, sababtoo ah naloxone ama saline waxaa la maamulay maalinta ugu dambeeya ee tijaabada ee xayawaanka lagu helay mary la midabtey naloxoon inta ay heleen khibrad jinsi ah (Berdihii. 5A). Waxaa jiray saameyn weyn oo muhiim ah oo ku saabsan maadays maalinle ah oo ku yaal buurta (Berdihii. 5B; F(2,27) = 30.031, p = 0.038) iyo isdhexgalka (Shaxda 2; F(2,27) = 10.686, p = 0.048). Ma jirin saameyn muhiim ah oo ku saabsan maadays maalinle ah oo ku saabsan ba'anShaxda 2; F(2,27) = 2.388, p = 0.109) Si la mid ah sida kor ku xusan, daweynta naloxoon inta lagu jiro wadaagga ma aysan saameynin fududaynta dabeecadaha galmada inta lagu guda jiro fadhiyada 5-tii hore ee galmada. Labada kooxood (saline-iyo daaweynta naloxone-daweynta sida lagu go'aamiyey daaweynta la helay intii lagu gudajiray tijaabada ugu dambeysay labadaba, labaduba waxay heleen naloxoon inta lagu jiro isu-duwaha) waxay muujiyeen habdhaqanka galmada ee sahlan ee maalinta 5 marka la barbardhigo maalinti 1 oo muujisay inay si aad ah u yareynayaan latenciesBerdihii. 5B; saline: p = 0.033; Naloxone: p = 0.014) iyo isdhexgalka (Shaxda 2; saline: p = 0.034; Naloxone: p = 0.026). Xayawaanka lagu qaato naloxone ama saliin on maalinta ugu dambeeya ee tijaabada lagu sameeyay ayaa waxay laydhsadeen inay sii dheeraadaan (Berdihii. 5B; saline: p = 0.018; Naloxone: p = 0.029) iyo isdhexgalka (Shaxda 2; saline: p = 0.019; Naloxone: p = 0.020) marka la barbardhigo maalintii shanaad ee waayo-aragnimada maadinta. Sidaa daraadeed, maamulka naloxone ama saline ee maalinta imtixaanka isla markiiba ka hor inta aanad moobin saameyn ku yeelashada saameynta daaweynta naloxoon inta lagu guda jiro kalfadhiyada galmada iyo feejignaanta fududeynta dhaqdhaqaaqa jinsiga muddada dheer waxay la mid tahay tan muujisay xayawaanka aan helin cirbado maalinta ugu dambeeya ee tijaabinta mate (Berdihii. 4).

Jaantus 5. 

Opioids endogen ophiid waxay muhiim u tahay muujinta muddada-dheer ee fududeynta khibrad-u-helidda dhaqanka galmada. A, Naqshad tijaabo ah oo lagu tijaabinayo saameynta daweynta NLX maalinta maalinta imtixaanka. B, Buurto xayiran maalmo 1 iyo 5 oo ka kooban shan maalmood oo isku xigta oo isku dhafan iyo maalmo tijaabin ah oo tijaabin ah (tijaabo) kadib marka la soo saaro saline (gray) ama naloxone (madow). Xogta waxay u taagan tahay SEM. * Waxay muujinaysaa faraqa u dhaxeeya maalinta 1 iyo maalinta 5 ee daaweynta. # waxay muujinaysaa faraqa u dhaxeeya Maalinta Imtixaanka iyo Maalinta 5 ee daaweynta. C, Naqshad tijaabo ah oo lagu tijaabinayo tijaabinta saameynta daaweynta naloxoon ka hor intaan la helin waayo-aragnimo galmo oo ku saabsan dabeecada macaamilka. D, Buurta dhoobada ee maalinta tijaabada ah ee tijaabada ah, 7 maalmood ka dib maalmaha 5 ee duriinka salineeska ama naloxone ee maqan la'aanta. Xogta waxay u taagan tahay SEM. E, Naqshad tijaabo ah oo lagu tijaabinayo tijaabinta in daaweynta naloxoontu ay saameeyeen bandhigga gaaban ee dabeecadaha galmada ee suurtogalka ah ee xayawaannada la xariira galmada. F, Buurta qorraxda ee maalinta 1 iyo maalinta 5 ee shan maalmood oo isku xiga oo ah maalmo isku-dhafan iyo maalinta dambi-baarista ah, maalinta 1 ka dib maalinta 5 ee joogitaanka saline (gray) ama naloxone (madow). Xogta waxay u taagan tahay SEM. * Waxay muujinaysaa faraqa u dhaxeeya maalinta 1 iyo maalinta 5 ee daaweynta. G, Naqshad tijaabo ah oo lagu tijaabinayo tijaabada si loo ogaado in daaweynta naloxoonta ay xannibtay saameynta wanaagsan ee dhaqanka galmada. H, Waqtiga lagu qaato qolka labka ah ee la duubay (ilbiriqsi) inta lagu jiro mudnaanta (caddaanka ah) iyo baarista ka dib (madow) ee xayawaanka lagu qaato naloxoon ama saline ka hor inta aanad moobin. Xogta waxay u taagan tahay SEM; * waxay muujinaysaa farqi weyn marka la barbardhigo ugu yaraan.

Eeg miiskaan: 

Jadwalka 2. 

Xogta la muujiyay ayaa ah latencies in la geliyo iyo shahwo (seconds) laga bilaabo tijaabooyinka la sameeyay ee lagu ogaanayo in saameynta MLX joojinta ee luminta xoojinta dhaqanka jinsiga muddada dheer ay ka timaaddo madax bannaani la'aanta maamulka naloxoonta maalinta dhammaadka tijaabada

Si loo go'aamiyo in ay ahayd daaweynta naloxoon marka la isku-tagay khibrad galmo oo aan lagu celinin naloxoon kasta oo sababay naafonimada habdhaqanka galmada 7 kadib daaweynta ugu dambeysa, xayawaannada jinsiga ah waxaa la siiyaa shan maalin oo irbado ah naloxoon ama saline oo la isku duro ka hor inta aan lagu baarin 7 d dambe (Berdihii. 5C). Looma helin faraqyo muhiim ah oo loogu talagalay xakameyn kasta oo isku dhafan oo u dhaxeeya kooxaha salineeska iyo saliida naloxone (Berdihii. 5D; dhiiqada buurta; Hoos-u-dhaca joogtada ah: saline 139.7 ± 40.3 vs naloxone 121.83 ± 42.55; dhererka xayawaanka: saline 887.9 ± 70.0 vs naloxone 1050.8 ± 327.31). Natiijooyinkani waxay muujinayaan in naloxone keliya uunan ku filneyn inuu bedelo habdhaqanka galmada ku xigta, oo la mid ah saameyn la'aanta naloxone oo keligiis ah oo ku jirta barta dopamine neuron.

Waxaan u maleynayaa in daweynta naloxoon inta lagu jiro helitaanka khibradda jinsiga ay carqaladeynayso muujinta muddada dheer ee khibrada jinsiga-u sahlaysa habdhaqanka galmada. Si loo tijaabiyo tan kale, saameynta daaweynta naloxoon inta lagu jiro isu-darka ayaa lagu tijaabiyay dabeecadaha galmada ee xigta inta lagu jiro tijaabada ugu dambeysa ee mating, kaas oo la sameeyey kaliya 1 d kadib marka la isku daro mishiinka (tijaabada tijaabada ah; Berdihii. 5E). Waxaa jiray saameyn weyn oo muhiim ah oo ku saabsan maadinta maalinta miiska (Berdihii. 5F; F(2,20) = 19.780, p <0.001) iyo daahitaannada soo-dhexgalka (Shaxda 2; F(2,20) = 19.041, p <0.001). Ma jirin saameyn weyn oo muhiim ah maalintii oo ku saabsan daahitaanka shahwada (Shaxda 2; F(2,20) = 3.042, p = 0.070). Si la mid ah sida kor ku xusan, dhammaan ragga (inkastoo daaweynta salineed ama naloxone) ay fududeeyeen fududeynta dabeecadaha galmada inta lagu guda jiro shanta sano ee khibradaha jinsiga oo tilmaamaya latencies gaaban oo ay ku xirantahay (Berdihii. 5F; saline: p = 0.002; Naloxone: p = 0.018) iyo isdhexgalka (Shaxda 2; saline: p = 0.006; Naloxone: p = 0.009) maalinta 5 marka loo eego maalinta 1. Sidoo kale, dabeecad galmo oo sahlan ayaa lagu soo bandhigay maalinta imtixaanka marka la barbar dhigo maalinta 1 oo tilmaamaysa latights gaaban oo qulqulaya (Berdihii. 5F; saline: p = 0.001; Naloxone: p = 0.020) iyo isdhexgalka (Shaxda 2; saline: p = 0.004; Naloxone: p = 0.009). Muhiimad ahaan, daaweynta naloxoon inta lagu jiro wadaagga ma aysan si weyn u saameynin khibradda galmada ee fududeynta habdhaqanka jinsiga marka la tijaabiyo 1 d ka dib khibrad jinsi, oo ka madax banaan daaweynta naloxoon on maalinta imtixaanka dhammaystiran.

Ugu dambeyntii, waxaan tijaabinay suurtagalnimada in naloxone saamaynta ay ku yeelan karto muujinta muddada dheer ee dabeecada galmada fududeysa ay sabab u tahay saameynta xannibaadda naloxone ee ku aaddan abaalmarinta astaamaha galmada. Si kastaba ha noqotee, naloxone si dhakhso leh loo maareeyay kahor intaanu u bislaanin ma bedelin sameynta CPP ee ku habboon galmadaBerdihii. 5G), taasoo soo jeedinaysa in daweynta naloxoon aysan wax ka bedelin abaalmarinta galmada. Labada kooxood ee saline- iyo naloxone-la daweeyey waxay sameeyeen CPP-ga muhiim u ah dabeecadaha galmada sida ku cad wakhti si weyn u kordhay qolka galmoodka ah (Berdihii. 5H; saline: p = 0.038; Naloxone: p = 0.002) inta lagu gudajirayo tijaabada kadib marka la barbardhigo kuwa ugu horreeya. Sidaa daraadeed, naloxunku ma saameynayo waxyeellada waxyeelada leh ee ilaalinta dabeecadaha galmada la fududeeyay iyada oo la xirayo abaalmarinta la xidhiidha dhaqanka galmada.

Fududeynta dabeecadda galmada waxay ku xiran tahay falka EOP ee VTA

Si loo xaqiijiyo in EOP ay si gaar ah ugu dhaqanto VTA si ay u soo jiidaan fududeynta mudada dheer ee habdhaqanka galmada, naqshadaynta tijaabada ah ee lagu soo koobay Jaantuska 3A waxaa lagu soo celiyey faafinta fayruuska intra-VTA naloxoon halkii lagu mudeyn lahaa nidaamka. Natiijooyinka waxay isku mid ahaayeen maamulka nidaamka kor ku xusan. Waxaa jiray saameyn weyn oo muhiim ah oo ku saabsan maadinta maalinta oo dhan dhammaan xaddiga habdhaqanka galmada (Berdihii. 6A, dherer buuran: F(2,33) = 4.494, p = 0.019; B, latency introitig: F(2,33) = 4.042, p = 0.027; C, dhererka biyo-xidhka: F(2,33) = 5.309, p = 0.010) iyo daweynta intra-VTA naloxone-ta ee latencies si loo dhigo (F(1,33) = 7.345, p = 0.011) iyo isdhexgalka (F(1,33) = 6.126, p = 0.019). Inta-VTA Naloxone-ka ma aysan horjoogsanayn fududaynta asaasiga ah ee habdhaqanka galmada inta lagu jiro 5 ee mating, maaddaama naloxoon la daweeyey ragga ay muujiyeen hoos-u-dhaca jeexjeexyada (Berdihii. 6A; p = 0.001), galmo (Berdihii. 6B; p <0.001), iyo biyo baxa (Berdihii. 6C; p = 0.001) maalinta 5 marka loo eego maalinta 1. Naloxone-la-daweeyey ragga ma aysan ka duwanayn ragga ay saline-ku-daweeyeen maalinta shanaad ee isu-duwanaashaha mid ka mid ah latansiyada. Daaweynta gudaha-VTA naloxone, sida nidaamka nidaamka, waxay sababtay inay si wayn u kordho buur (Berdihii. 6A; p <0.001) iyo daahitaannada soo-dhexgalka (Berdihii. 6B; p <0.001) maalintii ugu horreysay ee isku-darka marka la barbardhigo ragga cusbada lagu daweeyay, ee aan lagu arkin kal-fadhiyada xiga ee xiga (inta lagu jiro naloxone- iyo ragga cusbada lagu daweeyay ma kala duwanaan). Mid ka mid ah indha indheynta lama filaanka ah ayaa ahayd in tijaabadan, ragga cusbada lagu daaweeyay aysan muujineynin fududeyn heer sare ah oo daahitaan ah ama daahitaan la'aanta soo gelitaanka (sida lagu muujiyay dhammaan tijaabooyinka kor lagu sharaxay), oo kaliya daahitaanka dheecaanka ayaa la soo gaabiyay maalintii shanaad marka la barbar dhigo maalinta koowaad (cusbada: p = 0.001).

Jaantus 6. 

Dhibaatooyinka Asoono ee VTA-da dhexdhexaadinta khibrad-u-sahlanaanta habdhaqanka galmada iyo dayactirka muddada-dheer. Xeerarka habdhaqanka galmada ee loogu talagalay raga la daweeyay cusbada (Sal, cadad cad, n = 8) ama NLX (baararka madow, n = 6) oo leh maareynta intra-VTA. Xogta la muujiyay ayaa ah inay hoos u dhacaan (A), isdhexgalka (B), iyo dheecaan (C) maalmaha 1 iyo 5 oo ah shan maalmood oo isku xigta oo lab ah. Intaa waxa dheer, xogta ayaa lagu muujiyay maalinta ugu dambeysa ee tijaabinta maadada, 7 d ka dib maalinta 5 ee maqnaanshaha duritaanka salineed ama naloxoon. Xogta waxay u taagan tahay SEM; + wuxuu muujinayaa faraqa u dhaxeeya maalmaha 1 iyo 5 ee daaweynta; * waxay muujinaysaa faraqa u dhaxeeya maalinta iyo maalinta 5 ee daaweynta; # waxay muujinaysaa faraqa u dhaxeeya naloxone iyo kooxo Sal ah maalintii. Jaantusyada Schematic ee qaybaha VTA-ga (X, -4.60; I, -5.00, J, -5.25 oo ka soo jeeda bregma) oo tilmaamaya goobaha lagu duro gudaha VTA ee dhammaan xayawaanka ee tijaabinta 5 (saline, cad, naloxoon, madow, missed, cawl), Isticmaal sawirro template ah oo ka yimid Swanson Meeqa Maskaxda (Swanson, 2004). Cannulas waxay ahaayeen labadaba, laakiin goobaha cirbadaha ayaa si aan toos ahayn loogu soo bandhigay fududeynta soo bandhigidda. fr, Fasciculus retroflexus; ML, Maqsinnada Warbaahinta; SN, muhiim nigra.

Daaweynta naxwaha ee 'VTA-VTA' ayaa xannibay ilaalinta habdhaqanka galmada ee sahlan ee lagu arkay raga galmoodka khibrada leh, oo la mid ah saameynta naloconka nidaamka. Gaar ahaan, maalinta ugu dambeeya ee tijaabada ah ee naloxone-la daweeyey ragga waxay heleen latencies dheeri ah (Berdihii. 6A; p = 0.011), galmo (Berdihii. 6B; p = 0.010), iyo dheecaan (Berdihii. 6C; p = 0.015) marka la barbardhigo kulankooda shanaad ee mawduucyada iyo marka la barbardhigo ragga ku jira saline-la daweeyey maalinta ugu dambeeya (Berdihii. 6A, p = 0.006; B, p = 0.008). Taa bedelkeeda, xayawaannada daaweynta ee saline-daaweynta ma aysan kala duwaneyn latights si ay u fuushaan oo ay u galaan inta u dhaxaysa maalinta imtixaanka ugu dambeeya iyo maalinta 5 ee mate. Saameynahan waxay ahaayeen kuwo gaar u ah dhalidda naloxoonta VTA, sida ragga leh goobaha cannulation ee ku dhow laakiin aan la beegsan VTA (Berdihii. 6D; n = 3) wuxuu muujiyay fududeynta dhaqdhaqaaqa galmada ee mudada dheer sida xakamaynta sunta daaweynta (ML, IL = 53 ± 6.245, EL = 389 ± 299.5) oo si aad ah uga duwan marka la barbar dhigo xayawaanka VA naloxone ee maalinta tijaabada ah ee tijaabada ah (ML, IL: p = 0.029; EL: p = 0.0395).

Ficil EOP ayaa looga baahan yahay jinsiga la xidhiidha dhaqdhaqaaqa maskaxda ee curyaanka ah

Iyada oo ku saleysan natiijooyinka fog, waxaannu ku falanqeyneynaa in dhaqdhaqaaqa EOP-da ee VTA inta lagu jiro khibrada maadada iyo hoos u dhaca yaraanta ee VTA dopamine soma ay muhiim u tahay ku-tiirsanaanta dhiirigelinta dhiirigelinta si loo macaamilo dhaqdhaqaaqa abaal-marinta la xidhiidha iyo sida ugu dhakhsaha badan, dayactirka fududeynta dhaqanka galmada. Si loo baaro aragtidan, saameynta joojinta soo celinta opioid inta lagu jiro khibrada la xidhiidha dhaqdhaqaaqa neerfaha ee lagu soo bandhigay shuruudaha xaaladaha xaddidan ee saadaalinta abaalmarinta jinsiga (calaamadaha jinsiga la xiriira) ayaa la baaray. Xayawaannada jinsiga ah ayaa sidoo kale soo gaadhsiiyay sheekooyinka deegaanka, laakiin kuwani ma aysan la xiriirin waayo-aragnimada hore ee mawqifka, markaa waxay ahaayeen tilmaamo dhexdhexaad ah. Ugu dambeyn, heerarka PERK-da ayaa lagu go'aamiyey kooxo xag-jirka ah oo khibrad iyo jinsi ku dhisan oo ku hadhay baqashada guriga aynaan u soo bandhigin tilmaamo kasta (-No Cue). Xaqiijinta iyo kordhinta natiijooyinka hore (Balfour et al., 2004), soo bandhigista tilmaamaha macnaha guud ee la xidhiidha abaalmarinta jinsiga ee hore waxay si weyn u kordhiyeen ereyga "PERK" oo lagu muujiyay raga kufsiga ee qibrada leh ee NAc (Berdihii. 7) iyo mPFC (Berdihii. 8A-C), laakiin ma aysan keenin firfircoonaanta neuronalaha ee BLA (Berdihii. 8D) ama CPU (xogta aan la muujin). Waxaa jiray waxyeelo weyn oo soo gaartay faafinta cue ee NAc core (F(1,12) = 12.1941, p = 0.004), ACA (F(1,12) = 5.541, p = 0.038), iyo PL (F(1,12) = 5.241, p = 0.041), iyo daweynta naloxoon ee gudaha NAc (F(1,12) = 6.511, p = 0.025), ACA (F(1,12) = 15.242, p = 0.002), iyo PL (F(1,12) = 7.336, p = 0.019). Waxaa jiray isdhexgalka muhiimka ah ee asaasiga NAc (F(1,12) = 10.107, p = 0.008), ACA (F(1,12) = 16.060, p = 0.002), PL (F(1,12) = 8.235, p = 0.014), iyo IL ((F(1,12) = 6.965, p = 0.022). Ugu horreyntii, soo-gaadhista Cue ee la xidhiidha fayrasku wuxuu si ballaaran u kordhay xayawaanka laysku qurxiyo ee xayawaanka lagu yaqaan (sal Sal + Cue) marka la barbar dhigo koontooyinka aan loo soo bandhigin calaamadaha oo laga soo qaaday qafiska guriga (Exp Sal-No Cue) ee NAc core (Berdihii. 7A; p <0.001), iyo mPFC hoosaadyada ACA (Berdihii. 8A; p = 0.001), PL (Berdihii. 8B; p = 0.003), iyo IL (Berdihii. 8C; p = 0.029). Taa bedelkeeda, marka loo eego xayawaannada jilicsan ee la galmoodo, oo la xidhiidha calaamadaha xaddiga ah, ee aan la xiriirin abaalmarinta jinsiga, uma baahnin PERK meel kasta oo ka mid ah maskaxda (Naive Sal + Cue marka la barbardhigo Naib Sal-No Cue; Sawirro. 7, 8), oo muujinaya in indho-gashiga PERK uu gaar u yahay soo-gaadhista khibradaha jinsiga-la xiriira. Waxaa intaa dheer, waayo-aragnimada galmada oo kaliya wax isbeddel ah kama dhigin astaamaha asaasiga ah ee gobolada maskaxda, ma jirin wax khilaaf ah oo u dhexeeya kooxihii laga qaaday baqashada guriga, ha ahaato mid galmo ah ama waayo-aragnimo leh, oo lagu daaweeyo saline ama naloxone.

Jaantus 7. 

Ficil-galinta foosha-xumada ee loo yaqaan 'opioid action' ayaa looga baahan yahay firfircoonaanta neerfaha ee NAc oo ay sababtay amarrada la xidhiidha jinsiga. Nambarada PERK-unugyada ah ee mm2 ee nucleus xajmiga asaasiga ah (A) iyo qolof (B) jinsi ahaan (khafiif ah) iyo qibrad leh (xayiraan, madow) xayawaan lagu sameeyay NLX ama saline (sal) inta lagu jiro kulamo isku dhafan (ragga matala) ama kulamada xallinta (ragga labka ah). Kooxuhu waxay ahaayeen kuwo u muuqda sheekooyin qeexan (Cue), kuwaas oo ahaa calaamado la isku xiro oo ku saabsan ragga ragga iyo calaamadaha dhexdhexaadka ah ee xayawaanka lo'da ah, ama laga soo qaaday baqashada guriga (No Cue, oo muujinaya cue-label). Xogta waxaa lagu soo bandhigaa celcelis ahaan SEM; * waxay muujinaysaa farqi weyn marka la barbardhigo saline-pretreated ma jiro xakamaynta cue-exposure (Naive Sal-No Cue iyo Exp Sal-No Cue); # waxay muujinaysaa isbeddel weyn marka loo eego kooxda loo yaqaan 'Cl-treated Cue-expected group (Exp Sal ​​+ Cue). Sawirrada wakiilada ee unugyada PERK-IR ee halkii mm2 ee NAc core ee ragga ragga leh ee kufsiga leh Sal (C, D) ama NLX (E, F) kuwaas oo laga soo qaaday qafiska guriga (No Cue, C, E), ama ay u soo bandhigeen baaqyada ku saabsan mowqifka la xidhiidha macaamilka (Cue; D, F). N = 4 koox kasta marka laga reebo Naive NLX (No Cue), n = 3. ac, bareegga hore. Miiska barafka, 100 μm.

Jaantus 8. 

Saameynta naloxone oo ku saabsan maadada loo yaqaan 'PERK' ee lagu soo bandhigay gobollada kale ee bartilmaameedka VTA. Nambarada PERK-unugyada ah ee mm2 xaddiga galmada ah iyo khibrad leh (xayawaan, madow) xayawaan lagu sameeyay nidaamka NLX ama saline (sal) inta lagu jiro kalfadhiyada isku dhafan iyo waxay u muuqdaan sheekooyin qeexan (Cue) ama kafateeriga guriga (wax calaamad ah) ACA (A), PL (B), IL (C), iyo BLA (D). Xogta waxay u taagan yihiin SEM; * waxay muujinaysaa farqi weyn marka la barbardhigo saline-pretreated ma jiro xakamaynta cue-exposure (Naive Sal-No Cue iyo Exp Sal-No Cue); # waxay muujinaysaa farqi weyn marka la barbar dhigo kaneecada loo yaqaan 'sal-treated treated cue-control (Naive Sal + Cue).

Dhibaatada nooca hipotese, daaweynta nalaxoon inta lagu guda jiro waayo-aragnimada jinsiga ayaa si weyn u fiiqday PERK induction by culs-la xiriira cals. FASAXADDA LOOGU TALAGALAY NAFAQADA Nalxumo lagu daaweeyo ragga (khadka NLX + Cue) ma aysan ka duwin ereyada asaasiga ah ee jilicsan ama kooxaha khibradaysan ee laga qaado baqashada guriga (Naive Sal-No Cue ama Naive NLX- Cue lahayn). Waxaa intaa dheer, PERK faahfaahin ku saabsan naloxone-la-daaweyn ragga ragga ah ee khibrada leh (Exp NLX + Cue) waxay si aad ah uga hooseeyeen marka loo eego xayawaan-dabiiciga ah ee cayayaanka lagu daweeyey (Exp Sal ​​+ Cue) ee NAc core (Berdihii. 7A; p = 0.002) iyo qaybaha mPFC (Berdihii. 8A, ACA: p <0.001; B, PL: p = 0.002; C, IL: p = 0.015).

Qeybta NAc, falanqaynta labada-lugood ee ANOVA ma keenin saameyn isireed oo muhiim ah oo ku saabsan ciladaha soo gaara iyo daaweynta naloxoon. Si kastaba ha ahaatee, isbarbardhiga labanlaabku wuxuu muujiyay in ficil-celinta (PERK) ay ku dhexjiraan PERK-ga ee loo yaqaan 'sill-ku-daaweynta' (SAL + Cue) marka la barbardhigo iyadoo aan loo eegin kooxdii kantaroolka ah ee Saline-ga ee cagaarka ah (Berdihii. 7B; Naive SAL-Cue: p = 0.0163).

Dood

Daraasadani waxay muujineysaa in EOP ku dhaqmayso VTA inta lagu jiro mudada galmada, dabeecadda dabiiciga ah ee dabiiciga ah, waxay keentay hoos udhac badan laakiin dhimista kudhaca qaybta miisaanka VTA dopamine. Hoos udhaca qiyaasta xaddiga Soma ayaa lagu arkay Venter non-dopamine neurons, ama neefsiyada dopamine ee ku dhow miisaanka nigra, oo soo jeedinaya isbedelkan wuxuu gaar u ahaa unugyada dopamine VTA. Xayawaanka dopamine VTA-du waxay u muuqdaan kuwa la mid ah kuwa soo-gaadhay soo-gaadhista dabaysha ba'an (Sklair-Tavron et al., 1996; Russo et al., 2007; Mazei-Robison et al., 2011) waxayna keeneen dulqaad loo siman yahay abaal-marinta ka baxsan (morphine). Waxaan soo bandhignay in barta dopamine ee VTA ay muhiim u tahay muddada-dheer (dayactirka) laakiin ma ahan muddo gaaban (horumar), xoojinta habdhaqanka galmada iyo abaalmarinta la xiriirta hawlaha nuural (pERK) ee gobollada bartilmaameedka VTA: NAc iyo mPFC. Natiijooyinkaasi waxay muujinayaan doorka VTA dopamine baaxadda leh ee muujinta muddada-dheer ee salience dhiirigelinta abaalmarinta dabiiciga ah ee khayaaliga ah ama abaalmarinta xasuusta.

Waxaa si fiican loo diiwaangeliyey in khibrad jinsi ay u keentay fududeynta habdhaqanka galmada ee ku xigta, oo ay ku jirto bilawga si dhakhso ah u bilawga materka iyo waxqabadka kordhay (Balfour et al., 2004; Pitchers et al., 2010a,b, 2012). Hagaajinta ama xoojinta dhaqanka galmada waxaa lagu hayaa ugu yaraan 28 ka dib markii la isku maraayo (Pitchers et al., 2012). Intaa waxaa dheer, waxaa la muujiyey in dabeecadaha jinsiga iyo xaaladaha xaaladaha leh ee saadaalinta abaalmarinta jinsiga ay sabab u noqoto MOR gudaha VTA iyo uurjiifinta habdhiska neefsashada ee dhammaan habka mesolimbic, oo ay ku jirto VTA (dopamine iyo nondopamine neurons), NAc, PFC, iyo BLA (Balfour et al., 2004, 2006). Waxaa si wacan u dhisey Venter dopamine neurons oo door muhiim ah ka ciyaara barashada iyo ku-xirnaanta dhiirigelinta dhiirigelinta dareenka abaal-marinta la xiriira (Berridge iyo Robinson, 1998; Berridge iyo al., 2009; Flagel et al., 2011) iyo waxay muhiim u yihiin saadaasha abaalmarinta (Schultz, 2010). Natiijooyinka iminka socda ayaa balaadhinaya aqoontayada hadda iyadoo muujinaysa in VTA neuroplasticka abaal-marinta ay muhiim u tahay shaqooyinkan, waxayna ku xiran tahay hawlgalka MOR ee ETA ee VTA. Hadda lama yaqaano EOP waa MORANKA MORAN oo ka shaqeynaya VTA inta uu socdo dabeecada galmada. Inkasta oo labadaba β endorfin iyo enkephalin labadoodaba ay ku jiraan dhiirigelin dhiirigalin ah oo loogu talagalay cunto-xoojiyeyaasha (Hayward et al., 2002), tani waa mid loo aasaasayo dabeecad galmo lab ah. Waxaan horay u muujinay in qanjidhada 'β-endorphin neurons' aan la dhaqaajin inta lagu guda jiro moobjoogsiga, mana jirto koror mRNA; sidaas daraadeed, soo jeedinaysa in β endorfin aysan noqon karin EOP oo muhiim ah oo ku lug leh VTA inta lagu jiro mate (Davis et al., 2007). Xayawaankan dopamine VTA wuxuu muhiim u ahaa hawlaha neural ee mPFC, NAc, iyo VTA ka dib markii lagu soo bandhigay abaalmarinta jinsiga-saadaalinta calaamadaha deegaanka. Waxaa intaa dheer, xayawaanka dopamine VTA ayaa muhiim u ah muujinta muddada-dheer ee kor u qaadida bilaabista iyo waxqabadka galmada. Taas bedelkeeda, VTA neuroplasticity oo ay sababtay khibradda galmada loogama baahna jawaabcelinta kharashka sida abaalmarinta jinsiga (ay go'aamisay CPP) iyo fudaydka gaaban ee dhiirigelinta iyo waxqabadka galmada (inta lagu guda jiro waayo-aragnimadda galmada ama 1 d dambe) ayaa weli ku sii jiraya inkastoo MOR blockade inta lagu jiro isku darka (Mehrara iyo Baum, 1990). Taa baddalkeeda, xogta waxay soo jeedinaysaa in dopamine neuroplasticity dhexdhexaadinayso muddada dheer (7 d ka dib marka la waayo waayo-aragnimada galmada; Pitchers et al., 2012) muujinta "rabitaanka" abaalmarinta jinsiga iyo kordhinta jawaabaha dhiirigelinta ee laysku daro tilmaamaha (Miller iyo Baum, 1987; Berridge iyo Robinson, 1998).

Xayawaannada jinsiga ah waxay muujiyeen dulqaad dulqaad ah oo lagu abaalmariyo abaalmarinta morphine, oo la mid ah saamaynta wheel-ka ee jiirarka jilicsan, dabeecad kale oo dabiici ah oo dabiiciga ah, saameyn ku leh daaweynta naloxoon (Lett et al., 2001, 2002) oo lagu go'aamiyey in ay ku tiirsan yihiin barta unugyada unugyada VTA-ka (natiijooyinka hadda). Si la mid ah abaalmarinta dabiiciga ah, soo noqnoqoshada soo noqnoqda ee opiates morphine ama hirowiin waxay keenaysaa hoos u dhac ku yimid dhimashada VTA dopamine soma (Sklair-Tavron et al., 1996; Spiga iyo al., 2003; Russo et al., 2007; Mazei-Robison et al., 2011). Waxaa intaa dheer, soo-gaadhis la'aanta mudaharaad la'aanta wakhtiyada ka-baxsan waxay keenaysaa dulqaadka abaal-marinta, iyada oo la adeegsanayo qiyaaso sare oo daroogo loo baahan yahay si loo abuuro ururrada abaalmarinta (Shippenberg et al., 1987; Russo et al., 2007), oo keena in xayawaanka ay isku maamulaan si ay u kordhiyaan qaadashada daawada (Ahmed iyo al., 2000; Walker et al., 2003). Sidaa awgeed, EOP iyo opiates waxay u dhaqmaan dariiqooyinka caamka ah ee caanka ah si ay u soo jiidaan u dulqaadashada abaalmarinta muddada hore, taas oo laga yaabo inay ka tarjunto habdhaqan hab-nololeed oo magdhow ah si looga hortago dhiirigelinta soo noqnoqashada (Koob iyo Le Moal, 2005). Marka la barbardhigo, inta lagu jiro mudada dheer ee daroogada daroogada, dulqaadka waxaa loo beddelay dareen ah in hantida lagu abaalmariyo daroogada (Harris iyo Aston-Jones, 2003; Aston-Jones iyo Harris, 2004; Harris iyo Gewirtz, 2004). Waxaa xiiso leh, waayo-aragnimada galmada ee soo raaca xilliga xad-dhaafka galmada ee 7-28 d ayaa lagu ogaadey inuu keeno dareen-qabasho oo loogu talagalay abaalmarinta maskaxiyanimada (Pitchers et al., 2010a), taas oo ku xidhan habka loo yaqaan 'deltaFosB' iyo 'dopamine receptor 1 ee NAc (Pitchers et al., 2013). Sidaa awgeed, waayo-aragnimada jinsiga galmadu waxay keenaysaa dulqaadka abaal-marinta iyo abaal-marinta nafsaaniga ah, laakiin xitaa jimicsiga dheeriga ah ee galmada ee ku saabsan dulqaadashada morphine waa la tijaabin doonaa. Waxaannu ku qanacsannahay in saameyntan ka soo horjeeda ee ku saabsan abaal-marinta daroogadu ay u dhexayso qaabab kala duwan oo ah qaababka kala duwan ee nukliyeerka ee qaybaha kala duwan ee habka mesolimbic: Ficil VTA EOP iyo boobka dopamine ayaa dhexdhexaad u ah dulqaadashada abaalgudka (daraasadda hadda), halka NAc deltaFosB dusha ka ilaalinta dareenka nafsaaniga (Pitchers et al., 2013). Labada dhacdooyinkan waxay ka qayb qaadan karaan kor u qaadista daawada (Ahmed iyo Koob, 1998, 1999; Ahmed iyo al., 2000, 2002, 2003; Walker et al., 2003).

Farsamooyinka molecular ee ay EOP saameyn ku yeeshaan dareemayaasha dopamine VTA inta lagu jiro dabeecadda dabeeciga dabiiciga ah weli lama yaqaan. Wareegga IRS2-Akt-mTORC2 waa dhexdhexaadiye weyn oo ah xaddiga Soma ee yaraaday ee VTA ay sababtay morphine-ka soo noqnoqda (Jaworski et al., 2005; Russo et al., 2007; Mazei-Robison et al., 2011). Maamulka miro-dhiska oo lagu soo celiyay isbeddelka isbeddelka cabbirka dopamine neurons ee VTA waxaa laga hortegi karaa faafinta intra-VTA ee caan ka dhalata nörotrophic factor (BDNF; Sklair-Tavron iyo Nestler, 1995). BDNF waxay u hawlgelisaa wadadaa iyada oo loo marayo signalka TrkB (Russo et al., 2007), kinase reseptor oo leh jilid sare ee BDNF iyo qayb ka mid ah wadada IRS2-Akt (Seroogy iyo Gall, 1993; Numan iyo Seroogy, 1999), waxaana lagu muujiyay dopamine iyo GABA neurons ee VTA. Qiimeeynta qaybaha kala duwan ee IRS2-Akt ee isticmaalaya tiknoolajiyada fayraska xambaarsan fayraska ee fayrasku waxay ku takri falaan saamaynta raashinka dabadheeraad ah. Waxaa intaa dheer, saameynta badbaadinta opiate-ka waxaa lagu badbaadin karaa iyada oo dib u soo celinaysa waddadani tilmaamayso (Russo et al., 2007) iyo fara badan ee mtORC2 waxay ka hortagtaa hoos u dhigista maskaxda ee VTA dopamine soma (Mazei-Robison et al., 2011). Sidaa daraadeed, hawshii hore ee baaritaanka saameyn ku yeelatay dhibatooyinka daba dheeraadka ah ee kudhaca qaybta VTA dopamine soma waxay muujineysaa in hoos u dhigista muraayadda ee jabaqda IRS2-Akt-mTOR labadaba ku filan oo lagama maarmaan u ah saameyntani (Mazei-Robison iyo Nestler, 2012). Sidaa daraadeed, waxa la isku deyayaa in la qiyaaso in saameynta jimicsiga jinsiga ee VTA dopamine neuroplasticity ay isku mid tahay BDNF iyo IRS2-Akt-mTORC2.

Gebogebadii, daraasadda hadda waxay muujisay in VTA neuroplasticity ay sababto waayo-aragnimo leh habdhaqanka dabiiciga ah ee dabiiciga ah, gaar ahaan habdhaqanka jinsiga ee soo noqnoqda. Gaar ahaan, EOP waxay ku dhaqmeysaa VTA si loo yareeyo tirada dopamine soma, taas oo la qiimeeyo in ay la xiriirto kordhinta neerfaha iyo dopaminka wax ka yar oo keena nidaamka hypodopaminergic, oo beddelaya nidaamka mesolimbic ku shaqeynaya jawaabaha tilmaamaya abaalmarinta jinsiga. Intaa waxaa dheer, VTA neuroplasticity waxay muhiim u tahay dhiirigelinta dhiirigelinta iyo abaalmarinta xasuusta, laakiin maaha saameynta hedefoon ee dabeecadaha galmada. Ugu dambeyntii, VTA neuroplasticity waxaa keena habdhaqan dabiiciga dabiiciga ah oo soo raaca mudo gaaban oo abaalmarin ah oo saamayn ku leh abaal-marin kufisasho leh taas oo saameyn ku yeelan karta nuglaanshaha horumarinta daroogada maandooriyaha.

Qoraalada

  • La helay Janaayo 12, 2014.
  • Dib u eegid ayaa la helay May 17, 2014.
  • La aqbalay May 20, 2014.

  • Cilmi-baaristaan ​​waxaa taageeray deeqo ka timid Machadka Canadian-ka ee Cilmi-baarista Caafimaadka ee LMC iyo Guddiga Cilmi-baadhista Dabiiciga ah iyo Guddiga Cilmi-baarista ee KKP

  • Qorayaashu ma sheegaan danaha maaliyadeed ee tartanka.

  • Waraaqaha waa in lagu hagaajiyaa Dr Lique M. Coolen, Jaamacadda Mississippi Medical Center, Waaxda Dhaqanka iyo Biyofiziga, 2500 North Street Street, Jackson, MS 39216-4505. [emailka waa la ilaaliyay]

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