Kappa-Opioid Receptor Signaling ka Striatum e le monyetla Modulator ea Dopamine Transmission ho Cocaine Ho itšetleha ka (2013)

Ho lemalla koae ho tsamaisana le ho fokotseha ha matšoao a dopamine a dopamine, a lekantsoeng ka ho fokotseha ha dopamine D2 receptor e tlamang hammoho le tokollo ea dopamine e tlotsitsoeng ka har'a striatum. Liphetoho tsena phetisong ea dopamine li na le bohlokoa ba bongaka, 'me ho bonts'itsoe hore li lumellana le boitšoaro bo batlang koae le ho ts'oara kalafo bakeng sa ts'ebeliso ea koae. Leha ho le joalo, mekhoa e kenyang letsoho ho hypodopaminergic state ho lemaletseng koae e ntse e sa tsejoe. Mona re lekola lithuto tsa ho nahana ka positron emission tomography (PET) tse bonts'ang liphetoho tse teng ho phetiso ea D2 receptor e tlamang le phetisetso ea dopamine ho batho ba hlekefetsang koae. Ho ipapisitsoe le lithuto tsa liphoofolo le tsa batho, re fana ka tlhahiso ea hore mokhoa oa kappa receptor / dynorphin, ka lebaka la ts'usumetso ea phetiso ea dopamine le ho nyoloha ka mor'a ho pepesetsoa koae, e ka ba le seabo ho boemo ba hypodopaminergic bo tlalehiloeng ts'ebelisong ea koae, ka hona e ka ba sepheo se nepahetseng bakeng sa kalafo. ntshetsopele.

Melao-motheo ea PET imaging

Positron emission tomography (PET) e lumella monahano oa neurochemistry o amanang le tšebeliso ea lithethefatsi le joala bokong ba motho. Mokhoa ona oa ho nahana o sebelisa li-ligand tsa radionuclide tse ngotsoeng ho e amohelang e itseng, 'me li-radioligands li sebelisoa hangata khafetsa patlisisong ea bokhoba ba joala li-receptor tsa dopamine. Li-radiotracers tse reng mofuta oa lelapa la dopamine 2 (li bitsoa D2) le tsona li ka sebelisoa ho lekanya liphetoho ho dopamine ea extracellular. Sena se etsoa ka ho nahana ka li-radiotracers tse amehileng ka liphetoho dopamine ea extracellular, le ho fumana likheo pele le kamora tsamaiso ea psychostimulant (joalo ka amphetamine kapa methylphenidate). Lintho tsena tse khothatsang li eketsa li-dopamine tsa extracellular dopamine, tse hlahisang phokotso ea li-receptor tsa dopamine tse fumanehang ho tlama ho radiotracer, e bontsitsoeng ho Setšoantšo. Figure1.1. Bakeng sa mabaka a sa utloisisoeng ka botlalo, mokhoa ona o ka sebelisoa le li-radiotracers tse ngata tsa D2 empa eseng ka li-radiotracers tse tlama ho D1 receptor. Kahoo, liphuputso tse nahannoeng tse sebelisang li-radiotracers tsa D2 receptor (joalo ka [11C] raclopride kapa [18F] fallypride) li ka sebelisoa ho lekanya liphetoho ho dopamine ea morao, athe li-radiotracers tse thathamisang receptor ea D1 (joalo ka [11C] NNC112 kapa [11C]SCH23390) ha e khone (Abi-Dargham et al., 1999; Chou et al., 1999; Laruelle, 2000; Martinez le Narendran, 2010).

 

Setšoantšo sa 1

PET e hlahloba taolong e phetseng hantle le thuto e itšetlehileng ka koae. Papiso ea li-panels tse holimo (tsamaiso ea pele le ea post-amphetamine) taolong e phetseng hantle e bonts'a hore binding ea radiotracer ([11C] raclopride) e fokotsehile ho striatum e latelang amphetamine. ...

Tekanyo ea sephetho sa mantlha lithutong tsa ho nahana ka radioligand ke li-receptor tse tlamang ho radiotracer, e bitsoang BPND, e hlalositsoeng e le karo-karolelano ea ho tlangoa ka mokhoa o sa tobang (Innis et al., 2007). Phetoho ea dopamine ea extracellular dopamine e hlahisoang ke tsamaiso e matlafatsang e lekantsoe ka ho bapisa basp ea BPND (tsamaiso ea tšusumetso ea pele) le BPND kamora tse khothalletsang. Sena se sebelisetsoa ho fumana phetoho ea liperesente ho BPND, kapa ΔBPND, e hlalositsoeng e le [(BPNDbaseline - BPNDchallenge) / BPNDbaseline]. Boithuto bo fetileng ho li-primates tseo eseng tsa batho bo bonts'itse hore ΔBPND e lumellana hantle le liphetoho ho dopamine ea extracellular, e lekantsoeng ka micodialysis (Breier et al., 1997; Endres et al., 1997; Laruelle et al., 1997). Ka hona, ΔBPND e fana ka tekanyo e sa tobang ea ho lokolloa ha dopamine e tsoibilisang motho ka mong, 'me e ka sebelisoa ho tšoaea liphetoho tse teng ponong ea dopamine e etsahalang ho itšetlehileng ka koae.

PET ea ho nahana ka li-receptor tsa dopamine ho lemaletseng koae

Ho fihla joale, lithuto tse tšeletseng li se li entsoe ka ho nahana ka receptor ea D2 ho batho ba hlekefetsang koae, 'me tsena li lula li bontša ho fokotseha ha litlamo ho bapisoa le taolo e tsamaeang le (Volkow et al., 1990, 1993, 1997; Martinez et al., 2004, 2009a, 2011). Phokotso e batla e le 15-20% mme e etsahala kahare le ka har'a dorsal striatum. Habohlokoa, liphoofolo tse nang le maemo a tlase a D2 receptor ka har'a striatum, pele ho ts'oaetso ea lithethefatsi, li bontša boits'oaro bo boholo ba ho sebelisa koae (Morgan et al., 2002; Czoty et al., 2004;; Nader le al., 2006;; Dalley le al., 2007). Liphuputso tse entsoeng bathong li bonts'a hore li-receptor tse tlase tsa D2 tse tlamang ho tlhekefetso ea koae ka har'a striatum e ikamahanya le ho fokotseha ha metabolism ea tsoekere ho orbito-frontal cortex le cingulate gyrus, e sebetsang le ho ama, mme e ka lebisa ho tsoeleng pele ho ts'ebelisong le lithethefatsi (Volkow) et al., 1993, 1999). Bangoli ba 'maloa ba hlahisitse tlhahiso ea hore liphetoho tse tlisoang ke D2 receptor ha li lemalla li ka supa tlokotsi ea boits'oaro ba lithethefatsi, joalo ka ho hloka taolo ea kelello kapa ho eketseha ha khatello (Everitt et al., 2008;; Dalley le al., 2011; Groman le Jentsch, 2012).

Phuputso e le 'ngoe ea PET e lekantseng D1 receptor e tlamang tlhekefetsong ea koae (Martinez et al., 2009b). Boithuto bona bo bonts'itse phapang ea li-receptor tsa D1 tse tlamang ho batho ba hlekefetsang koae ha ba bapisoa le taolo, e lumellanang le thuto ea post-mortem ea striatal D1 receptor mRNA (Meador-Woodruff et al., 1993). Leha ho le joalo, tlhahlobo ea lipatlisiso e boetse e bonts'a hore, ka har'a lithuto tse itšetlehileng ka koae, ho amohela li-D1 receptor tse tlase ho "ventral striatum" ho ne ho amana le likhetho tse kholo tsa ho sebelisa k'hok'heine. Kahoo, ho fumana hona ho ka emela mofuta oa phenotype oo li-receptor tse tlase tsa D1 tse kopantsoeng le limbic striatum li amanang le ho ba kotsing e kholo ea litlamorao tse matla tsa koae. Sena se lumellana le lithuto tsa pharmacologic ho batho tse bonts'ang hore ho ts'oaroa ha li-receptor tsa D1 ho fokotsa, athe blockade ea D1 receptor e matlafatsa, litlamorao tse matlafatsang tsa koae (Haney et al., 1999, 2001). Ha li kopantsoe hammoho, liphuputso tsena li bonts'a hore ho fokotseha ha lets'oao le fumanoeng D1 receptor ho ka amahanngoa le boits'oaro bo eketsehileng ba ho ts'oara koae.

PET imaging dopamine e lokolloa ho batho ba hlekefetsang koae

Boithuto bo mabapi le ho lekanya tlhahiso ea dopamine ea pre-synaptic dopamine e bontša hore ho itšetleha ka koae ho amana le phokotso ea karabelo ea ts'ebetso ea dopamine ho phephetso e matlafatsang. Mohlala, ho baithaopi ba phetseng hantle ba batho, tsamaiso ea psychostimulant e hlahisa phokotseho ea [11C] raclopride binding (ΔBPND) ea 15-20% (Volkow et al., 1994; Drevets et al., 2001; Martinez et al., 2003; Munro et al., 2006), empa ho batho ba hlekefetsang koae ka koae ho fokotseha hoa tlamo ea [11C] ea raclopride ho tlatsitsoe haholo (Volkow et al., 1997; Malison et al., 1999; Martinez et al., 2007b, 2011). Kahoo, lithuto tse 'nè li bontšitse hore ho itšetleha ka koae ho kopantsoe le ho fokotseha hoa sebaka sa [11C] raclopride ho latela ts'ebetso e susumetsang ha ho bapisoa le taolo e phetseng hantle, e emelang phokotso ea tokollo ea dopamine ea pre-synaptic. Lithuto tsa ho nahana ka PET li boetse li bonts'a hore tlhekefetso ea koae e amahanngoa le bobeli bo fokotsehileng [18F] DOPA uptake le striatal vesicular monoamine transporter 2 binding, e fanang ka mehato ea mabenkele a pre-synaptic dopamine (Wu et al., 1997; Narendran et al., 2012).

Ntle le phokotso ea tokollo ea dopamine e susumetsang, maikutlo a PET a boetse a bonts'a hore maemo a dopamine maemong a phomolo (ntle le ts'ebetso efe kapa efe ea ts'usumetso) a fokotsehile ho ts'ehetso ea koae. Sena se etsoa ke ho nahana ka li-receptor tsa D2 pele le kamora ho fela ha dopamine ea morao-rao e sebelisang alpha-methyl-para-tyrosine (AMPT). Kahoo, ho nahanisisa ka mor'a ts'ebetso ea tsamaiso ea AMPT ho fella ka keketseho ea li-binding tsa [11C] tsa raclopride, ho fapana le ho fokotseha ho bonoang kamora taolo e susumetsang (Martinez et al., 2009a). Tsamaiso ea AMPT e felletse ka keketseho ea 11.1 ± 4.4% ho [11C] raclopride e tlamang ho striatum bakeng sa taolo e phetseng hantle, empa ke feela 5.7 ± 5.9% bakeng sa baithaopi ba itšetlehileng ka koae (Martinez et al., 2009a), ho bontša hore maemo a basal dopamine a fokotsehile ts'ebelisong ea koae.

Ho nkuoa hammoho, liphuputso tse nahannoeng ka tlhekefetso ea cocaine khafetsa li bonts'a phokotso ea phetisetso ea driamine ea driamine, ha e bapisoa le taolo e phetseng hantle, e lekantsoeng joalo ka ha e fokotsoe pre-synaptic dopamine (Volkow et al. 1997; Malison et al., 1999; Martinez et al., 2007b, 2011) le litekanyetso tsa motheo tsa dopamine ea morao-rao (Martinez et al., 2009a). Liphumano tse tšoanang li bontšitsoe ka litoeba (Parsons et al., 1991; Robertson et al., 1991; Rossetti et al., 1992; Weiss et al., 1992; Gerrits et al., 2002) le litloholoana tse seng tsa batho (Castner et al., 2000; Kirkland Henry et al., 2009). Kahoo, ho itšetleha ka koae ho amana le naha ea hypodopaminergic, e lumellanang le boits'oaro bo tlatselletsang ho lemeng le ho oeleng hape (Melis et al., 2005). Habohlokoa, sekhahla sa PET se bonts'ang blopted dopamine se fumanoe kamora libeke tse peli tsa ho khaotsa ho tsuba, ho qoba litlamorao tse mpe tsa cocaine ho dopamine signaling, le ka lebaka la bongaka bo amanang le nako ena ea nako. Liphuputso tse fetileng li bontšitse hore batho ba hlekefetsang koae ba ka sebelisang libeke tse 2 ba e-na le karabelo e ntlafatsang ea kalafo ha ba bapisoa le ba sa etsang (Bisaga et al., 2010; Oliveto et al., 2012).

Kappa receptor / dynorphin e tšoaeang

Dynorphin (DYN) ke sehlopha sa li-peptide tse qotsitsoeng ho prodynorphin, tse kenyeletsang dynorphin A le B (le ba bang) ba nang le tumellano e phahameng bakeng sa kappa receptor (KOR) (Chen et al., 2007). Hajoale, ke mofuta o le mong feela oa KOR subtype (mofuta oa 1) o entsoeng ka matsoho, 'me le ha mefuta ea 2 le 3 e se e hlahisitsoe ka bongata, e ntse e tlameha ho tsebahala ka botlalo (Shippenberg et al., 2007). Li-agonists tse ikhethileng le bohanyetsi ba KOR li hlahisitsoe lilemong tsa morao tjena, li lumella lipatlisiso mabapi le litla-morao tsa boitšoaro le boits'oaro tsamaisong ea DYN / KOR. The agorists ea KOR e kenyelletsa arylacetamides U69593 'me U50488, le salvinorin A, alkaloid e hlahang ka tlhaho e fumanehang semeleng Salvia divinorum (Von Voigtlander le Lewis, 1982; Lahti et al., 1985; Roth et al., 2002). Liphephetso tse khethiloeng tsa KOR li kenyelletsa kapa-binaltorphimine (kapa-BNI), 5'-guanidinonaltrindole (GNTI), le JDTic (Endoh et al., 1992; Jones le Portoghese, 2000; Carroll et al., 2004). Ho kenya ts'ebetsong ha KOR ho nka karolo ho batho le liphoofolo, 'me li-agorists tsa KOR ha li tsamaisoe ke liphoofolo (Mucha le Herz, 1985; Tang le Collins, 1985; Pfeiffer et al., 1986; Bals-Kubik et al., 1993; Walsh et al., 2001; Wadenberg, 2003), le ha ho ka boleloa se tšoanang ka batho ba bang.

KOR ho supa ho rarahane ebile ho bontšitsoe hore li-activist li qala ho sebetsa, ho inhibit le / kapa ha li na phello ea ho saena hoa tlase (ke hore, CAMP, IP3 / DAG, le Ca²⁺) ho latela maemo a liteko (Tejeda et al., 2012). Ho ka etsahala hore ebe li-agonists tsa KOR li bonts'a ho kheloha ULitlamorao -shape, ka lebaka la bokhoni ba KOR ho hira bobeli ba inhibitory Gβγ, Gcy_i, Gcy_o, Gcy_z, le Gcy₁₆, le e susumetsang, Gcy_s, G-protheine (Molao et al., 2000; Tejeda et al., 2012). Ho tsepamisa mohopolo ha Nanomolar ligand ho fella ka ho bokelloa ha liprotheine tsa G-inhibitory le ho fokotseha ha thabo ea membrane hammoho le tokollo ea transmitter ka tšusumetso ea K⁺Ketsahalo ea -channel (Grudt le Williams, 1993) le thibelo ea Ca²⁺-channel le pele ho synaptic ts'ebetso ea mechini e lokollang (Gross et al., 1990; Ninamonger, 2009). Ka lehlakoreng le leng, sub-nanomolar ligand concentrations e ka lebisa ho kopantseng ha KOR ho Gensi le ho hlahisa litlamorao tse fapaneng (Crain le Shen, 1996; Tejeda et al., 2012). Ho lokela ho hopoloa hore ts'ebetso ea KOR e ka fetolela ho fokotseha ho itšetlehileng ka D2 Autoreceptor-ho tsoa ho dopamine ka ho supa tšebelisano (Jackisch et al., 1994; Acri et al., 2001; Fuentealba et al., 2006).

Kappa receptor / dynorphin litseleng tse tobileng le tse sa tobang tsa striatum

Li-spiny neurons tse mahareng (MSNs) li ka aroloa likarolo tse bonyane tse peli ho latela libaka tsa bona tsa projeke le liprotheine tseo ba li hlahisang (Gerfen, 2000; Gerfen le Surmeier, 2011). Tsela ea "ka kotloloho" kapa "striatonigral" e entsoe ka li-MSN tse rerang monosynaptical ho medial globus pallidus le ho khutlela ho dopamine methapo ea sele ea "neuron" ea litho tsa "cell" tsa "gene "tsagene. Li-MSN tse tsoang tseleng e otlolohileng li bontša dopaminergic D1 receptor, M4 muscarinic acetylcholine receptor, ntho P, le dynorphin. Tsela e sa tsamaeang ka kotloloho ea striatopallidal e entsoe ka li-MSN tseo projeke e eang ho lateral globus pallidus, e fihlelang nigra eaantiene ka ho fetisoa ka tsela ea "synaptic" ka tsela ea morao ea globus pallidus le subthalamic nucleus. Li -MSN tsena li bontša li-receptor tsa dopaminergic D2, li-receptor tsa adenosine le enkephalin. Ho ke ho hlokomeloe hore karohano ea lipalo tsena tse peli tsa li-MSN e thehiloe dorsal striatum, empa liphuputso tse 'maloa li bonts'a hore karolo e nyane ea li-MSN ho NAc e bonahala e sebetsa' moho le li-receptor tsa D1 le D2 (George le O'Dolweni, 2007; Ntoa et al., 2009). Dopamine e ka kenya tšebetsong kapa ea thibela li-cyclic tse itšetlehileng ka AMP ka D1 receptor le D2 receptor ka tatellano, joalo ka ha re tla hlahloba ka tlase. Ka hona, dopamine e kanna ea ba le litlamorao tse fapaneng ho li -MSN tsa D1- le D2-e hlahisang lintlha tsa morao-rao li fana ka maikutlo a hore, tsamaiso ea koae e qala ts'ebetso ea ho saena ka D1-expression, empa ka mafolofolo e ba thibela ho D2-e hlalosang li-MSNs (McClung et al., 2004; Bateup et al., 2010), e ka ikarabellang bakeng sa ho se leka-lekane pakeng tsa litsela tse otlolohileng le tse sa amaneng le tšebeliso ea tahi (Lobo et al., 2010; Pascoli et al., 2012).

Li-receptors tsa D1 li kenyelletsa cyclase ea adenylyl ka ts'ebetso ea Gcy e matlafatsang_s protheine 'me ka lebaka leo e hlohlelletsa tlhahiso ea adenosine 3 ′, 5'-monophosphate (cAMP) e lebisang ts'ebetsong ea protheine kinase A (PKA) -devernt sign signways pathways. Ka lehlakoreng le leng, D2 receptor inhibits adenylyl cyclase le cAMP / PKA pathways ka ho hira inhibitory Gcy_i. Ka hona, cocaine e kenya ts'ebetsong tsela e tšoaeang PKA haholo ka ts'ebetso ea D1 receptor le ho qhekella ha tsela ena e fetola likarabo tsa boitšoaro ho koaeine (Girault, 2012). E 'ngoe ea lipheo tse tlase tsa PKA ke sepheo sa ho ngola CREB. Ho khahlisang ke hore, ha oxpxpression ea CREB e bokellaneng ea nyutlelie e fokotsa thepa e ruisang koae, ho ba le khatello e matla ea mofuta o seng ntle ho e ntlafatsa (Carlezon et al., 1998; Walters le Blendy, 2001; McClung le Nestler, 2008) ho fana ka maikutlo a hore ts'ebetso ea CREB e ka loants'a litlamorao tsa cocaine 'me ka hona ea fokotsa karabelo ea boitšoaro ho koae. E 'ngoe ea mefuta e theohelang ka tlase e laoloang ke CREB ka har'a li-nucleus accumbens encode preprodynorphin, sehlahisoa sa pele sa gene sa dynorphin (McClung le Nestler, 2008). Ho kenngwa tshebetsong ha kappa receptor ho fokotsa ho lokolloa ha dopamine ea koae (ho hlahlojoa, bona Wee le Koob, 2010; Muschamp le Carlezon, 2013). Ka hona, ts'usumetso ea D1 receptor e phahamisa polelo ea dynorphin, e ka koaloang le bahanyetsi ba li-receptor (Liu le Graybiel, 1998). Kahoo, ho bile le tlhahiso ea hore ts'ebetso ea ts'ebetso ea D1 / PKA / CREB e ka ba ho loants'a litlamorao tsa koae ka tlhahiso le tšollo ea dynorphin (bakeng sa tlhahlobo, bona Wee le Koob, 2010; Muschamp le Carlezon, 2013), e bonts'itsoeng ho Setšoantšo Figure22.

 

Setšoantšo sa 2

Model eo ka eona sistimi ea dynorphin / kappa e ka loantšang tokollo ea dopamine ea koae. Tsamaiso ea cocoaine e phahamisa maemo a dopamine. Ho tlama ha dopamine ho receptor ea D1 e hlahisitsoeng ke li-neuron tsa spiny tse mahareng tse tsoang tseleng ea striatonigral ...

Kappa receptor / dynorphin le lets'oao la dopamine

Sisteme ea DYN / KOR receptor e bontšitsoe e bapala karolo ea bohlokoa ho laola phetiso ea drietal dopamine. DYN immunoreactive axon terminals e tsoang ho li-DN receptor-expression MSNs e fumanoa ho caudate, putamen, le nucleus accumbens (Hurd le Herkenham, 1995; Van Bockstaele et al., 1995). KOR e hlahisoa ka bobeli pele le ka morao ho synaptic ho dopamine neurons, 'me K-pre-synaptic KOR e kenngoa ho DAT mecheng ea dopamine axon, e bonts'a hore sistimi ena e laola haufi-ufi li-neuropensele tsa dopamine tsa Sopos (Svingos et al., 2001).

Liphuputso tse ngata tsa liphoofolo li bontšitse hore tsamaiso ea ngaka ea agorist ea KOR e fokotsa maemo a dopamine sebakeng sa striatum le dopamine neuron sebakeng sa bokellane ba methapo le sebaka sa ventral tegmental (Di Chiara le Imperato, 1988; Heijna et al., 1990, 1992; Donzanti et al., 1992; Spanagel et al., 1992; Maisonneuve et al., 1994; Xi et al., 1998; Thompson et al., 2000;; Margolis le al., 2003; Zhang et al., 2004b). Ebile, ts'ebetso ea KOR e fokotsa maemo a dopamine a basal hammoho le ho lokolloa ha dopamine ea dopamine (cocaine) (Spanagel et al., 1990; Maisonneuve et al., 1994; Carlezon et al., 2006; Gehrke et al., 2008). Reverse dialysis ka har'a li-bokono tsa nucleus e fokotsa dopamine ea extracellular (Donzanti et al., 1992; Zhang et al., 2004a). Haholo, phello ena e bonoa ha agorist ea KOR e tsamaisoa striatum, athe tsamaiso ho VTA e bonahala e le mefuta e itšetlehileng ka (Spanagel et al., 1992; Chefer le al., 2005; Ford et al., 2006;; Margolis le al., 2006).

Ts'ebetso ea KOR e bonts'itsoe ho thibela ts'ebetso ea motlakase [³H] dopamine e lokolloe ka har'a li-nucleus accumbens (Heijna et al., 1992; Yokoo et al., 1992), e bonts'ang hape hore ts'ebetso ea receptor ena e fokotsa phetisetso ea driamine. Haufinyane tjena, Chefer et al. (2005) e bonts'itse hore ho tlosoa hoa KOR ho amana le ntlafatso ea tokollo ea basal dopamine. Ntle le moo, bahanyetsi ba KOR ba khothalletsa ho lokolloa ha dopamine ho striatum (Maisonneuve et al., 1994; U ka mo al. 1999; Beardsley et al., 2005). Qetellong, tsamaiso e pheta-phetoang ea KOR e fokotsa khatello ea methapo ea methapo ea D2 (Izenwasser et al., 1998). Liphumano tsena li bonts'a hore DYN / KOR e tšoaeang e fana ka taolo ea thibelo ea dopamine le dopamine receptor e bontšang striatum (Bruijnzeel, 2009; Wee le Koob, 2010) mme e bonts'a hore ts'ebetso e feteletseng ea KOR e fokotsa haholo phetiso ea dopamine, ntle le ts'ebeliso e sebelisitsoeng ho lekanya phetiso ea dopamine.

Haholo-holo, liphuputso tse nahannoeng li bonts'a hore, ntle le ts'ebeliso ea koae, ho lemalla lintho tse ling tsa tlhekefetso ho boetse ho fella ka tokollo ea dopamine ea pre-synaptic dopamine e lekantsoeng le PET. Ho sibolla hona ho boetse ho tlalehiloe lithutong tsa joala, methamphetamine, opiate, le ts'ehetso ea koae (Martinez et al., 2007a, 2012; Busto et al., 2009;; Wang et al., 2012). Ha lithuto tse ling li bonts'itse hore Sisteme ea DYN / KOR e bapala karolo ea tsona litsietsing tsena (bakeng sa tlhahlobo, bona Wee le Koob, 2010; Koob, 2013), phello ea ho pepesetsoa ha lithethefatsi ho KOR le DYN ha e hlake ebile e ka ba le taolo e tlase ho methamphetamine le ho its'etleha hoa opiate (Drakenberg et al., 2006; Frankel et al., 2007). Ho hlokahala lithuto tse ling ho hlakisa tšebelisano lipakeng tsa Sistimi ea DYN / KOR le ho bonts'a dopamine mathateng ana.

Tsamaiso ea cocoaine le dynorphin

Liphuputso tse ngata tsa liphoofolo li bontšitse hore tsamaiso ea koae e pheta-phetoang e eketsa litekanyetso tsa DYN, prodynorphin mRNA, le preprodynorphin mRNA. Lithuto tsa pele li ne li lekanya maemo a peptide 'me li bonts'a hore tekanyetso e sa foleng ea koae e eketsa litekanyetso tsa dynorphin ka litheko ka 40-100% (Sivam, 1989; Smiley et al., 1990). Lithuto tse ling tse lekanyang prodynorphin le preprodynorphin mRNA, sebakeng sa litekanyetso tsa peptide, li pheta lipatlisiso tsena. Daunais et al. (Daunais et al., 1993, 1995; Daunais le McGinty, 1995, 1996) e bonts'itse hore boikoetliso ba koae e eketsa koprodynorphin mRNA ka har'a caudate / putamen ka feta 100%. Liphetho tse tšoanang li tlalehiloe lithutong ke lihlopha tse ling hape, moo tsamaiso ea koae e bontšitsoeng ho eketsa maemo a preprodynorphin mRNA 50-100% ho caudate / putamen ea likhoto le litoeba (Yuferov et al., 2001; Zhou et al., 2002; Jenab et al., 2003; Schlussman et al., 2003, 2005; Zhang et al., 2013). Spangler et al. (1993, 1996) e bonts'itse hore koae e eketsa prodynorphin mRNA ho caudate / putamen ka 40%, le hore maemo ana a ile a lula a le maemong a phahameng ka matsatsi. Ka kakaretso, lithuto tse kaholimo ho litoeba li lula li tlaleha hore tsamaiso ea koae e eketsa DYN, prodynorphin, le prrodynorphin mRNA e nang le maemo a ka bang 40 ho isa ho 100%. Boithuto bo fetileng bo bonts'itse hore maemo a DYN peptide le prodynorphin / preprodynorphin mRNAs a kopanya le ngoe, a fana ka maikutlo a hore keketseho ea li-mRNA e bonts'a haufi le keketseho ea peptide ka boeona (Li et al., 1988; Sivam, 1996).

Liphumano tsena tse fumanoeng ka litoeba li 'nile tsa phetoa lithutong tsa litšoene tsa rhesus le batho. Fagergren et al. (2003) o entse lipatlisiso ho litšoene tsa "rhesus" tse sebelisang k'hok'heine 'me a supa hore maemo a prodynorphin mRNA a eketsehile ka har'a dorsolateral caudate (83%), caudate e bohareng (34%) le dorsal putamen (194%). Ho batho, Hurd le Herkenham (1993) ea pele e tlaleha hore tlhekefetso ea koae e amana le keketseho ea prrodynorphin mRNA ho putamen le caudate thutong ea post-mortem ea lithuto tse hlekefetsang koae ha li bapisoa le lithuto. Haufinyane tjena, Frankel et al. (2008) a lekanya maemo a peptide ea DYN thutong ea morao-rao ea batho ba hlekefetsang koae le lithuto tse laoloang, mme a tlaleha keketseho e kholo ho DYN ho caudate le mokhoa o lebisang keketseho e kholo ea putamen ha e bapisoa le lithuto. Keketseho e kholo haholo e ile ea bonoa ka hare ho potral pallidum empa ha ho phapang e ileng ea bonoa ho thalamus, frontal, temporal, parietal, le occipital cortices. Ha li kopantsoe hammoho, liphuputso tsena li bonts'a hore ho pepesetsoa hoa koae ho eketsa ho bonts'a li-DYN ho supa kappa receptor ka litoeba, li-primates tse seng tsa batho le batho. Ha re nahana ka phello ea DYN ho ho saena hoa dopamine, ho ka etsahala hore keketseho e tsitsitseng ea litekanyetso tsa DYN ka ho pepesetsoa koae e nka karolo ho boemo ba hypodopaminergic bo hlalositsoeng ho ba hlekefetsang koae.

Seo ba se fumaneng lithutong tsa batho le tsa liphoofolo se bontša hore kalafo tse lebisitsoeng ho KOR signaling li ka fetola boitšoaro ba ho batla koae. Leha ho le joalo, lithuto tsa liphoofolo tse fumanang phello ea Ts'ebetso ea agorist kapa tsamaiso ea bohanyetsi mabapi le taolo ea koae e tsoakiloe (bakeng sa ho lekola, bona Wee le Koob, 2010; Butelman et al., 2012). Karolo ena, phello ena e latela kemiso ea matlafatso e sebelisitsoeng, tekanyetso ea lithethefatsi e laetsoeng, le nako ea phello, kaha liphetoho KOR / DYN li na le ho qaleha butle (Wee et al., 2009; Knoll et al., 2011). Ho feta moo, Sisteme ea DYN / KOR e bonahala e bapala karolo ea bohlokoa ho hola litla-morao tse tlisoang ke ho pepesetsoa koae.

Kappa receptor / dynorphin le boits'oaro bo hatelletseng bo khothalletsang ho ts'oara koae

Boithuto ba liphoofolo bo lekotse kamano e teng lipakeng tsa ts'ebetso ea KOR le ts'ebetso ea ho batla khatello ea khatello ea kelello. DYN e lokolloa ho arabela khatello ea 'mele ho striatum, amygdala, le hippocampus (Shirayama et al., 2004; Mobu et al., 2008), le blockade ea KOR e fokotsa litlamorao tsa khatello ea maikutlo boits'oeng ba ho batla koae. McLaughlin et al. (2003) e bonts'itse hore khatello ea ho sesa le khatello ea ho hlola maemo setjhabeng ka bobeli li ntlafatsa maemo a boikhethelo a sebaka sa (cPP) bakeng sa koae ho litoeba. Phello ena e thibetsoe ke tsamaiso ea bohanyetsi ea KOR 'me ha e ea ka ea bonoa ho litoeba tsa prodynorphin tse kantle (McLaughlin et al., 2003, 2006). Ntle le moo, tsamaiso ea agorist ea KOR pele ho boemo ba koae e bontšitsoe e sebetsa hantle joalo ka khatello ea maikutlo mabapi le ts'ebeliso ea k'homphieutha ea morao-rao ea k'hok'heine (CLaughlin et al., 2006). Beardsley et al. (2005) e bonts'itse hore khatello ea "cocaine" e hatelloang ka lehare e khutlisoa ka litoeba tse latelang tse sa laoleheng, le hore phello ena e thibetsoe ke tsamaiso ea JDTic, mohanyetsi oa KOR. Haufi le mela e tšoanang, Redila le Chavkin (2008) e bonts'itse hore ho thothomela hoa maoto ka nako e telele, ho sesa ka thata, le tsamaiso ea agorist ea KOR kaofela ho khutlisetsa CPP ea cocaine litoeba. Phello ena e ne e koetsoe ka kalafo ea pele ho mohanyetsi oa KOR kapa-BNI, 'me ha ea ka ea hlaha ka litoeba tse haellang KOR kapa prodynorphin. Carey et al. (2007) e boetse e bonts'a hore kalafo ea pele ho moo e nang le mohanyetsi oa KOR e thibetse ho khutlisetsoa ha khatello ea kelello ea cocaine CPP.

Lithuto tsena li bonts'a hore ho supa ho KOR ho bapala karolo ea bohlokoa boits'ebetsong ba ho batla koae ka mor'a khatello ea maikutlo. Boithuto ba morao-rao bo boetse bo bontšitse hore DYN signaling le corticotropin releasing factor (CRF) e sebetsa hammoho ho eketsa litlamorao tse mpe tsa cocaine (Koob et al., 2004). Mobu et al. (2008) e sebelisitse anti-phospho-khetha antibody bakeng sa sebopeho se sebetsang sa KOR mme e bonts'a hore khatello ea maikutlo le tsamaiso ea CRF li felletse ka ts'ebeliso ea DYN e ts'ehetsoeng ke KOR. Valdez et al. (2007) e bonts'itse hore, ho litšoene, boitšoaro bo batlang cocaine bo khutlisoa ke tsamaiso ea agonist ea KOR, le hore phello ena e thibetsoe ke tsamaiso ea bohanyetsi ea CRF. Li-agonists tsa KOR li hlohlelletsa axis ea HPA ho litoeba le batho (Ur et al., 1997; Laorden et al., 2000), mme ho kile ha tlalehoa hore ts'ebetso ea KOR e etsa hore CRF e lokolloe (Nikolarakis et al., 1986; Pina le Takemori, 1992) le motlatsi (Land et al., 2008).

Boithuto ho batho ba hlekefetsang cocaine ea batho le bona bo bontšitse hore khatello ea maikutlo e eketsa kotsi ea ts'ebeliso e mpe ea lithethefatsi le ho khutla hape (De La Garza et al., 2009). Ts'ebetso ea pharmacological kapa ea kelello ts'ebetsong ea hypothalamic pituitary adrenal axis e bontšitsoe ho eketsa ho lakatsa takatso ho ekelletsa le monyetla oa ts'ebeliso ea koae ea cocaine e ngata (Elman et al., 2003; Shoptaw et al., 2004; Elman le Lukas, 2005). Sinha le basebetsi-'moho ba bontšitse hore litšoantšo tsa khatello ea maikutlo li eketsa matšoenyeho le ho lakatsa koae (Sinha et al., 1999, 2006; Fox et al., 2006). Habohlokoa, sehlopha sena se boetse se bonts'itse hore takatso ea koae e hatelletsoeng kelellong e amana le nako e khuts'oanyane ea ho khutlela hape lithutong tse itšetlehileng ka koae ka mor'a ho tsoa kalafo e sa sebetseng (Sinha et al., 2006). Ho fihla joale, lithuto tsa ho nahana ka bokhoba ba tahi ha li a lebisa tlhokomelo ho khutlisetsong e hatellang ea boitšoaro bo batlang koae, 'me lipatlisiso tsa nako e tlang li lokela ho shebisisa karolo ea dopamine le ho saena le khatello ea KOR.

Kahoo, ho supa lipontšo tsa DYN / KOR ho bonahala ho bapala karolo ea bohlokoa ho khutliseng boits'oaro ba ho batla lithethefatsi ka ho loants'a litlamorao tse mpe tse amanang le ho khaotsa lithethefatsi le ho ts'oara khatello ea lithethefatsi (Koob le Le Moal, 2008; Muschamp le Carlezon, 2013).

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