Litšebeletso tsa Neurobiological bakeng sa Lefifi le Mabeli la ho Ikitlaetsa ho Lemalla (2009)

Neuropharmacology. Sengoloa se ngotsoeng; e fumaneha ho PMC Jan 1, 2010.

PMCID: PMC2637927

NIHMSID: NIHMS86836

Moetso oa khatiso oa ho qetela oa mohatisi o fumaneha ho Neuropharmacology

Sheba lihlooho tse ling ho PMC hore Qotsa sehlooho se hatisitsoeng.

Eya ho:

inahaneloang

Ho lemalla lithethefatsi ho ka hlalosoa ka ho qobelloa ho batla le ho sebelisa lithethefatsi, tahlehelo ea taolo molemong oa ho kenella, le ho hlaha ha boemo bo bobe ba maikutlo ha phihlello ea lithethefatsi e thibetsoe. Tlhatlhobo ea lithethefatsi e ama mekhoa e mengata ea ts'ebetso mme e ka hlalosoa e le bothata bo tsoelang pele ho tloha ho kenella (ho matlafatsa). Ho theha matlafatso a fosahetseng ho hlalosoa e le ho nka lithethefatsi tse fokotsang boemo bo bobe ba maikutlo. Boemo bo bobe ba maikutlo bo etsang hore matlafatso a joalo a fosahetseng a thellelitsoe ho tsoa phihlelong ea lintho tsa bohlokoa tsa methapo e amanang le moputso le khatello kelellong kahare ho likarolo tsa basal tse amanang le "ventral striatum" le "amygdala". Lintho tse ikhethileng tsa li-neurochemical ka hara meaho ena ha li kenyelletse ho fokotseha feela ha mokokotlo oa moputso, joalo ka ho fokotseha hoa ts'ebetso ea dopamine le opioid peptide ts'ebetsong ea ventral striatum, empa hape le ho hira lits'ebetso tsa khatello ea kelello, joalo ka corticotropin-releasing factor (CRF), ho amygdala e atolositsoeng. . Ho tlosa ka matla lithethefatsi tsohle tse kholo tsa tlhekefetso ho hlahisa menyetla ea meputso, ho eketseha ha likarabo tse kang matšoenyeho, le keketseho ea maemo a CRF khubung ea khubu ea amygdala. CRF receptor antagonists e boetse e thibela tšebeliso e mpe ea lithethefatsi tse hlahisoang ke ho its'epahala. Sistimi e arabelang khatello ea kelello e khothalletsoa hore e khothalletsoe ke tšebeliso e mpe ea lithethefatsi tse ngata, ho ts'oaroa ha motho a khaotsa khafetsa, ho phehella ho ithiba, le ho kenya letsoho ho tlatselletsong ha bokhoba. Likarolo tse ling tsa tsamaiso ea khatello ea kelello ho amygdala e atamelaneng e sebetsanang le CRF mme e ka kenya letsoho boemong bo bobe ba ho tlohela ho kenyelletsa norepinephrine, dynorphin, le neuropeptide Y. Ho kopana ha tahlehelo ea mosebetsi oa moputso le ho hira lits'ebetso tsa khatello ea kelello li fana ka methapo e matla ea methapo ea kutlo. motheo oa boemo bo bobe ba maikutlo bo ikarabellang bakeng sa ho khanna ho matlafatsoa ha bonyane, bonyane ka karolo, ho qobelloa ha bokhoba.

Keywords: ho lemalla, ts'ebetso ea mohanyetsi, khatello ea maikutlo, amygdala e atolositsoeng, corticotropin-releasing factor

1. Litlhaloso le sebopeho se hlakileng sa ho qobella ho lemalla

Bokhoba ba lithethefatsi ke bokuli bo bocha bo sa foleng bo khethiloeng ke (i) ho qobelloa ho batla le ho sebelisa lithethefatsi, (iitahlehelo ea taolo ea phokotso ea tšebeliso ea lijo, le (iii) ho hlaha ha boemo bo bobe ba maikutlo (mohlala, dysphoria, ho tšoenyeha, ho se ts'oanelehe) ho bonts'ang lefu le khothalletsoang la ho tlohela ha ts'ebeliso ea ts'ebeliso ea lithethefatsi (e hlalositsoeng mona e le ts'episo) (Koob le Le Moal, 1997). lemalla ntho e ho nahanoa hore e ts'oana le lefu la Ho Itlhahisa ka Litaba (joalo ka ha ho hlalosoa ke Buka ea ho hlahloba le ea Statistical ea Mathata a kelello; American Psychiatric Association, 1994). Ka tloaelo le ka mehlala ea liphoofolo, tšebeliso ea lithethefatsi ka linako tse ling empa e na le 'nang bakeng sa tlhekefetso kapa ho ba le ts'oaetso ho fapana le tšebeliso e mpe ea lithethefatsi le ho hlaha hoa boemo bo sa foleng ba ts'ebeliso ea lithethefatsi.

Bokhoba ba lithethefatsi bo hlalositsoe e le bokuli bo kenyelletsang likarolo tsa bohlasoa le ho qobelloa, kae ho se tsotelle e ka hlalosoa ka boits'oaro e le "tebello ea karabelo e potlakileng, e sa reroang mehopolong ea kahare le kantle kantle le ho nahana ka litlamorao tse mpe tsa karabelo ena ho ba bang kapa ho ba bang" (Moeller et al., 2001). Ho susumetsa ho lekanngoa libakeng tse peli: khetho ea moputso o nyane, hang hang holim'a moputso o moholo, o liehang (Rachlin le Green, 1972) kapa ho se khone ho thibela boitšoaro ka ho fetola ketso kapa ho emisa karabo hang hoba e hlahisoe (Logan et al., 1997). Ho susumetsa ke sesosa sa mantlha litekong tsa tlhekefetso ea lithethefatsi (Allen et al., 1998) le lits'ebetsong tsa methapo ea methapo e amanang le khatello ea kelello. Ka ts'ebetso, mesebetsi ea ho lieha ho khotsofatsa (mesebetsi e liehang ho theola) (khetho e potlakileng) le setlamo sa ho emisa kapa ho ea / ho se tsamaee (boitšoaro bo ts'oanang) se sebelisitsoe e le mehato ea ho susumetsa (Fillmore le Rush, 2002; Green le al., 1994). Ho qobelloa e ka hlalosoa e le likarolo tsa boits'oaro bo lebisang mamellong ea ho arabela ha o tobane le litlamorao tse mpe kapa tiisetso ponts'ong ea likarabo tse fosahetseng maemong a khetho. Lintho tsena li khahlisoa ke matšoao a ho tlohela lithethefatsi joalokaha ho hlalositsoe ke Mokhatlo oa Amerika oa Phekolo: ts'ebeliso e tsoelang pele ea lithethefatsi leha e le tsebo ea ho ba le bothata bo phehellang kapa bo sa feleng ba 'mele kapa kelello le nako e ngata e sebelisitsoeng lits'ebetsong tse hlokahalang ho fumana ntho ena (Mokhatlo oa Mahlale oa Amerika, 2000).

Ho fokotsa mekhahlelo ea bohlanya le ho qobella ho hlahisa mekhahlelo e meraro ea ho lemalla e nang le mekhahlelo e meraro—preoccupation / Ho lebella, binge / botaoa, 'me drainare / Ho ama hampe- Moo ho itšunya-tšunya hangata ho hlahang mathateng a pele mme ho qobella ho laola maemong a lipolao. Ha motho a tloha ho tsubellellang ho ea bohlonong, phetoho e ba ho tloha ho matlafatsong e ntle ea ho khanna boitšoaro bo susumetsoang ho ea ho matlafatso e mpe ea ho khanna boitšoaro bo susumetsoang (Koob, 2004). Matlafatso ea tlhekefetso e ka hlalosoa e le ts'ebetso eo ho eona ho tlosoa hoa tšusumetso e nyarosang (mohlala, boemo bo bobe ba maikutlo ba ho tlohela lithethefatsi) ho eketsang monyetla oa karabelo (mohlala, tšebeliso ea lithethefatsi tse khothalletsoang). Mehato ena e meraro e nkuoe e le ho hokahana, e ba matla le ho feta, 'me qetellong e lebise ho boemo ba bophelo bo tsejoang ka hore ke bokhoba (Koob le Le Moal, 1997) (Lethathamo 1). Tlhahlobo e teng e tla shebisisa karolo ea mohlala oa phoofolo ea ho qobelloa ho tsoa boemong bo bobe ba maikutlo ba drainare / Ho ama hampe bohato ba potoloho ea ho lemalla.

Lethathamo 1 

Mehato ea potoloho ea ho lemalla.

Lithethefatsi tse fapaneng li hlahisa mekhoa e fapaneng ea bokhoba ka ho hatisa likarolo tse fapaneng tsa potoloho ea bokhoba. Li-opioids li ka nkuoa e le lithethefatsi tsa tlhekefetso hobane lithuto li kopana le litekanyetso tse ngata tse amanang le tlhagiso, ho kenyelletsa mamello e kholo le ho tlohela. Mokhoa oa ho sebelisa lithethefatsi tse kenang kahare kapa tse tsubang, ho kenyelletsa ho tahoa ho tebileng, kholiso ea mamello, ho ja haholo, le dysphoria e tebileng, ho hloka botsitso 'meleng le matšoao a bang teng ka nako e itseng nakong ea ho khaotsa ho tsuba. Ho ameha haholo ka ho fumana li-opioid (ho lakatsa) ho hlaha hangata ho tlang pele mats'oao a ho khaotsa mme ho sa amanngoe le ho hlohlelletsa feela ho susumetsoa ke ho fumana moriana empa hape le ho susumetsa ho amanang le ho tlohela le boemo bo hlohlelletsang. Mokhoa o hlaha moo moriana o lokelang ho fumanoa teng ho qoba letsoalo le tebileng le ho se thabe. Lithethefatsi tse ling tsa tlhekefetso le tsona li ka etsa se tšoanang binge / botaoa sethala (li-psychostimulants le joala) kapa tse fokolang binge / botaoa le tse ling drainare / Ho ama hampe 'me preoccupation / Ho lebella methati (nicotine le cannabinoids).

Ho lemalla joala, kapa bokhoba ba tahi, ho ka latela mokhoa o ts'oanang, empa mokhoa oa ho sebelisa lithethefatsi ka molomo hangata o tšoauoa ka ho itlopa joala bo ka ba liketsahalo tsa letsatsi le leng le le leng kapa matsatsi a malelele a ho tahoa haholo mme o tšoantšoa le lefu le matla la maikutlo le la ho ikhula. Boholo ba joala bo ntse bo tsoela pele ka mokhoa o joalo oa ho itlopa joala kapa nako ea ho khaola ka nako e telele, empa batho ba bang ba ka fetohela maemong a kang a opioid moo ba lokelang ho ba le joala bo fumanehang ka linako tsohle ho qoba litlamorao tse mpe tsa ho itlopa joala. Ho lemalla koae ho fapana ka mekhoa e boletsoeng ka holimo binge / botaoa sethala e etsa karolo e nyane ea ho itšetleha ka nicotine. Tloaelo ea ho ja ka nicotine ke e 'ngoe ea lithethefatsi tse nang le methapo e mengata ntle le ha u robala. Leha ho le joalo, nakong ea thibelo, basebelisi ba ba le maemo a sithabetsang a maikutlo, ho kenyelletsa dysphoria, ho hloka botsitso le takatso e matla. Marijuana Ho itlhahisa ho latela mokhoa o ts'oanang le opioids le koae, ka sethala sa bohlokoa sa ho tahoa, empa ha ts'ebeliso e sa foleng e tsoela pele, lithuto li qala ho bontša mokhoa oa tšebeliso oa ho tahoa ho sa feleng nakong ea ho tsosa le ho ikhula ho bonahatsoang ke dysphoria, ho teneha le mathata a ho robala. Psychostimulants, joalo ka koae le amphetamines, li bontša mohlala o tsepamisitsoeng ho binge / botaoa sethala moo ho kulang e ka bang lihora tse ngata kapa matsatsi ha nako e telele 'me hangata ho lateloa ke ho tlosoa ("ho oa") ho khetholloang ke dysphoria e feteletseng le ho se sebetse.

1.1. Ts'usumetso, ts'ebetso, le mohanyetsi

Khothatso ke boemo bo ka hlalosoang e le "tloaelo ea phoofolo eohle ho hlahisa mesebetsi e hlophisehileng" (Hebb, 1972), mme libaka tse joalo tsa tšusumetso ha li lule li le teng empa li fapana ha nako e ntse e tsamaea. Mosebetsi oa pele oa Wikler o hatelletse karolo ea liphetoho lipuong tsa drive tse amanang le ts'ehetso. Lithuto li hlalositse liphetoho tse tlisoang ke ho tlohela e le "tlala" kapa tlhoko ea mantlha le litlamorao tsa morphine setulong se kang "satiation" kapa ho khotsofatsa tlhoko ea mantlha (Wikler, 1952). Leha Wikler a pheha khang ea hore matlafatso a matla a bolokiloe esita le lithutong tse its'epahalletseng haholo (menyakoe ea entoidous ea opioid), ho ts'epa ho hlahisitse mohloli o mocha oa khotsofalo, oa ts'usumetso e mpe (bona ka holimo).

Mohopolo oa tšusumetso o ne o hokahanngoe ka mokhoa o sa lekanyetsoang le maemo a hedonic, a amanang, kapa a maikutlo ha a bapisoa le maemo a matla a nakoana ke mohanyetsi oa Salomo mohopolo oa tšusumetso. Solomon le Corbit (1974) e hatisitsoeng ea hore linaha tsa hedonic, tse amehang, kapa tsa maikutlo, ha li se li qalisitsoe, li iphetola ka boits'oaro ke methapo e kholo ea methapo ka methapo e fokotsang matla a maikutlo a hedonic. The tshebetso e kenyelletsa ho lula ka lapeng kapa ho mamella maemo a itseng b-tšebetso e kenyelletsa ho tlohela kapa ho ntša hedonic. The tshebetso ts'ebeliso ea lithethefatsi e na le likarabo tse ntle tsa hedonic, e etsahala nakoana kamora tlhahiso ea ts'usumetso, e lumellana haufi le botebo, boleng, le nako ea matlafatso, 'me e bonts'a mamello. Ka lehlakoreng le leng, the b-tšebetso ts'ebeliso ea lithethefatsi e hlaha kamora tshebetso e felile, e na le likarabo tse mpe tsa hedonic, 'me e lieha ho qala, e lieha ho haha ​​ho fihlela asymptote, e lieha ho bola, ebile e ba kholo ka ho pepesetsoa khafetsa. Taba mona ke hore mekhoa ea mohanyetsi e qala pele ho ts'ebeliso ea lithethefatsi, e bontša liphetoho mokhoeng oa moputso oa boko le khatello ea maikutlo, 'me hamorao e ba e' ngoe ea lisosa tse kholo tsa ho qobelloa ho sebelisa lithethefatsi.

Kahoo, ho its'etleha kapa ponahatso ea sesupo sa ho khaola kamora ho tlosoa hoa ts'ebetso ea lithethefatsi tse sa feleng ho hlalosoa ho latela ho susumetsa dikarolo tsa ho its'etleha joalo ka ho hlaha ha boemo bo bobe ba maikutlo (mohlala, dysphoria, matšoenyeho, ho hloka botsitso) ha phihlello ea lithethefatsi e thibetsoe (Koob le Le Moal, 2001), ho fapana le ho 'meleng mats'oao a ho ts'epa. Ka 'nete, ba bang ba pheha khang ea hore nts'etsopele ea boemo bo bobe joalo bo ka hlalosang ho ts'ehetsa ho latela ts'oaetso:

"Khopolo ea ho itšetleha ka lithethefatsi, ntho, karolo, ts'ebetso kapa mohloli ofe kapa ofe oa ts'usumetso e hloka karolo ea bohlokoa ea ts'usumetso e mpe e bang teng ha e le sieo. Tekanyo ea ho itšetleha e ka lekana le palo ea ts'oaetso ena e mpe, e ka tlohang ho ho se khotsofale ho fokolang ho isa mahlomoleng a feteletseng, kapa ho ka bapisoa le boima kapa boiteko bo hlokahalang ho etsa ntle le sehlahisoa, ntho, jj. ”(Russell, 1976).

Mamello e potlakileng ea ho mamella le ho hanyetsana le litla-morao tsa mohanyetsi ho arabela litlamorao tsa hedonic tsa koae li tlalehiloe lithutong tsa batho tsa ho tsuba koae (Van Dyke le Byck, 1982) (Setšoantšo sa 1A). Kamora seboka se le seng sa ho tsuba, ho qaleha le ho teba ha "ho phahameng" ho potlaka haholo ka ts'ebetso e tsubelletsoeng ea tsamaiso, mme mamello e potlakile e bonahala. "Phahameng" e fokotseha ka potlako ho sa na le litekanyetso tse ngata tsa mali tsa koae. Ho ho makatsang le ho feta ke hore batho bao e leng bafo le bona ba tlaleha “dysphoria” e latelang, hape leha maemo a phahameng a mali a koae. Cocaine e kenang ka bongata e ile ea hlahisa mekhoa e tšoanang ea "ho potlaka" ka potlako e lateloang ke "tlase" lithutong tsa laboratori ea batho (Breiter et al., 1997) (Setšoantšo sa 1B). Ka ho itaola kahare ho koae ka mefuta ea liphoofolo, liphahamiso tse joalo monyako oa moputso li qala ka potlako mme li ka bonoa nakong ea kemiso e le 'ngoe ea boits'oaro (Kenny et al., 2003) (Setšoantšo sa 2), e ts'oanang le litlaleho tse kholo tsa batho. Liphetho tsena li bonts'a hore bophahamo ba meputso ea boko bo fumanehang kamora nako e telele ea ts'ebeliso ea koae e sa atleha ho khutlela maemong a mantlha lipakeng tsa ho pepesetsoa nako e telele ea ts'ebetso ea cocaine (ke hore, hysteresis e setseng), ka hona e theha kholo e kholo ea "motheo" oa ICSS litheko. Lintlha tsena li fana ka bopaki bo susumetsang ba ho se sebetse ha moputso oa boko khoebong e phahameng e fanang ka tšehetso e matla molemong oa ho lemalla lithethefatsi tsa hedonic.

Setšoantšo sa 1Setšoantšo sa 1 

(A) Maikutlo a dysphoric a ile a latela thabo e kholo lithutong tsa liteko tse ileng tsa tsuba ho tsuba koae, leha khatello ea koae ka plasma ea mali e ntse e phahame haholo. Dysphoria e tšoauoa ka matšoenyeho, khatello ea maikutlo, ...
Setšoantšo sa 2 

Likhoto (n = 11) ba ile ba lumelloa ho itaola ka boeona 10, 20, 40, le 80 ka ente ea cocaine (0.25 mg ka ente), le menyetla ea moputso oa ho itšunya-tšunya e neng e lekantsoe 15 min le 2, 24, le 48 h kamora ho fela mong le e mong intravenous cocaine boits'oara ...

Liphetho tse ts'oanang li bonoe li bonts'a likarabo tse kang dysphoria tse tsamaeang le opioid e matla le ho tlosoa ha ethanol (Liu le Schulteis, 2004; Schulteis le Liu, 2006). Mona, tsamaiso ea naloxone e latelang liente tse le 'ngoe tsa morphine tse eketsang meputso e atolositsoeng, e lekantsoeng ke ICSS, le likhahla tse eketsehang tse nang le boiphihlelo bo phetoang ba morphine le naloxone tse susumetsang ho tlohelaLiu le Schulteis, 2004). Liphetho tse tšoanang li ile tsa bonoa nakong ea ha a ne a khaotsa ho hlobaela le ho feta ethanol (Schulteis le Liu, 2006).

Tekanyetso ea ts'ebetso ea moputso oa boko e amanang le ho khaotsa ho tsoa taolong e sa feleng ea lithethefatsi tsa tlhekefetso ke ntho e tloaelehileng litlhare tsohle tsa tlhekefetso. Ho tlohela koae e sa foleng (Markou le Koob, 1991), amphetamine (Paterson et al., 2000), li-opioids (Schulteis et al., 1994), cannabinoids (Gardner le Vorel, 1998), nicotine (Epping-Jordan et al., 1998), le ethanolSchulteis et al., 1995) e lebisa ho nyolohelo ea moroalo oa moputso nakong ea ho itima lijo ho sa hlokahale, 'me tse ling tsa linyatso tsena monyako li ka tšoarella ho fihlela beke e le' ngoe (Setšoantšo sa 3). Maikutlo ana a etsa hore ho be le tšebeliso ea maikutlo a hore mohanyetsi a ka etsa hore mohato o le mong o qobelloang moo ho sebetsanoang le mekhoa e mebe ea ho matlafatsa.

Setšoantšo sa 3 

(A) Litlamorao tsa ho tlosoa hoa ethanol hodima CRF-like immunoreactivity (CRF-L-IR) ho rat amygdala e behiloeng ke microdialysis. Dialysate e ile ea bokelloa ka makhetlo a mane a 2 h makhetlo a neng a fetoloa khafetsa ka linako tse sa tsitsang tsa 2 h. Linako tse nne tsa mehlala e ne e tsamaisana ...

Haufinyane tjena, mohopolo oa bahanyetsi o atolositsoe hore e be karolo ea methapo ea kutlo ea lithethefatsi ho tsoa ho pono ea methapo ea kutlo. Ho entsoe mokhoa oa ho hlonepha mekhoa ea ts'ebetso ea boko ho hlalosetsa liphetoho tse phehellang tse khothatsang tse amanang le ts'ebeliso ea ts'ebeliso ea bokhoba ba tahi (Koob le Le Moal 2001, 2008). Ka mofuta ona, bokhoba ba lithethefatsi bo hlalosoa e le mokhoa oa ho eketseha ha methapo ea boko / mekhoa e meng e tlisoang ke boemo bo seng botle ba maikutlo bo kentse letsoho ts'ebelisong e mpe ea lithethefatsi. Lits'ebetso tse amanang le litheko tsa ts'ebetso eo e leng karolo ea lithibelo tse tloaelehileng tsa homeostatic tsa mosebetsi oa moputso li sitoa ho khutla kahare ho sebaka se tloaelehileng sa homeostatic. Ts'ebetso tsena tse hanyetsanang li fetoloa hore li ka fetoloa ka mekhoa e 'meli: li-neuroadaptations tse ka hare ho system le neuroadaptations lipakeng tsa systemKoob le Bloom, 1988).

Neuroadaptation e ka hare ho sistimi, "karolo ea mantlha ea karabelo ea methapo ea methapo ka boeona e tla tloaela litla-morao tsa litla-morao; ho phehella ha litla-morao tse hanyetsanang kamora hore moriana o nyamele ho tla hlahisa karabelo ”.Koob le Bloom, 1988). Ka hona, neuroadaptation e ka hare ho sistimi ke phetoho ea limolek'hule kapa lisele ka hare ho potoloho ea moputso e amohelang ho amohela ho fetelletse hoa ts'ebetso ea hedonic e amanang le ho lemalla ho bakang ho fokotseha ha mosebetsi oa moputso.

Ho sithabela maikutlo ho amanang le drainare / Ho ama hampe sethala se ka boela sa kenyelletsa li-nouroadaptations tse pakeng tsa tsamaiso eo methapo ea methapo e meng ntle le e amehang liputsong tse ntle tse tlisoang ke lithethefatsi tsa tlhekefetso li nkuoang kapa ho soaoa ka ts'ebetso e sa feleng ea sistimi ea moputso (Koob le Bloom, 1988). Kahoo, neuroadaptation e pakeng tsa sistimi ke phetoho ea potoloho eo potoloho e ngoe e fapaneng (anti-moputso) e hlahisoang ke potoloho ea moputso ebile e na le liketso tse hanyetsanang, hape e fokotsa mosebetsi oa moputso. Morero oa tlhahlobo ena ke ho hlahloba liphetoho tse etsoang ka har'a methapo ea maikutlo ea boko ho ikarabella bakeng sa liphetoho tsa methapo e hlahisang mekhoa ea bohanyetsi 'me li khothalletsoa hore li be le karolo ea bohlokoa ho tlatseng bokhoba ba tahi.

1.2. Mefuta ea liphoofolo ea ho qobelloa ho lemalla lithethefatsi e lekantsoeng ke linaha tse mpe tse kang maikutlo: Sebakeng sa mefuta-futa, mefuta ea liphoofolo ea ho tšoenyeha le meputso ea meputso.

Mefuta ea liphoofolo ea drainare / Ho ama hampe sethala se kenyelletsa mehato ea ho hloea sebaka se itseng (ho fapana le ho rata) ho khaola kapa ho itšehla thajana ho tsoa taolong e mpe ea lithethefatsi, ho eketseha ha meputso e sebelisang moputso oa ts'usumetso ea kelello (Markou le Koob, 1991; Schulteis et al., 1994, 1995; Epping-Jordan et al., 1998; Gardner le Vorel, 1998; Paterson et al., 2000), le keketseho ea likarabo-joalo ka matšoenyeho (bakeng sa tlhahlobo, bona Shippenberg le Koob, 2002; Sanchis-Segura le Spanagel, 2006).

1.3. Mefuta ea liphoofolo ea ho qobelloa ho lemalla joala joalo ka ha ho hlalositsoe ke ho eketsa ts'ebeliso ea lithethefatsi: Phallo ea taolo ea lithethefatsi ka phihlello ea nako e telele

Keketseho e tsoelang pele khafetsa le matla a ts'ebeliso ea lithethefatsi ke e 'ngoe ea lintlha tse kholo tsa boits'oaro bo tšoaeang nts'etsopele ea bokhoba ba tahi mme e tobane le bonnete le litekanyetso tsa Buka ea ho hlahloba le ea Statistical ea Mathata a kelello: "Ntho ena hangata e nkuoa ka bongata le nako e telele ho feta kamoo e neng e reretsoe" (American Psychological Association, 1994). Moralo oa ho etsa liphetoho phetohelong ea tšebeliso ea lithethefatsi ho ea lithethefatsing tsa lithethefatsi o ka fumanoa mefuteng ea morao-rao ea liphoofolo ea ho fihlela nako e telele ho ikatiseng kahare ho koae. Ka nalane, mehlala ea liphoofolo ea ho itlhokofatsa ka koae e ne e kenyelletsa ho qalisoa ha boitšoaro bo tsitsitseng letsatsi le letsatsi ho lumella tlhaloso e tšepahalang ea data e fanoeng ke meralo e kahare ea sepheo sa ho hlahloba methapo ea methapo ea kutlo le neurobiological ea litlamorao tse matla tsa koae. Ho fihlela 1998, kamora ho fumana boits'ebetso, litoeba hangata li ne li lumelloa ho fihlella koae bakeng sa 3 h kapa ka tlase ho letsatsi ho theha maemo a tsitsitseng a ho ja le mekhoa ea ho araba lipakeng tsa lithuto tsa letsatsi le letsatsi. Ona e ne e le papali ea bohlokoa ea ho hlahloba methapo ea methapo ea kutlo bakeng sa litlamorao tse matla tsa lithethefatsi tsa tlhekefetso.

Leha ho le joalo, boitekong ba ho hlahloba monyetla oa ho fumana mokhoa o fapaneng oa ho itaola kahare ho koae ho ka hlahisa mekhoa e fapaneng ea tahi ea lithethefatsi, likhoto li ile tsa lumelloa ho fihlella ka mokhoa o ikemetseng oa taolo ea koae ka 1 kapa 6 h ka letsatsi (Ahmed le Koob, 1998). Ho fihlella ha hora (phihlello e khutšoane kapa ShA) ho koahelang koae ka ente ka nako e le ngoe ho hlahisitse tšebeliso e tlase le e tsitsitseng joalo ka ha ho hlokometsoe pejana. Ho fapana le moo, ho fihlella ha 6 h (phihlello e telele kapa LgA) ho hlahisa koae ho ile ha hlahisa lithethefatsi tseo butle-butle li ileng tsa eketseha ka matsatsi-tsatsi (Setšoantšo sa 4). Keketseho e eketsehileng e ile ea bonoa sehlopheng se atolositsoeng sa phihlello nakong ea hora ea pele ea kemiso, ka takatso e tsitsitseng ea nako eohle le phetoho e kholo mosebetsing oa phello ea tlhahiso, ho fana ka maikutlo a keketseho ea ntlha e behiloeng ea hedonic. Ha liphoofolo li ne li lumelloa ho fumana tekanyetso e fapaneng ea koae, ka bobeli liphoofolo tsa LgA le ShA li ne li ja k'hok'heine ea tsona, empa likhoto tsa LgA ka mokhoa o ikemetseng li sebelisitse cocaine habeli ho feta tekong efe kapa efe e lekiloeng moputso oa koae ho liphoofolo tse phahameng (Ahmed le Koob, 1999; Deroche-Gamonet et al., 2004; Mantsch et al., 2004). Escalation e boetse e amana le keketseho ea sebaka sa khefu bakeng sa cocaine lenaneong la tsoelo-pele le matlafatso, ho fana ka maikutlo a khothalletsoang a ho batla koae kapa ho ntlafala ha moputso oa cocaine (Paterson le Markou, 2003; Wee et al., 2008). Boitšoaro bo eketsehang joalo ba ho iphelisa ka liphoofolo tse itšetlehileng ka hona joale bo se bo bonoa ka koae, cypamphetamine, nicotine, heroin le joala (Ahmed le al., 2000; Ahmed le Koob, 1998; Kitamura et al., 2006; O'Dell et al., 2004; George et al., 2007) (Setšoantšo sa 4). Moetso ona ke karolo ea bohlokoa ea ho hlahloba bohlokoa bo susumetsang ba liphetoho tsa mohato oa mohanyetsi moputsong oa boko le litsamaiso tsa khatello kelellong tse lebisang ho tlatselletsong ha bokhoba. Liphetoho tse tšoanang ho tsona tsa ho matlafatsa le litlamorao tsa koae ka lebaka la ts'ebeliso ea lithethefatsi li shebiloe ho latela phihlello e atolositsoeng mme li kenyelletsa ho khutlisetsoa ho eketsehileng ha koae ka mor'a ho felisoa le ho fokotseha ha nako ea sepheo mohlaleng oa moputso oa phokotso ea cocaine (Deroche et al., 1999). Ka kakaretso, liphetho tsena li fana ka maikutlo a hore ho nka lithethefatsi ka ho fihlella nako e telele ho fetola tšusumetso ea ho batla moriana. Hore na ts'ebeliso ena ea lithethefatsi e ntlafalitsoeng e bonts'a maikutlo a moputso kapa boemo ba ho hafa moputso o ntse o tsoela pele ho buisanoa (Vezina, 2004), empa moputso oa boko le lithuto tsa neuropharmacological tse hlalositsoeng ka tlase li pheha khang ea moputso oa boemo ba phokotso ba ho khanna lithethefatsi tse eketsehileng nakong ea phihlello e atolositsoeng.

Setšoantšo sa 4 

(A) Kameho ea ho fumaneha ha lithethefatsi ka ho kenella ka har'a k'hok'heine ea koae (bolela ± SEM). Ho 6 h-fihlella nako e telele (LgA) likhoto (n = 12) empa eseng ho li-rats tsa 1 h-short (ShA) h (n = 12), ho bolela hore keketseho ea koae ka kakaretso e qalile ho eketseha haholo ho tloha 5 ea seboka (p <0.05; ...

Maikutlo a hore tšebeliso ea koae e qobelloang a tsamaisana le tšitiso e sa feleng kelellong ea moputso oa boko o 'nile oa lekoa mohlaleng oa phoofolo molemong oa tšebeliso ea lithethefatsi ka phihlello ea nako e telele e kopaneng le mehato ea menahano ea ts'usumetso ea boko. Liphoofolo tse kentsoeng ka har'a li-catheter tse kenang le tse lumelletsoeng phapang e ikhethileng ea ho ithekha ka koae ho bontšitse ho eketseha ha tsamaiso ea koae letsatsi le letsatsi sehlopheng sa batho ba fihlelang nako e telele (6 h; LgA) empa eseng sehlopheng sa batho ba fihlelang hanyane (1 h ; ShA). Ho pepeseha ho fapaneng taolong ea ho ts'oara koae ho bile le litlamorao tse kholo mokhoeng oa moputso o ileng oa eketseha butle-butle lithutong tsa LgA empa eseng ho ShA kapa ho laola litoeba nakong ea linako tsa tsamaiso tsa tsamaiso tse latellanang (Ahmed le al., 2002). Ho phahamisoa mokhoeng oa moputso oa mantlha ho ile ha etsoa pele ka nakoana mme ho ne ho hokahana le ho eketseha ha tšebeliso ea koae (Setšoantšo sa 5). Litlamo tse phahameng tsa kamora linako tsa moputso li ile tsa sitoa ho khutlela maemong a motheo pele ho kemiso e 'ngoe le e' ngoe ea boipuso e latelang, ka hona e ne e kheloha haholo maemong a taolo. Kholo e tsoetseng pele menyakong ea moputso e ne e amahanngoa le ho eketseha ho matla ha tšebeliso ea koae e kileng ea bonoa pejana. Kamora ho phahama ho hoholo ho etsahetse, phephetso e matla ea cocaine e nolofalelitse karabelo ea ts'ebetso ea boko ho isa tekanyong e lekanang le ea pele empa ea hlahisa meputso e phahameng haholo ea moputso ho LgA ha e bapisoa le likhoto tsa ShA (Ahmed le al., 2002). Liphetho tse tšoanang li bonoe ka phihlello e atolositsoeng ea heroin (Kenny et al., 2006). Likhoto li lumelletse ho fihlella ha 23 h ho heroin hape ho bontšitse keketseho e lebelletseng ea nako ea meputso e tšoanang le keketseho ea tekanyo ea ts'ebetso ea heroin (Setšoantšo sa 5).

Setšoantšo sa 5Setšoantšo sa 5 

(A) Kamano lipakeng tsa ho nyoloha molemong oa meputso ea ho itšunya-tšunya ea ho ikatisa le ho ja lijo tse matlafatsang tsa koae. (Ka ho le letšehali) Phetoho ea liperesente ho tloha litsing tsa motheo tsa ICSS. (Ka ho le letona) Palo ea liente tsa cocaine tse fumanoeng nakong ea hora ea pele. ...

2. Li-substrates tsa Neural bakeng sa boemo bo bobe ba maikutlo bo amanang le ho lemalla

2.1. Li-neuroadaptations tse ka hare ho system tse tlatsetsang ho maikutlo a mabe a karolo ea khatello

Moputso oa ts'ebetso ea ts'ebetso ea motlakase kapa boits'oaro ba ho ba le ts'usumetso e na le nalane e telele e le ts'ebetso ea ts'ebetso ea moputso oa boko le litlamorao tse matla tsa lithethefatsi tsa tlhekefetso. Lithethefatsi tsohle tsa tlhekefetso, ha li fanoa ka mokhoa o hlakileng, li fokotsa meputso ea meputso ea boko (Kornetsky le Esposito, 1979) le ha o fanoa ka mokhoa o sa lekanyetsoang eketsa meputso nakong ea ho ikhula (bona ka holimo). Moputso oa ho hlohlelletsa Brain ho kenyelletsa li-neurocircuitry tse pharalletseng bokong, empa libaka tse tebileng ka ho fetisisa tse hlalositsoeng ke litheko tse tlase haholo li kenyelletsa sebaka sa mokelikeli oa "medial forebrain bund" se hokahanyang sebaka sa likarolo tse ka hare tsa mokokotlo le basal forebrain (Ba baholo le Milner, 1954; Koob et al., 1977). Le ha khatiso e ne e shebane haholo le karolo ea mananeo a hloahloa a monoamine mokokotlong oa medial forebrain, litsamaiso tse ling tsa nondopaminergic tse ka hara bundle ea moriana o sa hlaka li na le karolo ea bohlokoa (Hernandez et al., 2006).

Li-neuroadaptations tsa ka hare ho system tsa ho pepesetsoa lithethefatsi ho kenyelletsa ho fokotseha ha ts'ebetso ea li-neurotransmitter system ka li-neurocircuits tse ts'oanang le litlamorao tse matla tsa lithethefatsi tsa tlhekefetso. Khopolo-taba e 'ngoe e tummeng ke hore ts'ebetso ea dopamine e sekisetsoa maemong a bohlokoa a potoloho ea bokhoba ba tahi, joalo ka ho khaotsa ho lebisa ho ts'usumetso ea maikutlo a sa amaneng le lithethefatsi le kutloelo-bohloko e eketsehang ea lithethefatsi tse hlekefelitsoeng (Melis et al., 2005). Ts'ebetso ea sistamine ea mesolimbic dopamine esale e tsejoa e le ea bohlokoa bakeng sa thepa e matlafatsang ea lithethefatsi tsa psychostimulant le ho amahanngoa le litlamorao tse matla tsa lithethefatsi tse ling tsa tlhekefetso (Koob, 1992; Di Chiara le Leboea, 1992; Nestler, 2005). Ho theoha ha ts'ebetso ea sisteme ea mesolimbic dopamine le ho fokotseha ha serotonergic neurotransication ho li-nucleus tsa li-nucleus ho etsahala nakong ea ho tlosoa ha lithethefatsi lithutong tsa liphoofolo (Rossetti et al., 1992; Weiss et al., 1992, 1996). Boithuto ba ho kenyelletsa batho ba lemaletseng lithethefatsi ba bontšitse phokotso ea nako e telele lipalo tsa dopamine D2 li-receptors ho batho ba sebelisang lithethefatsi hampe ha li bapisoa le taolo (Volkow et al., 2002). Ntle le moo, ba hlekefetsang koae ba fokotse khatello ea dopamine ka lebaka la phephetso ea pharmacological ka moriana o hlasimollang (Volkow et al., 1997; Martinez et al., 2007). Phokotso ea palo ea dopamine D2 li-receptors, hammoho le ho fokotseha hoa ts'ebetso ea dopaminergic, cocaine, nikotine, le boloi ba batho ba sebelisang joala hampe li fella ka ho fokotseha hoa maikutlo a lipotoloho tsa meputso ho susumetsoa ke lingaka tsa tlhaho (Martin-Solch et al., 2001; Volkow le Fowler, 2000). Liphumano tsena li fana ka maikutlo a phokotso e akaretsang ea kutloisiso ea karolo ea dopamine ea ho potoloha ha meputso ho likhothaletso tsa tlholeho le lithethefatsi tse ling ho batho ba lemaletseng lithethefatsi.

Ho khaotsa ha Psychostimulant ho batho ho amana le mokhathala, ho fokotseha ha maikutlo le ho khutlisetsoa hoa psychomotor le liphoofolong ho amana le tšusumetso e fokotsehileng ea ho sebeletsa meputso ea tlhaho (Barr le Phillips, 1999) le mesebetsi e fokotsehileng e fokotsehileng (Pulvirenti le Koob, 1993), litlamorao tsa boits'oaro bo ka kenyelletsang tšebetso ea dopaminergic e fokotsehile. Liphoofolo nakong ea phumollo ea amphetamine li fokotsehile ho arabela ka kemiso e tsoelang pele ea tekanyo ea tharollo e monate, 'me karabelo ena e fokotsehileng e ile ea khutlisoa ke dopamine karolo ea agonist terguride (Orsini et al., 2001), ho fana ka maikutlo a hore molumo o tlase oa dopamine o kenya letsoho ho fokolng ha sepheo se amanang le ho tlosoa ha psychostimulant.

Tlas'a moralo ona oa khopolo, li-neuroadaptations tse ling ka hare ho system li ka kenyelletsa kutloisiso ea mekhoa ea phetisetso ea li-receptor ho li-nucleus accumbens. Lithethefatsi tsa tlhekefetso li na le liketso tse matla tsa li-receptor tse amanang le litsela tse kenang tsa tlhaho tse ka tsamaeang le maemo a kalafo e sa foleng. Ho kenya ts'ebetsong ha adenylate cyclase, protheine kinase A, cyclic adenosine monophosphate Karolo ea Karolo ea Karolo ea (CREB), le ΔFosB e hlokometsoe nakong ea ha ho khaotsa opioid (Boithati le al., 1995; Shaw-Lutchman et al., 2002; Nye le Nestler, 1996; Nestler, 2004). Karabelo ea ΔFosB e hokahantsoe ho bontša phetoho ea neuroadaptive e eketsang nako e telele ea ho itela (Nestler le Malenka, 2004).

2.2. Pakeng tsa system-neuroadaptations tse tlatsetsang ho karolo e mpe ea maikutlo e bakang khatello

Lisebelisoa tsa methapo ea methapo ea kutlo tse amanang le ho feto-fetoha ha khatello ea maikutlo le tsona li ka kenella ka har'a methapo ea methapo ea khatello ea kelello molekong oa ho hlola boteng ba lithethefatsi tse nyarosang le ho khutlisetsa ts'ebetso e tloaelehileng le ha ho na le lithethefatsi. Ka bobeli hypothalamic-pituitary-adrenal axis le tsamaiso ea khatello ea kelello e kopantsoeng le corticotropin-releasing factor (CRF) ha e sebetse ka taolo e sa lekanyetsoang ea lithethefatsi tsohle tse kholo ka ts'ehetso kapa tlhekefetso, ka karabelo e tloaelehileng ea li-hormone tsa adrenocorticotropic tse phahameng, corticosterone, le amygdala. CRF nakong ea ha o ne o khaotsa haholo (Rivier et al., 1984; Merlo-Pich et al., 1995; Koob et al., 1994; Rasmussen et al., 2000; Olive et al., 2002; Delfs et al., 2000). Ho itokolla ka matla lithethefatsing tsohle tsa tlhekefetso ho boetse ho hlahisa boemo bo khathollang kapa bo ts'oenyehileng bo ka khutlisoang ke bahanyetsi ba CRF (bona ka tlase).

Mokhatlo oa neuroanatomical o ile oa bitsa amygdala e atolositsoeng (Heimer le Alheid, 1991) e ka emela kemiso e tloaelehileng ea anatomical e kopanyang methapo ea khatello ea kelello le methapo ea tšebetso ea hedonic ho hlahisa tšebetso ea mohanyetsi oa mahareng e thathamisitsoeng kaholimo. Amygdala e atolositsoeng e entsoe ka khubu e bohareng ea amygdala, mookotaba oa bethe ea stria terminalis, le sebaka sa phetoho ho subregion ea medial (khetla) subregion ea methapo ea methapo. E 'ngoe le e' ngoe ea libaka tsena e na le lintho tse tšoanang tse tšoanang le tsa potoloho ea lefatše.Heimer le Alheid, 1991). Amygdala e atolositsoeng e amohela liphatlalatso tse ngata ho tsoa ho li-organic organics tse kang basyatal amygdala le hippocampus mme e romella li-karolo tsa moea tsa pallidum ea ventral le polelo e kholo ho hypothalamus ea morao, ka hona, e ntse e hlalosa libaka tse ling tsa boko tse amanang le li-classical limbic (maikutlo) meaho e nang le motor motor extrapyramidal (Alheid et al., 1995). Amygdala e atolositsoeng haesale e tšelisoa hore e be le karolo ea bohlokoa eseng feela maemong a tšabo (Le Doux, 2000) empa hape le karolong ea maikutlo ea ts'ebetsong ea bohloko (Neugebauer et al., 2004).

2.3. Lithuto tsa Neuropharmacological tsa maikutlo a susumetsang a susumetsang a tlisoang ke ho tlohela lithethefatsi

Sebaka sa boikhathollo sa marang-rang se sebelisitsoe ho lekanya litlamorao tse tsosang takatso ea ho tlosoa, haholo maemong a li-opioids (Hand et al., 1988; Stinus et al., 1990). Ho fapana le se ratoang ke sebaka, likhoto li pepesitsoe tikolohong e itseng ha li ntse li tlosoa li-opioid nako e ngata, li sebelisa nako e nyane tikolohong e hulang moea o mongata kamora moo li hlahisoa ka khetho pakeng tsa tikoloho eo le tikoloho e sa sebetseng. Litlamorao tsena tse matlafatsang tse ka u thusang li ka lekanngoa ho tloha ho 24 h ho isa ho 16 libeke hamorao (Hand et al., 1988; Stinus et al., 1990, 2000). Sebaka sa boiketlo ha se hloke tlhokomelo ea opioid ho its'etleha ha eona. Mokhatlo o joalo o tsoela pele ho bonahala libeke kamora hore liphoofolo li "hlakoloe" (mohlala, kamora hore li-morphine li tlosoe) (bona Baldwin le Koob, 1993; Stinus et al., 2000). Ntle le moo, ho kheloha ha litoeba tse itšetlehileng ka opioid ho ka bonoa ka litekanyetso tsa naloxone tlase moo ho bonoang matšoao a ho khaola (Schulteis et al., 1994). Le ha naloxone ka boeona e tla hlahisa lehloeo la sebaka literekeng tse sa ts'epahaleng, tekanyo ea monyako e hlokoang ho hlahisa sebaka sa khopiso e fokotseha haholo ho likhoto tse ts'epahalang (Hand et al., 1988). Ho fapaneng ka mokhoa ona ke ho lekola sebaka se lekoala se hlahisoang ka mor'a ente ea lexone ka mora ente e le 'ngoe ea morphine.

Ho itšetleha haholo ka opioid ho 'nile ha hlalosoa e le mokhoa o tlisoang ke matšoao a kang oa ho khaola ke bahanyetsi ba opioid ba latelang tekanyetso e le' ngoe kapa tsamaiso ea nakoana ea oponid agonist (Martin le Eades, 1964). Likhoto li bonts'a sebaka se ts'abehang sa ho tsilatsila se kengoang ke lethal e le tlase le kamora ho tsoa ka ente e le 'ngoe ea morphine e bonts'ang karolo e susumetsang ea ho tlosoa ho hoholo (Azar et al., 2003). Ho tlosa Acio opioid ho boetse ho hlahisa menyetla ea meputso (Liu le Schulteis, 2004), khatello ea ho araba motho ea sebetsang (Schulteis et al., 2003) le boits'oaro bo ts'oanang le ho tšoenyeha bo tšoanang le ts'ebetsongZhang le Schulteis, 2008). U sebelisa sebaka sa maemo a leholimo a boiketlo ba batho ba sa tsotelleng, lethal dose ea agioist agonist luprenorphine ka mokhoa o ikhethileng e fokotse sebaka sa ho nyatsa se hlahisoang ke ho khaoloa ke opioid. Tsamaiso ea tsamaiso ea CRF1 receptor antagonist le tsamaiso e etsoang ka kotloloho ea intracerebral ea CRF ea peptide1/ CRF2 antagonist e boetse e fokotse mekhoa e khothalletsang sebaka ea ho khaotsa ho ikhula (opioid)Stinus et al., 2005; Heinrichs et al., 1995). Bohanyetsi ba ts'ebeliso e mpe ea "noradrenergic" e thibelletse sebaka se khothalletsang batho hore ba tlohele ho intšaid (Delfs et al., 2000).

Motho e mong ea khethang mathata a tlisoang ke ho khaotsa ho sebelisa lithethefatsi ke dynorphin. Bopaki bo bongata bo bonts'a hore dynorphin e eketseha ka har'a li-nucleus accumbens ka lebaka la ts'ebetso ea dopaminergic, hape, hore ts'ebetso e mengata ea dynorphin e ka fokotsa ts'ebetso ea dopaminergic. κ opioid agonists lia fapanyetsana (Land et al., 2008; Pfeiffer et al., 1986), le ho tlosoa hoa koae, opioid le ethanol ho amana le dynorphin e eketsehang ho li-nucleus accumbens le / kapa amygdala (Spangler et al., 1993; Lindholm et al., 2000; Rattan et al., 1992).

2.4. Lithuto tsa Neuropharmacological tsa litlamorao tse kang tsa ho tlosoa hoa lithethefatsi

Karabo e 'ngoe e tloaelehileng ea ho khaotsa ho matla le ho itima lijo ho lithethefatsi tsohle tse kholo tsa tlhekefetso ke ponahatso ea likarabo tse joalo ka letsoalo. Mefuta ea liphoofolo e senotse karabelo e kang ea ho tšoenyeha joalo ka lithethefatsi tsohle tse kholo tsa tlhekefetso nakong ea ho khaotsa ho matla. Phapang e ikemetseng hangata ke karabelo ea maikutlo moqoqong oa nova kapa / kapa oa maikutlo a makatsang, joalo ka lebala le bulehileng kapa karabo e phahameng, kapa karabelo e matla e khothalletsang, e kang ho patela projeke ea motlakase e nang le motlakase. Ho ikhula pusong ea khafetsa ea koae ho hlahisa karabo e kang ea bokuli maemong a phahameng a tlatsetso le teko ea ho patela, tseo ka bobeli li khutlisoang ke tsamaiso ea bahanyetsi ba CRF (Sarnyai et al., 1995; Basso et al., 1999). Ho khaotsa ho reroa ha opioid ka mokhoa o reriloeng ho boetse ho hlahisa litlamorao tse joalo ka (Schulteis et al., 1998; Harris le Aston-Jones, 1993). Ho tlosoa ha Ethanol ho hlahisa boitšoaro bo kang ba ho tšoenyeha bo khutlisoang ke tsamaiso ea intracerebroventricular ea CRF1/ CRF2 bahanyetsi ba peptidergic (Baldwin et al., 1991), CRF e nyane ea molek'hule1 antagonist (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007), le tsamaiso ea intracerebral ea CRF ea peptidergic1/ CRF2 antagonist ho amygdala (Rassnick et al., 1993). Barekisi ba CRF ba kentse intracerebroventricularly kapa ka mokhoa o hlophisehileng ba boetse ba thiba likarabo tse kang tsa ho tšoenyeha tse kang tsa khatello tse bonoang nakong ea ho itšireletsa ho sa feleng ka ethanol (Breese et al., 2005; Valdez et al., 2003). Litlamorao tsa bahanyetsi ba CRF li fumanehile sebakeng se bohareng ba amygdala (Rassnick et al., 1993). Ho khaotsa ho noka ho tloha ho nicotine ho hlahisa likarabo tse kang tsa ho tšoenyeha tse khutliselitsoeng ke bahanyetsi ba CRF (Tucci et al., 2003; George et al., 2007).

3. Likarolo tse tlase tsa Neural bakeng sa ho nka lithethefatsi tse eketsehileng ka phihlello e atolositsoeng

3.1. Ka hare ho system neuroadaptations

Liphuputsong tse ngata, li-agopist tsa dopamine tse sa aroleng ha lia bontšoa feela hore li khutlisa maikutlo a psychostimulant empa hape le ho thibela keketseho ea boitaolo ba psychostimulant e amanang le phihlello e atolositsoeng. Dopamine agonists ea nakoana e fokotsa litlamorao tse matlafatsang tsa lithethefatsi tsa psychostimulant maemong a sa lekanyetsoang a phihlello ea phihlello (Izzo et al., 2001; Pulvirenti et al., 1998). Leha ho le joalo, liphoofolo tse nang le phihlello e atolositsoeng li bonts'a maikutlo a eketsehang ho "dopamine" karolo ea agonist (Wee et al., 2007). Likhoto tse fihlellang nako e telele li tsamaisoa ke dopamine D2 agonist ea nakoana o bontšitse phetoho ho le letšehali la ts'ebetso ea karabelo ea tekanyetso le liphetho tse bonoang ke bahanyetsi ba dopamine (Ahmed le Koob, 2004). Liphetho tsena, li kopantsoe le ho bona hore dopamine karolo e itseng ea agonists le eona e ka khutlisetsa maikutlo a psychostimulant, e fana ka maikutlo a hore tšebeliso ea lentsoe la dopamine e ka kenya letsoho litlamorao tsa ho tlosoa hoa lithethefatsi.

Liphetho tse tšoanang li hlokometsoe ho itšetleha ha opioid ka agrenist ea pharenorphine ea opioid. Tekanyo ea Buprenorphine-ka tsela e itšetlehileng ka boeona e fokotse boitaolo ba hau ho likhoto tse itšetlehileng ka opioid (Chen le al., 2006).

3.2. Pakeng tsa system-neuroadaptations

Bokhoni ba bahanyetsi ba CRF ba ho thibela litlamorao tse kang tsa ho tšoenyeha le ho ts'oaroa ke takatso ea ho tlohela lithethefatsi bo ka bolela esale pele litlamorao tsa bahanyetsi ba CRF mehlaleng ea liphoofolo ea phihlello e atolositsoeng ea lithethefatsi. Bohanyetsi ba CRF ba ile ba thibela khetho ea lithethefatsi tse amanang le ts'ebeliso e eketsehileng ea ho ikakhela ka setotsoana khoebong ea koae (Specio et al., 2008), nicotine (George et al., 2007), le heroin (Greenwell et al., 2008a). Bohanyetsi ba CRF bo boetse bo thibetse ho ipusa ho eketsehang ha ethanol ho likhoto tse itšetlehileng (Funk et al., 2007) (Lethathamo 2).

Lethathamo 2 

Karolo ea phetoho ea corticotropin e bakang ho ts'epahalla.

Tsamaiso ea CRF1 bahanyetsi ba ile ba fetola mokhoa oa ho iphekola oa koae ka mokhoa o amanang le phihlello e atolositsoeng, 'me phetoho ena e ne e le litekanyetsong tsa antagonist tse neng li le tlase ho feta tse fokotsang boits'ebetso ba nako e khutšoane (Specio et al., 2008). Mona, likhoto li lumelletse phihlello ea 6 h ho koaeine e bontšitse keketseho ea takatso ea koae ka mor'a nako, athe likhoto tsa 1 h tsa ho fihlella li ile tsa lula li tsitsitse. CRF tse peli tse fapaneng1 bahanyetsi ba ile ba thibela ho itaola ha k'hok'heine ho likhoto tse fihlellang nako e telele ho feta tse neng li thibela ho itaola ha koae ka likhoto tse fihlellang nako e khuts'oanyane (Specio et al., 2008).

Joalokaha ho boletsoe kaholimo, CRF likarolong tsa amygdala e atolositsoeng e kenya letsoho litlamorao tsa ho susumetsa tsa ho tlosoa hoa opioid. CRF e khethiloeng1 antagonist antalarmin e thibetse lehloeo le hlahisoang ke naloxone ho litoeba tse itšetlehileng ka morphine (Stinus et al., 2005). CRF1 litoeba tse tsoang mona li ile tsa sitoa ho bonts'a ho hloea ha opioid e maemong a nepahetseng mme tsa sitoa ho bonts'a keketseho e susumetsoang ke "dynorphin mRNA"Contarino le Papaleo, 2005). CRF1 bahanyetsi ba boetse ba thibetse ka mokhoa o ikhethileng oa ho eketseha ha tsamaiso ea heroin e hlokometsoeng ho likhoto tse itšetlehileng ka heroine ka phihlello e atolositsoeng (Greenwell et al., 2008a).

Hape, joalo ka ha ho boletsoe kaholimo, ho itokolla ho nicotine e sa foleng ho hlahisitse litla-morao tse kang tsa CRF tse ileng tsa koaloa ke CRF1 receptor antagonist (George et al., 2007) le keketseho ea menyako ea meputso e ileng ea khutlisoa ke mohanyetsi oa CRF (Bruijnzeel et al., 2007). CRF ea extracellular e bontšitsoe hore e eketseha ho amygdala nakong ea ho khaola nicotine e sa foleng.George et al., 2007). Ho tsoa ponong ea nts'etsopele, ts'ebetso ea immunoreactivity e ts'oanang le CRF e bonoe liteketeng tsa batho ba baholo tse pepesetsoeng nicotine nakong ea bocha mme e hokahantsoe le phenotype e kang ea ho tšoenyeha (Slawecki et al., 2005). Tsamaiso ea tsamaiso ea CRF1 antagonist e thibetse ho itaola ho eketsehileng ha nicotine e amanang le ho khaotsa ho fihlella (23 h) liphoofolo (George et al., 2007). Liphetho tsena li fana ka maikutlo a hore CRF e maemong a basal le eona e ka ba le karolo ea bohlokoa ho ntlafatseng litlamorao tse susumetsang takatso e matla ea ho batla lithethefatsi e amanang le cocaine, heroin, le ts'ehetso ea nicotine.

Mohlala o makatsang oa litlamorao tsa ts'usumetso ea CRF ho itšetleha ka mehlala ea liphoofolo tsa taolo ea ethanol ho liphoofolo tse itšetlehileng ka eona. Nakong ea ho tlosoa ha ethanol, lits'ebetso tsa CRF tsa extrahypothalamic li fetoha tse matlafatsang, ka keketseho ea CRF ea kantle ho khubung ea khubu ea amygdala le bethe ea "stria terminalis" ea likhoto tse itšetlehileng ka eona (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002). Ts'isinyeho ea lits'ebetso tsa CRF ea boko ha e theoleloe feela ka boits'oaro bo ntlafalitsoeng joalo ka boits'oaro empa le boits'oaro bo ntlafalitsoeng ba ethanol bo amanang le ho tlosoa hoa ethanol. Ho tšehetsa khopolo ena, CRF9-41 le D-Phe CRF12-41 (intracerebroventricular tsamaiso) fokotsa ethanol ho itaola liphoofolong tse its'epileng (Valdez et al., 2004). Ho pepesehela khafetsa khafetsa ea phepelo ea ethanol e sa tsoheng ho hlahisitse keketseho e kholo ea ho kenella ha ethanol ho likhoto ka bobeli nakong ea ho khaotsa ho matla le nakong ea ho khaotsa ho tsitsitseng (libeke tsa 2 ka mor'a ho tlohela haholo) (O'Dell et al., 2004; Rimondini et al., 2002). Tsamaiso ea Intracerebroventricular ea CRF1/ CRF2 mohanyetsi o thibetse keketseho e tlisoang ke ho itaola ha ethanol nakong ea ho khaotsa ho matla le ho ithiba ho sa felengValdez et al., 2004). Ha e kenngoa ka kotlolloho kahare ho konopo e bohareng ea amygdala, CRF1/ CRF2 antagonist blocking ethanol self-management in ratsFunk et al., 2006, 2007). Li-injection tsa systemic tsa molek'hule-CRF e nyane1 antagonists e boetse e thibetse ho ja lijo tse ngata tsa ethanol tse amanang le ho khaotsa ho matla (Knapp et al., 2004; Overstreet et al., 2004; Funk et al., 2007). Lintlha tsena li fana ka maikutlo a karolo ea bohlokoa bakeng sa CRF, haholo-holo ka har'a khubu ea amygdala, ho arolelanang taolo e eketsehang ea boits'oaro e amanang le ho its'epa.

Le ha e sa ntlafatsoe hantle, bopaki bo teng bakeng sa karolo ea lits'ebetso tsa norepinephrine ho amygdala e atolositsoeng seterekeng se seng sa boiketlo le boikemelo bo eketsehang ba boits'oaro bo amanang le ts'ehetso. Li-antagonists tse sebetsang tsa Norepinephrine (β1 antagonist le α2 agonist) e kentsoe ka har'a mothapo o ka morao oa bethe ea stria terminalis e koetsoeng e hlohlontšitsoeng sebaka se khelosang (Delfs et al., 2000). Litlamorao tsa norepinephrine ho arola litlamorao tsa ho tlosoa hoa opioid li kenyelletsa tsamaiso ea "ventral noradrenergic". Litlatsetso tsa Ventral noradrenergic bundle tse tlatselitseng sebakeng sa ts'usumetso e tsoang ho opioid -Delfs et al., 2000), empa ho batla ho felletse ka marapo a thibeloang a dorsal noradrenergic ho tsoa sebakeng sa locus coeruleus ka "neurotoxin 6-hydroxydopamine e sitiloe ho thibela sebaka sa tlhekefetso e hlahisoang ke ho tlosoa hoa opioid" (Caille et al., 1999). Barekisi ba norepinephrine ba sebetsang ba thibela tšebeliso e mpe ea lithethefatsi tse amanang le ho itšetleha ka ethanol (Walker et al., 2008), cocaine (Wee et al., 2008), le li-opioids (Greenwell et al., 2008b). Ntlha ea bohlokoa ho tse ngata tsa litlamorao tsena ke amygdala e atolositsoeng empa e le maemong a bohlokoa ba mookotaba oa stria terminalis. κ Dynorphin, peptide ea opioid e khomarelang li-receptor tsa ito opioid, ke khale e tsejoa ho bontša ts'ebetso le taolo e sa feleng ea li-psychostimulants le opioids (Nestler, 2004; Koob, 2008), le li-agonist tsa ion opioid li hlahisa litla-morao tse ho liphoofolo le ho batho (Mucha le Herz, 1985; Pfeiffer et al., 1986). Mohanyetsi oa κ opioid o thibela joala bo bongata bo amanang le ho tlosoa le ethanolWalker le Koob, 2008). Bopaki bo bontša hore ts'ebetso ea κ receptor e ka hlahisa tokollo ea CRF (Pina le Takemori, 1992), empa haufinyane ba bang ba phehile khang ea hore litlamorao tsa dynorphin ho hlahisa maemo a mabe a maikutlo li kopantsoe ka ts'ebetso ea litsamaiso tsa CRF (Land et al., 2008).

Sebopeho se matla sa karabelo ea khatello ea methapo ea boko phephetsong se bontšoa ke tšebelisano e boletsoeng ea methapo ea methapo ea methapo ea methapo le lits'ebetso tsa methapo e bohareng ea methapo. E hlalosoa e le sistimi ea ho fepa pele maemong a mangata a makhopho le letsoalo la basal, CRF e kenya tšebetsong norepinephrine, le norepinephrine le eona e etsa tšebetso CRF (Koob, 1999). Bopaki bo bongata ba pharmacologic, physiologic, le anatomic bo tšehetsa karolo ea bohlokoa bakeng sa tšebelisano-hloko ea CRF-norepinephrine seterekeng sa locus coeruleus ho arabela li khatello tsa khatello (Valentino et al., 1991, 1993; Van Bockstaele et al., 1998). Leha ho le joalo, norepinephrine e boetse e susumetsa ho lokolloa ha CRF ka har'a kutu ea methapo ea hypothalamus (Alonso et al., 1986), mookotaba oa bethe ea stria terminalis, le khubu ea mantlha ea amygdala. Lisebelisoa tse joalo tsa phepelo li ile tsa hlalosoa tse ling hape hore li na le tšebeliso e matla ea ho susumetsa karabelo ea setho phephetsong ea tikoloho, empa mochine o joalo o ka hlaseleha habonolo ho ramatiki (Koob, 1999).

Neuropeptide Y (NPY) ke neuropeptide e nang le thepa e makatsang e ts'oenyehileng joalo ka ho ts'oaroa ho amygdala mme e ts'ellelitsoe hore e be le litlamorao tse fapaneng le CRF maemong a fosahetseng a ho tlohela lithethefatsi tsa tlhekefetso (Heilig le Koob, 2007). Bopaki bo bohlokoa bo fana ka maikutlo a hore ts'ebetso ea NPY karolong e bohareng ea amygdala e ka thibela likarolo tsa ts'usumetso ea ts'epahalo e amanang le taolo ea ethanol e sa foleng. NPY e fanoe ka intracerebroventricularly e thibelletse ts'ebetso e eketsehileng ea lithethefatsi e amanang le ts'ehetso ea ethanol (Thorsell et al., 2005a, b). Ho kenella ka NPY ka ho toba kahareng e bohareng ea amygdala (Gilpin et al., 2008) le polelo ea ntlafatso ea vaerase e ntlafalitsoeng ea NPY karolong e bohareng ea amygdala hape e thibetse ts'ebetso e eketsehileng ea lithethefatsi tse amanang le ts'epahalo ea ethanol (Thorsell et al., 2007).

Kahoo, ho itokolla ho lithethefatsi ka bongata ho eketsa CRF mookotong o kahare oa amygdala o nang le bohlokoa bo susumetsang bakeng sa litlamorao tse kang tsa ho ts'oaroa haholo le tšebeliso e mpe ea lithethefatsi tse amanang le ts'epo.Setšoantšo sa 6). Ho hula ka matla le hona ho ka eketsa ho lokolloa ha norepinephrine mokokotlong oa "stria terminalis" le "dynorphin" ka har'a li-nucleus tsa li-nucleus, 'me ka bobeli ba tsona li ka tlatsetsa ho boemo bo bobe ba maikutlo bo amanang le ho ts'epahalla. Ts'ebetso e fokotsehileng ea NPY sebakeng se bohareng ba amygdala le eona e ka tlatsetsa ho boemo bo joalo ba ho tšoenyeha bo amanang le ts'epahalo ea ethanol. Ts'ebetso ea ts'ebetso ea khatello ea kelello (CRF, norepinephrine, dynorphin) e kopantsoeng le inactivation ea methapo ea khatello ea kelello (NPY) e etsa hore ho be le khatello e matla ea maikutlo ho amygdala e atolositsoeng. Tekanyo e joalo ea ts'ebetso ea maikutlo e ka ba tlatsetso e kholo lits'ebetsong tsa mohanyetsi oa-system tse thusang ho boloka ts'ebelisano 'me li boetse li rala motheo bakeng sa liphetoho tsa mmuso tsa nako e telele maikutlong a joalo ka ho ila thipa nako e telele.

Setšoantšo sa 6 

Neurocircuitry e amanang le litlamorao tse matla tsa matlafatso ea lithethefatsi tsa tlhekefetso le tokisetso e mpe ea ts'ehetso le kamoo e fetohang phetohong ho tloha ho ts'ebeliso e mpe ea lithethefatsi ho isa ho ts'ebeliso e mpe ea lithethefatsi. Lintho tsa bohlokoa tsa moputso ...

4. Boiphetetso bokhobeng ba maikutlo: Pono e nyarosang

Ho qobella ho lemalla ho lemalla ho ka tsoa mehloling e mengata, ho kenyelletsa ho hlohlella ho matlafatsang, ho kenya letsoho ts'ebetsong ea tloaelo, le ho senyeha ha mosebetsi o moholo. Empa, tlasa e 'ngoe le e' ngoe ea mehloli ena ke boemo bo bobe ba maikutlo bo ka bang le tšusumetso e matla boikemisetsong. Nts'etsopele ea boemo bo bobe ba maikutlo bo susumetsang tšusumetso e mpe ea temallo e hlalositsoe e le "lehlakore le lefifi" la bokhoba ba tahi (Koob le Le Moal, 2005, 2008) 'me e fokotsehile hore e be b-tšebetso ea hedonic e matla e tsejoang e le mohanyetsi ts'ebetso ha tshebetso ke euphoria. Boemo bo bobe ba maikutlo bo kenyeletsang drainare / Ho ama hampe sethala se na le likarolo tsa bohlokoa tsa susumetso, joalo ka ho se ts'oenyehe ho sa feleng, bohloko ba maikutlo, malaise, dysphoria, alexithymia, le tahlehelo ea meputso ea tlhaho, 'me e tsebahala ka liphoofolo ka ho eketseha ha meputso ea meputso nakong ea ho tlohela lithethefatsi tsohle tse kholo tsa tlhekefetso. Mehato e 'meli e hokahantsoe ho theha motheo oa neurobiological bakeng sa b-tšebetso: tahlehelo ea tšebetsong ea moputso (kahare ho sistimi neuroadaptation) le ho hloa khatello ea maikutlo kapa lits'ebetso tse khahlano le moputso (lipakeng tsa-system neuroadaptation) (Koob le Bloom, 1988; Koob le Le Moal, 1997). Pholo e khahlanong le moputso ke moaho o thehiloeng ho khopolo ea hore methapo ea boko e teng bakeng sa ho fokotsa moputso (Koob le Le Moal, 2008). Ha ho its'etleha le ho nts'etsapele, lits'ebetso tsa khatello ea kelello joalo ka CRF, norepinephrine, le dynorphin lia khethoa hape, li hlahisa libaka tse khelohelang kapa tse kang khatello ea maikutlo (Koob, 2003; Nestler, 2001; Aston-Jones et al., 1999). Ka nako e ts'oanang, ts'ebetsong ea li-amygdala tse matlafatsang tsa ts'ebetso, ts'ebetso ea moputso ea fokotseha. Motsoako oa ho fokotseha hoa ts'ebetso ea "neurotransmitter" ea moputso le ho hira lits'ebetso tse khahlanong le moputso li fana ka mohloli o matla oa matlafatso e mpe e tlatselletsang boits'ebetsong bo batlang tlhabollo ea lithethefatsi le ho lemallaSetšoantšo sa 6).

Sehlooho se akaretsang sa maikutlo se phehisanoang mona ke hore ho lemalla lithethefatsi ho emela ho phomola ka mekhoa ea tlhaho ea homeostatic e laolang boemo ba maikutlo ba phoofolo. Ho sithabela ha maikutlo ho qala ka ho itlopa le ho tloha ka mor'a nako, empa ho siea mokhoa o salang o lumellang "ts'ebeliso e mpe" hape esita le likhoeli le lilemo kamora ho khaoloa le ho inehela. Kahoo, khatello ea maikutlo ea bokhoba ba lithethefatsi ea lithethefatsi e bontša ho fetang feela ho senyeha hoa tšebetso ea homeostatic; e boetse e emela khefu e matla le homeostasis ea sistimi ena e bitsoang allostasis.

Allostasis, e neng e entsoe ka morero oa ho hlalosa ho tsitsipana ha tšebetso le boiphetetso bo phehellang, e hlalosoa e le "botsitso ka phetoho." Allostasis e rarahane haholo ho feta homeostasis mme e na le litšobotsi tse 'maloa tse ikhethang (Sterling le Eyer, 1988). Allostasis e kenyelletsa mochine oa pele oa phepelo ho fapana le mekhoa e mebe ea ho fana ka maikutlo a homeostasis, ka ho lekola botjha tlhoko ea tlhoko le tokiso e tsoelang pele ea litekanyetso tsohle ho fihlela lintlha tse ncha. An naha e mameloang e ka hlalosoa e le boemo ba ho kheloha ho sa feleng ha tsamaiso ea taolo ho tsoa maemong a eona a tloaelehileng (homeostatic). Moroalo oa allostatic e hlalositsoe e le "litšenyehelo tsa nako e telele tsa allostasis e bokellanang nako e telele ebile e bonts'a pokello ea tšenyo e ka lebisang ho lipalo tsa maloetse" (McEwen, 2000).

Mechine ea allostatic e hlalositsoe hore e kenye letsoho ho boloka ts'ebetso ea moputso oa ts'ebetso ea boko e amanang le ts'ebetso ea ts'ebetso ea methapo ea kutlo.Koob le Le Moal, 2001). Likarolo tse peli li reretsoe ho fetolela phephetso ho phephetso bokong bo hlahisoang ke lithethefatsi tsa tlhekefetso: ho fetisa mehopolo e mengata ea boko le li-circuits le ho hira methapo ea boipelaetso ea boko kapa tsamaiso ea khatello ea kelello. Kahoo, mochine oa 'mele o lumellang likarabo tse potlakileng ho phephetso ea tikoloho e fetoha mohloli oa thuto ea kelello haeba nako e lekaneng kapa lisebelisoa li sa fumanehe ho koala karabelo (mohlala, tšebelisano pakeng tsa CRF le norepinephrine bokong ba kelello le basal phatsa e ka lebisang ho letsoalo la kelello ()Koob, 1999).

Liphephetso tse phetoang, joalo ka lithethefatsi tsa tlhekefetso, li lebisa boitekong ba kelello ka liphetoho tsa lisele, tsa cellular le tsa methapo ea kutlo ho boloka botsitso empa ka litšenyehelo. Bakeng sa sebopeho sa bokhoba ba lithethefatsi se hlalositsoeng mona, ho kheloha masala ho tsoa mokhoeng o tloaelehileng oa moputso oa boko ho rehiloe lebitso naha e mameloang. Mmuso ona o bonts'a motsoako oa ho phahama ho sa feleng hoa lintlha tse behiloeng ke moputso tse fokotsoang ke tšebetso e fokotsehileng ea mekoloko ea meputso le ho hira lits'ebetso tse khahlano le moputso, tseo ka bobeli li lebisang ho qobelloang ha ho batla lithethefatsi le ho sebelisa lithethefatsi. Mokhoa ona o fetoloa joang ke lits'ebetso tse ling tsa maikutlo tse amanang le boko tse fumanehang sebakeng sa basal, moo morero oa phepelo le tšebetso ea amygdala ho fetisa maikutlo, kamoo ho senyeha ha methapo ea maikutlo ho amang setsi sa ts'ebeliso ea kelello se amanang le ho senyeha hoa ts'ebetso ea botsamaisi le hore na batho ka bomong ba fapana joang ka tekanyo ea limolek'hule tsa tlhahlobo ea maqhubu ho hlahisa thepa lipokellong tsena e ntse e le mathata lipatlisisong tse tlang.

lumela hore baa fokola

Sengoli se rata ho leboha Michael Arends le Mellany Santos ka thuso ea bona e ikhethang mabapi le ho hlophisa buka ena e ngotsoeng ka letsoho. Patlisiso e ne e tšehelitsoe ke Lits'oants'o tsa Naha tsa Naha tsa bophelo bo botle AA06420 le AA08459 ho tsoa National Institute on Alcohol Abuse and Alcoholism, DA10072, DA04043, le DA04398 ho tsoa Setsing sa Naha sa Ts'ebeliso e Mpe ea Lithethefatsi, le DK26741 ho tsoa Setsing sa Naha sa Lefu la Ts'oaetso le Ts'oaetso ea Mafu le Mafu. Patlisiso e boetse e tšehelitsoe ke Setsi sa Pearson sa Alcoholism le Tlhatlhobo ea Bokhoba. Ena ke nomoro ea phatlalatso 19480 e tsoang ho TheHTMLps Research Institute.

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.

References

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