Manonyeletso a "purrose lowers" μ-opioid le dopamine D2 / 3 receptor fumaneha bokong ba porcine (2020)

Ho sebelisa chefo e ngata haholo ho etsa hore motho a lemalle joala bo kang bona bo ka eketsang seoa sena sa botena. Li-opioids le dopamine li buisana ka litlamorao tse tlisoang ke lithethefatsi tsa tlhekefetso, le meputso ea tlhaho e tsoang litlamong tse kang lijo tse monate. Re ile ra etsa lipatlisiso ka litlamorao tsa ho iketla re sebelisa litšoantšo tsa PET le [¹¹C] carfentanil (μ-opioid receptor agonist) le [¹¹C] raclopride (dopamine D2 / 3 receptor antagonist) ho li-minipigs tse supileng tse sa anesthetised tsa Göttingen. Ka mor'a moo re ile ra fa li-minipigs monyetla oa ho fumana tharollo ea hora e le ngoe ka matsatsi a 12 a latellanang 'me ra etsa litšoantšo hape ka mor'a lihora tse 24 ka mor'a hore re fihle ka kotloloho. Ka sampole e nyane ea li-minipigs tse hlano, re entse tse ling hape [¹¹C] carfentanil PET semelo ka mor'a pontšo ea pele ea sucrose. Re bale lintlha tse nang le bohlale tsa voxel (BP)_ND) Ho sebelisa cerebellum e le sebaka sa ho tlama se sa senyeheng, ho sekaseka liphapang ka 'mapa o seng oa lipalopalo, mme o entse tlhahlobo ea tikoloho. Kamora matsatsi a 12 a phihlello ea sucrose, BP_ND oa li-tracer ka bobeli li ne li theohile haholo ho li-striatum, li-nucleus accumbens, thalamus, amygdala, cingrate cortex le cortex ea pele, e lumellanang le taolo ea tlase ea methapo ea methapo ea methapo. Kamora ho hlahella ka nqena ho sucrose, re fumane ho fokotseha ha tlamiso ea [¹¹C] carfentanil ho li-bokellane tsa nucleus le cingrate cortex, e lumellanang le tokollo ea opioid. Ho fumaneha ho tlase ha li-opioid le dopamine receptors ho ka hlalosa bokhoni ba tlatsetso bo amanang le tšebeliso ea sucrose.

Liperesente tse hlano tsa baahi ba lefatše li batenya ka ho fetesisa¹. E le letšoao la lefu la metabolic, botenya bo amahanngoa le lefu la tsoekere la mofuta oa 2, lefu la pelo, mathata a ho hema, le monyetla oa ho tepella maikutlo le mohlomong 'dementia'². Ts'ebeliso e eketsehileng ea lijo tse matla tse matla e ekelitse phapang pakeng tsa tlala ea lapeng e latelang khaello ea lijo, le tlala ea hedon, kapa "ho lakatsa", e etsahalang ka lebaka la ho hloka^3,4. Joalo ka ha molao oa homeostatic o le mong o ke ke oa baka ho eketseha ha botona hona joale, ho tlamehile ho lekola sephetho sa meputso ea meputso le thabo ea thepa e ka tlisoang ke lijo tse fumanehang habonolo.

Ts'ebeliso ea Sucrose e amahanngoa le botenya, mme sucrose e ntse e nkoa e le ntho e lemalloang⁵. Liphumano tse ling li fapana phanong ena ka lebaka la mathata a ho arola lijo tse sa sebelisoeng hantle le likarabo tsa lijo tsa hedonic, le ho khetholleng motsoako o kenyelletsang lijo tse hlahisitsoeng, hammoho le mekhoa e fapaneng eo lijo li fetohang ho potoloha ha boko litseleng tsa tlhaho.⁶. Leha ho le joalo, maemong a ikhethang, ho ja ka mokhoa o itseng oa sucrose ho tlisa moputso le takatso, e ka bapisoang le boholo ba ba ts'oaroang ke lithethefatsi tse lemalloang, tse lebisang ho ho feteng tekano le ho tepeleng ka ho feteletseng.^6,7.

Tlala e amahanngoa le "ho batla" ho amanang haholo le litlamorao tsa dopaminergic neurotransication maemong a meputso a mangata⁸, empa ho lula ho sa hlake hore na ketso ea dopamine (DA) e fetoloa joang ho araba lijo tse qobelloang. Tšebeliso ea lijo tse matlafatsoang e hokahana le "ho rata", e kopantsoeng haholo le tsamaiso ea endio native operoid, haholo-holo μ-opioid receptor (μOR)^9,10, e ka khothalletsang ts'ebeliso e feteletseng ea ts'ebetso ha e hlakoloa. Tlalehong ea hona joale, re leka taba ea hore sucrose e lebisa ho opioid le dopamine ho lokolla ho fumaneha ha li-receptors tsa μOR le DA D2 / 3. Ho fumaneha ke index ea palo ea li-receptor tse sa sebetsoeng tse fumanehang bakeng sa ho ts'oaroa ha tracer mme ka moeli ha e khetholle pakeng tsa ho lula le ligand le letsoalo la receptor.¹¹.

Qaleho ea lijo tse qobelloang e itšetleha ka lintlha tse ngata, 'me lithuto tsa ho ikatisetsa ho batho li hlahisa litaba tsa boitšoaro. Boholo ba lithuto ka hona li shebana le boitšoaro ba ho fepa ho likhoto¹². Le ha likhoto li na le "leino le monate", mekhoa ea bona ea ho its'upa e bohlokoa ho nona, metabolism, le mofuta oa ho bokella mafura, li fapana haholo le tsa batho. Göttingen minipig ke phoofolo e kholo e sa tloaelehang e nang le kelello e tsoetseng pele ea gyrencephalic, e ka hlalosoang ka qeto e lekaneng. Libaka tsa eona tse hlalositsoeng hantle tsa subcortical le pele¹³ lumella phetolelo e tobileng haholoanyane ho ts'ebetso ea boko ba motho. Mona, re sebelisa liteko tsa positron emission tomography (PET) ho hlahloba Ka vivo availOR le DA D2 / 3 phumaneho ea minipig ea tšenyo ea subchronic sucrose. Ka sampole e nyane, re ile ra etsa lipatlisiso tsa litlamorao tsa ho lula ha μOR kamora ho pepesehela ho scrose. Qetellong, re ile ra leka kamano lipakeng tsa liphetoho lipakeng tsa li-tracot tsa ho fumaneha ha li-tracer tseo.

Limmapa tse kholo tsa parametric tsa [¹¹C] carfentanil le [¹¹C] raclopride e tlamang e ka khonehang (BP_ND) li bonts'itsoe ho feiga. 1. Ho sekaseka liphetoho tse hlahang kamora ho hlahella ha sucrose ka makhetlo a mahlano ho bapisoa le motheo, mme ka tsatsi le leng kamora tse 12^th ho fihlella ka bonolo ka ho li-minipigs tse supileng ha ho bapisoa le motheo, re sebelisitse tlhaiso-leseling ea lithuto tsa bongaka le tse sa thibelang tikoloho, e leng mokhoa o ratoang oa mehlala ea boholo bona¹⁴.

Karolelano ea maqhubu a bohlale a ke keng a lahleha ka kakaretso (BP)_ND) limmapa tse kholo holima litšoantšo tsa MRI ponong ea sagittal. Lintlha li hlahisoa bakeng sa [¹¹C] carfentanil BP_ND ea li-minipigs tse 5 tse bonts'itsoeng qalong, kamora ho pepesetsoa monyetla oa ho sucrose le kamora matsatsi a 12 a pepesitsoe ke sucrose (mola o kaholimo). [¹¹C] carfentanil BP_ND ea li-minipigs tse supileng tse bonts'itsoeng qalong 'me kamora matsatsi a 7 a phihlello ea sucrose li hlahisoa moleng o bohareng. [¹¹C] raclopride BP_ND ea li-minipigs tse supileng tse bonts'itsoeng qalong 'me kamora matsatsi a 7 a phihlello ea sucrose li bontšitsoe moleng o tlase. Hlokomela hore tekanyo ea mebala e bohlokoa haholo ho totobatsa [¹¹C] raclopride BP_ND libakeng tse haufi.

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Phatlalatso ea pele ea sucrose

Metsotsoaneng e mehlano e bonts'itsoeng le [¹¹C] carfentanil motheong oa motheo 'me hang ka mor'a ho pepesetsoa ha sucrose, re ile ra fumana tracer e fokolitsoeng haholo kahara cortex ea anterior le li-nucleus tse bokellanang ha li arabela ka sucrose, e bonts'itsoeng ka mebala ho Fig. 2, e bonts'ang p <0.05. Re fumane ha 14% e fokotsehile e tlamang ho tlama libaka libakeng ka bobeli ho bapisoa le motheo.

Bohlokoa bo fokotsehile ho [¹¹C] carfentanil BP_ND kamora ponahalo ea metsi ea pele ea sucrose ha e bapisoa le motheo (n = 5). Ke li-voxel feela tse bohlokoa (p Ho fokotseha ha <0.05) ho bonts'oa joalo ka libaka tse mebala-bala tse lebelletsoeng ho khaola MRI e boima ba T1 boemong ba anterior cingulate cortex (ka ho le letšehali) le nucleus accumbens (bohareng) ho tsoa ho stereotaxic minipig brain atlas. Hlokomela hore boemo ba bohlokoa bo ka fihlelloang le liphoofolo tse 5 ke 2^-5 ≈ 0.031 (bona lebala la mebala). Lintlha li hlahisoa likarolong tsa coronal tsa boko ba likolobe maemong a bontšitsoeng setšoantšong sagittal (ka ho le letona).

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Matsatsi a 12 a phihlello ea sucrose

Eaba re etsa tlhahlobo ea li-minipigs tse supileng tse ts'oantsoeng le [¹¹C] carfentanil motheong oa mantlha le kamora matsatsi a 12 a ho kenella ka mokhoa o ts'oanang mme a fumanoa a fokotsoe haholo ho tracer e tlamang ho liphoofolo tse pepesitsoeng tse lekanang le tsa mantlha. Libaka tse anngoeng haholo li bontšoa ka bofubelu ho feiga. 3 (le . Bakeng sa ho fumana BP_ND boleng le ho lekola phetoho ea liperesente, re ile ra etsa tlhahlobo ea tikoloho 'me ra fumana boleng ba setereke seterekeng se seng le se seng ka mor'a ho a sebelisa ka mokhoa o hlakileng (sa feiga. 4).

Bohlokoa bo fokotsehile ho [¹¹C] carfentanil e tlamang e ka bonoang (BP_ND) lipakeng tsa motheo le kamora matsatsi a 12 a tšenyo ea metsi a sucrose (n = 7). Li-voxels ka bohlokoa (p Ho fokotseha ha <0.05) ho bonts'oa joalo ka libaka tse mebala tse lebelletsoeng ho fokotsa litheko tsa MRI tsa T1 ho tsoa atlaseng ea boko ea stereotaxic minipig. Lintlha li hlahisoa likarolong tsa boko ba coronal maemong a bonts'itsoeng setšoantšong sa sagittal (ka tlase ho le letona). Hlokomela hore boemo ba bohlokoa bo ka fihlelloang le liphoofolo tse 7 ke 2^-7 ≈ 0.0078 (bona lebala la mebala).

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Tlhahlobo ea tikoloho ea [¹¹C] carfentanil e tlamang e ka bonoang (BP_ND) lipakeng tsa motheo le kamora matsatsi a 12 a tšenyo ea metsi a sucrose (n = 7). Lintlha li hlahisoa e le mokhoa oa "phoso" e tloaelehileng.

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Re sebelisitse [¹¹C] morusu joalo ka mohatsela oa li-receptor tsa DA D2 / 3 libakeng tse bokellaneng le tse sa bonahaleng tsa boko ho li-minipigs motheong oa motheo le kamora matsatsi a 12 a phihlello ea sucrose (sa feiga. 1). Re fumane litlamorao tse fokotsehileng tse tlamang liphoofolong tse pepesitsoeng tsa sucrose, ha li bapisoa le metheo ea mantlha (p <0.01) libakeng tsa preortal cortex, nucleus accumbens / ventral striatum, cingulate cortex, amygdala, thalamus, mesencephalon, libaka tsa hippocampal le libaka tse hlabang. (Feie. 5). Lintlha tse tsoang tlhahlobisong ea tikoloho li hlahisoa ho Fig. 6.

Bohlokoa bo fokotsehile ho [¹¹C] raclopride e tlamang e ka khonehang (BP_ND) lipakeng tsa motheo le kamora matsatsi a 12 a tšenyo ea metsi a sucrose (n = 7). Li-voxels ka bohlokoa (p Ho fokotseha ha <0.05) ho bonts'oa joalo ka libaka tse mebala tse lebelletsoeng ho fokotsa litheko tsa MRI tsa T1 ho tsoa atlaseng ea boko ea stereotaxic minipig. Lintlha li hlahisoa ka likarolo tsa coronal tsa boko ba kolobe maemong a bonts'itsoeng setšoantšong sa sagittal (ka tlase ho le letona). Hlokomela hore boemo ba bohlokoa bo ka fihlelloang le liphoofolo tse 7 ke 2^-7 ≈ 0.0078 (bona lebala la mebala).

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Tlhahlobo ea tikoloho ea [¹¹C] raclopride e tlamang e ka khonehang (BP_ND) lipakeng tsa motheo le kamora matsatsi a 12 a tšenyo ea metsi a sucrose (n = 7). Lintlha li hlahisoa e le mokhoa oa "phoso" e tloaelehileng.

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Likamano lipakeng tsa [¹¹C] raclopride le [¹¹C] data ea carfentanil

Re lekile khokahano e ka bang teng lipakeng tsa [¹¹C] raclopride le [¹¹C] boleng ba carpentanil ba BP_ND libakeng tse se nang mathata le tse sa amaneng le 'mele ka lipompong tsa motheo le ka mora matsatsi a 12 a ho ja, ho se mekhatlo e hlokometsoeng. Joale re ile ra hlahloba hore na ho theoha ha tracer ho tlatsana ho ile ha lekanngoa, 'me ra bapisa liphetoho tsa BP_ND bakeng sa [¹¹C] lebala le liphetoho tsa BP_ND bakeng sa [¹¹C] carfentanil feela ka har'a minipigs e neng e na le BP e tlase_ND ea li-tracer ka bobeli ka mor'a ho ja ka mokhoa o hlakileng (n = 6). Re fumane likamano tse mpe tse sa nepahalang ho maemo a akaretsang a rased (r² = 0.91, p <0.01), empa eseng libakeng tse ling tsa pelehi (sa feiga. 7).

Likhohlano lipakeng tsa li-pre- minus tsa peleho-¹¹C] raclopride le [¹¹C] carfentanil e nang le bokhoni ba ho ikatisa (BP_ND) ka li-minipigs tse nang le tracer e fokotsehileng ka mor'a ho kenella ka mokhoa oa sucrose (n = 6). Lintlha tse tsoang libakeng tse arohaneng tsa libaka tse holimo (holimo) le striatum (tlase) li hlahisoa. Coeffanele ea boikemisetso (r²) le boleng ba p bo bonts'itsoe ho graph e 'ngoe le e' ngoe.

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Re tsebisitse litlamorao tsa ho fihlella nako le nako ha motho a kenella ho kenella ho opioid le neurotransication ea DA bokong ba mammary. Longitudinal Ka vivo Ho nahanisisa ka PET ea li-receptor tsa μOR le DA D2 / 3 ho senotse ho fumaneha ha li-receptor potoloho eohle ea moputso, ho kenyelletsa le li-bokono tsa nucleus, cortex ea pele, le cortex ea ka ntle. Liphetho li bontša ka ho hlaka hore sucrose e ama mekhoa ea moputso ka mokhoa o ts'oanang le oa lithethefatsi tsa tlhekefetso.

Ho kenella hoa sucrose joalo ka ntho e fumanehang habonolo ho tsebahala ho lokolla DA le ho etsa hore batho ba itšetlehe ka litoeba¹⁵, e nang le sucrose e bontšitsoeng e khahlisa haholo ho feta koae ka litoeba maemong a itseng. Ka hona, litoeba li sebetsa ka matla haholo ho fumana ho chona ho feta koae, leha ho se na khaello ea lijo⁵. Leha ho le joalo, litlamorao tsa sucrose li laoloa ke tsamaiso ea homeostatic le li-circuits tsa moputso oa hedonic^16,17 e ka kopanyang phapang pakeng tsa likarolo tsa phepo e ntle le hedonic ea ketso ea ho ikemela¹⁸. Re ile ra khetha kemiso ea hora e le 'ngoe ka letsatsi e le ho khothaletsa "ho ts'oaroa", joalo ka ha lithuto tsa pejana ho litoeba li senotse ho ja haholo nakong ea hora ea pele ea phihlello ea letsatsi le letsatsi ka kemiso ea nakoana.^15,19. Boithuto ba boithuto ba tšebeliso ea lijo hangata bo lebisa ho liphoofolo tse sa thibeloang lijo, empa moralo o kanna oa se ke oa bonts'a mekhoa e tšoanang ea neural e sebetsang ho botenya. Likolobe thutong ea hajoale li ne li sa thibeloe ke lijo ebile li fepiloe lijo tse tloaelehileng ho tlatselletsa phihlello ea ho iketela.

Li-receptors tsa Opioid (OR) li hlahisoa ka bongata bokong, haholo-holo ka likarolo tse tsejoang ho fetola mekhoa ea ho ja le ea moputso²⁰. Li-OR li bontšitsoe hore li bohlokoa ho litlamorao le tse boelang hape tsa koae^21,22,23,24. Liphetoho tsa ho kopanya li boetse li hokahane le karabelo ea lapeng bakeng sa ho ja le monate o amanang le lijo tse monate²⁵. Haholo-holo, "ho rata" lijo ho hokahane le mofuta oa "endio" opioid, haholo-holo μOR^9,10 ka khetla ea nucleus accumbens le ventral pallidum²⁶. Litšoantšo tsa "agonist" tsa "agonist" ka likarolo tse ikhethileng tsa bokellarase le "ventral pallidum" li matlafatsa boits'oaro ba "ho rata", ho kenyelletsa le lipuisano tsa maleme le ho nyeka, ka mor'a ho ja lijo tse matlafatsang^27,28,29. Bopaki bo bong ba ho saena le opioid ts'ebetsong ea taolo ea hedonic bo tsoa ho bahanyetsi ba μOR ba lumellang tšebeliso ea kopatable chow ho tsona ka bobeli ad libitum-Nama le liphoofolo tse thibetsoeng lijo empa li na le tšusumetso e matla ho fumaneng li-pellets tse sa tloaelehang tse fumanehang^30,31. Bathong, bahanyetsi ba μOR ba fokotse takatso ea lijo ea nakoana le ho fokotsa monate oa lijo tse monate^32,33,34. Ho supa matšoao a opioid sebakeng sa basyara ea khale ho boetse ho tlatsetsa ho "lijo" ka lebaka la ho batla meputso le boleng ba lijo tse khothatsang.³⁵.

Le [¹¹C] carfentanil, re fumane litšoantšo tsa "tracer binding" tse amang maikutlo ka bobeli ho μOR le ho lokolla ha boko li-opioids tsa endo native^36,37. Re hlokometse tahlehelo ea hang-hang ea ho fumaneha ha inOR libakeng tse bokellaneng ba methapo ea methapo le methapo ea methapo, likarolo tse ikhethang tsa boko tseleng ea moputso, kamora tšebeliso ea pele ea sucrose ke li-minipigs tse hlano, tse lumellanang le tokollo ea endo native opioid. Liphuputso tse fetileng li bontšitse hore lijo tse monate li ka lebisa ho thabo³⁸ ka ho hlohlelletsa opioid tokollo. Kamora matsatsi a 12 a phihlello e nepahetseng, re hlokometse hore o fokotsehile [¹¹C] carfentanil binding, e nang le litlhaloso tse 'maloa tse ka khonehang³⁹ ho kenyelletsa ho lokolloa hoa moriana oa opioid le ho tlama μOR, izationOR ho kenella ka hare ka lebaka la ts'ebetso e eketsehileng ea opioid, le ho eketseha ha tšebetso ea DA D2 / 3 e lebisang ho hepatologous desensitization ea μOR⁴⁰.

Ho ts'ehetsa liphumano tse teng hona joale, [¹¹C] lithuto tsa carfentanil tsa bakuli ba nang le bulimia⁴¹botenya^42,43,44, le bothata ba ho ja⁴⁵, bonts'a phumaneho ea receptor e fokotsehileng. Leha ho le joalo, ana ke maemo a sa foleng empa a minipigs a amohela feela matsatsi a 12. Thutong ea boits'oaro bo matla ba ho fepa banna ba phetseng hantle, ho fepa ho lebisitse ho matla le ho phatloha hoa semmuso hoa tlhahiso ea phepo ea mmele, le ho ba teng ha hedonia, ho fana ka maikutlo a hore ho lokolloa ha opioid ho bonts'a likarabo tsa metabolic le homeostatic, hammoho le hedonic, likarabo²⁵. Phuputso ena, hammoho le e 'ngoe e bonahetseng bakuli kamora lijo tsa metsi tse nang le chokolete e nang le chokolete⁴⁴.

Cortex ea pele-pele e bohlokoa ha ho etsoa liqeto le boleng ba lintho, ka hona, μOR e ka pele ho cortex e ka ikarabella bakeng sa tlhahlobo e fetotsoeng ea boits'oaro ba lijo, e ka hlahisang matla a ho lemalla a lijo. Re fumane ho fokotseha ho tlama ho cortex ea pele, ho lumellana le lithuto tsa nakong e fetileng tse bonts'ang hore phepo e phahameng ea mafura e fokotsa maemo a ROR mRNA ka cortex ea pele.⁴⁶ le hore tlhahiso ea "agonist" ea "agonist" pele ho "cortex" e eketsa lijo tse monate⁴⁷. Leha ho le joalo, bothata bo boetse bo hlahisa hore na lijo tse nang le mafura a mangata ke boemo bo sa foleng boo hangata motho a ka bo sebelisang ho amohela boemo bo tlase, ha a bapisoa le moralo oa nakoana oa ho fepa batho ka mokhoa o fanang ka tlhahiso ea hore ho lokolloe li-opioid tsa nako e telele tse tlohelang mofetoleli oa nama ea tlotsitsoeng. , esita le ka mor'a matsatsi a 12 a ho ikatisa.

DA e kentse letsoho meputsong ka bobeli ho tsoa ho lithethefatsi le boits'oaro. Tšebeliso e mpe ea koae e fumanoe ho thibela sign sign ea DA⁴⁸. DA D1 le D2 / 3 maemo a li-receptor a fetoloa ke nicotine bokong ba likolobe⁴⁹, le litlalehong tsa batho bao e seng batho ba nang le nalane ea tlhekefetso ea koae⁵⁰, e lumellanang le ho theoha ha li-receptor tsa D2 / 3 bokong ba batho ba lemaletseng koae^51,52. Ha e le lithethefatsi tsa tlhekefetso, sucrose e bontšitsoe ho nyolla li-receptor tsa DA D1¹⁹ le ho eketsa tokollo ea DA⁵³, e matlafatsa karolo ea DA ho "ho batleng" mabapi le lijo tse fumanehang habonolo. Liphuputso tse fetileng tsa PET li bontsitse ho fokotseha ha ho fumaneha ha li-receptor DA D2 / 3 ho fumaneha hoa moriana oa moriana vs. boima bo boholo^54,55, e tšoanang ka boholo le phokotso ea bakuli ba lemaletseng lithethefatsi⁵⁶, le ho phoofolo e nang le mehlala ea botona⁵⁷. Lithutong tse ngata tsa litheko, ho fokotseha ha makhopho a D2 / 3 ho khothaletsa nts'etsopele ea lijo tse qobelloang tse batlang li-rats le phihlello ea lijo tse fumanehang habonolo.⁵⁷.

Litlhoko tsa rona tsa ho fumaneha ha li-receptor tsa D2 / 3 tse fokotsehileng li ka bonts'a maemo a DA a arabelang ho arabela ts'ebetsong ea ts'usumetso e amanang le ts'ebetso ea sucrose ho tloha ha DA e lokolloa e le karolo ea tlhokeho ea lithethefatsi tsa tlhekefetso le mesebetsi e meng e khahlisang.^52,58,59,60. Ha likolobe li sa sebetsoa ka mokhoa oa ho nahana, li bile li sa fumana li-sucrose ka lihora tse 24, D2 / 3 BP e fokotsehile_ND mohlomong e bonts'a phokotso ea palo ea li-receptor ka lebaka la keketseho ea nako e telele ea ho lokolloa ha DA ho le leng la matsatsi a 12 a phihlello ea sucrose. Phokotso e ka phahamisa meputso ea moputso oa bokong, e amanang le taolo e tlase ea li-receptors tsa DA D2 tsa maemo a holimo. Sena se ka 'na sa hlalosa ho eketsoa habonolo hoa lithethefatsi tsa tlhekefetso tse bonoeng lithutong tse fetileng tsa litoeba tse nang le tšenyo e ngata e lebisitseng ho tšebelisong ea kelello ea cocaine, hyperacaction ka mor'a amphetamine e fokolang, ho eketsa ts'ebeliso ea joala ha ho tlohela sucrose, le ho mamella litlamorao tsa li-analgesic tsa opiates⁶.

Phuputso e fetileng ea ho ba le botenya ho Göttingen minipig e bontšitse ho fokotseha ha phallo ea mali a methapo ea mali bokong⁶¹. Tumellanong le liphumano tsena, re bone ho fokotseha ha DA D2 / 3 e tlamellang sebakeng sa "profroforebrain" se nang le li-bokono tsa nucleus le "cortex" ea pele. Maemo a makatsang a DA a eketseha ka makhetlo a 3 ka har'a li-bokellase tsa nucleus ka mor'a ho kenella ka mokhoa o nepahetseng ho likhoto tse tsamaeang ka bolokolohi tlas'a li-Microdialysis⁶². Ho liphoofolo tse itšetlehileng ka sucrose, ho li ja hangata ka mokhoa oa "sucrose" ho ka lebisa ho lokolloe ha DA khetlong ea li-nucleus⁶³. Liphoofolo li fepa lijo tse lekantsoeng ka mokhoa o lekantsoeng oa ho kenella ho sucrose li ne li e-na le li-receptor tse tlase tsa DA D2 mokokotlong oa "nucleus accumbens" le "dorsal striatum"⁶⁴. Lijo tse nang le phepelo e phahameng ea lijo tse nang le mafura a mangata li ka lebisa ho fokotseheng hoa bongaka ba D1 le D2 receptor mRNA ka har'a nucleus⁶⁵. Phuputso e entsoeng ka Microbalal ea litlamorao tsa lijo tse matlafatsoang e senotse ho nyolla ha DA ka har'a li-bokono tsa bokalase le "cortex ea pele" ha lijo li ne li ntse li nkuoa e le rialo; hang ha likhoto li se li tloaetse lijo tse ncha, tokollo e eketsehang e ne e koahetsoe ka har'a li-nucleus tsa bokellane, empa eseng sethaleng sa pele.⁶⁶. Monyetla oa phapang ea ho lula le maemo a ts'ebetso libakeng tse peli o ka hlalosa keketseho e kholo e bonoang cortex ea pele ho feta ea li-minipigs tsa minipigs tse pepesitsoeng ke ntho e le ngoe e ntle e lahlehileng ka mor'a matsatsi a leshome le metso e 'meli. Leha ho le joalo, joalo ka ha re sa ka ra ba le setšoantšo sa minipigs le [¹¹C] raclopride ka mor'a tsamaiso ea pele ea sucrose, tlhaloso ena e nahannoe.

Preortal cortex modulates moduli ea sebetsang, ho etsa liqeto le boitšoaro⁶⁷. Ho se sebetse hantle ka tšebetso ea methapo ea DA maemong a tšimolohong ea cortex ho sitisa phetisetso ea moputso, ho fana ka maikutlo a ts'ebetso e kholo ea boemo bo phahameng le bokhoni ba ho etsa liqeto ho batho ba batenya.^68,69. Ho feta moo, thuto ea motho ea PET e kopantsoeng e fokotsehile metabolism ea cortex e fokotsitseng striatal D2 e ​​tlamang botenya⁷⁰. Mona, re fumana phumaneho ea receptor ea D2 / 3 e kentsoeng ka pele ho cortex ea pele le ho kenyelletsa orbitofrontal cortex ea likolobe tse pepesitsoeng molemong oa sucrose.

Dopaminergic neurons tsa VTA li romela likhakanyo ho hippocampus le amygdala, moo ba tšehetsang boits'oaro bo tšoanang le tloaelo⁷¹ le ho buisana ka mokhoa o phallang le ho khutlisetsa maemo maemong a lithethefatsi^72,73 le litheko tsa lijo^74,75. Menahano ea kelello ea motho e bontšitse ts'ebetso ea hippocampal ho arabela takatso ea lijo le ho latsoa⁷⁶. E lumellana le seo re se fumaneng mabapi le ho fumaneha ha "receptor" ea hippocampal le amygdalar D2 / 3 ka mokhoa oa karabo ea rona, 'mapa oa boko oa motho ka [¹⁸F] fallypride e bontsitse tokollo ea cocaine cue-e susumelitsoeng ho DA ho amygdala le hippocampus⁷⁷. Bokong ba litoeba, ho pepesetsoa hoa koae ho hlahisitse ho lokolloa ha DA ho amygdala⁷⁸, le liphetoho tsa maemo a DA a amygdala li bile le tšusumetso ea boikhabi ba ho batla koae⁷⁹.

Phuputsong ea batho ba batenya haholo, setsoalle se lipakeng tsa D2 / 3 le μOR, tse tsejoang hore se teng libakeng tse maphathaphathe tsa batho ba iketlileng, se ile sa sitisoa ka hare ho naha.⁸⁰. Re bapisitse boleng ba BP_ND ea li-tracer tse peli ho hlahloba hore na data e hlahisitse phello ena. Ho fapana le batho ba hlokang kelello, likelello tsa likolobe tse teng hona joale li ne li sena kamano pakeng tsa boleng ba BP_ND ea li-tracer tse peli, kaholimo kapa ka mor'a ho pepesehela. Joale re ile ra leka hore na liphoofolo tse nang le litheko tse kholo tsa tracer carlentril binding li ka ba le litheko tse kholo ho feta tsa tracer carfentanil binding, empa ho fapana le moo ra fumana khokahano e mpe libakeng tse arohantsoeng tse kholo, re fana ka maikutlo a hore liphoofolo tse nang le phetoho e kholo ea bokhoni ba tsona bo tlamang. tracer raclopride e bile le phetoho e tlase haholo ea matla a tlamang a tracer carfentanil. Kamano e fapaneng lipakeng tsa liphetoho e bonts'a hore litlamorao tsa tšebeliso ea sucrose mabapi le phallo ea li-receptor tse amehang li laoloa ka lehlakoreng le fapaneng. Hoa tsebahala hore tšebeliso e feteletseng ea lijo tse fumanehang habonolo, kapa lithethefatsi, e ka tsamaisoa ke ho batla kapa ho rata, kapa bobeli^60,81. Ho ka etsahala hore ebe boholo ba ho batla bo tsamaisoang ke dopamine bo hlokomoloha boholo ba ho rata bo tsamaisoang ke li-opioids, kapa ho fapana le bona. Bopaki ba morao-rao bo supa likarolo tsa GABA_A li-receptor ka VTA le lits'oants'o tsa cholinergic ho striatum mme mohlomong cortex e sebetsang e le liphetoho lipakeng tsa dopamine tse itšetlehileng ka methati e ikemetseng ea ts'ebetso ea opioid^82,83 e ka hlalosang ho phahama ha dopamine le litlamorao tsa opioid libakeng tsa porcine exteriorriatal tse hlalositsoeng mona.

Mokokotlo oa PET, hape le liphoofolo tse kholo, ke tharollo e fokolang ea sebaka sa tomography e amang sephetho ho tsoa libakeng tse fokolang tsa boko tse nkang boits'oaro bo amanang le lijo. Leha ho le joalo, leha ho na le matšoenyeho ana, [¹¹C] moralo oa peeletso o kopantseng pejana o ne o tlalehiloe ka bobeli literekeng le literekeng^84,85,86,87. Tšebeliso ea [¹¹C] raclopride ho ngola mofuta o tšoanang oa li-receptors ha e tsose ho tšoenyeha ka liphapang tse ka bang teng tsa tumellano tse ka amang ts'ebeliso ea li-tracers tse arohaneng tsa li-receptors tse tšoanang libakeng tse fapaneng. Boithuto ba moraorao bo kenyelelitse lirekoto tsa tlamo e fetelletseng ea¹¹C] lebala la lipapali. Alakurtti et al a. o fumane tlhahiso e ntle ea mehato ea striatal raclopride e tlamang striatum, empa e le hantle feela ho hlahisa boikoetliso bo itekanetseng cortex⁸⁵. Phuputsong e ileng ea etsoa hamorao, Svensson et al a. e tšohlile lintlha tse 'maloa tse amang tšebeliso ea [¹¹C] raclopride e le lets'oao la li-receptors tsa exteriorriatal D2 / 3 thutong ea batho ba phetseng hantle, ho kenyelletsa ho tsoaloa hape ka kotloloho ka cortex le ho fokotseha ho fokolang ha tlamahano ea exteriorriatal ka pele ho cortex ha a arabela moemeli oa thibelo ea D2 / 3⁸⁸. Papiso e khutlisetsang liteko e senotse ho fapana ha 4-7% lithutong le 13-59% libakeng tsa cortical, empa nako e pakeng tsa litlhahlobo e imenne matsatsi a 20, ho fapana le matsatsi a 1-2 a thuto a mangata. Mabaka a mangata bophelong ba lithuto tseo e kanna eaba o bile le nako ea ho susumetsa se fumanoeng. Ho joalo, re bonts'a mona hore ho kenyelletsa tšebeliso ea sucrose feela kemisong ea hoseng ka matsatsi a 12 e kanna ea ba le tšusumetso ea mehato e tlamang e fumanoeng libeke tse peli hamorao. Lintho tse ling tse tloaelehileng joaloka ho bapala lipapali tsa video, ho ea mabenkeleng, ho kena likamanong tse ncha tsa lerato le ts'ebetso ea thobalano, ho sebelisa lithethefatsi kapa ho fetola lijo le ho ikoetlisa ho ka susumetsa maemo a dopamine a extrariarial ka monyetla oa phapang e kholo ea datha. Boithuto ba hajoale ka li-minipigs bo hlahisitse phetisetso e laoloang hantle ka ho fapana feela ke ho ba sieo kapa ho ba teng ha sucrose lijong. Moelelong ona, tlhaiso-leseling e tsoang ho liphoofolo tse supileng e ne e na le phapang e lekaneng maemong a tlatselletsang ho supa phokotso ea bohlokoa ea lipalo ho latela sucrose.

Moeli oa thuto e teng hona joale ke tšebeliso ea li-anesthetics tse hlokahalang ho netefatsa ho se sebetse hantle nakong ea Ka vivo monahano oa liphoofolo. Litlamorao tsa ho hlohlona ka mokhoa o khethehileng, le ho sebelisana ha bona le lithethefatsi kapa ho kenella, ho ka ferekanya tlamo ea radioligands^89,90. Ketamine ke lithethefatsi tse khahlanong le glutamatergic tse nang le litlamorao tse potlakileng tsa litekanyetso tsa meriana e ka tlisoang ke lefutso^91,92,93, tse sa fokotseng striatal [¹¹C] raclopride e tlamang ho batho⁹⁴. Leha ho le joalo, S-ketamine e fumanoe e fokotsa ho fumaneha ha li-receptor tsa dopamine D2 / 3 ho striatum ea li-primates tse sa tsebeng batho.⁹⁵. Isoflurane ke mofuta o tloaelehileng oa bosholu ho PET ea liphoofolo. Lithutong tse fetileng, re fumane ho bokellana ho matla ha¹¹C] SCH23390, radioligand ea dopamine D1 receptors e phahame haholo ho minipigs e sa sebetseng ka isoflurane ho fapana le propofol, e fana ka maikutlo a ho hlaseloa ha methapo ea kutlo ea dopaminergic ho litlamorao tsa ho hlohlona ka thipa⁹⁶. Phuputsong ea morao-rao, li-minipigs tsohle li ne li bontšoa ka nako e le 'ngoe ka tlasa meriana ea ketamine pele le kalafo ea meriana.

Tšebeliso e ngata ea lijo tse matlafatsoang ka bobeli li ka baka, 'me ea e-ba sesosa sa, ho lemalla ho ba le litlamorao tse tobileng ho bophelo bo botle ke botenya. Re ile ra leka taba ea hore moputso oa opioids le dopamine mediate li bohlokoa, molemong oa ho pholoha hammoho le ts'ebeliso e mpe ea lithethefatsi. Li-minipigs tse nang le phihlello ea nako le nako ea tharollo ea sucrose ka matsatsi a 12 a latellanang li bontsitse ho fokotseha ha dopamine D2 / 3 le − io opioid receptor fumaneha libakeng tsa boko le litekanyo tsa kelello, ho fana ka maikutlo a hore lijo tse nang le ts'usumetso e kholo ea ts'usumetso ea ts'ebetso ea ts'ebetso ea boko ka litsela tse ts'oanang le tse tlisoang ke lithethefatsi tse lemalloang. lia jeoa. Ho pepesoa hang-hang ho sucrose ho ne ho tsamaisana le ho lokolloa ha opioid libakeng tsa boko tse sebetsang ka moputso. Liphetoho tsa ho fumaneha ha opioid le dopamine li hlalosa menyetla e ka tlisoang ke ho chona ea ho chesa ho feta tekano.

Melao ea boitšoaro ea liphoofolo

Boithuto bona bo amohetsoe le ho laoloa ke Sekolo sa Tlhahlobo ea Liphoofolo tsa Danish mme liteko tsohle li entsoe ho latela taelo ea 2010/63 / EU ea Paramente ea Europe le Lekhotla mabapi le Ts'ireletso ea Liphoofolo tse Sebelisoang ka Morero oa Saense le tataiso ea ARRIVE. Re sebelisitse li-minipigs tse supileng tsa basali tse nang le likhoeli tse leshome le metso e mene tsa Göttingen (Ellegaard, Dalmose, Denmark). Minipigs e ne e feptjoa lijo tsa pellet (6 dL, makhetlo a 2 ka letsatsi, Lits'ebeletso tse khethehileng tsa Lijo, Aarhus, Denmark) ka metsi a pompo a fumanehang ad libitum. Mocheso oa tikoloho o ne o le 20-22 ° C, mongobo o lekanang 50-55%, mme moea o ne o fetoloa makhetlo a robeli ka hora e 'ngoe le e' ngoe.

Tšebeliso e kenelletseng ea sucrose

Re tšoantšitse li-minipigs tse supileng le [¹¹C] raclopride le [¹¹C] carfentanil motheong oa motheo, hape hape ka letsatsi le le leng ka mor'a matsatsi a 12 a latellanang a tšilafatso ea metsi. Ho pepesetsoa ha Sucrose ho ne ho kenyelletsa hora e le 'ngoe ea sucrose (sucrose, Dansukker, Copenhagen, Denmark) phihlello ea metsi (ligrama tse 500 tsa sucrose ho lilithara tse 2 tsa metsi), letsatsi le letsatsi ka nako ea matsatsi a 12. Lenane la tšebeliso ea sucrose le eona e tlalehiloe 'me minipigs eohle e ja lilitha tse peli ka letsatsi. Re boetse re tšoantšisa li-minipigs tse ts'oanang le [¹¹C] carfentanil, metsotso e 30 kamora ho fihlella hoa pele, ho ithuta ka tokollo e mpe ea opioid.

Li-minipig li ile tsa fumana karolelano ea boima ba 'mele ba 13.6% ho tloha 25.4 kg (± 0.73 SEM) ho basement ho 28.9 kg (± 0.69 SEM) kamora ho pepeseha ha sucrose ea matsatsi a 12, e neng e phahame haholo (t-teko e le' ngoe, p < 0.001) ho feta keketseho e bonoeng sampoleng ea li-minipig tsa taolo tse fumanoeng lithutong tse fetileng, moo litekanyo li nyolohileng ka karolelano ka 4.9% feela, nakong e tšoanang ea nts'etsopele.

Brain PET Ho Kopanya

Re ile ra potlakisa likolobe bosiu bo le bong ka mokhoa oa ho fumana metsi mahala pele re nahana. Re ile ra thuisa ka ho sebelisa litlolo tsa mamelopiki pele le ka mokhoa o sa hlakoheng joaloka pele⁹⁷ 'me a ba beha li-supine ka har'a sesebelisoa sa PET / CT (Motorola Biograph 64 Truepoint PET). Re ile ra etsa tlhahlobo ea tekanyetso e tlase ea CT pele ho peter e 'ngoe le e' ngoe ea PET bakeng sa litlhaloso tsa anatomical le tokiso ea tlhahiso ea tlhahiso ea tlhahiso ea PET. Re tsamaisitse kahare ho [¹¹C] raclopride motheong oa basel (360 ± 18 MBq, tšebetso e ikhethang 77 ± 76 GBq / μmol, letheba le boima 0.12 ± 0.08 μg / kg) mme kamora matsatsi a 12 a sucrose (374 ± 54 MBq, ts'ebetso e ikhethang 127 ± 85 GBq / μmol, lethekeng boima 0.06 ± 0.05 μg / kg), le [¹¹C] carfentanil motheong oa motheo (377 ± 43 MBq, ts'ebetso e ikhethileng 311 ± 195 GBq / μmol, ente e boima 0.03 ± 0.02 μg / kg) mme kamora matsatsi a 12 a sucrose (337 ± 71 MBq, ts'ebetso e ikhethang 177 ± 157 GBq / μmol, ente e boima 0.06 ± 0.08 μg / kg) ka methapo ea tsebe, ka saline ea mililita e 10, nakong ea motsotso oa pele oa sekepe sa metsotso e 90. Re hlophisitse data e nchafalitsoeng ea PET re sebelisa TrueX 3D OSEM (3 iterations, 21 subsets), 256 × 256 × 109 matrix, le 2-mm Gauss filthara, re sebelisa sebopeho sa nako ea 5 × 60, 3 × 300, 4 × 600 , Metsotsoana e 2 x 900 (liforeimi tse 14 ka kakaretso, metsotso e 90). Motheong le kamora matsatsi a 12 a sucrose, minipigs e ile ea ts'oaroa le lits'oants'o tse peli tsa katoa ka nako ea bonyane metsotso e 100, ka lebaka la halofo ea bophelo ba [¹¹C] LITLHATSI tsa PET. Ha re qetile karolo ea ho qetela ea PET, re ile ra khothaletsa minipigs ka tlasa takatso e matla ea kelello ka ho sebelisa ka ho feteletseng pentobarbital (100 mg / kg).

Bohlahlobisiso ba litaba le lipalo

Re entse mehato e ntlafatsang re sebelisa PMOD 3.7 (PMOD Technologies Ltd, Zurich, Switzerland). Ho hlalosa likarolo tsa phetoho ea stereotactic ho tsoa linthong tse nkeloang nako PET, re sebelisitse litempele tse ikhethileng tsa ligand. Re sebelisitse li-matric tsa phetoho tse hlahisitsoeng le masimo a aroloang moqoqong o lumellanang oa nako ea PET. Re hlahisitse litšoantšo tsa parametric tsa [¹¹C] raclopride e tlamang e ka khonehang (BP_ND) ka mokhoa oa li-multilinear reference tis mokhoa oa Ichise le basebetsi-mmoho⁹⁸. Re thehile maske a entsoeng ka tloaelo ea "cerebellum" ntle le "vermis" ho fumana ts'ebetso ea "c" ea "cerebellar" ka nako e telele sebakeng sa litekanyetso tsa DA D2 / 3 receptor. Re hlahisitse litšoantšo tsa parametric tsa [¹¹C] carfentanil o sebelisa ts'ebetsong ts'ebetso ea mofuta oa Logan reference tishu^99,100 ka t * = 30 metsotso. Lithuto tsa [¹¹C] carfentanil e tlamang bokong ba motho ba sebelisitse occipital cortex e le sebaka sa ho bua³⁶; leha ho le joalo ka kolobe¹⁰¹. Ka hona, re khethile cerebellum e le sebaka sa lipatlisiso thutong ea hona joale.

Tlhahlobo ea statistical

Re ile ra beha limmapa tlhahlobisong ea bohlale ba voxel le 'Mapa oa Statistical Non-Parametric (SnPM v13.01, http://warwick.ac.uk/snpm) Lebokose la lisebelisoa la SPM le sebelisang khopolo ea tumellano e seng ea parametric ho fana ka moralo oa tlhahlobo ea lipalo, mokhoa o bonts'itsoeng o sebetsa hantle bakeng sa disampole tse nyane ka lebaka la taolo e thata ea positives ea bohata¹⁴ mme e sebelisoe joalo ka ha ho hlalositsoe pele¹⁰². Setsebi sa neanoanatomy ea likolobe (DO) se bapisitse litšoantšo tse tlisoang li ts'oaroe ho 5% bohlokoa ba boemo bo phahameng ba qeto e phahameng ea Göttingen minipig atlas^103,104 ho hlalosa le ho ngola libaka tsa DAD2 / 3 tse fokolisitsoeng le andOR BP_ND ho tloha motheong oa pele ho ea ho boemo ba morao-rao. Ka mor'a moo re ile ra etsa tlhahlobo ea tikoloho-ea-thahasello (ROI) ho hlahisa BP_ND boleng ba libaka tse ikhethang tse fumanoeng li khahla ho latela tlhahlobo ea SnPM, ho kenyelletsa le striatum, nucleus accumbens, thalamus, amygdala, cingate cortex le preortal preortal. Ha ho lipalo-palo tse ling tse ileng tsa etsoa tlhahlobisong ea ROI, kaha libaka tsena li ne li se ntse li fumaneha li le bohlokoa li sebelisa SnPM.

"Univesithi ea Aarhus" Grant ea merero ea nts'etsopele ea AU "ho AML e tšehelitse thuto. Re leboha tšehetso ea tekheniki e tsoang ho basebetsi ba Setsi sa PET sa Sepetlele sa Aarhus le Polasi ea Aarhus University bakeng sa thuso ka kalafo ea liphoofolo. Re leboha Moprofesara Morten Kringelbach, Moprofesa Jørgen Scheel-Kruger le Moprofesa oa Mosebetsi Arne Møller bakeng sa thuso mabapi le ho qala lithuto tsena.

Litšebelisano

1. Lefapha la Bongaka ba Nyutlelie le Setsi sa PET, Univesithi ea Aarhus, Aarhus, Denmark
   • LITABA TSA MOLIMO: Michael Winterdahl
   • , Ove Noer
   • , Anna C. Schacht
   • , Steen Jakobsen
   • , Aage KO Khutso
   • , Albert Gjedde
   •  & Anne M. Landau
2. Lefapha la Neurosurgery le CENSE, Sepetlele sa Aarhus University, Aarhus, Denmark
   • Dariusz Orlowski
3. Lefapha la Nuclear Medicine, University of Southern Denmark & ​​Odense University Hospital, Odense, Denmark
   • Albert Gjedde
4. Lefapha la Neuroscience, Yunivesithi ea Copenhagen, Copenhagen, Denmark
   • Albert Gjedde
5. Lefapha la Neurology le Neurosurgery, Univesithi ea McGill, Montreal, Canada
   • Albert Gjedde
6. Setsi sa phetolelo sa Neuropsychiatry, Univesithi ea Aarhus, Aarhus, Denmark
   • Anne M. Landau

Menehelo

MW le AML li thehile thuto le tlhahlobo; ACS le SJ ba kopantsitse li-tracer tsa PET; MW, AKOA le AML ba sebetsana le minipigs le ho etsa liteko tsa PET; MW, ON le AML li entse tlhahlobo ea data; HA E fane ka setsebi sa anatomical, MW, AG le AML ba hlalositseng data; MW le AML ba ngotse buka e ngotsoeng ka letsoho ka tšehetso ea AG; bangoli bohle ba ile ba amohela phetolelo ea buka e ngotsoeng ka letsoho.

Mongoli ea tšoanang

Ngollano ho Anne M. Landau.

Lithahasello tse tsitsitseng

Bangoli ha ba phatlalatse lithahasello.

Tsebiso ea mohatisi Boemo ba Motsoako bo lula bo sa jele paate mabapi le litlaleho tsa molao ka limepi tse hatisitsoeng le mekhatlo ea lihlopha.

Lipapatso le Litumello