Mekhoa ea methapo ea likokoana-hloko bakeng sa mekhoa ea ho susumetsa batho ba nang le tšusumetso e mpe (2008)

Philos Trans R Soc Lond B Biol Sci. Oct 12, 2008; 363 (1507): 3113-3123.

E phatlalalitsoe marang-rang Jul 24, 2008. Doi:  10.1098 / rstb.2008.0094

PMCID: PMC2607326

Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.

Eya ho:

inahaneloang

Khopolo ea ho lemalla lithethefatsi e le tlhekefetso e nang le tšebeliso e ngata ea lithethefatsi le tahlehelo ea taolo ea tahi e hlokang ts'ebetso ea ts'usumetso. Ts'ebetso ea mohanyetsi e le mohopolo oa tšusumetso ea ho matlafatsoa hampe ha ts'ebeliso ea lithethefatsi haesale o hloka tlhaloso ea methapo. Lintho tsa mantlha tsa methapo e kenyang moputso le khatello kelellong ka hare ho meetso ea basal forebrain tse kenyelletsang sebaka sa ventral striatum le amygdala tse atolositsoeng li kenngoa tšebetsong ka ts'ebeliso ea litheko ho fetisa lits'ebetso tsa mohanyetsi tse tsamaisang ts'epahalo. Lintho tse ikhethileng tsa li-neurochemical ka har'a meaho ena ha li kenyelletse ho fokotseha feela ha li-neurotransmission tsa moputso tse kang dopamine le li-peptide tsa opioid ka har'a ventral striatum, empa hape le ho bokella lits'ebetso tsa khatello ea kelello tse kang corticotropin-releasing factor (CRF), noradrenaline le dynorphin ho amygdala e atolositsoeng. Ho tlosa ka matla lithethefatsi tsohle tse kholo tsa tlhekefetso ho hlahisa menyetla ea meputso, likarabo tse kang matšoenyeho le maemo a kantle ho CRF karolong e bohareng ea amygdala. CRF receptor antagonists e thibela ho ja lithethefatsi tse ngata tse hlahisoang ke ho its'epaha. Sistimi e arabelang khatello ea kelello e khothalletsoa hore e khothalletsoe ke tšebeliso e mpe ea lithethefatsi tse matla haholo, ho khothaletsoa nakong ea ho khaotsa khafetsa, ho phehella ho ithiba le ho kenya letsoho ho oeleng hape kelellong. Motsoako oa ho lahleheloa ke ts'ebetso ea moputso le ho bokelloa ha lits'ebetso tsa khatello ea kelello li fana ka motheo o matla oa tšebetso bakeng sa ts'usumetso e matla ea mohanyetsi ea ikarabellang bakeng sa ts'ebetso e mpe ea ho khothaletsa ho lemalla.

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

1. Litlhaloso le sebopeho sa mohopolo

Tlhekefetso ea lithethefatsi, e tsejoang hape ka ho itšetleha ka thepa, ke bokuli bo bocha bo sa foleng bo khetholloang ke: (i) ho qobelloa ho batla le ho nka lithethefatsi, (ii) tahlehelo ea taolo ho lekanyelleng ho ja, le (iii) ho hlaha ha boemo bo bobe ba maikutlo (mohlala. dysphoria, matšoenyeho, ho teneha) ho bonts'a sesupo sa ho se tlohe ha ho kena litlamong ho thibetsoe (ho hlalosoa mona e le ts'episo; Koob & Le Moal 1997). lemalla ntho e ho nahanoa hore e ts'oana le lefu la tšebeliso ea lithethefatsi (joalo ka ha ho hlalosoa ke Buka ea ho hlahloba le ea lipalo-palo ea mafu a kelello, 4th edn., American Psychiatric Association 1994). Ka kotloloho, ka linako tse ling empa tšebeliso e mpe ea lithethefatsi 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 ho nkeha maikutlo le ho qobelloa (Koob & Le Moal 2008). Lintho tse susumetsang le ho qobella ho hlahisa tloaelo ea bokhoba ba taolo e nang le mekhahlelo e meraro—preoccupation / Ho lebella; binge / botaoa; le drainare / Ho ama hampe (Setšoantšo sa 1) - - eo hangata ho susumetsoa ke matla ho atileng methating ea pele le khatello e matla e atileng methating ea 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). Mehato ena e meraro e na le khopolo ea ho hokahana e mong le e mong, e ba matla le ho feta 'me qetellong e lebisa ho boemo ba bophelo bo tsejoang ka hore ke bokhoba (Koob & Le Moal 1997). Lithethefatsi tse fapaneng li hlahisa mekhoa e fapaneng ea bokhoba ka ho hatisa likarolo tse fapaneng tsa potoloho ea bokhoba ba tahi.Koob et al a. 2008). Lintho tse tloaelehileng li kenyelletsa ho itlopa joala / ho tahoa (ho makatsang ka li-psychostimulants le ethanol empa ho sa be teng ka nicotine), ho tlosa / ho ama hampe (ho makatsang ka li-opioids le joala empa ho tloaelehile ho lithethefatsi tsohle tsa tlhekefetso) le preoccupation / tebello (e tloaelehileng lithethefatsi tsohle tsa tlhekefetso). Tlhahlobo ea hona joale e tla shebisisa karolo ea moputso oa boko le litsamaiso tsa khatello kelellong e le 'ngoe ea mantlha le ts'ebeliso e tloaelehileng ea tlhekefetso: karolo ea ho khaola / e mpe e amanang le potoloho ea ts'ebetso ea tlhekefetso.

Setšoantšo sa 1 

Setšoantšo se hlalosang potoloho ea bokhoba ba tahi-peleho / ho lebella ('ho lakatsa'), ho itlopa joala le ho tahoa / ho ama hampe - ka litekanyetso tse fapaneng tsa ts'ebeliso ea ntho e kentsoeng ho tsoa ho Ho khetholla le ...

2. Ts'ebetso ea mohanyetsi le bokhoba ba hae

(a) Ts'usumetso le mohato oa bohanyetsi

Khothatso ke boemo bo ka hlalosoang e le 'tloaelo ea phoofolo eohle ho hlahisa mesebetsi e hlophisehileng' (Hebb 1972), mme maemo a joalo a susumetsang ha a fetohe empa a fapana ho ea ka nako. Khopolo ea tšusumetso e ne e hokahantsoe ka mokhoa o ke keng oa aroloa le li-hedonic, tse amang maikutlo kapa maikutlo a ho lemalla maemong a nakoana ke mohopolo oa mohanyetsi oa Solomone khopolo ea tšusumetso. Solomone & Corbit (1974) e phatlalalitsoeng hore linaha tsa hedonic, tse amehang kapa tse nang le maikutlo, ha li qaliloe, li iphetola ka boits'oaro ke methapo e kholo ea methapo ka methapo e fokotsang matla a maikutlo a hedonic. Mohopolo oa mohanyetsi oa tšusumetso o hlalosoa ke lits'ebetso tse peli. The tshebetso e kenyelletsa ho lula ka lapeng kapa ho mamella maemo a itseng b-tšebetso e kenyelletsa ho tlohela kapa ho ntša hedonic. Ts'ebetso e na le likarabo tse ntle kapa tse mpe tsa hedonic, e etsahala nakoana kamora tlhahiso ea ts'usumetso, e lumellana haufi le botebo, boleng le nako ea mochini oa ho tiisa le ho bontša mamello. Ka lehlakoreng le leng, ts'ebetso ea b e hlahile kamora hore ts'ebetso e felile ebile e lieha ho qala, e liehe ho haha ​​ho fihla asymptote, e liehe ho bola ebe e hola ka ho pepesehela khafetsa. Kahoo, matlafatso a ts'ebetso ea mohanyetsi mohopolo a hlahisa sepheo se secha le menyetla e mecha ea ho matlafatsa le ho matlafatsa boitšoaro (Solomon 1980).

Ho latela pono ea ts'ebeliso ea lithethefatsi ea lits'ebetso tsa ts'ebetso ea ts'ebetso ea boko, litlamorao tse matla tsa lithethefatsi (the-process kapa tse ntle tsa karabelo ea hedonic) li ile tsa nkoa hore li hanyetsoe kapa li hanyetsoa ke b-process e le liphetoho tsa homeostatic litsamaisong tsa boko (Setšoantšo sa 2). Tsamaiso ena ea taolo e amang e ne e nkuoe e le karabo e le 'ngoe e mpe kapa mohanyetsi ea hanyetsang maemo a tsosang a khothatsang mme a hatella kapa ho fokotsa ho tloha ho se nke lehlakore hoa hedonic (Solomone & Corbit 1974; Siegel 1975; Poulos & Cappell 1991). Mebuso e amehang, e khahlisang kapa e le maikutlo a mabe, e ne e nahanoa hore e hanyetsanoe ka boits'oaro ba mekhatlo e bohareng e fokotsang botebo ba linaha tse amehang. Khopolo-taba ena ea mohanyetsi, ho mamella le ho ts'epahalla ho hokahane ka mokhoa o hlakileng (Solomone & Corbit 1974). Maemong a ts'ebeliso ea ts'ebeliso ea lithethefatsi, Solomone o pheha khang ea hore litataiso tse 'maloa tsa pele tsa ts'ebetso ea lithethefatsi tsa opiate li hlahisa mokhoa oa liphetoho tse tšoanang le tsa ts'ebetso kapa euphoria, ebe e latela ho theoha ha matla. Kamora hore litlamorao tsa ts'ebetso ea lithethefatsi li felise, ho hlaha boemo bo hanyetsang, bo sa thabiseng ba maikutlo, joalo ka ha b-process.

Setšoantšo sa 2 

Khopolo ea bahanyetsi e sebetsa mabapi le litumelo tse tlatselletsang. (a) Tloaelo e tloaelehileng ea matla a botsitso a hlahisoang ke tšusumetso e batlang e le sieo ea tšusumetso (liphihlelo tse 'maloa tsa pele). (b) Mokhoa o tloaelehileng oa matla a bonts'itsoeng a hlahisoang ...

Haufinyane tjena, khopolo ea ts'ebetso ea mohanyetsi e atoloselitsoe libakeng tsa neurobiology ea ho lemalla lithethefatsi ho latela pono ea methapo ea pelo. Ho hlophisitsoe mofuta oa allostatic oa tsamaiso ea tšusumetso ea boko ho hlalosa liphetoho tse sa khaotseng tsa tšusumetso tse amanang le ho itšetleha ka bokhoba ba tahi (Koob & Le Moal 2001, 2008). Moqomong ona, bokhoba ba litumelo bo hlalosoa e le mokhoa oa ho eketseha ha litheko tsa boko / mekhoa e khahlano le moputso, e hlahisang boemo bo seng botle ba maikutlo bo kentse letsoho ts'ebelisong e mpe ea lithethefatsi. Lits'ebetso tsa ts'ebetso e ts'oanang le mohanyetsi b-process, eo e leng karolo ea ts'oaetso e tloaelehileng ea homeostatic ea moputso, e hloleha ho khutlela kahare ho tloaelo ea homeostatic e tloaelehileng.

Ts'ebetso tsena tse hanyetsanang li fetoloa ka hore li ka fetoloa ke lits'ebetso tse peli.Koob & Palesa 1988). Ka har'a neuroadaptation ea kahare ho sistimi, 'karolo ea mantlha ea karabelo ea lisele ho sethethefatsi ka boeona e ka ikamahanya le ho nyenyefatsa litlamorao tsa sethethefatsi; Ho phehella hoa litlamorao kamora hore moriana o nyamele ho ka hlahisa karabelo ea ho hula '(Koob & Palesa 1988, leq. 720). Ka hona, neuroadaptation e ka hare ho sistimi ke phetoho ea limolek'hule kapa lisele ka har'a potoloho ea moputso e fanoeng ho amohela ts'ebetso e fetisisang ea ts'ebetso ea hedonic e amanang le ho lemalla ho bakang ho fokotseha ha mosebetsi oa moputso.

Ka neanoadaptation e pakeng tsa sistimi, lits'ebetso tsa methapo e meng ntle le tse amehang liputsong tse ntle tse tlisoang ke lithethefatsi tsa tlhekefetso lia ngolisoa kapa li sa sebetse ka ts'ebetso e sa feleng ea tsamaiso ea moputso (Koob & Palesa 1988). Ka hona, neuroadaptation e pakeng tsa sistimi ke phetoho ea potoloho eo potoloho e 'ngoe e fapaneng (potoloho e khahlanong le 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 tse amanang le methapo e hlahisang mekhoa ea bohanyetsi, eo, re re, hypothesize, e nang le karolo ea mantlha boikhatellong ba bokhoba ba tahi.

(b) Mefuta ea liphoofolo tse lemalloang mabapi le ts'ebetso ea mohanyetsi

Mefuta ea liphoofolo tse lemalloang lithethefatsing tse kang li-stimulants, opioid, joala, nikotini le Δ9-tetrahydrocannabinol e ka hlalosoa ke mehlala e amanang le mekhahlelo e fapaneng ea potoloho ea bokhoba. Mefuta ea liphoofolo ea moputso le e matlafatsang (sethala sa ho itlopa joala) e atile ebile e netefalitsoe, 'me e kenyelletsa boits'oaro ba lithethefatsi tse kenang kahare, khetho ea sebaka le khetho ea mohopolo oa ho susumetsa bokong (Shippenberg le Koob 2002; tafole 1). Mefuta ea liphoofolo ea boemo ba ho tlohela / e mpe e kenyelletsa mehato ea mokhoa oa ho fetohela sebakeng (ho e-na le ho rata) ho khaola ka mokhoa o sa tsitsang kapa oa ho itlhahisa ho tsoa taolong e sa lekanyetsoang ea lithethefatsi, ho eketseha ha meputso e sebelisang moputso oa ts'ebetso ea ts'ebetso ea kelello le ts'ebeliso ea ts'ebetso ea kholo ea ts'ebetso ea lithethefatsi le ts'ebeliso ea litheko. boits'oaro bo bobetafole 1). Ts'ebetso e joalo ea ho itaola liphoofolong tse tšepileng e se e bonoa ka koae, methamphetamine, nikotini, heroin le joala (Ahmed le Koob 1998; Ahmed et al a. 2000; O'Dell et al a. 2004; kitamura et al a. 2006; George et al a. 2007; Setšoantšo sa 3). Moetso ona e tla ba karolo ea bohlokoa ea ho hlahloba bohlokoa bo susumetsang ba liphetoho tsa ts'ebetso ea mohanyetsi moputsong oa boko le litsamaiso tsa khatello maemong a boletsoeng ka tlase. Mefuta ea liphoofolo ea mokhahlelo oa ho lebela / ho lebella ('ho lakatsa') ho kenyelletsa ho khutlisetsoa hoa lithethefatsi tse latelang ho felisoa ka mokhoa o fetisisang ke lithethefatsi ka bo tsona, ka litheko tse hokahaneng le lithethefatsi le ho pepesehela khatello ea maikutlo (Weiss et al a. 2001; Shaham et al a. 2003le mehato ea ho itšireletsa nako e telele (tafole 1). Ka ho khutlisetsoa ka matla khatello ea maikutlo, khatello ea maikutlo e matla e ka khutlisetsa boits'oaro ba ho batla lithethefatsi ho liphoofolo tse felisitsoeng. Litekong tse nang le nalane ea ts'ebeliso ea lithethefatsi, ho itšila nako e telele ho ka hlalosoa e le nako kamora hore ho khaotsa ho matla ho nyamele, hangata libeke tse peli ho isa ho tse robeli ka mor'a lithethefatsi.

Setšoantšo sa 3 

Keketseho ea tšebeliso ea lithethefatsi e amanang le ho fihlella le ho itšetleha ka nako e telele. (a) Kameho ea ho fumaneha ha lithethefatsi ka ho kenella ka har'a k'hok'heine ea koae (bolela ± sem). Lifate tsa nako e telele (LgA) (n= 12; mekotla e tlatsitsoeng) empa eseng ka likhokahanyo tse khutšoane tsa (ShA) (n= 12; ho potoloha), ...
Lethathamo 1 

Mehato ea potoloho ea ho lemalla.

3. Ka hare ho system neuroadaptations tlatsong

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 & Esposito 1979). Moputso oa ho hlohlelletsa Brain ho kenyelletsa li-neurocircuitry tse atileng bokong, empa libaka tse tebileng ka ho fetisisa tse hlalositsoeng ke litheko tse tlase haholo li kenyelletsa sehlopha sa methapo ea methapo ea methapo e hokahanyang sebaka sa "" "Vial) se nang le" basal forebrain "Batho ba baholo le Milner 1954). Le ha khatiso e ne e shebane haholo le karolo ea mananeo a hloahloa a monoamine mokokotlong oa medial forebrain, litsamaiso tse ling tseo e seng tsa dopaminergic ka sekhukhung sa medial forebrain li na le karolo ea bohlokoa (Hernandez et al a. 2006).

Mehato ea ts'ebetso ea moputso oa boko nakong ea ho itima lithethefatsi tsohle tse kholo tse nang le bokhoni ba ho itšepa e senotse keketseho ea meputso ea moputso oa boko e lekantsoeng ka moputso o tobileng oa ts'usumetso ea boko (Markou & Koob 1991; Schulteis et al a. 1994, 1995; Epping-Jordan et al a. 1998; Gardner le Vorel 1998; Paterson et al a. 2000). Keketseho ena ea meputso ea meputso e ka bonts'a ho fokotseha hoa ts'ebetso ea li-system tsa neurotransmitter ho mpa ea bohareng le ho kenella phatleng ho kenelletseng litlamorao tse matla tsa lithethefatsi.

Litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso li tsamaisoa ke ts'ebetso ea dopamine (DA), serotonin, li-peptides tsa opioid le li-system tsa γ-aminobutyric acid (GABA) ebang ke ketso tse ikhethileng ho "basal forebrain" (haholo-holo li-bokellase tsa nucleus tsa "main"). amygdala) kapa ka liketso tse sa tsamaisaneng le VTA (Koob & Le Moal 2001; Nestler 2005; Koob 2006). Bopaki bo bongata bo teng ho ts'ehetsa maikutlo a hore tsamaiso ea mesolimbic DA e matlafalitsoe haholo ke lithethefatsi tsa psychostimulant nakong ea ho ipusa le ho fihlela litekanyetso tsohle tsa lithethefatsi tsohle tsa tlhekefetso. Lisebelisoa tsa Serotonin, haholo-holo tse amang serotonin 5-HT1B ts'ebetso ea li-receptor ka har'a li-nucleus accumbens, le tsona li bile le tšusumetso ho litlamorao tse matla tsa lithethefatsi tsa psychostimulant. Li-peptide tsa opioid ka har'a "ventral striatum" li sebelisitsoe hore li buelle litlamorao tse matlafatsang tsa boitaolo ba ethanol, haholo-holo ka litlamorao tsa bahanyetsi ba opioid. Li-receptor tsa μ-Opioid ka har'a li-nucleus tsa li-nucleus le VTA li kenella lipakeng tsa litlamorao tse matlafatsang tsa lithethefatsi tsa opioid. Sistimi ea GABAergic e sebetsa pele ho nako le ka mora nako ea bongolo ho amygdala ka litekanyetso tse tahang, mme bahanyetsi ba GABA ba thibela boitšoaro ba ethanol (bakeng sa litlhahlobo, bona Nestler 2005; Koob 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. Ho theoha ha ts'ebetso ea sistolo ea mesolimbic DA le ho fokotseha ha serotonergic neurotransication ho li-bokono tsa nucleus ho etsahala nakong ea ho tlosoa ha lithethefatsi lithutong tsa liphoofolo (Weiss et al a. 1992, 1996). Lithuto tse entsoeng tsa batho ba lemaletseng lithethefatsi li bontšitse ho fokotseha ho hoholo hoa palo ea DA D2 li-receptors ho batho ba sebelisang lithethefatsi hampe ha li bapisoa le taolo (Volkow et al a. 2002). Ntle le moo, ba hlekefetsang koae ba fokotsa koae ea DA ho arabela phepheng ea pharmacological ka moriana o hlasimollang (Volkow et al a. 1997; Martinez et al a. 2007). Phokotso ea palo ea DA D2 li-receptors, hammoho le ho fokotseha hoa ts'ebetso ea dopaminergic, ts'ebelisong ea koae, nikotine le bokhoba ba joala, li baka ho fokotseha hoa kutloisiso ea lipotoloho tsa meputso ho susumetsoa ke li-femele tsa tlhaho (Volkow le Fowler 2000; Martin-Solch et al a. 2001). Liphumano tsena li fana ka maikutlo a phokotso e akaretsang ea kutloelo-bohloko ea karolo ea DA ea ho potoloha ha meputso ho batho ba khothalletsang tlhaho le lithethefatsi tse ling ho batho ba lemaletseng lithethefatsi.

Bopaki ba bohlokoa ba kutloelo-bohloko ea methapo ea phetisetso ea li-receptor ka har'a li-nucleus bokellwang, ho kenyelletsa ts'ebetso ea adenylate cyclase, protheine kinase A, cyclic adenosine monophosphate Karolo-e tlamang ea protheine (CREB) le ΔFosB, e hlokometsoe nakong ea tsamaiso ea lithethefatsi tsa tlhekefetso (Self et al a. 1995; Nye & Nestler 1996; Shaw-Lutchman et al a. 2002; Nestler 2004;; bona Nestler 2008), mme karabelo ea ΔFosB e hokahantsoe ho emela phetoho ea neuroadaptive e eketsang nako e telele ea ho ithibela nako e telele (Nestler le Malenka 2004).

Ho itšetleha ka joala haesale ho amahanngoa le liphetoho ho Gabaergic neurotransmission. Motsoako o sa feleng o fokotseha GABAA mosebetsi oa receptor (Morrow et al a. 1988) le keketseho ea tokollo ea GABA maemong a mahareng a khubung e bohareng ea amygdala (Roberto et al a. 2004). Tlhokomeliso e tekanyetso e tlase haholo ea GabaA agonist muscimol, ha e kenella ka har'a khubu ea methapo ea amygdala, thibela ts'ebetso ea "ethanol" e amanang le ho tlosoa ho hoholo e fana ka maikutlo a hore liphetoho tsa tšebetso ea GABAergic karolong e bohareng ea amygdala li ka ba le bohlokoa bo itseng ba ts'usumetso ho itšetleha ka ethanol (Roberts et al a. 1996).

Kahoo, ho fokotseha ha neurotransication ea moputso ho ntlafalitsoe hore ho bonts'e neuroadaptation e ka hare ho sistimi mme e be le seabo haholo ho boemo bo bobe ba ho susumetsoa bo amanang le ts'ebeliso e mpe ea lithethefatsi. Ts'ebetso ea meputso e fokotsehileng le eona e kanna ea tsoela pele ka mefuta ea liphetoho tse telele tsa biochemical tse tlatsetsang ho tleleniki ea bongaka ea ho tela le ho ba kotsing ea ho khutla. Mohlala, ha ts'ebetso ea CREB le c-fos tse bakoang ke ts'ebetso ea ts'ebetso ea lits'ebetso tsa DA li phela hakhutšoanyane, liphetoho tse telele tsa lintlha tse ling tse kang ΔFosB li kanna tsa nka libeke (Nestler et al a. 2001).

4. Pakeng tsa-system neuroadaptations tlatsong

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, khubu ea bethe ea stria terminalis le sebaka sa phetoho ho medial (khetla) subregion ea li-nucleus accumbens. 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 a. 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 a. 2004).

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 tenang 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 arolelanoang ke 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 a. 1984; Koob et al a. 1994; Merlo-Pich et al a. 1995; Delfs et al a. 2000; Rasmussen et al a. 2000; Olive et al a. 2002). Ho itokolla ka matla lithethefatsing tsohle tsa tlhekefetso ho hlahisa boemo bo kang ba ho tšoenyeha bo ka khutlisoang ke bahanyetsi ba CRF, 'me bahanyetsi ba CRF le bona ba thibela ho eketsa lithethefatsi tse amanang le ts'ebeliso (tafole 2).

Lethathamo 2 

Karolo ea CRF ho itšetleha (nt, e sa lekoa; CeA, khubu ea khubu ea amygdala).

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 (Merlo-Pich et al a. 1995; Olive et al a. 2002; Funk et al a. 2006; tafole 2). Ts'isinyeho ea lits'ebetso tsa CRF ea boko e fokotsoa ka tlase ho boits'oaro bo ntlafalitsoeng joalo ka boits'oaro le taolo e ntlafalitsoeng ea ethanol e amanang le ho tlosoa hoa ethanol. Ho tšehetsa khopolo ena, bahanyetsi ba CRF receptor ba sa ikhetheng ba CR-helical CRF9-41 le d-Phe CRF12-41 (tsamaiso ea intracerebroventricular) e fokotsa boitšoaro bo ka bobeli ba ethanol bo khathollang joalo ka boits'oaro le boitšoaro bo itlhommeng pele ho liphoofolo tse its'epileng (Baldwin et al a. 1991; Rimondini et al a. 2002; O'Dell et al a. 2004; Valdez et al a. 2004). Ha e kenngoa ka kotloloho mokokotlong oa bohareng ba amygdala, li-antFonist tsa CRF receptor le tsona li latsoa boits'oaro bo kang ho tšoenyeha (Rassnick et al a. 1993) le tsamaiso ea ethanol literekeng tse itšetlehileng ka ethanol (Funk et al a. 2006, 2007; Setšoantšo sa 4). 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.

Setšoantšo sa 4 

(a) Litlamorao tsa CRF1 receptor small-molecule antagonist R121919 on ethanol self-management in wate (lithibelo tse tlatsitsoeng) le likhoto tse sa its'epahallang (tse bulehileng). Ho itšetleha ka Ethanol ho bakiloe ke ho pepesetsoa ha mongobo oa ethanol libeke tse 'ne. Liphoofolo ...

Li-injection tsa systemic tsa molek'hule-CRF e nyane1 bahanyetsi ba boetse ba thibela likarabo tse kang tsa ho tšoenyeha le tšebeliso e matla ea "ethanol" e amanang le ho ikhula ho matla (Knapp et al a. 2004; Overstreet et al a. 2004; Funk et al a. 2007). Litšebelisano tse tšoanang le CRF li hlokometsoe ka ts'ehetso e amanang le phihlello e atolositsoeng ea ho itaola kahare ho cocaine (Specio et al a. 2008), nicotine (George et al a. 2007) le heroin (TN Greenwell, CK Funk, P. Cotton, HN Richardson, SA Chen, K. Rice, MJ Lee, EP Zorrilla & GF Koob 2006, liphetho tse sa phatlalatsoang).

Le ha e se batho ba ntlafalitsoeng hantle, li-antadonaline (NA) tse sa sebetseng tse thibelang ho ts'oaroa ke khatello ea maikutlo le lithibelo tse tlisoang ke ho khaotsa opiate hape li thibela tšebeliso e mpe ea lithethefatsi tse amanang le ts'epo ea ethanol (Walker et al a. 2008), cocaine (Wee et al a. 2008) le li-opioid (TN Greenwell, CK Funk, P. Cotton, HN Richardson, SA Chen, K. Rice, MJ Lee, EP Zorrilla & GF Koob 2006, liphetho tse sa phatlalatsoang). Ntlha ea bohlokoa bakeng sa tse ngata tsa litlamorao hape ke amygdala e atolositsoeng empa boemong ba mokokotlo oa bethe oa stria terminalis.

Sebopeho se matla sa karabelo ea methapo ea khatello ea kelello phephetsong se bontšoa ke tšebelisano e phatlalalitsoeng ea methapo ea methapo ea methapo le tsamaiso ea methapo e kholo ea methapo. E hlalositsoe e le sistimi ea ho fepa pele maemong a mangata (mohlala, lipotong le matsohong a basal), CRF e kenya ts'ebetsong NA le NA ka lehlakoreng le leng e etsa CRF (Koob 1999). Lits'ebetso tse joalo tsa phepelo ea lijo li ile tsa nkuoa hape hore li na le moelelo o matla oa ts'ebetso bakeng sa ho matlafatsa karabelo ea sebopuoa phephetsong ea tikoloho, empa mochini o joalo o kanna oa ba tlokotsing ea mafuKoob 1999).

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. Ma-agonist a κ-Opioid ke a ferekanyang (Pfeiffer et al a. 1986; naheng et al a. 2008), le ho khaotsa ho sebelisa koae, li-opioid le ethanol ho amahanngoa le dynorphin e ntseng e eketseha ho li-nucleus accumbens le / kapa amygdala (Rattan et al a. 1992; Spangler et al a. 1993; Lindholm et al a. 2000). Motho ea qhekellang o thibela ho itlopa joala ho tlisoang ke ho tlosoa hoa ethanol le ho its'epaha (Walker & 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 (naheng et al a. 2008).

Bopaki bo bohlokoa bo boetse bo fana ka maikutlo a hore ts'ebetso ea ts'ebetso ea neuropeptide Y (NPY) karolong e bohareng ea amygdala e ka thibela likarolo tsa ts'usumetso ea ho ts'epahalla ho amanang le taolo ea ethanol e sa foleng. NPY e laetsoeng intracerebroventricularly e thibela litlamorao tse kang tsa ho tlosoa ho ethanol (NG Gilpin 2008, puisano ea botho) mme e thibela ts'ebetso e eketsehileng ea lithethefatsi e amanang le ts'ehetso ea ethanol (Thorsell et al a. 2005a,b). Ho kenella ka NPY ka ho toba kahareng e bohareng ea amygdala (Gilpin et al a. 2008) le polelo e ntlafalitsoeng ea vaerase ea NPY karolong e bohareng ea amygdala hape e thibela tšebeliso e matla ea lithethefatsi tse amanang le ts'epahalo ea ethanol (Thorsell et al a. 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 5). Ho hula ka matla le hona ho ka eketsa ho lokolloa ha NA ka mokokotlong oa bethe ea stria terminalis le dynorphin ho li-nucleus tsa li-nucleus, tseo ka bobeli li ka tlatsetsang boemong bo sithabetsang ba maikutlo bo amanang le ts'episo (Setšoantšo sa 5). 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 lits'ebetso tsa khatello ea kelello (CRF, NA, dynorphin) e kopantsoeng le ho inactivation ea methapo ea khatello ea khatello ea kelello (NPY) ho amygdala e atolositsoeng e ka etsa hore ho be le khatello e matla ea maikutlo e amanang le ho lemalla. 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 5 

Neurocircuitry e amanang le litlamorao tse matla tsa matlafatso ea lithethefatsi tsa tlhekefetso le matlafatso e mpe ea ho ts'epa le kamoo e fetohang phetohong e tsoang ho (a) lithethefatsi tse sa its'epahalleng ho ea ho (b) ts'ebeliso e mpe ea lithethefatsi. Lintho tsa bohlokoa tsa ...

Neuroadaptations e hlalositsoeng kaholimo e kanna ea tlatsetsa bothateng bo matla ba ho lemalla lithethefatsi, e leng ho oela hape, moo batho ba lemaletseng lithethefatsi ba khutlang nako e telele ka mor'a hore ba khaotse haholo. Mokhahlelo oa ho itšunya-tšunya / ho lebella (ho lakatsa) moetlo oa bokhoba o sa le o hlalositsoe e le ntho ea bohlokoa ea ho khutlela ho batho hape o hlalosa tlhekefetso e le bothata bo sa foleng ba ho khutla hape. Ho lakatsa ho ka hlalosoa e le khopotso ea litlamorao tse tlisoang ke lithethefatsi ntle le maikutlo a fosahetseng.

Ho tsoa ho sebopeho se ka hare ho sistimi, liphetoho tse tsamaisong ea dopaminergic tse tsoelang pele hantle haholo ho tlosa ho ts'oaroa ho matla ho kentse letsoho ho lakatseng le ho kenyelletsa sensorization ea psychomotor le ho eketseha ha litšusumetso tsa ts'usumetso (Robinson le Berridge 1993), e fokotseha ho DA D2 receptors (Volkow et al a. 2002) le liphetoho tse sa khaotseng tsa phetiso ea matšoao tse ka tlatsetsang ho dysphoria e sa foleng (ts'ebetso ea CREB) le maikutlo a ho lakatsa (ΔFosB; Nestler 2005). Bopaki bo bonts'ang maemo a tlase a khethiloeng sechabeng nakong ea ntšetso-pele bo bontšitse ho ba kotsing ea ho sebelisa k'hok'heine 'me e fokolitse haholo DA D2 li-receptors li fana ka bopaki bo susumetsang ba hore molumo oa dopaminergic o ka laola ntlha e behiloeng ka ntle ho ho itlhahisa ho matla lithethefatsing tsa tlhekefetso (Morgan et al a. 2002).

Ho tsoa ponong ea li-neuroadaptations tse lipakeng tsa system, lits'ebetso tsa khatello ea kelello tse boletsoeng kaholimo li haptjoa ho kenya letsoho ka kotloloho moetlong oa ho itšunya-tšunya / ho lebella (ho lakatsa) ka boiketsetso bo tsoetseng pele. Ho thibela pelehi ho ka hlalosoa e le ho phehella ha boemo bo bobe ba maikutlo nakong e fetileng ho tlosoa ho hoholo. Mmuso ona ho batho o tšoauoa ka dysphoria ea boemo bo tlase, likhathatso tsa boroko le ho eketseha ha maikutlo ho sithabetsang le bohloko. Ho liphoofolo, ho itšila nako e telele ho bontšoa ke ho ata ha khatello ea maikutlo le ho eketseha hoa lithethefatsi ho tloha nako e telele kamora ho itokolla ho matla, tseo ka bobeli li hlokometsoeng lithutong tsa joala (Valdez le Koob 2004). E sebelisa CRF joalo ka mohlala ho tsilatsileng, "CRF" e ts'eletsoa ho kenya letsoho maemong a sithabetsang a maikutlo a fanang ka motheo oa ho batla lithethefatsi (Valdez et al a. 2002; Valdez le Koob 2004).

5. Ts'ebetso ea mohanyetsi, ntlha ea moputso le allostasis

Nts'etsopele ea boemo ba maikutlo bo ferekanyang bo bakang ts'ehetso e mpe ea tahi e hlalositsoe e le 'lehlakore le lefifi' la tahi (Koob & Le Moal 2005, 2008) hape ho nahanoa hore ke mohato oa b-tšebetso ea matla a hedonic e tsejoang e le mohanyetsi ha morero o felisoa. Boemo bo bobe ba maikutlo bo kenyelletsang nako ea ho khaola / e mpe e hlalositsoeng kaholimo e na le lintlha tsa bohlokoa tsa susumetso, joalo ka ho se ts'oarehe ho sa feleng, bohloko ba maikutlo, mala, dysphoria, alexithymia le tahlehelo ea meputso ea tlhaho, 'me e tsebahala ka liphoofolo ka ho eketseha ha moputso. Monyako nakong ea ho khaola lithethefatsi tsohle tse kholo tsa tlhekefetso. Mekhahlelo e 'meli e kenyellelitsoe ho theha motheo oa neurobiological bakeng sa ts'ebetso ea b: tahlehelo ea ts'ebetso lits'ebetsong tsa moputso (hare-system neuroadaptation) le ho hira khatello ea khatello ea kelello kapa li-anti-moputso (pakeng tsa sistimi neuroadaptation; Koob & Palesa 1988; Koob & 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 Moal 2008). Ha ts'ebetso ea ho ts'epahalla le ho tlohela e ntse e eketseha, litsamaiso tsa khatello ea kelello tse kang CRF, NA le dynorphin lia khethoa (Setšoantšo sa 5), e hlahisa linaha tse khelohelang kapa tse kang khatello ea maikutlo (Aston-Jones et al a. 1999; Nestler 2001; Koob 2003). 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 bokhoba ba tahi (Setšoantšo sa 5).

Sehlooho se akaretsang sa maikutlo se qholotsoang mona ke hore ho lemalla lithethefatsi ho emela phomolo e nang le methapo e laolang homeostatic e laolang boemo ba maikutlo ba phoofolo. Leha ho le joalo, maikutlo a hore bokhoba ba lithethefatsi bo emela karohano e bonolo le homeostasis ha ea lekana ho hlalosa likarolo tsa bohlokoa tsa bokhoba. Bokhoba ba lithethefatsi, bo tšoanang le mafu a mang a sa foleng a 'mele a joalo ka khatello e phahameng ea mali e ntseng e mpefala ha nako e ntse e ea, bo angoa ke tšusumetso e kholo ea tikoloho mme bo siea le tšenyo e setseng e lumellang' tšebeliso e mpe 'hape le likhoeli esita le lilemo kamora ho khaotsoa le ho tsuba. Litšobotsi tsena tsa bokhoba ba lithethefatsi ha li bolele feela hore ke taolo ea homeostatic ea tšebetso ea hedonic le mosebetsi oa botsamaisi, empa ho fapana le ho ikarola ha matla le homeostasis ea lits'ebetso tsena, tse 'nileng tsa bitsoa allostasis.

Allostasis, e neng e entsoe ka morero oa ho hlalosetsa moriti o sa khaotseng oa tšebetso ea boithabiso le ea boikemelo, e hlalosoa e le 'botsitso ka phetoho' le phetoho e tsoelang pele ea litekanyetso tsohle ho leba sebakeng se secha sa (Sterling & Eyer 1988). Kahoo, a 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). Kahoo, mochine oa 'mele o lumellang likarabo tse potlakileng ho phephetso ea tikoloho ho fetoha enjine ea mafu a kelello haeba nako e lekaneng kapa lisebelisoa li sa fumanehe ho koala karabelo.

Likarolo tse peli li reretsoe ho fetolela phephetso ho bokaholimo bo hlahisoang ke lithethefatsi tsa tlhekefetso ho etsa tšebetso e tšoanang le ena: (i) ho fetisa mehopolo le lipotoloho (ii) ho hira methapo ea boko e khahlanong le moputso kapa khatello ea khatello ea kelello (Setšoantšo sa 5). Liphephetso tse phetoang, joalo ka lithethefatsi tsa tlhekefetso, li lebisa boitekong ba kelello ka liphetoho tsa lisele, tsa cellular le tsa neurocircuit 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 bitsoa naha e matla. Mmuso ona o emetse motsoako oa sebaka se phahameng sa meputso e sa feleng se tsoang mohanyetsing, pono ea sepheo ka ho fokotseha ha lipotoloho tsa meputso le ho hira litsamaiso tse khahlano le moputso, tseo ka bobeli li lebisang ho qobelloang ha ho batla lithethefatsi le ho ts'oara lithethefatsi. Mokhoa ona o fetoloa joang ke lits'ebetso tse ling tsa maikutlo tse amanang le boko tse fumanehang ho amygdala (mohlala, vasopressin, orexin, nociceptin), moo merero e atolositsoeng ea amygdala ho fetisa maikutlo a pherekano, le hore na batho ka bomong ba fapana joang ka tekanyo ea molek'hule le liphatsa tsa lefutso ho fetisa moralo. li-circuits tsena e ntse e le liphephetso bakeng sa lipatlisiso tsa nako e tlang.

lumela hore baa fokola

Sengoli se rata ho leboha Mike Arends ka thuso ea hae e ikhethang mabapi le ho hlophisa buka e ngotsoeng ka letsoho. Patlisiso e ts'ehelitsoe ke National Institutes of Health Grants AA06420 le AA08459 ho tsoa ho 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 phatlalatso che. 19396 e tsoang ho TheHTMLps Research Institute.

Mongolo o botlaaseng ba leqephe

Tlatsetso e le 'ngoe ea 17 Tlatsong ea Seboka sa Puisano' Mokhoa oa ho ba le bothata ba ho lemala: lits'ebeletso tse ncha '.

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Lingoloa tse tsoang ho Philosophical Transaction of the Royal Society B: Litsebi tsa baeloji li fanoe mona ka mokhoa o motle oa Mokhatlo oa Royal