Crosstalk lipakeng tsa Kappa Opioid le Dopamine Sistimi ho Li-Behaviors tse Qobellang (2020)

Selelekela

Sistimi ea Dopaminergic ho Likhatello tse Ikemetseng

Ho qobelloa ke monyetla o sa khoneheng oa ho emisa ho etsa ketso e tloahelehileng ka sephetho se tsebahalang, leha o bile le litlamorao tse mpe (Robbins et al., 2012). Boitšoaro bo qobelloang ke matšoao a boloi bo sa tsotelleng (OCD) le bokhoba ba lithethefatsi, hara mafu a mang a kelello. Boitšoaro ba ho hlahloba bo atile haholo likhethong tsa ponelopele tse bonts'ang maikutlo li tšoauoa ka ho pheta-pheta khafetsa hoa tloaelo e itseng, ka tsela e sothehileng kapa ea moetlo (Williams et al., 2013). Litloaelo tse fapaneng tse fapaneng (mohlala, ho hlahloba, ho hlatsoa, ​​ho hlatsoa matsoho joalo-joalo) li ka fetoha bakuli ba OCD mme ka kakaretso li hlaha ka lebaka la menahano e hlokofatsang le e sithabetsang e bakang matšoenyeho. Ka mokhoa o ts'oanang, ho batla le ho jella lithethefatsi tsa tlhekefetso ho ba ho tlatsetso ho lithethefatsi tsa lithethefatsi Joalo ka OCD, ho tšoenyeha ho bapala karolo ea bohlokoa ho hlohlelletsang ts'ebeliso e mpe ea lithethefatsi ho ba sebelisang lithethefatsi hampe. Phokotso e tšoanang ts'ebetsong ea moputso le ts'ebetso ea kotlo e bonoa maemong ohle ka bobeli (Figee et al., 2016), e entseng hore bangoli ba bang ba bue ka OCD e le tšibollo ea boitšoaro (Holden, 2001).

Mokhoa o mong o ka lebisang hotsong e qobelloang o kopantsoe ka har'a khopolo ea tšusumetso ea takatso e matla eo khothatso e eketsoang ("ho batla") bakeng sa ts'ebeliso ea lithethefatsi ntle le ts'ebetso ea ts'ebeliso ntle le ho hlahisa sephetho se ntlafalitsoeng ("ho rata") (Berridge le al., 1989; Berridge le Robinson, 2016). Ho khothaletsa maikutlo a moputso / potoloho ea ts'usumetso e kenyelletsa ho kenella ho matlafatso ea maikutlo a khothalletsoang a amanang le ho batla lithethefatsi. Moputso / potoloho e khothalletsang e kopantsoe le li-neurbrain dopamine neurons tsa substantia nigra (SN) le sebaka se khubung ea mokokotlo (VTA), se shebileng litheko tse kenang kahare le tse kenang kahare. Dopamine neurons projeke eo ho "ventral striatum" kapa "nucleus accumbens" (setso) e se e ntse e amana le boits'oaro bo nang le sepheo, athe dopamine neurons eo projeke e eang ho dorsal striatum e kopantsoe le ho fumana mekhoa (Everitt le Robbins, 2005; Bohlale, 2009; Yager et al., 2015; Volkow et al., 2017).

Sensitization ea moputso / khothatso ea potoloho e bonoa ka litoeba ha keketseho ea butle-butle ea ts'ebetso ea tšebeliso ea maikutlo e fanoa ke taolo e pheta-phetoang ea litekanyetso tse ka bang tlatsetso ea lithethefatsi tse nang le tšebeliso e mpe ea lithethefatsi.Pierce le Kalivas, 1997; Robinson le Berridge, 2001). Boitlhotlhollo ba locomotor ke ntho e tšoarellang kaha e bonoa kamora libeke, likhoeli esita le selemo kamora ho tloheloa hoa lithethefatsi (Robinson le Berridge, 1993). Ho ile ha fanoa ka tlhahiso ea hore ho khothaletsa moputso / khothalletso ea potoloho ho kenya letsoho ho qobelloeng ha lithethefatsi (Robinson le Berridge, 1993). Ho latela moo, sensitization sensorotor e thusa ho itaola ka mokhoa o ikemetseng oa koae e batlang ho khutlisetsoa (De Vries et al., 2002). Ho feta moo, likhoto tse nang le phihlello e pharaletseng ea ho itaola ka koae li bontša karabelo e kholo ea koae ho feta likhoto tse nang le phihlello e fokolang (Ferrario et al., 2005). Ntle le moo, liphetoho tsa methapo ea kutlo tse ka tlas'a maikutlo a locomotor ho li-psychostimulants li boetse li bonoa ho kenyelletseng ho batla lithethefatsi (Steketee le Kalivas, 2011; Giuliano et al., 2019). Lintlha tsena li tšehetsa ngollano ea pele-pele e pakeng tsa maikutlo a locomotor le takatso e qobelloang ea lithethefatsi e bonoang bathong (Robinson le Berridge, 1993; Vanderschuren le Kalivas, 2000). Ka mokhoa oa tekheniki, taolo e pheta-phetoang ea lithethefatsi tsa tlhekefetso e lematsa liserekisi tsa mesolimbic dopamine e eketsa dopaminergic neurotransmission. Psychostimulants, joalo ka cocaine kapa amphetamines, e thibelang transporter ea plasma membrane dopamine (DAT), e etsa hore ho be le keketseho e kholo ea dopamine sebakeng sa synaptic ho striatum le NAc, ka hona e hlohlelletsa pherekano (Steketee le Kalivas, 2011). Joalo ka ts'ebeliso ea lithethefatsi, ho susumetsoa ha moputso oa dopamine / potoloho ea ts'usumetso ho kenya letsoho maikutlong a qobelloang a bonoang ho OCD. Ka sebele, ts'ebetso e pheta-phetoang ea li-receptor tsa dopamine D2 (D2Rs) e lekane ho susumetsa maikutlo a locomotor le ho lekola boitso ka likhoto le litoeba (Szechtman et al., 1998; Szechtman et al., 1999; Letsatsi le al., 2019). Tsamaiso e pheta-phetoang ea quinpirole, agonist ea D2R / D3R, ke mohlala o amohetsoeng oa OCD ha o hlakisa sefahleho, ka keketseho ea tlhahlobo e qobelloang le boits'oaro bo bobe, ho nepahala ha ponelopele, joalo ka ha ho bonoa ka ho fokotseha hoa boits'oaro bo qobelloang kamora kalafo e sa foleng le serotonin ho pheta-pheta. inhibitors (SRI) le ho etsa bonnete ba ha likarolo tsa boko tse amehang mohlaleng ona li arolelanoa le ba ramatiki (Stuchlik et al., 2016; Szechtman et al., 2017). Ka kakaretso, ts'ebetso e pheta-phetoang ea phetisetso ea dopamine, ekaba ka pre-synaptic (dopamine e lokolla) kapa mekhoa ea post-synaptic (activation of D2R) e lebisa ho sensomization ea locomotor le boits'oaro bo hatelletsang.

Sistimi ea kappa opioid ke e 'ngoe ea litokisetso tsa pele tse laolang phetisetso ea dopamine ho potoloho ea moputso / khothatso. Bopaki bo bontša hore phetisetso ea kappa-opioid e hanana le litlamorao tsa dopamine; ts'ebetso e mpe ea li-receptor tsa kappa opioid (KORs) li hanyetsa mosebetsi oa locomotor o hlahisoang ke psychostimulants (Gray et al., 1999). Ka lehlakoreng le leng, ts'ebetso e pheta-phetoang ea KOR e boloka le ho ntlafatsa ho ts'oaroa ha lithethefatsi le tloaelo (Koob, 2013). Tšebeliso ea lithethefatsi tsa tlhekefetso e hohela phepelo e ntlafatsang ea kappa opioid ea homeostatic, mohlomong e tlatsetsa ho maikutlo a mabe a dysphoria (Koob, 2013) ho baka tšebeliso e mpe ea lithethefatsi (Chavkin le Koob, 2016). Ebile, blockade ea KOR e ile ea thibela khatello ea kelello - empa eseng e bakiloeng ke lithethefatsi (nikototine) (Jackson et al., 2013), cocaine (Beardsley et al., 2005) le ethanolSperling et al., 2010). Tumellanong le seo a se fumaneng, KOR blockade e khutlisetsa liphetoho dopaminergic ho dorsolateral striatum of amphetamine sensitised rats, ntle le ho fetola karabelo ea bona e ntlafalitsoeng ea locomotor ho sethethefatsi (Azocar et al., 2019). Ka hona, Sisteme ea KOR e bonahala e ntlafatsa boleng bo matla ba tlatsetso ea lithethefatsi. Ho OCD, matlafatso a fosahetseng a hlohlelletsoa ke litabatabelo, tse matlafatsang khatello e fanoeng e le ho qoba ho tsilatsila ho joalo. Le ha e so ka e hlahlojoa ka kotloloho, ho matlafatsoa ka mokhoa o fosahetseng ho ka bapala karolo ho tsitsitseng maikutlo a quinpirole. Ehlile, D2R e kentse letsoho molatong oa matlafatso e mpe. Mohlala, thibelo ea sebaka se nang le morapo oa ho tlosa morphine ha ea ka ea hlahisoa ka litoeba tse haelloang ke mohopolo o molelele oa D2R (Smith le al., 2002) kalafo e phetoang ea quinpirole nakong ea ho tsilatsila e boetse e tiisa koae le ho ts'oana le heroin ho paradigm ea tsamaiso ea likoloi, e leng sephetho se amanang le tšusumetso e matla ea quinpirole (De Vries et al., 2002), e fana ka tlhahiso ea mekhoa e arolelanoang pakeng tsa psychostimulant le sensinization e susumetsang ea quinpirole. Ntle le moo, ho kenyelletsoa hoa ntloana ea lehae, empa eseng pale e ntšo, ho leba lebaleng le bulehileng ho fokotsa maikutlo le boitšoaro bo potlakileng ba ho hlahloba (Szechtman et al., 2001), e bonts'a hore mekhoa ea polokeho / tloaelo e ka qothisana lehlokoa le tikoloho tse khahlisang maikutlo. Ka mokhoa o ts'oanang le tlhokomeliso ea maikutlo ea psychostimulant, ts'ebetso e pheta-phetoang ea KOR e thusa sensitization ea locomotor (Escobar et al., 2017) le boits'oaro bo lekang ba ho hlahloba (Perreault et al., 2007) hlohlelletsoa ke tsamaiso e pheta-phetoang ea quinpirole. Hore na phello ena e mpe ke phello ea ntlafatso e mpe e ntse e tlameha ho hlakisoa.

Tlhahlobo e phethahetseng e entsoeng haufinyane e bonts'a hore phello ea sistimi ea kappa-opioid ho phetisetso ea dopaminergic e rarahane: ho latela tsela ea dopamine e amehang (Margolis et al., 2006; Margolis et al., 2008), le ho nako pakeng tsa ts'ebetso ea receptor ea KOR le ts'ebetso ea recopor ea dopamine (Chartoff et al., 2016). Tumellanong le ho rarahana hona, tšebeliso ea kalafo ea li-ligands tsa KOR e ka buisanoa haholo. Ho nahanoa hore agorist ea KOR e ka ba molemo maemong a bongaka nakong ea ts'ebeliso ea lithethefatsi, e fumanang lithethefatsi tse thethefisitseng hyperdopaminergia (Shippenberg et al., 2007). Ka lehlakoreng le leng, mohanyetsi oa KOR a ka ba molemo ho phekoleng lefu le tlisoang ke ho eketseha ha polelo ea dynorphin ka mor'a ho sebelisa lithethefatsi khafetsa (Wee le Koob, 2010). Ka lebaka leo, ho hlahisitsoe tlhahiso ea hore KOR karolo ea agonist (Béguin et al., 2012) e kanna ea ba khetho ea kalafo ho phekola tšebeliso e mpe ea lithethefatsi le matšoao a bang teng ho batho ba lemalloang (Chartoff et al., 2016; Callaghan et al., 2018). Thutong ena, re sekaseka ho feto-fetoha ha maemo ho itšetlehileng ka maemo / dikahare tsa dopaminergic tsa maikutlo a boits'oaro le ho qobelloa.

Anatomical and Functional Crosstalk lipakeng tsa Kappa Opioid le Dopaminergic Systems libakeng tsa Striatal le Midbrain

Libaka tsa Litereke

Li-KOR ke li-receptor tsa Gi / o protein-coupled tse hlahisitsoeng haholo ho sistimi ea dbamine ea midbrain (Mansour et al., 1996). Li-receptor tsena ke tsa lelapa la li-opioid receptors tse qapiloeng ke mu (MOR), delta (DOR) le kappa (KORs). Li-agonists tsa endo native tsa li-receptor tsena ke li-endorphin, enkephalin le dynorphin, ka ho latellana. Ho striatum, dynorphin e entsoe ka dopamine D1receptor (D1R) - e nang le li-neurons tse mahareng tse mahareng (li-MSN) tse nang le li-axon tse pheta-phetoang tse sebetsang ho li-KOR tse tsoang moleng o le mong (Mansour et al., 1995). Litšoantšo tsa Electron microscopy tsa rat NAc li bonts'a hore li-KOR li fumaneha hangata mehahong e nang le li-presynaptic ha e le karolo e nyane ea KORs localize ka li-dendrites ha li se li etsoa ho isa ho DAT (Svingos et al., 2001; Kivell et al., 2014). Lithuto tsa Immunofluorescent tse bonts'a litokisetso tsa presynaptic-synaptosomal tse tsoang ho NAc li bonts'a hore KORs le D2Rs ba ratana haholo li-synaptosomes tse nang le dopamine synthetizing enzyme, tyrosine hydroxylase (TH) (Escobar et al., 2017). Ho feta moo, li-KOR li ngata mefuteng ea lisele ea NAc le striatum, le colocalize e nang le D2R ka seleng e kholo (Escobar et al., 2017). Ka leseli la liphatsa tsa lefutso le limolek'hule, ho khothalelitsoe hore karolo ea 20% ea KOR e tlamang ho striatum e bonoa litulong tsa DA ((Van't Veer et al., 2013). Ho feta moo, Tejeda et al. (2017) e bonts'itse hore D1R le D2R MSN li hlahisa KOR ka khetho e phahameng bakeng sa D1R e nang le li-MSN (Tejeda et al., 2017). Data ena ea anatomical e bonts'a hore li-KOR li teng pele le ka postynaptically, li laola dopamine neurotransmission ho moputso / khothatso ea potoloho.

Mekhoa e 'maloa ea liteko e bontša hore ts'ebetso ea KORs inhibits dopamine release. Ts'ebetso e mpe ea li-KORs ka ente ea systemic kapa infusions ea lehae ea li-agonists e fokotsa maemo a tsoang ho dopamine ho NAc (Di Chiara le Imperato, 1988; Spanagel et al., 1992; Fuentealba et al., 2006) le dorsal striatum (Gehrke et al., 2008). Ho ts'ehetsa ts'ebetso ea tonor inhibitory ea KORs holim'a dopamine neurotransication, ts'ebetso e tobileng ea mohopolo oa nako e telele le o khethang KOR antagonist nor-binaltorphimine (nor-BNI) (Broadbear et al., 1994) e eketsa litekanyetso tsa basal tsa dopamine ho NAc (Spanagel et al., 1992) le tokollo ea dopamine ka har'a dorsal striatum (Azocar et al., 2019). Bopaki ba ho qetela ba thibelo ea dopamine ea KOR ea dopamine e bontšitsoe ho litoeba tsa KOR Knoutout, tse bonts'itseng litekanyetso tse eketsehileng tsa dopamine ho striatum le NAc (Chefer et al., 2005). Mekhoa e ikarabellang bakeng sa thibelo ea KOR ea tokollo ea dopamine ha e hlakisoe ka botlalo. Leha ho le joalo, hoa tsebahala hore ts'ebetsong ea li-KOR e lebisa ho keketseho ea K + le ho fokotseha ha lipallo tsa Ca2 +, ka hona ho baka ho ts'oaroa ha sele le ho thibeloa ha tokollo ea methapo ea mali (Bruchas le Chavkin, 2010; Margolis le Karkhanis, 2019).

Ho phaella moo, in vitro 'me Ka vivo datha e sebetsang e fana ka maikutlo a hore li-KOR li fetola maemo a dopamine extracellular ka ho fetola tšebetso ea DAT. Mohlala, ts'ebetso ea li-KOR tsa lisele tsa EM4 tse kopanyang li-KOR le DAT, li lebisa ho ho eketseha hoa dopamine e lekantsoeng ke voltammetry (Kivell et al., 2014). An Ex vivo Ts'ebetso hape e sebelisa voltammetry ho lisele tse sa lumellaneng, e bonts'itse hore ente ea systemic ea KOR agonist U-69593 e eketsehile ho fumana dopamine ho NAc (Thompson et al., 2000). Sengoloa se ts'oanang sa morao-rao se bonts'a hore nor-BNI e thibela ho eketsoa ha dopamine kahare le ka mpeng ea dorsal striatum, e hlahisitsoeng ke ente e mpe ea systemic ea MP1104, Kappa / Delta opioid reconor agonist e kopaneng.Atigari et al., 2019). Leha ho le joalo, phello ea ts'ebetso ea KOR ts'ebetsong ea dopamine ha e so hlakisoe ka botlalo. Tsamaiso ea tsamaiso ea KOR karolo ea maemo a agonist nalmefene e fokotse tekanyo ea "striatal dopamine uptake" ka mokhoa o ikhethileng, e emisitsoeng ke sekhahla sa "cyclic voltammetry" (FSCV) e potlakileng.Rose et al., 2016). U sebelisa microdialysis ea se-net flux ho litekanyetso tsa banna ba baholo, ho thibela KOR ho ne ho tsamaisana le keketseho ea karoloana ea leseli (Ed), e leng tekanyo e sa tobang ea ho ts'oaroa ha dopamine (Chefer et al., 2006; Azocar et al., 2019), ho fana ka maikutlo a hore ts'ebetso ea tonic ea KOR e fana ka taolo ea thibelo mosebetsing oa DAT (dopamine uptake). Liphetho tsena li bonts'a karolo e rarahaneng ea tšebetso ea morao ea KOR mosebetsing oa ho etsa dopamine ho laola maemo a dopamine extracellular. Litsela tse phahameng tsa ho rarolla bothata ba nakoana ka mokhoa oa FSCV li hlotsoe ho bonts'a phello ea KOR ho hloekisoang ha dopamine (Ebner et al., 2010; Ehrich et al., 2015; Hoffman et al., 2016), ho fana ka tlhahiso ea hore KOR e ntlafatsa ts'ebetso ea DAT libakeng tse nang le mathata., ntlafatso ea KOR-Mediated ea ts'ebetso ea DAT e ka hlalosoa ka keketseho ea palo ea DAT ho li-membrane tsa sele tse hlahisitsoeng ke ts'ebetso ea KOR, joalo ka ha ho tlalehiloe ho li-synaptosomes tsa striatal le sele mela (Kivell le al, 2014).

Libaka tsa Midbrain

Litlhapiso tsa Autoradiographic tse etsoang ho ratbb ea "ratb" li bonts'a tlamo e kholo bakeng sa li-KORs holima rostrocaudal axis ea SN le VTA (Speciale et al., 1993). Ka lehlakoreng le leng, data ea microscopy ea elektrone e bontša hore li-terminals tse nang le dynorphin li theoha ka kotloloho ho li-dendrites tse ntle tsa TH ho SN le VTA (Sesack le Pickel, 1992), e fana ka maikutlo a hore KORs ea lehae libakeng tsa somatodendritic li-dopamine neurons. StNatal D1R-e nang le li-MSN ke e 'ngoe ea likenyelletso tsa dynorphin ho methapo ea methapo ea methapo ea methapo. Ho khahlisang, blockage ea KORs ha e fetole phello ea inhibitory ea D1R-MSNs ho VTA dopamine neurons, e bonts'a hore inhibition ena e kopantsoe ke GABA (Edward et al, 2017). Li-KOR li fetolela likarabo tsa somatodendritic tsa dopamine midbrain neurons. Boithuto ba electrophysiological bo bonts'a hore ts'ebetso ea li-KORs ho hyperpolarize ea VTA le ho fokotsa sekhahla sa ho thunya ha li-spontaneus tsa dopamine neurons (Margolis et al., 2003). Ka lebaka leo, ts'oaetso ea li-agonists tsa KOR e fokotseha somatodendritic dopamine efflux (Smith le al., 1992; Dalman le O'Malley, 1999). Leha ho le joalo, phello ena ea inhibitory ea li-KOR tsa li-dopamine neuron e bonahala e its'etleha. Ts'oaetso ea li-agonists tsa kappa-opioid ho VTA e fokotsa ho lokolloa ha dopamine ho medial prefrontal cortex (mPFC) (Margolis et al., 2006) empa eseng ho NAc (Devine et al., 1993; Margolis le al, 2006). Ho feta moo, Margolis le ba bang. (2006) e fumane hore KORs inhibit VTA dopamine neurons e ts'ebetsang mPFC le basolateral amygdala, empa eseng tseo projeke e eang ho NAc. Selemong sona seo, Ford et al. (2006) e bonts'itse hore ts'ebeliso ea boroko ea li-agorists tsa KOR lipapaling tsa mouse VTA e bakile ts'ebetso e holimo ea kantle ho li-dopamine neuron tse projeke e eang ho NAc ha e bapisoa le tsa projeke ho basolatal amygdala, ho bonts'a hore KORs e na le thibelo e kholo ea li-neurop tsa dopamine morerong ona ho NAc ho feta ho amygdala. Ho feta moo, ts'ebetso ea KOR e fokotsa ho nyoloha hoa thabo (Margolis et al., 2005) le inhibitory (Ford et al., 2007) maqhubu a postynaptic a kenang methapong ea methapo ea kutlo. Phapang lipakeng tsa mefuta le mefuta e rarahaneng ea VTA ho mPFC le NAc (Van Bockstaele le Pickel, 1995; Carr le Sesack, 2000) etsa hore e be phephetso ho tseba hore na li-KOR li thibela ka boomo lipalo tsa li-dopamine tsa neuronal ho VTA. Leha ho le joalo, lintlha tse fuperoeng mona li bonts'a hore li-KOR li ka har'a soma le lits'oants'o tsa li-dopamine neuron, hammoho le litlatsetsong tse li laolang, ka hona li behiloe ka mokhoa o ts'oanelang ho laola ts'ebetso ea synaptic ea methapo ea methapo ea methapo ea mmele.

Karolo ea li-KOR tse Laolang ho fetisoa ha methapo ea kutlo ho Dopamine ho li-Psychostimulants-Induction Sensitization le Compulsive Behaviors.

Ho lemalla lithethefatsi ke ts'ebetso e kenyelletsang ho batla lithethefatsi ho tloha pele tse amanang le litlamorao tsa tsona tse matlafatsang. Ka lehlakoreng le leng, ho qobelloa ke litšobotsi tse bonoang ke bokhoba ba lithethefatsi. Li-neuroadaptations tse 'maloa litseleng tsa dopaminergic li hlahisitsoe ho ikarabella bakeng sa ho batla lithethefatsi tse kenelletseng le ho ja ka mor'a ho pepesehela lithethefatsi tsa tlhekefetso khafetsa (Everitt le Robbins, 2005; Koob le Volkow, 2016). E 'ngoe ea li-hypotheses tse khothalelitsoeng ho khanna ho ja lithethefatsi ka matla ke ho susumetsa litlamorao tsa eona tse matlafatsang (Koob, 2013). Taolo ea inhibitory ea sistimi ea kappa opioid mabapi le ho lokolloa ha dopamine e ka kenya letsoho ho matlafatsang thepa e matlafatsang ea lithethefatsi tsa tlhekefetso. Leha ho le joalo, litlamorao tsa ts'ebetso ea KOR ts'ebetsong ea dopamine neurotransication le lithethefatsi tse qobelloang li batla li bonahala li le thata ebile li bonahala li hanyetsane. Ka sebele, tokollo ea dopamine e hlohlellelitsoeng ke amphetamine le koae e bontšoa ke tsamaiso e kopanetsoeng ea li-agonists tsa KOR (Heidbreder le Shippenberg, 1994; Maisonneuve et al., 1994; Thompson et al., 2000esita le ho fokotsa ho itlhokofatsa ka koae (Negus et al., 1997). Ho feta moo, KORs e fana ka maikutlo a thibelo mabapi le ho lokolloa ha dopamine tseleng ea mesolimbic ho arabela ts'ebetsong e tsitsitseng ea post-synaptic D1R joalo ka ha e etsahala khafetsa ho psychostimulants (Cole et al., 1995; Nestler, 2001). Ka mokhoa o makatsang, ts'ebetso ea KORs e ka boela ea tsamaisa tokollo ea dopamine tseleng ea moputso / khothatso (Fuentealba et al., 2006; Fuentealba et al., 2007) le tšebeliso ea li-psychostimulants (Wee et al., 2009). Fuentealba et al. (2007) e bonts'itse kamora ho qeta matsatsi a mane a laisa U69593, agonist ea KOR, e eketsang tlhahiso ea dopamine ho NAc. Haufinyane, ho bontšitsoe hore ho thibela KORs ho khutlisetsa liphetoho phetohong ea dopamine le ho ts'oara ho dorsal striatum e etsahalang nakong ea maikutlo a locomotor a hlohlellelitsoeng ke amphetamine (Azocar et al., 2019). Ka kakaretso, datha tsena li fana ka maikutlo a hore ts'ebetso ea KORs le eona e ka kenya letsoho ho matlafatsang thepa ea lithethefatsi tsa tlhekefetso (Chartoff et al., 2016).

Ntle le moo, ts'ebetso ea KORs e boetse e bonahala e kenya letsoho ho qobelloang ho batla lithethefatsi; KORs blockade e fokotsa koae (Wee et al., 2009), heroin (Schlosburg et al., 2013) le methamphetamine (Whitfield et al., 2015ho ja likhoto tse nang le phihlello e sa lekanyetsoang ea lithethefatsi (Wee et al, 2009). Tšusumetso ena e boetse e bonahala ponong ea lithethefatsi tse susumetsang khatello ea maikutlo. Mohlala, litoeba tsa KOR tsa ho kokota ha li a ka tsa bontša khetho ea sebaka sa koae ka mor'a khatello ea kelello ea ho sesa (McLaughlin et al., 2006a). Ho thibeloa ha KORs ho bonts'a sebaka se ikhethileng sa sebaka seo motho a bang le takatso ea sona ka lebaka la ho pepeseha ha a ts'oenyeha (Smith le al., 2012). Ho khahlisang, ho thibeloa ha KOR ho bonts'a koae le nicotine e batlang e ts'oaroang ke khatello ea maikutlo empa ha e ame ho batla ho susumetsoang ke phephetso ea lithethefatsi (Beardsley et al., 2005; Jackson et al., 2013). Ts'ebetso ena ea morupeli ea KOR e susumetsoang ke khatello ea maikutlo e bonahala e kopantsoe ke moputso / khothatso ea potoloho (Shippenberg et al., 2007; Wee le Koob, 2010). Phuputsong e ntle e entsoeng ke Dr. Kauer le sehlopha sa hae, ho ile ha bontšoa hore ho thibela KORs ho VTA, ebang ke nakong e fetileng kapa kamora khatello ea maikutlo, ho thibela ts'ebetso ea ho batla koae, phello e amanang le pholoso ea nako e telele- potentiation of inhibitory synapses in dopamine neurons (Graziane et al., 2013; Polter et al., 2014).

Ho tataisoa ha li-psychostimulants tse hlokoang ke KORs ho bonahala ho ipapisitse le fensetere ea nako malebana le ho pepesetsoa ha lithethefatsi. Tsamaiso ea KOR agonist U50488 1 h pele ho pepesetsoa koae e ka hlahisa khetho ea sebaka sa cocaine le tokollo ea dopamine e ts'oeroeng e ts'oeroe ke cocaine ho NAc, athe litlamorao tse fapaneng li bonoa ha li fuoa metsotso e 15 pele ho moo (McLaughlin et al., 2006a; Ehrich et al., 2014). E sebelisa ho ikhatholla ho intracranial Chartoff et al. (2016) o hlokometse hore setsebi sa kelello sa KOR Salvinorin A, se na le tšekamelo ea morao-rao ea ho khopamisa le ho lieha ho tlisa moputso, se tsamaeang le ho fokotseha le keketseho ea tlhahiso ea dopamine e matla ho NAc, ka ho latellana. Lintlha tsena kaofela hammoho li bonts'a phello ea nako ea ts'ebetso ea KOR ho thepa e ruisang ea koae, 'me e supa ts'ebetsong ea KOR ea khatello ea maikutlo e le sebapali sa mantlha sa nts'etsopele ea ho batla lithethefatsi ka mokhoa o qobelloang.

Quinpirole-E susumetsoa ke Boitšoaro ba Boitšoaro le Boitšoaro bo Qobellang

Linnete tsa hore ts'ebetso ea dopamine e kentse letsoho molatong oa maikutlo le ts'usumetso e matlafatsoa ke boits'oaro bo bonoang litšoantšong tse phekotsoeng le agonist ea D2R, quinpirole. Ka bokhutšoanyane, li-D2R ke li-receptors tsa Gi tse kopantsoeng ka ho pharaletseng tse boletsoeng ka mokhoa oa potoloho / khothatso; li hlahisoa ka mokhoa o ikhethang le litulong tsa axon tsa dopamine neurons (Sesack et al., 1994), mme ts'ebetso ea eona e fokotse maemo a dopamine extracellular (Imperato le Di Chiara, 1988). Boemong ba striatum, li-D2R li boetse li fumaneha li-postynaptical ho li-spiny neurons tse mahareng (Sesack et al., 1994) mme ts'ebetso ea eona e thibela tsela e sa tobang e lumellang ts'ebetso ea locomotor.

Dr. Henry Szechtman o qalile ho ithuta ka litlamorao tsa quinpirole ka boits'oaro ba likhoto tse qetellang lilemo tse leshome tsa 1980. Liphuputso tsa bona tsa pele li bonts'itse hore taolo e matla ea quinpirole e na le phello e itšetlehileng ka tekanyetso mesebetsing ea locomotor. Ka litekanyo tse tlase (0.03 mg / kg) e fokotsa ts'ebetso ea locomotor, ha e le litekong tse phahameng (> 0.5 mg / kg), e ea eketseha. (Eilam le Szechtman, 1989). Litla-morao tsena li amana le ts'ebetso ea li-D2R tse amanang le tšebetso e phahameng le litokelo tsa batho ba maemo a tlase tse amanang,Usiello et al., 2000). Ka tšohanyetso, tsamaiso e pheta-phetoang (letsatsi le leng le le leng) ea quinpirole e etsa keketseho e tsoelang pele le e tsitsitseng ea pherekano, e ts'oanang le maikutlo a locomotor a susumetsoang ke psychostimulants (Szechtman et al., 1993; Szechtman et al., 1994). The sensomotor sensitizing athari e ile ea bontšoa ho latela li-D2R, hobane khaello ea litoeba bakeng sa sebui sena ha e ntlafatse maikutlo a locomotor ho quinpirole (Escobar et al., 2015).

Mathoasong a lilemo tsa bo-90, Szechtman le Eilam ba tlalehile hore hammoho le ts'ehetso ea locomotor, likhoto li ile tsa ba le boits'oaro bo matlafatsang, bo matlafatsoang le tsamaiso e ngoe le e ngoe ea quinpirole (Eilam le Szechtman, 1989; Szechtman et al., 1993). Kajeno, tsamaiso ea quinpirole e pheta-phetoang ke mohlala o netefalitsoeng bakeng sa OCD (Szechtman et al., 1999; Szechtman et al., 2001; Eilam le Szechtman, 2005; Stuchlik et al., 2016; Szechtman et al., 2017), ho ipapisitse le tlhokomeliso ea hore boitšoaro ba litoeba bo fetoha bo hlophisehileng haholo ebile bo sa fetohe, bo hopotsa moetlo oa moetlo o bonts'ang boitšoaro bo potlakileng ba ho hlahloba (Szechtman et al., 1998; Szechtman et al., 2017). Boithuto ba morao-rao bo bonts'a hore quinpirole e pheta-phetoang e boetse e kenya boits'oaro bo phehellang ho litoeba, joalo ka ho hlahloba ka ho qobella (Letsatsi le al., 2019), boits'oaro bo bobebe bo tloaelo le ho hlafuna bo qobelloang (Asaoka et al., 2019), e khutliselitsoeng morao-rao ke D2Rs blockade ho striatum, e ts'ehetsa ka ho eketsehileng hore ts'ebetso e phehellang ea D2R e hlokahala ho susumetsa boits'oaro bo hatellang. Ka bobeli data e supa karolo ea bohlokoa ea li-D2R kahare ho litsela tse bohareng ba dopamine ho kenya ts'usumetso ea maikutlo le ts'usumetso. Tsamaiso e phetoang ea quinpirole e phetoang khafetsa (cocaine-ikiwa)Thompson et al., 2010) le litlamorao tsa phello ea amphetamine (Cope et al., 2010), ho matlafatsa mohopolo oa hore ts'ebetso ea D2Rs e tlasa ts'usumetso ea maikutlo le ho fana ka maikutlo mabapi le ts'ebetso e arolelanoang lipakeng tsa quinpirole le psychostimulants-induct sensitization. Ho khahlisang, phello e khahlisang ea ts'ebetso e phetoang ea D2R e bonahala e le matla ho feta e khothalletsoang ke psychostimulants, hobane rat e 'ngoe le e' ngoe e tšoaroang ka quinpirole e ntšefatsa sensomization ea locomotor (Escobar et al., 2015), ha liperesente tse mashome a tšeletseng tsa likhoto li khothaletsa amphetamine (Escobar et al., 2012; Casanova et al., 2013).

Boikutlo bo mabapi le boitšoaro bo susumetsoang ke ts'ebetso e phetoang ea li-D2R li tsamaisana le liphetoho maemong a moputso / khothatso. Likhohla tse anngoeng ka quinpirole li na le molumo o tlaase oa dopaminergic ho NAc, e bonoang e le basal e fokotsehileng (Koeltzow et al., 2003) le tokollo ea dopamine ea tonic le phasicEscobar et al., 2015), ho bonts'a ho fokotseha ha dopamine ho lokolla bokhoni ba potoloho ea dopamine midbrain. Maemo a dopamine a Synaptic dopamine ho NAc a laoloa ke ts'ebetso ea mesebetsi ea bobeli, ea DAT le ea dopamine (Goto le Mohau, 2008), e Ka vivo e na le ho thunya tonic le ho phatloha ho hoholo (Wilson et al., 1977; Mohau le Bunney, 1980). Litlaleho tsa pejana li bontša hore likhoto tsa "quinpirole-sensitised" li bontša palo e nyane ea li-neurone tsa dopamine ka tonic mme e phatloha ho thunya ho VTA (Sesia et al., 2013). Hajoale lintlha tsena li bontša hore ho fokotseha ha tokollo ea dopamine ho bonoang ka mor'a kutloisiso ea quinpirole ke phello ea ho fokotseha hoa ts'ebetso e akaretsang ea li-neuron tsa dopamine. Boitšoaro bo qobellang le ts'ebetso ea sensomotor e susumetsoang ke kalafo e phetoang ka quinpirole e ka ba sesosa sa maikutlo a li-D2R, ka lebaka la phokotso ea lentsoe la dopaminergic ho NAc. Ka sebele, likhoto tse nang le maikutlo a quinpirole li bonts'a ho eketseha ha dopamine D2R (Culver et al., 2008) le keketseho ea boemo ba tumellano ba li-receptor tsena (Perreault et al., 2007), ho tšehetsa khopolo ena.

Tšebelisano ea KOR-Dopamine ho Quinpirole-E Behantsoe ke Behaviors

Boithuto ba pele mabapi le karolo ea KOR ho boits'oaro bo susumetsoang ke D2R le bona bo tsoa labong ea Szechtman. Sehlopha sena se hlahlobile tsamaiso e lumellanang ea KOR agonist U69593 le quinpirole mabapi le ts'ebetso ea locomotor. Ka ho khetheha, bangoli ba ne ba fana ka liente tse ka tlasa letlalo ho likhoto tse nang le motsoako oa U69593 le quinpirole, ho fihlela liente tsa 8 ho isa ho 10 li phethetsoe. Ho fapana le phello ea hypolocomotor ea U69593 feela, hyperlocomotion e ile ea bonoa ha e tsamaisoa ka nako e le 'ngoe le litekanyo tse tlase tsa (presynaptic) le tse phahameng (postsynaptic) tsa quinpirole. U69593 e fetotse phello ea hypolocomotor ea tekanyetso ea presynaptic ea quinpirole ho ea ho hyperlocomotion mme ea ntlafatsa phello ea hyperlocomotor ea leqhubu la postynaptic la quinpirole (Perreault et al., 2006). Co-activation of KORs e boetse e potlakisitse ho kenngoa ha sensomotor sensitization mme e bile le phello ea ts'ebetso ea D2Rs, kaha pherekano e kholo e fihletsoeng ke kalafo e habeli e pheta sephetho sa locomotor se hlahisoang ke quinpirole feela (Perreault et al., 2006; Escobar et al., 2017). Co-activation of KORs e boetse e potlakisa ho fumana boitshwaro bo tlamang ba ho hlahloba (Perreault et al., 2007). Litlamorao tsena tse ka 'nang tsa baka tsa KOR ho boits'oaro bo phehellang ba quinpirole li hloka tšebetso e pheta-phetoang ea KOR. Ebile, ente ea acute ea KOR agonist U69593 ha e-ea ka ea ntlafatsa mosebetsi oa locomotor ka likhoto tse utluoang ka quinpirole (Escobar et al., 2017). Ha ho tsejoe hore na mochine oa mofuta oa KOR o susumetsang oa D2R. Monyetla o mong ke hore tsamaiso ea kappa opioid ka boeona e hokahanya sensitization e thehiloeng ho D2R. Leha ho le joalo, monyetla ona o ile oa lahloa ka ho bonts'a hore pele ho taolo ea NorBNI ha e fetole maikutlo a locomotor ho quinpirole, ho fana ka maikutlo a hore dynorphin ha e lokolloe ts'ebetsong ea ts'ebetso ea D2R (Escobar et al., 2017). Tlhahiso-leseling ena ha e fane ka qeto ea hore dynorphin e ka ba le karolo ea ho susumetsa boits'oaro bo khothalletsang, mohlala, khatello e etsa hore ho lokolloe ha dynorphin le ts'ebetso ea li-KOR tse tataisang boitšoaro bo hatelletseng (McLaughlin et al., 2003; McLaughlin et al., 2006a; McLaughlin et al., 2006b).

Crosstalk pakeng tsa D2Rs le KOR li rarahane mme ho bonahala ho latela hore na ts'ebetso ea li-receptor ka bobeli e kopane kapa e arohane ka nakoana. Lintlha tsa anatomical li bonts'a hore crosstalk pakeng tsa D2R le KOR li ka hlaha ka mokhoa o ikhethileng ka li-axon le soma ea dopamine neurons, hammoho le li-postynaptically ho li-MSN tsa striatum. Le ha e sa ahlole karolo bakeng sa li-KOR tse fumanehang litsing tsa methapo e meng ea methapo, tlhaiso-leseling ea anatomical e supa karolo e tobileng ea li-KOR tse laolang li-D2R. Ebang ke a hlobaetsang kapa a pheta-phetoang, ts'ebetso ea li-KOR e fokotsa mosebetsi oa inhibitory D2Rs ho dopamine neurons. Boithuto ba electrophysiology bo bonts'itse hore ts'ebetso e matla ea KOR ho dopamine neurons ea VTA le SN inhibits D2R-Mediated inhibitory postsynaptic current, athari e kenelletsoeng ke mekhoa ea pele le ea postynaptic ha KOR e fokotsa ho lokolloa ha dopamine mme dynorphin e thibela phello ea thibelo ea dopamine (Ford et al., 2007). Lithuto tsa Neurochemical li bonts'itse hore ts'ebetso e pheta-phetoang ea li-KORs e thibela D2R-e kenyelitsoeng inhibition ea dopamine ho lokolloa ho NAc (Fuentealba et al., 2006). Ho feta moo, li-D2R tse kopanetsoeng le ts'ebetso e matla ea KORs e fokotsa thibelo ea tokollo ea dopamine ho NAc ha e bapisoa le phello ea li-receptor ka 'ngoe (Escobar et al., 2017). Ka hona, li-KORs tsa presynaptic ha li sebetse ka mokhoa o fetelletseng kapa tumellanong le li-D2R tsa presynaptic, ka lehlakoreng le leng, li-KORs e ka thibela kapa occlude D2R inhibitory. Mochine ona o ka hlalosa phello ea activomotor ea lethal e matla la li-agorists tsa KOR tse tšoanang le lethalinyana le tlaase la quinpirole (Perreault et al., 2006).

Phuputso ea morao-rao e bonts'a hore ts'ebetso ea KOR ho VTA e buisana le boits'oaro bo khothalletsoang joalo ka boits'oaro bo thibelang boits'oaro le ho patoa hoa 'mabole (Abraham et al., 2017), e tiisa mohopolo oa hore ts'ebetso ea KOR ke ts'usumetso ea ts'usumetso. Lintlha tse phatlalalitsoeng ke Margolis le ba bang. (2006; 2008) e bonts'a hore ho sebelisana ha KORs le D2Rs ho lokela ho etsahala ho li-dopamine neuron tse lebisang mPFC (Margolis et al., 2006; Margolis et al., 2008). Leha ho le joalo Ford et al. (2006; 2007) e fumane hore thibelo ea KORs ea D2R e tsamaellanang le IPSC e etsahala ho li-dopamine neurons tse lebisang NAc (Ford et al., 2006; Ford et al., 2007). Ka bobeli lintlha tsena li bonts'a hore tšebelisano ea KOR le D2R sebakeng sa somatodendritic compact ea dopamine neurons li ka hlaha ka lebaka la crosstalk ho "dopamine neuron" e le 'ngoe. Hore na sena se etsahala mecheng ea mesolimbic kapa mesocortical e ntse e le phehisano.

Ho makatsang ke hore KOR e fumanoe ho li-MSN tsa NAc (Escobar et al., 2017; Tejeda et al., 2017), ka tsela eo e bonts'a hore bokhoni ba ts'ebetso e qobelloang ea D2R bo khothalletsoang bo ka hlaha hape ka liketso tse tobileng liseleng tse tobileng tsa dopamine neurons. Mabapi le sena, ho loketse ho bolela hore taolo e pheta-phetoang ea U69593 e eketsa palo ea D2R maemong a phahameng a kopanetsoeng (Perreault et al., 2007). Lintlha tsa Neurochemical li bontša hore litekanyetso tse fokotsehileng tsa dopamine li amana le sensitization ea D2R. Co-activation ea KOR ha e fokotsehe ho ea pele maemo a dopamine a extracellular a NAc a seng a fokotsehile ke ts'ebetso e phetoang ea li-D2R (Escobar et al., 2017), ho ahlola karolo bakeng sa Preservaptic KOR ho potlakisa kapa ho eketsang maikutlo a D2R ho NAc ka mochine ona. Ka hona, li-KOR li etsa hore lietsahala tsa limolek'hule li liehe ho bonts'a litlamorao le boits'oaro ba D2R, a fana ka maikutlo a hore ntlafatso ea maikutlo a ts'oaro e ka ba ka lebaka la adaptynaptic e tsitsitseng eseng phello ea Presynaptic. Mabapi le sena ts'ebetso e phetoang ea KORs e ka baka tšitiso ea D2R e sa tsamaeng ka kotloloho tseleng ea D1R / D2R ho fihlela D1R e hlohlelletsa ho qobella (Setšoantšo sa 1).

Pharologanyo ya thobalano ya tirisanommogo ya KOR-Dopamine mo mebeleng e e Amoanang

Lithuto tsa kliniki li bonts'itse phapang ea thobalano ka boits'oaro bo qobelloang ho kenyelletsa ho batla lithethefatsi ka mokhoa o tlamang. Ho qala hoa matšoao a OCD ho bonoa ho banna ha ho bapisoa le basali (Mathis et al., 2011), le basali ba bonts'a tšoaetso e ngata ea tšoaetso le matšoao a ho hloekisa (Labad et al., 2008). Mabapi le phapang ea thobalano bokhobeng ba lithethefatsi, bopaki ba tleliniki bo bontša hore le ha tšebeliso ea lithethefatsi e atile haholo ho banna, basali ba bontša tsoelo-pele e potlakileng ho feta ea banna ho batleng lithethefatsi tse tlamang (Hernandez-Avila et al., 2004; Fattore le Melis, 2016).

Haufinyane, bopaki ba pele ho tleliniki bo totobalitse ka matla motheo oa neurobiological o tšehetsang phapang ea thobalano ea tlhekefetso ea lithethefatsi e hlokometsoeng lithutong tsa kliniki (Becker le Chartoff, 2019). Tlhokomeliso ea pejana e sebelisang "non-net flux micodialysis" e bonts'itse hore khatello ea dopamine extracellular ka har'a dorsal striatum e fapana nakong ea potoloho ea estrous ka maemo a holimo ho proestrus le estrus ha e bapisoa le diestrus. Ho feta moo, le ha ovariectomy e fokotseha litšoelesa tsa litšoelesa tse tsoang ho likhoto tsa basali, ho liheloa ha litoeba tse tona ha ho fetole mahlahana a dopamine striatal extracellular concentration (Xiao le Becker, 1994), ho fana ka maikutlo a karolo ea bohlokoa ea lihormone tsa mahe ka tšebetso ea dopamine. Ntle le moo, lihormone tsa basali li laola karabelo ho li-psychostimulants. Pele a vitro liteko li bontšitse hore estradiol le progesterone e khutlisa tokollo ea dopamine e amphetamine e tsoang litoneng tsa striatal tse fumanoeng ke likhoto tsa basali tse ovariectomised (Becker le Ramirez, 1981). Haufinyane tjena, lithuto tsa li-cyclic voltammetry tse potlakileng li bontšitse hore basali ba bonts'a ho lokolla le ho phahamisa motlakase ho feta bapisoa le ba batona (Walker et al., 2000). Liphapang tsena tsa botona le botšehali tsa dopamine neurotransication li ka ikarabella bakeng sa cocaine e phahameng le e batloang ke amphetamine e bonoang ho basali. (Roberts le al., 1989; Cox et al., 2013).

Taolo ea KOR maemong a dopamine extracellular le eona e bonts'a phapang ea thobalano (Chartoff le Mavrikaki, 2015). Ho sebelisa ho intlafatsa ho intlafatsa le cytlic voltammetry, Conway et al. (2019) e bontšitse hore kutloisiso e tlase ea phello e matla ea anhedonic ea setsebi sa kelello sa KOR se bonoang litekong tsa basali ha se bapisoa le likhoto tsa banna, se tsamaisana le thibelo e tlatsitsoeng ea tokollo ea dopamine e matlafalitsoeng ho NAc (Conway et al., 2019). Ho 'nile ha fanoa ka maikutlo a hore estradiol e kenya letsoho ho thibelo e sa nepahalang ea tokollo ea dopamine e hlokometsoeng ho likhoto tsa basali ka mor'a ts'ebetso ea KOR (Abraham et al., 2018). Ha crosstalk pakeng tsa KORs le dopamine signaling e ithutile ho ba batona (Tejeda le Bonci, 2019), patlisiso mabapi le tšebelisano ena le phello ea eona ts'ebetsong ea bokhoba ba basali e ea fokola (Chartoff le Mavrikaki, 2015). Ho litoeba tsa basali, tsamaiso e matla ea "KOR agonist U69593" e sebelisitse hyperlocomotion ea koae ka bobeli, taolo le litoeba tsa ovariectomized. Ho khahlisang, tsamaiso e pheta-phetoang ea U69593 e ile ea fumana hyperlocomotion e sebelisang koae ka mokhoa o itšetlehileng ka estradiolPuig-Ramos et al., 2008). Lintlha tsena li fana ka maikutlo a hore estradiol e proka liketso tsa KOR lipapaling tsa basali, phello e ka amanang le phapang ea thobalano karabong ea khatello ea maikutlo (Puig-Ramos et al., 2008). Hore na litekatsong tsa basali ts'ebetso e pheta-phetoang ea KOR e thusa ho lokolloa ha dopamine joalokaha ho bonoe ho monna ke potso e sa arabeloang.

Le ha tlhahiso-leseling ho lokollotsoeng ha dopamine ea psychostimulant e bonoa ho basali ha e bapisoa le likhoto tsa banna, liphapang tse amanang le thobalano litekanyetsong tsa dopamine tse ka tlasa sensorization ea amphetamine ha li so hlakisoe ka botlalo (Becker, 1999). Ho pepesetsoa khafetsa ka amphetamine ho etsa hore ho be le ts'ebetso e kholo ho bona ka bobeli, (Mathews le McCormick, 2007) le likhoto tsa basali ba baholo (Media-Hallé et al., 2007), le likhoto tsa lilemong tsa bocha tsa basali tse bonts'ang maikutlo a matla a maholo ka mora ho pepesetsoa khafetsa ho amphetamine. Ho kenella ka neonatal activation ea D2 receptor ho hlahisitse tšusumetso ea boitšoaro ea amphetamine ho litoeba tsa basali (Brown et al., 2011). Joalokaha ho se ho boletsoe pejana, ho hlokometsoe ho litekete tsa banna ho pepesetsoa khafetsa ho D2 agonist induces locomization sensitization le boits'oaro bo qobelloang (Dvorkin et al., 2006). Ho feta moo, ts'ebelisano 'moho ea KOR e susumetsa maikutlo a locomotor a susumetsoang ke ho pepesehela khafetsa quinpirole, e nolofalletsang taolo ea thibelo ea li-receptors tsa D2 tokollong ea DA ho NAc (Escobar et al., 2017). Liphapang tse amanang le thobalano joalo ka maikutlo a tlase a bonoang ho phello ea inhibitory ea KOR tokollong ea dopamine ho basali (Conway et al., 2019) e kanna ea ikarabella bakeng sa monehelo o fapaneng oa KOR ho batla lithethefatsi ka matla.

Nahanisisa

KORs e fetolela dopamine e bontšang ho ntlafatsa boits'oaro bo botle joang, hona ho fella ka boitšoaro bo qobelloang neng? Lintlha tsa anatomical li bonts'a hore li-KOR li boemong ba ho laola ts'ebetso ea synaptic ea methapo ea kutlo ea midbrain dopamine. Lintlha tsa ts'ebetso li bonts'a hore KORs e laola DAT le D2R e sebetsang le sekhahla sa ho thunya ha dopamine. Bopaki ba pele bo bonts'ang hore ts'ebetso e matla ea KORs e fokotseha ho lokolloa ha dopamine e khothalletsoang ke lithethefatsi tsa tlhekefetso e tlatselitsoe le data e bonts'ang hore ts'ebetso e phetoang ea KOR e thusa ho lokolloa ha dopamine le ho ts'oara lithethefatsi tse tlamang. Dopamine e bonts'a lits'ebetso tse tsoang ka kotloloho le tse sa tobang tse tsoang libakeng tse thobang (Setšoantšo sa 1A). Ho ba le tšusumetso e sa feleng le li-psychostimulants tse eketsang tokollo ea dopamine e sebetsang ka bobeli D1R le D2R (Setšoantšo sa 1B) kapa quinpirole e sebetsang feela D2R (Setšoantšo sa 1C) e fella ka maikutlo a locomotor le boits'oaro bo qobelloang ke tsela e sa tsamaeang ea D2R e sa tsamaiseng tsela, 'me ka tsela eo e fetole tekanyo tseleng e e tsamaisang ea D1R. Ho fetisoa ha KOR ho matlafatsoa nakong ea ho ja ka nako e sa lekanyetsoang ke psychostimulant ka ho eketseha ha dynorphin ho methapo ea methapo ea methapo ea D1 (Setšoantšo sa 1B). Phetoho e ntlafalitsoeng ea KOR e etsisoa mohlaleng oa pharmacological oa OCD ka ho tsamaisa U69593. Ts'ebetso ena e kopaneng ea KOR e mpefatsa tsela e sa tsamaeang ea D2 (Setšoantšo sa 1C). Patlisiso ea nako e tlang e lokela ho etsoa ho hlakisa litlamorao tsa ts'ebetso ea KOR ts'ebetsong ea DAT, ho utloisisa karolo ea endorgeous KOR system ho quinpirole e kenyellelitsoeng ho hatella le ho tseba hore na monehelo oa tsamaiso ea KOR ho tsa thobalano e boneng ka boits'oaro bo qobelloang.

Menehelo ea Mongoli

AE, MA, le JF ba ile ba kenya letsoho molemong oa taba e ngotsoeng e ngotsoeng. AE le JF ba ngotse moralo oa pele oa buka e ngotsoeng ka letsoho ka tlhahiso e tsoang ho MA. MA le JC ba kentse letsoho tlhahlobisong le phetolelong e kholo ea buka e ngotsoeng ka letsoho. Bangoli bohle ba e amohetse hore e phatlalatsoe.

dithuso tsa ditjhelete

Mosebetsi oa bangoli ba boletsoeng tlhahlobisong ena o tšehelitsoe ke linomoro tsa liphallelo tsa FONDECYT: 1110352 le 1150200 ho MA; 1141088 ho JF; DIPOG fana ka 391340281 ho JF; FONDECYT Postdoctoralellow 3170497 ho JC le 3190843 ho AE.

Khohlano ea Thahasello

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

Moqapi o tsamaisang o ntse a hlophisa sehlooho sa lipatlisiso le e mong oa bangoli JF, mme o tiisa ho ba sieo ha tšebelisano e 'ngoe.

References