Glutamatergic syntaptic plastikiity tsamaisong ea mesocorticolimbic ho lemalla (2015)

Front Cell Neurosci. 2015 Jan 20; 8: 466. Doi: 10.3389 / fncel.2014.00466. eCollection 2014.

van Huijstee AN¹, Mansvelder HD¹.

inahaneloang

Lithethefatsi tse lemalloang li nchafatsa mokokotlo oa moputso oa boko, tsamaiso ea mesocorticolimbic dopamine (DA), ka ho susumetsa mekhoa e atileng ea litheko tsa glutamatergic. Polasetiki ena e kopantsoeng le lithethefatsi ho nahanoa hore e kenya letsoho nts'etsopeleng le ho phehelleng ha lithethefatsi. Tlhahlobo ena e totobatsa liphetoho tse ntlafalitsoeng tse khothalletsoang ke Ka vivo ho pepesehela lithethefatsi tse lemalloang 'me ho hlalosa kamoo liphetoho tsena tse kopantsoeng ke lithethefatsi li ka tlatselletsang likarolong tse fapaneng tsa boitšoaro bo tlatsetsang, joalo ka tšebeliso e mpe ea lithethefatsi leha e le litlamorao tse mpe ebe o khutlela morao. Pele, ho pepesetsoa ha lithethefatsi tse lemalloang ho etsa hore ho be le liphetoho tse fetolang tikolohong ea "ventral tegmental" (VTA). Tlhahiso ena e kopantsoeng le lithethefatsi tse hlahisoang ke lithethefatsi ho VTA kamorao ho moo e baka liphetoho tsa synaptic libakeng tse tlase tsa sisteme ea mesocorticolimbic, joalo ka li-nucleus accumbens (NAc) le preortalal cortex (PFC), ka tšebeliso e eketsehileng ea lithethefatsi. Liphetoho tsena tsa glutamatergic synaptic joale ho nahanoa hore li kopanya matšoao a mangata a boitšoaro a khethollang ho lemalla. Mehato ea kamoso ea polasetiki ea glutamatergic synaptic ho NAc mme haholo ho PFC e bapala karolo ea ho boloka bokhoba ba tahi le ho khutlisetsa phosong ea ho ts'oara lithethefatsi tse susumetsoang ke lithahasello tse amanang le lithethefatsi. Ho nchafatsa li-circuits tsa glC tsa mantle tsa PFC ho ka phehella ho ba motho e moholo, ho etsa hore tlokotsi e sa feleng e khutlele morao. Re tla tšohla hore na liphetoho tsena tsa neurobiological tse hlahisoang ke lithethefatsi tsa tlhekefetso li ka fana joang ka lipehelo tse ncha tsa maano a menyetla ea kalafo bakeng sa ho lemalla.

Keywords: bokhoba ba lithethefatsi, lithethefatsi tsa tlhekefetso, polasetiki ea synaptic, glutamate, dopamine, sebaka sa ho kenella ka mokokotlo, li-bokono tsa nucleus, cortex ea pele.

Selelekela

Ka nako e telele, bokhoba ba tahi bo ne bo sa bonoe e le bokuli, empa e le khetho ea motho. Ka hona, ho ile ha etsoa boiteko bo fokolang ho fumana maano a loketseng a kalafo bakeng sa batho ba lemaletseng lithethefatsi. Lilemong tse mashome tse fetileng batho ba hlokometse hore lithethefatsi tse lemalloang li baka phetoho ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea boko, le hore ho lemalla ke bokuli bo sa foleng. Bokhoba ba tahi, kapa "ts'ebeliso ea lithethefatsi" joalo ka ha ho hlalositsoe ho DSM-5 (American Psychiatric Association, 2013), e tšoauoa ka tšebeliso e matla ea lithethefatsi leha e le litlamorao tse mpe le litheko tse phahameng tsa ho khutla hape. Lefatšeng ka bophara, batho ba hakanyetsoang ba limilione tse 27 ke ba sebelisang lithethefatsi tsa opiates, cocaine, cannabis kapa amphetamines le 1 ho lefu le leng le le leng la 100 har'a batho ba baholo ho pakoa ka tšebeliso e seng molaong ea lithethefatsi (Ofisi ea Machaba a Kopaneng ea Lithethefatsi le Tlolo ea Molao, 2014). Ho feta moo, WHO e hakanya hore litheko tsa sechaba tsa tšebeliso ea lithethefatsi tse seng molaong li ne li le haufi le 2% ea sehlahisoa se seholo sa lapeng ho 2004 linaheng tse e lekantseng (Mokhatlo oa Lefatše oa Bophelo, 2008). Bongata ba litšenyehelo tsena bo ne bo amahanngoa le botlokotsebe bo amanang le lithethefatsi. Leha boemo ba lithethefatsi ba Europe bo ntse bo tsitsitse lilemong tsa morao tjena, ts'ebeliso ea lithethefatsi Europe e ntse e phahame ka litekanyetso tsa nalane (EMCDDA, 2013). Holim'a moo, litjeo le lefu ka lebaka la ts'ebeliso e mpe ea lithethefatsi tse amoheloang sechabeng, tse kang ho tsuba koae le ho noa joala, li kholo haholo. Ho latela WHO, koae e bolaea batho ba ka bang limilione tse 6 selemo se seng le se seng mme batho ba limilione tse 3.3 ba shoa selemo se seng le se seng ka lebaka la tšebeliso e mpe ea joala. Sena ha se nahane ka likamano tsa lisosa pakeng tsa tšebeliso e mpe ea joala le ho tsuba koae le mathata a mangata a kelello le a boitšoaro (Volkow le Li, 2005). Ka kakaretso, moroalo oa lefatše lohle oa ho lemalla o moholo haholo. Ka bomalimabe, mekhoa ea kalafo ea hona joale ea ho lemalla lithethefatsi e ntse e sa sebetse. Ho ntlafatsa maano a kalafo, ho bohlokoa ho utloisisa hamolemo liphetoho tse amanang le methapo ea kutlo.

Le ha ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebetso ea ts'ebeliso ea kelello Tsamaiso ea mesocorticolimbic e na le sebaka sa "ventral tegmental" (VTA) le likarolo tsa bokong tse kahare ho likhakanyo tse tsoang VTA, tse kang li-nucleus accumbens (NAc), preortalal cortex (PFC), amygdala, le hippocampus (Swanson, 1982). Sisteme ea mesocorticolimbic e bohlokoa bakeng sa moputso le matlafatso ea ts'ebetso, ts'usumetso, le boitsoaro bo tataisang sepheo (Schultz, 1998; Bohlale, 2004). Lithethefatsi tsohle tse lemalloang li sebetsa ka har'a mesocorticolimbic system, li eketsa maemo a DA tsamaisong ena (Di Chiara le Imperato, 1988). Mefuta e fapaneng ea lithethefatsi e eketsa maemo a li-mesocorticolimbic DA ka mekhoa e ikhethileng ea li-cellular. Nikotine e eketsa maemo a DA ka ho hlohlelletsa ka ho toba li-neurons tsa VTA DA ka li-receptors tsa nicotinic tsa α4β2 tse nang le nicotinic (Maskos et al., 2005). Lithethefatsi tse ling tse 'maloa, tse kang benzodiazepines, opioids le cannabinoids, li hlahisa litholoana tsa tsona ka ho thibela li-interneuron tsa GABAergic ho VTA, ka tsela eo li fokotsa ho thibeloa ha li-neuron tsa DA (Johnson le North, 1992; Szabo et al., 2002; Tan et al., 2010). Psychostimulants, joalo ka koae le amphetamine, e eketsa maemo a DA ka ho sebelisana le sepolesa sa DA, ka tsela ena e thibela ho pheta-pheta ha DA (Williams le Galli, 2006). Keketseho ea maemo a mesocorticolimbic DA e thusa lipakeng tsa litlamorao tse matlafatsang tsa lithethefatsi tse lematsang. Leha ho le joalo ha e hlalose litlolo tse tšoarellang tsa nako e telele tse bonoang ke ho lemalla, hobane tsena li ntse li le teng ha lithethefatsi li se li hlakotsoe 'meleng le maemo a DA a se a khutletse ho tloaelehileng. Nts'etsopele le polelo ea boitšoaro bo lematsang li bakoa ke li-neuroadaptations tse sa feleng tsa ts'ebetso ea mesocorticolimbic system.

Bopaki bo akaretsang bo bontša hore lithethefatsi li hlile li baka liphetoho tsa nako e telele bokong. Haholo-holo, lithethefatsi tsa tlhekefetso li fetola phetiso ea synaptic tsamaisong ea mesocorticolimbic. Ketsahalo ena e bitsoa li-drugaptuction synaptic plasticity (Lüscher le Malenka, 2011). Tlhahlobo ena e bua ka polasetiki ea synaptic e hlahisitsoeng ke Ka vivo ho pepesehela lithethefatsi tsa tlhekefetso. Leha mefuta e mengata ea li-synapses e fetotsoe ke lithethefatsi tse lemalloang, lithethefatsi tse lemalloang ho nahanoa hore li fetola phetiso ea glutamatergic (Lüscher, 2013). Ho feta mona, polasetiki e hlahisoang ke lithethefatsi ea phepelo ea glutamatergic e ithutile haholo. Re tla totobatsa tse fumanoeng tsa morao-rao tse amanang le ts'oaetso ea li-transaptic tse tlisoang ke lithethefatsi ka sepheo sa ho fetisetsa lithethefatsi, ka sepheo sa ho hlakisa hore na mekhoa e tloahelehileng e ka morao ea liphetoho tsena tsa testaptic ke efe, le hore na liphetoho tsena tse bakiloeng ke lithethefatsi li kenya letsoho joang likarolong tse fapaneng tsa boits'oaro bo lemalloang.

Liphetoho tsa pele ho phetiso ea synaptic

Synaptic polasetiki e sebakeng sa ventral tegmental (VTA)

Liphetoho ho phepelo ea synaptic li se li etsahetse kamora ho pepesetsoa sethethefatsi se lematsang. E le 'ngoe Ka vivo ho pepesehela lithethefatsi tse lemalloang ho etsa hore ho be le keketseho ea matla a synaptic ho li-synaptic synapses ho li-neuron tsa DA tsa VTA. Ho ile ha fanoa ka ente e le 'ngoe ea cocaine e senang boitšoaro Ka vivo ho litoeba le likhoto, le 24 h hamorao, li-transynaptic currents (EPSCs) tse nyakallisang li tlalehiloe ka li-neurop tsa dopaminergic maemong a liphoofolong tsa liphoofolo tsena ho hlokomela liphetoho ka har'a matla a synaptic (Ungless et al., 2001). Tekanyo ea AMPAR- vs. NMDAR-Mediated EPSCs (AMPAR / NMDAR ratio) ho li-neurons tsa VTA DA e ile ea eketseha haholo. Keketseho ena e ka bontša keketseho ea maqhubu a AMPAR kapa ho fokotseha ha maqhubu a NMDAR kapa ho kopana ha bobeli. Ha e le hantle, maqhubu a ntseng a eketseha a AMPAR le ho fokotseha ha maqhubu a NMDAR ka bobeli ho etsahala ebile ho baka keketseho ea AMPAR / NMDAR kamora ho pepesetsoa sethethefatsi se lematsang. Ungless et al. (2001) e bonts'itse hore phetiso ea AMPAR e ntlafalitsoe ho li-glutamatergic synapses ho li-neurons tsa DA tsa VTA, hobane li-amplitude le maqhubu a li-EPSC tsa AMPAR-Mediated miniature li ile tsa eketseha haholo kamora Ka vivo ho pepesetsoa koae. Sena se ile sa ts'ehetsoa hape ke ho fumana hore AMPA e sebelisa li-neurons tsa VTA DA haholo 'me e lebisitse ho melapo e meholo e kenyellelitsoeng ke AMPA mekhoeng e tsoang ho litoeba tse amohetseng ente ea koae ho fapana le linokoe tse tsoang ho litoeba tse nang le letsoai. Habohlokoa, ts'ebetso ea nako e telele ea cocaine e susumetsoang ke nako e telele ea li-frequency tsa AMPAR e bonts'itsoe e le e ikhethang bakeng sa li-neurons tsa DA tsa VTA, kaha ha ho na ts'ebeliso e fumanoeng hippocampus kapa Gaba neurons ho VTA. Keketseho e bakoang ke cocoaine ka karolelano ea AMPAR / NMDAR ha ea ka ea e-ba teng ha koae e ne e tsamaisoa hammoho le mohanyetsi oa NMDAR, e bonts'a hore keketseho ea tekanyo ea AMPAR / NMDAR e itšetleha ka ts'ebetso ea NMDAR. Kahoo, ho pepesetsoa ha motho a le mong oa koae ea "cocaine" ho kenya polasetiki ea methapo ea kutlo ho li-neurons tsa VTA tse tšoanang le NMDAR e itšetlehileng ka nako e telele ea ts'ebeliso ea nako e telele (LTP). Tumellanong le sena, li-synaptic plasticity tse hlahisitsoeng ke lithethefatsi li latela ts'ebetso ea morao-rao ea morao-rao e fana ka maikutlo a hore mefuta ena e 'meli ea polasetiki e arolelana metheo ea (Ungless et al., 2001; Liu et al., 2005; Argilli et al., 2008; Luu le Malenka, 2008).

Kamora ho sibolloa ha Ka vivo polasetiki e kentsoeng koae, ho ile ha fuputsoa hore na lithethefatsi tse ling tsa tlhekefetso li etsa hore ho be le liphetoho tse tšoanang phetisong e khahlisang ea VTA. Ho tloha a vitro lithuto li ne li se li ntse li tsebahala hore ts'ebeliso ea esita le lethalinyana le tlase la nicotine e etsa hore PDP e kopane le maikutlo a thabisang ho li-neurons tsa VTA DA (Mansvelder le McGehee, 2000), e tšehetsa mohopolo ona. Ho joalo, lithethefatsi tsohle tse lemaletseng ho fihlela joale (har'a tsona morphine, nicotine, benzodiazepines le ethanol) li hlahisa phetisetso ea phetisetso ea AMPAR ho VTA DA neurons 24 h kamora Ka vivo Tsamaiso ea tekanyetso e le 'ngoe (Saal et al., 2003; Tan et al., 2010). Litekanyo tsa AMPAR / NMDAR ha lia ka tsa eketsoa kamora Ka vivo Tsamaiso ea lithethefatsi tse sa sebetseng tsa psychoactive fluoxetine le carbamazepine (Saal et al., 2003). Taba ea hore litlelase tse fapaneng tsa lithethefatsi, ka mekhoa e fapaneng ea ts'ebetso ea molek'hule, e ts'oara mofuta o ts'oanang oa polasetiki ea VTA DA neurons e ne e le sesupo sa pele sa hore mofuta ona oa polasetiki ea synaptic o kanna oa amana le thepa ea bokhoba ba lithethefatsi tsena.

Patlisiso e tsoelang pele mabapi le mekhoa e tlatselletsang keketseho ea AMPAR / NMDAR e bonts'itse hore ts'ebetso e hlokahalang ea NMDAR e hlokahalang bakeng sa polasetiki e kopantsoeng le lithethefatsi e etsahala ka ho hlohlelletsa DA D₅ li-receptors, kaha ha ho na ts'usumetso e entsoeng ka koae e fumanoeng kamora ho sebelisoa ha D₁/D₅ receptor antagonist kapa ho D₅ lithetsi tsa li-receptor li-knockout (Argilli et al., 2008). Nikotine e kentsoeng polasetiki ea synaptic a vitro hape ho latela DA D₅ li-receptors (Mao et al., 2011). Phetisetso e ntlafalitsoeng ea AMPAR e bakoa ke ho kenngoa ha li-AMPAR tse haellang tsa GluA2 ho synapse e latelang. Ka vivo tlhahiso ea lithethefatsi tse lemalloang (Bellone le Lüscher, 2006; Argilli et al., 2008). Mosebetsi oa pele ke Fitzgerald et al. (1996) e se e fane ka leseli la hore polasetiki e hlahisoang ke lithethefatsi ho li-glutamatergic synapses ho li-neuron tsa DA tsa VTA li kenyelletsa phetoho ea li-AMPAR tse hlokang GluA2. Pontšo ea li-subunits tsa GluA1, empa eseng GluA2 subunits, e ile ea eketseha ka li-neurons tsa VTA DA kamora ho pepesetsoa koae (Citzgerald et al., 1996). Ho fumana bopaki bo tobileng ba phetoho ho li-AMPAR tse se nang GluA2, Bellone le Lüscher (2006) o sebelisitse litšobotsi tse ikhethileng tsa li-GluA2-tse se nang AMPAR. Li-AMPAR tse haelloang ke GluA2 ke Ca²⁺-Sireletsehile, li na le boits'oaro bo boholo, li hlophisa kahare mme li thibetsoe ke polyamines (Washburn le Dingledine, 1996; Isaac et al., 2007). Phokotso ea li-EPSC tsa AMPAR-mediated e ile ea eketseha kamora ts'ebetso ea ts'ebetso ea koae, le tsamaiso ea polyamine toxin Joro spider toxin (JST) e koetsoeng ka mokhoa oa EMPAR-Mediated EPSC ka litoeba tse tšoaroang ke koae, e tiisa ho kenngoa ha li-AMPAR tsa GluA2 tse haellang (Bellone le Lüscher, 2006). Li-receptor tsena li ka kenngoa ka holim'a letamo le leng le le teng la li-AMPAR tsa GluA2 kapa ba ka nkela li-receptor tse nang le li-GluA2, ba boloka palo e felletseng ea li-AMPAR ho li-synapse kamehla. Immunogold labeling ea GluA2 subunits e bonts'itse hore letamo la cytoplasmic la GluA2-le nang le AMPAR le ntlafalitsoe kamora ho pepesetsoa koae, ha GluA2 ea ngolisang mantsoe ka har'a synapse e fokotsehile (Mameli et al., 2007). Kahoo, ho pepesetsoa lithethefatsi tse lemalloang ho baka phapanyetsano ea li-GluA2 tse nang le li-AMPAR tse haelloang ke GluA2, tse bakang phetisetso ea AMPAR ka lebaka la boits'oaro bo phahameng ba seteishene sa li-AMPAR tse se nang GluA2.

Qalong, lithuto tse tlalehileng tšibollo ea tšusumetso ea lithethefatsi ea AMPAR-mediated transmit ho li-neurons tsa VTA DA li ile tsa etsoa 24 h kamora taolo ea lithethefatsi, empa ke nako e feng ea netefatso ea ts'ebetso kamora ho pepesetsoa ha lithethefatsi? Argilli et al. (2008) e fumane hore polasetiki ea synaptic e etsahetse ka potlako haholo kamora ts'ebetso, hobane ts'ebetso ea AMPAR e fumanoe e le teng kahare ho 3 h (Argilli et al., 2008). Cocoaine e kenyellelitsoeng ka har'a cocoaine e kopantsoe le nakoana, hobane ts'ebeliso ea synaptic e ne e ntse e bonoa kamora matsatsi a 5, empa eseng kamora matsatsi a 10 (Ungless et al., 2001). Kaha phetisetso ho "glutamatergic synapses" ea VTA DA neurons e tloaelehile kamora hoo e ka bang beke, ts'ebetso e hanyetsanang le liphetoho tse susumetsoang ke lithethefatsi e tlameha ho ameha. Ho khahlisang, polasetine e kopantsoeng ea koae e khutlisoa ke ts'ebetso ea li-receptor tsa mGluR1 ho VTA. Haholo-holo, ente ea intraperitoneal ea module e ntle ea mGluR1 e khutlisitse phepelo ea phetisetso ea koae-e hlahisang koae (AMPAR) ea ts'ebetso ea koae (Coneone le Lüscher). 2006). Tšitiso ea lehae ea ts'ebetso ea mGluR1 ho li-neurons tsa VTA ka lehlakoreng le leng e ile ea eketsa tšusumetso ea motsoako oa koae ho VTA (Mameli et al., 2009). Kahoo, ka mor'a ho pepesetsoa lithethefatsi, phetisetso ea glutamatergic synaptic e thathamisitsoe ke mGluR-based LTD, e nang le phetoho ea li-AMPAR tse se nang GluA2 tse nang le boits'oaro bo tlase ba GluA2 e nang le li-AMPARs (Mameli et al., 2007).

Ho fihlela joale, phetiso ea AMPAR e ntlafalitsoeng e tšohliloe e le lebaka la keketseho ea AMPAR / NMDAR e kentsoeng ke Ka vivo tlhahiso ea lithethefatsi. Leha ho le joalo, ho kenngoa ha li-AMPAR tse haelloang ke GluA2 ho hlile ho tla fokotsa palo ea AMPAR / NMDAR ho + 40 mV, hobane GluA2 e haelloang ke AMPAR ha e sebetse hantle litsing tse ntle tsa membrane ka lebaka la thibelo ea polyamine. Ka hona, likhahla tsa AMPAR / NMDAR tse nyolohileng li tlameha ho bakoa ke ho fokotseha ha maqhubu a NMDAR. Ho joalo, karo-karolelano ea AMPAR / NMDAR le eona e fumanoe e le ka lebaka la ho fokotseha ha phetisetso ea NMDAR (Mameli et al., 2011). Phokotso ena e hlaha ka lebaka la phetoho ea sebopeho sa subunit ea NMDAR. GluN2B ho GluN2A ratios ea eketseha kamora ho pepesetsoa le koae (Yuan et al., 2013). Ho feta moo, li-NMDAR tse nang le GluN3A, tse nang le Ca tse tlase haholo²⁺ permeability, e kenngoa ka har'a synapse ka mor'a ho pepesetsoa ha koae (Yuan et al., 2013). Ka kopanelo, liphuputso tsena li fana ka maikutlo a hore koae e khanna ho kenngoa ha synaptic ea tri-heteromeric GluN1 / GluN2B / GluN3A-e nang le li-NMDAR tse nkang sebaka sa GluN1 / GluN2A le GluN1A / GluNUM. Liphetoho tse susumetsoang ke koae ka bobeli ho ts'oaetso ea AMPAR le phetoho e hlahisitsoeng ke koae ho NMDAR li fumanoe li ipapisitse le ho kenngoa ha li-NMDARs tsa GluN2A, kaha ho ne ho se na litoeba tse hlahisoang ke koae ho GluN2A kapa ho tsoa ente ea vaerase e amanang le adeno. vector e hlalosang RNA-GluN3A-hairpin RNA e khutšoanyane (Yuan et al., 2013). Kamora nako, ts'ebetso ea mGluR1, e khutlisang phetisetso ea subco ea cocaine e entsoeng ke koae, e boetse e khutlisetsa phetiso ea subunit ea NMDAR (Yuan et al., 2013). Kahoo, ho kenyelletsoa ha li-synaptic tsa li-AMPAR tse nang le GluN3A ho bonahala ho le bohlokoa bakeng sa ho hlahisa polasetiki e hlahisitsoeng ke koae.

Ntle le ho kenella ha glutamatergic, li-neurons tsa VTA DA li boetse li amohela lipehelo tsa GABAergic, tse tsoang lipakeng tsa lehae le lipakaneng tse tsoang ho NAc le ventral pallidum (VP; Kalivas et al., 1993; Steffensen et al., 1998). Litla-morao tsena tse thibelang likokoana-hloko tsa VTA DA le tsona li feta polasetiki ea synaptic kamora ho pepesetsoa lithethefatsi tse lemalloang. Morphine, cocaine le nicotine kaofela li bontšitsoe ho nyenyefatsa tšebeliso ea nako e telele ea li-synapses tsa GABAergic ho li-neurons tsa VTA DA, leha ho le joalo ka lithuto tse fapaneng tsa nako (Niehaus et al., 2010). Ka lehlakoreng le leng, lisebelisoa tsa GABAergic tse amanang le li-interneuron tse inhibitory ho VTA li na le monyetla oa ka mora Ka vivo ho pepesehela lithethefatsi, ka ho etsa joalo ho thibela li-neuron tsa DA (Tan et al., 2010; Bocklisch et al., 2013). Ka kopanelo, keketseho e eketsehang ea AMPAR / NMDAR ho glutamatergic synapses ho VTA DA neurons, tahlehelo ea LTP ea GABAergic synapses ho li-neurons tsa VTA DA, le ts'oaetso ea li-neurons tsa VTA DA ka tšebeliso ea li-synapses tsa GABAergic ho li-interneurons tsa VTA li kanna tsa ntlafatsa thabo. Vta DA neurons. Tabeng ea nicotine, ho kenella ha GABAergic ho li-neurons tsa VTA DA ho fokotseha le ho feta ka lebaka la takatso ea li-nicotinic acetylcholine receptors (NAChRs) ho GABAergic neurons (Mansvelder et al., 2002). Kaha ts'ebetso ea li-nAChRs e nyenyefatsa li-neurons tsa GABAergic, takatso ena e lebisa ho tepelletseng ha phetisetso ea GABAergic. Phello ena ke e kholo ka ho fetesisa ho li-neurons tsa GABAergic tseo ka tloaelo li natefeloang ke phetiso ea endo native cholinergic. Ho sithabela ha maikutlo a ho kenella ka GABAergic ka lebaka la takatso ea nachR ho ka baka keketseho ea VTA DA neuron thabo, leha litšebelisano tse rarahaneng pakeng tsa ts'ebetso ea GABA le DA tsa neuron li bonahala li bapala karolo (Tolu et al., 2013).

Ts'ebeliso ea polasetiki e hlahisoang ke lithethefatsi ho VTA ha e etsahale lefatšeng ka bophara, e ama li-neurons tsohle tsa VTA DA ka ho lekana. Liphumano tsa morao-rao li bonts'itse hore lithethefatsi li ama ka mokhoa o fapaneng likarolo tse fapaneng tsa li-neuron tsa VTA DA tse nang le likhakanyo libakeng tse fapaneng tse lebisitsoeng. (Lammel et al., 2013). Ente e le 'ngoe ea koae e khethiloeng ka mokhoa o ikhethileng oa glutamatergic synapses ho li-neuron tsa DA tse kenellang mokokotlong oa NAc empa li sa lumellane ho li-neuron tsa DA tse kenang ho mPFC (Lammel et al., 2011). Litla-morao tse khahlisang tse mabapi le li-neurons tsa DA tse kenang ho MPFC leha ho le joalo li fetotsoe ke tšusumetso e matla, e fana ka maikutlo a hore mehopolo e monate le e nyarosang e ama litlatsetso tse fapaneng tsa methapo ea DA ho VTA. Mekhatlo ea DA e kenellang khetla ea NAc, e anngoeng ke lithethefatsi, e fumana mohopolo oa eona ho tsoa mokokotlong oa bongoana, athe li-neurons tsa DA tse kenang mPFC, e anngoeng ke tšusumetso e ts'oanang, li fumana litlatsetso tsa bona ho tsoa hamorao habenula (Lammel et al ., 2012).

Single Ka vivo litlatsetso ho lithethefatsi tsa tlhekefetso li etsa liphetoho tsa synaptic tse ntseng li le teng nako e telele kamora hore meriana e hlakoloe 'meleng, bonyane matsatsi a 5. Leha ho le joalo, sena ke sa nako e khuts'oane haholo ho hlalosa litla-morao tsa boits'oaro bo tšoarellang bo bonoang ke ho lemalla. Ekamora ho tsamaisoa ha koae ka makhetlo a mangata (liente tse supileng tsa letsatsi le letsatsi), keketseho ea koae ka karolelano ea AMPAR / NMDAR lenaneong la methapo ea methapo ea VTA DA e lieha ho feta mme e ke ke ea hlola e bonoa matsatsi a leshome kamora ho felisoa ha taolo ea koae ente e le 'ngoe (Borgland et al., 2004). Leha ho le joalo, lithutong tsena tsohle ho ile ha sebelisoa taolo ea lithethefatsi tse sa laoleheng. Kameho ea ho itaola ea lithethefatsi tse lemalloang e tšoarella ho feta phello ea tsamaiso e sa laoleheng ea lithethefatsi. Kamora likhoeli tsa 3 tsa ho khaotsa ho itaola, koae e kopantsoeng le koae e ne e ntse e le teng har'a li-neurons tsa VTA DA ka likhoto (Chen et al., 2008). Ho phehella hona ha tšebeliso ea lithethefatsi tse khothalletsoang ke lithethefatsi ho li-neurons tsa VTA kamora ho itaola ha lithethefatsi ho fana ka maikutlo a hore ketsahalo ena e ka ba lebaka la mantlha le nts'etsopele ea boits'oaro bo lemaletseng.

Liphetoho life tse ikhethileng tse bakoang ke polasetiki e hlahisitsoeng ke lithethefatsi ho VTA? Lits'oants'o tse nang le tlhahlobo ea tlhaho ea GluA1 subunit kapa GluN1 subunit ka mokhoa o khethiloeng ho li-neurons tsa DA li ne li haelloa ke polasetiki e hlahisitsoeng ke lithethefatsi ho li-neurons tsa VTA DA, empa k'hok'heine e ne e ntse e baka khetho e tloaelehileng ea sebaka ho litoeba tsena (Engblom et al., 2008). Phuputsong e 'ngoe, litoeba tse haelloang ke karolo ea GluN1 subunit feela ho li-neuron tsa DA le tsona li bontšitse maikutlo a tloaelehileng a boits'oaro, empa CPP e felisitsoe ho litoeba tsena (Zweifel et al., 2008), ho fapana le liphetho tsa Engblom et al. (2008). Phapang ena pakeng tsa lithuto e ka bakoa ke liphapang tsa protocol ea CPP. Ka kakaretso, bopaki ba hore ts'ebetso ea polasetiki e khothalletsoang ke lithethefatsi ho li-neurons tsa VTA DA e kenyelletsa litlamorao tsa nakoana tsa boits'oaro ba ho pepesetsoa lithethefatsi li na le moeli. Leha ho le joalo, polasetiki e hlahisoang ke lithethefatsi ka har'a li-neuron tsa VTA DA e ka ba mohato oa bohlokoa oa pele bakeng sa boitsoaro ba morao-rao ba litekanyetso. Ho litoeba tse haelloang ke GluN1 ho li-neuron tsa DA, ho khutlisetsoa hoa mekhoa ea ho batla lithethefatsi ho CPP ho felisitsoe (Engblom et al., 2008). Ntle le moo, ntlafatso e liehang ea boits'oaro e hlahang kamora ho khaotsa nako e telele ea koae ha e a ka ea hlaha ho litoeba tsa GluN1 Knoutout (Zweifel et al., 2008). Liphetoho tsena tsa boits'oaro ba morao-rao mohlomong ha se litlamorao tse tobileng tsa polasetiki ea synaptic ho VTA, empa li ka etsahala haholo ho bakoa ke liphetoho tsa synaptic libakeng tse ling tsa kelello tse bakoang ke polasetiki ea synaptic ho VTA. Pulopiki e hlahisoang ke lithethefatsi ho VTA e lebisa ho polasetiki ea synaptic e latelang likarolong tse ling tsa boko, e bohlokoa haholo bakeng sa liphetoho tsa boitšoaro tse bonoang ho lemalla ho feta polasetiki ea synaptic ho VTA ka boeona (bona ka tlase). Ka VTA, lithethefatsi tsa tlhekefetso li fetola melao ea ts'ebetso ea polasetiki e itšetlehileng ka ts'ebetso mme ka tsela eo e etsa liphetoho tse tlang tlase ho phallela ho potoloha ea mesocorticolimbic (Creed le Lüscher, 2013). Tliphetoho tsa hese likarolong tse tlase tsa bokong, haholo ho NAc le PFC, joale ho nahanoa hore li amana le tlhekefetso e tšoarellang ea boits'oaro e bonoang ke ho lemalla.

Bophahamo ba polasetiki e kopantsoeng le lithethefatsi ho VTA ho kenyelletsa melao bakeng sa polasetiki e itšetlehileng ka ts'ebeliso e itšetleha ka phano ea peo ea AMPAR le subntits tsa NMDAR (Yuan et al., 2013). Ka tloaelo, LTP e itšetlehile ka NMDAR mme e kenella ha tokollo ea "presynaptic glutamate" e tsamaisana le depolarization ea membrane ea postynaptic, hobane Mg²⁺-Block ea NMDARs e khutlisoa ho bokhoni ba membrane ba depolarized, bo lumella Ca²⁺ ho kena. Leha ho le joalo, cocaine e kenya phetoho ea sebopeho sa subunit ea NMDAR, e theha li-NMDAR tse nang le Ca e tlase haholo.²⁺ permeability (Yuan et al., 2013). Ka hona, ts'ebetso ea li-NMDAR ha e sa hlohlelletsa LTP. Ka lehlakoreng le leng, cocaine e khanna ho kenyelletsa ha li-AMPAR tse haelloang ke GluA2, tseo e leng Ca²⁺-a tsebahala. Ka hona, kamora ho pepesetsoa hoa koae, mofuta oa LTP o ka kenngoa ho li-neurons tsa VTA tse itšetlehileng ka ho kenella ha calcium ka li-AMPAR mme o ikemetse ka NMDARs (Mameli et al., 2011). Leha ho le joalo, AMPAR e haellang ea GluA2 ha e sebetse hantle litsing tse ntle tsa membrane, ka lebaka la polasetiki ea polyamine block. Ha hyperpolarization e le matla le ho feta, li-AMPAR tse haelloang habonolo ke GPA e etsa calcium. Ka hona, cocaine e etsa hore melao ea ts'ebeliso ea ts'ebeliso ea "synaptic" e fetohe, hobane ho kenngoa ha PDP hona joale ho hloka ho ts'oaroa ha mosebetsi oa Presynaptic ka hyperpolarization ea cellynaptic cell sebakeng sa depolarization (Mameli et al., 2011). Hore na sena ke 'nete bakeng sa lithethefatsi tsohle tsa tlhekefetso ho sa le joalo ho lokela ho lekoa.

Joalokaha ho boletsoe ka holimo, glutamatergic polasetiki ea polasetiki ea VTA e baka polasetiki ea synaptic e latelang likarolong tse ling tsa sisteme ea mesocorticolimbic. Liphetoho tsa Synaptic li etsahala pele ho VTA pele ho polasetiki ea synaptic libakeng tse ling tsa sisteme ea mesocorticolimbic. Ntle le moo, liphetoho ho VTA li etsahala kamora ho pepesoa a le mong, athe polasetiki libakeng tse pharalletseng ka kakaretso e hloka ho pepesetsoa lithethefatsi tse ngata (Kourrich et al., 2007), leha e hloka ho hlokomeloa hore Mato et al. (2004) e bonts'a seo ho litoeba Ka vivo tsamaiso ea THC e fetotsoeng synaptic polasetiki ho NAc (Mato et al., 2004). Ntle le moo, polasetiki ea "cocaine-evoke synaptic" ea NAc e etsahala feela haeba polasetiki ea synaptic e VTA e phehella. (Mameli et al., 2009). Ho fetola polasetiki ea synaptic ho VTA ka ho kenella ka ente ea maiketsetso ea module ea mGluR1 e thibetsoeng polasetiki ea synaptic ho NAc (Mameli et al., 2009). Ka lehlakoreng le leng, kamora ho senyeha hoa ts'ebetso ea mGluR1 ho li-neurons tsa VTA, tse eketsang tšusumetso e bakoang ke lithethefatsi ho VTA, jekete e le 'ngoe ea cocaine e ne e lekane ho kenya polasetiki ea synaptic ho NAc, ho sa tloaelehang ho ba joalo. Liphumano tsena li fana ka maikutlo a mokhatlo o hlophisehileng oa polasetiki o nang le lithethefatsi tse nang le lithethefatsi, 'me VTA e le setsi sa pele sa polasetiki, e lateloa ke polasetiki ea glutamatergic synaptic libakeng tse tlase tsa sisteme ea mesocorticolimbic. Mekhoa e tlatselletsang methating ena ea morao-rao ea polasetiki e tšohloa karolong e latelang.

Mehato ea kamoso ea ho nchafatsoa hoa mantsoe

Polasetiki e hlahisoang ke lithethefatsi ka har'a li-nucleus tsa li-nucleus

Li-neurons tse ka sehloohong tsa NAc, GABAergic medium spiny neurons (MSNs), li amohela lipehelo tsa glutamatergic tse tsoang libakeng tsa boko le bokong, ho kenyeletsa le PFC le amygdala (Groenewegen et al., 1999). Liphetho tse tsoang liphuputsong tse 'maloa li bonts'a hore phetisetso ea glutamatergic ho NAc e bapala karolo ea bohlokoa ho batleng lithethefatsi. Microinjection ea AMPA ho NAc e etsa hore boitšoaro bo batlang k'hok'heine bo boele bo fumanehe, athe microinjection ea mohanyetsi oa AMPAR ho NAc e thibela ho khutlisoa ha motho ea batlang k'hok'heine (Cornish le Kalivas, 2000; Ping et al., 2008). Ntle le moo, ho nahanoa hore tšebetso ka hara NAc e nka maikutlong a boits'oaro (Koya et al., 2009, 2012). Kaha ho tšoaetsoa ke glutamatergic ho NAc ho bapala karolo ea bohlokoa boits'ebetsong ba ho lemalla, polasetiki ea synaptic ho glutamatergic synapses ho NAc MSNs e kanna ea ba karolo ea ho lemalla.

Ho fapana le VTA, ente e le 'ngoe ea koae ha e lekane ho kenya polasetiki ea synaptic ho NAc (Kourrich et al., 2007). Ke kamora ho phekoloa khafetsa ka koae, ho fetoha hoa matla a synaptic ho hlahang ho li-synapsic glutamatergic synapses ho NAc MSNs. Tataiso ea polasetiki ena ea synaptic e itšetlehile ka nako ea ho tlosoa ha lithethefatsi (Kourrich et al., 2007). Kourrich et al. (2007) o tsamaisitse liente tse hlano hang ka letsatsi tsa cocaine ho litoeba tsa banna mme a lekola karolelano ea AMPAR / NMDAR ho NAc shell neurons ka bobeli 24 h le 10-14 matsatsi ka mor'a ho ente ea ho qetela. Nakong ea ho khaola pejana, 24 h kamora ho ente ea ho qetela, ho fokotseha ho hoholo ha li-ratiine tsa AMPAR / NMDAR ho fumanoe ho NAc shell neurons ea litoeba tse tšoaroang ke koae. Leha ho le joalo, kamora nako e se nang lithethefatsi ea matsatsi a 10-14, li-ratios tsa AMPAR / NMDAR li ile tsa eketseha ho li-neuron tsa shell tsa NAc. Ho feta moo, ho pepesetsoa hape hoa lithethefatsi ho lebisitse ho fokotseha ha tekanyo ea AMPAR / NMDAR 1 letsatsi hamorao, ho khutlisa ka tšohanyetso bokhoni ba synaptic. Matšoenyeho a Synaptic kamora ho pepesetsoa ho eketsehileng ha koae ka mor'a nako e se nang lithethefatsi ho boetse ho hlalositsoe lithutong tsa pejana (Thomas et al., 2001; Brebner et al., 2005). Thomas et al. (2001) ho feta moo e bonts'itse hore ho fokotseha ha sekhahla sa AMPAR / NMDAR ho bonts'a phokotso ea phetiso ea AMPAR.

Ho tseba sesosa sa karo-karolelano ea AMPAR / NMDAR ho li-neuron tsa NAc ka mor'a ho tlohela nako e telele, Kourrich et al. (2007) rekotoe li-mPMs tsa litaba tsa AMPAR. Bophahamo le bokhutšoanyane ba li-mPMs tse tsamaeang le AMPAR li ile tsa eketseha haholo litoneng tse tšoaroang ka koae (Kourrich et al., 2007), e fana ka tlhahiso ea phetisetso ea phetiso ea synaptic ea AMPAR-kamora kamora ho khaotsa nako e telele. Liphetho tsena li tsamaellana le liphetho tsa Boudreau le Wolf (Boudreau le Wolf, 2005), ea fumaneng sebaka sa selefouno se eketsehang sa AMPAR subunits ho NAc ea likhoto kamora matsatsi a 21 a ho tlohela. Leha mekhoa e tlatselletsang ea ts'ebeliso ea lithethefatsi tse bakiloeng ke lithethefatsi ka hara khetla ea NAc kamora ho khaotsa ka nako e telele e sa tsejoe, hoa tsebahala hore ts'ebeliso ea "synaptic" e itšetlehile ka ts'ebetso ea tsela ea extracellular-regated kinase (ERK) ka tsela ea phosphorylation ea ERK (Pascoli et al., 2012). Khafetsa khafetsa ea li-mPMs tsa AMPAR, hammoho le ho fumana hore karolelano ea mosebetsi oa paired-pulse (tekanyo ea mosebetsi oa presynaptic) e ne e sa fetohe, e fana ka maikutlo a hore ho pepesetsoa koae khafetsa ho ka lebisa ho thehoeng ha li-synapses tse ncha ho NAc MSNs. Sena se ts'ehetsoa ke ho fumana hore palo ea li-spendritic spine ho NAc MSNs e eketsehile kamora ho pepesetsoa khafetsa cocaine, amphetamine le nikotine (Robinson le Kolb, 2004). Kahoo, ho pepesetsoa ha koae khafetsa ho hlahisa bokhoni ba synaptic khetla ea NAc e ntseng e fetoha nakong ea ho khaotsa lithethefatsi, mohlomong ka lebaka la sebopeho sa li-synapses tse ncha, tse lateloang ke khatello ea maikutlo e sa fetoheng ka mokhoa o hlakileng ha motho a pepesetsoa hape. Leha ho le joalo, ka bobeli ka mor'a ho tlohela ka nako e telele le ka mor'a ho pepesetsoa ts'ebetso e le 'ngoe ea lithethefatsi, phetisetso ea NMDAR ha ea phahamisoa (Kourrich et al., 2007). Ntle le moo, ha ho na bopaki ba phetoho boteng ba li-AMPAR tse haellang tsa GluA2 nakong ea phetoho e fumanoeng, hobane index ea tokiso ea li-EPSC tsa AMPAR e ne e sa fetoloe litoeba tse tšoaroang ke koae ka mor'a ho khaotsa nako e telele le kamora ho pepesetsoa ha koae.

Lithuto tsena li sebelisitse tsamaiso ea lithethefatsi tse sa laoleheng ho etsa hore polasetiki ea synaptic e fihle. Kamora ho ikakhela ka setotsoana sa cocaine, khatello ea maikutlo ea phetisetso ea phetisetso e nyarosang e fumanoe khetla ea NAc nakong ea ha a khaotsa ho tloha cocaine (Schramm-Sapyta et al., 2006), e ileng ea lateloa ke phetiso e eketsehang ea AMPAR kamora ho khaotsa nako e telele (Conrad et al., 2008). Leha ho le joalo, ho fapana le se fumanoeng ke Kourrich et al. (2007), keketseho ena e fumanoe e le ka lebaka la ho kenyelletsoa ha li-AMPAR tsa GPA2 tse haellang. Bmaemo a mang a holimo le a mahareng a GluA1 a ile a eketseha haholo ho NAc kamora matsatsi a 45 a ho tlohela, tokiso ea kahare ea li-EPSC tsa AMPAR e ile ea eketseha haholo mokokotlong oa NAc ea likhoto tse tšoaroang ka koae (Conrad et al., 2008). Maemo a GluA2 ha aa ka a fetoloa, a fana ka maikutlo a hore li-AMPAR tse hlokang GluA2 li kentsoe kaholimo ho letamo le leng teng la li-AMPAR tsa GluA2. Ho tloha ha Kourrich et al. A hlahloba liphetoho tsa synaptic kamora matsatsi a 10-14 a ho tlosoa, athe Conrad et al. liphetoho tse hlahlojoang tsa synaptic kamora matsatsi a 42-47 a ho tlosoa, ho ka etsahala hore ho kenyelletsoa ha li-AMPAR tse haellang tsa GluA2 ho NAc ho etsahala feela kamora nako e tsitsitseng ea ho tlohela. Sena se tsamaisana le ho fumana hore maemo a NAc GluA1 a ile a eketseha hanyane ka mor'a matsatsi a 21 a ho tlohela, ho bontša hore maemo a GluA1 a eketseha butle kamora ho tlohela (Conrad et al., 2008). Boithuto bo entsoeng ke Mameli et al. (2009) e tšehetsa mohopolo oa hore Li-AMPAR tse haellang tsa GluA2 li kenngoa ka har'a li-synapses kamora ho khaotsa ho tlositsoeng ho pepesetsong ea koae khafetsa. Lenane la ntlafatso le eketsehileng le fumanoe ho NAc MSNs kamora matsatsi a 35 a ho khaotsa kamora ts'ebetso ea bobeli ea cocaine e sa laoleheng le ho itaola ka mokhoa oa cocaine (Mameli et al., 2009). Ka hona, maemo a subunit ea AMPAR ea subaptit ho NAc MSNs a fetoha bakeng sa libeke tse 'maloa ka mor'a ho pepesetsoa ha koae.

Ka bobeli Thomas et al. (2001) le Kourrich et al. (2007) e fumane ho fokotseha ho hoholo ha tekanyo ea AMPAR / NMDAR ho NAc shell neurons ea litoeba tse tšoaroang ke koae nakong ea ho khaola kapele, ho neng ho thoe ke phokotseho ea phetisetso ea AMPAR (Thomas et al., 2001). Leha ho le joalo, keketseho ea AMPAR / NMDAR e fokotsehileng e ka boela ea bakoa ke moloko oa li-synapses tse khutsitseng. Li-synapses tse khutsitseng ke li-synapses tsa glutamatergic tse nang le li-NMDAR, empa ha ho na li-AMPAR tse sebetsang (Isaac et al., 1995). Thomas et al. (2001) ha e fumane liphetoho tse tlisoang ke koae ka phetiso ea NMDAR, empa sena ha se qhele monyetla oa hore palo ea li-synapses tse khutsitseng e eketsoe ke ho pepesetsoa hoa koae. Ho joalo, kamora ho pepesetsoa hoa koae e sa pheoang khafetsa palo ea li-synapses tse khutsitseng e ile ea eketseha ho NAc shell MSNs (Huang et al., 2009). Li-synaps tsena tse ncha tse khutsitseng li ile tsa hlahisoa butle-butle nakong ea ho pepesetsoa ha koae, ho hlahisa keketseho e kholo ea liperesente tsa li-synapses tse khutsitseng ho tloha ka letsatsi la boraro la kalafo ea koae. Moloko o khothalletsoang ke cocaine o kentsoeng ka har'a li-synapses tse khutsitseng o ile oa kenella ka ho kenngoa ha membrane ea li-NMDAR tse ncha tsa GluN2B (Huang et al., 2009). Bokaholimo le kakaretso ea GluN2B, empa eseng GluN2A, e ile ea eketsoa, ea kopantsoe le boemo bo eketsehileng ba tlatsetso ea subluits ea GluN1. Ntle le moo, ka mor'a ho thibela li-NMDAR tsa GluN2B tse nang le khetho e ikhethang, ha ho na keketseho ea li-synapses tse khutsitseng tse ka fumanoang. Nakong ea ho tlosoa, palo ea li-synapses tse khutsitseng li theohile hape (Huang et al., 2009). Leha ho le joalo, sena ha se bolele hore li-synapses tse hlahisitsoeng li ile tsa nyamela hape. Ho ka boela ha bolela hore li-synapses tse sa tsoa khutsisoa tse sa tsoa hlahisoa li ne li sa ngolisoe ka ho kenngoa ha synaptic of (GluA2-tlhaela) AMPAR. Ona e ka ba o mong oa mekhoa e tlatselletsang ponahalong e phahameng ea sele ea litho tsa AMPAR le keketseho e nyane ea AMPAR / NMDAR ho NAc shell neurons kamora ho qeta nako e telele. Kahoo, liphetoho tse bonoang karolelanong ea AMPAR / NMDAR le liphetoho tse bonoang palo ea li-synapses tse khutsitseng li ka tsamaisana. Ho feta moo, moloko oa li-synapses tse khutsitseng o ka tsamaisa polasetiki ea morao ea synaptic.

Bohlokoa ba boitšoaro ba ho fokotseha ho litekanyetso tsa AMPAR / NMDAR nakong ea ho tlohela pele ha bo e-so hlake. Ho 'nile ha etsoa tlhahiso ea hore khatello ea maikutlo e khothalletsoang ke lithethefatsi e ka' nang ea baka lithethefatsi tsa NAc e ka 'na ea se amehe haholo ka tšusumetso e ntle ea tlhaho, e ka bakang maikutlo a anhedonia le dysphoria (Van den Oever et al., 2012). Sena se ka holisa takatso ea lithethefatsi. Boitšoaro bo bakoang ke khatello ea maikutlo ea synaptic kamora ho pepesetsoa ts'ebetso e le 'ngoe ea lithethefatsi ho nahanoa e le polelo e bohloko ea maikutlo a boitšoaro (Brebner et al., 2005). Ho thibela ho kenngoa ha khatello ea maikutlo ea synaptic ka ho kenella kahare ho intrane le peptide ea membrane e amohelang endocytosis ea GluA2 e thibela ts'ebetso e eketsehileng ea locomotor e khothalletsoang ke tlhahiso ea amphetamine.

Monyetla o tsoelang pele oa phetisetso ea AMPAR nakong ea ha a khaotsa nako e telele a ka 'na a kopanya "ho kenella litakatsong tsa lithethefatsi", taba ea hore takatso ea litakatso le lithethefatsi e ntse e eketseha butle-butle likhoeling tsa pele kamora ho tlohela lithethefatsi tse hlekefelitsoeng (Grimm et al., 2001). Monyetla oa phetisetso ea AMPAR e ntlafatsa karabelo ea NAc MSNS litekatsong tse amanang le lithethefatsi, e lebisang ho ntlafatseng takatso e matla ea lithethefatsi tsa cue le takatso ea lithethefatsi. Ho batla koae ka lebaka la cueine le kamora ho tlohela nako e telele ho itšebeletsa koae ho ile ha fokotseha ka ho kenella ka thibelo ea li-AMPAR tse haellang tsa GluA2 tse se nang NAP (Conrad et al., 2008). Ntle le moo, ho kenella kahare hoa li-AMPAR tse haellang tsa GluA2 libakeng tsa amygdala-to-NAc synapses ka Ka vivo ho hlohlelletsoa ha optogenetic ka mor'a ho khaotsa nako e telele ho fokotsehile ho kenella ha takatso ea koae (Lee et al., 2013). Kameho ea ts'ebetso ena e ne e le ho khutsisa ha li-synapses tse ling tse sa sebetsoeng, ho fana ka maikutlo a hore phetoho ea li-synapses tse khutsitseng le eona e tlatsetsa ho keneng takatso ea koae.

Liphetoho tse hlalositsoeng tse kenyellelitsoeng lithethefatsing tsa NAc li etelletse pele Bellone le Lüscher (2012) le Dong le Nestler (2014) ho etsa tlhahiso ea hypothesis ea phetisetso ea phetiso ea synaptic nakong ea ts'ebeliso ea koae, e etsa mefuta ea li-synapses tseo ka tloaelo li amanang le nts'etsopele ea bongoana (Bellone le Lüscher, 2012; Dong le Nestler, 2014). Mehlala ke moloko oa li-synapses tse khutsitseng le ho kenyelletsoa ha li-AMPAR tse haelloang ke GluA2. Ho pepesehela k'hok'heine ho boetse ho bula nako ea bohlokoa ea nts'etsopele ea sesebelisoa sa mesocorticolimbic. Li-synapses tse nyane li na le bokhoni bo phahameng ba ho fetoha le liphetoho tsa polasetiki tse tšoarellang nako e telele. Sena se nahanoa hore se hlalosa kamoo lithethefatsi li ka tlisang liphetoho tsa polasetiki tse matla joalo ka nako e telele, tse lebisang mehopolong e matla le e tšoarellang e amanang le lithethefatsi (Dong le Nestler, 2014). Hypothesis e nchafatsang e boetse e atoloha le phetoho ea synaptic ho VTA, joalo ka ho hlaha hape hoa li-NMDAR tsa GluN3A. Taba ea hore li-synapses tse nyane li na le bokhoni bo phahameng ba ho etsa liphetoho tse itšetlehileng ka polasetiki li ka boela tsa hlalosa hore na ke hobaneng ha bacha ba le kotsing ea ho lemalla.

Glutamatergic synaptic plasticity ha e etsahale feela nakong ea ho pepeseha lithethefatsi le ho tlohela. Ho etsahala hape nakong ea khutlisetso ea cue-e hlohlelletsang ho batla lithethefatsi. Tlhahiso ea likhakanyo tse amanang le koae ka lebaka la ho se be teng ha koae li fumanoe li etsa hore ho be le keketseho e potlakileng ea boholo ba mokokotlo oa dendritic le karo-karolelano ea AMPAR / NMDAR karolong ea mantlha ea NAc ea litoeba e neng e na le nalane ea boits'oaro ba koae (Gipson et al. , 2013a). Keketseho ena e ne e se e ntse e le teng 15 min kamora ho hlahisoa ha cueine e amanang le koae le keketseho ea tekanyo ea AMPAR / NMDAR le bophara ba lesapo la mokokotlo ho 15 min li ne li amana hantle le matla a ho batla lithethefatsi. Sena se fana ka maikutlo a hore matla a kopantsoeng a potlakileng a cue-induction a kopantsoeng le li-NAN tsa mantlha e ka ba mochine o etsang hore o boele o boele. Lihora tse peli kamora ho qala ho khutlisetsoa ka hare ho cue-ikiwa, boholo ba mokokotlo oa dendritic le karo-karolelano ea AMPAR / NMDAR li ne li khutletse maemong a pele a ka oela hape. Ts'ebetso ho prelimbic cortex (PL), subregion ea morial PFC (mPFC) e romellang likhakanyo tsa glutamatergic ho mantlha ea NAc, e bonts'itsoe e amehile ka sehlōhō, kaha microinjection ea agonists ea GABAR ho PL e thibela liphetoho tsa cue-ikiwa tse peli tse bakiloeng. ho batla lithethefatsi (Gipson et al., 2013a). Hore na ts'ebetso e tlisoang ke glutamatergic PL-to-NAc synapses e lekane ho ts'oha ho oela hape, kapa hore na liphetoho tse kopantsoeng le cue-ikiwa li hlokahala le hore motho a boele a li tsebe. Leha ho le joalo, patlisiso e sa tsoa pheha khang ea hore ho na le khokahano ea Causal pakeng tsa polasetiki e hlahisang koae ea "cutine" mPFC-to-NAc synapses le ho khutlela morao (Pascoli et al., 2014).

Tšusumetso ea ts'ebetso ea cue-e kentsoeng ho glutamatergic PL-to-NAc synapses e ntlafatsoa ke ho fokotsoa ha maemo a basal extracellular glutamate ho NAc e amanang le ho tlosoa lithethefatsi tse lemalloang (Gipson et al., 2014). Tekano ea glalamate ea basal extracellular ho NAc e fokotsehile kamora ho pepesetsoa ha koae le ho se ts'oenyehe ha motsoako ka lebaka la ts'ebetso e theohileng ea "glial cystine-glutamate exchanger" e fetisang glutamate sebakeng sa kantle ho naha (Kalivas, 2009). Sena se etsa hore molumo oa glutamate o fokotsehe ho li-preynaptic inhibitory mGluR2 le li-mGluR3 receptors, tseo ka tsona li fokotse thibelo ea tokollo ea "presynaptic glutamate" (Gipson et al., 2014). Sena se lebisa tokollong e eketsehileng ea synaptic ea glutamate ho arabela likotsi tse amanang le lithethefatsi. Ntle le moo, glutamate e lokollotsoeng ha e tlosoe ka nepo ho ts'ebetsong ea synapse, hobane polelo ea glial glutamate transporter 1 (GLT-1), e arolelanang ho ts'oaroa ha glutamate, e fokotsehile kamora ho pepesehela lithethefatsi (Knackstedt et al., 2010; Shen et al., 2014). Ka hona, litloaelo tse amanang le lithethefatsi li etsa hore ho be le litla-morao tse feteletseng ho li-NAc glutamatergic synapses, tse ka hlalosang hore na ke hobaneng mekhoa ena e ka ba le phello e matla joalo ea boitšoaro.

Ntle le ho ntlafatsa ka ho toba matla a synaptic ho NAc, lithethefatsi tsa tlhekefetso li boetse li nahanoa hore li fetola bokhoni ba li-synces tsa NAc ho latela polasetiki ea synaptic e latelang. Ho lemalla koae ho kopantsoe le ho senyeha ha NPDAR e itšetlehileng ka NPP le LTD ho li-synapses tsa glutamatergic ho mokokotlo oa NAc (Martin et al., 2006; Moussawi et al., 2009; Kasanetz et al., 2010). LTD e ne e senyehile ka mantlha mokokotlong oa NAc, empa eseng ka har'a khetla ea NAc, kamora matsatsi a 21 a ho khaotsa ho litoeba tse neng li itšebeletse k'hok'heine (Martin et al., 2006). Ho senyeha ho bakoang ke lithethefatsi ka har'a polasetiki ea synaptic ho ka tlatsetsa boits'oarong bo bobebe, bo qobelloang bo nang le tšekamelo ea ho lemalla mme bo ka hlalosa tšebeliso ea lithethefatsi leha ho na le litlamorao tse mpe tsa bophelo bo botle bathong. Bohlokoa ba ts'ebetso e sa sebetseng ea NMDAR e amanang le ts'oaetso ea koae e hatelletsoe ke ho fumana hore litoeba feela tse iphelisang tsa koae li ile tsa bonts'a ts'ebetso e tsoelang pele ea ts'oaetso, ha LTD e ne e hlaphoheloa liphoofolong tse bolokang tšebeliso ea lithethefatsi tse laoloang (Kasanetz) et al., 2010). Liphetho tse tšoanang li fumanoe kamora ho itaola ha ethanol. LTD e itšetlehileng ka NMDAR e ile ea senyeha haholo kamora ho khaola ho hoholo ha litoeba tse amanang le ethanol, empa eseng ho litoeba tse tšoaroang ke ethanol tse ileng tsa hloleha ho ntlafatsa tloaelo ena ea boitshwaro (Abrahao et al., 2013). D-serine, 'moho-oa-moea oa NMDAR, a ka bapala karolo ea ts'enyehelo e tlisoang ke lithethefatsi ho polasetiki e itšetlehileng ka NMDAR e itšetlehileng ka synaptic (D'Ascenzo et al., 2014). D-serine e bohlokoa bakeng sa LTP e itšetlehileng ka NMDAR le LTD maemong a NAc le D-serine e fokotsehile mokokotlong oa NAc oa likhoto tse tšoaroang ke koae (Curcio et al., 2013). Ka mekhabiso e tsoang ho likhoto tse tšoeroeng ke koae, ho tlotsoa ka D-serine ka botlalo ho khutlisetsoa LTP le LTD induction. Kahoo, bofokoli bo susumetsoang ke koae ka polasetiki e tsamaeang le NMDAR e itšetlehileng ka NAc bo lokela, bonyane ka karolo, ho fokotsa maemo a D-serine.

Joalo ka VTA, ho na le bopaki bo bong ba hore lithethefatsi ha li bake liphetoho tsa synaptic tsa lefats'e ho NAc, empa hape li ka ama likarolo tse fapaneng tsa li-MSNs (Wolf le Ferrario, 2010; Creed & Lüscher, 2013). Tlatsetso ea Synaptic khetla ea NAc e hlahang nakong ea ho khaotsa lithethefatsi ho nahanoa hore e etsahala ka mokhoa o ikhethileng sebakeng sa D1-receptor-expression MSNs, 'me eseng li-synapses ho D2-receptor-expression MSNs (Pascoli et al., 2012). Haufinyane, ho ile ha fumaneha hore mokhoa ona oa synaptic potentiation ho li-synapses ho D1-receptor-expression MSNs o itšetlehile ka ho thehoa ha li-complexes tsa D1R / GluN1 (Cahill et al., 2014). Ho thibela mokhatlo oa D1R / GluN1, ha u ntse u boloka sesupo sa motho ka mong sa D1R le NMDAR, e thibetse ts'ebetso ea ERK, e hlokahalang bakeng sa ts'ebeliso ea synaptic.

Synaptic polasetiki ho medial prefrontal cortex

Morero o mong o ka sehloohong oa projeke ea DA e simolohileng ho VTA ke medial prefrontal cortex (mPFC). Li-neurophylidal neurons tsa mPFC li fumana likhakanyo tsa glutamatergic tse tsoang libakeng tse ngata tse fapaneng tsa boko, ho kenyelletsa le basolateral nucleus ea amygdala (BLA), mme e romelle merero ea glutamatergic ho VTA, NAc le ho khutlela ho BLA (Gabbott et al., 2005; Hoover le Vertes, 2007; Van den Oever et al., 2010). Ho lemalla ho amahanngoa le ts'ebetso ea neuronal ea "basal" e fokotsitsoeng, kapa "hypofrontality" (Volkow et al., 2003), e ka bonoang hape ho litoeba ka mor'a ho itlhokofatsa khafetsa ka koae (Sun le Rebec, 2006). MPFC e ka aroloa hore e be dorsal (ho kenyelletsa le PL) le karolo ea ventral (ho kenyelletsa infralimbic cortex) e nang le litšobotsi tse fapaneng tsa anatomical le tšebetso (Van den Oever et al., 2012). Anatomically, dorsal mPFC ho nahanoa hore e kahare ea mantlha ea NAc, ha mPFC ea hare e romella likhakanyo ho khetla ea NAc (Heidbreder le Groenewegen, 2003). MPFC ea dorsal le ea ventral ho boetse ho nahanoa hore e bapala likarolo tse fapaneng tsa ho lemalla. Ketsahalo ho dorsal mPFC ho nahanoa hore e qala ho batla lithethefatsi mme e bohlokoa bakeng sa ho khutlisetsoa morao hoa takatso ea cue ka ho batla lithethefatsi (Gipson et al., 2013b). Ka lehlakoreng le leng, ts'ebetso ho ventral mPFC e ka hatella likarabo tse batlang lithethefatsi (Peters et al., 2008; LaLumiere et al., 2012). Ka kakaretso, mPFC e nahanoa e bapala karolo ea bohlokoa taolong ea boitšoaro bo khutlela morao.

Ke lithuto tse 'maloa feela tse entseng lipatlisiso tsa polasetiki tse hlahisitsoeng ke lithethefatsi ka har'a mPFC. Ka hona, re na le tsebo e lekanyelitsoeng feela mabapi le karolo ea polasetiki e hlahisitsoeng ke lithethefatsi ho mPFC. In vitro lithuto li bontšitse hore nicotine e ka eketsa menyetla ea ho kenella ts'ebetsong ea ts'ebeliso ea nako ea ts'ebetso ea spike ho li-synapses tsa glutamatergic ho mouse mPFC layer V pyramidal neurons ka ho ntlafatsa litlatsetso tsa GABAergic ho li-neurons tsena (Couey et al., 2007). Ka lehlakoreng le leng, matsatsi a 5 kamora ho khaotsa ho pepesetsoa koae e sa phetoang (lisenthimithara tse supileng tsa letsatsi le letsatsi), ho kenella ha LTP ho ile ha nolofalletsoa lipuisanong tsa thabo tsa "HTML mPFC" V pyramidal neurons ka lebaka la phallo ea GABA (Lu et al., 2010). Sena se ne se kopantsoe ke ts'ebetso ea "neurotrophic factor" e tsoang bokong_A li-receptors ho mPFC, e lebisang ho qobello ea thibelo ea GABAergic. Leha boits'oaro bo amanang le polasetiki ena e ntlafalitsoeng bo sa ka ba fuputsoa haholo, ho na le bopaki bo sa reroang ba hore ho tsamaisoa ha ts'ebetso ea LTP ho mPFC ho ka kenyelletsa maikutlo a boitšoaro ka mor'a ho khaotsa koae (Lu et al., 2010).

Leha ho fokotseha ha MPFC LTP ke ts'ebeliso e mpe ea nicotine, ho kenella ka matla a matla a synaptic ho mPFC ho tsamaisoa ke ho tlosoa ha nikotine, ho ts'oanang le cocaine. Ka nako le ha latela Ka vivo kalafo ea nicotine, glutamatergic synaptic potentiation e ile ea fokotsoa ho mPFC ea litoeba tsa bocha, ha LTP ena e ile ea eketseha haholo mPFC ea likholo tsa 5 tsa batho ba baholo ka mor'a libeke tsa kamora ho amohela kalafo ea nicotine nakong ea bocha (Goriounova le Mansvelder, 2012). Liphetho tsa Bidirectional tsa ho pepesetsoa ha nicotine nakong ea bohlankana ho bokhoni ba synaptic li ka khoneha li kopantsoe le liphetoho tsa bidirectional maemong a synaptic a inhibitory metabotropic glutamate receptor 2 (mGluR2). Kamora ho pepesetsoa ha nicotine nakong ea bohlankana, maemo a protheine ea mGluR2 ho li-membrane tsa synaptic tsa rat mPFC a ile a eketseha ka letsatsi la pele la ho tlohela, empa a fokotsa libeke tsa 5 kamora ho pepesetsoa ha nicotine (Counotte et al., 2011). U sebelisa li-agonists tsa mGluR2, ts'usumetso e matlafalitsoeng ea nicotine e ka thibeloang, ha bahanyetsi ba mGluR2 ba thusa ts'ebetso ea synaptic (Goriounova le Mansvelder, 2012).

Ho koaleha ha nakoana ho kenyelletsoa ha PDP ho ka etsahala hore ho bakoe hape ke keketseho ea nakoana ea polelo ea li-nAChR tse nang le α4 le β2 subunits ho mPFC hantle kamora ho pepesetsoa ha nicotine nakong ea bocha, e leng mochini o ka mora ts'ebetso ea Gabaergic e ntlafalitsoeng e bakang sena. blockchage ea LTP (Counotte et al., 2012). Ho khahlisang, keketseho ea polelo ea li-nAChR tse nang le í4 le li-subunits tsa β2 ho mPFC e fumanoe feela ka mor'a ho pepesetsoa ha nicotine nakong ea bocha, mme eseng ka mor'a ho pepesetsoa ha nicotine nakong ea bongoana (Counotte et al., 2012). Ka mokhoa o tšoanang, thuto e entsoeng ke Goriounova le Mansvelder (2012) e bontšitse phapano lipakeng tsa litlamorao tsa ho pepesetsoa ha nicotine nakong ea bohlankana le nakong ea ho ba motho e moholo. Ho pepesetsoa ha Nikotine nakong ea ho ba motho e moholo ha hoa ka ha lebisa ho liphetoho tse sa feleng ho LTP. Tumellanong le sena, ho pepesetsoa ha nicotine ea bongoaneng, empa ho sa hlahise phello ea tlhokomeliso ea nicotine nakong ea bongoana, ho lebisa ho fokotseng ts'ebetso ea tlhokomelo le keketseho ts'ebetsong e sa tsitsang ea 5 libeke ka mor'a kalafo ho litoeba (Counotte et al., 2009, 2011). Ho pepesetsoa ha Nikotine nakong ea bocha ho etsa hore ho be le phokotso e sa feleng ea maemo a synaptic mGluR2 le ntlafatso ea tšebeliso ea nako e telele ea nako e telele ho RP mCF e ka bakang khaello ea kelello nakong ea kholo. Ka kakaretso, lithuto tsena li bonts'a hore nako ea bohlankana ke nako e mahlonoko ea ho hlaseloa habonolo bakeng sa litlamorao tsa nako e telele tsa nicotine ho PFC.

Kamora ho khaotsa nako e telele, liphetoho lipapatsong tsa subunit tsa glutamate li ile tsa bonoa lithutong tse 'maloa. Mohlala, polelo e eketsehang ea GluA2 / 3, GluA4, le GluN2B mPFC e tlalehiloe kamora libeke tsa 2 tsa ho tlohela ts'ebetso ea boits'ebetso ea koae ea cocaine (Tang et al., 2004). Leha ho le joalo, ha ho na tšusumetso ea nako e telele ho polelo ea synaptic membrane ea glutamate receptor subunits ho mPFC e fumanoe kamora ho itaola ha heroin (Van den Oever et al., 2008). Ho ka etsahala hore liphetoho lipakeng tsa glutamate receptor subunit kamora ho khaotsa nako e telele li hlaha feela kamora ho fihlella ka botlalo ha lithethefatsi. Sena se tšehelitsoe ke thuto ke Ben-Shahar et al. (2009), eo hape a ileng a fumana polelo e eketsehileng ea GluN2B kamora libeke tsa 2 tsa ho ila, empa e le feela ho likhoto tse neng li atisitse phihlello ea ho fumana cocaine (Ben-Shahar et al., 2009).

Kaha mPFC ho nahanoa hore e bapala karolo ea bohlokoa ho khutlisetseng litekong tsa lithethefatsi ho felletseng, ho boetse ho fuputsoe hore na polasetiki ea synaptic e etsahala mPFC nakong ea ha a khutlela mokhoeng oa ho batla lithethefatsi. Ho pepesetsoa hoa lits'ebetso tse amanang le heroin kamora libeke tsa 3 tsa ho tlohela taolo ea heroin ho bakile khatello ea maikutlo e potlakileng ea meputso ho mPFC ea likhoto (Van den Oever et al., 2008). Polelo ea membrane ea membrane ea AMPAR e tsamaisang GluA2 le GluA3 ho mPFC e ile ea fokotsoa, 'me polelo ea "Clathrin-coat Assembly protein" AP2m1, e kenyelletsoeng ho proathrin-based endocytosis, e ile ea eketseha. Sena se fana ka maikutlo a hore ho pepesetsoa hoa lits'ebetso tse amanang le "heroin" tse bakiloeng ke li-endocytosis-mediated endocytosis tsa GluA2 / GluA3 AMPAR. Ntle le moo, karolelano ea AMPAR / NMDAR e fokotsehileng le lenane la ntlafatso le fumanehang ho mPFC pyramidal neurons, ho netefatsa ho ba teng hoa endocytosis ea li-AMPAR tsa GluA2. Litekong tsena, ho se kopane pakeng tsa dorsal le ventral mPFC ha hoa etsoa. Ka hona, ha ho tsejoe hore na khatello ea cue-induced synaptic e etsahala ho mPFC eohle kapa ho e 'ngoe feela ea likhetho. Leha ho le joalo, litlamorao tsa boits'oaro ba ho thibela li-cue-indedu endocytosis tsa GluA2-tse nang le AMPAR li ile tsa hlahlojoa ka thoko bakeng sa likhetho tse peli tsa mPFC. Ho khahlisang, ho thibela GluA2 endocytosis ka ho khetheha ho "ventral mPFC" e fumanoeng ke cue-induction e khutliselitsoeng ho heroin e batlang, ha e ntse e thibela GluA2 endocytosis ka har'a mPFC ea dorsal ha e (Van den Oever et al., 2008). Sena se fana ka maikutlo a hore endocytosis e potlakileng ea li-AMPAR tse loantšanang le GluA2 le khatello ea maikutlo ea sephetho se teng ka har'a mPFC ea bohloka ke ea bohlokoa bakeng sa ho khutlisetsoa morao ho cue-ho felletseng ka ho batla ha heroin. Sena se lumellana le mohopolo oa hore polar mPFC e fana ka taolo ea thibelo ho ts'ebeliso ea lithethefatsi. Ka kakaretso, ho ka nahanoa hore khatello ea methapo ea kutlo e tlisoang ke cue-e kenyellelitseng pherekano ea mPFC e sitisang taolo ea thibelo ea lithethefatsi, ka ho etsa joalo, e boelana le ho khutlela bothateng ba heroin.

Ditheknoloji tse kopantsoeng le lithethefatsi bokong ba motho

Ts'ebeliso ea polasetiki e hlahisoang ke lithethefatsi tsamaisong ea mesocorticolimbic e tlatsetsa nts'etsopeleng le ho phehelleng ha lithethefatsi. Na lithethefatsi tsa tlhekefetso li hlile li kenya polasetiki ea synaptic bokong ba motho? Boithuto ba ho nahana ka batho bo bontšitse hore ho lemalla batho ho kenyelletsa liphetoho lipakeng tsa likarolo tse tšoanang tsa boko tseo ho tsona ho ileng ha bontšoa liphetoho tse tšoanang mefuteng ea liphoofolo (Van den Oever et al., 2012). Le ha lithuto tsena li sa ka tsa etsa lipatlisiso tsa polasetiki ea synaptic ka kotloloho, li bonts'a hore temallo e baka ho feto-fetoha ha maemo ho sisteme ea mesocorticolimbic ho batho. Ke liphuputso tse fokolang feela tse entseng lipatlisiso ka ho toba tsa polasetiki ea glutamatergic synapses bokong ba motho, mme ka lebaka leo, bopaki ba polasetiki e kopantsoeng le lithethefatsi bo sa bonahale. Ka mokhoa o ts'oanang, ts'ebetso ea polasetiki e itšetlehileng ka nako ea li-motor-evoked potentials (MEPs) e ka ts'oaroa lithutong tsa batho ka ho ts'oara ho tsosa maikutlo a methapo ea kutlo (PNS, analogous to presynaptic stimulation) ka transcranial sumimous (TMS) ea motor cortex (Stefan et al. , 2000, 2002; Wolters et al., 2003; De Beaumont et al., 2012; Lu et al., 2012). Ho susumetsa ho kopantsoeng ha joalo ka marang-rang (PAS) ho ka etsa hore keketseho ea mofuta oa LTP le ho fokotseha hoa mofuta oa MEP, ho latela nako eo li susumetsoang ka eona (Wolters et al., 2003, 2005; Thabit et al., 2010; De Beaumont et al., 2012; Lu et al., 2012; Conde et al., 2013;; Koch et al., 2013). Boemong ba synaptic, ho ile ha fumaneha hore litekeng tsa boko tsa motho tse entsoeng ka mokhoa o fapaneng, li-synapses tsa cortical glutamatergic li ka feta ka bobeli ho LTP le LTD ho fihlela motho e moholo, ha a arabela mebuso e tšoanang ea nako joalo ka ha e ne e sebelisoa PAS lithutong tsa batho (Testa-Silva et al., 2010, 2014; Verhoog et al., 2013). Bokhabane bona ba li-synapses tsa batho ba baholo bo ne bo itšetlehile ka li-NMDAR tsa postynaptic le lisele tsa calcium tsa gated mofuta oa L. Grundey et al. (2012) e sebelisitse PAS lithutong tsa batho mme e fumane hore nakong ea ho khaoloa ha nicotine, polasetiki e tšoanang le enjene e kopantsoeng le PAS e felisitsoe ho batho ba tsubang, empa hore e ka pholosoa ke tsamaiso ea patch ea nicotine (Grundey et al., 2012). Sena se fana ka maikutlo a hore mekhoa ea polasetiki e khothalletsoang ke lithethefatsi le eona e ka bapala karolo ea bohlokoa bokong ba motho. Ho hlakile hore liphuputso tse eketsehileng lithutong tsa batho le linthong tse phelang tse ntlafalitsoeng tsa boko ba motho li hlokahala ho netefatsa hore liphetoho tse entsoeng ke lithethefatsi tse fumanoeng litonong ka sebele li bapala karolo ea boko ba motho. Katleho e ngoe e se e fumanoe leha ho lekoa litekong tsa bokhoba ba batho bakeng sa kalafo e bululetsoeng ke lipatlisiso tsa methapo, joalo ka ha re tla bua ka tlase, ho ts'ehetsa mohopolo oa hore liphetoho tse fetotsoeng ke lithethefatsi le litlamorao tsa boits'oaro li hlile li bohlokoa bakeng sa nts'etsopele ea litlhare tsa litlhare.

Lits'oants'o tsa novel bakeng sa maano a teng a kalafo a ho lemalla

Na polasetiki e khothalletsoang ke lithethefatsi e ka ba sepheo sa mekhoa e ka 'nang ea phekola batho ba lemaletseng joala? Re tla tšohla mehopolo e meng e ipapisitseng le lipatlisiso tsa lithethefatsi tse lemalloang ke hobaneng lipolasetiki li ka fana ka lipheo tse tšepisang. Kaha li-synaptic polasetiki tse hlahisitsoeng ke lithethefatsi ho VTA li emela mohato oa pele oa mofets'e oa liphetoho tsa synaptic tsamaisong eohle ea mesocorticolimbic, ho kenella pele maemong a VTA ho kanna ha thibela liphetoho tsa synaptic libakeng tse tlase tsa bongo tse kang NAc. Litapoleng, polasetine e kopantsoeng le "cocaine-ikiwa" e ka khutlisoa ka ts'ebetso ea li-receptors tsa mGluR1 (Bellone le Lüscher, 2006). Ho hlohlelletsoa ha li-receptors tsa mGluR1 ho hlahisa mofuta oa LTD o itšetlehileng ka mGluR, e nang le phetisetso ea AMPARS e haelloang ke GluA2 e nang le li-AMPAR tse tlase tse tsamaisang GluA2 (Mameli et al., 2007). Sena se fetisa phetiso ea synaptic. Ntle le moo, mofuta ona oa mGluR e itšetlehileng ka mGluR e boetse e khutlisa phetisetso ea NMDARs ea cocaine e susumetsoang ke koae. 2013). Ka mokhoa o ikhethileng oa polasetiki ea synaptic ho VTA e lekane ho thibela polasetiki ea synaptic e latelang ho NAc le ho fumana cocaine e ts'oaroang ke cocaine kamora ho khaotsa ka nako e telele ho litoeba (Mameli et al., 2009), ho fana ka maikutlo a hore leano lena le ka sebetsa hantle kalafong ea bokhoba ba koae ka bokong ba methapo. Ho NAc, li-modulators tse ntle tsa mGluR1 li ka boela tsa khutlisa polasetiki e hlahisitsoeng ke lithethefatsi e bonoang kamora ho khaotsa ka nako e telele (Wolf le Tseng, 2012). Ka hona, mGluR1s e kanna ea se ke ea ba feela sepheo sa ho phekola bokhoba ba bokhoba ba nako, empa hape e ka sebetsa maemong a morao a lefu lena le ho kenella takatsong ea lithethefatsi. Hore na ts'ebetso ea mGluR1 e hlile e fokotsa tšebeliso ea lithethefatsi, ho lakatsa lithethefatsi le ho khutlisetsa litheko hape ho ntse ho hloka lipatlisiso. Hape, hore na ts'ebetso ea mGluR1 e kenyelletsa matla a synaptic ho VTA e latelang polasetiki ea synaptic e kentsoeng ke lithethefatsi tse ling tsa tlhekefetso ho feta cocaine ha e tsejoe.

Morero o mong o ts'episang o ka bang teng ke seterata sa ion ea maikutlo sa acid-1A (ASIC1A), se thibelang polasetine ea cocaine-evoked synaptic ho NAc (Kreple et al., 2014). Mesebetsi ea ASIC1A e bonts'a boitšoaro bo amanang le bokhoba ba tahi. ASIC1A e ngata e nang le khatello ea kelello ho RNA e ile ea fokotsa ho itaola ha koae e ntse e senyeha ha ASIC1A e ntse e eketseha ka bobeli morphine-CPP le cocaine-CPP ka litoeba (Kreple et al., 2014). Ho ntlafatsa ts'ebetso ea ASIC1A ka hona ho ka ba molemo ho phekolo ea bokhoba ba tahi. Ts'ebetso ea ASIC1A e nahanoa hore e fokotsehe ka enzyme carbonic anhydrase IV (CA-IV), e nang le karolo ho taolo ea ho butsoa ha extracellular pH bokong (Kreple et al., 2014). Ka hona, likhomphutha tse kang CA-IV inhibitor acetazolamide e ntlafatsang ts'ebetso ea ASIC1A, e kanna ea ba moetapele o ts'episang ho latela.

Leano le fapaneng le ka ipaka le na le molemo kalafong ea bokhoba ba tahi ke ho pholosa liphoso tse tlisoang ke lithethefatsi ho polasetiki ea NMDAR e itšetlehileng ka NAc, e kenyang boitšoaro bo sa fetoheng, bo hatelletsang bo nang le tšekamelo ea ho lemalla (D'Ascenzo et al., 2014). Kaha bofokoli bo tsamaeang le polasetiki ea NMDAR e itšetlehileng ka Nc ho nahanoa hore bonyane ke karolo e itseng ka lebaka la litekanyo tsa D-serine tse fokotsitsoeng, ho supa ho saena le D-serine ho ka boloka ts'episo bakeng sa kalafo ea ho lemalla lithethefatsi. Mefuta ea D-serine ka mohlala e ka khutlisoa ka tsamaiso ea inhibitor ea enzyme D-amino acid oxidase, e nyenyefatsang D-serine (D'Ascenzo et al., 2014). Ho fihlela joale, karolo ea D-serine e ithutile feela maemong a bokhoba ba koae. Hore na D-serine le eona e kenyelletsa ho lemalla mefuta e meng ea lithethefatsi tsa tlhekefetso ha e tsejoe.

Mekhoa e mengata ea phekolo ea bokhoba ba tahi e na le katleho e fokolang ka lebaka la litheko tse phahameng tsa ho khutlela morao. Mekhoa ea phekolo e shebileng ho fokotsa sekhahla sa ho khutla e ka ba e ts'episang. Ka lebaka la karolo ea mPFC taolong ea boitšoaro bo bocha, maano a phekolo ea nalane a ka rereloa ho fokotsa ts'ebetso ho dorsal mPFC kapa ho ntlafatsa phetiso ea glutamatergic ho mPFC ea ventral. Haholo-holo, li-agents tse thibelang endocytosis ea cluA2 e nang le li-AMPAR li ka ba molemo ho thibela ho oela hape. Sena se entsoe ho rat mPFC ka peptide ea TAT, TAT-GluR2_3γ (Van den Oever et al., 2008), e thibelitseng GluA2-e nang le AMPAR endocytosis le ho fokotsa mohopolo oa "heroine" oa cue o kentsoeng ho likhoto tsena.

Sebakeng sa ho fokotsa ts'ebetso ho dorsal mPFC, mokhoa o mong oa ho thibela ho oela hape hoa cue e ka ba ho fokotsa matla a ts'ebetso ena ho li-synopes tsa glutamatergic mPFC-to-NAc ho NAc. Nakong ea ho tlohela lithethefatsi tse lemalloang, litekanyetso tsa glutamate tsa extracellular ho NAc lia fokotseha, e leng ho matlafatsang palo ea glutamate e hlahisoang mPFC-to-NAc synapses kamora ho pepesetsoa lithahasello tse amanang le lithethefatsi (Gipson et al., 2014). Ho feta moo, litekanyetso tsa GLT-1 tse fokotsang li fokotsa ho nkuoa hoa glutamate ho tloha synapse. Ho khutlisetsa maemo a glT-1 ea glT-1 le extracellular e ka ba mokhoa oa ho thibela ho oela hape hoa moea oa cue-indued E 'ngoe ea likhomphutha tse khutlisetsang maemo a GLT-XNUMX le glutamate ea extracellular ho NAc ke antioxidant N-acetylcysteine (NAC; Gipson et al., 2014). Phekolo ea NAC e se e lekiloe litekong tsa batho, 'me e fumanoe e fokotsa litakatso tsa lithethefatsi le tšebeliso ea koae (LaRowe et al., 2007; Mardikian et al., 2007).

Qeto le lintlha tsa nako e tlang

Liphetoho tse bakoang ke lithethefatsi tse tlisoang ke lithethefatsi li kenya letsoho kholisong le phehelisong ea bokhoba ba tahi. Le ha tsebo ea rona ka polasetiki e bakiloeng ke lithethefatsi e sa felle hole, setšoantšo se hlaha moo polasetiki e glutamatergic e libakeng tsa mesocorticolimbic e phethang karolo ea bohlokoa tlatsong ea lithethefatsi (Setšoantšo. (Figure1) .1). Pele, ho pepesetsoa lithethefatsi tse lemalloang ho etsa liphetoho tsa synaptic ho VTA. Ho li-neurons tsa VTA DA, ho pepesetsoa ha lithethefatsi ho hlahisa ho kenngoa ha synaptic ha boitšoaro bo phahameng ba GluA2-e haelloang ke AMPAR bakeng sa boitšoaro bo tlase bo nang le li-AMPAR tsa boitšoaro bo tlase ba GluA2. Tlhahiso ena e kopantsoeng le lithethefatsi tse tlisoang ke lithethefatsi ho VTA kamorao ho moo e baka liphetoho tsa synaptic libakeng tse tlase tsa sisteme ea mesocorticolimbic (joalo ka NAc, PFC, le amygdala) ka ho pepesehela lithethefatsi. Litloaelo tsena tsa synaptic joale li hokahanya matšoao a mangata a boitšoaro a khethollang ho lemalla. Tekanyo e fokotsehileng ea AMPAR / NMDAR ho NAc nakong ea ho ikhula kapele e ka thusa maikutlo a ho hloka hore moriana o ikutloe o thabile, ka ho etsa hore li-neurons li se ke tsa ameha haholo ka tšusumetso e ntle ea tlhaho. Monyetla o latelang oa butle-butle oa phetiso ea AMPAR, butle-butle ho feto-fetoha ha maemo a khutsitseng, le litekanyetso tse fokotsitsoeng tsa moea oa "basc" tse akaretsang polelo ea ho kenella litakatsong tse bakoang ke ho tseba, ka ho ntlafatsa karabelo ea li-NAc MSN ho litakatso tse amanang le lithethefatsi. Lithuto tsa nako e tlang tseo ho tsona lipatlisiso tsa li-synaptic (le litlamorao tsa boitšoaro ba tsona) li ntseng li etsoa liphuputso ka har'a mantlha ea NAc le khetla li hlokahala ho senya karolo ea mantlha ea NAc le khetla mohlaleng ona o sebetsang. Ho tloaelana le lithethefatsi tse fetotsoeng ke lithethefatsi ho PFC ho bapala karolo ea bohlokoa ho khutla hape. Pherekano e potlakisang khatello ea kelello e bakang karohano e potlakileng ea pPFC e sitisa karohano le monyetla oa ho pepesehela litloaelo tse amanang le lithethefatsi, ka ho etsa joalo, ba boelana le ho batla lithethefatsi hape. Neuroadaptations e hlahisitsoeng ke lithethefatsi ho dorsal mPFC ka lehlakoreng le leng ketso ea ho ntlafatsa sephetho se hlahisang thabo ho tsoa ka tlasa molao ona oa mantlha oa NAc, o tsamaisang takatso ea lithethefatsi.

Setšoantšo sa 1

Setšoantšo sa 1

Mohlala o sebetsang oa karolo ea polasetiki e kentsoeng ke lithethefatsi tsamaisong ea mesocorticolimbic tšebelisong ea lithethefatsi.. Schematic e nolofalitsoeng ea libaka tsa boko tsa mesocorticolimbic tse tsejoang ho angoa ke polasetiki e hlahisitsoeng ke lithethefatsi, liphetoho tsa bohlokoa tsa synaptic ...

Ho hlokahala lipatlisiso tse eketsehileng ho netefatsa le ho holisa mofuta ona oa ho sebetsa, hobane liphetoho tse kopantsoeng le lithethefatsi tse tlatsetsang li ngata ebile li rarahane. Lipotso tse 'maloa tsa bohlokoa li lula li sa arajoa. Mohlala, polasetiki ea evaptic e kentsoeng ke lithethefatsi e ithutile haholo ho VTA le NAc, empa tsebo ea rona mabapi le liphetoho tsa synaptic ho mPFC le litlamorao tsa bona tsa boitshwaro e ntse e le tse fokolang. Ntle le moo, li-neuroadaptations tse entsoeng ke lithethefatsi li etsahala likarolong tse ling tsa boko tse nkang karolo e le karolo ea bokhoba, joalo ka amygdala le habenula (Maroteaux le Mameli, 2012; Van den Oever et al., 2012; Lecca le al., 2014), moo polasetiki e ka hlahang haholo? Boholo ba lithuto tse builoeng tlhahlobisong ena li ile tsa hlahlobisisa ka ho khetheha cocaine-induction synaptic plasticity. Na se fumanoang se akaretsa lithethefatsi tse ling tsa tlhekefetso? Sena ke sa bohlokoa haholo hobane mefuta e fapaneng ea lithethefatsi e ka ba le litlamorao tse fapaneng phetisong ea synaptic (Wolf le Ferrario, 2010). Taba e 'ngoe e sa rarolloang ke motheo oa neural oa ho se tšoanelehe ho lemong la lithethefatsi. Boithuto bo bapisang litlamorao tsa lithethefatsi tse lemalloang liphoofolong tse eketsang boits'oaro bo joalo ba litlamorao le litlamorao tsa lithethefatsi tse tlatsetsang liphoofolong tse sa tlatseng ho kenya letsoho ho fumana li-correaptates tsa synaptic tsa tlokotsi ea ho lemalla (Kasanetz et al., 2010; Abrahao et al., 2013). Kamora nako, lithethefatsi tsa tlhekefetso li ka ama ka mokhoa o fapaneng phapang ea li-neuron kahare ho karolo e itseng ea boko (Wolf le Ferrario, 2010; Creed & Lüscher, 2013). E tla ba ho thabisang ho ithuta kamoo likarabo tse matla tsa likaroloana tse ikhethang tsa li-neuron ho lithethefatsi le litheko tse amanang le lithethefatsi libakeng tse fapaneng tsa mesocorticolimbic li hlahisa likarolo tse fapaneng tsa bokhoba.

Khohlano ea polelo 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.

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