LITABA: The DeltaFosB e ithuta hangata re qotsa tsohle tse tsepamisitsoeng maikutlo nucleus accumbens (setsi sa meputso), mme a fumana hore thobalano e tsamaea haholo ka mokhoa o ts'oanang oa boko le meth & cocaine. Ho tsoa boithutong ba bohlokoa ba mofuputsi enoa (Meputso ea Tlhaho le Meriana Molao oa Common Neural Plasticity Mekhoa e nang le DFFB e le Mokena-lipakeng oa Motlakase (2013)):
Kahoo, meputso ea tlholeho le ea lithethefatsi ha e kopane feela tseleng e tšoanang ea methapo, e kopana ho baemeli ba limolek'hule tse tšoanang, mme mohlomong ho li-neuron tse tšoanang ho Nucleus Accumbens, ho susumetsa botsitso le "ho batla" mefuta e 'meli ea meputso.
Ho tlosoa: meth, cocaine le ho kopanela liphate bohle ba etsa lintho tse tšoanang tsa motheo ho lisele tse nang le methapo ea mantlha setsing sa moputso (nucleus accumbens), eng kapa eng eo ba ka e etsang ka tsela e sa tšoaneng kae kapa kae bokong. Tlhaloso ena e qhetsoeng ka mokhoa o tloaelehileng oa ho bua hore meputso ea tlhaho le lithethefatsi li fapane ka mekhoa le liphello.
Phuputso ena e ncha e hlahlobile seo thobalano e se etsang ho VTA. VTA ke moo lisele tsa methapo e hlahisang dopamine li qalang teng - 'me li ea li-nucleus accumbens, frontal cortex le amygdala. Ha e le hantle VTA ke mohloli (seliba) oa boholo ba dopamine ea rona. Sheba litšoantšo tsena tsa 2 tsa potoloho ea moputso: Pic1, Pic2
Bafuputsi ba fumane hore ho kopanela liphate (tlhōrō) ho etsa hore litopo tsa VTA li fokotsehe ka nakoana (ka banna). Lihlopha tsa selefouno le basebeletsi ba tsona kenyelletsa taba e bohlooho ea boko. Sena ke sona seo heroine e lemalloang ho se etsa ho VTA (Hase nako e le 'ngoe ea heroine, empa heroin e sa foleng e sebelisoa). Hlokomela hore shrinkage e tšoanang ea lihlopha tsa cell phone tsa VTA e etsahala ka heroin ea batho e lemalloang.
Tšebeliso ea cell shrinkage ea ho kopanela liphate e nka bonyane matsatsi a 7. Liphetoho tse bakoang ke thobalano li ne li khutletse ho tloaelehileng matsatsing a 30, empa bafuputsi ba lekanya matsatsi a 1, 7 le 30.
Ho fokotseha ha 'mele ea lisele tse lemalloang ke heroine ho fella ka dopamine e tlase ho li-nucleus accumbens - kapa seo re se bitsang ho hloka boithati. Bafuputsi ba ile ba fana ka morphine ho likhoto ho lekola karabelo ea bona (kamora thobalano), empa ha ho letho le etsahetseng. Hangata likhoto li rata morphine haholo, empa mona li ne li hlotsoe ka nakoana. Ka bokhutšoanyane, potoloho ea moputso oa likhoto ea kamora ho qeta nako e ne e sa arabele boemong bo tlase ba heroine. Bafuputsi ba ile ba hakanya hore litekanyetso tse phahameng li tla hlokahala ho etsa hore ho be le karabelo e "tloaelehileng" ea likhoto.
Ho akaretsa - Thobalano (ka nakoana) e etsa ntho e ts'oanang ho VTA joalo ka ho lemalla heroin: shrinkage ea dopamine e hlahisang 'mele ea lisele tsa methapo. Sena se lebisa ho tlase dopamine setsing sa moputso, le karabelo e nyane ho li-narcotic - mme ho nka bonyane matsatsi a 7 hore boko ba likhoto bo fole.
J Neurosci. 2014 Jun 25;34(26):8825-36. doi: 10.1523 / JNEUROSCI.0133-14.2014.
Pitchers KK1, Coppens CM2, Beloate LN3, Fuller J2, Van S2, Frohmader KS2, Laviolette SR2, Lehman MN4, Coolen LM5.
inahaneloang
Moputso oa tlhaho le lithethefatsi tsa tlhekefetso li fetoha tseleng ea mesolimbic le ho etsa hore mokhoa o tloaelehileng oa pelasetiki oa neural e nucleus accumbens. Ho pepeseha ha li-opiate nako e telele ho etsa hore polasetiki e be le li-neurone tsa dopaminergic sebakeng sa ventral tegmental (VTA), e leng se laolang mamello ea morphine.
Mona, re leka liteko tsa hore ho lokolloa ha batho ba nang le li-opioid tse kholo tsa VTA ho tsoaloang ke mafu ho etsa hore ho be le liphetoho tsa morphological tsa lisele tsa VTA dopamine tse nang le likhoto tsa banna, tseo ka nako e le 'ngoe li laolang boikutlo ba nako e telele ba boiphihlelo-bo susumelitsoeng ho matlafatsa boitšoaro ba thobalano.
Ntlha ea pele, boiphihlelo ba thobalano bo fokotsitse VTA dopamine soma boholo ba 1 le matsatsi a 7, empa eseng matsatsi a 30 kamora sekhetlo sa ho qetela sa ho kopanya liphate. Phello ena e ne e koetsoe ka nalxone pele ho setlhopha se kopane. ka hona, VTA dopamine cell plasticity e ne e itšetlehile ka ketso ea li-opioid tse sa feleng.
Ka lehlakoreng le leng, polasetiki ea VTA e ne e amahanngoa le moputso oa opiate o fetotsoeng, kaha banna ba nang le phihlelo ea ho kopanela liphate ha baa ka ba etsa khetho ea sebaka sa 0.5 mg / kg morphine.
Ka mor'a moo, ho ile ha etsoa qeto ea hore na bohato bo sa feleng ba opioid bo kopanya moputso oa thobalano le mohopolo linthong tsa banna tse tšoaroang le naloxone nakong ea boiphihlelo ba ho kopanya, ebang ke systematic kapa intra-VTA. Naloxone ha ea ka ea thibela boiphihlelo ba pele ba ho ba le phihlelo ea boitšoaro bo bobe ba ho kopanela liphate ka ho pheta-pheta mekhahlelo ea ho kopanela liphate, kapa sebaka se khethiloeng bakeng sa ho nyalana. Leha ho le joalo, phekolo ea naloxone e ile ea lebisa tlhokomelo ea nako e telele ea boiphihlelo bo bakoang ke phihlelo ea boitšoaro bo bobe ba ho kopanela liphate le ho sebelisoa ha neural metseng ea mesolimbic e bakoang ke litlamorao tse amanang le ho kopanela liphate.
Ka kakaretso, lintlha tsena li bonts'a hore li-opioid tse mamellang nakong ea ho nyalana li kenyelletsa polasetiki ea neural VTA dopamine neurons e bonahalang e le mahlomola bakeng sa moputso oa morphine le mohopolo oa nako e telele bakeng sa boitšoaro ba moputso oa tlhaho.
Selelekela
Boitšoaro ba meputso ea tlhaho bo nahanngoa ke tsamaiso ea mesocorticolimbic (Meisel le Mullins, 2006; Hoebel et al., 2009; Frohmader et al., 2010a; Pitchers et al., 2010a; Young le al., 2011; Blum et al., 2012). Lithethefatsi tsa tlhekefetso li baka liphetoho tsa neural tsamaisong ena, eo ka eona e tlatsetsang nts'etsopele le polelo ea tšebeliso e mpe ea lithethefatsi (Hyman et al., 2006; Nestler, 2012). Re kile ra etsa qeto ea hore phihlelo ea boits'oaro ba tlhaho, ke hore, ho ba le phihlelo ea ho kopanela liphate ka likhoto tsa banna, le hona ho baka pelasetiki ea neural nucleus accumbens (NAc), ho kenyeletsa le ho eketseha ha limela tsa dendritic (Pitchers et al., 2010a) le deltaFosB (Pitchers et al., 2013). Ka lehlakoreng le leng, polasetiki ena e bakoang ke ho kopanela liphate ke ea bohlokoa bakeng sa liphello tsa ho kopanela liphate ka ho kopanela liphate ka mor'a moo, ho bontšoa e le ho tsamaisa ho qalella le ho sebetsana le boitšoaro ba thobalano (Pitchers et al., 2010b, 2012, 2013). Ho feta moo, phihlelo ea ho kopanela liphate e fetola boitlamo ho li-psychostimulants, ho kenyeletsoa ho matlafatsa mosebetsi oa batho ba sebetsang le ho fumana moputso o ntlafetseng (Frohmader et al., 2010a; Pitchers et al., 2010a, 2013).
Nac ke sepheo se seng sa tlase sa dopaminergic neurons sebakeng sa ventral tegmental (VTA). VTA dopamine neurons e ts'oaroa nakong ea ho nyalana le ka mor'a ho pepeseha ho latela maemo a hlalositsoeng ka mokhoa o feteletseng oa ho kopanela liphate (Balfour et al., 2004; Frohmader et al., 2010a), ka peptide e nang le opioid e mamellang (EOP) -e phehelang li-receptors tsa μ-opioid (LITABA; Matthews le Sejeremane, 1984; Johnson le North, 1992; Klitenick et al., 1992; Ikemoto et al., 1997; Balfour et al., 2004). Ka lebaka leo, ho pepesehela maemo a ho iketsetsa setho sa boitšoaro bo bobe ba thobalano ho baka ho lokolloa ha EOP le VTA dopamine-cell activation, e fanang ka ts'ebeliso ea thobalano (Mitchell le Stewart, 1990; van Furth le al., 1995; van Furth le van Ree, 1996) le ho lokolloa ha dopamine ka NAc (Fiorino et al., 1997).
Ho pepeseloa ha li-opiate tse sa tloaelehang ho baka liphetoho tsa morphological VTA (Mazei-Robison et al., 2011; Mazei-Robison le Nestler, 2012), e fokotsoe boholo ba soma ea VTA dopamine neurons (Sklair-Tavron le al., 1996; Spiga et al., 2003; Chu et al., 2007; Russo et al., 2007; Mazei-Robison et al., 2011), ho theohile likarolo tse ngata tsa liprotheine tsa kankere (Beitner-Johnson et al., 1992), ho eketsa menyetla ea lisele tsa dopamine, le ho fokotsa ho tsamaisa li-axoplasmic le dopamine e nkiloeng ho NAc (Beitner-Johnson et al., 1992; Mazei-Robison et al., 2011). Liphetoho tsena tsa VTA dopamine neuron li etsa hore morphine e be le mamello ea ho ba le melemo 'me e fokotsa nakoana ha e ntse e qeta likhoeli tse seng kae ka nako ea ho ithiba ha lithethefatsi (Russo et al., 2007). Hona joale ha ho hlaka hore na polasetiki ea VTA dopamine neurons e ikhetha ho liketso tsa opiate kapa haeba e boetse e hlahisoa ke ho lokolloa ha EOP nakong ea boitšoaro bo nang le melemo ea tlhaho.
Ha re le mona, re leka tekano ea hore phihlelo ea moputso oa tlhaho e bakoa ke li-neuroplasticity tse tšoanang le tse bakoang ke li-opiate, kahoo, li-opiate li fetola mochine oa polasetiki o bohlokoa bakeng sa boitšoaro ba moputso oa tlhaho le mohopolo oa moputso. Re etsa tlhahlobo ea hore na boiphihlelo ba thobalano lipakeng tsa banna bo fokotsa boholo ba soma ba VTA dopamine neurons ka mokhoa o itšetlehileng ka ketso ea EOP VTA. Ho feta moo, re hlahloba hore na liphetoho tse entsoeng ke EOP li-VTA dopamine neurons li amahanngoa le ho matlafatsoa ha boitšoaro ba tlhaho bo khotsofatsang le ho fanoa ka matla a khothatsang ho amanang le moputso oa tlhaho, ha a ntse a etsa hore moputso oa morphine o mamellane.
Lisebelisoa le mekhoa
Animals
Maqeba a banna ba baholo ba Sprague-Dawley (200-225 g) a ile a fumanoa ho tloha Nōkeng ea Charles 'me a lula ka bobeli ka likamore tse khantšitsoeng ka mahlakoreng a khantšo ea 12 h / litebelong tsohle (ho khantša 10: 00 AM haese feela tlhahlobo ea mamello ea morphine , li khanya ho 5: 00 PM). Lijo le metsi li ne li fumaneha ad libitum haese nakong ea tlhahlobo ea boitšoaro. Li-sululus tse tšehali li ne li lefshoa 'me li kenngoa ka tlase ka 5% 17-β-estradiol benzoate SILASTIC capsules (1.98 mm ka hare, bolelele ba 0.5 cm, Dow-Corning). Likokoana-hloko tsa progesterone (ka tlaase, 500 μg ho 0.1 ml ea oli ea sesame) li ne li tsamaisoa 3-6 h pele li lekoa ho etsa hore batho ba amohele thobalano. Mekhoa eohle e ile ea amoheloa ke Univesithi ea Bophirimela ea Ontario le Likomiti tsa Bophelo ba Litlhapi tsa Univesithi ea Michigan, 'me ea ipapisa le Canadian Council on Animal Care le melao ea Sechaba ea Bophelo ea Mekhatlo ea Bophelo ea lihlahisoa tse akarelletsang liphoofolo tsa liphoofolo tse entsoeng ka liphoofolo tsa lipatlisiso.
Nako ea nako ea VTA dopamine soma size changes
Litlhophiso tsa letsatsi le letsatsi.
Ho ithuta nako ea liphetoho ka boholo ba dopamine neuron soma VTA, liphoofolo tse nang le tsebo ea ho kopanela liphate le tse se nang bokooa li bolailoe 1, 7, kapa 31 d (n = 5-8 ka sehlopha) ka mor'a letsatsi la ho qetela la ho nyaloa (ho ba le phihlelo) kapa ho sebetsana (ho se tsebe). Lihlopha tse nang le likamano tsa botona le botšehali li ne li lekana bakeng sa boitšoaro ba ho kopanela liphate nakong ea nako ea ho qetela ea ho kopanya, hammoho le palo e feletseng ea ejaculations ka mananeo a mahlano (e leng karolelano ea 5 bakeng sa sehlopha ka seng), 'me ha ea ka ea fapana le tsela efe kapa efe ea boitšoaro ba thobalano.
Mehlala ea ho kopanya.
Banna ba nang le bokooa ba thobalano ba ne ba abetsoe ho tse ling tsa maemo a mabeli a liteko: batho ba nang le thobalano kapa ba nang le phihlelo ea ho kopanela liphate. Liphoofolo tse nang le likamano tsa botona le botšehali li ile tsa lumelloa hore li tšoaroe ka makhetlo a mahlano ka matsatsi a latellanang le basali ba amohelang litlhaku tse koetlisitsoeng ka makhetlo a mararo (60 × 45 × 50 cm) ho fihlela ho bontšoa ho ejaculation kapa ho fihlela ho 1 h (e leng ntho e tlang pele). Metsoalle e ne e hloekisitsoe ka botlalo le tharollo ea 70% ethanol le ho robala ho hloekileng ho ile ha eketsoa pakeng tsa menyetla ea ho kopanya. Boits'oaro ba botona le botšehali bo ne bo etsoa nakong ea lefifi (2-6 h ka mor'a ho qala lefifi). Lihlahisoa feela tse ileng tsa kenngoa nakong ea bonyane lihlopha tse 'nè ho tse hlano tsa ho nyalana li ne li nkoa e le tsebo ea ho kopanela liphate' me li kenyelelitsoe litsing tsa liteko Litekanyetso tsohle tsa ho nyalana li ne li hlokomeloa 'me boitšoaro ba thobalano bo tlalehiloe Palo ea likhahla (M) tse fokolang (IM), latency ea matha (ML; nako ho tloha ho kenyelletso ea basali ho ea pele holima), latency latency (IL; nako ho tloha kenyelletsong ea basali ho ea pele), le latency ejaculation (EL; nako ho tloha ho qala ho kenya letsoho ho ea ho khaoloa) e tlalehiloe (Agmo, 1997). Liphoofolo tse nang le liphoofolo li ne li kenngoa kahare ea tlhahlobo e hloekileng bakeng sa 1 h hang-hang le banna ba nang le phihlelo ea ho kopanela liphate ba kopanelang ka kamoreng e le 'ngoe, e le hore ba pepeseha monko oa basali ba hōle, le maemo a mang a khathatso le mokhoa o ts'oanang oa tikoloho e le banna ba nang le boiphihlelo.
Lebitso la immunofluorescence.
Liphoofolo li ne li sa sebelisehe hantle ka ho sebelisa sesedium pentobarbital (270 mg / kg, ip) le ho sebelisoa hampe ka 50 ml ea 0.9% saline, e lateloa ke 500 ml ea 4% paraformaldehyde ho 0.1 m sodium phosphate buffer (PB). Bokooa bo ile ba tlosoa 'me ba kenngoa ka morao ho 1 h ka mocheso oa motsoako (RT) ka mokhoa o tšoanang, ebe ba qoelisoa 20% sucrose le 0.01% sodium azide ho 0.1 m PB bakeng sa ho boloka ho 4 ° C. Likarolo tsa Coronal li ne li khaotsoa ka 35 μm ka microtome e bolileng (H400R, Microm) 'me li ne li bokelloa ka lihlopha tse' nè tse tšoanang le sekhahla sa cryoprotectant (30% sucrose, 30% ethylene glycol ho 0.1 m PB) ebe e bolokiloe 20 ° C. Ts'ebetso eohle e ne e etsoa ka RT ka ts'oaetso e bonolo le li-rinses tse ngata tse nang le 0.1 m PBS, pH 7.35, pakeng tsa ho tsuba. Likarolo li ne li pepesehetse 1% H2O2 bakeng sa 10 min ho felisa peroxidases e sa tsitsang, ebe e thibetsoe 1 h ka tharollo ea ho kenya likhoeli (PBS +: PBS e nang le 0.4% Triton X-100; Sigma-Aldrich) le 0.1% serum albumin (Jackson Immuno Research Laboratories). Ka mor'a moo, likarolo li ne li kenngoa bosiung bo bong ka RT ka mouse ea tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Ka mor'a ho kenyelletsa li-antibody pele, likarolo li ne li kenngoa ho anti-mouse ea AlexaFluor 555-conjuguated goat anti-mouse (1: 100; Invitrogen, Eugene, OR) bakeng sa 30 min. Qetellong, likarolo li ne li hlatsitsoe ka 0.1 m PB, li khabisitsoe ka li-slides tsa Superfrost Plus, tse omisitsoeng, tse koahetsoeng ka gelvatol tse nang le 1,4-diazabicyclo (2,2) octane (DABCO; 50 mg / ml, Sigma-Aldrich; Lennette, 1978).
Tlhahlobo ea lintlha: boholo ba sesepa sa soma.
Litšoantšo tsa li-NE-immunoreactive (IR) neurons VTA li ne li nkiloe 40 × ho phahamisa ka litekanyetso tse tharo tsa rostral ho caudal (Balfour et al., 2004). Ho ne ho se na ho se tšoane ho fumanoang pakeng tsa lisele tse fapaneng. Boholo ba soma ba lit-neurons tsa TH-IR bo ne bo hlahlojoa ka ImageJ (National Institutes of Health). Sebaka se bohareng, sekhahla, le selikalikoe se ne se lekantsoe joalokaha se hlalositsoe Sklair-Tavron le al. (1996). Ka karolelano lisele tsa 25 ka phoofolo (li kopantsoe le litekanyetso tsohle tsa 3 VTA) li ile tsa hlahlojoa 'me lisele feela tse nang le nucleus e bonahalang ka ho hlaka li kenyelelitsoe. Bakeng sa phoofolo e 'ngoe le e' ngoe, sebaka se bolelang, sekhahla, le selikalikoe se ne se baloa. Bakeng sa lipalo-palo tsa litsela tse peli ANOVA e ne e sebelisoa [lisosa: boiphihlelo ba ho kopanela liphate (thobalano e nang le phihlelo kapa ea ho kopanela liphate) le nako (1, 7, kapa 31 d)] e lateloa ke post hoc litšoantšiso tse sebelisang mokhoa oa Holm-Sidak ka boemo ba bohlokoa ba 0.05.
VTA liphetoho tse se nang dopamine
Litlhophiso tsa ho kopanya li-biweekly.
E le ho hlahloba hore na boiphihlelo ba ho kopanela liphate nakong ea letsatsi le letsatsi bo hlokahalang ho fokotseha ka boholo ba TH-IR neuron soma, VTA dopamine neurons ea liphoofolo tse neng li lutse nakong ea lihlopha tse hlano tsa ho kopanya likhahla li ile tsa hlahlojoa. Mehlala ea ho itlhakisa e ne e tšoana le e hlalositsoeng ka holimo, empa ka nako ea libeke tsa 2.5. Bokooa bo ile ba bokelloa 7 d ka mor'a ho kopanya kapa ho sebetsana le ho qetela.
Litlhaku tsa immunoperoxidase.
Ho phaella moo, e ile ea hlahlojoa hore na ho sebelisoa mekhoa e metle ea ho silafatsa le immunoperoxidase le chromogen ho lemoha, e ne e tla boela e lumelle ho bonahatsa liphetoho tsa boholo-holo tsa TH-IR soma. Ho sebetsana le lisebelisoa tsa mahlaseli le liphatsa tsa lefutso e ne e le boitšoaro bo hlalositsoeng ka holimo Ho latela kalafo ka 1% H2O2 le PBS +, likarolo li ne li koaletsoe bosiu bo le bong ka RT ka mouse-polyclonal tyrosine hydroxylase (TH) -antibody (1: 20 000; Millipore). Ka mor'a ho kenya likokoana-hloko tse ka sehloohong, likarolo li ne li kenngoa ka IgG (1 h, 1: 500 ka PBS +; Vector Laboratories), xNUMX-horseradish peroxidase (1 h, ABC elite; 1: 1 000 PBS ; Vector Laboratories), le 3,3'-diaminobenzidine tetrahydrochloride (10 min, 0.02%, DAB; Sigma-Aldrich) e ntlafatsoa ka selphate ea nickel (0.02% ho 0.1 m PB) le hydrogen peroxide (0.015%). Likarolo li hlatsuoa ka botlalo ho 0.1 m PB ho felisa tsela eo li arabelloang ka eona ebe li kenngoa holim'a li-slide tse khabisitsoeng ka ho fetisisa tsa Superfrost le li-glass (Fisher) tse nang le 0.3% gelatin ka ddH2O. Ka mor'a hore metsi a fokotsehe, li-slide tsohle li ne li koahetsoe ka sekhahla sa DPX (dibutyl phthalate xylene; Sigma-Aldrich).
Tlhahlobo ea lintlha: boholo ba sesepa sa soma.
Lisele tsa TH-IR li ile tsa hlahlojoa bakeng sa sebaka, potoloho le sephara joalo ka ha ho hlalositsoe kaholimo. Ntle le moo, ho ile ha hlahlojoa lisele tsa TH-IR ka har'a substantia nigra (SN), ka likarolo tse tšoanang tse sebelisitsoeng ho sekaseka lisele tsa VTA TH-IR. Kamora nako, kamorao ho tlhahlobo ea lisele tsa VTA le SN TH-IR, likarolo li ile tsa emisoa li sebelisa cresyl violet mme lisele tse e seng tsa TH-IR li ile tsa hlahlojoa li sebelisa mekhoa e ts'oanang le e hlalositsoeng kaholimo. Phapang lipakeng tsa lihlopha tse sa rutehang le tse nang le boiphihlelo li ne li bapisoa le ho sebelisa tse peli tsa taolo ea Seithuti t liteko tse nang le boemo ba bohlokoa ba 0.05.
Liphello tsa naloxone ka ho fokotseha ha boholo ba boholo ba dopamine bo nang le phihlelo
Ho fumana hore na MOR e bapala karolo ea liphetoho tse bakoang ke ho kopanela liphate ka boholo ba dopamine neuron soma, MOR e ne e thibetsoe nakong ea boitšoaro ba thobalano. Karolo ea halofo ea liphoofolo e ile ea e-ba le phihlelo ea ho kopanela liphate, ha halofo e 'ngoe e sebetsoa empa e ile ea lula e se na bokooa. Liphoofolo tse nang le likamano tsa botona le botšehali li lumelloa ho nyalana ka matsatsi a 5 a latellanang. Ka har'a lihlopha tse nang le phihlelo ea ho kopanela liphate le tse se nang tsebo, liphoofolo li ile tsa tšoaroa le mohanyetsi oa MOR ea nonselective LExone (10 mg / kg, sc; Sigma-Aldrich, e qhibilihantsoeng ka 0.9% saline) kapa saline 30 min pele ho kenoa ha basali (ba nang le phihlelo) kapa pele ba sebetsana (ho se tsotelle); kahoo ho theha lihlopha tse 'nè tsa liteko: ho na le saline ea ho kopanela liphate (Naive Sal), naxone ea nang le thobalano (Naive NLX), ea nang le phihlelo ea ho kopanela liphate (Exp Sal), le naloxone e nang le thobalano (Exp NLX; n = 5-8 ka sehlopha). Kalafo ea Naloxone e ne e se na liphello tse kholo holima leha e le efe ea liketso tsa thobalano, leha e le efe ea 5 d, le lihlopha tse tšoaroang ka salxone le tsa saline li ne li tšoana le tsebo ea thobalano. Liphoofolo tsohle li ile tsa bolaoa ka tsela ea intracardial perfusion 7 d kamora nako ea ho qetela ea ho kopanya. Ho arola li-immunohistochemistry le ho hlahloba litlaleho (litsela tse peli tsa ANOVA; lisosa: boiphihlelo ba thobalano le kalafo ea lithethefatsi) bakeng sa boholo ba dopamine soma bo ile ba etsoa joalokaha ho hlalositsoe ka holimo.
Morphine o kentse maikutlo a sebaka seo a se ratang
Tlhahlobo ea liteko.
Nakong e fetileng, Russo et al. (2007) o ile a bontša hore morphine e sa foleng e etsa hore ho be le mamello ho morphine. Kaha phihlelo ea ho kopanela liphate le morphine e sa foleng e baka ho fokotseha ho tšoanang ha boholo ba soma ea dopamine neurons VTA, ts'ebetsong ea morphological e bakoang ke thobalano e ile ea lekoa bakeng sa moputso oa morphine. Liphoofolo tse nang le likamano tsa botona le botšehali le tse se nang tsebo li arotsoe ka lihlopha tse tšeletseng tsa liteko (n = 9-13 ka sehlopha) ho itšetlehile ka boitšoaro bo bobe ba ho kopanela liphate (ba nang le bothata ba ho kopanela liphate kapa ba nang le phihlelo) le tekanyo ea morphine (0.5, 5.0, kapa 10.0 mg / kg, ip) 'me ba lekoa bakeng sa khethollo ea sebaka sa boemo ba boemo ba morphine.
Morphine-CPP.
Boemo bo ile ba etsahala 1 d ka mor'a thuto ea ho qetela ea ho kopanya lihlopha le lihlopha li lekana bakeng sa ts'ebetso ea thobalano nakong ea thupelo ea ho qetela ea ho nyalana. Paradigm e sebelisitsoeng ke CPP e ne e e-na le matsatsi a boiketlo, a boemo bo botle, le kamora 'tlhahlobo,' me lisebelisoa li thehiloe ho Tenk et al. (2009). Ka bokhutšoanyane, lisebelisoa tsa CPP (MED Associates) li ne li na le likamore tse tharo tse ikhethileng. Pakeng tsa seboka se seng le se seng, lisebelisoa li ile tsa hloekisoa ka botlalo ka tharollo ea 70% ea ethanol ho fokotsa lits'oants'o tse sa feleng. Ho tseba khetho ea motho ka mong, boikaketsi bo ile ba etsoa nakong eo liphoofolo li fuoang phihlello ea mahala ea lisebelisoa tsohle bakeng sa 15 min. Ha e le sehlopha, liphoofolo li ne li sa bontše khetho ea bohlokoa bakeng sa kamore e itseng, empa phoofolo ka 'ngoe e ne e na le khetho ea pele. Likhoto tse bonts'itseng khetho e kholo bakeng sa e 'ngoe ea likamore (> 200 s phapang lipakeng tsa nako e sebelisitsoeng ho e' ngoe le e 'ngoe ea likamore; <5% ea liphoofolo) nakong ea boikaketsi ha ba kenyelelitsoe thutong. Nakong ea boemo bo botle, sethethefatsi se ne se kopantsoe le phaposi eo ba e ratang pele kapa e sa khethoang ba sebelisa paradigm e se nang leeme (Tzschentke, 2007) le liphoofolo li koaletsoe likamoreng tsa 30 min. Liphoofolo li ne li kenngoa ka saline (ip) hoseng (9: 00 AM ho 12: 00 PM) 'me e kenngoa kamoreng e nang le li-saline (taolo). Motšehare oa mantsiboea (1: 00-4: 00 PM), liphoofolo li ne li kenngoa ka morphine (ip, 0.5 mg / kg, 5.0 mg / kg kapa 10.0 mg / kg; morphine sulfate e qhibilihisitsoeng 0.9% saline, Johnson Matthey) ho kamore ea morphine-paired. Liphoofolo li ne li e-na le matsatsi a mabeli a phomolo. Letsatsing le hlahlamang (3 d ka mor'a letsatsi la ho qetela la ho nyalana) tlhahlobo ea kamora 'nete, e ts'oanang le mokhoa oa boipheliso, e ile ea etsoa. Bakeng sa tlhahlobo ea lipalo-palo, nako e sebelisitsoeng kamoreng ea morphine-lipakeng nakong ea kamora 'tlhahlobo e ne e bapisoa le nako e sebelisitsoeng kamoreng ea saline nakong ea kamora' tlhahlobo ea batho ba kopanelang liphate kapa banna ba nang le phihlelo ka hare ho tekanyo e 'ngoe le e' ngoe e sebelisoang ka bobeli. t teko. p <0.05 e ne e nkuoa e le ea bohlokoa. Lihlopha tse ling tsa taolo ea liphoofolo tse se nang tsebo ea ho kopanela liphate le tse nang le boiphihlelo li ile tsa fumana letsoai likamoreng tse peli tse nang le lipara le tse sa sebetsoang e le taolo e mpe. Ha ho liphapang tsa nako e sebelisitsoeng pakeng tsa likamore tse fumanoeng bakeng sa sehlopha ka seng.
Liphello tsa naloxone ea mokhoa o sebetsang ka boithuto bo bakoang ke phihlelo ea boitšoaro ba thobalano
Tlhahlobo ea liteko.
Boiphihlelo ba thobalano bo fella ka ts'ebeliso ea boitšoaro ba thobalano bo bolokiloeng bonyane khoeli ea 1 (Pitchers et al., 2012). E le ho hlahloba phello ea ho thibela MOR ka mokhoa o ts'ehetsoeng ke boiphihlelo oa ho kopanela liphate, liphoofolo tse nang le phihlelo ea ho kopanela liphate li amoheloa ke naloxone kapa saline pele liboka tse hlano tse latellanang tsa ho kopanela liphate (n = 12 ka mong) joalokaha ho hlalositsoe ka holimo. Beke e 'ngoe ka mor'a thupelo ea ho qetela ea ho kopanya likhallelo, tlhahlobo ea ho qetela ea ho kopanya e ile ea etsoa nakong eo liphoofolo tsohle li lumelloa hore li sebetsane ho fihlela ho ejaculation kapa ho fihlela ho 1 h. Ha ho naxxone kapa phekolo ea saline e neng e fanoa pele e qeta letsatsi le le leng la teko. Lipalo tsa ho kopanya li ne li bapisoa le ho tseba hore na naxone e amme kapa ho fokotsa ts'ebeliso ea ho kopanela liphate (letsatsi la 1 vs 5 letsatsi) kapa ho hlokomeloa ha mokhoa ona (letsatsi la 5 vs tlhahlobo) ho sebelisa ANOVA [lisosa: phekolo (saline vs.usxxone) ) le letsatsi (letsatsi la 1, letsatsi la 5, kapa teko)] le mokhoa oa Holm-Sidak bakeng sa post hoc papiso. Bakeng sa liteko tsohle tsa lintlha, p <0.05 e ne e nkuoa e le ea bohlokoa lipalo-palo.
Lintlha tse ling tsa ho laola liteko
E sebetsang le naroxone ka letsatsi la teko.
Ho bontša hore boitšoaro ba ho kopanela liphate bo fetotsoeng letsatsing la ho qetela la ho kopanya likhahla ha hoa ka ha e-ba teng ka lebaka la ho ba sieo ha naloxone, re ne re tsamaisa nang le naloxone kapa saline letsatsing la ho qetela la ho nyalana ho liphoofolo tse ileng tsa fumana ho nyalana li kopantsoe le naloxone ha li ntse li fumana phihlelo ea thobalano. Ka ho khetheha, liphoofolo tsohle li ile tsa fuoa ente ea naloxone (10 mg / kg, sc) 30 min pele ho nyalanya ho ejaculation e le nngwe nakong ea 5 matsatsi a latellanang. Ka mor'a letsatsi la tlhahlobo ea 7 hamorao, hoo e ka bang halofo ea liphoofolo e ile ea fuoa lengolo la naloxone (10 mg / kg, n = 7) kapa saline (n = 6) Metsotso ea 30 pele ho kenyelletsoa ha mosali ea amohelehang. Boitšoaro ba thobalano bo ne bo hlokomeloa ' Lipalo tsa ho kopanya li ne li bapisoa le ho tseba hore na naxone e amme kapa ho fokotsa ts'ebeliso ea ho kopanela liphate (letsatsi la 1 vs 5 letsatsi) kapa ho hlokomeloa ha mokhoa ona (letsatsi la 5 vs tlhahlobo) ho sebelisa ANOVA [lisosa: phekolo (saline vs.usxxone) ) le letsatsi (letsatsi la 1, letsatsi la 5, kapa teko)] le mokhoa oa Holm-Sidak bakeng sa post hoc papiso. Bakeng sa liteko tsohle tsa lintlha, p <5% e ne e nkuoa e le ea bohlokoa lipalo-palo.
Liphello tsa naloxone ka polelo e khutšoanyane ea boitšoaro bo bobe ba ho kopanela liphate.
Liphello tsa naloxone (10 mg / kg, sc) kalafo nakong ea ho nyalana li ile tsa lekoa ka boitšoaro bo latelang ba ho kopanela liphate nakong ea ho qetela ea tlhahlobo ea ho kopanela liphate, e neng e etsoa feela 1 d ka mor'a ho kopanya likhallelo tsa ho qetela (saline, n = 5; naloxone, n = 4).
E tloaelehileng ea nalxone pele ho phekolo.
Ho fumana hore na ho pheta-pheta phekolo ea naloxone ka boeona ho baka tšenyo ea boitšoaro bo bobe ba 7 d kalafo ea ho qetela, liphoofolo tse nang le bokooa ba ho kopanela liphate li fumane lengxone e mehlano ea letsatsi le letsatsi (10 mg / kg, sc) kapa lisebelisoa tsa saline ka matsatsi a latellanang pele XMUMX test mating ka mor'a naloxone ea ho qetela kapa ente ea saline. Letsatsing lena la ho qetela la liteko, liphoofolo ha lia ka tsa fumana ente. Boitšoaro ba thobalano bo ne bo hlokomeloa 'me bo ngotsoe joalokaha bo hlalositsoe ka holimo Litlhaloso tsa ho nyalana li ne li bapisoa pakeng tsa lihlopha tse se nang thuso t liteko. Bakeng sa liteko tsohle tsa lintlha, p <5% e ne e nkuoa e le ea bohlokoa lipalo-palo.
E tloaelehileng ea naloxone le moputso oa thobalano.
Monyetla o mong oa litlamorao tsa naloxone tse bonts'ang pontšong ea tlhokomelo ea boitšoaro ba thobalano ke hore naloxone e thibela litholoana tse ntle tsa boitšoaro ba thobalano. Ho lekola monyetla ona, paradigm ea CPP e ile ea etsoa bakeng sa boitšoaro ba thobalano hang hang ka mor'a leijonone kapa ente ea letsoai ho banna ba se nang boiphihlelo ba pele ba thobalano. Ts'ebetso ea CPP e ne e ts'oana le e hlalositsoeng kaholimo bakeng sa morphine-CPP, ho kenyelletsa boitšisinyo, matsatsi a boemo, le tlhahlobo ea kamora.
Boitšoaro ba thobalano bo ne bo kopane le kamoreng ea pele e sa boleloang. Ka mokhoa o mong le o mong, phoofolo e 'ngoe le e' ngoe e fumane lengolo la naloxone (n = 12) kapa saline (n = 11) 30 min pele o fumana monyetla oa ho fumana mosali ea amohelehang. Nako e tloaelehileng ea nako ea ho kopanya e ne e le ~13 min. Metsotso e 'meli ka mor'a ho phomola, phoofolo e behiloe kamoreng e nang le marang-rang bakeng sa minara ea 30. Ka letsatsi le leng la phomolo, liphoofolo li ile tsa fuoa ente ea nang le naloxone kapa saline (ho sa tsotellehe seo ba ileng ba se fumana pele ba nyalana), 'me ba kenngoa ka kamoreng e sa sebetseng ea 30 min. Ka mor'a moo, tlhahlobo ea poso e ne e khannoa, e tšoana le ea boipiletso. E le hore ho khethoe khetho ea kamoreng, nako e sebelisitsoeng ka kamoreng e kopantsoeng ha e bapisoa le ho feta ha e bapisoa. Bakeng sa tlhahlobo ea lintlha, ba paile t liteko li ne li sebelisetsoa ho bapisa likarolo tsa ho rata le ho fapana ha nako, le nako ka kamoreng e kopanetsoeng nakong ea boipiletso le pele ho tlhahlobo ho bona hore na morero o moholo oa CPP o thehiloe bakeng sa boitšoaro ba thobalano. p <0.05 e ne e nkuoa e le bohlokoa.
Liphello tsa intra-VTA naloxone ka boithuto bo bakoang ke phihlelo ea boitšoaro ba thobalano
Tlhahlobo ea liteko.
Ho fumana hore na ketso ea EOP ka ho khetheha ho VTA, e ne e ikarabella ka liphello tsa liphetoho tse bakoang ke likamano tsa botona le botšehali boitšoarong ba thobalano, liphoofolo li ile tsa tšeloa ke naloxone kapa saline ka VTA pele liboka tse hlano tsa letsatsi le leng le le leng. Tsela ea boitšoaro e ne e tšoana le teko ea systemic naloxone. Liphoofolo tse nang le likamano tsa botona le botšehali li lumelloa ho nyalana nakong ea matsatsi a 5 a latellanang ho fihlela ho ejaculation kapa ho fihlela ho 1 h. Metsotso e leshome le metso e mehlano pele o kenyelletsa mosali ea amohelang, litoeba tse tšehali li fumanoe ka botšepehi ba naloxone (10 μg / μl ka ho hemphane; 0.5 μl volume; qhibilihisoa 0.9% saline) kapa saline (0.5 μl ka hemisphere). Li-microinjection tse kopanetsoeng li ne li tsamaisoa ka tekanyo ea phallo ea 0.5 μl / min ka nako ea 1 metsotso e lateloa ke meriana e eketsehileng ea 1 le kankere e entsoeng ka majoe e tlohetsoeng sebakeng sa ho phalla. Moriana oa kankere o ile oa nkeloa sebaka ke canumula ea dummy le capu ea lerōle. Beke e 'ngoe ka mor'a letsatsi la ho qetela la ho nyaloa (letsatsi la teko), liphoofolo tsohle li khabisoa hape ka ho kha metsi ntle le ho tšeloa ke naloxone kapa saline. Setšoantšo sa 3A e hlalosa tlhahiso ea liteko. Tlhahlobo ea lintlha e ile ea etsoa joalokaha ho hlalositsoe tekong ea systemic naloxone.
Ho buuoa ka thōko.
Lipoe tsa banna li ne li sa sebelisetsoe ke enteperitoneal (0.1 ml / kg) ea ketamine (0.87 mg / ml) le xylazine (0.13 mg / ml), ebe e kenngoa lisebelisoa tsa stereotaxic (Kopf Instruments). Lintho tse peli tse sebelisoang ka ho fetisisa tsa 21-gauge li-cannulas (Plastics One) li ile tsa theoleloa ka likoti tse nyenyane tse nang le likoti tse lekaneng ho ea ho VTA ho -4.8 mm AP, ± 0.75 mm ML ho tloha bregma le -7.8 mm DV ho tloha ka holim'a lehata. Paxinos le Watson (2013). Li-cannula li ne li sirelelitsoe ka li-acrylic tsa meno tse neng li khomarela lisebelisoa tse tharo tse behiloeng lekaneng. Liphoofolo li ile tsa fuoa nako ea ho phomola ka libeke tsa 2, 'me tsa sebelisoa letsatsi le leng le le leng bakeng sa tloaelo ea ho sebetsana le lisebelisoa tse sebelisoang nakong ea tlhahlobo ea boitšoaro.
Tlhaloso ea ho kenya lihlahisoa.
Ho kenngoa ha cannula ho ne ho hlahlojoa ho sebelisa TH-immunostaining ho netefatsa hore VTA e ne e lebisitsoe ka nepo. Ke liphoofolo feela tse nang le libaka tse loketseng tse kenyelletsoeng tse kenyelletsoeng lipatlisisong (boholo ba lihlopha tsa ho qetela: saline e nang n = 8; bilexone e nang le phihlelo n = 6). Liphoofolo tse ling tse tharo tse ileng tsa fumana li-intra-VTA naloxone tse entsoeng ka ntle ho VTA li ne li bokelloa sehlopha sa "ho hloloheloa" se entsoeng ka ente. Sehlopha se hlokomolohileng se ile sa hlahlojoa ka sekhahla ho sebetsa e le taolo ea li-anatomical le Mann-Whitney U teko e ne e sebelisetsoa ho bapisa boitšoaro ka letsatsi la ho qetela la teko le nang le naloxone le banna ba nang le phihlelo ea phekolo ea saline.
Tlhaloso ea pERK e kenyelletsoeng ho sebelisana le litaba
Tlhahlobo ea liteko.
Ho pepesehela lehare leo ka lona banna ba fumaneng boiphihlelo ba ho kopanela liphate ba bontšitsoe ho etsa hore MOR e sebelisoe VTA le mesebetsi ea mahlaseli a mahlaseli a VTA le NAc (Balfour et al., 2004). Ka lebaka leo, tikoloho ea ho nyalana e sebetsa e le boemo bo hlokomelisoang ba moputso oa thobalano. Phuputso ea morao-rao e ile ea leka hore na ts'ebetso ea MOR nakong ea boiphihlelo ea thobalano e hlokeha bakeng sa ts'ebetsong ea neural activated cue-induced. Naloxone kapa saline e ne e tsamaisoa ka mokhoa o hlophisitsoeng (ip) 30 min pele o kenngoa lebaleng la ho lekana le ho kenngoa ha mosali ea amohelang ho kopanela liphate, kapa pele ho laola mokhoa oa ho laola o neng o e-na le ho behoa ha mokotla o sa sebetseng ntle le tlhahiso ea basali (ba sa nke lehlakore tikoloho; naive). Ka hona, lihlopha tse 'nè tsa liteko li entsoe: Naive Sal, Naive NLX, Exp Sal, le Exp NLX. Beke e le 'ngoe ka mor'a ho qetela ho kopanya likhallelo, halofo ea liphoofolo sehlopheng ka seng e ne e pepesoa kahare ea mating (banna ba Exp: litlamorao tse amanang le thobalano) kapa ho sebetsana le cage (banna ba se nang boithati: li-cue tse se nang thuso), athe halofo e' ngoe e ne e sa pepesehe ngoe le e 'ngoe' me ho e-na le hoo e sala ka matlong a koaletsoeng malapeng (ho etsa qeto ea polelo ea motheo ea pERK). Paradigm ena ea liteko e hlahisitse lihlopha tsa 8: Khotso ea Sal-No Cue, Khofu ea Nako e Nang le Ntoa, Khofu ea Ntoa-Nako, Nako ea Ntoa-Ntoa, Nako ea Phatlalatso ea Ntoa, ea Hlalosang Nako-ea Hlasehang, ea Nako ea Ntoa + (n = 4 e mong le e mong ntle le Nile ea Nile-No Cue, n = 3). Liphoofolo li ne li sebelisoa hampe 10-15 metsotsoana ka mor'a tlhahiso ea mahlaseli. Liphoofolo tsa ho laola li ile tsa tlosoa matlong a tsona a koaletsoeng 'me tsa sebelisoa ka nako e le' ngoe.
Immunohistochemistry.
Ho aroloa le immunohistochemistry ho ne ho khannoa joalokaha ho boletsoe ka holimo. Mona, re ne re sebelisa anti-antibody ea mmutla khahlanong le p42 le p44 MAP Kinases ERK1 le ERK2 (pERK; 1: 4 000; Technology Signaling Technology). Anti-antibody e ka sehloohong e tsebahala haholo ka lingoliloeng (Roux le Blenis, 2004; Murphy le Blenis, 2006; Frohmader et al., 2010b). Ho feta moo, ho se lumelloe ha sesole sa pele se thibelang ho itšireletsa mafung le ho hlahloba ha Bophirimela tsa linama tsa boko ba rat ho senola lihlopha tse peli ho litekanyo tse loketseng tsa limolek'hule.
Tlhahlobo ea lintlha.
lisele tsa pERK-immunoreactive (-IR) li ne li baloa libakeng tse 'maloa tsa boko ba sebelisa penta ea lucida ea k'hamera e kopantsoeng le Leica Microscope ea DMRD: NAc [mokokotlo (C) le shell (S); 400 × 600 μm; koranta ea lipere tsa boipheliso; mPFC; anterior cingulate sebakeng (ACA); prelimbic cortex (PL); infralimbic cortex (IL); 600 × 800 μm mong le e mong], caudate-putamen (CP; 800 × 800 μm), le li-amygdala (BLA; 900 × 1200 μm; Balfour et al., 2004; Frohmader et al., 2010b; Pitchers et al., 2010b). Likarolo tse peli li ne li baloa sebakeng se seng sa boko le lipalo tsa lisele tse libakeng tse tloaelehileng tsa lisebelisoa li bile li baloa e le litekanyo tsa lisele ka mm2. Lipalo tse peli li ne li lekanngoa ka phoofolo ka phoofolo bakeng sa ho balloa ha sehlopha se bolelang. Lihlopha tsa sehlopha ka har'a lihlopha tse nang le phihlelo ea ho kopanela liphate kapa tse se nang boithati li ile tsa bapisoa ho sebelisa li-ANOVA tse peli [lisosa: phekolo ea lithethefatsi (NLX kapa Sal) le cue (cue kapa no cue)] e lateloa ke post hoc Litšoantšiso tse sebelisitsoeng Holm-Sidak kapa Mann-Whitney li hlahloba moo ho loketseng ka boemo ba bohlokoa p <0.05. Khetleng ea NAc ea liphoofolo tse nang le boiphihlelo ba thobalano, ho ne ho e-na le mokhoa o matla oa ho sheba lintlha mme ka hona, papiso ea bobeli ba eona e ile ea etsoa ho bapisa lihlopha tsa saline (Sal-No Cue) le saline cue (Sal + Cue) feela.
Litšoantšo.
Litšoantšo tsa di-di-digital li ne li nkiloe ka ho sebelisa CCD kamera (Macrofire, Optronics) e kopantsweng ho Leica microscope (DM5000B) le lisebelisoa tse tsitsitseng tsa khamera. Litšoantšo li kenngoe ka har'a software ea Adobe Photoshop 9.0. Litšoantšo ha lia ka tsa fetoloa ka tsela leha e le efe ntle le ho fetola khanya le phapang.
Results
Liphetoho tse bakoang ke likamano tsa botona le botšehali tsa lisele tsa VTA dopamine
Ho ba le thobalano ho ile ha fella ka ho fokotseha ha boholo ba VTA dopamine soma (Feie. 1A-C). Boiphihlelo ba thobalano bo fokolitse haholo sebaka le palo ea soma ea lisele tsa VTA TH-IR (sebaka: F(1,31) = 23.068, p <0.001; pherimitha, F(1,31) = 18.225, p <0.001). Ho ne ho boetse ho na le tšusumetso e kholo ea nako (sebaka: F(2,31) = 6.377, p = 0.005; moeli, F(2,31) = 4.389, p = 0.021) le puisano e kholo pakeng tsa phihlelo le nako (sebaka: F(2,31) = 5.284, p = 0.011; moeli, F(2,31) = 4.347, p = 0.022). Ho bapisa ka tsela e fapaneng ho senotse hore sebaka le moeli oa lisele tsa TH-IR li fokotsoe haholo 1 le 7 d ka mor'a letsatsi la ho qetela la boitšoaro ba ho kopanela liphate ka liphoofolo tse nang le phihlelo ea ho kopanela liphate ha li bapisoa le litekanyetso tsa ho kopanela liphate [Feie. 1B, sebaka: p = 0.002 (1 d), p <0.001 (7 d); C, moeli: p = 0.009 (1 d), p <0.001 (7 d)]. Phello ea boitšoaro ba thobalano e ile ea qhalana ha e lateloa ke nako ea ho ithiba ha moputso ha boholo ba soma ba li-neuron tsa TH-IR bo khutliselitsoe ho 31 basele kamora seboka sa ho tlolelana ha thobalano (Feie. 1B, sebaka: p = 0.798; C, moeli: p = 0.785). Liphetoho tse bakoang ke ho kopanela liphate ha lia ka tsa fumanoa ka circularity nako efe kapa efe ea nako (Feie. 1D). VTA dopamine soma diminse ea boholo bo ne bo sa itšetleha ka litekanyetso tsa letsatsi le leng le le leng, kaha phihlelo ea ho kopanela liphate nakong ea likhallelo tse hlano tsa ho nyalana ha hae e boetse e hlahisitse boholo ba VTA dopamine soma size (Feie. 2A,B, E-H, sebaka: p = 0.004; moeli: p <0.001). Ka lehlakoreng le leng, boiphihlelo ba thobalano ha boa ka ba ama boholo ba TH-IR soma ho substantia nigra (Feie. 2C, Ke-J, sebaka: p = 0.13; moeli: p = 0.16) ebile ha e fetole boholo ba soma metseng e haufi ea VTA e seng ea TH-IR neurons (Feie. 2D, E-H, sebaka: p = 0.46; moeli: p = 0.45).
Liphetoho tsa boholo-holo tsa soma tse entsoeng ke opioid liphetoho tsa VTA dopamine neurons. A, Litšoantšo tsa litšoantšo tsa VTA dopamine neurons ho liphoofolo tse nang le bokooa ba likobo le tse nang le phihlelo tse bontšang ho fokotseha ha boholo ba soma 7 d ka mor'a hore nako ea ho qetela e kopane. Sebaka sa sekala, 5 μm. Boitsebiso bo bongata bo bontšang hore phihlelo ea ho kopanela liphate (Exp, batsho ba batsho) e bakile ho fokotseha haholo sebakeng (B;; ka μm2) le moeli (C;; ka μm) ea lisele tsa VP dopamine, 1 d (Naive, Exp; n = 6) le 7 d (Ntle, n = 5; Exp, n = 6), empa eseng 31 d (Nnave, n = 6; Exp, n = 8) kamora ho nyalana ha ho qetela, ha ho bapisoa le taolo ea boikhohomoso ba botona kapa botšehali. Sebaka se fokotsoe ho 84% ho banna ba nang le phihlelo ha ho bapisoa le taolo ea boipheliso ho 1 kapa 7 d. Mofuputsi o fokotsoe ho 91.6 le 90% lihlopheng tse nang le phihlelo ha li bapisoa le taolo ea 1 le 7 d resp. Ho ne ho se na phello holim'a circularity (D). Sebaka sena sa dopamine cell plasticity sebakeng seo (E) le moeli (F) e thibetsoe ke naloxone (NLX, n = 8), empa e se saline (Sal, n = 7) kalafo nakong ea ho nyalana, 7 d ka mor'a ho qetela ho kopanela liphate ha li bapisoa le taolo ea ho kopanela liphate (Sal, n = 5; NLX, n = 6). Boitsebiso bo emela ± SEM; * e bontša phapang e kholo ho bapisoa le taolo ea ho kopanela liphate ka letsatsi le le leng (B, C) kapa ha ho bapisoa le ho laola litla-morao tsa thobalano le batho ba nang le thobalano (joalo-joalo)E, F).
Boiphihlelo ba thobalano ha boa fokotsa boholo ba soma ka substantia nigra dopamine neurons kapa VTA nondopamine neurons. VTA TH-IR neuron soma sebakeng (A;; ka μm2) le moeli (B;; ka μm) ka liphoofolo tse nang le bohloeki (ba makhooa) le liphoofolo tse nang le tsebo (tse ntšo) tse ileng tsa fumana phihlelo ka ho kopanya ka makhetlo a mabeli ka beke ho e-na le ka matsatsi a latellanang. Substantia nigra TH-KH soma sebakeng (C) le VTA sebaka se seng-TH-IR soma sebakeng seo (D) litabeng tsa bosodoma (tse tšoeu) le liphoofolo tse nang le tsebo (batsho). Boitsebiso bo emela ± SEM; * e bontša phapang e kholo ho bapisoa le taolo ea ho kopanela liphate. Litšoantšo tse emelang li-neuron tse nang le TH-IR (tse sootho) ka VTA tsa batho ba nang le thobalano (E), le phihlelo (F) banna. G, H, Setšoantšo se phahameng-hōle sa neuron se bontšitsoeng ke motsu ho E 'me F ka ho latellana. Lisele tse nang le litšila tsa Nissl li bontšoa ka buluu litšoantšong tsena. Litšoantšo tse emelang batho ba bontšang lit-neurons tsa TH-IR SN ea batho ba nang le thobalano (I) le ba nang le phihlelo (J) banna. Mekoallo ea mekhahlelo: E-J, 20 μm.
Ho fokotseha ha boholo ba soma ka lebaka la thobalano ea VTA dopamine neurons ho itšetlehile ka ho ts'ebetsoa ha opioid receptor
Ho fokotseha ha boholo ba VTA dopamine neuron soma bo bakoang ke boiphihlelo ba thobalano bo thibetsoe ke mohanyetsi oa MOR ea nonselective naloxone, o tsamaisoang pele ho nako e 'ngoe le e' ngoe ea ho kopanya. Kalafo ea Naloxone pele mekhahlelo ea ho nyalana e na le phello e kholo sebakeng (F(1,22) = 4.738, p = 0.041) 'me e ts'oanela ho ba le phello e kholo ho potoloho (F(1,22) = 2.892, p = 0.052). Kamano e kholo pakeng tsa phihlelo le phekolo ea naloxone e fumanoe sebakeng (F(1,22) = 5.578, p = 0.027) le moeli (F(1,22) = 8.167, p = 0.009). Litšoantšiso tse fapaneng li bontšitse hore phihlelo ea thobalano ea liphoofolo tse tšoaroang ka letsoai e fokotsoe haholo sebakeng le sekhahla sa VTA dopamine neurons 7 d kamora ho qetela ha li kopana le banna ba nang le thobalano ba nang le thobalano (Feie. 1E, sebaka: p = 0.018; F, moeli: p = 0.007). Ka lehlakoreng le leng, liphoofolo tse ileng tsa tšoaroa ke lexonyone tsa ho kopanela liphate li ne li sa fapane le banna ba neng ba tšoaroa ke nangxone (Feie. 1E, sebaka: p = 0.483; F, moeli: p = 0.330). Ho feta moo, boholo ba liphoofolo tse nang le phihlelo ea saline bo ne bo fokotseha haholo ha bo bapisoa le liphoofolo tse nang le phihlelo ea naloxone (Feie. 1E, sebaka: p = 0.002; F, moeli: p = 0.002). Phello ena ea naloxone e ne e totobetse bakeng sa boiphihlelo ba thobalano, kaha phekolo ea naloxone feela e ne e sa ama boholo ba TH-IR cell soma ho banna ba nang le thobalano ba nang le thobalano le ba nang le bothata ba ho kopanela liphate ha ba bapisoa le lithibelo tsa phekolo ea saline (Feie. 1E,F). Ho feta moo, phello ena ea naloxone ka ho fokotseha ha boholo ba soma e ne e se ka lebaka la liphello tsa naloxone boitšoarong ba thobalano, kaha boitšoaro ba ho itšoara ha boa ka ba fapana ka ho feletseng pakeng tsa nalexone le banna ba tšoaroang ke saline, ntle le nako e telele ea ho qala ho nyalana ka mor'a ho khaotsa (kamora nako ea ho khaotsa) ho banna ba tšoeroeng ke naloxone nakong ea thuto ea pele ea bobeli le ea bohlano.p = 0.03 le p = 0.004, ka ho latellana). Bobeli ba saline- le banna ba tšoaroang ke naloxone ba ile ba etsisoa ho ejaculation nakong ea lihlopha tse hlano tsa ho nyalana.
Morphine e bakoang ke likamano tsa botona le botšehali e le moputso oa mamello
Litholoana tsa boiphihlelo ba thobalano ka boholo ba VTA dopamine soma ka ketso ea EOP ho VTA li tšoana le tse tlalehiloeng bakeng sa li-opiate tse sa tloaelehang (Sklair-Tavron le al., 1996; Russo et al., 2007). Ka hona, e ile ea lekoa hore na VTA dopamine cell plasticity e entsoeng ka moputso e ama moputso oa opiate morphine. Ka sebele, phihlelo ea thobalano e entse hore morphine e be moputso oa mamello, e tšoanang le liphello tsa li-opiates tse sa foleng (Russo et al., 2007). Banna ba nang le thobalano ba sa khone ho hlahisa CPP bakeng sa tekanyo ea 0.5 mg / kg morphine; athe banna ba nang le thobalano ba kopanelang liphate ba ile ba theha CPP bakeng sa tekanyo ena, joalokaha ho bontšoa ka ho qeta nako e ngata ka kamoreng ea morphine-lipakeng tsa kamore ea saline nakong ea tlhahlobo ea tlhahlobo (post-test)Feie. 3; p = 0.039). Lihlopha tse peli tsa thobalano le tse nang le boiphihlelo li qeta nako e ngata haholoanyane kamoreng ea morphine-paired ha e bapisoa le kamore ea saline e nang le lipere tse nang le tekanyo e phahameng ea morphine: 5.0 mg / kg (Feie. 3;; Naïve: p = 0.029; Exp: p = 0.012) le 10.0 mg / kg (Feie. 3;; Naïve: p <0.001; Nako: p = 0.002).
Litholoana tsa phihlelo ea thobalano morphine moputso. Linako tse sebelisoang ka saline- (Sal) kapa morphine-paired (Mor; 0.5, 5 kapa 10 mg / kg bodyweight) likamore nakong ea kamora 'tlhahlobo ea ho kopanela liphate (Naive, n = 10-13) kapa phihlelo (Exp, n = 9-13) banna. Litaba tse hlahisitsoeng e le tsa bohlokoa ± SEM; * e bontša phapang e kholo ho bapisoa le kamore ea Sal-paired ka har'a liphoofolo tse tšoanang. NS, Hase bohlokoa.
Ho ba le ts'ebeliso ea ho kopanela liphate ho etsoang ke thobalano ho itšetlehile ka ts'ebetso ea ho amohela li-opioid receptor
Lintho tse fumanoeng ho fihlela joale li bontša hore EOP e sebetsanang le VTA nakong ea 5 nako e khutšoanyane ea ho itšehla thajana e etsa hore polasetiki ea VTA dopamine neurons e tšoane le liphello tsa lefu le sa foleng la heroine kapa heroin ea boipheliso (Russo et al., 2007; Mazei-Robison et al., 2011). Re ne re nahana hore ho fokotseha ha VTA dopamine-size-size ke habohlokoa bakeng sa ho ithuta ka moputso le ka ho khetheha bakeng sa ts'ebeliso ea ho kopanela liphate ka lebaka la ho kopanela liphate ka boitšoaro ba thobalano ka lebaka la tšusumetso le ts'ebetso. Tlhahlobo ena e ile ea lekoa ka ho thibela MOR ho sebelisa lengxone nakong ea ho nyalana le ho hlahloba liphello ho tsamaisa boitšoaro bo bobe ba ho kopanela liphate bo bakoang ke phihlelo ea thobalano nakong ea lihlahisoa tse hlano tsa letsatsi le letsatsi. Lintlha li hlahisoa Setšoantšo sa 4 bakeng sa likarolo tsa pele le tsa bohlano tsa ho kopanya feela, kaha tsena ke boitsebiso bo bonts'ang boiphihlelo bo bakoang ke phihlelo-ho susumelletseha ho ts'oaroang ha boitšoaro bo botle. Ho feta moo, liphello tsa nako e telele tsa phekolo ea naloxone nakong ea likhallelo tsa ho nyalana li lekoa ho boloka boiphihlelo bo bakoang ke phihlelo ea boitšoaro ba ho kopanela liphate, nakong ea tlhahlobo ea ho qetela ea likhahla tsa 1 beke hamorao. Setšoantšo sa 4A e bontša moqapi oa liteko. Ho ne ho e-na le phello ea bohlokoa ea thuto ea ho kopanya liphate ka likarolo tsohle tsa boitšoaro ba thobalano (latency mount: F(2,55) = 11.286, p <0.001; tšenyo ea nako ea ho kena: F(2,55) = 8.767, p <0.001; ejaculation latency: F(2,55) = 10.368, p <0.001) le kalafo ea naloxone ho latency ho hloa (F(1,55) = 6.585, p = 0.013) le ho kenya letsoho (F(1,55) = 7.863, p = 0.007). Ho bapisa ka tsela e fapaneng ho bontšitse hore phekolo ea naloxone e amme boitšoaro ba thobalano nakong ea thuto ea pele ea likhallelo hobane liphoofolo tsa naloxone li ne li e-na le nako e telele haholo ea ho ea pele (p = 0.002) le ho kenya letsoho (p = 0.002) ha e bapisoa le taolo ea saline letsatsing la pele la ho nyala. Tšusumetso ena ea bilexone boitšoarong ba pele ba ho kopanela liphate e ile ea fokotseha ka boiphihlelo ba thobalano 'me ha ea ka ea hlokomeloa nakong ea liketsahalo tse latelang tsa ho kopanela liphateLethathamo 1). Ho feta moo, tsamaiso ea naloxone pele e mong le e mong oa lihlahisoa tse hlano tsa ho kopanya liphiri ha ea ka ea sitisa ho tsamaisa mokhoa oa pele oa thobalano le phihlelo ea thobalano Tumellanong le liphello tse matlafatsang tsa boiphihlelo ba ho kopanela liphate, banna ba tšoaroang ka letsoai ba bonts'itse ho fokotseha ha latencies ho nyoloha (Feie. 4B; p = 0.032) ho fokotsa maikutlo (Feie. 4C; p = 0.033) le ejaculation (Feie. 4D; p <0.001) nakong ea karolo ea bohlano ea ho tlolelana ha liphoofolo ha e bapisoa le nako ea pele ea ho tlolelana ha liphoofolo, e bonts'ang ho nolofatsa boitšoaro ba thobalano. Ka mokhoa o ts'oanang, banna ba tšoaroang ke naloxone ba bontšitse maqhubu a makhuts'oane haholo ho hloa (Feie. 4B; p <0.001), ho kenella (Feie. 4C; p <0.001), le ejaculation (Feie. 4D; p = 0.017) ka la bohlano ha e bapisoa le letsatsi la pele. Ho feta moo, banna ba tšoaroang ke naxone ba ne ba sa fapane le taolo ea saline ka nako leha e le efe ea nakoana nakong ea bohlano.
Li-opioids tse sa feleng li phetha karolo ea bohlokoa ho thusang ho ba le phihlelo ea boitšoaro ba thobalano. A, Moqapi oa tlhahlobo. B-D, Mekhoa ea boitšoaro ba thobalano bakeng sa banna ba tšoaroang ka saline (Sal, makhooa a masoeu, n = 11) kapa naloxone (NLX; libaka tse ntšo, n = 12) ka tsamaiso ea tsamaiso. Lintlha tse bontšitsoeng ke latency ho phahamisa (B;; metsotsoana), tlhahiso-pele (C;; metsotsoana), le ejaculation (D;; metsotsoana) ka matsatsi a 1 le 5 matsatsing a mahlano a latellanang a ho nyalana. Ho phaella moo, dintlha li bontswa bakeng sa teko ea ho qetela ea ho nyalana, 7 d kamora nako ea bohlano. Litaba li hlahisoa e le tsa bohlokoa ± SEM; + e bontša phapang e khōlō pakeng tsa matsatsi a 1 le 5 nakong ea phekolo; * e bontša phapang e khōlō pakeng tsa tlhahlobo ea letsatsi le letsatsi 5 nakong ea phekolo; # e bontša phapang e khōlō pakeng tsa nalxone le lihlopha tsa saline ka hare ho letsatsi.
Tsamaiso ea Naloxone pele ho ho nyaloa e eketsehile latencies ho nyoloha le ho kenya letsoho feela letsatsing la pele la ho nyala
Ka lehlakoreng le leng, phekolo ea naloxone nakong ea thuto ea thobalano e ile ea sitisa tlhokomelo ea boiphihlelo bo bakoang ke phihlelo ea boitšoaro ba thobalano letsatsing la ho qetela la ho nyalana. Letsatsi la teko le ile la khannoa 7 d ka mor'a hore ho be le nako ea ho qetela ea ho nyalana ha ho se na joko ea naloxone. Tsamaiso ea banna ba sebetsanoang le Saline e bontšitse boiphihlelo bo lebeletsoeng-ho susumelletseha ho susumelletseha boitšoaro ba thobalano. Ha e le hantle, latencies e ne e sa fapane pakeng tsa karolo ea bohlano ea likhallelo le letsatsi la ho qetela la tlhahlobo (Feie. 4B-D). Leha ho le joalo, banna ba tšoeroeng ke naloxone ba bontšitse keketseho e kholo ea latencies ho phahamisa (Feie. 4B; p = 0.033), ho kenya letsoho (Feie. 4C; p = 0.036) le ejaculation (Feie. 4D; p = 0.049) letsatsing la teko ha le bapisoa le thuto ea bohlano ea ho kopanya. Hape, letsatsing la tlhahlobo liphoofolo tsa naloxone li fumanoe li lieha haholo ho feta banna ba tšoaroang ka letsoai ba bontšitsoeng ke latencies tse telele ho ea holimo (Feie. 4B; p = 0.017) le ho kenya letsoho (Feie. 4C; p = 0.043). Ka lebaka leo, phekolo ea naloxone e thibelitse tlhokomelo, empa eseng ea pele, nts'etsopele ea boithuto bo bakoang ke phihlelo ea boitšoaro ba thobalano. Liphuputso tsena li bontša karolo e boima bakeng sa polelo ea EPA e bakoang ke EOP e entsoeng ka potlako ka nako e telele ea polelo ea ho matlafatsa boitšoaro ba meputso ea tlhaho.
Ho ile ha etsoa liteko tse 'maloa tsa ho laola lits'ebetso ho fumana hore liphello tsa opioid receptor blockade ka ho lahleheloa ke nako e telele ea ts'ebeliso ea thobalano li ile tsa ikemela ka lebaka la ho hloka taolo ea naloxone letsatsing la ho qetela la ho nyalana (Feie. 5A,B), li ne li totobetse ho lahleheloa ha nako e telele, empa e seng tlhokomelo ea nako e khutšoanyane ea ho tsamaisa litlhoko tsa malapa (Feie. 5E,F), ha lia ka tsa bakoa ke ho pepeseha letsatsi le letsatsi ho naloxone feela (Feie. 5C,D), 'me ha lia ka tsa bakoa ke tahlehelo ea thobalano ho banna ba tšoaroang ke nangxone (Feie. 5G,H). Ntlha ea pele, ho bontša hore boitšoaro ba ho kopanela liphate bo fetotsoeng ha boa ka ba e-ba teng ka lebaka la ho ba sieo ha naloxone, kapa lekono kapa saline e ne e tsamaisoa letsatsi le le leng la tlhahlobo ea ho nyalana ho liphoofolo tse ileng tsa fumana ho nyalana li kopantsoe le naloxone ha li ntse li fumana boiphihlelo ba thobalano (Feie. 5A). Ho ne ho e-na le phello e kholo ea letsatsi la ho nyalana ho latencies ho latella (Feie. 5B; F(2,27) = 30.031, p = 0.038) le ho kenya letsoho (Lethathamo 2; F(2,27) = 10.686, p = 0.048). Ho ne ho se na tšusumetso e kholo ea letsatsi la ho nyalana ka latency ho ea ho ejaculation (Lethathamo 2; F(2,27) = 2.388, p = 0.109) Joalokaha ho hlalositsoe ka holimo, phekolo ea naloxone nakong ea ho kopanya liphate ha ea ka ea ama mokhoa oa ho tsamaisa boitšoaro ba thobalano nakong ea liboka tse hlano tsa pele tsa thobalano. Lihlopha ka bobeli (saline le lihlopha tse tšoaroang ke naloxone tse khethiloeng ke phekolo e fumanoang nakong ea tlhahlobo ea ho qetela ea ho nyalana; ka bobeli li amoheloa ke naloxone ka nako ea ho nyalana) li bontšitse boitšoaro bo hlephileng ba ho kopanela liphate letsatsing la 5 ha li bapisoa le letsatsi la 1 'me li bonts'a nakoana e khutšoanyane ho ea pele (Feie. 5B;; saline: p = 0.033; naloxone: p = 0.014) le ho kenya letsoho (Lethathamo 2;; saline: p = 0.034; naloxone: p = 0.026). Liphoofolo tse ileng tsa fuoa nang le naloxone kapa saline letsatsing la ho qetela la ho nyalana li ne li e-na le nako e telele ea ho phahama (Feie. 5B;; saline: p = 0.018; naloxone: p = 0.029) le ho kenya letsoho (Lethathamo 2;; saline: p = 0.019; naloxone: p = 0.020) ha e bapisoa le letsatsi la bohlano la phihlelo ea ho hōlisa. Ka hona, tsamaiso ea naloxone kapa saline ka letsatsi la teko hang-hang pele ho nyalana ha ea ka ea susumetsa phello ea phekolo ea naloxone nakong ea likamano tsa ho kopanela liphate le ho hlokomoloha nako e telele ho tsamaisa boitšoaro ba thobalano ho ne ho tšoana le ho bontšitsoeng liphoofolong tse sa kang tsa fumana eng ka letsatsi la ho qetela la ho nyalana (Feie. 4).
Li-opioids tse sa feleng li bohlokoa nakong ea nako e telele ea boipiletso bo bakoang ke phihlelo ea boitšoaro ba thobalano. A, Tlhahlobo ea tlhahlobo ea liteko bakeng sa teko ea phello ea NLX kalafo letsatsing la teko. B, Thaba ea latency ka matsatsi a 1 le 5 ea matsatsi a mahlano a latellanang le ho qeta letsatsi la tlhahlobo ea ho nyalana (teko) ho latela saline (grey) kapa injection ea naloxone (e ntšo). Litaba li emela ± SEM. * e bontša phapang e kholo pakeng tsa letsatsi la 1 le letsatsi la 5 nakong ea phekolo. # e bontša phapang e khōlō pakeng tsa letsatsi la teko le Letsatsi la 5 nakong ea kalafo. C, Tlhahlobo ea tlhahlobo ea liteko bakeng sa teko ea ho hlahloba phello ea naxone pele ho phekolo feela ntle le phihlelo ea ho kopanela liphate boitšoarong ba ho kopanela liphate. D, Thaba ea Latency ka letsatsi la ho qetela la ho nyalana, matsatsi a 7 ka mor'a matsatsi a 5 a entsoeng ka saline kapa ea naloxone ka ho ba sieo ha likhahla. Litaba li emela ± SEM. E, Tlhahlobo ea tlhahlobo ea teko ea ho leka ho hlahloba hore na kankere ea naloxone e ama pontšo ea nakoana ea boitšoaro bo bobe ba ho kopanela liphate liphoofolong tse nang le phihlelo. F, Thaba ea latency ka letsatsi 1 le letsatsi la 5 matsatsi a mahlano a latellanang le ho qetela letsatsi la tlhahlobo ea ho nyalana, letsatsi la 1 letsatsi le letsatsi 5 ka pel'a saline (lehlohlo) kapa lejoe la naxone (e ntšo). Litaba li emela ± SEM. * e bontša phapang e kholo pakeng tsa letsatsi la 1 le letsatsi la 5 nakong ea phekolo. G, Tlhahlobo ea tlhahlobo ea liteko bakeng sa teko ea hore na kokoxone e ka thibela liphello tse putsang tsa boitšoaro ba thobalano. H, Nako e sebelisitsoeng ho phahamisa kamoreng e kopantsoeng (ka metsotsoana e seng mekae) nakong ea pele (e bosoeu) le ka mor'a tlhahlobo (batsho) bakeng sa liphoofolo tse amohelang lengxone kapa saline pele li nyalana. Boitsebiso bo emela ± SEM; * e bontša phapang e kholo ho bapisoa le bo-pretest.
Lintlha tse bonts'itsoeng ke li-latency ho kenngoa ka hare ho tlhaho le ho khaola (metsotsoana) ho tloha lits'ebetsong tsa taolo e entsoeng ho fumana hore liphello tsa ho thibela MOR ho lahleheloa ke nako ea nako e telele ea ho kopanela liphate li itšetlehile ka ho hloka taolo ea naloxone letsatsing la ho qetela la ho nyalana.
Ho fumana hore na e ne e le phekolo ea naxone ha e kopanngoa le phihlelo ea thobalano le e sa phetetsoe ho naloxone ka sehe e ileng ea baka tšenyo ea boitšoaro bo bobe ba 7 d kalafo ea ho qetela, liphoofolo tse nang le bokooa ba thobalano li fumane liente tse hlano tsa letsatsi le leng le le leng tsa li-injine tsa saline kapa saline pele tlhahlobo ea ho qetela ea 7 d hamorao (Feie. 5C). Ha ho liphapang tsa bohlokoa tse neng li fumanoa bakeng sa parameter e kopanetsoeng pakeng tsa saline le li-sehlopha tse nang le bilexone pele ho moo (Feie. 5D;; thaba ea latency; latency latency: saline 139.7 ± 40.3 vs naloxone 121.83 ± 42.55; latency latency: saline 887.9 ± 70.0 vs naloxone 1050.8 ± 327.31). Liphello tsena li bontša hore le naloxone e le mong ha e lekane ho fetola boitšoaro bo bong bo latelang ba thobalano, ho tšoana le ho hloka liphello tsa naloxone feela ka VTA dopamine neuron plasticity.
Re nahana hore phekolo ea naloxone nakong ea ho fumana phihlelo ea ho kopanela liphate e ferekanya nako e telele ea boikutlo ba ho kopanela liphate-ho susumelletseha ho susumelitsoeng boitšoarong ba thobalano. E le ho leka sena ka ho eketsehileng, liphello tsa phekolo ea naloxone nakong ea ho nyalana li ile tsa lekoa ka boitšoaro bo latelang ba ho kopanela liphate nakong ea tlhahlobo ea ho qetela ea ho nyalana, e neng e etsoa feela 1 d ka mor'a ho kopanya ho qetela (tlhahlobo ea liteko; Feie. 5E). Ho ne ho e-na le phello e kholo ea letsatsi la ho nyalana holimo (Feie. 5F; F(2,20) = 19.780, p <0.001) le maqhubu a ho kena kahare (Lethathamo 2; F(2,20) = 19.041, p <0.001). Ho ne ho se na tšusumetso e kholo ea letsatsi ho ejaculation latency (Lethathamo 2; F(2,20) = 3.042, p = 0.070). Joalokaha ho hlalositsoe ka holimo, bohle ba batona (ho sa tsotellehe phekolo ea saline kapa mekhoa ea naloxone) ba ile ba bontša ho kenyelletsa boitšoaro ba thobalano nakong ea mekhoa e mehlano ea likamano tsa botona le botšehali e bontšoang ka nakoana e khutšoanyane ea ho kopanela (Feie. 5F;; saline: p = 0.002; naloxone: p = 0.018) le ho kenya letsoho (Lethathamo 2;; saline: p = 0.006; naloxone: p = 0.009) letsatsing la 5 le bapisoa le letsatsi la 1. Ka mokhoa o ts'oanang, mokhoa o ts'ebetsong oa thobalano o ile oa bontšoa ka letsatsi la teko ha ho bapisoa le letsatsi la 1 le bontšitsoeng ka latency e khutšoanyane haholo ho phahamisa (Feie. 5F;; saline: p = 0.001; naloxone: p = 0.020) le ho kenya letsoho (Lethathamo 2;; saline: p = 0.004; naloxone: p = 0.009). Habohlokoa le ho feta, phekolo ea naloxone nakong ea ho nyalana ha ea ka ea ama tšebetso ea ho kopanela liphate ka lebaka la ho kopanela liphate ha e lekoa 1 d ka mor'a ho ba le thobalano, e sa itšetlehe ka phekolo ea naloxone letsatsing lena la ho qetela la ho nyalana.
Kamora nako, re ile ra leka monyetla oa hore litla-morao tsa naloxone li iphumanele ponaletso ea nako e telele ea boitšoaro bo botle ba thobalano ke ka lebaka la tšitiso e nang le matla le thepa ea moputso ea thobalano. Le ha ho le joalo, naloxone e laetsoeng hang-hang pele e tloheloa e sa fetole kaho ea CPP ea ho ruruha (Feie. 5G), ho fana ka maikutlo a hore phekolo ea naloxone ha ea fetola moputso oa thobalano. Li-saline ka bobeli-le lihlopha tse tšoaroang ke naloxone li ile tsa theha karolo ea bohlokoa ea liketso tsa thobalano joalokaha ho bontšoa ke nako e eketsehileng ea nako e sebelisitsoeng ka kamoreng ea likamano tsa thobalano (Feie. 5H;; saline: p = 0.038; naloxone: p = 0.002) nakong ea tlhahlobo ea kamora 'tlhahlobo ha e bapisoa le ea pele. Ka lebaka leo, naloxone ha e na phello e kotsi ho tlhokomelo ea boitšoaro bo hlephileng ba thobalano ka ho thibela moputso o amanang le boitšoaro ba thobalano.
Ho tsamaisa boitšoaro ba thobalano ho itšetlehile ka ketso ea EOP VTA
Ho netefatsa hore EOP e ikemiselitse haholo ho fana ka ts'ebeliso ea nako e telele ea boitšoaro ba thobalano, moqapi oa liteko o hlalositsoeng ka Setšoantšo sa 3A o ile a phetoa ka li-intra-VTA tsaxx infusions ho e-na le liente tsa systemic. Liphetho li ne li tšoana le tsamaiso ea tsamaiso e hlalositsoeng ka holimo. Ho ne ho e-na le phello e kholo ea letsatsi la ho nyalana ka litsela tsohle tsa boitšoaro ba thobalano (Feie. 6A, latency ea thaba: F(2,33) = 4.494, p = 0.019; B, latency latent: F(2,33) = 4.042, p = 0.027; C, latency ejaculation: F(2,33) = 5.309, p = 0.010) le phekolo ea intra-VTA ea naloxone ka latencies ho phahamisa (F(1,33) = 7.345, p = 0.011) le ho kenya letsoho (F(1,33) = 6.126, p = 0.019). Intra-VTA naloxone ha ea ka ea thibela boiphihlelo ba pele ba ho ba le phihlelo ea boitšoaro ba thobalano nakong ea 5 ea ho nyalana, joalo ka banna ba tšoaroang ke naxone ba bontšitse ho fokotseha ha latencies ho nyoloha (Feie. 6A; p = 0.001), ho kenya letsoho (Feie. 6B; p <0.001), le ejaculation (Feie. 6C; p = 0.001) letsatsing la 5 le bapisoa le letsatsi la 1. Banna ba tšoeroeng ke Naloxone ba ne ba fapane le banna ba tšoeroeng ke saline ka letsatsi la bohlano la ho nyaloa ka nako leha e le efe ea matšoao. Intra-VTA kalaxone kalafo, joalo ka tsamaiso ea tsamaiso, e entseng hore ho be le ho eketseha ha thaba (Feie. 6A; p <0.001) le maqhubu a ho kena kahare (Feie. 6B; p <0.001) ka letsatsi la pele la ho tlolelana ha liphoofolo ha ho bapisoa le tse tšoaroang ka letsoai, tse neng li sa bonoe nakong ea likhato tsa kamora tse latelang (nakong eo banna ba tšoaroang ke naloxone le letsoai ba neng ba sa tšoane) Maikutlo a mang a neng a sa lebelloa ke hore tekong ena, banna ba tšoaroang ka letsoai ha ba bonts'a ho nolofatsa hoa bohlokoa ha li-mount kapa intromission latency (joalo ka ha ho bonts'itsoe litekong tsohle tse hlalositsoeng kaholimo), mme ke latency ejaculation feela e khutsufalitsoeng ka letsatsi la bohlano ha e bapisoa le letsatsi la pele (letsoai: p = 0.001).
Li-opioid tse nang le mamello ea li-opioids li-VTA li phehella mokhoa oa ho thusa batho ba nang le phihlelo ea boitšoaro ba thobalano le tlhokomelo ea nako e telele. Matšoao a boitšoaro ba thobalano bakeng sa banna ba tšoaroang ka saline (Sal, makhoba a makhooa, n = 8) kapa NLX (maballo a matšo, n = 6) le tsamaiso ea intra-VTA. Lintlha tse bontšitsoeng ke latency ho phahamisa (A), ts'ebetsong (B), le ejaculation (C) ka matsatsi a 1 le 5 matsatsing a mahlano a latellanang. Ho phaella moo, dintlha di bontswa bakeng sa letsatsi la ho qetela la ho phalla, 7 d letsatsing le hlahlamang 5 ha ho se na saline kapa joxone e entsoeng. Boitsebiso bo emela ± SEM; + e bontša phapang e khōlō pakeng tsa matsatsi a 1 le 5 nakong ea phekolo; * e bontša phapang e khōlō pakeng tsa tlhahlobo ea letsatsi le letsatsi 5 nakong ea phekolo; # e bontša phapang e khōlō pakeng tsa lihlopha tsa naloxone le Sal ka hare ho letsatsi. Litšoantšo tsa litšoantšo tsa likarolo tsa VTA tse nang le li-coronal (H, -4.60; I, -5.00; J, -5.25 ho tloha bregma) e bontšang libaka tsa injection tsa intra-VTA bakeng sa liphoofolo tsohle Tlhahlobo 5 (saline; e tšoeu; sebelisa litšoantšo tsa template ho tloha Swanson Brain Maps (Swanson, 2004). Li-cannula li ne li e-na le likarolo tse peli, empa libaka tsa lisebelisoa li emela unilaterally bakeng sa bonolo. fr, Fasciculus retroflexus; ML, Medial lemniscus; SN, ts'ebeliso ea lichelete.
Intra-VTA naxolone kalafo e thibelitse tlhokomelo ea boitšoaro bo hlephileng ba ho kopanela liphate bo boletsoeng ka banna ba nang le botona kapa botšehali, ba tšoanang le liphello tsa naloxone ea mokhoa o tloaelehileng. Ka ho khetheha, letsatsing la ho qetela la teko, banna ba tšoeroeng ke naxone ba ne ba e-na le maqhubu a mangata a ho feta (Feie. 6A; p = 0.011), ho kenya letsoho (Feie. 6B; p = 0.010), le ejaculation (Feie. 6C; p = 0.015) ha e bapisoa le ea bona ea bohlano ea likhahla le ho bapisoa le banna ba tšoaroang ka letsoai letsatsing la ho qetela la teko (Feie. 6A, p = 0.006; B, p = 0.008). Ka lehlakoreng le leng, liphoofolo tse tšoaroang ka letsoai li ne li sa fapane le latencies ho phahamisa le ho kenya letsoho pakeng tsa letsatsi la ho qetela la tlhahlobo ea letsatsi le letsatsi 5 ea ho nyalana. Liphello tsena li ne li totobetse ho hlahisa naloxone ho VTA, e le banna ba nang le libaka tsa ho senya haufi le moo empa ba sa lebise VTA (Feie. 6D; n = 3) e bonts'oa nako e telele ho tsamaisa mokhoa oa thobalano o ts'oanang le lits'ebetsong tsa phekolo ea letsoai (ML, IL = 53 ± 6.245, EL = 389 ± 299.5 mme e fapane ka ho fapaneng ha e bapisoa le liphoofolo tsa intra-VTA tsa naloxone letsatsing la ho qetela la likhahla (ML, IL: p = 0.029; EL: p = 0.0395).
Khato ea EOP e hlokeha bakeng sa ts'ebetso ea neural activation e kenyelletsoeng ka ho kopanela liphate
Ho itšetlehile ka lintho tse fumanoeng ho fihlela joale, re ne re nahana hore ts'ebetso ea EOP ho VTA nakong ea boiphihlelo ba ho kopanela liphate le ho fokotseha ha boholo ba boholo ba VTA dopamine soma ho bohlokoa haholo bakeng sa ho fana ka matla a ho susumetsa ho ts'oanela ho ts'oanela mekhoa ea thobalano. Ho leka tlhahiso ena, liphello tsa ho thibela li-receptor tsa opioid nakong ea boiphihlelo ba ho kopanela liphate ho etsa mesebetsi ea neural e bakoang ke ho ipapisa le maemo a boemong ba boemo bo boletsoeng pele ho ts'oaetso ea thobalano (lintlha tse amanang le likamano tsa thobalano) li ile tsa hlahlojoa. Liphoofolo tsa botona le botšehali tsa botona le botšehali li ne li boetse li tsejoa ke maemo a tikoloho, empa li ne li sa kopane le phihlelo ea ho kopanela liphate pele, kahoo li ne li sa nke lehlakore. Qetellong, litekanyetso tsa motheo tsa pERK li ne li khetholloa ka lihlopha tse laolang thobalano le tse nang le boikhohomoso tse neng li setse matlong a koaletsoeng malapeng 'me li se ke tsa pepeseha ho tse ling tse ling. Ho netefatsa le ho atolosa liphuputso tsa pele (Balfour et al., 2004), ho hlahella litabeng tsa maemo a amanang le moputso oa nakong e fetileng oa thobalano ho ile ha eketseha polelo e hlakileng ho banna ba nang le botona kapa botšehali ka NAC (Feie. 7) le mPFC (Feie. 8A-C), empa ha ea ka ea baka activation ea neuronal BLA (Feie. 8D) kapa CPu (data e sa bontšoang). Ho ne ho e-na le liphello tse kholo tsa ho pepeseha ha cue ho NAC core (F(1,12) = 12.1941, p = 0.004), ACA (F(1,12) = 5.541, p = 0.038), le PL (F(1,12) = 5.241, p = 0.041), le phekolo ea naloxone ho NAC core (F(1,12) = 6.511, p = 0.025), ACA (F(1,12) = 15.242, p = 0.002), le PL (F(1,12) = 7.336, p = 0.019). Ho ne ho e-na le puisano e kholo ho NAC core (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), le IL ((F(1,12) = 6.965, p = 0.022). Ntlha ea pele, ho hlahisa likokoana-hloko tse amanang le ho kopanela liphate ho ile ha eketseha haholo ka liphoofolo tse nang le thobalano e sebelisoang ke saline (Exp Sal + Cue) ha li bapisoa le litsamaiso tse neng li sa tsejoe ke leha e le efe le tse nkiloeng ntlong ea lehae (Ex Sal-No Cue) ho NAC core (Feie. 7A; p <0.001), le mPFC likaroloana tsa ACA (Feie. 8A; p = 0.001), PL (Feie. 8B; p = 0.003), le IL (Feie. 8C; p = 0.029). Ka lehlakoreng le leng, liphoofolong tsa thobalano tse sebelisoang ka letsoai, ho ipapisa le maemo a itseng, a neng a sa amane le moputso oa ho kopanela liphate, ha ea ka ea etsa hore ho be le libaka tse ling tsa boko (Naive Sal + Cue ha li bapisoa le Sal-No Cue; Lifeiga. 7, 8), ho bonts'a hore ho kenya letsoho ho hlahang ho hlakile ho ho pepeseha ha thobalano-tse amanang le tsona. Ho feta moo, boiphihlelo ba thobalano feela ha boa fetola polelo ea motheo ea PERK sebakeng leha e le sefe sa boko, kaha ho ne ho se na phapang pakeng tsa lihlopha tse nkiloeng matlong a koaletsoeng, ho sa tsotellehe hore na ho na le maikutlo afe a ho kopanela liphate kapa phihlelo, le ho phekoloa ka saline kapa naloxone.
Khato e tsoelang pele ea opioid e hlokahalang bakeng sa ts'ebetso ea neural ho NAc e bakoang ke likamano tse amanang le thobalano. Linomoro tsa lisele tsa IR-IR ka holimo ho mm2 ka nucleus accumbens core (A) le shell (B) liphoofolo tse nang le bothata ba ho kopanela liphate (bohloeki) le liphoofolo tse nang le boiphihlelo (Exp; batsho) tse neng li nkoa ka systemic NLX kapa saline (Sal) nakong ea ho kopanya (Exp male) kapa ho sebetsana le mananeo (banna ba nang le boithati). Lihlopha li ne li pepesehile ho tse ling tsa maemo (Cue), tse neng li e-na le lihlopha tse amanang le ho kopanya lihlahisoa tsa banna le lipolotiki tse seng li sa nke lehlakore, kapa li nkiloe malapeng a lehae (Che Cue; e bontšitsoe ka ho hloka taelo ea Cue). Litaba li hlahisoa e le tsa bohlokoa ± SEM; * e bontša phapang e kholo ho bapisoa le taolo e hlakileng ea letsoai (Naive Sal-No Cue le Exp Sal-No Cue); # e bontša phapang e kholo ho bapisoa le sehlopha sa Exp-exposed exposed to Sal-Cue (Exp Sal + Cue). Litšoantšo tsa litšoantšo tsa lisele tsa PERK-IR ka mm2 ho NAC ea banna ba nang le phihlelo ea ho kopanela liphate le Sal (C, D) kapa NLX (E, F) tseo e ka bang li nkiloe matlong a lehae (Che Cue, C, E), kapa tse pepeneneng le li-contextual cues (Cue; D, F). N = 4 sehlopha ka seng ntle le Naive NLX (No Cue), n = 3. khalaletso, ts'ebetso ea Anterior. Sebaka sa sekala, 100 μm.
Liphello tsa naloxone ka polelo ea pERK e kenyelletsoeng ke maqheka ho tse ling tsa libaka tse ling tsa VTA. Linomoro tsa lisele tsa IR-IR ka holimo ho mm2 le liphoofolo tse nang le phihlelo ea ho kopanela liphate le tse nang le phihlelo (Ex; batsho) tse neng li haelloa ke systemic NLX kapa saline (sal) nakong ea likhallelo tsa ho kopanela liphate 'me li pepesoa ho latela maemo (Cue) kapa lehae la lehae (no cues) ACA (A), PL (B), IL (C), le BLA (D). Litaba li emela '± SEM; * e bontša phapang e kholo ho bapisoa le taolo e hlakileng ea letsoai (Naive Sal-No Cue le Exp Sal-No Cue); # e bontša phapang e kholo ho bapisoa le litaelo tsa ho kopanela liphate tse bontšitsoeng ka letsoho (Salve Sal + Cue).
E le ho tšehetsa khopolo ea rona, phekolo ea naloxone nakong ea boiphihlelo ba thobalano e ile ea thibela ho kenngoa ha maikutlo ka maikutlo a ho kopanela liphate. Tlhaloso ea PERK ho banna bana ba nang le phihlelo ea Expression of NLX + e nang le nalxone e ileng ea tšoaroa ke naxone e ne e sa fapane le polelo ea motheo ea PERK ho sehlopha leha e le sefe sa lihlopha tsa tšoaetso ea ho kopanela liphate le tse nang le phihlelo tse nkiloeng matlong a matlo a lehae (Naive Sal-No Cue kapa Naive NLX- Ha ho Cue). Ho feta moo, polelo ea PERK ho banna ba nang le phihlelo ea Expression of NLX + e nang le nalxone e ileng ea tšoaroa ke naxone e ne e le tlaase haholo ha e bapisoa le liphoofolo tse nang le phihlelo tse hlahisitsoeng ka letsoai (Exp Sal + Cue) ka NAC core (Feie. 7A; p = 0.002) le metse e mPFC (Feie. 8A, ACA: p <0.001; B, PL: p = 0.002; C, IL: p = 0.015).
Nakong ea NAc shell, litsela tse peli tsa ANOVA tlhahlobo ha lia ka tsa fana ka liphello tse kholo tsa lisosa tsa maemo a hlakileng le phekolo ea naloxone. Leha ho le joalo, papiso ea bobeli e bontšitse hore ho pepeseha ha eona ho ile ha etsa hore ho be le sehlopha se sebetsanang le thobalano e sebetsanang le thobalano (Exp SAL + Cue) ha se bapisoa le sehlopha se laolang sa Saline se nang le boits'oaro (Feie. 7B;; E-na le lefu la SAL-Che Cue: p = 0.0163).
Puisano
Phuputso ea morao tjena e bonts'a hore EOP e sebetsang VTA nakong ea boitšoaro ba thobalano, boitšoaro ba tlhaho ea moputso, e entse hore ho be le ho fokotseha ka matla ho nako ea soma ea lisele tsa VTA dopamine. Ho fokotseha ha boholo ba soma ha hoa ka ha hlokomeloa ka VTA e seng dopamine neurons, kapa ka dopamine neurons haufi le substantia nigra, e bontšang hore phetoho ena e ne e totobetse lisele tsa VTA dopamine. Sena VTA dopamine plasticity e bonahala e tšoana le e bakoang ke ho pepesa opiate e sa foleng (Sklair-Tavron le al., 1996; Russo et al., 2007; Mazei-Robison et al., 2011) le ho etsa hore mamello e tšoanang le ea opiate (morphine) e putsoe. Re ile ra bontša hore VTA dopamine plasticity e bohlokoa bakeng sa nako e telele (tlhokomelo) empa e se nako e khutšoanyane (nts'etsopele), ho matlafatsa boitšoaro bo bobe ba likamano tsa botona le botšehali le liketsahalo tse amanang le moputso o amanang le moputso (PERK) libakeng tse nang le sepheo sa VTA: NAc le mPFC. Liphuputso tsena li bontša hore karolo ea VTA dopamine plasticity e phetha karolo ea nako e telele ea boikutlo bo susumelletsang ba moputso oa tlhaho oa predictive cues kapa moputso oa mohopolo.
Ho 'nile ha boleloa hantle hore phihlelo ea thobalano e fella ka ho ntlafatsa boitšoaro bo bobe ba likamano tsa botona le botšehali, ho akarelletsa le ho qala ka potlako ho qalisoa ha ho nyalana le ts'ebetso e eketsehileng (Balfour et al., 2004; Pitchers et al., 2010a,b, 2012). Ts'ebetso ena kapa ho matlafatsa boitšoaro bo bobe ba thobalano ho boloka bonyane 28 d ka mor'a ho nyalana (Pitchers et al., 2012). Ho phaella moo, ho bontšitsoe hore boitšoaro ba ho kopanela liphate le boemo bo hlakileng ba ho ba le likamano tsa ho kopanela liphate ka lebaka la ho kopanela liphate ho etsa hore MOR e kene ka har'a VTA le ho etsa hore ho sebelisoe neuronal ho pholletsa le tsamaiso ea mesoli, ho akarelletsa le VTA (dopamine le nondopamine neurons), NAC, PFC, le BLA (Balfour et al., 2004, 2006). Ke hantle VTA dopamine neurons e phetha karolo ea bohlokoa ho ithuta le ho fana ka ts'ebetso ea ho khothatsa ea ts'oaetso e amanang le moputso (Berridge le Robinson, 1998; Berridge le al., 2009; Flagel et al., 2011) 'me li bohlokoa bakeng sa ho bolela esale pele ka moputso (Schultz, 2010). Liphuputso tsa morao-rao li atolosa tsebo ea rona ea joale ka ho bonts'a hore VTA e bakoang ke moputso e bakoang ke moputso ke ea bohlokoa bakeng sa mesebetsi ena, 'me e itšetlehile ka ho ts'oaroa ha MOR ka EOP ho VTA. Hona joale ha e tsebe hore na EOP ke MOR ligand e sebetsanang le VTA nakong ea boitšoaro bo bobe ba thobalano. Le hoja bobeli ba β endorphin le enkephalin li kentse letsoho molemong oa ho susumelletsa batho ho matlafatsa lijo (Hayward et al., 2002), sena se ntse se lokela ho thehoa bakeng sa boitšoaro ba banna ba thobalano. Re kile ra bontša hore li-β-endorphin neurons ha li sebelisoe nakong ea ho nyalana, leha e le hore ho na le keketseho ea PMC mRNA; kahoo, ho fana ka maikutlo a hore β endorphin e ka 'na ea se ke ea e-ba EOP ea bohlokoa e sebetsanang le VTA nakong ea ho nyalana (Davis et al., 2007). VTA plastiki ena e ne e le ea bohlokoa bakeng sa mesebetsi ea neural mPFC, NAc, le VTA ka mor'a ho pepesehela ho thobalano-ho bolela esale pele ka tikoloho. Ho feta moo, VTA dopamine plasticity e ne e le ea bohlokoa bakeng sa pontšo ea nako e telele ea ts'ebetso e eketsehileng le ts'ebetso ea boitšoaro ba thobalano. Ka lehlakoreng le leng, VTA e ne e sa hlokahale bakeng sa karabo ea likamano tsa thobalano (e thehiloeng ke CPP) le ho fokotsa nako e khutšoanyane ea tšusumetso ea thobalano le ts'ebetso (nakong ea phihlelo ea thobalano kapa 1 hamorao) e ile ea lula e tiile le hoja MOR e ile ea thibela nakong ea ho nyalana (Mehrara le Baum, 1990). Ho e-na le hoo, boitsebiso bo bontša hore VTA dopamine neuroplasticity e phelisana le nako e telele (7 d ka mor'a boiphihlelo ba ho kopanela liphate ka ho qetela; Pitchers et al., 2012) polelo ea "ho batla" ka moputso oa thobalano le ho hlahisa likarabo tse susumelletsang ho likhallelo tsa mating (Miller le Baum, 1987; Berridge le Robinson, 1998).
Liphoofolo tse nang le likamano tsa botona le botšehali li bontšitse ho mamellana ha morphine moputso, ho tšoana le liphello tsa ho khanna ka litoeba, mokhoa o mong oa tlhaho o putsang, phello e koetsoeng ka phekolo ea naloxone (Lett et al., 2001, 2002) mme ba ikemiselitse ho itšetleha ka VTA dopamine cell plasticity (tse fumanoang hona joale). Ho tšoana le meputso ea tlhaho, ho pepeseloa hangata ho opiates morphine kapa heroin ho fella ka ho fokotseha ha nakoana ka boholo ba VTA dopamine soma (Sklair-Tavron le al., 1996; Spiga et al., 2003; Russo et al., 2007; Mazei-Robison et al., 2011). Ho feta moo, ho tlohella ho ba le nako e khutšoanyane ea ho tlohela ho etsa hore motho a be le mamello e lekaneng, kaha ho na le litekanyetso tse phahameng tsa lithethefatsi tse hlokang ho theha mekhatlo ea meputso (Shippenberg et al., 1987; Russo et al., 2007), 'me o etsa liphoofolo ho ithaopela ho eketsa ho noa lithethefatsi (Ahmed le al., 2000; Walker et al., 2003). Ka lebaka leo, EOP le li-opiate li sebetsa ka li-substrate tse tloaelehileng tsa neural ho etsa hore ho be le mamello ea monehelo nakong ea ho tlosoa ha nakoana, e ka 'na ea bontša mokhoa o hloekisang homeostatic ho thibela ho tsosolosoa (Koob le Le Moal, 2005). Ka lehlakoreng le leng, nakong ea nako e telele ea ho tlohela lithethefatsi, ho mamellana ho fetoloa ho utloahala ho thepa e khotsofatsang ho lithethefatsi (Harris le Aston-Jones, 2003; Aston-Jones le Harris, 2004; Harris le Gewirtz, 2004). Hoa thahasellisa hore boiphihlelo ba thobalano bo latetsoeng ke nako ea ho ikhutsisa thobalano ea 7-28 d e fumanoe ho baka tšusumetso e kholo ea moputso oa psychostimulant (Pitchers et al., 2010a), e itšetlehileng ka tlhaloso ea deltaFosB e susumelitsoeng ke ho kopanela liphate le dopamine receptor 1 ts'ebetso ho NAc (Pitchers et al., 2013). Kahoo, phihlelo ea thobalano e etsa hore opiate e be le melemo ea ho mamelloa le psychostimulant moputso oa matlafatso, le hoja nako e telele ea ho ikhutsa thobalano morphine moputso oa mamello e ntse e lekoa. Re fana ka maikutlo a hore liphello tse fapaneng tsa moputso oa lithethefatsi li ka sebelisoa ka mefuta e sa tšoaneng ea polasetiki ea meriana maemong a fapaneng a mokhoa oa ho fokola ka matla: Khato ea VTA EOP le polasetiki ea dopamine e phelisana le ho mamelloa ha moputso (o ntse o ithuta hona joale), athe NAC deltaFosB e bua ka ho laola psychostimulant sensitization (Pitchers et al., 2013). Liketsahalo tsena ka bobeli li ka tlatsetsa ho eketseha ha lithethefatsi tse nkiloeng (Ahmed le Koob, 1998, 1999; Ahmed le al., 2000, 2002, 2003; Walker et al., 2003).
Mekhoa ea limolek'hule eo EOP e nang le eona e susumetsang VTA dopamine neurons nakong ea boitšoaro ba meputso ea tlhaho ha e tsejoe. Tsela ea IRS2-Akt-mTORC2 ke mokena-lipakeng o moholo oa boholo ba soma VTA e bakoang ke morphine e pheta-phetoang (Jaworski et al., 2005; Russo et al., 2007; Mazei-Robison et al., 2011). Phetoho e phetoang ea morphine e susumelitseng liphetoho ka boholo ba dopamine neurons VTA e ka thibeloa ke ho ruruha ha intra-VTA ea neurotrophic factor (BDNF; Sklair-Tavron le Nestler, 1995). BDNF e khelosa tsela ena ka pontšo ea TrkB (Russo et al., 2007), mochine o amohelehang ka kamano e phahameng ea BDNF le karolo ea tsela ea IRS2-Akt (Seroogy le Gall, 1993; Numan le Seroogy, 1999), 'me e hlalositsoe ka li-dopamine le li-neurons tsa GABA VTA. Ho theoha ha maemo ka likarolo tse fapa-fapaneng tsa tsela ea IRS2-Akt ho sebelisa thekenoloji ea liphatsa tsa kokoana-hloko ea likokoana-hloko ho etsisa liphello tsa ho lula ha li-opiate tse sa foleng. Ho feta moo, liphello tsa ho pepesa opiate li ka pholosoa ka ho tsosolosa tsela ena ea pontšo (Russo et al., 2007) le ho tepella maikutlo haholo ka karolo ea mTORC2 ho thibela ho fokotsa moralo oa VTA dopamine soma (Mazei-Robison et al., 2011). Ka hona, mosebetsi oa pele oa ho hlahloba liphello tsa li-opiate tse sa foleng ka boholo ba VTA dopamine soma e bontša hore ho fokotsa taolo ea morphine ea tsela ea IRS2-Akt-mTOR ho lekane ebile ho hlokahala bakeng sa phello ena (Mazei-Robison le Nestler, 2012). Ka hona, ho leka ho nahana hore liphello tsa boiphihlelo ba ho kopanela liphate ka VTA dopamine neuroplasticity li tšoana le lipakeng tsa BDNF le IRS2-Akt-mTORC2.
Qetellong, phuputso ea morao-rao e bontšitse hore VTA e bakoa ke boiphihlelo bo bakoang ke boiphihlelo le boitšoaro ba tlhaho bo khotsofatsang, haholo-holo ka boitšoaro bo hlephileng ba banna ba thobalano. Ka ho khetheha, EOP ketso ea VTA ho fokotsa boholo ba dopamine soma, e leng ho fetisetsoa ho kopanngoa le ho eketseha ha neural excitability le palo e tlaase ea dopamine e bakoang ke hypodopaminergic system, le ho fetola tsamaiso ea mesolimbic e sebetsang ho latela likarolo tse hlalosang moputso oa thobalano. Ho phaella moo, VTA ea ho itšireletsa mafung ke ea bohlokoa bakeng sa ts'usumetso le ts'ebetso ea mohopolo, empa eseng bakeng sa tšusumetso ea hedonic ea boitšoaro ba thobalano. Qetellong, VTA e bakoang ke maikutlo a bakoang ke mekhoa ea boipheliso ea tlhaho e lateloa ke nako e khutšoanyane ea moputso ho ba le tšusumetso e matla ea ho tlosa lithethefatsi 'me ka hona e ka ama ts'oaetso ea ts'ebeliso ea lithethefatsi.
Mongolo o botlaaseng ba leqephe
- E amohetse January 12, 2014.
- Phetolelo e amohetse May 17, 2014.
- E amohetse May 20, 2014.
Phuputso ena e ne e tšehetsoa ke lichelete tse tsoang Mokhatlo oa Canada oa Bophelo bo Botle ho LMC le Natural Sciences le Engineering Research Council ho ea KKP
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