Phetiso ea Glutamatergic mokhoeng oa lithethefatsi: sepheo sa ho lemalla lithethefatsi (2015)

Manoranjan S. D'Souza^*

Batho ba lemaletseng lithethefatsi tsa tlhekefetso joalo ka joala, nikotini, cocaine le heroin ke moroalo o bohlokoa ho lits'ebeletso tsa bophelo bo botle lefats'e. Litlamorao tse matlafatsang (tse matlafatsang) tsa litlhare tse boletsoeng ka holimo li bapala karolo e kholo ho qaleng le ho lokiseng tloaelo ena ea ho sebelisa lithethefatsi. Kahoo, ho utloisisa mekhoa ea methapo e tlatselletsang litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso ho bohlokoa ho fokotsa moroalo oa bokhoba ba lithethefatsi sechabeng. Lilemong tse mashome a mabeli tse fetileng, ho bile le lintlafatso tse ntseng li eketseha mabapi le karolo ea karolo e nyakallisang ea neurotransmitter glutamate ea lithethefatsi tsa lithethefatsi. Thutong ena, ho tla buisanoa ka bopaki ba meriana le tsa liphatsa tsa lefutso tse tšehetsang karolo ea glutamate ho loants'a litlamorao tse tlisoang ke lithethefatsi tsa tlhekefetso tse boletsoeng kaholimo. Ntle le moo, tekolo e tla tšohla karolo ea phetisetso ea glutamate libakeng tse peli tse rarahaneng tsa bokong, e leng li-nucleus accumbens (NAcc) le sebaka sa ventral tegmental te (VTA), se kopanyang litlamorao tse tlatselletsang tsa lithethefatsi tsa tlhekefetso. Ntle le moo, meriana e 'maloa e amohetsoeng ke Tsamaiso ea Lijo le Lithethefatsi e sebetsang ka ho thibela phetiso ea glutamate e tla tšohloa molemong oa moputso oa lithethefatsi. Qetellong, tlhahlobo ena e tla bua ka lithuto tsa nakong e tlang tse hlokahalang ho sebetsana le likheo tsa tsebo e sa arabeloang, tse tla hlakisa karolo ea bohlasoa liphellong tse khahlisang tsa lithethefatsi tsa tlhekefetso.

Kakaretso ea phetisetso ea glutamate

Glutamate ke "neurotransmitter" e kholo ka ho fetisisa bokong ba 'mele,' me e ikarabella ka 70% ea phetiso ea synaptic tsamaisong ea methapo ea kutlo (Nicholl, 1993; Niciu et al., 2012). Ketso ea glutamate e kopantsoe le likamore tse peli tse potlakileng tsa ligand-gated ion, tseo hangata li bitsoang li-receptor tsa ionotropic glutamate, le li-receptor tse sebetsang butle tsa G-protein tse boetse li tsejoa e le metabotropic glutamate (mGlu) receptors 1993; Niswender le Conn, 2010). Li-receptor tsa ionotropic glutamate li kenyelletsa N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), le li-receptor tsa kaine. Li-receptors tsa NMDA ke li-heterotetramers tse entsoeng ka NR1, NR2 (NR2A-D), mme ha se seoelo tse fanang ka liphallelo tsa NR3 (Zhu le Paoletti, 2015). Li-receptors tsa NMDA ke li-receptor tse rarahaneng 'me li hloka ho tlangoa ke glutamate, glycine e kopanetsoeng, le depolarization ea membrane bakeng sa ho tlosoa ha setopo sa magnesium. Depolarization ena ea membrane e etsahala ka ts'ebetso ea li-receptor tsa AMPA, tse hlalosoang e le li-workhorses har'a li-receptors tsa glutamate. Li-receptor tsa AMPA le tsona ke li-tetemter hape li entsoe ka li-subunits tsa GluR 1-4 (Hollmann le Heinemann, 1994). Likopanyo tse ikhethileng tsa subunit li kopanya thepa e khethollang glutamate e tšoaeang thepa ho li-NMDA le li-AMPA receptors.

Ntle le li-receptor tsa ionotropic, ho fumanoe li-receptor tse robeli tsa mGlu 'me li arotsoe ka lihlopha tse tharo (I, II, le III) ho latela tsela ea phetisetso ea pontšo, Homology le tatellano ea meriana 1995; Niswender le Conn, 2010). Li-receptor tsa sehlopha sa I (mGlu1 le mGlu5) li fumaneha haholo ho li-postynaptically, mme sehlopha sa II (mGlu2 le mGlu3) le Sehlopha sa III (mGlu4, mGlu6, mGlu7, le mGlu8) li-receptors tsa gum. Haholo-holo, sehlopha sa II le li-mGlu receptors li laola hampe phetisetso ea glutamate, ke hore, ts'ebetso ea li-receptors tsena e fokotsa tokollo ea glutamate. Ka mantsoe a mang, modon ea agonist kapa e ntle allrateic ho Sehlopha II kapa III mGlu receptors e fokotsa phetisetso ea glutamate. Ho shebiloe ho eketsehileng karolo ea li-metabotropic receptors moputsong oa lithethefatsi le ho lemalla (Duncan le Lawrence, 2012). Ts'ebetso ea li-receptor tsa ionotropic kapa mGlu e etsa hore ho be le mekhoa e ts'oaroang ea ho saena, 'me qetellong e lebise ho "neuronal plasticity". Ebile, polasetiki e hlahisoang ke lithethefatsi ho fetisetsoa ke glutamatergic e kenella ka matla ho nts'etsopele ea bokhoba ba lithethefatsi (Kalivas, 2004, 2009; van Huijstee le Mansvelder, 2014).

Extracellular glutamate e hlakisoa ho tsoa ho synapse ke li-amino acid tse tsamaisang thabo (EAATs) le li-vesicular glutamate transporters (VGLUTs). Li-EAAT li lutse li-terminals tsa glutamate le lisele tsa presynaptic glial mme li bapala karolo ea bohlokoa ho glutamate homeostasis (O'Shea, 2002; Kalivas, 2009). Ho fihlela ka letsatsi mefuta e fapaneng e fapaneng ea EAAT e tlalehiloe ho liphoofolo (GLT-1, GLAST, le EAAC1) le ho batho (EAAT1, EAAT2, le EAAT3) (Arriza et al., 1994). Li-VGLUT li ikarabella haholo ho bokeng le ho hlophiseheng ha glutamate ho li-vesicles tsa Presynaptic bakeng sa polokelo. Hajoale ho se ho fumanoe li-isoforms tse tharo tse fapaneng tsa VGLUTs (VGLUT1, VGLUT2, le VGLUT3) (El Mestikawy et al., 2011). Glutamate e ka boela ea isoa sebakeng sa extrasynaptic ka cypine-glutamate antiporter e fumanehang liseleng tsa glial (Lewerenz et al., 2012). Cystine-glutamate antiporter e fapanyetsana cystine ea extracellular bakeng sa glutamate e ikhethileng mme e sebetsa e le mohloli oa tokollo e seng ea vesicular glutamate. Batsamaisi ba lihlahisoa tsa glutamate e ka ba lipheo tsa ho fumana litlamorao tse tlisang melemo ea lithethefatsi tsa tlhekefetso (Ramirez-Niño et al., 2013; Rao et al., 2015a).

Lithethefatsi tsa tlhekefetso le phetoho ea phetisetso ea glutamate

Lithethefatsi tsa tlhekefetso li fetola phetiso ea glutamate ka mekhoa e fapaneng. Sebaka sa mantlha sa ts'ebetso ea koae ke phetisetso ea dopamine uptake (DAT; Ritz et al., 1987). Cocaine e thibela DAT mme e eketsa litekanyetso tsa dopamine, tse bohareng li hlahisang melemo e tlisoang ke koae. Keketseho e susumetsoang ke cocaine maemong a dopamine ea synaptic e kenya tšebetsong li-presynaptic kapa li-postynaptic D1 dopamine receptors, tseo ka tsela e sa tobang li eketsang phetisetso ea glutamate. Ts'ebetso ea li-receptors tsa presynaptic D1 e laola keketseho e susumetsoang ke koae ka litekanyetso tsa glutamate (Pierce et al., 1996b). Ho feta moo, dopamine e ka tlama ho li-receptors tsa DynNUMX tsa postynaptic mme e laola phetisetso ea ionotropic glutamate ka NMDA le AMPA receptors (bakeng sa tlhahlobo ea Wolf et al., 2003). Mohlala, ts'ebetso ea li-receptor ea D1 e eketsa ho ts'oaroa ha AMPA le ho kenngoa kahare ho membrane ka protheine kinase A-Mediated phosphorylation (Gao le Wolf, 2007). Ntle le moo, ts'ebetso ea li-receptor tsa D1 e eketsa li-signature tsa NMDA-Mediated ka ho eketsoa ho kenyellelitsoeng ho membrane ea postynaptic kapa puisano e sebetsang pakeng tsa D1 le li-receptors tsa NMDA (Dunah le Standaert, 2001; Ladepeche et al., 2013).

Ka lehlakoreng le leng nicotine, e hlohlelletsang e 'ngoe, e eketsa phetisetso ea glutamate ka ho tlama ho li-receptor tsa ome7 homomeric nicotinic acetylcholine receptors tse fumanehang litsing tsa "presynaptic glutamate" (Mansvelder le McGehee, 2000). Ntle le moo, nicotine e ka eketsa mats'oao a glutamate ka mekhoa ea dopaminergic joalo ka e hlalositsoeng cocaine (Mansvelder et al., 2002). Ka kakaretso, psychostimulants e kang cocaine le nikotine li eketsa phetisetso ea glutamate ntle le ho kenella ka kotloloho le li-receptors tsa glutamate.

Boithuto bo sebelisang mekhoa ea patch-clamp le mekhoa e meng ea electrophysiological likhatisong tsa boko li tlaleha hore joala bo thibela phetiso ea postynaptic NMDA- le non-NMDA-mediated glutamate transmit (Lovinger et al., 1989, 1990; Nie et al., 1993; Carta et al., 2003). Ho feta moo, lithuto tsa electrophysiology li fana ka maikutlo a hore joala bo thibela ho lokolloa ha glynamic glutamate (Hendricson et al., 2003, 2004; Zis mosa-Conhaim et al., 2003). Ka lehlakoreng le leng, ho sebelisa Ka vivo microdialysis, lithuto tse ling li tlaleha keketseho ea maemo a glutamate kamora ho tsamaisoa ha joala (Moghaddam le Bolinao, 1994). Keketseho ena e bakiloeng ke joala e tlisoang ke ho lokolloa ha glutamate e kanna ea bakoa ke ho sitisa li-interneuron tsa GABAergic tseo ka nako eo li thibelang lits'oants'o tsa preynaptic glutamate. Mokhoa o mong oa preynaptic bakeng sa keketseho e bakoang ke joala ho fetisetsoa ha glutamate e ka ba ka ts'ebetso ea li-receptor tsa D1 (Deng et al., 2009; bakeng sa tlhahlobo bona Roberto et al., 2006). Boithuto ba electrophysiological bo fana ka maikutlo a hore ho pepesetsoa joala khafetsa ho thusa ho fetisoa ha li-presynaptic le postynaptic glutamate transmit (Zhu et al., 2007).

Kamora nako, heroin, e tlamahanyang haholo le li-opioid receptors, e fetola phetisetso ka phetisetso e fapaneng. Mohlala, ts'ebetso ea li-receptor tsa mu opioid e fokotseha phetisetso ea NMDA- le eo e seng NMDA e sebelisang li-transynaptic mechanism (Martin et al., 1997). Ho feta moo, tšebelisano e tobileng lipakeng tsa li-op opioid receptors le li-receptor tsa NMDA li bontšitsoe libakeng tse 'maloa tsa boko (Rodriguez-Muñoz et al., 2012). Ho khahlisang, ts'ebetso ea li-mu-opioid receptor e eketsa phetisetso ea postynaptic NMDA-Mediated glutamate transmit ka activation of protein kinase C (Chen and Huang, 1991; Martin et al., 1997). Heroin, e ts'oanang le joala, e ka eketsa phetiso ea glutamate ka ho thibela li-interneurons tsa GABAergic, e thibelang li-terminals tsa "presieaptic glutamate" (Xie le Lewis, 1991). Kamora moo, heroin e ka eketsa glutamate e supa ka kotloloho ka mekhoa ea dopaminergic joalo ka ha ho hlalositsoe kaholimo bakeng sa koae (bakeng sa tlhahlobo ea Svenningsson et al., 2005; Chartoff le Connery, 2014).

Ika kakaretso, har'a lithethefatsi tsa tlhekefetso tse ntseng li tšohloa tekong ena, ke joala feela bo kenang ka kotlolloho le li-receptors tsa glutamate. Litlhare tse ling tsa tlhekefetso tse tšohliloeng tekong ena li fetisetsa phetisetso ea mafu ka kotloloho ntle le methati ea "presynaptic" le "postynaptic". Karolong e latelang, re tla tšohla litlamorao tsa ho thibela phetiso ea glutamatergic re sebelisa likhakanyo tsa meriana litekanyetsong tsa boits'oaro ba meputso ea lithethefatsi.

Blockade ea phetisetso ea glutamatergic le boits'oaro ba meputso ea lithethefatsi

Tsamaiso e hlophisehileng ea metsoako ea meriana e thibelang phetisetso ea glutamate e fumane melemo e matlafatsang ea lithethefatsi tsa tlhekefetso (bona Lethathamo Tafole1) .1). Mohlala, tsamaiso ea methapo ea bahanyetsi ba li-receptor ba NMDA ba ile ba itaola ka mokhoa o ikemetseng oa cocaine (Pierce et al., 1997; Pulvirenti et al., 1997; Hyytiä et al., 1999; Allen et al., 2005; Blokhina et al., 2005; empa bona le Hyytiä et al., 1999), joala (Shelton le Balster, 1997), le nikotine (Kenny et al., 2009). Ntle le moo, tsamaiso e hlophisehileng ea bahanyetsi ba li-receptor ba NMDA ba kenyellelitse k'hok'heine ea koae le cocaine-joala joala (Cervo le Samanin, 1995; Biala le Kotlinska, 1999; Boyce-Rustay le Cunningham, 2004; Maldonado et al., 2007) hammoho le ho theoha ha likhopolo tsa nicotine tse bakiloeng ke likotsi tsa ICSS (Kenny et al., 2009). Ka kopanelo, lithuto tse kaholimo li tšehetsa karolo ea li-receptor tsa NMDA litlamorao tse khahlisang tsa koae, nikotine le joala. Ho khahlisang, tsamaiso ea methapo ea lihanyetsi tsa li-receptor tsa NMDA e ile ea eketsa ho itaola ha heroin. Keketseho ea boits'oaro ba heroin e ile ea bonoa ka hora ea pele ea kemiso ea ho itaola ea lihora tse tharo, ka hona, e fana ka maikutlo a hore keketseho ea boits'oaro ba heroin e kanna ea ba ea ho leka ho lefella ho fokotseha ha litlamorao tse matla tsa heroin (Xi) le Stein, 2002). Ntle le moo, phetisetso ea glutamate e kopantsoeng le NMDA e kanna ea ba le karolo e fapaneng pholisong ea heroin ha e bapisoa le cocaine, nikotine le joala. Mosebetsi o eketsehileng o sebelisa kemiso e tsoelang pele ea tekanyo o tla hlokahala, ho tseba hore na NMDA receptor blockade e eketsa kapa e fokotsa litlamorao tse atlehang tsa heroin. Ka bokhutšoanyane, motho a ka fihlela qeto ea hore tsamaiso ea methapo ea lihanyetsi tsa li-receptor tsa NMDA ka kakaretso e fana ka litholoana tse ntle tsa lithethefatsi tsa tlhekefetso.

    

Lethathamo 1

Litholoana tsa ho thetsoa ha lithethefatsi ka bongateng ba ho fetisoa hoa glutamatergic ka mehato ea boitšoaro ea moputso oa lithethefatsi.

Ka ho tsotehang, lithuto tse 'maloa tsa liphoofolo li bontšitse hore li-receptor tsa NMDA li na le litlamorao tse ntle tsa tsona (Carlezon le Wise, 1993). Ntle le moo bathong, bahanyetsi ba NMDA ba hlohlelletsa boemo ba kelello bo kang ba psychosis (Malhotra et al., 1996). Litlamorao tsa kelello, leha ho le joalo, ha li bue hakaalo kapa ha li eo ho bahanyetsi ba bang ba li-receptor tsa NMDA le bahanyetsi ba li-receptor tsa NMDA ba amohetsoe ho sebelisoa ho batho. Mohlala, FDA e amohetse memantine, mohanyetsi ea sa hlolisaneng oa NMDA, bakeng sa kalafo ea lefu la Alzheimer (Cummings, 2004). Ho khahlisang, lithuto tsa tleliniki li tlaleha hore memantine e fokotse litlamorao tse ntle tsa ho tsuba koae le ho kenella ka matla ho li-heroin lithutong tsa batho (Comer le Sullivan, 2007; Jackson et al., 2009). Ka lehlakoreng le leng, tekanyetso e phahameng ea memantine e ile ea eketsa litlamorao tsa cocaine ho batho (Collins et al., 1998). Acamprosate, FDA e amohetseng meriana bakeng sa kalafo ea ts'ebeliso ea tšebeliso ea joala, e fokotsa phetisetso ea glutamatergic ka ho thibela phetiso ea NMDA-Mediated glutamate (Rammes et al., 2001; Mann et al., 2008; empa bona Popp le Lovinger, 2000). Ho liphoofolo, acamprosate e ile ea fumana melemo e tlisoang ke joala le koae (Olive et al., 2002; McGeehan le Olive, 2003a). Kamora nako, mohanyetsi e mong ea se nang tlholisano ea NMDA ea bitsoang ketamine, ea seng a amohetsoe ke FDA, o bonts'itse ts'episo kalafong ea bakuli ba tepelletseng maikutlo (bakeng sa tlhahlobo ea Coyle le Melao, 2015). Ka kopanelo, meriana e hlalositsoeng kaholimo e bontša hore NMDA receptor ke sepheo se sebetsang bakeng sa nts'etsopele ea lithethefatsi nakong e tlang.

Phetisetso ea glutamate e pakeng tsa NMDA e ka khathatsoa ho sebelisoa mekhoa e meng. Mokhoa o mong o joalo e ka ba ts'ebeliso ea bahanyetsi ba li-receptor ba khethiloeng ba NMDA joalo ka ifenprodil, e khethang mochini oa NR2B subunit ea NMDA receptor. Tsamaiso ea ifenprodil ha ea ka ea fokotsa taolo ea tahi ea molomo kapa CPP e tsamaisang joala (Yaka et al., 2003). Leha ho le joalo, karolo ea li-receptor tse ikhethang tsa NMDA e fana ka litlamorao tse khotsofatsang tsa lithethefatsi tse ling tsa tlhekefetso ha e so ka e sebetsoa ka mokhoa o hlophisehileng. Hajoale, ho haella ha li-ligands tsa bongaka tse ikhethileng tsa NMDA ke tšitiso tekong ea tsamaiso ea karolo ea li-receptors tsa NMDA e entsoeng ka likhetho tse fapaneng tsa moputso oa lithethefatsi. Phetisetso ea glutamate e kopantsoeng le NMDA le eona e ka fokotsoa ke ho laola sebaka sa glycine sa li-receptors tsa NMDA. Glycine ke co-agonist e hlokahalang bakeng sa ts'ebetso ea receptor ea NMDA le tsamaiso ea agonist e sa kopaneng e ts'oereng setsi sa glycine sa NMDA receptor se theohile boits'oaro ba koae (Cervo et al., 2004) le nikotine (Levin et al., 2011). Ntle le moo, ACPC, e buellang maemo a sa foleng sebakeng sa glycine sa NMDA receptor, e fumane k'hok'heine ea koae le ea nicotine e kenyellelitseng batho ba bang (Papp et al., 2002; Yang et al., 2013).

Fokotseha phetisong ea glutamate ea ionotropic-mediated ka blockade ea li-receptors tsa AMPA li ipehetse tsamaiso ea k'hok'heine (Pierce et al., 1997) le joala (Stephens le Brown, 1999). Ntle le moo, ts'ebetso ea li-receptor tsa AMPA li nolofalitse mohopolo o matla oa ts'ebetso oa heroin-CPP (Xu et al., 2015). Ka bobeli, lithuto tsena li tšehetsa karolo ea li-receptor tsa AMPA moputsong oa lithethefatsi. Topiramate, moriana o khahlanong le lefu la sethoathoa o amohetsoeng ke FDA, o fumana phetiso ea glutamate e tsamaisang AMPA (Gryder le Rogawski, 2003). E amana le tlhahlobo ena, tsamaiso ea topiramate e fokotse tšebeliso ea joala ho litoeba tsa C57BL / 6J ha li bapisoa le koloi, e ts'ehetsa karolo ea li-receptor tsa AMPA litlamorao tse matlafatsang tsa joala. Haholo-holo, ho batho ba tsubang ba sa tsubeng, kalafo ea topiramate e ile ea eketsa litlamorao tsa ho tsuba koae. Keketseho ena liphellong tse khotsofatsang tsa ho tsuba koae e ka ba ka lebaka la keketseho ea ho khaotsa ho tsuba ho batang ba tsubang (Reid et al., 2007). Ho ts'ehetsa maikutlo ana, patlisiso e tlaleha hore blockade ea li-receptor tsa AMPA e hlohlelletsa litlamorao tse kang tsa ho khaola tse tšoanang le likhotong tse itšetlehileng ka nicotine (Kenny et al., 2003). Haufinyane tjena, phuputso e entsoeng pele e tlaleha hore topiramate ha e bapisoa le placebo e bakile litefiso tse phahameng tsa ho khaotsa ho tsuba (Oncken et al., 2014). Ntle le ho thibela li-receptor tsa AMPA, topiramate e ka sebetsa ka mekhoa e meng ho kenyelletsa li-blockade of presynaptic voltage-gated calcium le sodium ionels, tse lokelang ho bolokoa kelellong ha li ntse li toloka liphetho tsa lithuto tse hlalositsoeng ka holimo (Rosenfeld, 1997). Ho nka hore lithethefatsi tsa tlhekefetso, haholo-holo li-psychostimulants, li ama ka ho teba khoebo ea AMPA-receptor (Wolf, 2010), hoa makatsa hore karolo ea li-receptor tsa AMPA moputsong oa lithethefatsi ha e e-so ithutoe haholo. Lithuto tsa nako e tlang tse shebileng li-subnoits tse khethehileng tsa AMPA li ka thusa ho utloisisa haholoanyane karolo ea li-receptor tsa AMPA moputsong oa lithethefatsi. Haufinyane tjena, FDA e amohetse mohanyetsi ea se nang tlhaselo ea AMPA ea sa sebetseng, perampanel, bakeng sa kalafo ea lefu la sethoathoa. Leha litlamorao tsa perampanel mabapi le moputso oa lithethefatsi li e-so fumanoe, tumello ea mohanyetsi ea amohelang AMPA bakeng sa ts'ebeliso ea bongaka e fana ka maikutlo a hore li-receptors tsa AMPA e kanna ea ba sepheo se bolokehileng le se sebetsang bakeng sa ho sibolloa le nts'etsopele ea lithethefatsi tse lebisang moputso oa lithethefatsi le kalafo ea lithethefatsi. temallo.

Blockade ea phetisetso ea glutamate ka li-receptors tsa mGlu le eona e bonts'a litlamorao tse ntle tsa lithethefatsi tsa tlhekefetso. Blockade ea li-receptors tsa mGlu1 li kenyellelitse CPP e kentsoeng joala (Kotlinska et al., 2011). Karolo ea li-receptors tsa mGlu1 litlamong tse thabisang tsa lithethefatsi tse ling tsa tlhekefetso ha e so ka e bonoa. Ho thibela phetisetso ea glutamate ka li-receptor tsa mGlu5 sebelisa mGlu5 receptor negative allosteric modulators MPEP kapa MTEP e ikemetseng ea tsamaiso ea koae (Tessari et al., 2004; Kenny et al., 2005; Martin-Fardon et al., 2009; Keck et al., 2014), nikotine (Paterson et al., 2003; Paterson le Markou, 2005; Liechti le Markou, 2007; Palmatier et al., 2008), joala (Olive et al., 2005; Schroeder et al., 2005; Hodge et al., 2006; Tanchuck et al., 2011), le heroin (van der Kam et al., 2007). Ho ekelletsa moo, blockade ea li-receptor tsa mGlu5 tse sebelisang likhomphutha tse kaholimo li sebelisa cocaine- le motsoako oa nicotine o kentsoeng (McGeehan le Olive, 2003b; Herzig le Schmidt, 2004; Yararbas et al., 2010). Ka kakaretso, lithuto tse kaholimo li fana ka maikutlo a hore phetisetso ea mGlu5-Mediated glutamate e tsamaisana le litlamorao tse khahlisang tsa koae, nicotine, joala le heroin.

Ka lehlakoreng le leng, ha se lithuto tsohle tse lumellanang mabapi le karolo ea li-receptor tsa mGlu5 moputsong oa lithethefatsi. Mohlala, blockade ea li-receptor tsa mGlu5 tse sebelisang li-allrateic modulators MPEP kapa MTEP e ne e se na litlamorao ho nicotine- le cocaine-ikiwa ea CPP, ka ho fapana (Herzig le Schmidt, 2004; Veenman et al., 2011). Ho fapana le hoo, phuputso e 'ngoe e fumane hore mGlu5 negative allosteric modulator MPEP e nolofalletsa cocaine-, nicotine-, le heroin-ikiwa ea CPP (van der Kam et al., 2009a; Rutten et al., 2011). Ntle le moo, MPEP e ne e laoloa ke likhoto mme e kenyelletsa CPP ha e tsamaisoa e le 'ngoe feela har'a likhoto (van der Kam et al., 2009b). Liphumano tsena li bonts'a hore MPEP mohlomong e na le thepa ea eona e ruisang, e ka 'nang ea thusa cocaine-, nicotine-, le heroin-ikiwa ea CPP. Ho makatsang ke hore ha e laoloa ka mokhoa o sa tsotelleng, MPEP e phahamisa meputso ea moputso oa boko, e fana ka maikutlo a hore MPEP e hlohlelletsa mmuso o khelohileng (Kenny et al., 2005). Liphumano tsena tse hanyetsanang li ka bakoa ke phapang ea mekhoa lipakeng tsa lithuto, joalo ka mefuta ea liphoofolo tse sebelisitsoeng, tekanyetso ea MPEP, mokhoa oa tsamaiso (intravenous vs. intraperitoneal), mohlala o sebelisitsoeng ho lekola moputso (CPP vs. ICSS), le moralo oa Mofuta oa CPP ka boeona. Kamora nako, MPEP e ka sebetsa ka lipheo tse ling tse joalo ka ba tsamaisang li-norepinephrine le li-mGlu4 receptors (Heidbreder et al., 2003; Mathiesen et al., 2003). Ho hlokahala mosebetsi o eketsehileng ho utloisisa karolo ea li-receptor tsa mGlu5 liphellong tse khotsofatsang tsa lithethefatsi tsa tlhekefetso.

Joalokaha ho hlalositsoe pejana, ts'ebetso ea sehlopha sa II (mGlu2 / 3) le Sehlopha III (mGlu7 le mGlu8) li-receptors tsa mGlu li fokotsa phetisetso ea glutamate. Ka tatellano, tsamaiso ea mGlu2 / 3 agonist LY379268 e fokotsehile ho itaola ka mokhoa oa cocaine (Baptista et al., 2004; Adewale et al., 2006; Xi et al., 2010), nikotine (Liechti et al., 2007), le joala (Bäckström le Hyytia, 2005; Sidhpura et al., 2010). Ho phahamisa ho eketsehileng ha N-acetylaspartylglutamate (NAAG), agonist ea endo asili ea mGlu2 / 3 receptors, e sebelisa NAAG peptidase inhibitor, boits'oaro ba cocaine bo ikemetseng le ho theola ho thefuleha ha litefiso tsa moputso oa boko (Xi et al., 2010). Ka kopanelo, lithuto tsena li supa karolo ea bohlokoa bakeng sa li-receptor tsa mGlu2 / 3 litlamorao tse matlafatsang tsa koae, joala le nicotine. Empa LY379268 e boetse e kentse taolo ea lijo ho litekanyetso tse bonts'ang litlamorao tsa nicotine (Liechti et al., 2007). Kahoo, litlamorao tsa mGlu2 / 3 agonist li ne li sa khetheha bakeng sa moputso oa lithethefatsi. Ho feta moo, LY379268 e kenya tšebetsong li-mGlu2 le li-mGlu3 receptors. Ho khetholla pakeng tsa karolo ea li-receptor tsena tse peli tsa mGlu, li-ligands tse khethiloeng tsa mGlu2 li ile tsa qaptjoa. MGlu2 receptor positive allosteric modulators (PAMs) e fokotse ts'ebetso ea ts'ebetso ea cocaine le nikotine, empa eseng ho itaola ka lijo (Jin et al., 2010; Sidique et al., 2012; Dhanya et al., 2014). Ho feta moo, blockade ea li-receptor tsa mGlu2 tse sebelisang mohanyetsi oa mGlu2 (LY341495) ba nolofalletsa tšebeliso ea joala (Zhou et al., 2013). Ka kopanelo, lintlha tsena li tšehetsa karolo ea li-receptor tsa mGlu2 moputsong oa lithethefatsi. Karolo ea li-receptors tsa mGlu3 moputsong oa lithethefatsi, ka lehlakoreng le leng, e hloka ho hlahlojoa ka ho eketsehileng. Ho fumaneha ha li-ligands tse khethiloeng bakeng sa li-mGlu2 le li-mGlu3 receptors nakong e tlang ho tla thusa ho utloisisa hantle ts'ebetso ea li-receptor tsa mGlu2 le mGlu3 moputsong oa lithethefatsi.

Blockade ea phetisetso ea glutamate ka ts'ebetso ea li-receptors tsa mGlu7 li fumane tsamaiso ea boitšoaro ea cocaine (Li et al., 2009) le CPP e kentsoeng joala (Bahi et al., 2012). Karolo ea li-receptors tsa mGlu7 ho nicotine le moputso oa heroin e ntse e lokela ho hlahlojoa. Ka mokhoa o ts'oanang, ts'ebetso ea li-receptors tsa mGlu8 e ipehetse taolo ea tahi, e fana ka maikutlo a hore li-receptors tsena li kentse letsoho litlamong tse matlafatsang tsa nicotine (Bäckström le Hyytia, 2005). Karolo ea li-receptors tsa mGlu8 litlamorao tse thabisang tsa lithethefatsi tse ling tsa tlhekefetso ha e so ka e bululeloa.

Phetisetso ea glutamate le eona e ka fokotsoa ka ho kengoa tšebetsong le / kapa ka ho nyolleloa ha glutamate transporter GLT-1. Tsamaiso ea activator ea GLT-1 e fokotsehile CPP e khothalletsoang ke koae (Nakagawa et al., 2005). Ho ekelletsa moo, khafetsa taolo ea ceftriaxone, e sebelisang lino tse tahang ka har'a paradigm ea likhetho tse peli (Sari et al., 2011). Ceftriaxone e kenyellelitsoeng ts'ebeliso ea tšebeliso ea joala e kopantsoe ke ho nyolisoa ha GLT-1 ho NAcc le preortal cortex (PFC). Ho feta moo, tsamaiso ea GPI-1046 e bonts'a tšebeliso ea joala ho joala e rata li-P-rats, mohlomong ka lebaka la ho ngolisoa ha GLT-1 ho NAcc (Sari le Sreemantula, 2012). Ts'ebeliso ea joala ho litheko tsa P e boetse e fokotsehile kamora ho tsamaisoa ha 5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) (Alhaddad et al., 2014b). Sena se kopantsoeng ke ts'ebeliso ea lino tse tahang sa MS-153 se ka 'na sa kopanngoa le ts'ebetso ea GLT-1 le / kapa xCT (leseli la leseli la cystine-glutamate exchanger) libakeng tse' maloa tsa boko ho kenyelletsa NAcc, amygdala le hippocampus (Alhaddad et al. , 2014b; Aal-Aaboda et al., 2015). Ho feta moo, lithuto tsena li boetse li bonts'itse hore ts'ebetso ea marang-rang ea MS-153 e kopantsoe le ts'ebeliso ea litsela tsa p-Akt le NF-kB. Ka bokhutšoanyane, liphuputso tsena li fana ka maikutlo a hore ho hlakisoa hantle ha glaptamate ea synaptic ho thusa ho fokotsa litlamorao tse khahlisang tsa koae le joala.

Phetisetso ea glutamate e ka boela ea laoloa ke ho lokolloa ha glutamate le ho ho fihlela ka lisele tsa glial. Ho kenya ts'ebetsong ha cystine-glutamate exchanger, ho sebelisa N-acetylcysteine, e eketsa maemo a glutamate a extrasynaptic. Ho makatsang ke hore N-acetylcysteine ​​atticated nicotine boits'elo ba likhoto (Ramirez-Niño et al., 2013). Tlhaloso e 'ngoe e ka fumanoang bakeng sa liphetho tse tlalehiloeng ke hore keketseho ea litekanyetso tsa glutamate tsa extrasynaptic tse susumetsoang ke N-acetylcysteine ​​le eona e tsosa li-recynthic mGlu2 / 3 li-receptors, ebe li fokotsa ho lokolloa ha synaptic glutamate (Moussawi le Kalivas, 2010).

Mokhoa o mong oa ho fumana phetisetso ea glutamate ke ka ho thibela liteishene tsa calcium ion tse fumanehang liteisheneng tsa presynaptic glutamate. Lithethefatsi tse fokotsang presynaptic glutamate release li kanna tsa thusa ho fumana melemo e tlisoang ke lithethefatsi tsa tlhekefetso. Gabapentin, moriana oa antipileptic o lumelletsoeng ke FDA, o fokotsa ho lokolloa ha li-neurotransmitters tse ngata, ho kenyeletsa le glutamate, ka ho thibela lits'oants'o tsa α2δ-1 subunit ea liteishene tsa khalsiamo tsa calcium-gated (Gee et al., 1996; Fink et al., 2000). Rekoto ea lisele tsa setsi sa cell patch e bonts'a hore gabapentin e fumane motlakase ka ts'usumetso ea methapo ea methapo ea methapo e fumanoang liphoofolong tsa NAcc tse fumanoang liphoofolong tse nang le boiphihlelo ba koae (Spencer et al., 2014). Ho feta moo, tlhahlobo e tšoanang e bonts'itse hore boinotlo ba boikoetliso ba koae bo eketsa polelo ea subunit ea α2δ-1 ho NAcc. Ntle le moo, polelo ea subunit ea α2δ-1 e ile ea eketseha ka cortex ea motsoako ka mor'a ho pepesetsoa joala, methamphetamine, le nicotine (Hayashida et al., 2005; Katsura et al., 2006; Kurokawa et al., 2011). Phuputso ea morao tjena e tlalehile hore gabapentin e fumane methamphetamine-induct CPP (Kurokawa et al., 2011). Leha ho le joalo, litlamorao tsa gabapentin kapa tse ling tsa α2δ-1 li-antunonist tse mabapi le litlamorao tse thabisang tsa lithethefatsi tse ling tsa tlhekefetso ha li so hlahlojoe ka kotloloho. Moriana o mong o amoheloang oa antiepileptic o lumelloang ke FDA, lamotrigine, le ona o fokotseha ho lokolloa ha glutamate lisetineteng tsa presynaptic glutamate (Cunningham le Jones, 2000). Ka likhoto, lamotrigine e kenyellelitseng k'hok'heine e hlahisang koketso ea boko (Beguin et al., 2012). Empa, ts'ebetso ena ea lamotrigine e ile ea bonoa ho litekanyetso tse phahamisang meputso ea boko ea boko ha e sebelisoa feela, e fana ka maikutlo a hore lamotrigine e kanna ea tsosa moferefere ho liphoofolo. Leha ho le joalo, litekong tsa bongaka, lamotrigine ha ea ka ea fetola litlamorao tsa cocaine (Winther et al., 2000). Litlamorao tsa lamotrigine litlamorao tse thabisang tsa lithethefatsi tse ling tsa tlhekefetso ha li so ka tsa bonoa ka mokhoa o hlophisitsoeng. Le ha ho le joalo, ho lokela ho hopoloa hore ntle le ho thibela ho tlosoa ha glutamate, lamotrigine e na le mekhoa e meng ea ts'ebetso (Yuen, 1994).

Ka bokhutšoanyane, bopaki bo ntseng bo eketseha bo fana ka maikutlo a hore metsoako e thibelang phetisetso ea glutamate e fumana litlamorao tse tlisoang ke lithethefatsi tsa tlhekefetso. Li-receptor ka bobeli tsa ionotropic le mGlu li kentse letsoho ho arolelana litlamorao tse tlisoang ke lithethefatsi tse fapaneng tsa tlhekefetso. Kutloisiso e ntlafatsang ea karolo ea li-receptor tsa lihlopha tsa sehlopha sa III moputsong oa lithethefatsi ea hlokahala mme ho ka etsahala hore ho khonehe ha ligands tse ntle tsa pharmacological bakeng sa li-receptor tsena li fumanehe.

Lits'oants'o tsa bokamoso: Moputso oa glutamate le lithethefatsi

Lisele tsa Glial tse sebakeng sa extrasynaptic ke libapali tsa bohlokoa taolong ea phetisetso ea glutamate le puisano ea neuronal (Scofield le Kalivas, 2014). Ka lebaka leo, modumo oa ts'ebetso ea glial o ka khona ho fumana melemo e tlisoang ke lithethefatsi tsa tlhekefetso. Ho ts'ehetsa hypothesis ena, tsamaiso ea ibudilast, moduli oa sele ea glial, o kentse joala joala ho paradigm ea likhetho tse peli ka mokhoa o ikhethileng o khethang likhoto, a fana ka maikutlo a hore e fokotsa litlamorao tse matla tsa joala (Bell et al., 2015). Le ha litlamorao tsa ibudilast litlamorao tse thabisang tsa heroin li sa ka tsa hlahlojoa, ibudilast attenuated morphine-ikiwa le CPP, le keketseho ea NAcc dopamine kamora taolo ea morphine (Hutchinson et al., 2007; Bland et al., 2009). Mochine oa ts'ebetso oa ibudilast ha o utloisisoe ka botlalo, 'me ha ho hlake hore na li-ibudilast alters li fetisa joang. E boetse e ntse e tlameha ho khethoa haeba ibudilast e ka ama litlamorao tse thabisang tsa lithethefatsi tse ling tsa tlhekefetso, joalo ka cocaine le nikotine. Leha ho le joalo, ho fetola litlamorao tse ntle tsa lithethefatsi tsa tlhekefetso ka ho susumetsa ts'ebetso ea lisele tsa glial e kanna ea ba leano le thata la bokamoso.

Ho khahlisang hape ke taba ea hore li-glutamate receptors li bua ka kotlolloho ka kotloloho kapa ka lipontšo tsa phetisetso ea maqhubu ka liteishene tsa ion (mohlala, liteishene tsa khalsiamo) le li-receptors tsa li-neurotransmitters tse ling tse kang serotonin, dopamine, le GABA (Kubo et al., 1998; Cabello et al., 2009; Molinaro et al., 2009). Ka hona, tsela e le 'ngoe ea ho fokotsa phetisetso ea glutamate ho fumana litlamorao tse tlisang litlamorao tsa lithethefatsi tsa tlhekefetso e ka ba ka tšebeliso ea mechini e meholo ea heterooligomeric e thehiloeng lipakeng tsa li-glutamate le li-non-glutamate receptors kapa li-ion chants 2012). Phuputso ea morao-rao e tlalehile lipuo tse potileng pakeng tsa li-mGlu2 receptors le 5HT_2C li-receptors (González-Maeso et al., 2008). Ka 'nete, blockade ea 5HT_2C li-receptors ho NAcc e bonts'ang keketseho e hlahisitsoeng ke koae ka litekanyetso tsa glutamate ho liphoofolo tse nang le boiphihlelo ba koae (Zayara et al., 2011). Ka mokhoa o ts'oanang, ho na le bopaki ba tšebelisano pakeng tsa li-mGlu5 receptors le adenosine A_2A li-receptors (Ferre et al., 2002). Tsamaiso ea adenosine A_2A receptor antagonist e fumane keketseho ea litekanyo tsa striatal glutamate tse bonoang kamora tsamaiso ea mGlu5 receptor agonist (Pintor et al., 2000). Ha li kopantsoe hammoho, liphuputso tsena li fana ka maikutlo a hore matšoao a glutamate a ka fetoloa ka li-receptors tse seng glutamate. Leha ho le joalo, ho na le mosebetsi o mongata o ntseng o tlameha ho utloisisa tšebelisano ea li-receptor tsa glutamate tse nang le li-receptor tse seng glutamate, 'me ha ho tsejoe haeba li-complexes tsena tsa receptor li ka qhekelloa ho fumana litlamorao tse tlisoang ke lithethefatsi tsa tlhekefetso.

Lithethefatsi tsa tlhekefetso joalo ka joala le cocaine li eketsa polelo ea li-microRNA (miRNA) tse ling libakeng tsa boko tse amanang le moputso (Hollander et al., 2010; Li et al., 2013; Tapocik et al., 2014). Ebile, polelo e thetsang ea li-miRNA li ka hlahisa litholoana tse monate tsa koae le joala (Schaefer et al., 2010; Bahi le Dreyer, 2013). Li-MiRNA li boetse li laola polelo ea glutamate receptor le tšebetso (Karr et al., 2009; Kocerha et al., 2009). Ntle le moo, li-miRNA tse ling, tse kang miRNAs-132 le 212, li laoloa ka ho khetheha ke li-mGlu receptors, empa eseng li-ionotropic receptors (Wibrand et al., 2010). Ka hona, lithuto tsa nako e tlang li ka hloka ho hlahloba hore na litlamorao tse tlatselletsang tsa lithethefatsi tsa tlhekefetso li ka fumaneha ka ho laola li-miRNA tse laolang ho saena hoa glutamatergic. Leha ho le joalo, motho o tlameha ho ba hlokolosi, kaha polelo e qhekellang miRNA e ka ama ts'ebetso ea litefiso tse ngata mme e kanna ea thibeloa ho glutamate signaling (Bali le Kenny, 2013).

Ho lemalla lithethefatsi ho batho hangata ho qaloa ke tšebeliso ea lithethefatsi lilemong tsa bocha. Ebile, ho batho, ts'ebetso ea meputso e fapana lipakeng tsa batho ba baholo le bacha (Fareri et al., 2008). Ka mokhoa o ts'oanang, liphuputso tse 'maloa li tlalehile liphapang tsa melemo ea lithethefatsi tsa tlhekefetso lipakeng tsa likhoto tsa batho ba baholo le ba banyenyane (Philpot et al., 2003; Badanich et al., 2006; Zakharova et al., 2009; Doherty le Frantz, 2012; Schramm-Sapyta et al., 2014; Lenoir et al., 2015). Ho feta moo, bong bo susumetsa tšebeliso ea lithethefatsi ho batho (Rahmanian et al., 2011; Bobzean et al., 2014; Graziani et al., 2014) le litlamorao tse khotsofatsang tsa lithethefatsi tsa tlhekefetso ho liphoofolo (Lynch le Carroll, 1999; Russo et al., 2003a,b; Torres et al., 2009; Zakharova et al., 2009). Ho feta moo, joala bo ama ka mokhoa o fapaneng litekanyetso tsa basal glutamate ho banna ha li bapisoa le likhoto tsa basali (Lallemand et al., 2006, 2011). Leha ho le joalo, tšusumetso ea lilemo le bong, ekaba o le mong kapa o kopane, boikarabellong ba moputso oa lithethefatsi ha o so ka o hlahlojoa ka nepo. Lithuto tsa nako e tlang tse rarollang mathata a lilemo le bong ho phumants'o ea glutamate le moputso oa lithethefatsi li tla matlafatsa kutloisiso ea rona ea karolo ea bokhoba ba bokhoba ba lithethefatsi.

VTA

VTA e fumana litlatsetso tse pharalletseng tse tsoang liphoofolong tse fapaneng tsa limbic, cortical, le subcortical, joalo ka amygdala, PFC, habenula ea morao-rao, hypothalamus ea morao-rao, "ventral pallidum", "medial septum" , 2005; Geisler le Bohlale, 2008; Watabe-Uchida et al., 2012). VTA dopaminergic neurons le eona e amohela likhakanyo tsa glutamatergic tse tsoang ho sebopeho sa brainstem, joalo ka mesopontine reticular form, laterodorsal tegmental, le pedunculopontine tegmental nucleus, cuneiform nucleus, median raphe, le colliculus e phahameng (Geisler le Trimble, 2008). Lisebelisoa tsena tsa glutamatergic li laola ho phatloha ho hoholo ha li-neurons tsa VTA dopaminergic mme ka hona li ka laola litlamorao tse tlisoang ke lithethefatsi (Taber et al., 1995; Overton le Clark, 1997). Ho feta moo, ente ea ka kotloloho ea bahanyetsi ba receptor ba glutamate ho VTA e hlahisitsoeng ke keketseho e bakoang ke nicotine le NAcc dopamine (Schilstrom et al., 1998; Fu et al., 2000).

Lithethefatsi tsa tlhekefetso le maemo a glutamate a VTA

Litlamorao tsa lithethefatsi tsa tlhekefetso maemong a VTA glutamate li bonts'oa Lethathamong Lethathamo3.3. Tsamaiso ea cocoaine e ile ea eketsa maemo a glutamate a VTA ka bobeli liphoofolong tsa cocaine-naïve le. Ho liphoofolo tse nang le boiphihlelo ba koae, keketseho ea "cocaine" e khothalletsoang ke cTAine e fumanoe litekong tse amanang le litlamorao tsa cocaine (Kalivas le Duffy, 1998; Zhang et al., 2001). Ka lehlakoreng le leng, ho liphoofolo tsa cocaine-naïve, keketseho ea glutamate e ne e khuts'oane hape e sa bonoe haholo ha e bapisoa le e bonoang liphoofolong tse nang le boiphihlelo ba koae (Kalivas le Duffy, 1995; Zhang et al., 2001). Ho tataisoa ha tokollo ea glutamate kamora ho pepesetsoa hoa koae ka makhetlo a mangata ho tsamaisoa ke ho emisoa ha li-receptor tsa D1 mme ho fumanoe ke blockade ea D1 dopamine receptors (Kalivas le Duffy, 1998; Kalivas, 2009). Tumellanong le lithuto tsena tse kaholimo, keketseho ea boemo ba glutamate ba VTA e ile ea bonoa kamora ho iphekola hoa koae ho liphoofolo tse nang le boiphihlelo ba koae, empa eseng ho liphoofolo tsa cocaine-naïve tse nang le boiphihlelo ba ho ithaopa (U et al., 2007). Leha ho le joalo, keketseho ea boemo ba glutamate ba VTA ho liphoofolo tse nang le boiphihlelo ba koae e ne e le nakoana mme e sa bonoe ho pholletsa le nako ea ho itaola ea koae. Ho khahlisang, keketseho ea tekanyo ea VTA glutamate liphoofolong tse nang le boiphihlelo ba koae e boetse e bonoe kamora ho itaola ha saline, ho fana ka maikutlo a hore tokollo ea VTA glutamate e ka amahanngoa le tebello ea cocaine le ho susumetsoa ke lithahasello tse amanang le cocaine (Wise, 2009). Ka ho makatsang, keketseho ea boemo ba glutamate ba VTA e ile ea boela ea bonoa phoofolo e nang le boiphihlelo ba koae ka mor'a ho kenella ka ente ea cocaine methiodide e sa keneleng mothapo oa boko ba mali (Wise et al., 2008). Lintlha tsena li tšehetsa khopolo ea hore mekhabo-puo e kopanyang e amanang le cocaine e ka lekana bakeng sa tokollo ea VTA glutamate. Leha ho le joalo, ho hlokahala mosebetsi o mongata ho tseba haeba liphetoho maemong a VTA glutamate tse bonoang kamora ho tsamaisoa ha koae le / kapa lithahasello tse amanang le koae li hlahisoa ke ts'ebetso ea likatsetso tse tšoanang kapa tse fapaneng tsa kelello ho VTA.

    

Lethathamo 3

Litlamorao tsa lithethefatsi tsa tlhekefetso ho litekanyetso tsa glutamate libakeng tse itseng tsa boko.

Tumellanong le litlamorao tsa koae ka likhakanyo tsa glutamate tsa VTA, keketseho ea maemo a glutamate ea VTA e ile ea boela ea bonoa kamora ho tsamaisoa ha nikotine ho sebelisa Ka vivo microsalysis (Fu et al., 2000). Hape hape, Fu le basebetsi mmoho le bona ba hlokometse keketseho ea maemo a glutamate a VTA a holimo haholo ho feta a hlokoang ho bona litlamorao tsa nicotine. Haufinyane tjena, patlisiso e tlaleha keketseho ea nakoana ea maemo a bophahamo ba VTA kamora ho kenella kahare ho nicotine infusion (0.03 mg / kg) e sebelisa Ka vivo voltammetry (Lenoir le Kiyatkin, 2013). Ho fapana le cocaine le nicotine, taolo ea joala ha ea ka ea tlisa keketseho ea litekanyetso tsa VTA glutamate maemong a lithethefatsi tse sebelisang joala ba lithethefatsi le naïve (Kemppainen et al., 2010). Anatomically, VTA e ka aroloa ka anterior le posterior VTA (Sanchez-Catalan et al., 2014). Phuputso e sa tsoa feta e tlalehile karabo ea biphasic glutamate ka morao ho VTA ho litekanyetso tse fapaneng tsa joala ho likhoto tsa Wistar tsa basali (Ding et al., 2012). Tekanyo e tlase (0.5 g / kg; ip) ea joala e hlahisitse keketseho e kholo ea litekanyetso tsa glutamate ha li bapisoa le motheo ho liphoofolo tsa joala-naïve. Ka lehlakoreng le leng, tekanyo e phahameng ea joala (2 g / kg; ip) ea joala e ile ea fella ka ho fokotseha ha sekhahla sa litekanyetso tsa glutamate tsa VTA. Habohlokoa le ho feta, tsamaiso ea tekanyetso e phephetsang ea 2 g / kg (ip) ea joala liphoofolong tse nang le joala le eona e felletse ka ho fokotseha ha maemo a glutamate ea VTA. Phapang pakeng tsa liphumano lipakeng tsa Kemppainen et al. (2010) le Ding et al. (2012) lithuto li kanna tsa bakoa ke phapang ea mekhoa e kang ho tsebisoa ka 'mankhonthe sebakeng sa VTA le khatello ea likhoto (joala bo kenyang likhoto tsa Wistar) tse sebelisitsoeng lithutong tsena tse peli.

Ho fapana le cocaine, ho itlhokomela ha heroin ha hoa ka ha fetola maemo a bonyane a VTA ho liphoofolo tse nang le boiphihlelo (Wang et al., 2012). Leha ho le joalo, phuputso e tšoanang e boetse e tlaleha hore ho itaola ha saline ho liphoofolo tse nang le tsebo ea heroine ho felletse ka keketseho ea maemo a glutamate a VTA. Ha li kopantsoe hammoho, liphumano tsena li fana ka maikutlo a hore tokollo ea VTA glutamate e arabela ho lithahasello tse amanang le heroin empa e thibeloa ke heroin ka boeona. Ho tlameha ho boleloa mona hore litlamorao tsa "heroin e ipatileng" maemong a glacam ea VTA ho liphoofolo tse nang le boiphihlelo li entsoe kamora seboka se le seng sa ho felisoa, se ka beng se fetotse tebello ea moputso oa heroin. Ka kakaretso, cocaine, nikotine, le taolo ea joala ho eketsa litekanyetso tsa VTA glutamate. E latelang, litla-morao tsa thibelo ea phetisetso ea VTA glutamate litlamorao tse khahlisang tsa lithethefatsi tsa tlhekefetso li tla tšohloa.

Phetisetso ea VTA glutamatergic le mekhoa ea boits'oaro ea moputso oa lithethefatsi

Blockade ea phetisetso ea glutamatergic ho VTA ka thibelo ea li-receptor tsa ionotropic glutamate e fokotse litlamorao tse ntle tsa lithethefatsi tsa tlhekefetso (bona Lethathamo Tafole4) .4). Mohlala, blockade ea NMDA kapa AMPA kapa li-receptor ka bobeli ho VTA e kentsoeng nicotine (Kenny et al., 2009) le taolo ea taolo ea joala (Rassnick et al., 1992; Czachowski et al., 2012). Ntle le moo, li-blockade tse kopaneng tsa NMDA le li-receptor tsa AMPA ho VTA li kentse CPP e kentsoeng koae (Harris le Aston-Jones, 2003). Ho khahlisang, li-blockade tsa li-receptor tsa AMPA ho VTA li ile tsa eketsa ho itaola ha heroin ha ho bapisoa le taolo (Xi le Stein, 2002; Shabat-Simon et al., 2008). Keketseho ea boits'oaro ba heroin e ile ea bonoa bakeng sa lethal dose e phahameng ea li-heroin (0.1 mg / kg / inf) eo ka tloaelo e ileng ea baka likarabo tse fokolang tsa tsamaiso. Motheong oa mokhoa ona oa ho arabela, keketseho e bonoang ea boitaolo ba heroin ha e le hantle e nahanoa hore e bakoa ke ho fokotseha hoa litlamorao tsa heroin. Ho khahlisang, Shabat-Simon et al. (2008) e bontšitse hore li-receptor tsa AMPA ho VTA e ka ntle, empa eseng VTA ea morao-rao, e ile ea buisana le litlamorao ho tsamaiso ea heroin. Ka kakaretso, karolo ea li-receptor tsa AMPA ho VTA mabapi le litlamorao tse matlafatsang tsa heroin ha e hlake, 'me lithuto tse tsoelang pele li sebelisa kemiso e tsoelang pele ea tekanyetso, e lekang tšusumetso ea phoofolo hore e sebeletse tlhahiso ea heroin, e hlokahala. Ka kakaretso, phetisetso ea glutamate ka li-receptor tsa ionotropic ho VTA e tsamaisana le litlamorao tse monate tsa joala, cocaine, nikotine, mohlomong le heroin.

    

Lethathamo 4

Litholoana tsa ho thetsisa ha lithethefatsi ho fetoleng lefu la glutamatergic kamora ho tsamaisoa ke intracranial libakeng tse itseng tsa boko meputsong ea lithethefatsi.

Blockade ea glutamatergic neurotransication ka metabotropic receptors ho VTA le eona e bonts'itse litlamorao tse khotsofatsang tsa lithethefatsi tsa tlhekefetso. Mohlala, blockade ea phetisetso ea glutamate ho VTA ekaba ka ts'ebetso ea li-mGlu2 / 3 receptors kapa blockade ea mGlu5 receptors e fokotse ts'ebetso ea boithati ba nicotine (Liechti et al., 2007; D'Souza le Markou, 2011). Li-microinjection tsa mGlu2 / 3 agonist kapa mGlu5 negative allosteric modulator lithutong tsena li ne li lebisitsoe ho VTA e kamorao. Ho khahlisang ke hore thibelo ea li-receptors tsa mGlu5 ho VTA e boetse e fokolitse boipuso ba lijo (D'Souza le Markou, 2011). Ka hona, li-receptors tsa mGlu5 ho VTA li bonahala li tsamaisana le litlamorao tse matlafatsang tsa meputso ea tlhaho le ea lithethefatsi. Hape hape, ho lokela ho hopoloa mona hore karolo ea li-mGlu receptors litlamong tse matlafatsang tsa koae, joala le heroin ha li so fumanoe. Ho feta moo, liphoofolo li ipeha k'hok'heine le joala ka kotloloho ho VTA e ka morao, empa eseng ho VTA e ka ntle (Rodd et al., 2004, 2005). Karolo ea glutamate ho e kahare kapa e ka morao ea VTA litlamorao tse matlafatsang tsa koae le joala ha e e-so tsejoe.

Li-bokella tsa nyutlelie

Joalo ka VTA, NAcc e amohela likhakanyo tse pharalletseng tse tsoang ho PFC, amygdala, hippocampus, le thalamic nuclei (Brog et al., 1993). Glutamate e ka boela ea hlahisoa ka kopanelo le dopamine ho NAcc ke VTA dopaminergic neurons e buang ka VGLUT (Hnasko et al., 2012). Ka kopanelo, lipokello tsena li fana ka tlhaiso-leseling ea nako le maemo, ho tseba hore na ho na le tlhokomelo e kae ho susumetsoang, ho thibela boits'oaro bo potlakileng, le ho laola likarabo tse susumetsang le tse susumetsang maikutlo. Ka hona, NAcc e bapala karolo ea bohlokoa molemong oa ho etsa liqeto ho fumana meputso ea lithethefatsi. Anatomically, NAcc e arotsoe ka mokhoa o fapaneng likarolo tsa mantlha le likhetla (Zahm le Brog, 1992), le khetla ea NAcc e tlalehiloe ho buisana le litlamorao tse tlisoang ke lithethefatsi tsa tlhekefetso (Di Chiara, 2002).

Khohlano ea polelo ea thahasello

Sengoli se phatlalatsa hore lipatlisiso li entsoe kamora ho se be le kamano efe kapa efe ea khoebo kapa ea lichelete e ka nkuoang e le khohlano e ka bang teng ea phaello.

Mosebetsi ona o tšehelitsoe ke Bower, Bennet, le Bennet Endlings Chair Research Award e fuoeng MD ke The Raabe College of Pharmacy, Ohio North University (ONU), Ada, Ohio. Sengoli se rata ho leboha Drs. Rachel Muhlenkamp le Nurith Amitai bakeng sa litlhaloso tse hlakileng mabapi le mongolo o ngotsoeng.

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