Tšebeliso ea Lithethefatsi e le Pathology ea ho Etsa ha Neuroplasticity e Etsoang (2007)

Neuropsychopharmacology (2008) 33, 166-180; doi: 10.1038 / sj.npp.1301564; e phatlalalitsoeng marang-rang 5 September 2007

Peter W Kalivas1 le Charles O'Brien2

  1. 1Mafapha a Neuroscience, Univesithi ea Bongaka ea South Carolina, Charleston, SC, USA
  2. 2Lefapha la Psychiatry, Setsi sa Bongaka sa Philadelphia VA, Univesithi ea Pennsylvania, Philadelphia, PA, USA

Lengolo: Dr P Kalivas, Lefapha la Neuroscience, Univesithi ea bongaka ea South Carolina, 173 Ashley Ave, BSB 410, Charleston, SC 29425, USA. Mohala: + 1 843 792 4400; Fekse: + 1 843 792 4423; Lengolo-tsoibila: [imeile e sirelelitsoe]

inahaneloang

 

Ho sebelisa lithethefatsi tse lemalloang ho ka fetoha molemong oa tšebeliso ea taolo ea sechaba ho kena bohlankeng bo ikarabellang bo bocha bo khethollang bokhoba. Phetoho ena ea ho lemalla e hlahisoa ke bofokoli ba liphatsa tsa lefutso, nts'etsopele, le bophelo sechabeng, hammoho le polasetiki e kentsoeng thekisong ea bongaka e matlafatsang boits'oaro bo amanang le lithethefatsi molemong oa ho arabela ka mokhoa o hlakileng bakeng sa meputso ea tlhaho. Tsoelo-pele e fetang lilemo tse leshome tse fetileng e bontšitse hore liserekisi tsa boko li kotsing e haufi le ho feta ea liphetoho tse tlisoang ke lithethefatsi, hammoho le tse ling tse amanang le limolek'hule le morphological. Tsebo ena e ntseng e hola e tlatselitse kutlwisisong e kholo ea kamoo lithethefatsi li sebelisang likereke tse tloaelehileng tsa ho ithuta ho theha litekanyetso tsa ho lemalla, joalo ka ha ho bonahala ka ts'ebetso ea boithatelo ea li-circuits tsa meputso ho arabela litumelo tse amanang le lithethefatsi le litlaleho tse tšoanang tsa takatso ea lithethefatsi. Kutloisiso ena e ncha e fana ka menyetla e ke keng ea bonoa ea litheko tsa litlhare tsa meriana ho phekola bokhoba. Ho bonahala ho na le polasetiki e amanang le ts'ebetso ea bokhoba ka kakaretso le liphetoho tse hlahisoang ke bokhoba ba sehlopha se itseng sa lithethefatsi tse lematsang. Liphumano tsena li boetse li fana ka motheo oa kutloisiso ea hona joale ea bokhoba e le lefu le sa foleng, le khutlisetsang bokong ka liphetoho tse phehellang nako e telele kamora ts'ebeliso ea ho qetela ea moriana. Mona, re hlalosa neuroplasticity ho li-circuits tsa boko le ts'ebetso ea lisele tse khothalletsoang ke lithethefatsi tse lemalloang tseo ho nahanoang hore li etsa tlatsetso ea ho qala ts'ebeliso ea lithethefatsi, 'me re buisana ka hore na tsebo ena e susumetsa joang ho hlahloba le ho lekola mekhoa ea phekolo ea bokhoba ba tai.

Ho lemalla lithethefatsi ka tloaelo ho ananeloa e le lefu le thehiloeng ho neuropathology (O'Brien, 2003). Maikutlo a hore batho ba lemaletseng lithethefatsi ba tlameha ho qoba boitšoaro bo kotsi bo tsamaeang le ts'ebeliso ea lithethefatsi, bo sitisitse sechaba ho nka ts'ebeliso e mpe ea lithethefatsi e le bothata bo sa foleng ba bongaka. Lilemo tsa 20 tsa ho qetela tsa lipatlisiso li hlakisitse hore ts'ebeliso ea lithethefatsi e thehiloe ho liphetoho tsa ts'ebetso ea ts'ebetso ea ts'ebetso ea boko e hlahisoang ke ho nyefoloa khafetsa ha pharmacological ho li-circuits tsa boko tse laolang tsela eo motho a fetolelang le ho etsa ka boits'oaro ka eona ho susumetso e loketseng. Kahoo, lithethefatsi tse lemalloang li sebelisana 'moho le ho fetola li-circuits tsa boko tse re lumellang ho ithuta le ho phela ka tsela e lumellanang le maemo a bohlokoa a tikoloho, hore na ke mokhoa oa ho fumana meputso e kang lijo kapa thobalano, kapa ho qoba maemo a kotsi.Kelley, 2004; Everitt le Robbins, 2005). Ka ho fetola mokhoa oa ho khothaletsa lithethefatsi, lithethefatsi tse lemalloang li sitisa nts'etsopele ea maano a boits'oaro ho susumetso ea tloaelo ea boits'oaro e tsoelang pele ho mekhoa ea ho batla lithethefatsi le maano a ho sebelisa lithethefatsi (Kalivas le Volkow, 2005). Habohlokoa, liphetoho tsena ke tsa nako e telele 'me hajoale ha li fetohe habonolo (Hyman et al a, 2006).

Tlhaloso ea sejoale-joale ea ho lemalla e qaliloe ka lekhetlo la pele ho DSM IIIR ke Mokhatlo oa Amerika oa Psychiatric Association ho 1987 (APA, 1987). Setšoantšo sa kliniki se tšoailoe ke tšebeliso e mpe ea lithethefatsi eo motho eo a ke keng a e laola ka botlalo. Matšoao a ho mamella le ho ikhula a kanna a ba teng, empa ha ho hlile ha a bolele hore motho o lemaletse. Sebakeng seo, lintlha tsa bohlokoa li na le boits'ebetso bo phehellang le bo batlang ba ho batla lithethefatsi ka litšenyehelo tsa ho lelekisa meputso e tloaelehileng. Tlhaloso e nahanne, ntle le bopaki bo hlakileng ho 1987, hore ho na le "mantlha" ea ts'ebeliso ea lithethefatsi eo lithethefatsi tse fapaneng tsa tlhekefetso li ka li hlahisang. Thutong ena, re marshal bopaki bo teng hona joale ba ho hlalosa lefu lena la mantlha e le ts'ebetso ea methapo ho limolek'hule le lipallo tsa boitšoaro bo susumetsoang. Ho latela pono ena, bokhoba ke mokhoa oa ts'ebetso oa methapo ea methapo ea boko e sebelisetsoang ho tsebahatsa mekhoa e metle ea boitšoaro e netefatsang hore e tla phela. Kahoo, ho mamella li-neuroplasticity tse sebelisang lithethefatsi ho theha tikoloho e bonts'ang likarolo tse peli tsa mok'hadinale, (1) bokhoni ba ho laola taolo ea ho fumana le ho sebelisa lithethefatsi (ke hore, ho khutla hape, le (2) drive e theotsoeng ho fumana meputso ea tlhaho.

Ka holimo ho leqephe

NEUROPLASTICity LE LIT STOBOTSI TSE FUMANENG

Bakeng sa tlhahlobo ena, neuroplasticity e tla aroloa ka mekhahlelo e 'meli: ea pele, liphetoho tse liehang ho feta tsa tšebetso ea methapo ea kutlo e tsoelang pele lihora tse ngata ho isa libekeng tsa ho tlohela lithethefatsi,' me ea bobeli, liphetoho tse tsitsitseng tse tšoarellang ho tloha libeke ho ea ho liphetoho tse sa feleng. Neuroplasticity ea nakoana e tsamaisana le liphetoho tse hlokahalang tse amanang le ho ba le boitšoaro bo bocha, athe neuroplasticity e ts'oanang le leseli le tsitsitseng le khutlisoang ho tataisa ts'ebetso ea boitšoaro bo ithutileng. Molemong oa bokhoba ba tai, mehato ena e hlalosoa e le ho lemalla (ho ho ithuta ho ba lekhoba la tahi) le boemo bo tsitsitseng ba ho ts'oha hape ka mor'a ho emisa ts'ebeliso ea lithethefatsi. Nts'etsopele ea ts'ebeliso ea lithethefatsi e fumaneha hangata ka tšebeliso ea lithethefatsi sechabeng khafetsa, 'me e kenyelletsa liphetoho tse ngata tse iphetileng tsa nakoana ho k'hemistri ea boko le physiology e thehiloeng haholo ho molek'hule oa meriana ea lithethefatsi ka boeona (Nestler, 2005). Ho Setšoantšo sa 1a, sethaleng sena ho thoe ke ts'ebeliso ea sechaba. Mokhahlelo oa bobeli o etsoa ke ho rohakana khafetsa ha lithethefatsi, 'me ho ipapisitse le liphetoho tse teng phallology ea synaptic ea li-circuits tsa boko tse laolang karabelo ea kutloisiso le maikutlo maikutlong a bohlokoa a tikoloho. Sena se bontšoa ka Setšoantšo sa 1a ka mekhahlelo e 'meli ea ho khutlela morao. Mokhahlelo oa pele oa ho khutlela morao o hlalosoa e le ho khutla ho laoletsoeng, 'me ea bobeli e le ho khutla hape ka tšohanyetso. Ho khutla ho laoletsoeng ho bolela mokhoa o etsang qeto oa ho etsa liqeto moo mothetsi oa hae a ikemiselitseng ho etsa qeto ea ho o tlohela hape. Mohlala, motho ka mong a ka etsa khetho pakeng tsa ho thusa ngoana oa bona ka mosebetsi oa sekolo kapa ho noa senoelo sa veine. Boemong bona, motho ea lemaletseng joala hangata o etsa khetho e nepahetseng sechabeng. Ha motho a khutlela hape ka mokhoa o qobelloang, ha a etse khetho e bohlale. Mohlala, leha ho thusa ngoana oa bona ka mosebetsi oa sekolo e kanna ea ba mananeo a mantsiboea, ho pepesehela litloaelo tse fapaneng tsa tikoloho kapa khatello ea maikutlo eo motho eo a amanang le tšebeliso e mpe ea lithethefatsi e etsa hore motho a batle lithethefatsi, 'me ha ho mohla ho kileng ha etsoa qeto e bohlale, motho eo ka boeona e khutla.

Setšoantšo sa 1.

Setšoantšo sa 1 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Papiso ea kamano lipakeng tsa neuroplasticity, ho ithuta ho susumetsang, ho potoloha ha boko, le methati ea ho lemalla. (a) Manane a tlhekefetso ho tloha tlhabisong ea bokhoba ba tšebeliso (tšebeliso ea sechaba) ho ea tlokotsing ea ho khutla (phetoho ho tloha ho laoloang ho qobelloa). Hape ho bontšoa ts'ebeliso e khothalletsoang ea litlhare le litlhare le ts'ebetso ea boitšoaro. (b) Ho etsa lipalo tse tloaelehileng tsa ts'usumetso ea ho ithuta le phetisetso e nepahetseng ea dopaminergic le glutamatergic mekhahlelong ea bokhoba.

Palo e feletseng le pale (88K)Khoasolla slide ea Power Point (344 KB)

 

Ho totobetse hore ho khutlela mokhoeng o qobelloang ke karolo e matla ho feta eo, joalo ka ha re tla bona, e na le lipheo tsa neuropathological tsa ho nts'etsapele ho kenella ha litlhare tsa meriana. Joalokaha ho bontšitsoe ka Setšoantšo sa 1, re tla fana ka tlhahiso ea pheletsong ea tlhahlobo ena e thehiloeng ho ts'ebetso ea methapo ea kutlo e qobelloang e le mofuta oa neuroplasticity, karolo ea mantlha ea psychopharmacology ho phekola bokhoba ba lithethefatsi ke ho theha lithethefatsi tse khothalletsang ho khutla hape ka taolo. Ka mantsoe a mang, har'a litlhare tsa meriana tsa bohlokoahali e tla ba tse tsamaisang ho etsa liqeto tse sebetsang, ho lumellang motho ea lemaletseng ho khetha ho se nke moriana. Ho fapana le hoo, phetoho ho tloha ho khutliselitsoeng taolong ea ts'ebeliso ea ts'ebeliso ea sechaba kapa ts'ebeliso ea bongaka e sebetsoa hamolemo ka kopants'o ea litlatsetso tsa bohlola le boits'oaro tse tiisang le ho ts'ehetsa liqeto tse nepahetseng (Karolo ea tšepe et al a, 2005). Mohlala, ts'ebetso ea ts'ebetso ea boits'oaro e ka tloha ho mekhoa ea khale joalo ka thupelo ea ho felisoa le kalafo ea boits'oaro ea kelello, ho fumana mosebetsi o tsitsitseng kapa ho kopana hape le baratuoa.

Mekhahlelo ea bokhoba le maemo a thuto e tloaelehileng ea moputso

Setšoantšo sa 1b Leka ho re hlakisa kutloisiso ea hajoale ea mohopolo oa moputso oa tlhaho le mekhoa ea ho ithuta methating ea bokhoba (Kelley, 2004; LaLumiere le Kalivas, 2006). Kahoo, ho fumana mehopolo le ho ntlafatsa likarabo tsa boitšoaro tse feto-fetohang molemong oa bohlokoa ho boleloa e le ho fumana thepa le ho tsamaisana le tšebeliso ea lithethefatsi sechabeng. Mofani oa ho khutla ka mokhoa o laoloang ke ho khutlisetsa mehopolo e fokotsehang, ke hore, mehopolo e hlalosoang ka mantsoe 'me e sebelisoa ha ho etsoa liqeto. Kamora nako, ho khutlela morao ka mokhoa o qobelloang ho ka nkoa ho lekana le litloaelo tsa tloaelo kapa tsa tsamaiso. Ho khutla ha mehopolo ea ts'ebetso ha ho bolelisoe ka molomo, mme ho tataisa ts'ebetso e sa tsebeng letho ea boits'oaro bo tsamaeang ka koloi. Boitšoaro bona bo ithutile hantle mme bo tsoela pele hantle ntle le ho nka liqeto tse sa feleng (mohlala, ho palama baesekele, kapa ho bula lemati la sehatsetsi ha ho lapile).

Ho bile le tsoelo-pele e kholo lilemong tse leshome tse fetileng kutloisisong ea rona ea ts'ebetso ea mantlha ea boko le li-neurotransmitters tse bapala karolo ea bohlokoa ho kamoo mehopolo e khothalletsang e fumanoang, le boits'oaro bo ithutileng. Ho khahlisang, boholo ba tsebo ena e bile teng ka lebaka la ho sibolla lintho tse bohloko pakeng tsa bafuputsi ba ithutang mekhoa e tloaelehileng ea ho ithuta e susumetsoang le ba ithutang bokhoba ba lithethefatsi e le mokhoa oa ho ithuta o tloaelehileng. Setšoantšo sa 1b e bontša kamoo li-circuits tsa bohlokoa tsa boko le li-neurotransmitters li tsamaellanang ka teng maemong a ho lemalla. Kahoo, ho ithuta ho ba lekhoba la tšebeliso ea lithethefatsi sechabeng ho kenyelletsa haholo lisele tsa dopamine sebakeng sa ventral tegmental (VTA) e lokollang dopamine ho preortal cortex (PFC), amygdala, le nucleus accumbens (NA) (Berridge le Robinson, 1998; Kelley, 2004; Schultz, 2004; Bohlale, 2004; Jones le Bonci, 2005). Tatelano e 'ngoe e ts'ehetsoeng ke mehlala ea liphoofolo ke hore ha ho batla lithethefatsi ho ithuta hantle, ho its'epahala ka boits'ebetso ba menyetla ea glutamatergic ho tloha ho PFC ho ea NA e hlaha (Pierce le Kalivas, 1997; Mok'hadinale le Everitt, 2004; phiri et al a, 2004). Kahoo, ho khutlisetsoa ka mokhoa o laoloang ka kotloloho ho its'etleha ho khutliseng mehopolo e amanang le lithethefatsi le ho kopanngoa ha mehopolo ena e nyarosang ka lipakanyo tsa glutamatergic tse tsoang ho PFC ho ea NA. Ha glutamate e ntse e bapala karolo e kholo ho khutlisetsong e phehellang mohlaleng ona, phetoho ea potoloho ea glutamatergic ho tloha ho sekhahla se eketsehileng, batsamaisi ba pele ba likoloi ba tloaetse ho tloaela tloaelo e kenyelletsang lijenereithara tsa khale tsa cortico-striato-thalamic boits'oaro bo ithutileng hantle (Barnes et al a, 2005; Everitt le Robbins, 2005).

Likarolo tse ling tsa tlhatlhobo ena li kenyelletsa karohano e tebileng ea methapo ea kutlo, le ho ikopanya ha neuroplasticity ho tebello ea nts'etsopele ea lithethefatsi tse ncha ho tsoa lipapatsong tse qobelloang ho khutlela mokhoeng o laoloang.

Ka holimo ho leqephe 

TLHOKOMELISO EA HO FINYELETSA HA HO BONAHALA KENYETSO EA MOTSOALLE

Joalokaha ho hlalositsoe Setšoantšo sa 1, tšebeliso ea lithethefatsi tse sa khaotseng (tšebeliso ea lithethefatsi sechabeng) e kenyelletsa ho lokolloa khafetsa ha dopamine ho tsoa liseleng tsa VTA ho ea ho PFC, striatal tata (ho kenyeletsa NA), le amygdala. Potoloho ena e bontšoa ka Setšoantšo sa 2a. Akin e susumetsang ka mokhoa o susumetsang oa tlhaho, lithethefatsi tsohle tse lemalloang li eketsa tlhahiso ea dopamine kahare ho potoloho ena, le mekhoa e fapaneng ea limolek'hule (Jay, 2003; Kelley, 2004; Nestler, 2005). Kopano ena pakeng tsa phetisetso ea dopamine e feteletseng le boits'oaro ba ho ithuta ho fumana moputso e lebisitse kutloisisong ea hore ho lokolloa ha dopamine ke ketsahalo ea bohlokoa ho nolofalletsa ho ithuta. Kahoo, liphuputso tse ngata li bonts'a hore ho thibela phetiso ea dopamine ho fokotsa ts'usumetso le ho ithuta, athe hangata dopamine e hlohlelletsa ho hapa boitšoaro ba boithuto. Ho lokolloa ha dopamine ho hlalositsoe e le ho emisa ketsahalo ka sesosa, ho theha mohopolo oa kahare oa hore ke ketsahalo e bohlokoa e hlokang ho ntlafatsoa ha karabelo ea boitšoaro (Berridge le Robinson, 1998). Phapang ea bohlokoa e teng pakeng tsa dopamine e ntšitsoeng ke lithethefatsi tse lemalloang vs susumetso e mabapi le tikoloho e susumetsang, 'me ho khethollotsoa hona ho bohlokoa bakeng sa nts'etsopele ea taolo ea lithethefatsi e laoloang le e qobelloang.

Setšoantšo sa 2.

Setšoantšo sa 2 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Corticolimbic dopaminergic pathways le lipapiso tsa kelello pakeng tsa tokollo ea dopamine e susumetsoang ke tšusumetso ea bohlokoa ea tlhaho le lithethefatsi tse lemalloang. (a) Potoloho ea Corticolimbic e laolang ho ts'oara lithethefatsi, ho kenyelletsa le sebaka sa bolulo sa dopaminergic ho tloha VTA, ho ea ho PFC, basolateral amygdala (BLA), le NA; likhakanyo tsa glutamatergic tse tsoang ho PFC le BLA ho li-bokellase tsa li-nucleus; Morero oa GABAergic / peptidergic o tsoang ho NA ho ea VP. (b) E thehiloe haholo holima lingoliloeng tsa Microdialysis, phetoho ea maikutlong kholisong ea dopamine ho arabela ka ts'usumetso ea bohlokoa ea tlhaho (meputso e khothatsang kapa e tlosang maikutlo) vs tsamaiso ea lithethefatsi tse lemalloang. Hlokomela hore lithethefatsi li etsa hore dopamine e lokolloe haholoanyane bakeng sa nako e telele, le ts'ebetso e phehellang ea taolo (litala tse tala) ha e hlahisoe ke tokollo ea dopamine e tlisoang ke lithethefatsi.

Palo e feletseng le pale (69K)Khoasolla slide ea Power Point (254 KB)

 

Setšoantšo sa 2b e bontša phapang e 'meli e kholo lipakeng tsa tokollo ea dopamine kamora tšusumetso ea tlhaho ea tlhaho vs ka mor'a ho pepesetsoa sethethefatsi se lematsang. Taba ea pele, ho lokolloa ha dopamine ka lithethefatsi tse lemalloang ho bohlokoa haholo ebile ho telele ho feta ho ka fumanoang ka mekhoa ea 'mele. Ka mantsoe a mang, pharmacology ea lithethefatsi e etsa hore dopamine e lokolloe ho feta meeli ea 'mele ka ho hlola mekhoa e tloaelehileng ea homeostatic bakeng sa ho laola ho lokolloa ha dopamine. Mohlala, li-psychpherate tsa mofuta oa amphetamine li thibela ho felisoa ha dopamine ho li-synapses, 'me maemong a mang li khothaletsa tokollo ea dynamine ea presynaptic (E beiloe et al a, 1993), athe lithethefatsi tse ling tse kang nicotine kapa opioids li sebetsa ho fetola melaoana ea lisele tsa dopamine, e leng ho eketsang tšebetso ea sele ea dopamine. Kahoo, nicotine e khothalletsa phetiso ea glutamate e thabisang ho VTA, athe li-opioids li fokotsa tokollo ea GABA ea inhibitory holima dopamine neurons (Nader le van der Kooy, 1997; Laviolette le van der Kooy, 2004; Pierce le Kumaresan, 2006). Phapang ea bobeli e kholo e bonts'itsoeng Setšoantšo sa 2b pakeng tsa lithethefatsi tse tlisoang ke dopamine tse hlahisoang ke lithethefatsi le tse hlahisoang ke tšusumetso ea likokoana-hloko, ke hore mamello e tsoela pele ho lokolloa ha dopamine ka tšusumetso ea tlhaho, athe lithethefatsi tse lemalloang li lokolla dopamine nako le nako ha moriana o nooa. Ho basebelisi ba sa foleng, dosing e eketsehileng ea hlokahala ka lebaka la mamello, empa ka tekanyo e lekaneng, keketseho ea dopamine e ka tšeptjoa. Kantle ho sena ho kenyelletsa ho itlopa joala le li-psychostimulants tse kang amphetamine, tse ka bakang ho theoha ha nakoana hoa basebelisi ba dopamine le ba sa foleng ba tlalehileng ba sa tsotelleng kapa ba mamella litlamorao tsa ts'ebetso ea lithethefatsi ka mekhoa e seng e sa tsejoe (Martinez et al a, 2007). Kahoo, bakeng sa meputso ea likokoana-hloko, hang ha motho a ithutile boitšoaro bo sebetsang ka ho fetisisa ho fumana moputso, ho lokolloa ha dopamine ho nolofalletsa thuto e tsoelang pele ha ho hlokahale ebile ha ho etsahale (Deutch le Roth, 1990; Schultz, 2004). Leha ho le joalo, ho bohlokoa ho hlokomela hore dopamine e ntse e tsoela pele ho supa ho fihla ha moputso ka maemo a susumetsoang ke maemo (Schultz, 1998). Mohlala, leha ho tsamaisoa ha moputso oa lijo ka lebaka la cue e nang le moea o lekaneng ho ka se hlohlelletse phetisetso ea dopamine ho phoofolo e koetlisitsoeng, ponahalo ea sejoale-joale e amanang le phepelo ea lijo e tla eketsa ho fokotseha ha sele, ho lokisetse phoofolo ho qala lijo tse feto-fetohang. Karabo e makatsang. Kahoo, ka har'a paramethara ea 'mele, dopamine e sebeletsa mesebetsi e' meli, (1) ho tsamaisa thuto ea pele ea ho arabela ka mokhoa o hlakileng ho susumetso ea bohlokoa, le (2) ho tseba ho khutlisa tlhaiso-leseling e hlokahalang ho phetha karabelo ea boitšoaro e lumellanang ha maemo a tikoloho a bolela esale pele hore lijo ke e haufi. Ho fapana le hoo, ts'ebetso e 'ngoe le e' ngoe ea moputso oa lithethefatsi tse lemalloang e amahanngoa le tokollo e kholo ea dopamine e ka lebelloang ho nts'etsapele thuto e ncha (ke hore, likamano tse ncha lipakeng tsa lithethefatsi le tikoloho) kapa ho tiisa thuto ea pele, hammoho le ho ts'oara motho ea lemaletseng lithethefatsi. etsa boits'oaro bo batlang lithethefatsi (ke hore, ho oela hape). Mehlaleng ea liphoofolo, lisekele li ka eketsa karabelo ho tse matlafatsang 'me ka hona tsa hlahisa karabelo e khahlisang tekong e fuoeng ea sefutho. Ka tsela ena, tšebeliso e sa khaotseng ea lithethefatsi tse lemalloang e etsa hore ho be le likamano tse ntseng li eketseha lipakeng tsa lithethefatsi le liketsahalo tsa bophelo, athe tlhaho ea bohlokoa ha e na eona. Sena se ka baka lebaka la ho sebelisa lithethefatsi khafetsa ho etsa hore boitšoaro bo batlang lithethefatsi bo kenelle likarolong tsohle tsa bophelo ba letsatsi le letsatsi ha motho eo a ntse a tšepa motho haholo.

Joalokaha ho bontšitsoe kaholimo, lithethefatsi tse fapaneng tsa tlhekefetso li lokolla dopamine ka mekhoa e fapaneng ea limolek'hule. E 'ngoe ea liketso tsa ethanol ke ts'ebetso ea ts'ebetso ea endo native opioid e le hore haeba li-opiate receptors li thibetsoe ke mohanyetsi ea joalo ka naltrexone, keketseho ea dopamine e hlahisitsoeng ka joala ha e etsahale mme moputso o koetsoe (Gonzales le Weiss, 1998). Kahoo, liponahatso tsa boits'oaro ba polasetiki bokhobeng ba batho li ka fapana ho latela sethethefatsi. Ka bokhoba ba heroin, mohlala, ts'ebeliso e mpe ea lithethefatsi e hlahisa mamello e nang le maemo a fanang ka likarabo tse khahlano le lithethefatsi kapa tse tlisoang ke ho tlohela chelete (O'Brien, 1975; O'Brien et al a, 1977). Litekanyetso tsa lithethefatsi ho batho ba lemaletseng koae li hlahisa takatso ea koae le ho ts'oaroa ha litho tsa setho sa setho sa cocaine (Ho ba le bana et al a, 1999) le tokollo ea dopamine e amanang.Volkow et al a, 2006). Ka kakaretso, ho batho ba lemaletseng batho, ho mamella ke neuroadaptation e atisang ho utluoa hangata esita le ho lithethefatsi tsa koae.O'Brien et al a, 2006). Sena se fella ka hore litekanyetso tse eketsehang tsa lithethefatsi tse ipatileng li fihlelle litlamorao tsa lithethefatsi tse tsoang pele.

Dopamine-Indedu Neuroplasticity Tlas'a Ntshetsopele ea Taolo e Laoloang le e Qobelloang

D1 le delta-FosB li-Cascade tse bonts'ang

 

Ho lokolloa ha dopamine ka litlhare tse susumetsang kapa tse lemalloang ho hlahisa liphetoho ka moo methapo ea kutlo e kopanyang neurotransmission e thabisang le ea inhibitory. Litlamorao tsa ts'ebetso ea dopamine receptor li rarahane mme khethollo e teng lipakeng tsa ts'ebetso ea D1-like vs Li-receptor tse joalo ka D2 ho latela ho ba teng ha li-preisation tsa post- le tsa postynaptic kahare ho potoloho ea lehae ea konopo e fanoeng. Ho na le litlhahlobo tse 'maloa tse ntle tse hlalosang boemo ba hajoale ba tsebo mabapi le ho chona dopamine ka ha e amana le thuto ea ho lemalla le ho khothaletsoa ho ithuta (Berke le Hyman, 2000; Nicola et al a, 2000; El-Ghundi, 2007). Molemong oa rona, Setšoantšo sa 3 e bonts'a liketsahalo tse ling tsa bohlokoa tse kentsoeng ka kotlolloho ke D1 receptor activation eo ho nahanoang hore ke lintlha tsa bohlokoa tsa ho theha liphetoho tse tšoarellang physology ea neuronal e tlatselleng ho thehoeng ha boits'oaro bo khahlisang ba liketsahalo tse amehang tse khothatsang, hammoho le boits'oaro bo bobe ba ho batla lithethefatsi. Habohlokoa, ts'oaetso ena e kenyang litlatsetso e kenyelletsa liphetoho phetisong ea mofuta oa gene le phetisetso ea chromatin eo ho nahanoang hore e theola phetoho ho tloha ts'ebeliso ea sechaba ho ea ho ts'ebetsong e laoloang le e qobelloang. Kahoo, ho hlohlelletsoa ha li-receptor tsa D1 ka har'a striatum le cortex ho eketsa cAMP, protheine e itšetlehileng ka cAMP (PKA), le protheine ea karabelo ea cAMP (CREB) e khothalletsang ho hatisoa ha mefuta e mengata e kentsoeng ts'ebetsong, joalo ka cfos, deltaFosB, Homer, le preprodynorphin (Hurd le Herkenham, 1993; Nestler et al a, 2001; McClung le Nestler, 2003; Benavides le Bibb, 2004). Habohlokoa, ho phahama ha CREB ho NA 'me, ho isa tekanyong e nyane, VTA e hokahane le matlafatso ea matlafatso ea tšusumetso ea lithethefatsi (Carlezon et al a, 1998; Nestler, 2005). Le ha e se lithethefatsi tsohle tse lemalloang tse bonahalang li eketsa CREB ho li-accumbens (Pandey et al a, 2004), ho hlonama ka ho feteletseng ha CREB ka har'a li-accumbens ho sitisa melemo e atlehang ea li-psychostimulants, li-opioid, le meputso ea likokoana-hloko, athe ho qhekella ho matla ha CREB ho matla ho phahamisa moputso oa lithethefatsi (Barrot et al a, 2002; Lu et al a, 2003; McClung le Nestler, 2003). Ho khahlisang, liphuputso tse ling li bonts'a hore CREB e hlokahala bakeng sa litlamorao tse khotsofatsang tsa lithethefatsi tse lemalloang le ntlafatso ea likokoana-hloko (Jin et al a, 2005; Walters et al a, 2005; Khetho et al a, 2006), e fana ka monyetla oa hore molaong o matla oa CREB o hlokahala bakeng sa boitšoaro bo susumetsoang, ho phetoa hangata ha CREB ho etsa hore ho mamelloe litlamorao tse matlafatsang tsa ho susumetsa ho khotsofatsang. Mefuta e meng e laoloang ke CREB, e joalo ka preprodynorphin, NAC-1, le Homer, ntle le pelaelo e kenya letsoho phello ea matšeliso e eketsang CREB ho fokotsa boleng ba moputso oa lithethefatsi. Mohlala, dynorphin e eketsehileng e thibela ts'ebetso ea lisele tsa dopamine le tokollo ea dynamine ea presynaptic (Carlezon et al a, 1998; Chepe et al a, 2000; Hyman et al a, 2006), le vaerase e feteletseng ea NAC-1 kapa Homer1c ho li-accumbens e sitisa nts'etsopele ea boits'oaro ba motor sensitised ka cocaine e pheta-phetoang (Mackler et al a, 2000; Szumlinski et al a, 2006). Habohlokoa, tse peli tsa liprotheine tsena, preprodynorphin le NAC-1 li bonts'a mamello e sa feleng, e bonts'ang thibelo ea nako e telele ea thibelo ea lithethefatsi (Hurd le Herkenham, 1993; Cha et al a, 1997). Ka bomalimabe, joalo ka ha ho hlalositsoe ka botlalo ka tlase mona, boleng ba moputso oa lithethefatsi le bona bo ka holisa moputso oa tlhaho.

Setšoantšo sa 3.

Setšoantšo sa 3 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Dopamine D1 e tsamaeang le li-receptor e itšetlehileng ka lisele tsa spiny tsa nucleus e bokella hypothesised ho tlasa phetoho ea ts'ebeliso ea ts'ebeliso ea sechaba ho fihlela ho mamella ho ba kotsing ea ho khutla. Ka ho susumetsa motsoako oa cAMP 'me qetellong ho etsa phosphoryating le ho kenya tšebetsong bongoli ba mongolo oa CREB, menyetla ea liphetoho lipakeng tsa protheine e etsahala ka ho kenyelletsa balaoli ba tlatsetso ba sengoloa (mohlala, c-Fos le ΔFosB). Hape, motsoako oa liprotheine o kenyellelitsoe e le li-control tsa bohlokoa tsa complication ea mesebetsi ea li-cellular mme li kenya letsoho ho li-neuroplasticity tsa lithethefatsi tse telele (bona sengoloa bakeng sa lipuisano tsa liprotheine tse ikhethang).

Palo e feletseng le pale (63K)Khoasolla slide ea Power Point (300 KB)

 

Ho liphatsa tsa lefutso tse laoloang ke CREB, keketseho ea molaoli oa lingoliloeng, deltaFosB, e ipakile e khahla haholo (Nestler et al a, 2001). Keketseho ea lingoloa tse ngata tse hatisang le mefuta ea pele ea lithethefatsi tse tlatsetsang kapa tšusumetso ea tlhaho ea tlhaho, joalo ka cfos, Arc, Homer1a, le e bohale, ea fokotseha kamora ho pepesetsoa khafetsa. Ka lehlakoreng le leng, deltaFosB e ipokella masimong a dopamine ho cortex le striatum (Nestler et al a, 2001; McClung le Nestler, 2003). Ho bokellana hona ho etsahala ka lebaka la taolo e sa fetoheng ea lithethefatsi tsohle tsa tlhekefetso tse lekiloeng ho fihlela joale, hammoho le ho arabela khahlisong ea bioloji e khothalletsang. Kahoo, ho bokelloa ha deltaFosB ho kanna ea hlokahala bakeng sa ho ithuta le ho ntshetsa pele mekhoa e susumetsang ka kakaretso. Tabeng ea lithethefatsi tse lemalloang, tšitiso ea bongaka kapa liphatsa tsa lefutso tsa papali ena e sitisa tsoelo-pele ea mefuta e itseng ea boits'oaro bo amanang le ts'ebeliso ea lithethefatsi, joalo ka boits'oaro ba maikutlo a motor (Nestler et al a, 2001; McClung le Nestler, 2003). Akin ho liphatsa tsa lefutso tse laoloang ke CREB, mefuta e meng e laoloang ka ho toba ke deltaFosB e ka ba tlatsetso mme ea sebeletsa ho fokotsa matlafatso ea lithethefatsi, mohlomong le ho batla lithethefatsi (Nestler, 2005). Kahoo, ho kenella ha phdophorylates ea phofo ea Cdk5 phophatase DARPP-32, ka tsela eo e thibela phosphorylation le ts'ebetso ke PKA (Benavides le Bibb, 2004). Leha ho le joalo, ho kenngoa ka mefuta ea mefuta e meng ke deltaFosB mohlomong ho phahamisa moputso oa lithethefatsi mme boholo ba lithuto bo bonts'a hore ho fetella ha deltaFosB ho eketsa moputso oa lithethefatsi (Kelz et al a, 1999; Colby et al a, 2003; Zachariou et al a, 2006). Mehlala ea melawana ea deltaFosB ea liphatsa tsa lefutso e tla khothaletsa moputso oa lithethefatsi e kenyelletsa ho kenngoa ha GluR2 khetla ea maqhubu (Todtenkopf et al a, 2006), le khatello ea polelo ea dynorphin (Zachariou et al a, 2006). Habohlokoa, ho kenngoa ha deltaFosB le lihlahisoa tseo li li laolang ho bonahala ho sa nke nako ebile ho tloaelehile nakong ea ho ila. Ka hona, leha e le bohlokoa bakeng sa ho fumana mekhoa ea ho batla lithethefatsi, deltaFosB ka boeona ha se mohlala oa ts'ebetso e tsitsitseng ea lithethefatsi tse amanang le lithethefatsi ka ho toba e kenang ts'ebetsong ea ho khutlisetsoa ka mokhoa o laolehileng kapa o qobelloang. Kannete, ke mofuta oa nakoana oa polelo ea "deltaFosB" e etsang hore e be khetho e ntle bakeng sa protheine e arolelanang phetoho e tlohang ts'ebelisong ea sechaba ho khutlisetsa tšebeliso ea lithethefatsi (Nestler et al a, 2001). Ka hona, athe deltaFosB e laoloang ke liphatsa tsa lefutso ka boeona e haella, neuroplasticity e laoloang ke mefuta ena e ka ba e tsitsitseng haholo nakong ea thobalano. Mohlala, keketseho e sa feleng ea ho imeloa ha lesapo la mokokotlo la dendritic ho tlalehiloe liseleng tsa spiny nakong ea ho itšireletsa ho tsamaiso e sa feleng ea psychostimulant (Robinson le Kolb, 2004), mme keketseho ena e kopantsoe le karolo ke tlhasimollo ea deltaFosB ea Cdk5 (Norrholm et al a, 2003).

Ka kakaretso, ts'ebetso ea ts'ebetso ea D1, CREB, le deltaFosB e bohloka ho hlokahala bakeng sa ho khanna ts'ebetso ea neuroplasticity e thehiloeng lithutong ka bobeli tsa tlhaho tse khothalletsoang tsa ho ithuta le ho nts'etsapele mekhoa ea boits'oaro ea lithethefatsi (Nestler, 2001; Hyman et al a, 2006). Leha ho le joalo, likarolo tsa phetoho e bakiloeng ke lithethefatsi ka har'a komishene ena ha ho etsoa ts'ebetso ea ho batla lithethefatsi kapa ho ba kotsing ea ho ts'oara hape e rarahane. Mohlala, "neuroplasticity" ea nakoana le e tšoarellang e hlahisoang ke ts'ebetso ea CREB hangata e bonts'oa ho fana ka ts'ebetso ea mats'ebetso ho fokotsa dopamine kapa phetisetso ea glutamate ka har'a li-accumbens, athe li-deltaFosB tse eketsehileng li laola polelo ea gene ka tsela e lumellanang. ) le tšehetso ea moputso oa lithethefatsi (GluR5; dynorphin e fokotsehile). Liphetoho tsena ka kakaretso li ka fokotsa boleng ba matla a susumetsang a tlhaho, 'me sena se ka tlatsetsa ka mokhoa o sa tobang tlokotsing ea ho khutlela bothateng ba lithethefatsi. Kahoo, ka ho sebetsa ka mokhoa o qobellang ho nka meputso eohle, litlamorao tse mamellehang tsa ts'oaetso ea nakoana ea D2-CREB signaling Cascade (mohlala, dynorphin, NAC1, le Homer1c) li khothaletsa ho batla lithethefatsi molemong oa ho fumana meputso ea tlhaho.

Brain-Derered Neurotrophic Factor Regulation ea Synaptic Plasticity ha e le joala

Phetoho e 'ngoe e itšetlehileng ka dopamine ho motsoako oa liprotheine o shebahalang o le bohlokoa haholo ho theha' mele le neuroplasticity e hlahisoang ke lithethefatsi ke ho phahama hoa bongata ba neurotrophic factor (BDNF). BDNF e sehlopheng sa liphatsa tsa lefutso tsa psychostimulant tse laoloang hang-hang, ho kenyeletsoa Arc, c-fos, le zif / 268 (Dunais le McGinty, 1994; Moratalla et al a, 1996). Leha ho le joalo, BDNF le Arc li shebahala li ikhethile hobane mRNA ea bona e kentsoe ka matla mme e tsamaisoa ka har'a li-dendrites ke ts'ebetso ea maqhubu.Steward le Worley, 2001). Ka thahasello e ikhethang, 'me ho bonahala e fapane le mefuta ea tlhaho e laoloang ke deltaFosB, hammoho le mefuta e meng e itšetlehileng ka tšebetso e hlahisoang ke li-psychostimulants, liphetoho tse bang teng ho BDNF lia ipokella ka linako tse ntseng li eketseha tsa ho ila (Grimm et al a, 2003; Lu et al a, 2004a; Filip et al a, 2006). Hape, li-receptors tse hlasimollang tsa BDNF ho amygdala, NA, kapa VTA li khothaletsa (Horger et al a, 1999; Lu et al a, 2004b; Graham et al a, 2007; Pu et al a, 2006), athe microinjection ea BDNF ho PFC e thibela ho batla lithethefatsi (Berglind et al a, 2007), e bonts'a ts'ebetso ea deltaFosB, BDNF e sebeletsa karolo e akaretsang ea 'mele ho ts'ehetsa neuroplasticity e tlisoang ke lithethefatsi tse lemalloang ho etsa hore qetellong e thehe bocha hape hape.

BDNF e tsebahala ka ho kgothaletsa mefuta ea polasetiki ea synaptic, joalo ka pele-le kamora nako e telele ea potentiation (LTP), hape e khothaletsa sebopeho sa mokokotlo oa dendritic (Bramham le Messaoudi, 2005). Mekhoa e tlatselletsang molemong oa keketseho ea phetiso ea maikutlo e fapane, mme e kenyelletsa ho eketsoa ha synaptic vesicle docking, ho eketseha ha glutamate, le ho khothaletsa ho saena hoa postynaptic NMDA. Ka lebaka la mekhoa ena ea selefounu, ha ho makatse hore ebe BDNF e kentsoe ts'ebetsong ea neuroplasticity tlas'a mekhoa e tloaelehileng ea ho ithuta le ea memori. Mabapi le bokhoba ba lithethefatsi, BDNF e sebetsa le ts'ebeliso ea phetisetso e matla ea phetisetso ea lisele tsa dopamine ho VTA e khothalelitsoeng ke tsamaiso e pheta-phetoang ea koae.Pu et al a, 2006), hammoho le tokollo ea orexin (Borgland et al a, 2006), e ka kenya letsoho lethathamong le khahlisang la lipatlisiso tsa PDP tse nang le ts'oaetso liseleng tsa VTA dopamine ka mor'a ts'ebetso e le 'ngoe ea lithethefatsi tse lemalloang (bakeng sa ho lekola liphumano tsena le kamoo li ka kenyang letsoho ho kenya mekhoa ea ho mamella mefuta ea li-neuroplasticity tse ntseng li khutla hape, bona. Jones le Bonci, 2005). Habohlokoa, boemo ba BDNF ho VTA, hammoho le NA le amygdala, bo eketseha butle-butle nakong ea ho ila (Grimm et al a, 2003). Keketseho ena e tsoetseng pele e tšelitsoe hore e thelle keketseho e tsoelang pele ea ho batla lithethefatsi e bang teng nakong ea ho khaotsa koae, e ka bang teng, ka karolo e 'ngoe, ka ho eketsa dopamine D3 receptor expression (Guillin et al a, 2001; Le Foll et al a, 2005). Taba ea hore BDNF e phahame ka tsamaiso ea lithethefatsi tse mpe hape e lula e phahame libakeng tse ling tsa boko kamora ho khaotsa ho ts'oaroa ho tšoaea protheine ena ka mokhoa o tsitsitseng oa neuroplasticity o ka kenyang letsoho ho fumana ts'ebeliso ea lithethefatsi le ts'ebetso ea ho batla lithethefatsi kamora ho atolosoa linako tsa ho ila.

Transitory Neuroplasticity E Kopantsoeng le Molecular Site of Drug Action

Mefuta e meng e fetohang ea neuroplasticity e khothalletsoang ke lithethefatsi tse lemalloang le eona e hlalositsoe. Leha ho le joalo, ho fapana le tsela ea lets'oao ea D1-CREB-deltaFosB, liketsahalo tsena tse tšoaeang li bua haholo ka lithethefatsi ka bomong. Mohlala, liphetoho tse tsamaeang le baeti ba dopamine li amahanngoa le li-psychothermetants tsa amphetamine (Mela et al a, 2002), Liphetoho tsa GABA-A receptor li hlokometsoe kamora joala bo sa foleng (Charlton et al a, 1997), mme nicotine e lakatsa ho amohela li-nicotinic receptors (Mansvelder le McGehee, 2000). Liphetoho tsena tse amanang le lithethefatsi li kenya letsoho mehopolong ea bohlokoa ea ho lemalla sethethefatsi se seng le se seng, haholoholo, li-syndromes tsa ho ntša li na le litšobotsi tse ikhethang bakeng sa sehlopha ka seng sa lithethefatsi. Hape, liphetoho tse amanang le lithethefatsi li susumetsa "potoloho" ea bohlokoa bakeng sa moputso o tloaelehileng le ho ithuta ka lithethefatsi. Ka kakaretso, litlamorao tse amanang le lithethefatsi li ka nq'ane ho lintlha tsa tlhahlobo ea hona joale tse shebiloeng ho tse bonahalang e le likarolo tse tloaelehileng tsa bongoana bo arolelanoang ke lingaka tsohle kapa lithethefatsi tsohle tsa tlhekefetso mme ka kakaretso, li arolelanoa le tšusumetso ea tlhaho ea tlhaho.

Kakaretso ea Neuroplasticity Tlas'a Katello ea Ts'ebeliso ea Lithethefatsi le Phetoho ho tloha Ts'ebeliso ea Lithethefatsi ea Sechaba ho ea Khutlong e Laoloang le e Qobelloang

Setšoantšo sa 4 e bonts'a mekhahlelo e fapaneng ea nakoana ea neuroplasticity e amanang le ts'ebeliso e sa khaotseng ea lithethefatsi tse lemalloang le ho ila ka morao ho moo. Ho bohlokoa ho hlokomela hore liteko tse entsoeng ka tsamaiso ea psychostimulant e phetoang, le ka li-opioids tse fokolang, li fana ka tlhaiso-leseling e ngata e tlasa lipaterone tse bonts'itsoeng Setšoantšo sa 4a. Ho khothalletsoa mekhahlelo e meraro ea kakaretso. Mokhahlelo oa pele o kenyelletsa ho kenngoa hoa mefuta ea ts'ebetso e itšetlehileng ka ts'ebetso ea taolo e matla, le nts'etsopele ea mamello ho ts'ebetso ena e latelang taolo e pheta-phetoang. Liprotheine tse sehlopheng sena li kenyelletsa c-fos, Arc, Homer1a, narp, le zif / 268. Taba ea bohlokoa ke hore, kamora nako ea ho khaotsa ho tsuba, mamello ea ho mamella le liprotheine tsena li ka boela tsa ts'oaroa ka kalafo e matla ea psychostimulant, hangata maemong kapa maemong a polelo a fapaneng le a hlahisitsoeng ke tšibollo ea lithethefatsi ea pele. Liprotheine tsena ho nahanoa hore li bohlokoa bakeng sa ho qala neuroplasticity e hlokahalang bakeng sa ho fumana boits'oaro bo bocha, hammoho le ho ntlafatsa boits'oaro bo ithutileng, ho kenyeletsa ho batla lithethefatsi.

Setšoantšo sa 4.

Setšoantšo sa 4 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Mehato ea methapo ea kutlo. (a) Mefuta ea nakoana ea neuroplasticity, hangata e kenyelletsang kholiso ea mamello le taolo e phetoang; mohlomong e bohlokoa ho kgothaletsa ts'ebeliso ea lithethefatsi sechabeng. . ho nahanoa hore ke ea bohlokoa phetohong ho tloha sechabeng ho ea ho se sebelisang lithethefatsi. (c) Mefuta e tsitsitseng ea polasetiki e hlahang nakong ea tšebeliso e mpe ea lithethefatsi kapa nakong ea ho ila. Maemong a mang, liphetoho tsa liprotheine sehlopheng sena li eketseha butle-butle nakong ea ho itima lijo, 'me ho nahanoa hore li tlatsetsa ho feliseng tšoaetso ea ts'ebetso ea ts'ebeliso ea lithethefatsi ke mok'hadinale. Metsu e nyane e bontša ho pheta-phetoa hoa lithethefatsi.

Palo e feletseng le pale (95K)Khoasolla slide ea Power Point (350 KB)

 

Mokhahlelo oa bobeli o tšoauoa ka liprotheine tseo polelo ea tsona e eketsehang kapa e fokotsehang ka ho pepesetsoa lithethefatsi khafetsa, 'me e mamella linako tse fapaneng tsa ho itlopa joala. Likaroloana tse peli li bonts'itsoe Setšoantšo sa 4b. Ea pele e kenyelletsa liphetoho tsa protheine tse mamellang lihora tse ngata ho isa ho matsatsi a ho itima 'me hangata li tsamaellana le liphetoho tse amanang haufi le sebaka sa liketso tsa limolek'hule. Sehlopha se seng se ka tlase se tšoantšetsoa ke ho bokella deltaFosB, moo maemo a phahameng a ka mamellang matsatsi kapa libeke. Sehlopha sena sa morao-rao se nahanoa hore se kenya letsoho ho fumaneng thuto e khothatsang, empa habohlokoa ke hore, ka lebaka la ts'ebeliso e mpe ea lithethefatsi, deltaFosB e 'nile ea nkoa e le mohopolo oa ho kenella phetohong ea ts'ebeliso ea lithethefatsi ea sechaba le ts'ebeliso ea ts'ebeliso hape (Nestler, 2005).

Mokhahlelo oa boraro o na le liprotheine tse phahamisitsoeng kapa tse fokotsoang kamora ho khaotsa nako e telele. Likarolo tse peli tsa tikoloho li tšohloa ho Setšoantšo sa 4c. Ea pele e tšoauoa ke BDNF e bokellanang libakeng tse ling tsa boko kamora ho pheta-pheta psychostimulant mme ho bokellana hona ho tsoela pele ka nako e telele ea ho itima lijo (Grimm et al a, 2003; Lu et al a, 2004a). Karolo ea bobeli e tla hlahlojoa ka botlalo ka tlase, 'me e na le liprotheine tse sa fetoheng hantle nakong ea taolo ea lithethefatsi, empa li phahame kapa li fokotsoe nakong ea ts'ebeliso ea lithethefatsi. Ho nahanoa hore sehlopha sena se na le liketsahalo tsa neuroplastic tse ka 'nang tsa ikarabella bakeng sa boemo ba tlokotsi hore bo boele bo boele. Boholo ba liphetoho tsena tse sa feleng ha lia bontšoa hore li etsahala ho arabela ha motho a qeta ho bua ka tšusumetso ea tlhaho ea tlhaho ebile e ka ba li-biomarkers bakeng sa ts'ebetso ea methapo ea kutlo.

Ka holimo ho leqephe 

HO FINYELETSA LITLHAKISO TSE TSOANG HO BONT THEA BOPHELO

Joalokaha ho hlalositsoe kaholimo, hang ha boitšoaro bo etselitsoe ho fumana moputso kapa ho qoba sephetho se seng se seng se se se ithutile, karolo ea phetoho ea dopamine ho tloha ho e ngoe ea ho ntšetsapele thuto e ncha ho ea ho nolofaletsa ts'ebeliso ea tlhaiso-leseling e ithutileng ho etsa hantle karabelo ea boitšoaro e lumellanang (Schultz, 2004). Ka lehlakoreng le leng, phetisetso ea glutamate e tsoang cortex le rendortex (mohlala, amygdala le hippocampus) ho ea tsamaisong ea makoloi a makoloi (ho kenyeletsa le NA) e hlaha e le ea bohlokoa bakeng sa ho etsa ts'ebetso ea ho ithuta (Kalivas le Volkow, 2005). Ntle le moo, ho nahanoa hore ha boitšoaro bo ntse bo phetoa khafetsa, karolo ea "corticofugal glutamate projeke e tsoang ho PFC le amygdala ho NA, ha e sa bohlokoa joalo molemong oa morero oa glutamate ho tloha libakeng tsa sensory motor cortical ho ea dorsal striatum (Everitt le Robbins, 2005). Ka tsela ena, boitsoaro bo fetoha ho fetoha ntho e nyarosang e kenyelletsang ts'ebetso ea botsamaisi ba pele ho tloaelo e tloahelehileng e sebelisang "memory memory" (Barnes et al a, 2005). Ka mokhoa oa 'mele, phetoho ena ho tloha boits'oarong ho ea boits'oarong e ka fetoha ka ho lumella boitšoaro bo ithutoang hantle hore bo tsoelle hantle ntle le ho nka karolo,' me haeba khothaletso kapa liphetoho tsa bohlokoa, ts'ebetso ea botsamaisi e kena-kenana le ho sitisa tloaelo ena e le karolo ea ho ntlafatsa boitšoaro bo bocha. e loketseng phetoho ea tikoloho. Tabeng ea ho batla lithethefatsi, phetoho ena ho tloha ho pele ho ea ho tloaelo ea ho potoloha makoloi e supa tahlehelo ea taolo le ho khutlela morao ka ho qobelloang. Bohlokoa bakeng sa ts'ebetso ea ts'ebeliso ea lithethefatsi, matla a mantlha, a potolohang a ho kena-kenana le ho senya tloaelo ea ho batla lithethefatsi a senyehile, ho etsa hore ho be thata le ho feta qeto e kholo ea ho kenella ho batleng lithethefatsi (Everitt le Robbins, 2005; Kalivas le Volkow, 2005). Ho utloisisa ts'ebetso ea methapo e matlafatsang phetoho ena e mpe ho tsoa ho melaoana e qobelloang ho batla lithethefatsi, le ho senyeha ha matlafatsong ea taolo ea pele ea ts'ebeliso ea lithethefatsi ho hloka kutloisiso mabapi le ts'ebeliso ea methapo ea methapo e entsoeng ka tšebeliso ea lithethefatsi khafetsa. Haholo-holo, sena se kenyelletsa ho supa liphetoho lipakeng tsa phetisetso ea glutamate le ho hlaha ha hypofrontality tse lumellang takatso ea lithethefatsi ho tsoela pele ntle le ts'ebetso e hlokolosi (Jentsch le Taylor, 1999; Goldstein le Volkow, 2002).

Ho mamella Neuroplasticity ho Cortical Glutamate Circuitry: Neuroimaging ea batho

Boholo ba neuroplasticity makaleng a cortical bo bonoe ka ho toba ho litlolo ho sebelisa mekhoa e fapaneng ea neuroimaging. Kahoo, ho na le phokotso e akaretsang ea mehato ea pele ea cortical ea metabolism ea cellular le phallo ea mali ho batho ka bomong ba lemaletseng lithethefatsi tse fapaneng, ho tloha cocaine ho ea ho opioids ho joala (Goldstein le Volkow, 2002). Sena se kenyelletsa libaka tse kang anterior cingrate le ventral orbital cortex. Ha ho fanoa ka kamano pakeng tsa ts'ebetso ea "cingrate" ea ka ntle le ho kenya letsoho boits'oarong bo nepahetseng ba tlhaho (Khokahano et al a, 2002), le lipakeng tsa ts'ebetso ea "cortex ea" ventral orbital cortex le bokhoni ba ho fetola boitšoaro bo ithutoang hantle hore bo fetole boitšoaro bo bocha (Kolb et al a, 2004), hypofrontality ena e bontšitsoe e le sesupo se matla sa bokhoni bo fokotsehileng ba ho laola ho batla lithethefatsi. Phokotso ea li-neuron tsa "cortical" tsa pele le tsona ho tlalehiloe bokhoba ba lithethefatsi tse se nang lithethefatsi tsa koae.Franklin et al a, 2002), empa ha ho tsejoe hore na matšoao ana a sebetsang le a anatomical a hypofrontality e ne e le mabaka a tlokotsing a neng a le teng pele ho tšebeliso ea koae kapa litlamorao tsa tšebeliso e sa foleng ea matla. Ho khahlisang, ha ho pepesoa lekhoba le neng le amana le tšebeliso ea lithethefatsi le tlatsang takatso ea lithethefatsi, ho na le ts'ebetso e bonts'itsoeng ho PFC, ho kenyelletsoa le cterate ea ka ntle le kharetene ea orbital (Goldstein le Volkow, 2002; Wilson et al a, 2004; Kalivas le Volkow, 2005). Lithutong tse ngata, ts'ebetso e eketsehileng ho PFC e tsamaellane hantle le matla a takatso ea lithethefatsi ea cue. Kahoo, phapang e teng pakeng tsa tšebetso ea mantlha lipakeng tsa motheo le maemo a susumetsoang ke litheko tsa lithethefatsi e kholo ho feta se etsahallang taba ea taolo ha ho arabeloa le litheko tse amanang le moputso oa tlhaho, joalo ka tšusumetso ea pono e tsosang takatso ea thobalano. Ntle le moo, ho ts'oaroa le ts'ebeliso ea lithethefatsi ho bonahala ka karolo ka karabelo e fokotsehileng ea meputso ea tlhaho, ha lithethefatsi tsa koae li ne li hlahisoa ka ts'usumetso ea thobalano, ts'ebetso ea pelehi e ne e sa sebetse hantle haholo ha e bapisoa le taolo (Sekepe et al a, 2000). Boiteko ba ho hanela takatso ea ho arabela cocaine e boetse bo tlalehiloe bo eketsa ts'ebetso ea pele ea lobe (Ho ba le bana et al a, 2007), ho fana ka maikutlo a hore ts'ebetso ea mokokotlo o sa sebetseng e ka kenyelletsa ho sitoa ho hanela botjha.

Phello e 'ngoe e makatsang e tsoang liphuputsong tse entsoeng ka neuroimaging e bonts'ang karabelo e fokotsehileng ea moputso oa tlhaho ho ba lemaletseng ke phokotso ea ts'ebetso ea dopamine ho arabela litekanyetso tse tlase tsa psychostimulants (Volkow et al a, 2004, 2005). Kahoo, tlhahiso ea dopamine ea methylphenidate-induction e kenngoa ka har'a striatum e kenella haholo ho lithethefatsi tsa koae. Hape, ho sa tsotelehe sehlahisoa sa lithethefatsi se sebelisoang hampe, lithethefatsi li bonts'a litekanyetso tsa li-receptor tsa D2 ho striatum (Volkow et al a, 2004). Hoo boholo ba li-receptor tsa D2 tse fokotsehileng li bonts'a blancing ea phetisetso ea dopamine, ha ho makatse hore batho ba lemaletseng litlaleho ba tlaleha ho theola sekhahla kapa thabo ha ba arabela methylphenidate e amanang le lithuto. Ho fapana le moo, athe methylphenidate e etsa hore motho a be le litakatso tse matla litlamong, ha ho na takatso ea ho ithuta ha a bapisoa. Leha ho le joalo, lithuto tse sa sebeliseng lithethefatsi tse sa sebeliseng lithethefatsi li fapana ho latela maemo a bona a mongobo oa D2 receptor density. Ba nang le letsoalo le tlase la D2 ba tlaleha litlamorao tse khahlisang, tse khahlisang tse tsoang methylphenidate, athe ba nang le matla a phahameng a D2 ha ba rate litlamorao tsa khothalletso ena (Volkow et al a, 2002). Ho fumana hona ho lithuto tse tloaelehileng tsa motho ho bapisoa le ho fumana ho tšoanang lithutong tse seng tsa motho (Nader le Czoty, 2005).

Ha li kopantsoe hammoho, lithuto tsena tse natefisang li supa ho mamella liphetoho lipakeng tsa mesocorticolimbic circry. Kahoo, maemong a motheo, motho ea lemaletseng litlamorao o batla a susumetsoa ke tšusumetso ea tlhaho ea tlhaho, joalo ka ha a bona bopaki ba li-neuroadaptations, (1) tse fokotsang mosebetsi ho PFC, le (2) li fokotsehile maemo a dopamine DeptNUMX. Mohlomong ho bohlokoa le ho feta lithutong tsa bokhoba ba tahi, bokhoni ba ts'usumetso ea bioloji bo sebetsang ba ho kenya tšebetsong PFC ha bo na matla. Ka mokhoa o ts'oanang, ts'oaetso ea dopamine litabeng tsa theknoloji le maikutlo a tsamaisanang le eona a ho nyoloha kapa ho ithabisa a senyehile. Leha ho le joalo, tšusumetso e amanang le lithethefatsi e hlohlelletsa PFC haholo ho lithethefatsi ka tsela e lumellanang le takatso ea lithethefatsi. Ha e kopantsoe hammoho, lintlha tsena tse natefisang li fana ka template ea methapo bakeng sa likarolo tsa mantlha tsa bokhoba ba tahi; ho arabela ka mokhoa o feteletseng, o sa laoleheng bakeng sa lithethefatsi, le karabelo e fosahetseng kapa e sa lokang bakeng sa tšusumetso ea bohlokoa ea tlhaho.

Ho mamella Neuroplasticity ho Cortical Glutamate Circuitry: Mehlala ea Liphoofolo

Ho utloisisa motheo oa cellular oa hore na liphetoho tsena corticolimbic circry li etsahala joang le ho ts'ehetsa ka ts'epo mekhoa ea ho khutlisa kapa ho bala liphetoho, ho bohlokoa ho sebelisa mehlala ea liphoofolo, e lumellang tlhahlobo ea mahlale. Habohlokoa, liphoofolo li ipehela lithethefatsi tse lemalloang ho batho, le phetoho e thehiloeng ho dopamine e thehiloeng ho litheko tsa lithethefatsi ho isa ts'ebetsong e thehiloeng ke glutamate ea ho batla lithethefatsi e bonahala lithutong tsa liphoofolo.

Mokhoa o sebelisoang haholo oa ho oela hape o kenyelletsa lithupelo tsa ho ikoetlisa ho etsa lithethefatsi, ho beha phoofolo hore e se ke ea ikoetlisa ka ho ikoetlisa kapa ntle le ho ikoetlisa, ebe e pepisa liphoofolo molemong oa lithethefatsi, lits'ireletso tse ikhethileng ka tlhabollo ea lithethefatsi, khatello kapa sethethefatsi ka boeona (Epstein et al a, 2006). Ho arabela ts'usumetso ena, phoofolo e koetliselitsoeng lithethefatsi e tla etsa ts'ebetso ea ho batla lithethefatsi le haeba e sa fumane setlhare.

Lithuto tsa pejana tsa ho khutla hoa liphoofolo li ne li kenyelletsa ts'ebeliso ea likhoto tse itšetlehileng ka opiate tse phekotsoeng le naloxone kapa naltrexone. Moputso oa Opiate o ile oa koaloa 'me ka mor'a ho arabela ka lekhetlo la pele, ho theoha ka potlako (Davis le Smith, 1974). Haufinyane tjena, boits'ireletso ba joala bo fumanoe ho kenya ts'ebetsong ts'ebetso ea endo native opioid e hlahisang tlhahiso ea dopamine ho NA le joala bo batlang phoofolo.Gonzales le Weiss, 1998). Likhoto tse koetliselitsoeng ho itlopa joala ebe li fuoa naltrexone li tla bontša ho khaotsa ho eketseha ha dopamine ho NA le ho tlohela taolo ea tahi. Moetso ona o hlakileng oa ho felisoa o bonahala ho lino tse tahang tsa batho tse tlalehang moputso oa joala o theohileng kapa o le sieo ha o phekoloa ka naltrexone (Volpicelli et al a, 1995).

Haufinyane tjena, ts'ebetso ea li-nuclei tse fapaneng tsa boko tse nang le li-agonists tsa GABA kapa metsoako e thibelang bokhoni ba ts'ebetso, boko ba kelello bo hlokahalang ho etsa ts'ebetso ea lithethefatsi bo fumanehile (McFarland le Kalivas, 2001; Bona, 2002; McFarland et al a, 2004). Liphetho tsa lithuto tsena tse entsoeng lilemong tse leshome tse fetileng li ts'oana hantle le lithuto tse boletsoeng esale pele tsa monahano oa batho. The dorsolateral striatum ke karolo ea boko e bonts'itsoeng e tlamehile ho sa tsotelloe ka mokhoa oa ho fetohela ho batla lithethefatsi, kapa ho ba teng kapa ho ba sieo ha thupelo ea ho felisoa. Hona ho supa ho nka karolo ha tloaelo ea ho tsamaea ka makoloi maemong a koetlisitsoeng hantle joalo ka ho batla lithethefatsi. Ho makatsang ke hore, ntle le haeba liphoofolo li sa fumane thupelo ea ho timela, ho batla lithethefatsi ka ho khutlisetsa liphoofolo maemong a lithethefatsi ha ho amehe ka ho thibela sebopeho leha e le sefe sa kelello se amanang le thuto e khothalletsoang kapa takatso e matla ea lithuto tse lemalloang (mohlala, libaka. ea PFC, amygdala, kapa NA) (Makhooa et al a, 2006). Leha ho le joalo, haeba phoofolo e feta thupelong ea ho timela, ho batla lithethefatsi ho susumetsoa ke likhoele, khatello ea maikutlo, kapa sethethefatsi ka boeona ho nka potoloho e ntlafalitsoeng haholoanyane, e nang le potoloho e tsejoang mohopolong oa batho ba lemaletseng lithethefatsi. Mohlala, haeba motho ea lekang moo a thibelang leha e le efe ea li-nuclei ka har'a potoloho ea li-dopamine e tlohang ho VTA ho ea ho dorsal PFC, projeke e behang ho tloha PFC ho ea ho NA kapa GABA / peptide projeketso ho tloha ho li-accumbens ho ea porral pallidum (VP), ho batla lithethefatsi ho phoofolo e tima ho koetsoe. Kahoo, koetliso ea ho timela e kenya likarolo tsa boko tse nkang karolo ts'ebetsong e nyarosang le maikutlong haholoanyane boits'ebetsong ba ho batla lithethefatsi (McFarland le Kalivas, 2001; Bona, 2002; McFarland et al a, 2004), e bolelang polelo ea phetoho ea boits'oaro bo phahameng. Ho tsamaisana le thupelo ea ho felisoa ho tlisang taolo ea boits'oaro, palo ea ho batla lithethefatsi (mohlala, khatello ea maikutlo) e hlahisoang ke boemo ba lithethefatsi ho liphoofolo tse ts'oeroeng e phahame ho feta ho batla lithethefatsi ho liphoofolo tse felisitsoeng (Makhooa et al a, 2006). Ka bobeli, tlhaiso-leseling ea boits'oaro le boitšoaro e bonts'a potoloho e ntlafalitsoeng haholo e amanang le ho batla lithethefatsi lithutong tse felisitsoeng e sebeletsa ho laola ho batla lithethefatsi. Ho ts'ehetsa monyetla ona, boikoetliso ba ho felisoa bo etsa hore GluR1 le GluR2 glutamate subunits e NA ea likhoto tse koetlisitsoeng ka koae (Sutton et al a, 2003). Ka mokhoa o ts'oanang, Koetliso ea ho felisoa ha liphoofolo tse nang le maemo a ts'abo e kenyelletsa ts'ebetso ea mokokotlo oa infralimbic o projeke ea NA (Sierra-Mercado et al a, 2006). Kahoo, joalo ka ha ho kenella maikutlong le bokhobeng ba batho litabeng tsa bokhoba ba batho ho leka ho khutlisetsa taolo setulong sa ho batla lithethefatsi, thupelo ea ho timela liphoofolong e na le potoloho e ntlafalitsoeng ea mantlha e fetolang ts'ebeliso ea lithethefatsi ka lebaka la likhathatso, khatello, kapa sethethefatsi ka boyona.

Ho ts'oana ha pele ho potoloha lipakeng tsa liphoofolo tse koetlisitsoeng ke lithethefatsi le bokhoba ba batho ho boetse ho bonahala ka ho phahama ho hoholo ha phetisetso ea glutamate nakong ea ha motho a batla lithethefatsi. Kahoo, likhoto tse koetliselitsoeng ho ikhalemela koae kapa heroin li bonts'a keketseho e kholo ea tokollo ea glaptamate ea synaptic ho NA ha e arabela ts'ebelisong ea lithethefatsi kapa e khothalletsang khatello ea maikutlo (McFarland et al a, 2003, 2004). Ho feta moo, keketseho ena e felisoa ke thibelo ea dorsal PFC, mme ha e hlahe ka saline e jaroang kapa li-cocaine tse kentsoeng kapa lihlopha tsa taolo ea heroine. Ka mantsoe a mang, ho sa tsotelehe khafetsa taolo ea lithethefatsi, haeba liphoofolo li sa kopanele ts'ebetsong ea ho batla lithethefatsi ha ho fanoe ka mokhoa o hlakileng oa ho lokolloa ha glaptamate ea synaptic. Ka hona, tsamaiso ea lithethefatsi tse matla e le 'ngoe ha e ea lekana ho kenya tšebetsong tsela e tlang pele ea bokantle, empa tsela ena e hloaea ke liphoofolo tse ithutang mosebetsi o batlang lithethefatsi. Ho bohlokoa, ha ho na keketseho ea glutamate e ileng ea bonoa nakong eo ho batloang lijo liphoofolong tse koetliselitsoeng ho iphelisa, ho bonts'a hore neuroplasticity ena ha e susumetsoe ke ho ithuta ho batla meputso ea likokoana-hloko (McFarland et al a, 2003). Ho ts'ehetsa bohlokoa ba taolo ho phatlalatseng ha glutamate ho tsamaiseng boits'oaro ba ho batla lithethefatsi, tsamaiso ea methapo ea methapo ea kutlo e thibela ho batla lithethefatsi, joalo ka ha ho etsoa inactivation ea PFC (Li-Cornish le Kalivas, 2000; Di Ciano le Everitt, 2001). Haufinyane tjena, ho ithutile tse ling tsa limolek'hule tsa limolek'hule tsa bongaka ba methapo ea kutlo. Ntle le moo, lipatlisiso tse ling tse tšoarellang tsa ho lokolloa khafetsa ha glutamate nakong ea ho batla lithethefatsi li fumanoe lipatlisiso.

Neuroplasticity E kenya letsoho Tlatsong e Sa Lekaneng ea Glutamate

Ha tokollo e matlafalitsoeng ea glutamate e ntse e tsoela pele, polasetiki e tsamaellanang le eona e ntse e tsoela pele. Ntlha ea bohlokoa lipakeng tsa liphetoho tsena tsa limolek'hule ke ho fokotsoa ha phapanyetsano ea cystine-glutamate (xc−) (Baker et al a, 2003). xc− ke mohato o fokotsang sekhahla moo lisele li fumanang cystine ho etsa hore glutathione e kenang e kenelle, 'me e etsahala ka ho fapanyetsana hoa tefo ea cystine e le ngoe bakeng sa ho lokolla molek'hule e le' ngoe ea glutamate e ka hare sebakeng sa extracellular (McBean, 2002). Ka tloaelo, mokhoa ona oa ho natefisa monyollo oa nonsynaptic o hlahisa maemo maemong a ka ntle a lekaneng ho tsosa inhibitory presynaptic metabotropic glutamate autoreceptors (mGluR), 'me ka hona e lokolle tokollo ea glaptamate ea glaptamate (Moran et al a, 2005). Leha ho le joalo, ho fokotseha ha xc− ho NA kamora hore koae e sa foleng e felise thibelo ena ea tonic, ho eketsa monyetla oa tokollo ea synaptic glutamate. Phokotso ena ea molumo e kopantsoe le ho supa ho fokotsehileng ho fetela ho li-mGluRs, tseo ho nahanoang hore li bakoa ke phosphorylation e eketsehileng (receptor phosphorylation (Xi et al a, 2002), le kenyelletso ea protheine e bitsoang activator of G-protein signaling 3 (AGS3), e sebeletsang ho fokotsa ho saena hoa li-receptor ka Giα sehlopha sa liprotheine tsa G (Blumer le Lanier, 2003; Bowers et al a, 2004; Yao et al a, 2005). Kamano ena e bontšoa ka Setšoantšo sa 5.

Setšoantšo sa 5.

Setšoantšo sa 5 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Molek'hule ea neuroplasticity e amanang le li-synapses tse thabisang ho NA hypothesised ho beha tlokotsi ea ho khutlela ho koae le mohlomong lithethefatsi tse ling tse lemalloang. Ho hlohlelletsa boitšoaro bo ithutileng ho atamela moputso oa tlhaho ho fella ka tokollo ea glutamate ka pele ho bokellana tseleng e hlophisitsoeng hantle. Khothatso e tsosang takatso ea koae e hlahisa tokollo e kholo ea glutamate e ka lekanngoang le ho phalla ha metsi a tsoang kantle ho metsi. Ts'oaetso e futsitsoeng e hlahisa karolo e tsoang ho xc− e theotsoeng le ho fokotsa ts'ebetso ea li-receptors tsa inhibitory mGluR. Ho ntšoa hape ha glutamate khafetsa ho boetse ho nts'etsapele "dendritic dysmorphisms" - ho kenyelletsa letsoele le leholo la mokokotlo ka lebaka la ho eketseha ha li-actin. Ho eketseha ha 'mala o mofubeli sebakeng sa kantle ho linaleli ho bolela ho eketseha ha glutamate,' me mekhahlelo e metala e lumellana le cystine.

Palo e feletseng le pale (153K)Khoasolla slide ea Power Point (418 KB)

 

Ho lokolloa ho sa khaotseng ha glaptamate ea synaptic nakong ea liketsahalo tse pheta-phetoang tse batlang lithethefatsi ho nahanoa hore ho kenya letsoho phetohong e 'ngoe ea phetoho ea postynaptic. Ntho ea mantlha har'a tsena ke liphetoho tse etselitsoeng methapo ea kutlo ea lesapo la mokokotlo e bonoang sebakeng sa NA le libakeng tse tlang pele ho kotlo ea lithethefatsi tse tlatsetsang (Robinson le Kolb, 2004). Ho thehiloe ka nepo hore ho sebelisa glutamate ho li-neuron ka setso ho fetola letsoalo la lesapo la mokokotlo, ekaba ho eketseha kapa ho fokotseha ho latela tekanyo ea ts'usumetso ea glutamate receptor mme mohlomong le li-subtypes li khothalelitsoe (Lippman le Dunaevsky, 2005; Richards et al a, 2005). Kahoo, ha ho makatse hore ho latela hore na ke moriana ofe o sebelisoang hampe, ho na le keketseho (li-psychostimulants) kapa ho fokotseha (opioids) ho letsoalo la lesapo la mokokotlo (Robinson le Kolb, 1999, 2004; Jedynak et al a, 2007). Mekhoa e ka tlase ea methapo ea methapo ea methapo ea kutlo e amanang le lesapo la mokokotlo ke sebaka se sa tsoa hlaha sa boithuto bo matla haholo. Leha ho le joalo, molaoana oa "actin cytoskeleton" o ka tsitsitseng kapa oa fetola morine morphology, ke moemeli ea ka sehloohong bakeng sa ts'ebetso e ka fetolang botsitso ba lesapo la mokokotlo (Rao le Craig, 2000; Lisman, 2003; Li-Blanpied le Ehlers, 2004; Matso, 2005). Ka hona, ho na le keketseho e sa feleng ea actin cycling ka mor'a ho tlohela ho tsamaiso e sa foleng ea psychostimulant (Kaofela et al a, 2006). Keketseho ea "cyin" ea cyin e etsahala, bonyane ka karolo, ho tsoa phokotsong ea Lim kinase, e laolang ka mokhoa o hlakileng F-Actin depolymerization, hammoho le lesapo la mokokotlo (Meng et al a, 2002; Soosairajah et al a, 2005). Ntle le liphetoho tsa lesapo la mokokotlo le 'mele o mong litholoana tse ling tsa ho phahama ha li-actin e tla ba liphetoho lipakeng tsa ho rekisa liprotheine ho membrane ea postynaptic (Kasai et al a, 2003). Le ha ho sa hlokahale joalo ka phello ea keketseho ea "actin cycling", phetoho e kholo ea ho ts'oaroa ha postynaptic receptor ke keketseho e sa feleng ea ho kenyelletsoa ha li-membrane tsa li-receptor tsa AMPA glutamate (Mangiavacchi le Wolf, 2004; Sun et al a, 2005; Boudreau le Wolf, 2005). Ho makatsang, leha ho le joalo, keketseho ea li-receptor tsa AMPA e amahanngoa le ho se khone ho etsa khatello ea maikutlo ea nako e telele (eo ka kakaretso e amanang le li-receptor tsa AMPA tse fokolisitsoeng) (Martin et al a, 2006). Leha sepheo sena se sa tsoa qothisana lehlokoa le sona phuputsong e bonts'ang hore kamora ho khaotsa k'hok'heine ho na le keketseho e bonts'itsoeng ea AMPA ea hona joale ka liseleng tsa spiny (Kourrich et al a, 2007). Ka kakaretso, likhakanyo tsa motlakase tsa ho lemalla liseleng tsa spiny hona joale ke sebaka sa pherekano ho lingoliloeng (Kalivas le Hu, 2006).

Ho khahlisang, li-receptor tse hlasimollang tsa BDNF li khothaletsa li-actin cycling le modulates lesapo la mokokotlo (Bramham le Messaoudi, 2005), e bonts'a hore phallo e boletsoeng esale pele ea BDNF nakong ea ho ikhula e ka kenya letsoho ka kotlolloho phetisong ea phetisetso e thabisang. Ka ho hanana le khopolo ena, ho hlohlelletsa li-receptors tsa BDNF ka har'a li-accumbens ho khothaletsa ho batla koae (Graham et al a, 2007), phello e boetse e hlahisoa ke ho thibela ho ts'oaroa ha actin ho NA (Kaofela et al a, 2006). Leha ho le joalo, phuputso ea morao-rao e bontšitse hore ho lokolloa ha BDNF ka har'a li-accumbens ka mor'a tsamaiso ho PFC ho thibetse ho batla lithethefatsi ka bobeli le ho ts'oaroa ha glutamate e amanang le ho tsoma koae (Berglind et al a, 2007). Ho ne ho nahanoa hore BDNF e laetsoeng ho PFC e tsamaisitsoe ka mokhoa o sa tsamaeang le ho lokolloa ho NA hore e hlahise phello ea boitšoaro (Aletare et al a, 1997). Ka hona, ho lokolloa hoa BDNF ho tsoa ho litumellano tsa pele ho NA ho ka hlahisa phello e fapaneng le ea li-pharminological tse ngata.

Leha ho mamella li-neuroplasticity ho NA le striatum ho ka bonts'a hypofrontality e bonoang ho litheko tsa neuroimaging, ho nahanoa hore ho mamella neuroplasticity ho etsahala ka kotloloho ho PFC. Ka sebele, tsamaiso ea psychostimulant e pheta-phetoang e eketsa letsoalo la lesapo la mokokotlo liseleng tsa pele ho piramidi (Robinson le Kolb, 2004). Ho fapana le lisele tsa spiny ka har'a li-accumbens moo ho eketsang letsoalo la lesapo la mokokotlo ho amahanngoa le thabo e fokolang ea membrane ea membrane (Zhang et al a, 1998), lisele tsa pele tsa piramide li bonahala li hlohlelletsoa habonolo (Dong et al a, 2005). Sena se lumellana le keketseho e kholo ea glutamate e lokollotsoeng ho NA e hlahisitsoeng nakong ea ho batla lithethefatsi, 'me, ka karolo e itseng, e amanang le neuroadaptations tsa selefounung tse kang ho fokotsa ho saena ka li-receptors tsa Gi-coupled ka lebaka la AGS3 e phahameng.Kalivas et al a, 2005). Ka hona, ha liphetoho tsa mookotaba oa D2 tse amohelang ho thunya ha sele pele li hlaha li sa sebetse kamora ho khaotsa koae e sa foleng, litlamorao tsa ho kenya letsoho li-receptor tsa Gs-coupled D1 lia eketseha (Nogueira et al a, 2006). Sena se ka tlatsetsa ho eketseheng hoa thabo le tahlehelo ea bistility ea membrane e tlalehiloeng ho li-neuron tsa pele ho kamora cocaine e sa foleng (Trantham et al a, 2002), ha D1 receptor e hlohlelletsa ho kenngoa ha AMPA receptor ka hara membrane (Sun et al a, 2005). Taba ea hore ts'usumetso ea D1 receptor ho PFC e hlokahala bakeng sa ho khutlisa ho batla lithethefatsi e lumellana le monyetla ona (Mehala et al a, 2003; Letsatsi le Rebec, 2005).

Kakaretso ea Neuroplasticity Tlas'a Polao ea Tsamaiso e Laoloang le e Qobelloang

Joalokaha ho bontšitsoe ho Setšoantšo sa 4c, mefuta ea neuroplasticity e mamellehang nakong ea ho khaotsa ho tsuba e fana ka methapo ea methapo ea kutlo e tlatselitseng bothateng bo sa feleng ba ho khutlela mokhoeng oa ho lemalla. Lithuto tse fapaneng li ts'ehetsa ho nts'etsopele ha glutamate ea mantlha pele ho NA joalo ka mokena-lipakeng oa bohlokoa oa ho batla lithethefatsi. Ka mokhoa o ts'oanang, liphetoho tse tšoailoeng ho li-signynaptic glutamate signaling, ho kenyelletsa le liphetoho tsa morphological ho li-neuron tsa striatal li ka 'na tsa kenya letsoho liphetoho. Ts'ebetso ea polasetiki ea cellular e thehileng boikarabello ba bohloka ka nako ea motheo le karabelo e matla ea PFC le litlamorao ho NA nakong ea ho batla lithethefatsi kapa litakatso tsa lithethefatsi e se e qala ho hlakisoa, joalo ka ha ho hlalositsoe ka tlase, ho theha libaka tse ncha tsa ts'ebetso ho nts'etsapele litlhare tsa meriana bakeng sa kalafo. temallo.

Ka holimo ho leqephe 

LITLHAKISO TSA HO FIHLA LE LITLHAKISO TSA CLINICAL

Ha re ntse re eketsa kutloisiso ea rona ka mekhoa ea ho potoloha le ea theknoloji eo ho pepesetsoa lithethefatsi khafetsa ho eketsang kotsi ea ho oela hape, litheko tse ncha tsa lithethefatsi li bonahala. Phetoho ena ea ho ba kotsing ea ho hlaseloa pakeng tsa ho khutlisetsoa ha meriana e mecha le e qobelloang e thusa joang bakeng sa nts'etsopele ea meriana e mecha, hammoho le kutlwisiso e eketsehileng ea mekhoa eo meriana e ka ntlafatsang litholoana tsa kalafo ea kelello le ea kelello.

Ho Fetoha ho Qobella ho Khutlisa Hape

Ho sebelisa litlhare tsa meriana ho nolofalletsa matla a bokhoba ba ho kenyelletsa ho putlama, ho etsa liqeto ho khutlisa ho bohlokoa ho fokotsa ho khutla hape. Joalokaha ho hlalositsoe kaholimo, phetoho ea ho boelana hape e le tloaelo e thehiloeng mohopolong o sa tsebeng letho oa ho sebetsa o kenyelletsa tahlehelo ea taolo ea pele. Ka lithethefatsi tse ling tsa tlhekefetso sena se bonahatsoa ke bofokoli ba kelello ba ts'ebetso e amanang le tlhokomelo, ho hloka matla le bokhoni ba ho fetola boitšoaro bo thehiloeng tsebong e ncha. Motheong oa liphumano tsena, ho etsa meriana ka tloaelo kapa ho bala li-neuroplasticity ka har'a naha ho ka bontša mokhoa oa bohlokoa. Joalokaha ho hlalositsoe kaholimo, liphetoho tsa limolek'hule li kenyelletsa ho nyenyefatsa ho hoholo hoa moputso oa tlhaho ka ho fetisoa ha dopamine, le ho khothaletsoa pele ho bokella phetiso ea glutamate ho nts'etsapele pele ho batla lithethefatsi. Kahoo, lithethefatsi tse fetohang phetisetso ea dopamine, phetisetso ea glutamate kapa phetisetso ea GABA ke bao e ka bang likhetho. Ntle le moo, projeke ea GABA e tsoang ho NA e hlophisitsoe ka mefuta e fapaneng ea li-neuropeptide (McGinty, 2007), le li-peptide tsena, hammoho le ba bang ho corticolimibic le bona ke likhetho bakeng sa nts'etsopele ea lithethefatsi.

Dopaminergics

 

Phepelo ea dopamine e feta tlasa liphetoho tse fapaneng ho latela mofuta oa "receptor subtype". Kahoo, ho na le phokotso ea ho emisa li-D2 receptor signaling (Volkow et al a, 2004), keketseho e ka bang teng ea ho saena hoa D1 (Kalivas et al a, 2005), le bophahamo bo tšoailoeng ho li-receptor tsa D3 ka lebaka la mamello e eketsehang ho BDNF (Neisewander et al a, 2004). Sena se etsa hore ho be thata ho bolela esale pele hore na o ka fetisa phetisetso ea dopamine ka ho fetisisa joang. Leha ho le joalo, ho na le data e ntle e hlakileng e tšehetsang ts'ebeliso ea bahanyetsi ba D3 ho thibela ho batla lithethefatsi (Xi et al a, 2006).

Glutamatergics

 

Ho ipapisitse le neuroplasticity e boletsoeng ka holimo, ho thibela ho lokolloa ha glaptamate ea synaptic e amanang le ho batla lithethefatsi ho ka bonahala e le mokhoa o motle oa ho fokotsa tšusumetso ea ho khutla. Leha ho le joalo, ha ho khonehe ho sebelisa lihanyetsi tse felletseng tsa li-ionotropic glutamate receptors ka lebaka la litlamorao tse sa amoheleheng. Ka hona, ho na le mekhoa e fapaneng ea litheknoloji ea ho fetola limela ntle le ho thibela phetiso ea glutamate. Tse ling tsa metsoako ena li se li kene liteko tsa bongaka 'me li bonts'a katleho e itekanetseng. Mohlala, acamprosate le topiramate li na le liketso tse fokolang joalo ka bahanyetsi ba AMPA receptor (Myrick le Anton, 2004; Cubell, 2006). Ho boleloa hore Topiramate e fokotsa ho khutla hape ho lemaletseng lithethefatsi tsa koae (Kampman et al a, 2004). Hape, modafinil le N-acetylcysteine ​​e sebelisang ho eketsa glutamate e tsoang kantle ho naha, 'me ka tsela ena e susumetsang tšusumetso ea mGluR-induction ea phokotso ea synaptic glutamate e bontšitse ho sebetsa hantle ho khutliseng koae kapa ho ts'oaroang ke takatso ea cueine, ka ho latellana (Dackis et al a, 2005; LaRowe et al a, 2007). Likarolo tse tharo tse ikemetseng li tlalehileDackis, 2004; Malcolm et al a, 2006; Hart et al a, 2007) hore modafinil e fokotsa cocaine e phahameng mohlomong ka ho eketsa glutamate e tsoang kantle le ho kenya tšebetsong inhibitory mGluR joalo ka ha ho hlalositsoe kaholimo. Ntle le moo, ho bontšitsoe li-agonists tsa mGluR2 / 3 tse thibelang ho batla lithethefatsi (Baptista et al a, 2004; Peters le Kalivas, 2006).

GABAergics

 

Mehlala ea preocaine ea koae le heroin li bonts'itse hore ho theohile GABA ho VP ke barekisi ba NA ho amana le ho batla lithethefatsi (Caille le Parsons, 2004; Tang et al a, 2005). Ho ts'ehetsa bohlokoa ba phetoho ena, lithethefatsi tse khothalletsang phetisetso ea GABA li bonts'itse ts'episo lithutong tsa bongaka le tsa kalafo, vigabatrin (inhibitor of GABA transferase), gabapentin (mochine o hlakileng), le baclofen (GABAb agonist). 'Mali o bua ka lipatliso tse ngata tsa ts'ebeliso ea GABAergics ho phekola bokhoba ba lithethefatsi (O'Brien, 2005; Vocci le Ling, 2005).

Peptidergics

 

Li-neuropeptide tse ngata li colocalized le GABA moqomong oa NA ho kenyelletsa neurotensin, DP, dynorphin, le CART (McGinty, 2007). Leha tsebo ea rona ea hore li-peptide tsena li kenya letsoho joang kapa che ho li laola tse batlang lithethefatsi tse sebelisoang ke li-savbens ho li-pallidum projection li fokola haholo, ho bontšitsoe hore ho thibela li-receptor tsa enkephalin ho VP ho thibela ho tsoma koae ka mefuta ea liphoofolo (Tang et al a, 2005), phello e ka 'nang ea kenya letsoho ts'ebelisong ea naltrexone ho lekhoba la ethanol (Vocci le Ling, 2005).

Nahanisisa

Leha ho bile le tsoelo-pele ea bohlokoa kutloisisong ea rona ea neuroplasticity e thehileng nts'etsopele ea bokhoba ba tahi le ho ts'oenyeha ho kotsing ea ho khutla hape, re mothating oa ho tseba ho sebelisa tsebo ena e ncha ho phekola bokhoba. Leha re na le lingaka tsa litlhare tse thehileng litlhare bakeng sa ho laola li-neurotransication lipakeng tsa li-neuron ka har'a potoloho e bonts'itsoeng e le bohlokoa, ho thata ho thetsa neuroplasticity e hlahisitsoeng ka ho saena kahare ho bohlokoa hoo ho leng bohlokoa haholo ho ho lemalla. Ho sebelisa tlhahisoleseling ena e ncha ho emetse nts'etsopele ea likhomphutha tse khethiloeng bakeng sa liprotheine tse lebisitsoeng litselaneng tsa ho saena, 'me habohlokoa le ho feta, e bolela ho fana ka likhakanyo. Le ha ho le joalo, mefuta ea li-neuroplasticity tse khethiloeng ho fihlela joale e supa tsela e lebisang phekolong ea nako e tlang e tla ba teng ha theknoloji ea ho tsamaisa lintho e ntse e fetoha.

Ka holimo ho leqephe 

Notes

QETHA

Ngaka O'Brien o sebelitse e le moeletsi lilemong tse tharo tse fetileng ho Alkermes, Cephalon, Forest le McNeil Laboratories. Dr Kalivas ha a na letho leo a ka le senolang.

Ka holimo ho leqephe 

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Boithuto bo Felletseng: Ho lemalla lithethefatsi e le Pathology ea Staged Neuroplasticity

Peter W Kalivas1 le Charles O'Brien2, 1Departments of Neurosciences, Medical University of South Carolina, Charleston, SC, USA 2Department of Psychiatry, Philadelphia VA Medical Center, University of Pennsylvania, Philadelphia, PA, USA, Ngollano: Ngaka P Kalivas, Mafapha ea Neuroscience, Univesithi ea Bongaka ea Carolina Boroa, 173 Ashley Ave, BSB 410, Charleston, SC 29425, USA. Mohala: + 1 843 792 4400; Fekse: + 1 843 792 4423; Imeile: [imeile e sirelelitsoe],;

inahaneloang

Ho sebelisa lithethefatsi tse lemalloang ho ka fetoha molemong oa tšebeliso ea taolo ea sechaba ho kena bohlankeng bo ikarabellang bo bocha bo khethollang bokhoba. Phetoho ena ea ho lemalla e hlahisoa ke bofokoli ba liphatsa tsa lefutso, nts'etsopele, le bophelo sechabeng, hammoho le polasetiki e kentsoeng thekisong ea bongaka e matlafatsang boits'oaro bo amanang le lithethefatsi molemong oa ho arabela ka mokhoa o hlakileng bakeng sa meputso ea tlhaho. Tsoelo-pele e fetang lilemo tse leshome tse fetileng e bontšitse hore liserekisi tsa boko li kotsing e haufi le ho feta ea liphetoho tse tlisoang ke lithethefatsi, hammoho le tse ling tse amanang le limolek'hule le morphological. Tsebo ena e ntseng e hola e tlatselitse kutlwisisong e kholo ea kamoo lithethefatsi li sebelisang likereke tse tloaelehileng tsa ho ithuta ho theha litekanyetso tsa ho lemalla, joalo ka ha ho bonahala ka ts'ebetso ea boithatelo ea li-circuits tsa meputso ho arabela litumelo tse amanang le lithethefatsi le litlaleho tse tšoanang tsa takatso ea lithethefatsi. Kutloisiso ena e ncha e fana ka menyetla e ke keng ea bonoa ea litheko tsa litlhare tsa meriana ho phekola bokhoba. Ho bonahala ho na le polasetiki e amanang le ts'ebetso ea bokhoba ka kakaretso le liphetoho tse hlahisoang ke bokhoba ba sehlopha se itseng sa lithethefatsi tse lematsang. Liphumano tsena li boetse li fana ka motheo oa kutloisiso ea hona joale ea bokhoba e le lefu le sa foleng, le khutlisetsang bokong ka liphetoho tse phehellang nako e telele kamora ts'ebeliso ea ho qetela ea moriana. Mona, re hlalosa neuroplasticity ho li-circuits tsa boko le ts'ebetso ea lisele tse khothalletsoang ke lithethefatsi tse lemalloang tseo ho nahanoang hore li etsa tlatsetso ea ho qala ts'ebeliso ea lithethefatsi, 'me re buisana ka hore na tsebo ena e susumetsa joang ho hlahloba le ho lekola mekhoa ea phekolo ea bokhoba ba tai.