Addicted Synapse: Mekhoa ea Synaptic le Mapolanka a Motheo ho Nucleus Accumbens (2010)

Mekhoa ea Neurosci. Sengoloa se ngotsoeng; e fumaneha ka PMC 2011 June 1. E phatlalalitsoe ka foromo e hlophisitsoeng ea ho qetela e le:

Trends Neurosci. 2010 June; 33(6): 267-276.

E phatlalalitsoe marang-rang 2010 March 5. doi:  10.1016 / j.tins.2010.02.002

Scott J. Russo,1,* David M. Dietz,1 Dani Dumitriu,1 Robert C. Malenka,2 'me Eric J. Nestler1                        

inahaneloang

Lithethefatsi tse tlatsetsang li baka ntlafatso e sa khaotseng ea mefuta e 'maloa ea lisele tsa neuronal libakeng tsa maoto a bokong tse nahanoang hore li ikarabella bakeng sa ts'ebeliso ea nako e telele ea ts'ebeliso ea ts'ebetso ea polasetiki. Le ha liphetoho tsena tsa sebopeho li ngotsoe hantle ka har'a li-neuron tsa "spiny" tse nyane, ha ho tsejoe letho ka mekhoa ea molek'hule. Ho kenyelletsa moo, ho ntse ho sa hlaka hore na polasetiki ea sebopeho le li-convertericant tsa eona tse tsamaisanang le tsona li khanna boits'oaro bo bobebe, kapa hore na li bonts'a puseletso ea homeostatic ho moriana o sa amaneng le bokhoba ka seng. Mona, re tšohla data ea morao-rao e makatsang, e ts'ehetsang kapa e hanyetsanang le maikutlo a hore liphetoho tse susumetsoang ke lithethefatsi litheko tsa dendritic li baka boitšoaro bo bobe. Re hlalosa libaka tseo ho tsona lipatlisiso tsa nako e tlang li ka fanang ka setšoantšo se qaqileng haholoanyane sa tlhophiso e kopantsoeng le lithethefatsi, ho kenyelletsoa le lithuto tsa mahlale tsa maqhubu.

Keywords: dendritic spines, ho lemalla lithethefatsi, ho khutlela morao, sisteme ea mesolimbic dopamine, tšebeliso ea nako e telele (LTP), khatello ea maikutlo e telele (LTD), methapo ea methapo ea methapo (MSN), α-amino-3-hydroxyl-5-methyl-4-isoxazole -propionate (AMPA), N-methyl D-aspartate (NMDA), ΔFosB, cyclic AMP reaction element binding (CREB), factor factor kappaB (NF VerB), le myocyte-factor factor 2 (MEF-2)

Selelekela

Bokhoba ba lithethefatsi bo tšoailoe ke liphetoho tsa nako e telele boits'oarong, joalo ka ho lakatsa le ho oela hape. E amanang le tlhekefetso ena e tsitsitseng ea boits'oaro ke ntlafatso e phehellang ea mefuta e mengata ea lisele tsa neuronal libakeng tse bokong ba boko. Mefuta e 'meli e akaretsang ea sebopeho sa polasetiki e hlokometsoe: liphetoho ka boholo ba' mele ea lisele [1] le liphetoho lipakeng tsa dendritic arborizations kapa spine morphology [2]. Mabapi le ea morao-rao, ho latela sehlopha sa lintho tse lemalloang, mofuta oa paradigm ea taolo ea lithethefatsi (mohlala, liteko tse sebetsanang le boithati) le mofuta oa lisele tsa neuronal tse hlahlojoang, lithethefatsi tsa tlhekefetso li ka fetola ho rarahana ha lekala la dendritic, esita le palo le boholo ba masapo a dendritic ho li-neuron libakeng tse 'maloa tsa boko (Lethathamo 1). Bopaki bo mabapi le maikutlo bo fana ka maikutlo a hore liphetoho tse ling tsa morphological ke babuelli ba bohlokoa ba boitšoaro bo lemalloang. Mohlala, morphine le cocaine li fetola methapo ea methapo ea methapo ho li-spiny neurons tse mahareng (MSNs) ho li-nucleus accumbens (NAc), e leng sebaka sa bohlokoa sa moputso oa boko, ho isa tekanyong e kholo ea liphoofolo tse fanang ka ts'ebeliso ea lithethefatsi, ha li bapisoa le liphoofolo tse fuoeng lithethefatsi ke mofuputsi, a fana ka tlhahiso ea hore volition e ka ba ea bohlokoa bakeng sa likarolo tsa bohlokoa tsa polasetiki (e hlahlojoe ho [3]). Ntle le moo, liphetoho tse susumetsoang ke koae ka cocineine e fetotsoeng moahong oa dendritic e kopantsoe hantle le ts'ebetso ea maikutlo a boitšoaro [4]: litekanyetso le li-paradigms tsa taolo ea lithethefatsi tse khothalletsang ts'usumetso ho matlafatsa ts'ebetso ea methapo le ho makala. Leha ho na le bopaki bona, leha ho le joalo, boleng ba boitšoaro ba polasetiki bo ntse bo sa tsejoe. Boithuto bo 'maloa ba morao-rao bo sebelisang phetisetso ea liphatsa tsa lefutso ea vaerase le mekhoa e meng ho utloisisa hamolemo boiphihlelo le liphetoho tsa molek'hule ka lebaka la liphetoho tse entsoeng ka tšebeliso ea li-MSN li hlahisitse litholoana tse hanyetsanang, ka lingoliloeng tse peli tse ngotsoeng tse tšehetsang hypotase eo koketso ea cocaine e e bakileng mokokotlong oa dendritic. segokanyipalo sa maikutlo a bohareng a maikutlo le ba bang ba babeli ba se hanyetsa ka mokhoa o fapaneng [5-8]. Thutong ena, re tšohla lintlha tsa hona joale tsa liteko tsa tlhahlobo le ho theha libaka bakeng sa lipatlisiso tsa nako e tlang. Re qaqisa lintlha tsa bohlokoa, ho qala ka mefuta ea polasetiki ea synaptic e susumetsoang ke lithethefatsi tsa tlhekefetso le matšoao a tšoaeang methapo a tsamaisang lithethefatsi, le ho hatela pele lipuisanong tse hlakileng haholoanyane tsa karolo ea morine morphometry le karolo e sebetsang ea karolo ea actin ho kopantseng boteng.

Lethathamo 1  

Liphetoho tse hlahisitsoeng ke lithethefatsi ho moronalology ea neuronal

Metheo ea polasetiki e susumetsoang ke lithethefatsi tsa opereate le tse hlasimollang tsa tlhekefetso

Dithrite e hlahisitsoeng ke lithethefatsi ea dendrites e ile ea hlalosoa ka lekhetlo la pele ho 1997 (e hlahlojoa ho [3, 9, 10]). Ho tloha ka nako eo, lilaboratori tse ngata li bontšitse hore taolo e sa fetoheng ea hoo e batlang e le lithethefatsi tsohle tse sebelisang tlhekefetso e etsa polasetiki ea moputso. Lithuto tsena li boetse li hokahanya liphetoho tsa sebopeho kahare ho likarolo tse itseng tsa boko ho ea boits'oarong bo amanang le bokhoba. Ho tloha ha litlaleho tsa mantlha tsa Robinson le basebetsi-mmoho (li hlahlojoe ho [3]), bafuputsi ba bangata ba kentse letsoho ho lingoliloeng tsena tse ntseng li hola mme ba sibolla litlamorao tse poteletseng le tse amanang le lithethefatsi ho morphology ea neuronal. Mohlala, opiates le li-activates li laola polasetiki ea sebopeho ka lehlakoreng le fapaneng. Li-Opiates li fokotsa palo le ho rarahana ha methapo ea dendritic ho NAc MSNs, medial prefrontal cortex (mPFC) le hippocampus pyramidal neurons, hape le ho fokotsa boholo ba soma ea "ventral tegmental sebakeng" (VTA) dopaminergic neurons [1, 3, 11, 12]. Ho fihla joale, ho na le mokhelo o le mong ho tse fumanoeng: morphine e sa foleng e eketsa palo ea lesapo la mokokotlo ho orbitofrontal cortex (oPFC) pyramidal neurons [13]. Ho fapana le opiates, li-stimulants tse kang cocaine, amphetamine, le methylphenidate li lula li eketsa ho rarahana ha dendritic le letsoalo la lesapo la li-NAc MSNs, VTA dopaminergic neurons, le mPFC pyramidal neurons [2, 8, 14-17]. Ho ea ka pono ea boits'oaro, morphine e fokotsa letsoalo la lesapo la mokokotlo le ho thatafala ho sa tsotelehe hore na e tsamaisoa khafetsa ho hlahisa mamello le ts'ehetso, kapa nako le nako ho phahamisa maikutlo, athe li-paradigms tse matlafatsang tse eketsang letsoalo la lesapo la mokokotlo le ts'ebeliso eohle li sebelisa habeli makhetlo a 'maloa a kenang kahare lithethefatsi ho susumetsa maikutlo a lithethefatsi [3, 9].

Liphetoho tse fapaneng tsa morphological tse hlahisitsoeng libakeng tsa moputso oa boko ka li-opiates le li-stimulants lia makatsa kaha lithethefatsi tsena tse peli li baka mokhoa o ts'oanang oa boits'oaro. Li-opiates le li-activates ka bobeli li kenya ts'ebetso ea locomotor hantle le locomotor le ho fana ka maikutlo a khafetsa [9]. Ka bobeli le tsona li etsa mekhoa e tšoanang ea ho nyoloha ha lithethefatsi hammoho le boemo bo bobe ba maikutlo (dysphoria) nakong ea ho tlohela [18]. Kahoo, haeba liphetoho tse fapaneng tsa morphological tse susumetsoang ke li-opiates le li-susumetso ke babuelli ba bohlokoa ba bokhoba, ba tlameha ho ba le thepa ea ho reka, eo ka eona phetoho ho tloha mehatong ka bobeli e hlahisang mokhoa o ts'oanang oa boitsoaro, kapa ho na le lintlha tsa bohlokoa mabapi le ts'ebetso ea synaptic eo. ha e ts'oaroe ka ho lekanya liphetoho tse feteletseng ho letsoalo la mokokotlo oa dendritic kaha sena se ka buselisoa ka phetoho ea matla a kopantsoeng ea synaptic ho boloka phello ea kakaretso ea synaptic ka neuron kamehla [19]. Mohlala, joala bo fokotsa ho rarahana ha neuronal le letsoalo ha bo ntse bo kopanya li-synapses tse neng li le teng pele [20], mme ho kanna ha etsahala hore opiate le li-stimulants li hlahise litlamorao tse tšoanang le boholo ba boholo ba postynaptic density (PSD) e lebisang phetohong e ts'oanang ea ts'ebetso ea synaptic. Ha ho hlake hore na ho pepesehela li-opiate kapa li-stimulants nako e telele ho lebisa ho liphetoho tse tšoanang tsa motlakase ho li-synces tsa NAc, joalo ka ha ho ka lebelloa ha ho fanoa ka likarolo tse arolelanoang tsa phenotype e lemalloang. Qetellong, re lokela ho nahana hore phetoho e susumetsoang ke lithethefatsi ea nomoro ea synaptic le ho sebetsa hantle sebakeng se le seng sa boko li ka baka ho matlafatsoa kapa ho fokola ha khokahano le libaka tse ling tsa boko, mme ho ka tsamaisa likarolo tse ikhethileng tsa boits'oaro bo bobebe [21-23].

Neurophysiological bohlokoa ba polasetiki e susumetsoang ke lithethefatsi

Patlisiso ea mantlha mabapi le bohlokoa ba liphetoho tsa mokokotlo oa dendritic ho hippocampus le cortex ea cervex e bontša hore boholo le sebopeho sa methapo e le 'ngoe li lumellana le mefuta ea polasetiki ea bolelele ba nako e telele (LTP) le khatello ea maikutlo ea nako e telele (LTD) [24, 25]. Ho lumeloa hore botsitso ba mokokotaba o sa tsitsang, o sa emeng ho fihlela mokokotlong o tšoarellang, o sebetsang o hlaha ka ts'ebetso e itšetlehileng ka mosebetsi (e lekantsoe ho [26]). Liprotheine tsa ho hlohlelletsa tse susumetsang LTD li amahanngoa le shrinkage kapa ho hlakola lesapo la mokokotlo [27-29], athe ho kenella hoa PDP ho amana le ho etsoa ha methapo e mecha le katoloso ea methapo e teng [27, 28, 30]. Boemong ba limolek'hule, ho lumeloa hore LTP le LTD li qala liphetoho tseleng ea ho tšoaea, le ho hlophiseheng le liprotheine tsa cytoskeletal, tse fetolang polymerization ea actin ho ama ho holofala ha lesapo la mokokotlo le ho tsitsa le ho ts'oaroang kapa ho hlasimolla α-amino-3 -hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) li-glutamate receptors ho hlahisa mokokotlo o sebetsang haholoanyane (LTP) kapa ho hlakola lesapo la mokokotlo (LTD) [24, 26]. Kamora botsitso, methapo e fetoha sebopeho sa li-mushroom, e ba le likhoele tse kholo tsa postynaptic [31], bonts'a polelo e eketsehang ea li-receptor tsa AMPA, 'me e phehelle likhoeli [29, 32]. Liphetoho tsena li bonts'a ketsahalo ea cellular e tsitsitseng haholo eo e ka bang tlhaloso e utloahala bakeng sa liphetoho tse itseng tsa nako e telele tsa boits'oaro tse amanang le bokhoba.

Mosebetsi oa morao-rao mefuteng ea bokhoba ba tahi o hlile o bonts'itse liphetoho tse sebetsang ho li-NAc MSN tse ts'ehehileng haholo ka nako le mokelikeli nakong ea ts'ebetso ea bokhoba (Setšoantšo sa 1). Linakong tsa pejana ka mor'a ho pepesetsoa ha koae, ho na le keketseho ea methapo e tšesaane (polasetiki e ngata haholo) le khatello ea maikutlo [33, 34], e ka emelang letamo le eketsehileng la li-synapses tse khutsitseng [35, 36]. Li-synapses tse khutsitseng li na li-receptors tsa N-methyl-D-aspartate (NMDA) empa li-receptors tse fokolang kapa ha li na letho tsa AMPA, li bua ka li-curcator tsa li-postynaptic tse tsitsitseng tsa NMDA, hape ke likarolo tse ntle bakeng sa LTP [36, 37]. Nakoana kamora kalafo ea koae, litlatsetso tse joalo tse khutsitseng ho NAc li bonahala li bontša palo e eketsehang ea li-receptors tsa NR2B tse nang le NMDA [35], se fumanehang se lumellanang le li-synaps tsena hore se secha ebile ha se na botsitso [38, 39]. Nakong ea ho khaotsa koae, metsoako ena e sa tsoa etsoa e bonahala e le ea nakoana ebile e ka khutlisetsa kapa ea kopanya likarolo tsa bokahare ba li-mushroom [33], ketsahalo e tsamaeang le keketseho ea polelo ea holim 'a li-receptor tse se nang thuso tsa AMPA tsa GluR2 le lebaka le ka hlahisoang ke li-synapses tsena tsa glutamatergic [40-42]. (Li-receptors tsa GluR2 tse haelloang ke AMPA li bonts'a Ca e kholo2+ le boitšoaro ka kakaretso ha bo bapisoa le li-receptor tsa GluR2 tse nang le AMPA.) Boitšoaro, ho kenella litakatsong tsa koae ho bonoa nakong ea ho khaotsa ho itaola; hona ho bontšoa ke keketseho e tsoelang pele le e tsoelang pele ea ho batla koae le ho tsilatsila ho khutla, e leng se ka hlokang liphetoho tsena ho stoichiometry ea li-recaptor tsa AMPA tsa synaptic [42, 43]. Leha ho le joalo, lithuto tsa boits'oaro bo sebelisang phetisetso ea liphatsa tsa lefutso tsa vaerase li bonts'a hore ho nona ho feta ha AMPA GluR1 subunit ka tsela e makatsang ho fokotsa maikutlo a boitšoaro ho cocaine, ho hlakisa tlhoko ea lipatlisiso tse ling sebakeng sena [44]. Bopaki bo eketsehileng bo bontša hore ho pepesetsoa ha koae hape ka mor'a matsatsi a 14 kapa 30 ea ho khaola ho hlahisa sepheo sa hlooho ea mokokotlo [33], polelo e theohileng ea li-receptor tsa AMPA [40], le khatello ea maikutlo ka linako tse ling [45]. Nakong ea liphetoho tsena tse sa feleng sebopeho sa sebopeho sa motsoako le sebopeho, ho boetse ho na le liphetoho tse kholo tšebetsong ea RhoGTPase liprotheine tse bonts'ang tse hlokahalang bakeng sa polanete ea actin, phello e kanna ea ikarabella bakeng sa ntlafatso ea lesapo [46]. Lintlha tsena li supa tšebelisano e rarahaneng pakeng tsa sebopeho sa hlooho ea lesapo, thepa ea motlakase ea NAc MSNs, le boitšoaro bo amanang le bokhoba. Ka lebaka la hore liprotheine tse ngata tsa synaptic li ka laola liketsahalo tsena, ho tla ba bohlokoa ho tseba li-network tse nepahetseng tsa limolek'hule tse amehang taolong ea tsona.

Setšoantšo sa 1  

Moetso oa polasetiki e amanang le bokhoba le polasetiki

Mekhoa ea polasetiki ea opiate- le e susumetsang e susumetsang

Bohlokoa ba tšebetso ba polasetiki ea sebopeho mefuteng ea bokhoba ba tahi bo rarahane, joalokaha ho hlokometsoe pejana, ke taba ea hore morphine le cocaine li na le litlamorao tse fapaneng le letsoai la MSN spine. Ho feta moo, ho na le tlhahlobo e fokolang e tobileng ea liketso tsa lithethefatsi tse theohelang ho hlalosa dichotomy ena ka polasetiki e hlophisitsoeng. Le ha ho na le lithuto tse ngata tse kholo tsa microarray tse hlahlobang liphetoho liphatsong tsa lefutso kamora ho tsamaisoa ha psychostimulant, ho na le monyetla o lekanang oa tlhaiso-leseling e joalo e fumanehang bakeng sa opiates. Ntle le moo, lithuto tsa phetoho ea polelo ea liphatsa tsa lefutso mabapi le morphine kapa cocaine li sebelisitse lintlha tsa nako tse fapaneng, li-regimens le litekanyetso, li etsa hore papiso e tobileng e se khonehe. Leha ho e-na le likatse tsena, ho hlakile hore lithethefatsi tse mpe le tse susumetsang tsa tlhekefetso li laola mefuta e mengata ea liprotheine tse tsamaisang cytoskeleton. Mohlala, ho NAc, morphine e fokotseha Homer 1 le PSD95 [47], liprotheine tse scaffold tse amanang le postynaptic cytoskeleton. Ho khahlisang, koae ka mokhoa o ts'oanang e fokotsa liprotheine tsena ho NAc [48-51]. Ho feta moo, morphine e fokotseha RhoA, Rac1, le Cdc42, GTPase tse nyane tse laolang actin cytoskeleton (bona ka tlase) [47]. Ts'ebetso ea li-GTPase tsena le sepheo sa tsona se tlase li fokotsoa ke cocaine hape [52]. Lithuto tsena li ne li sa etsetsoa ho bapisa ka kotloloho taelo ea morphine le cocaine ea mefuta e amanang le sebopeho, empa lithethefatsi ka bobeli li fumanoe li etsa liphetoho tse ngata tse tšoanang le ha li ne li le molaong o fapaneng oa li-regendic spines tsa NAc MSNs. Sena se fana ka maikutlo a hore taolo ea tsela ena e ka sebetsa e le moqapi oa polasetiki; leha ho le joalo, ha e hlalose dichotomy pakeng tsa opiate- le e susumetsang- e susumetsang polasetiki ea sebopeho.

Taba ea hore opiates le li-activator ka mokhoa o ts'oanang li ts'oara mefuta e mengata ea taolo ea cytoskeleton e kanna ea hlahisoa ke ts'ebetso ea bona ea balaoli ba tšoanang ba transcriptal, ho kenyelletsa lintlha tsa sengoloa, ΔFosB le cyclic AMP reaction element binding (CREB), ho NAc [53-56] (Setšoantšo sa 2). ΔFosB e qobelloa ho NAc ke mefuta eohle ea lithethefatsi tsa tlhekefetso [57] hape e ntlafatsa litlamorao tse phello tsa morphine le koae [58, 59]. ΔFosB e bonahala e ikarabella bakeng sa 25% e haufi ea mefuta eohle e laoloang ho NAc ke cocaine e sa foleng, ho kenyelletsa mefuta e 'maloa e amanang le polasetiki ea synaptic joalo ka cofilin, proteni e amanang le protheine-4 (ARP4), le protheine ea cytoskeletal (Arc) e laoloang ke mesebetsi.58, 60]. Ntle le moo, "osFosB e hlokahala ebile e lekane bakeng sa liphetoho tse susumetsoang ke koae" ho dendritic spineensens [7]. Leha ho le joalo, haeba ka bobeli morphine le cocaine li susumetsa ΔFosB, 'me ΔFosB e le mokena-lipakeng oa spinogenesis e ntlafalitsoeng, ke hobaneng morphine e sa foleng e fokotseha le NAc MSN spine density? Monyetla o mong ke oa hore ΔFosB e laola likarolo tse ikhethileng tsa mofuta oa morphine le tsamaiso ea koae, ho latela liphetoho tse ling tse amehang, kapa morphine e etsa liphetoho tse ling ho li-neuron tsa NAc tse fetisang pontšo ea ΔFosB, e le 'ngoe e tsosang spinogenesis. Ho hlokahala lithuto tse ling ho sebetsana le litlhaloso tsena le tse ling.

Setšoantšo sa 2  

Lits'oaetso tse tšoaeang tse amanang le ho hlophisa bocha ha cytoskeleton

Ho fapana le ΔFosB, karolo eo CREB e e phethang ho ts'ebetso ea methapo e entsoeng ke lithethefatsi e feta tekano. Leha ho na le bopaki ba hore ho kenngoa ha CREB ho NAc ho sebetsa pakeng tsa ho mamella le ho itšetleha ka moputso oa morphine le koae (o hlahliloe ho [61]), ho na le datha tse fokolang tse hlahlobang hore na CREB e buisana le liphetoho tsa sebopeho kamora ho pepesetsoa lithethefatsi tsa tlhekefetso. Likarolong tse ling tse 'maloa tsa boko, CREB e kenya spinogeneis [37, 62, 63], litlamorao tse ka etsoang lipakeng tsa lipampiri tsa transcriptal tse kang myocyte e ntlafatsang factor 2C (MEF2C) le brain-based neurotrophic factor (BDNF), tseo ka bobeli le tsona li kenyelletsoeng ho ts'oaraneng le bokhopo bo amanang le tahi [5, 64, 65]. CREB e ka boela ea buisana le polasetiki ka ho kenella ka MicroRNA, mir132, e sa tsoa bontšoa ho kenya ts'ebetso ea methapo ea methapo ea kutlo ea "hippocampal neurons" moetlong, ka karolo e itseng, ka ho fokotsa maemo a GTPase p250GAP [66]. Ha ho fanoa ka bopaki bo bongata bo amang karolo ea CREB ea polasetiki ea sebopeho makaleng a mang a neural, phuputso e tobileng ea karolo ea CREB ho arolelanang polasetiki e kentsoeng ke lithethefatsi ho NAc ke ntho e ka pele-pele lipatlisisong tse tlang. Le mona, leha ho le joalo, ho na le ntho e makatsang e hlohlelletsang le ho hlohlelletsa mesebetsi ea CREB ho NAc ha e ntse e baka litlamorao tse fapaneng sebopeho sa dendritic.

Mechine ea limolek'hule e kopanyang polasetiki e entsoeng ka koae

1. Lits'oaetso tsa RhoGTPase tse tšoaeang li laola polasetiki ea sebopeho

Liphetoho tsa sebopeho ka har'a actin cytoskeleton li karolong e kholo e laoloang ke lelapa la GTPases tse nyane, e leng Rho, cell karohano 42 (Cdc42), Ras le Rac (bona Setšoantšo sa 2). Li-GTP tsena tse nyane li hlahisoa ke lintlha tsa phapanyetsano ea li-guanine nucleotide (GEF), joalo ka Ras-guanine nucleotide releasing factor (RasGRF1 / 2), VAV, Kalirin 7, le Tiam1, tseo kaofela li susumetsang phapanyetsano ea GDP bakeng sa GTP [67-71]. Li-GEF ka botsona li qaptjoa ke matšoao a mangata a kantle ho lisele, ho kenyelletsa le boko bo tsoang ho neurotrophic factor (BDNF) ka ts'ebetso ea ts'ebetso ea tyrosine receptor kinase (TRKB), tumor ukuaji factor-B (TGF-B), liprotheine tsa khomphutha ea lisele (li-processor), le li-receptor tsa NMDA ka li-receptors ka bongata. keketseho ea Ca2+ le ts'ebetso ea Ca2+/ Proteodulin-e amanang le protheine kinase-II (CAMKII) [71-74]. Ho tlama ha GTP ho kenya tšebetsong li-GTP tsena, ebe li lebisa ts'ebetsong ea batsamaisi ba theohileng ba actin cytoskeleton, ho kenyelletsa lim domain kinase (LIMK), liprotheine tsa Wiskott-Aldrich Syndrome (WASPs), ARP, le WASP-lelapa verprolin Homologues (WAVEs) [75-77]. Leha ho le joalo, mehato e qaqileng ea limolek'hule tse liprotheine tsena tse fapaneng li laoloang ke matšoao a tsoang kantle ho naha, 'me ka lehlakoreng le leng, mekhoa eo ba laolang moetlo, ho e hlakola, kapa ho e kopanya hape ka sebopeho sa dendritic ea motho ka mong, e ntse e sa utloisisehe hantle.

Haufinyane, li-GTP tsena tse nyane le batšehetsi ba tsona ba GEF ba 'nile ba fuputsoa bakeng sa karolo eo ba e phethang ka har'a polokeho ea tšebeliso ea lithethefatsi. Lits'ila tse haelloang ke GEF Ras-GRF1 li bonts'a maikutlo a cocaine, ha ho bua ka mokhoa o fetelletseng bokong bohle ho matlafatsa maikutlo le litheko [78]. Ntle le moo, Ras-GRF1 e bonahala e le tšubuhlellano ea polelo ea ΔFosB [78], joalo ka ha ho boletsoe pejana e khothaletsa spinogenesis ho NAc MSNs [6, 7] Ho khahlisang ke hore, cocaine e sa foleng e sa tsoa bontšoa ho fokotsa maemo a RPA e tsamaeang ka GTP, ka mohlomong e lebisa ho fokotseha hoa limolek'hule tse tlase tsa actin tse kang LimK le cofilin [52].

Sebopeho se sebetsang sa GTPases se nyane se felisoa ke liprotheine tse sebetsang tsa GTPase (GAPs), tse ntlafatsang hydrolysis ea GTP mme ka hona li sebetse e le batsamaisi ba fosahetseng ba RhoGTPases. Le ha ho tsejoe hanyane mabapi le karolo ea GAPs ho ho lemalla, phuputso e 'ngoe e bontšitse hore liphetoho tse bang teng RhoGAP18B li fana ka maikutlo a fetotsoeng a ethanol, nikotine le cocaine ho Drosophila [79]. Liphetho tsena li totobatsa tlhokeho ea lipatlisiso tse ngata tsa nako e tlang ho hlalosa molao oa RhoGTPases le liprotheine tsa ona tsa taolo ea ha motho a pepesetsoa koae kapa lithethefatsi tse ling tse lemalloang.

2. Lingoloang tsa bongoli ba polasetiki ea sebopeho

Leha mehato e hlakileng ea "limolek'hule" eo ΔFosB e sebelisang phetoho ea methapo ea lesapo la mokokotlo ho li-NAc MSN e lula e sa tsejoe, lithuto tse 'maloa tsa morao-rao li bontšitse mofuta oa ba khethiloeng ho theosa le ΔFosB o kanna oa nka karolo ho fetoloeng ha kutlo (bona. Setšoantšo sa 2). E sebelisa tlhahlobo e pharalletseng ea genome, osFosB e bontšitsoe ho laola mefuta e mengata e tsejoang e le ho kenella ka har'a spinogenesis [58]. E 'ngoe e lebelletsoeng ke cyclin e itšetlehileng ka kinase 5 (Cdk5), e hlohlelletsoang ke koae ho NAc ka ΔFosB [80] hape e tsejoa ka lits'ebetso tse ling ho tsamaisa RhoGTPases. Thibelo ea lehae ea Cdk5 e thibela ho ata ha lesapo la mokokotlo le koahelang cocineine ho NAc [8]. Pakane e le 'ngoe bakeng sa Cdk5 ke MeF2: ho kenngoa ha phosphorylates ea Cdk5 le inhibits MEF2, eo ka lehlakoreng le leng e eketsang methapo ea methapo ho NAc MSNs [5]. Khatello ea ts'ebetso ea MEF2 ha e arabela cocaine e ka lumella ho hatisoa ha liphatsa tsa lefutso tse amanang le cytoskeleton, N-WASP le WAVEs, tse nang le libaka tsa binding tsa MEF libakeng tsa tsona tsa proximal promoter. Ho boetse ho na le bopaki ba ho fana ka maikutlo a hore protheine e le 'ngoe ea WAVE, WAVE1, e laola mokokotlo oa mokokotlo ka tsela e itšetlehileng ka Cdk5 [81, 82]. Kahoo, ho kenella ha Cdk5 ke cocaine e sa foleng ka ΔFosB, ho ka baka taolo ea ts'ebetso ea WAVE, ha MEF2 e kanna ea laola boemo ba eona ba polelo bakeng sa ho fetolela liphetoho tsa nako e telele tse kenyelletsoang tlatsong. Ho tsoa ponong e sebetsang, inhibition ea Cdk5, kapa activation ea MEF2, tseo ka bobeli li ka hananang le litlamorao tsa koae ka li-spine tsa dendritic tsa NAc, ka mokhoa o makatsang e ntlafatsa likarabo tsa boitšoaro mabapi le koae [5, 83, 84]. Liphumano tsena tse sa lebelloang li fana ka maikutlo a hore liphetoho tse tebileng ho boholo ba lesapo la mokokotlo li ka 'na tsa se ke tsa lebisa karabong ea lithethefatsi ka setheo se le seng, empa e ka ba lebaka la "mekhoa e ikhethileng ea lapeng" ho lefella liphetoho tse ling tse hlahisoang ke ho pepesoa ke koae e sa foleng, joalo ka ho fokotsa tsitsipano ea glutamatergic ea li-MSN ke barekisi ba tlatselletsang pele34, 85].

Phuputsong e ileng ea latela, re ile ra hlahloba ntlha e 'ngoe ea mongolo, elementali ea nyutlelie (N2B). Re fumane hore k'hok'heine e etsa hore mosebetsi oa NFcacB o be le NAc le hore ts'ebetso e hlahisang NFcacB e ea hlokahala bakeng sa sebopeho sa lesapo la mokokotlo la "cocaine-ikiwa"6]. Joalo ka Cdk5 -UMF2 tsela, ΔFosB e hlokahala bakeng sa ho ts'oaroa ha koae ka litlatsetso tsa NF VerB, ho bonts'a hore ΔFosB e laola lenaneo le leholo la polelo e fetotsoeng ea mofuta oa gene e isang qetellong ho spinogenesis ea NAc MSNs. Ho khahlisang hape, re fumane hape hore thibelo ea tsela ea NFstrB e sitisang likarabo tsa boitšoaro ho cocaine, tumellanong le tšibollo ea maikutlo tšimong eo cocaine e kenyelitseng ho eketseha ha kutloelo-bohloko ea mokokotlo oa mokokotlo [6].

Phapang e makatsang pakeng tsa litlamorao tsa boitšoaro ba Cdk5-MEF2 vs. litlamorao tsa NF VerB, leha e le taba ea hore ho kenella litselaneng ka bobeli ho kopantsoe ka ΔFosB le ho eketsa letsoalo la dendritic spine, ho totobatsa ho rarahana ha litsela tsena tse makatsang le bohlokoa ba lipatlisiso tsa nako e tlang. Khopolo-taba ea rona ke hore litlamorao tsa koae ke ho susumetsa, ka ΔFosB, le letsoapo la mokokotlo oa NAc ka lits'ebetso tse ngata tse tlase (mohlala, NF VerB, Cdk5-MEF2, ba bang ba bangata) 'me litlamorao tsa eona li hlahisoa ka karabelo ea boitšoaro ba koae. Ka nako e ts'oanang, tsela e 'ngoe e lebelletsoeng joaloka Cdk5-MEF2 e kanna ea arola litla-morao tsa boits'oaro ka litlamorao tsa eona tse fapaneng tsa molek'hule. Kahoo, ho bohlokoa hore lithuto tsa nako e tlang li supe tsela ea "cocaine" e ngata le sepheo sa ΔFosB sa ho fumana leseli mabapi le monehelo o mong le o mong oa ts'ebeliso ea koae le koae. Liphetho tsena tse sa tšepahaleng li ka hlalosoa hape ke liphapang tse amanang le litoeba tsa transgenic le tsa Knitout kapa tsamaiso ea vaerase e feteletseng. Mefuta ena, e bohlokoa haholo ho ithuteng mekhoa ea limolek'hule e amehang polasetiki ea sebopeho, e ka hlahisa litlamorao tsa gene le ho kenya lihlahisoa tsa liphatsa tsa lefutso ka tekanyo e fetang e bonoeng kamora ho pepesetsoa lithethefatsi. Kamora nako, re tlameha ho amohela hore, ka ho lekanya palo eohle ea mokokotlo oa dendritic feela, re lahleheloa ke tlhahisoleseling ea bohlokoa mabapi le hore na methapo ena e etsa li-synapses tse sebetsang mme ka hona e fetola phallo ea tlhahisoleseling ho potoloha potoloho. Ka likelello tsena kelellong, lithuto tsa nako e tlang lia hlokahala ho hlahloba liphetoho tse hlakileng ka sebopeho sa lesapo la mokokotlo le sebopeho sa bona le likatsetso tsa bona tsa Presynaptic (lebokose 1) hammoho le litlamorao tsa motlakase oa manonyeletso ana molemong oa mokokotlo o hlahisitsoeng ke lithethefatsi le polasetiki ea synaptic (lebokose 2).

Box 1 Mekhoa ea ho lekanya polasetiki ea sebopeho ho NAc MSNs

(A) Morphology le letsoalo la methapo ea dendritic li ithutile mekhoa e mengata, e 'ngoe le e' ngoe e le matla le bofokoli. Libala tsa Golgi ha li theko e tlase ebile ho bonolo ho li etsa. Polelo e kopantsoeng le bongata ea liprotheine tsa fluorescent tse kang GFP e lumella bokhoni ba ho etsa lipatlisiso tsa methapo ea limolek'hule tse tsamaisang polasetiki e hlophisitsoeng. Leha ho le joalo, Golgi kapa phetisetso ea vaerase ha e lumelle tlhahlobo e hlakileng ea 3-dimensional (3D) ea sebopeho sa palo kapa palo. Mekhoa e mecha ea diolistics (mofuta oa tlhahiso ea lithunya tsa gene - hangata e atileng haholo - dae ea carbocyanide DiI) le microinjection ea limolek'hule tse kang Fluor dyes le Lucifer Yellow, hammoho le qeto ea sephiri ea 3D, e fana ka ponelopele e sa bonahaleng ho morphology ea methapo ea mokokotlo. (B) Mohlala oa microinjection (kapa ho laolla lisele) tsa li-neuron tsa NAc tse nang le setšoantšo sa Lucifer Yellow ho 10X (phanele e ka tlase), 40X (phanele e kaholimo), le 100X (phanele e ka ho le letona). (C) Ka ho sebelisa litoeba tsa transgenic tse hlalosang GFP ka mokhoa o ikhethileng ho Drd2- kapa Drd1-expression neurons (phanele ea leqele), re ka lebisa li-diolistics kapa dae microinjections ho ithuta liphetoho tsa mofuta oa cell ka morphology. (D) Monyetla o mong oa microinjection ke hore e netefalitsoe hore e sebelisoe le NeuronStudio, e leng lenaneo la ho etsa tlhahlobo ea 3D ka boiketsetso ea letsoapo la lesapo le morphology, hammoho le karohano e sa hlakoheng ea methapo ea kutlo hore e be makhopho a mosesane, makhopho le li-subtypes tse ling.http://www.mssm.edu/cnic/tools-ns.html). Sistimi e ts'oanang e teng bakeng sa ho sebelisoa ka dae e tlameletsoeng kahara membrane e joalo ka DiI [33]. (E) Mekhoa eohle e bobebe e thehiloeng ho microscope e na le bofokoli ba bohlokoa ha bo bapisoa le microscopy (EM). EM, tekanyetso ea khauta ea ho bona li-synapses, e sebelisa tšobotsi e ikhethang ea li-synapse: li-density tsa li-postynaptic (PSDs) li entsoe ka elektrone ebile li ka bonoa habonolo. Ntle le moo, likarolo tse ling tsa li-synaptic tse kang li-bouton tse ngata tsa synaptic (seqha sa mosehla) le li-synapses tse entsoeng hantle (lebokose la lamunu) li ka bonoa feela ke EM. Boholo ba li-PSD bo fana ka tekanyo ea matla a ntlafatsoang kaha boholo ba PSD bo hokahantsoe le mosebetsi oa synaptic le polasetiki [91]. Boemo bona ba tlhaiso-leseling bo ka ba bohlokoa mefuteng ea bokhoba ba tahi. Mohlala, ho ka etsahala hore sethethefatsi sa tlhekefetso se fetola letsoalo la mokokotlo ntle le ho fetola tšebetso ea sele, ekaba ka ho kopanya li-synapses tse seng kae empa li le matla, kapa ka ho etsa li-synapses tse ncha empa tse khutsitseng. Ka lehlakoreng le leng, phetoho e susumetsoang ke lithethefatsi ka boholo ba sebopeho sa mokokotlo - mme ka hona e sebetsa - e ka hlaha ha ho se phetoho ea palo eohle ea mokokotlo. Ho sebetsana le lipotso tsena lithutong tse tlang, re tla hloka ho bapisa polasetiki ea opiate- le e susumetsang ea tšohanyetso ea NAc le li-neuron tse ling tse sebelisang microscopy e bobebe le elektrone, le 3D morphometric morphometric mofuta oa lesapo la mokokotlo, hammoho le ho lekanya likhakanyo tsa methapo ea motlakase ea electrophysiological ea naha ea synaptic. . Ntle le moo, liteko tse sebelisang microscopy e nang le li-multon tse ngata tse kopantsoeng le ho se khonehe ha glutamate e koetsoeng, kapa ho tsosa tse boletsoeng esale pele li-termynals tsa methapo ea methapo ea methapo le methapo ea methapo, li hlokahala ka kotlolloho ts'ebetso le ts'ebetso ea methapo e mecha ea setho. Bona lebokose 2 bakeng sa litlhaloso tse qaqileng tsa lithuto tsena tse sebetsang. Scale bar: 5 μm ho (A), 1 μm ho (E). Ho (D) botala, bokhubelu, botala bo bonts'a tšesaane, li-mushroom, mofuta oa feiga ka tatellano. Ho (E) shading e putsoa e bontša axon, shading e pinki e bontša lesapo la mokokotlo, metsu e supa ho li-PSD.

Box 2 Quantifying matla a synaptic ho li-synapses tsa MSN ka bomong: ke hobane'ng ha see se hlokahala?

Ntho ea bohlokoa ea bohlokoa lipatlisisong tsa tlhekefetso ea lithethefatsi ke ho lekanya matla a synaptic maemong a lesapo la mokokotlo e le hore ho ka ba le khokahano pakeng tsa liphetoho tsa mokokotlo le liphetoho tse sebetsang tsa phetiso ea synaptic. Hajoale, sena se ka etsoa hantle ka ho kopanya li-microscopy tse ngata tsa Photon laser ho bona litšoantšo ka lehare tse nang le laser e nang le lifoto tse ngata tse sa tsitsang tsa glutamate e ts'oanang e le ho kenya tšebetsong likarolo tse tšoanang tsa motho.92, 93]. Tsoelo-pele ea bohlokoa ea mahlale e tla ba bokhoni ba ho bona litlatsetso tse ikhethileng tse etsang hore ho be le lits'oants'o tse fapaneng, hobane liphetoho tse khothalletsoang ke lithethefatsi tsa sebopeho sa synaptic le ts'ebetso li ka fapana ho latela tlhahiso (mohlala, hippocampal Versus amygdala ha e bapisoa le liphetho tsa cortical tsa NAc MSNs. mokhoa o khahlisang empa o phephetsang oa ho etsa sena ke ho bonts'a lits'ebetso tse bobebe tse ts'ebetso, joalo ka li-rhodopsins tsa seterateng, li-termaptals tsa synaptic tsa lipallo tse ikhethileng tse amanang le sena. Sena se ka lumella ts'ebetso ea lipono tse ka tsejoang, tse fapaneng ka kotloloho ha o ntse o nahana ka methapo e meng eo Qetellong, joalo ka ha ho hatisitsoe temeng, mofuta oa sele ea NAc e khethehileng e hloka ho khetholloa, hobane liphetoho tse entsoeng ka tšebeliso ea lithethefatsi le tšebetso li ka fapana lipakeng tsa li-MSN tsa Drd1- le Drd2-expression le mefuta e fapaneng ea li-interneurons ho NAc.

3. Mefuta ea mofuta oa sele e ikhethileng ea sebopeho sa polasetiki

Li-NAc MSN li teng ka har'a li-subtypes tse peli tse kholo, haholo-holo tse nang le Drd1 kapa Drd2 dopamine receptors. Litsela tse kenang ka hare ho noka tsa li-receptor li fapana haholo, ka hona methapo ea limolek'hule e tataisang sebopeho sa methapo ea kutlo e ka fapana ka tsela e tšoanang. Le ha ho kenyelletsoa ha methapo ea dendritic kamora ho phekoloa khafetsa ka li-psychostimulants ho etsahala ho Drd1- le Drd2 e hlalosang li-MSN, botsitso ba nako e telele ba li-spines tse ncha bo bonahala bo le boholo ho li-neuron tsa Drd1. Litlhokomeliso tsena li tšehetsa mohopolo oa hore litsela tse kenang ka nqane ho lets'ollo ea Drd1 li ka tsamaisa methapo ea nako e telele ea ho tsitsisa ho feta ho li-neuron tsa Drd2 [17, 86]. Ka sebele, ho phehella ha li-spendritic spine tse ntseng li e-na le li-MSN tse tsamaeang le li -DNL ho lumellana haholo le ho kenella ka mokhoa o phehellang ha ΔFosB ho Drd1 MSNs le maikutlo a karabelo a boitšoaro bo botle ponelleng ea lithethefatsi tse sa feleng [87, 88]. Ka hona, ho ka etsahala hore morphine le cocaine li laole li-cascade tse ikhethang tsa intracellular ho Drd1 le Drd2 MSNs. Potso ea bohlokoa ke hore na lithethefatsi tse fapaneng tsa tlhekefetso li laola sebopeho sa neuronal ka mokhoa o ikhethileng oa taolo ea liphatsa tsa lefutso li-NAc MSNs tse ikhethileng. Ena ke taba ea bohlokoa kaha lipalo tsena tse peli li amehile ka likarolo tse fapaneng tsa ts'ebetso ea NAc, e ntse e hlalositsoe ka mokhoa o phethahetseng, ho kenyelletsa menehelo e fapaneng litlamorao tsa boitšoaro ba koae. Mohlala, ho kokota ho khethiloeng ha dopamine le phochoprotein e laoloang ea 32 kDa (DARPP-32) ho tsoa ho Drd1 khahlanong le lisele tsa Drd2 li hlahisa litlamorao tse fapaneng ho ts'oenyeho ea koae [ea koae]89]. Ntle le moo, ho kokota ka sethethefatsi se bitsoang glucocorticoid receptor e tsoang Drd1 neurons ho fokolitse tšusumetso ea cocaine le khatello e matla litekong tse fapaneng [90]. Bokhoni ba hona joale ba ho sebelisa mekhoa e hlokolosi haholoanyane bakeng sa ho hlahloba liphetoho tsa limolek'hule ho Drd1 le Drd2 MSNs (lebokose 1) e tla re thusa ho utloisisa hore na liphetoho tsa limolek'hule tse hlahang mefuteng ena ea lisele tsa neuronal li ka lebisa ho liphetoho tse fapaneng sebopeho sa neuronal ho arabela lihlopha tse fapaneng tsa lithethefatsi tsa tlhekefetso, le hore na liphetoho tsena li susumetsa boitšoaro bo bobe hakae.

Nahanisisa

Prasetiki e entsoeng ke lithethefatsi ke e 'ngoe ea liphetoho tse etsahalang hangata le tse tšoarellang tse amanang le meetso ea bokhoba. Lithuto tse ngata tse amanang, le lithuto tse 'maloa tse sebetsang, li fana ka bopaki bo kholisang ba hore li-neuroadaptations tsena li bohlokoa bohareng ba maikutlo a boits'oaro ho cocaine. Leha ho le joalo, ho boetse ho na le litlaleho tse 'maloa tse sebetsang tse fanang ka maikutlo a hore ts'ebetso ea mokokotlo o hlahisoang ke lithethefatsi ke ntho e amanang le epi e sa amaneng le maikutlo. Ho totobetse hore ho hlokahala mosebetsi o eketsehileng ho utloisisa ka botlalo ho kenella ha polasetiki ea synaptic le sebopeho litekanyetsong tsa boits'oaro. Mothating ona, ke pele ho nako ho ngangisana ka mokhoa o hlakileng ka lehlakoreng le leng, kaha lithuto tse hatisitsoeng haholo li itšetleha ka litekanyo tsa boholo ba dendritic spine density, li hlokomolohile likarolo tse ngata tsa polokelo ea lesapo la mokokotlo (bona lebokose 1). Ho tekolo ena kaofela, re hlalositse libaka tsa bohlokoa bakeng sa lipatlisiso tsa nako e tlang, tse akaretsang ka Lethathamo 2, tse hlokahalang ho hlakisa tlhaiso-leseling ea liteko tsa parado le ho thusa ho hlalosa karolo ea polasetiki ea dendritic spine ho lemalla. Boithuto ba nako e tlang bo sebelisang li-multon-photon le elektrone ea elektronike bo tla hlokahala ho bapisa litlamorao tsa lithethefatsi tsa opiate le tse khothatsang tsa tlhekefetso mefuteng e qaqileng ea li-synapses tsa thabo, tse kang palo ea li-dockles tsa polokelo ea polokeho ea polokelo ea metsi, PSD le bolelele bo sebetsang. letsoalo la hlooho le molumo. Sena se tla thusa ho araba potso ea hore na phapang e makatsang e bonoang ho boholo ba methapo ea kutlo ea dendritic kamora morphine le cocaine li hlile li bonts'a phapang ea palo le matla. Ntle le moo, ka lebaka la sebopeho sa nakoana sa liphetoho tse ngata tsa motlakase, re hloka tlhaiso-leseling e hlakileng ea nako e telele ea dendritic polasetiki, ea LTD / LTP, le ho kenyelletsa kapa ho kenella ka har'a li-receptors tsa glutamate tse susumetsoang ke opiates le li-stimulants tse ka bonts'ang likarolo tse itseng tsa boits'oaro ba temallo. Ho theha ho ts'oenyeha, re tla hloka ho fumana hore na e 'ngoe ea liphetoho tsena tse sebetsang le sebopeho e ama joang boits'oaro bo joalo. Ntlha ena ea ho qetela e bohlokoa haholo 'me e tla hloka ho kopanngoa ha mekhoa e mengata. Taba ea pele, tsela ea limolek'hule e khetholloa e le taolo ea lithethefatsi tsa tlhekefetso le mefuta e tlase ea sepheo e hlahisitsoeng bakeng sa mefuta efe kapa efe e amanang le polasetiki e amanang le polasetiki. Joale, ka ho sebelisa phetiso ea liphatsa tsa lefutso e fetisang vaerase, polelo ea shRNA, kapa litoeba tse sa fetoheng tsa liphatsa tsa lefutso ho sebelisa mekhoa ena ea limolek'hule, ho tla ba bonolo ho tseba likarolo tsa bona tse ikhethang mabapi le phetoho ea lithethefatsi tsa elektroniki. Kamora nako, lithuto tsena kaofela li tlameha ho nahanoa ka mofuta oa sele le bokong bo ikhethang bakeng sa kutloisiso e nepahetseng ea methati e nepahetseng ea methapo ea methapo ea kutlo.

Lethathamo 2  

Lipotso tse ikhethang

lumela hore baa fokola

Litokisetso tsa tlhahlobo ena li ile tsa tšehetsoa ke lithuso tse tsoang Setsing sa Naha sa Ts'ebeliso e Mpe ea Lithethefatsi

Lethathamo la Lipehelo tsa lenane

Boitšoaro bo amanang le bokhoba ba tahi
Hangata sena se ithutoa ka tšebeliso ea litlhare tsa taolo ea lithethefatsi, ho kenyelletsa sepheo sa ho iphelisa, ho tlosa le ho felisoa, hammoho le ho khutlisetsoa hape (ho khutla hape)
Mekhoa ea kalafo e matlafatsang
Sena se kenyelletsa cocaine amphetamine, kapa nicotine ka tekanyo e itseng le khafetsa ka nako e itseng. Joale liphoofolo li hlahlojoa ka linako tse fapaneng ka mor'a tekanyetso ea ho qetela ea lithethefatsi
Litlhare tsa kalafo ea Opiate
Sena se kenyelletsa morphine o lekang kapa o ikemetseng, heroin, kapa lithethefatsi tse ling tsa tlhekefetso ka tekanyo e itseng le khafetsa ka nako e itseng. Joale liphoofolo li hlahlojoa ka linako tse fapaneng ka mor'a tekanyetso ea ho qetela ea lithethefatsi
Libaka tsa moputso oa boko
Tsena li kenyelletsa li-neuron tsa "midbrain dopaminergic neurons" sebakeng sa "ventral tegmental" le libaka tse emeng moo methapo ena e kenang ho tsona, ho kenyelletsa le li-nucleus accumbens (ventral striatum) amygdala, hippocampus, le libaka tse 'maloa tsa preortalal cortex (mohlala, medial, orbitofrontal, jj.)
Li-receptors tsa Glutamate
Li-receptor tse kholo tsa ionotropic glutamate bokong li reheletsoe li-agonists tse khethehileng, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) le N-methyl-D-aspartate (NMDA)
Dopamine receptor
Mefuta e 'meli e meholo ea li-receptor tsa dopamine e hlahisoa ka li-nucleus accumbens, tse nang le Drd1 kapa Drd2 receptors, tse fapaneng mekhoeng ea bona ea post-receptor signaling. Li-receptor tsa Drd1 li Gs-li kopantsoe ebile li susumetsa cyclase ea adenylyl, ha li-receptors tsa Drd2 li Gi / o-kopantsoeng le ho thibela bohato ba adenylyl, li kenya ts'ebetso kahare ho lokisa K+ liteishene, le inhibit voltage-gated Ca2+ dikanale. Li-receptor ka bobeli li ka boela tsa laola likhakanyo tsa li-extracellular sign regated kinase (ERK)
RhoGTPases
Liprotheine tsena tse nyane tsa G li bapala karolo ea mantlha taolong ea "actin" cytoskelelton, eo ho nahanoang hore e bohlokoa molemong oa kholo le ho khutsisa ha methapo ea methapo. Li hlahisoa ke lintlha tsa phapanyetsano ea "guanine nucleotide" (GEF) hape e thibelletsoe ke liprotheine tse sebetsang tsa GTPase (GAPs)
Lintho tse ngotsoeng
Tsena ke liprotheine tse tsamaeang le tatellano e itseng ea DNA (e bitsoang likarolo tsa karabelo) kahara liphatsa tsa lefutso tse ikarabellang ebe ka tsela eo li eketsa le ho fokotsa sekhahla seo mefuta eo e ngolisitsoeng ka eona. Mehlala ea lintlha tse ngotsoeng tse laolang li-dendritic spines ke: ΔFosB (protheine ea lelapa ea Fos), cyclic AMP Karolo ea Karabelo ea Phatlalatso (CREB), ntho ea nyutlelie (N2BB), le myocyte-factor factor-2 (MEF2)
Protein kinases
Li-protein tsa 'mele tse' maloa, li-enzyme tse fanang ka liprotheine tse ling ho laola tšebetso ea tsona, li bile le tšusumetso taolong ea sebopeho sa lesapo la mokokotlo, ho kenyeletsa le Ca2+/ proteinodase-based protein kinase-II (CaMKII), cyclin-wate kinase-5 (Cdk5), p21-activated kinase (PAK1), le lim domain kinase (LIMK), hara ba bang ba bangata
Liprotheine tse amanang le Actin
Acinin cytoskeleton e laoloa ke liprotheine tse ngata, leha ho le joalo, karolo e qaqileng ea karolo e 'ngoe le e' ngoe qetellong ho hola kapa ho theola lesapo la mokokotlo, kapa ho fetola boholo le sebopeho sa lesapo la mokokotlo, e lula e sa utloisisehe hantle. Mehlala e kenyelletsa liprotheine tse amanang le Actin (ARPs), liprotheine tsa Wiskott-Aldrich Syndrome (WASPs), WASP-lelapa verprolin Homologues (WAVEs), le cofilin, hara tse ling tse ngata.

Mongolo o botlaaseng ba leqephe

Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.

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