Ho imeloa kelellong le ho lemalla: monehelo oa tsamaiso ea corticotropin e lokollang (CRF) tsamaiso ea neuroplasticity (2012)

Front Mol Neurosci. 2012; 5: 91. E hatisitsoe Inthaneteng 2012 September 6. doi:  10.3389 / fnmol.2012.00091

Karolina L. Haass-Koffler1,2 'me Selena E. Bartlett1,3,*

inahaneloang

Corticotropin releasing factor (CRF) e bonts'itsoe ho susumetsa liphetoho tse fapaneng tsa boitšoaro tse amanang le ho ikamahanya le khatello ea maikutlo. Ho senyeha ha tsamaiso ea CRF ka nako efe kapa efe ho ka lebisa ho mafu a mangata a kelello, ho kenyeletsa le mathata a tšebeliso ea lithethefatsi (SUDs). CRF e amahantsoe le matlafatso ea ts'ebeliso ea lithethefatsi. Lingoliloeng tse pharalletseng li bonts'itse CRF ho bapala karolo ea bohlokoa mekhoeng ea limolek'hule e lebisang keketseho ea ts'ebetso e tlisoang ke ho khutla ho SUDs. Sisteme ea CRF e na le karolo e kholo ho SUDs. E ntlafatsa litlamorao tse mpe tsa lithethefatsi tsa tlhekefetso mme hape e ikarabella ho phello ea neuroplasticity e tsoang ho lithethefatsi nakong ea ho tlohela. Re hlahisa tlhahlobisong ena likarolo tsa boko le li-circuits moo CRF e hlahisoang mme re ka nka karolo ho ts'ebelisong e mpe ea lithethefatsi. Kamora nako, re leka ho sekaseka karolo ea ho fetola sistimi ea CRF e le leano la kalafo le ka khonehang la ho phekola khatello ea maikutlo bo bakoang ke matlafatso e matla ea lintho tsa tlhekefetso le matlafatso a fosahetseng a hlahisoang ke ho tlohela.

Keywords: neuroplasticity, ho lemalla, corticotropin ho lokolla sistimi, ethanol, ho tšoenyeha, khatello ea maikutlo

Selelekela

Bokhoba ba lithethefatsi ke boemo bo sa foleng bo khetholloang ka linako tsa ho itlosa bolutu le ho khutlela morao. Litlamorao tsa lithethefatsi tsa tlhekefetso holima ts'ebetso ea boko li hlahlobisitsoe haholo ka sepheo sa ho nts'etsapele mekhoa ea phekolo e ka thibelang ho khutla hape ea nolofalletsa kalafo ea mathata a ts'ebeliso ea lithethefatsi (SUDs). Lingoliloeng tse pharalletseng li bontšitse hore lithethefatsi tse lemalloang li ama lits'ebetso tse laolang tsela ea meputso (mesolimbic dopaminergic pathway), mekhoa ea ho ithuta le ea memori (hippocampus), maikutlo (amygdala), le mesebetsi ea kutloisiso (preortalal cortex). Litlamorao tse matlafatsang tsa tlhekefetso ea lithethefatsi li hlahisitsoe ke liketso tse tsamaisong ea maoto le litloaelo tse susumetsang, maikutlo le boits'oaro (Rezayof et al., 2002; David et al., 2008; Martin et al., 2008; Nielsen et al., 2011; Xue et al., 2012) le bakeng sa litlhahlobo bona (Koob, 1992;; Pierce le Kumaresan, 2006; Feltenstein 'me ua bona, 2008). Haholo-holo, phetoho ea ts'ebetso ea moputso (Wise, 1998, 2005) e fumanoe e le sesosa se bohlokoa se lebisang keketseho ea monyetla oa ho khutla (Koob le Le Moal, 1997; E-et et al., 1999; Koob et al., 2004;; Everitt le Robbins, 2005). Nts'etsopele ea li-SUD ke tsoelo-pele e qalang ka ho pepesehela lithethefatsi ebe e fela ka ts'ehetso ea 'mele le ea kelello.

Leha lintho tsa tlhekefetso li na le mekhoa e fapaneng ea ts'ebetso, ho pepesetsoa khafetsa ho bontšitsoe ho lebisa ho liphetoho tse tšoanang tsa neural. Ho lemalla sehlopha sa lithethefatsi ho hlalositsoe e le mokhoa oa ho ithuta. Batho ka bomong ba ithuta ho tloaelana lipakeng tsa litlamorao tse tlisoang ke lithethefatsi le mekhoa ea tikoloho e rerang ho ba teng ha lithethefatsi. Li-Neuroadaptations libakeng tse amanang le ho ithuta le ho hopola (hippocampus le amygdala) lia ameha kamora ketsahalo e le 'ngoe ea ts'ebeliso ea lithethefatsi efe kapa efe ka ho susumetsa phetiso ea synaptic. Ftšebeliso e mpe ea lithethefatsi tse sa foleng, ho batla ho phetheselang le ho se laoleheng ho lebisa ho liphetoho tsa nako e telele ho polasetiki ea synaptic, joalo ka liphetoho ho synaptic solidth.

Lithuto tsa batho (Gawin le Kleber, 1986; Wallace, 1989) le liteko ka mehlala ea boitšoaro (Thatcher-Britton le Koob, 1986; Piazza et al., 1990; Li-Goers le Guerin, 1994; Kreibich et al., 2009) ba supile khatello ea maikutlo e le sesosa sa bohlokoa ts'ebetsong ea bokhoba ba lithethefatsi, ho kenyelletsa ho khutlisa hape. Corticotropin releasing factor (CRF) e kentse letsoho ho neuroendocrine le likarabo tsa boitšoaro ho khatello ea maikutlo (Britton et al., 1982; Koob le Bloom, 1985). E bontšitsoe hore e qalile nakong ea ho khutlisetsoa hoa lithethefatsi tse bakang khatello ea maikutlo, moo e nkang ts'ebetso ea ho tsamaisa ts'ebetso hape le ho eketsa matšoenyeho nakong ea ho ikhula ho matla le ho sa foleng (Shaham et al., 1995; Ambrosio et al., 1997; Koob, 1999) 'me u bone (Sarnyai et al., 2001; George et al., 2011) bakeng sa tlhahlobo e batsi.

Liphetoho tsa li-neuroplastic tsa CRF tse hlahisitsoeng ke CRF li ithutile ka bobeli makaleng a mesolimbic bokong bo kenyelletsang sebaka sa "ventral tegmental" (VTA) le nucleus accumbens (NAcc) (Ungless et al., 2003;; Wang et al., 2007a; Hahn et al., 2009) hape le libakeng tsa boko tse amanang le maikutlo, joalo ka amygdala (Fudge le Emiliano, 2003; Pollandt et al., 2006; Fu et al., 2007; Kash et al., 2008; Francesconi et al., 2009).

Leha ho na le lipatlisiso tse pharaletseng tse tšehetsang karolo ea CRF bokhobeng ba lithethefatsi, ho nka karolo ha CRF ho polasetiki e khothalletsoang ke lithethefatsi tse lebisang ho oeleng hape ha ho a ka ha thibeloa.

Tlhahlobo ena e tla leka ho hlahloba lipatlisiso tsa morao-rao mabapi le karolo ea CRF le tšebelisano ea eona le polasetiki e kopantsoeng le lithethefatsi. Vta le amygdalar nuclei moo CRF e hlahisoang haholo e tla hlalosoa. Re tla tšohla hore na CRF e thusa kapa e thibela matla a synaptic ho tsoa maemong a basal. Kamora nako, re tla leka ho kenyelletsa liphetoho tsa neurobiological tse hlahisoang ke tšebelisano ea lintho tse sebelisang tlhekefetso ka khatello ea maikutlo ho hlahloba litheko tse ling tsa lithethefatsi bakeng sa kalafo ea liteko ho thibela ho khutla le ho tsamaisa kalafo ea li-SUD.

Mathata a ts'ebeliso ea lithethefatsi (SUDs) le khatello ea maikutlo

Li-SUD ke boemo bo sa foleng le bo bo khutlang bo khetholloang ke takatso e matla ea ho sebelisa lithethefatsi nakong ea ho tlohela. Ts'ebetso ena ea ho lakatsa e lebisa moetlong ho tloha tšebelisong ea tšusumetso ea pele ho ea tšebelisong e qobelloang le tloaelo ea ho etsa tšebeliso e bakang tahlehelo ea taolo ea ho fokotsa ts'ebeliso le ho se khonehe ha morao ho fetola tloaelo e tsoetseng pele ha nako e ntse e feta. E 'ngoe ea liqholotso tse kholo lipatlisisong tsa bokhoba ba lithethefatsi e bile ho hlakisa litsela tse lebisang tahlehelong ea taolo ea ts'ebeliso ea lithethefatsi le sepheo sa ho khutla hape.e (Koob le Le Moal, 1997). As e hlalositsoeng ke Mohlala oa Ts'ebetso ea Mohanyetsi, tšebeliso e pheta-phetoang ea lintho tse lemalloang e fetola lipotoloho ka ho fokotsa maemo a thabo e kholo le ka ho eketsa boemo bo latelang bo sa thabiseng. Kamora ho khaotsa ho pepesetsoa lithethefatsi tse lemalloang, ho ba le maikutlo a khothalletsang a hanyetsang litlamorao tsa lithethefatsi - matšoao a ho tlohela. Phokotso ea matšoao a bang teng ka lebaka lena e ka emela ntlafatso e mpe. Phokotso ea boemo bo sa thabiseng ba matšoao a ho khaotsa ho fetoha ts'ebetso e kholo ts'ebetsong e tsoelang pele ea lithethefatsi. Ka pono e nolofalitsoeng ea dopamine khopolo (O bohlale, 1978, 2008;; Berridge le Robinson, 1998;; Everitt le Robbins, 2005; Diana, 2011), ts'ebetso e matla ea euphoric e fumanoeng ke ho itlopa joala e emetse ts'ebetso ea ts'ebetso ea dopaminergic, ha karolo e mpe e hlahisoang ke nako ea ho khaola e tšoailoe ke phokotso ea ts'ebetso ea dopamine (Tomkins le Barekisi, 2001). Kenyelletso ea chefo e sebetsang (Weiss le Koob, 2001), e amanang le mmuso o sa thabiseng oa ho ntša o tlisoang ke ho hira neurotransmitter ea khatello ea maikutlo, CRF, e ile ea holisa le ho feta dopamine khopolo joalo ka ha ho sebetsa le tlatsong.

Corticotropin releasing factor (CRF) sistimi

CRF, eo hape e tsejoang ka hore ke corticotropin Release hormone (CRH), e bontšitsoe ho kenya liphetoho tse fapaneng boits'oaro bo amanang le ho ikamahanya le khatello ea maikutlo. Ho felloa ke matla ha tsamaiso ea CRF ka nako efe kapa efe ho ka lebisa ho mafu a mangata a kelello a kang khatello ea maikutlo, ho qhekella ho sa feleng, khatello ea maikutlo le khatello ea kelello ka mor'a lefu la kelello.s (Cole et al., 1990; Sarnyai et al., 1992, 2001; Cador et al., 1993; Koob le Kreek, 2007; Koob le Le Moal, 2008a). Matšoenyeho a susumetsoang ke Footshock a bontšitsoe hore a sebetsa hantle ho khothalletseng ho khutlisetsa joala hape (Le et al., 1998, 2000; Gass le Olive, 2007; Richards et al., 2008), nikotine (Buczek et al., 1999), koae (Erb et al., 1996), opiate le psycostimulants (Lu et al., 2003) le heroin (Shaham et al., 1997) ho batla. Ka ho khetheha CRF e amahantsoe le ho khutlisetsoa hoa lithethefatsi (Shaham et al., 1997; Le et al., 2002; Liu le Weiss, 2002; Funk et al., 2006). CRF e boetse e bontšitsoe ho hlahisa mekhoa e ts'oanang le ho tšoenyeha nakong ea ho khaola ethanol e sa foleng (Baldwin et al., 1991; Hahahahahhaha et al., 2004) hape o ka ikarabella bakeng sa ho se sireletsehe ho tsietsing le ho khutla hape.

The Sistimi ea CRF e na le ligands tse 'ne: CRF, urocortin (UCN) (Vaughan et al., 1995) 1, 2, le 3, li-receptor tse peli tsa G-protein-coupled (GPCR), CRF-receptor 1 (CRF-R1) le CRF-receptor 2 (CRF-R2), hammoho le protheine e patiloeng ea CRF (CRF- RXNUMX). BP); sheba Lethathamo Table11 le (Bale le Vale, 2004) bakeng sa tlhahlobo ea tsamaiso ea CRF.

Corticotropin Release Factor (CRF) sistimi.

lebitsoTypeReceptor e tlamangPolelo ea CNSPolelo ea PeripheralHo kenya letsoho karabong ea khatello ea maikutlo
CRFligandEA-R1> CRF-R2synthesized ho PVN e tsamaisoa ka bongataka mpeng, letlalong, lehlohlo la adrenalMokokotlo oa HPA: e etsa hore ho lokolloe ACTH kantle ho axis ea HPA: ho laola likarabo tsa boits'oaro le boitšoaro
CRF-R1mokamoli-CC, CB, MS, HIP, VTA, amygdala, pituitaryβ li-pancreas tsa selemokhathala
CRF-R2mokamoli-RN, LS, HY, CPpelo, GI, lung, mesifa ea masapo, vasculatureanxiogenic / anxiolytic
CRF-BPprotheine e tlamang-CC, HY, amygdala, VTAPlasma, mokelikeli oa amniotic, placenta, gland ea pituitary, sebetePeriphery: neutralates CRF CNS: e sa thibeloe
UCN 1ligandCRF-R1 / CRF-R2EWGI, testis, myocyte ea pelo, thymus, letlalo, spleenPeriphery: o phahamisitsoe ke ho hloleha ha pelo (Wright et al., 2009) CNS: fetisetsa phetisetso e fetelletsang ea glutamatergic synaptic (Liu et al., 2004)
UCN 2ligandCRF-R2HY, tsamaiso ea kelello, lesapo la mokokotlopelo, lisele tsa mali, tšoelesa ea adrenaltaolo e bohareng ea boitaolo le takatso ea lijo (Reyes et al., 2001) phapang ea botona le botšehali maemong a tepelletsang joaloka (Chen et al., 2006)
UCN 3ligandCRF-R2HY, amygdalaGI, manyemematla homeostasis (Li et al., 2007) litlamorao tse tšoenyang haholo (Valdez et al., 2003)

CeA, khubu ea bohareng ba amygdala; CB, cerebellum; CC, cortex ea likhoerekhoere; CP, choroid plexus; EW, litopo tsa sele ea Edinger Westphal nucleus; GI, pampitšana ea ka mpeng; HIP, hippocampus; HY, hypothalamus; LS, hamorao septum; MS, medial septum; OLF, sebaka sa likotsi; PVN, motsoako oa "patothricular" oa "hypothalamus"; RN, raphe nuclei.

 

Corticotropin Release Factor (CRF) sistimi.

Pele e ne e tsebahala e le sesosa sa hypothalamic se ikarabellang bakeng sa ho tsosa secretion ea adrenocorticotropic hormone (ACTH) ho tsoa mokhatlong oa anterior (Guillemin le Rosenberg, 1955; Saffran et al., 1955) moo e eketsang synthet ea glucocorticoid le secretion for the adrenal cortex (Turnbull le Rivier, 1997). Lebitso la lona le thehiloe lilemo tse mashome a mararo pele le tsejoa ka biochemical ka li 1980's (Vale et al., 1981) ha e ntse e tsejoa ka mofuta oa eona Setsing sa Naha sa Tlhahisoleseling ea Biotechnology (NCBI) ke CRH. Ke peptide ea 4.7-kilo-Dalton (kDa) mme e na le masala a 41-amino acid. Neurosecretory neurons ea paraventricular nucleus (PVN) ea hypothalamus e hlophisa CRF (Meloni et al., 2005). CRF e ntšoa ka har'a methapo ea mali e tsamaeang le setho sa methapo ea mali ho leba gland ea ka ntle moo e hohelang ho tsoa hoa ACTH tsamaisong ea kemiso. Mokokotlo oa hypothalamic-pituitary-adrenal (HPA) o laoloa ke karabo e mpe e tsoang ho li-glucocorticoids tse sebetsang ka li-receptor tsa glucocorticoid ka ho khetheha ho PVN le hippocampus. CRF e boetse e hlahisoa kantle ho axis ea HPA ho laola likarabo tsa boits'oaro le boitšoaro ho bahatelli (Palkovits et al., 1983; Swanson et al., 1983) ho kenyeletsoa ho khutlisetsoa ha khatello ea maikutlo ka lebaka la khatello ea maikutlo.

CRF e arabella likarabo tsa khatello ea 'mele ka ho kenya tšebetsong CRF-R1 le CRF-R2, e ajoang ho potoloha le bokong (De Souza, 1995; Bale le Vale, 2004). Ho lumeloa hore tlamo ea CRF ho CRF-Rs ke mochini oa mehato e 'meli. N-terminus ea receptor qalong e tlama ho C-terminus ea CRF, e qalang ho hlophisa botjha ha receptor (Grace et al., 2007). CRF N-terminus e ikopanya le libaka tse ling tse fumanehang ho receptor ho qala ho saena hoa cellular (Vale et al., 1981; Rivier et al., 1984) 'me ka hona kenya ts'ebetso ea protheine ea G (Nielsen et al., 2000; Nete ​​et al., 2004; Rijkers et al., 2004; Yamada et al., 2004; Hoare, 2005). Sisteme ea CRF e na le li-peptide tse ling le "HomF" e hlophisitsoeng hantle. UCN 1 e bonts'a boits'oaro ba 45% ba tatellano le CRF mme e amana le kamano e phahameng ho bobeli ba CRF receptor subtypes (Perrin et al., 1995), athe CRF e amana haufi le CRF-R1 (Vaughan et al., 1995; Burnett, 2005). UCN 2, e boetse e tsejoa ka hore ke peptide e amanang le khatello ea maikutlo, le UCN 3, eo hape e tsejoang ka hore ke stresscopin e tlama ka kotloloho ho CRF-R2 (Hsu le Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001).

CRF-R1 e na le masalla a 415 amino acid mme e hlahisoa ho potoloha le ho CNS (Chang et al., 1993; Chen et al., 1993; Vita et al., 1993; Potter et al., 1994; Tsai-Morris et al., 1996; Sanchez et al., 1999; Van Pett et al., 2000). Matšoenyeho a sa feleng a kopantsoeng le ts'ebetso ea CRF-R1 ke CRF e amahantsoe le nts'etsopele ea mathata a ho tšoenyeha (Arborelius et al., 1999); Barekisi ba CRF-R1 ba bontšitsoe ho fokotsa boitšoaro bo joalo ka ho tšoenyeha (Funk et al., 2007). Litoeba tsa Transgenic tse tlositseng CRF-R1 (CRF-R1 knockout (KO) litoeba) li fokolitse karabelo ho khatello ea maikutlo le matšoenyeho, bakeng sa tlhahlobo e felletseng ea bona (Bale le Vale, 2004). Phello ena e tšoenyang, leha ho le joalo e kanna ea hlahisoa ke phokotso ea li-glucocorticoids tse potolohang mefuteng ea preclinical (Tronche et al. 1999). Lera ea mouse ea maemo a nang le maemo e ile ea hlahisoa ho khetholla boits'oaro ho tsoa ho li-neuroendocrine CRF-mediated CRF-R1 litsela tse tšoaeang. Inactivation e khethiloeng ea likarolo tsa limbic, empa eseng ea Sistimi ea HPA e bontšitse hore CRF-R1 e sebetsana le boits'oaro bo ts'oanang le boits'oaro mme e ikemetse ho HPA (Muller et al., 2003). Ho feta moo, ho nahanoa hore CRF-R1 e eketsa menyetla ea ho tlohela boits'oaro bo tahang (Hansson et al., 2006; Heilig le Koob, 2007). Phuputso ea morao-rao e hlahlobile karolo ea CRF kahare le ka ntle ho HPA e bonts'itse hore CRF ka lets'oao la CRF-R1 e kanna ea ba le litlamorao tse fapaneng taolong ea joala e amanang le khatello ea maikutlo (Molander et al. 2012).

CRF-R2 e na le mefuta e meraro: α, β, le γ. Α e entsoe ka masala a 411 amino acid mme β e entsoe ka masala a 413-418 amino acid. Ka bobeli li fumanoa bokong le pariphery; leha ho le joalo, CRF-R2β e fumanoa haholo pelong le vasculature (Lovenberg et al., 1995a,b; Kimura et al., 2002; Burnett, 2005). The γ variant ke peptide e nyane e nang le masalla a 397 amino acid feela, mme e fumanoa feela bokong ba motho (Kostich et al., 1998). Karolo e tobileng ea CRF-R2 taolong ea karabelo ea khatello ea maikutlo ke taba ea ho etsa lipatlisiso tse tebileng. Lithuto tsa mofuta oa mouse ea genetic ka ho tlosoa hoa litoeba tsa CRF-R2 (CRF-R2 KO) li bontšitse hore ts'ebetso ea CRF ea CRF-R2 e ka lebisa ho karabelo e eketsehang kapa e fokotsehileng ho ba khatello ea maikutlo (Bale et al., 2000, 2002; Coste et al., 2000; Kishimoto et al., 2000).

Ho haella ha antisera e itseng e tšehetsang liteko tsa immunohistochemical le tharollo e tlase ea mekhoa ea ligand e tlamang ho fokotsitse lithuto ho hlakisa ho hasoa ha CRF-Rs le ho fokotsa tlhahlobo maemong a mRNA. Ho hlola tšitiso ena, panya ea transgenic e tlalehang polelo ea CRF-R1 e nang le protheine e tala ea fluorescent (GFP) e hlahisitsoe ka katleho ho fana ka sesebelisoa sa lipale ho etsa lipatlisiso mabapi le karolo ea CRF-R1 ea ho bonts'a khatello ea khatello ea maikutlo (Justice et al., 2008).

CRF-BP ke protheine e sa qhibilihang ka metsi, 37 kD 'me e na le masala a 322 amino acid (Bale le Vale, 2004). Ke glycoprotein e patiloeng, e bolokiloeng ka nepo ka har'a litlolo tsa sephiri ebe e lokolloa sebakeng se kantle ka exocytosis (Blanco et al., 2011). E na le li-oligosaccharides tse hokahantsoeng tsa Npar e bohlokoa haholo bakeng sa CRF-BP e tlamang CRF (Suda et al., 1989). Liteko tsa pejana tsa ho tseba molek'hule e nyane ea limolek'hule tsa CRF-BP li hlahisitse katleho e fokolang ka lebaka la ts'ebelisano e kholo (picomolar) ea CRF e tlamang CRF-BP (Behan et al., 1995a) hape hape hobane CRF-BP bolelele bo felletseng (FL) e ka qhekelloa ke liprotheine tsa autocatalytic (Woods et al., 1999). The spontaneous proteinolytic cleavage e hlahisa sekhechana se seholo sa N-terminal sa 27 kD, CRF-BP (27 kD), e bolokang sebaka sa marang-rang bakeng sa CRF le sekhechana sa 9.6 kD C-terminal, CRF-BP (10 kD) (Woods et al., 1999) ntle le karolo e bonalang ya mmele kapa ya setho. Sebaka se ikhethang sa cleavage ho CRF-BP (FL) se fumanoe pakeng tsa masala a amino acid serine 234 le alanine 235. Moloko oa likhechana tse peli o entse hore ho be thata haholo ho hloekisa ka nepo CRF-BP (FL) ka botlalo ho ithuta likarolo tsa protheine ea tlhaho. CRF-BP e phatlalalitsoe ka mokelikeli oa plasma, amniotic le synovial fluid, placenta, gland ea senya, sebete, le libakeng tse fapaneng tse fapaneng tsa boko, ho kenyelletsa le cortex ea "cerebral", hippocampus (Behan et al., 1995a), amygdala (Herringa et al., 2004) le VTA (Wang le Morales, 2008). Boemong bo potelletseng, CRF-BP e potolohang e khelosa liketso tsa 'mele tsa CRF (Kemp et al., 1998). Ka lebaka la tšebelisano e phahameng le CRF, ho lumeloa hore CRF-BP e bapala karolo ea buffer ka ho fokotsa palo ea CRF ea mahala. Bokong, leha ho le joalo, CRF-BP e tlameletsoe haholo ho li-membrane ebile e hlahisoa ka bongata liseleng tsa methapo ea kutlo le li-neuroglial cell (Behan et al., 1995b). Ka har'a lisele tsa neuronal, liphuputso tsa morao-rao li bonts'itse hore likarolo tse ling tsa "disc" tsa dopaminergic le and-aminobutyric acid (GABAergic) li hlahisa CRF-BP (Wang le Morales, 2008). Karolo ea 'mele ea CRF-BP tsamaisong ea methapo ea methapo (CNS) e ntse e sa hlaka. Ntle le moo, likhopolo li fana ka maikutlo a hore mohlomong CRF-BP e ka thusa ho hlakisa ha CRF 'meleng mme e ka boela ea sireletsa CRF ho tlotlolloeng (Seasholtz et al., 2002). Liphuputso tsa mofuta oa mouse ea genetic ka ho tlosoa ha litoeba tsa CRF-BP (CRF-BP KO) li bonts'itse ho na le keketseho ea boits'oaro bo ts'oanang le ho tšoenyeha (Karolyi et al., 1999). Elithuto tsa lectrophysiology li bonts'itse hore matšoao a CRF ka CRF-R2 ho nka monyetla oa N-Methyl-D-aspartate (NMDA) -mediated postsatoryaptynaptic currents (EPSCs) ho VTA (Ungless et al., 2003). Ntle le moo, ho sebelisa CRF (6-33), peptide e qothisanang lehlokoa le CRF sebakeng sa khokahano ea CRF-BP, empa e sa ikopanye le CRF-R2, ho bonts'itsoe hore e thibetse ts'ebetso ea CRF e susumetsoang ke NPSD-Mediated EPSC (Ungless et al., 2003). Ha li kopantsoe hammoho, liphetho tsena li fana ka maikutlo a hore CRF-BP e na le karolo e fapaneng ho fetoheng CRF-system. Joalokaha ho hlalositsoe ke a vitro 'me Ka vivo lithuto, ho hloekisa CRF-BP ea motho (FL) ka bongata bo lekaneng bakeng sa lipatlisiso ha li so ka li atleha ho fihlela joale (Woods et al., 1997). Ha ho so ka ho ba le lisebelisoa tsa lipatlisiso tse fumanehang ho khetholla karolo ea CRF-BP ho CNS ka ho hlahisa CRF-BP ka seleng ea sele. Ka hona, ha ho a ka ha khonahala ho tseba hore na CRF-BP e nka karolo ka ho khetheha ho saena CRF-R2. Kakaretso ea ho kenya letsoho ha CRF boitlamo ba ho lemalla e hlalositsoe ho Tafole Table22.

Ho kenella ha CRF e tlamang boits'oarong bo bobe.

CRF-R1 bahanyetsiPhetetsa khatello ea maikutlo e bakiloeng ke ho batla lithethefatsi le liphetoho tse amanang le ho khaotsa ho tsuba; limolek'hule tse nyane le li-peptide lia fumaneha bakeng sa lipatlisiso
CRF-R2 bahanyetsiTaolo ea karabelo ea khatello ea maikutlo le boits'oaro ba ho lemalla ha e hlake; limolek'hule tse nyane le li-peptide lia fumaneha bakeng sa lipatlisiso
CRF-BP bahanyetsiModulation ea ts'ebetso ea neuronal e ka ba sepheo sa eona ka bobeli lithethefatsi tsa tlhekefetso le karabelo ea khatello ea maikutlo; ke li-peptide feela tse fumanehang bakeng sa lipatlisiso

 Lethathamo 2

Ho kenella ha CRF e tlamang boits'oarong bo bobe.

Khatello ea lithethefatsi tse bakang khatello ea maikutlo: CRF-Mediated neurotransication le polasetiki

Matlafatso: Sebaka sa ventral tegmental (VTA) le li-bokellase tsa nucleus (NAcc)

Lithethefatsi tse tlatsetsang li bontšitsoe ho eketsa khatello ea dopamine ho NAcc. Ntle le moo, keketseho ea dopamine e amahantsoe le ho eketsoa hoa matla a hedonic a ntlafatso e ntle (Fibiger, 1978; Berridge et al., 1989) le nts'etsopele ea mekhoa e lemalloang (Yokel le Wise, 1975; Bonci le Malenka, 1999; Bohlale, 2008). NAcc e amohela litlatsetso ho tsoa ho VTA mme ho nahanoa hore tsela ena e kanna ea ikarabella eseng feela bakeng sa phello e matla ea menyetla ea lithethefatsi, empa hape le ts'ehetso e mpe le litlamorao tsa litakatso tse amanang le boits'oaro bo batlang lithethefatsi (Koob le Nestler, 1997).

Ho nka karolo ha cellular ho VTA

VTA e amohela likhakanyo tsa CRF hangata ho tsoa ho limbic forebrain le PVN ea hypothalamus (Rodaros et al., 2007) ke mofuta oa li-synapses tsa glutamatergic le li-symmetric GABAergic synapses (Tagliaferro le Morales, 2008). PVN ke sebaka sa CRF synthesis (Meloni et al., 2005) le boholo ba li-asymmetric synapses (glutamatergic) li hlahisoa ka CRF- le li-neuron tse nang le dopaminergic. VTA dopaminergic neurons e bontša CRF-R1 (Van Pett et al., 2000) mme patlisiso e sa tsoa feta e bontšitse hore tboholo ba li-neurons tsa VTA tse hlalosang CRF-BP ke dopaminergic (Wang le Morales, 2008).

The CRF system modulates dopaminergic neurons ka ho kenya letsoho ho CRF-R1 le CRF-R2; le ha ho le joalo, CRF ha e amehe feela ho neuroexcitability ea dopaminergic system. E kanna ea ikarabella ho fetolela liphihlelo tsa thabo le lithibelo tsa inhibitory kaha VTA e amohela litlatsetso tse tsoang ho li-neuron tsa CRF-glutamatergic- le CRF-GABAergic tse nang le li-neurons (Tagliaferro le Morales, 2008) le bakeng sa tlhahlobo sheba Borgland et al. (2010).

CRF e eketsa lebelo la ho thunya ha li-neuron tsa VTA dopaminergic (Korotkova et al., 2006; Wanat et al., 2008) ka CRF-R1, mme e kenyelletsa phospholipase C (PLC) –protein kinase C (PKC) tsela e bonts'ang tsela ka ntlafatso ea Ih (hyperpolarization-activated inward current) (Wanat et al., 2008). CRF hape e ka kenya ts'ebetso ea nakoana ea nts'etsopele ea butle-butle ea phetisetso ea NMDA-Mediated synaptic ka CRF-R2 le ts'ebetso ea ts'ebetso e tšoaeang ea PLC-PKC. CRF-R2-mediated potentiation e bontšitsoe ho hloka boteng ba CRF-BP (Ungless et al., 2003). Mokhoa oa tšebetso oa CRF-R2 le CRF-BP o ntse o ntse o tsoela pele ho etsoa lipatlisiso kaha lisebelisoa tsa ho etsa lipatlisiso tse hlokahalang ho ithuta CRF-BP le antisera tse tobileng CRF-R2 ha li e-so fumanehe.

CRF e bonahala e na le liketso tse nyarosang le tse thibelang methapo ea methapo ho dopaminergic neurons ho VTA. Boithuto bo sebelisang cocaine le methamphetamine li bonts'a seo phello e thabisang ea CRF ho li-neuron tsa dopaminergic e kenyelletsa liketsahalo tse potlakileng, mohlala, mohato o ka fokotsang sekhahla sa ho thunya le phetiso e pakeng tsa NMDAR, ha litlamorao tsa CRF li kenyelletsa mefuta e liehang ea phetiso ea synaptic e ka hlahisang polasetiki ea nako e telele (Ha Beckstead et al., 2009). Seo ba se hlokometseng se bonts'itse hore CRF e kanna ea ba le liketso tse fapaneng ho li-receptors tse kenyang tšebetso ea synaptic ho dopamine. Mokhoa ona oa cellular o ka ntlafatsa karolo ea khatello ea maikutlo ke liketso tsa CRF ka boits'oaro bo kopaneng ba dopamine (Ha Beckstead et al., 2009).

Joalokaha ho bontšitsoe hore bokhoni ba CRF-R2, empa eseng CRF-R1, ho saena ho hloka ho ba teng ha CRF-BP (Ungless et al., 2003), ho bile le tlhahiso ea hore CRF-BP le CRF-R2 li sebetsane le mekhoa e tšoarellang ea testaptic (Bonci le Malenka, 1999). Bsensitization tse ling tsa boits'oaro le tšebeliso ea nako e telele (LTP) li arolelana litšobotsi tse ngata joalo ka ho kenya letsoho ha ts'ebetso ea NMDAR bakeng sa ho kenngoa ha PDP ho VTA dopaminergic neurons (Bonci le Malenka, 1999; Ungless et al., 2001). AKa lebaka leo, ho 'nile ha fanoa ka maikutlo a hore polasetiki ea "synaptic" ka nako e nyarosang ea li-neurons tsa VTA e ka bapala karolo ea mantlha ho baka phetoho ea boitšoaro. Kaha ts'ebetso ea NMDAR e hlokahala bakeng sa ho kenyelletsa ts'ebetso ea LTP ho li-neuron tsa VTA dopaminergic, ts'ebetso ea CRF-Rs e ka fetola mefuta ea nako e telele ea polasetiki (Bonci le Malenka, 1999; Ungless et al., 2001; Bonci le Borgland, 2009).

CRF-Mediated neurotransication le polasetiki

Li-adaptation tsa Synaptic tse hlokometsoeng ha li nchafatsa li-circonal tsa neuronal lithutong tsa lithethefatsi tse tlatsetsang li bonts'oa li na le moelelo mekhoeng ea boitšoaro le ea ho hopola lintho tse hlahang ho li-SUD. Melemo ea "neuroplasticity" e hlahisitsoeng ke lithethefatsi e hlahisitse 'mele o ntseng o hola oa bopaki o fanang ka maikutlo a hore e ka supa tšusumetso ea limolek'hule e bohlokoa ho fetoleng mekhoa e lemalloang e tlatselletsang boits'ebetsong bo lematsang.

Axon terminals ea CRF neurons e kenella ho VTA neuronal dendrites (Tagliaferro le Morales, 2008) mme ho bonahala eka khatello ea maikutlo e ama tokollo ea CRF sebakeng sena (Wang et al., 2006). Boithuto ba electrophysiological bo bontšitse hore CRF-BP e hlokahala bakeng sa phetisetso e tsoelang pele, ea nakoana ea phetisetso ea phetisetso ea NMDAR-Mediated synaptic elicited ke CRF ka CRF-R2 ka ho khetheha (Ungless et al., 2003). Liphetho tsena li ntlafalitsoe ke lithuto tsa boits'oaro tse khethileng ts'ebetso ea khatello ea maikutlo ho tsitsitseng glutamate le ho lokolloa ha dopamine ka ho batla koae ea litoeba tse nang le boiphihlelo (Wang et al., 2007b). Ubina mefuta ea kalafo ea koae e sa foleng, thuto e bonts'itse ts'ebetso e ntle e amanang le CRF, haholo-holo tšebelisano ea CRF / CRF-R2 / CRF-BP le dopaminergic system. Seo ba se fumaneng se ts'ehetsa boiteko bo eketsehileng ba lipatlisiso ba ho hlahisa mekhoa e meng e amanang le CRF-BP ka seleng.

Qetellong, CRF e eketsa ts'ebetso ea VTA glutamatergic synaptic, e ka etsang hore VTA e phatlohe ho thunya kapa ho kenngoa ha polasetiki ea synaptic ho ka bakoang ke ho pepesetsoa hangata hoa lithethefatsi tsa tlhekefetso. Ts'ebetso ena e ka hlahisa li-neuroadaptations tsa nako e telele tse fetolang likarabo tsa khatello ea maikutlo le ho matlafatsa ho batloa ha lithethefatsi. Lithuto tsa electrophysiological tse kopaneng le lithuto tsa boitsoaro li hlahisitse hore boiphihlelo ba nakong e fetileng le lithethefatsi tsa tlhekefetso bo ka nolofatsa bokhoni ba khatello ea maikutlo ho khanna ho batla lithethefatsi, ka hona, bocha. Liphetho tsena li fana ka maikutlo a hore CRF e kanna ea bohlokoa bakeng sa polasetiki e hlahisoang ke lithethefatsi ho VTA dopaminergic neurons mme e ka emela molek'hule o hlalosang karabelo le khatello ea maikutlo nakong ea ho tlohela lintho tse hlekefetsang.

Ho kenella ha selefouno ho CRF ho amygdala

Amygdala ho lumeloa hore ke karolo ea bongoana ea bohlasoa bakeng sa karabelo ea maikutlo mme ho bohlokoa bakeng sa ho fana ka salience e lumellanang le tlhahisoleseling ea maikutlo (Adolphs et al., 1994; LeDoux, 2003; Phelps le LeDoux, 2005). Likarabo tse fosahetseng mabapi le tšebeliso li ithutoe ka li-nuclei tse ikhethang tsa amygdala ka ho ithuta karabelo ea boemo ba tšabo (Davis, 1992a,b). Amygdala e hokahane ka bophara le libaka tse ling tsa maoto moo e nkang karolo ho kopaneng leseli la maikutlo le kelello (LeDoux, 1992, 1993). Bopaki ba boithuto bo fana ka maikutlo a matla a hore lithethefatsi tsa tlhekefetso li sebetsa sistemeng ena mme li ka fetola liketsahalo tsa synaptic haholo-holo nakong ea ho tlohela. Ha VTA e ntse e amahanngoa le litlamorao tse matlafatsang tsa ethanol (Gatto et al., 1994), ts'ebetso ea Sistimi ea GABAergic e amahanngoa le phello ea matšoenyeho a joala (Frye le Breese, 1982). Ntle le lits'ebetso tse khahlisang tsa khetla ea NAcc, le libaka tsa boko tse hlahisitsoeng ke khatello ea meriana, tse kang yohimbine le footshock li fumanoe li tobile ho "basolateral" le "amygdalar nuclei" le "nucleus ea" ea stria terminalis (BNST). (Funk et al., 2006). Boithuto ba Preclinical bo bontšitse hore ho pepeseha le ho khaola ho tsoa ho ethanol ho etsa hore ho be le liphetoho tse sebetsang le tsa biochemical ho amygdala ea likhoto, ho bonts'a hore potoloho ena e kenyelletsa keketseho ea nako e telele ea boits'oaro bo joalo ka boits'oaro bo latelang ho pepesetsoa ha ethanol e sa feleng (Christian et al., 2012).

Li-amygdala mediates li fana ka likarabo tse sa arajoang le tse sa utloahaleng mabapi le tšusumetso e matla (Davis le Whalen, 2001) 'me ho fumanoe lipatlisiso ho sebelisa boemo ba tšabo ba Pavlovian ka ho taka mohopolo o nang le tšusumetso e nang le tšusumetso e se nang boikemisetso. Ho senoloa hape ha mohopolo o sa boleloang ho etsa hore ho be le tšabo e nang le boemo bo tlisoang ke mokhatlo o sa tsotelleng (Pitts et al., 2009). Letšoao la mokhatlo le etsahala sebakeng sa basystale amygdala (BLA) ebe se fetisetsoa sebakeng se bohareng ba amygdala (CeA) (McDonald, 1998; Maren, 1999; Davis le Shi, 2000; Pitkanen et al., 2000; Parete al., 2004). Ts'ebetso ena ea phetisetso e kenyelletsa litloaelano tse ntle le tse mpe.

Likarolo tsohle tsa sistimi ea CRF, CRF, CRF-Rs le CRF-BP li hlahisitsoe ho amygdala (Potter et al., 1994). Furthermore, amygdala ke mohloli o moholo oa extrahypothalamic oa li-neuron tse nang le CRF (Palkovits et al., 1983; Van Pett et al., 2000). Ka bobeli li-BLA le CeA li bapala karolo ea karabelo ea khatello ea maikutlo (Richter et al., 1995; Merali et al., 1998; Koob le Heinrichs, 1999). Boithuto bo bongata bo bontšitse hore Sisteme ea CRF e nka karolo ho kopaneng ea mohopolo e kenyelletsang potoloho ea BLA-CeA (Roozendaal et al., 2002; Hubbard et al., 2007). Ho hlokometsoe hore ho lokolloa ha CRF ho amygdala ho eketseha nakong ea ho tlosoa ho matla (Richter le Weiss, 1999); ka hona ho nahanoa hore CRF e ka 'na ea fetola polasetiki e khopisitsoeng ke lithethefatsi (Ungless et al., 2001, 2003) le bakeng sa tlhahlobo ea morao-rao, bona (Luscher le Malenka, 2011). Motheo oa neuronal oa ho matlafatsa hampe ha o utloisisoe hantle; leha ho le joalo, lithuto tsa morao-rao tsa boits'oaro li bonts'itse hore CRF e khona ho tsamaisa maqhubu a fetisisang a matla a fetisisang ka CRF-R1 ho CeA libeke tse peli kamora ho itokolla cocaine (Pollandt et al., 2006).

Phuputso ea morao-rao e bontšitse hore CRF-R1 ka ho khetheha e na le karolo ea bosholu ba ho tšoenyeha (Refojo et al., 2011). Ha ho tlosoa ha CRF-R1 mokokotlong oa "brain dopaminergic neurons" ho eketsa boits'oaro bo ts'oanang le ho fokotsa ho lokolloa ha dopamine kahare ho cortex ea pele, ho tlosoa ha CRF-R1 marangrang a neuronal glutamanergic neuronal ho fokotsa ho tšoenyeha le ho sitisa phetiso ho amygdala le hippocampus (Refojo et. al., 2011).

Karolo ea CRF e boetse ea hlahlojoa haholo ts'ebetsong ea boithaopo ea ethanol ka boithaopo ho sebelisa mofuta oa gene le ho feto-fetoha hoa liphatsa tsa lefutso mehlaleng e sa bonahaleng (Bjork et al., 2010) bakeng sa tlhahlobo e batsi. Ho liphoofolo tse pepesitsoeng ke ethanol, ho kenella hoa ethanol ho fokotsehile ka tsamaiso ea mohanyetsi oa CRF-R1, mme ho lekoa ka ho kenella ho tsa bongaka tse fokotsang boits'oaro bo kang mats'oenyeho (Logrip et al., 2011; Zorrilla le Koob, 2012). Phokotso ea takatso ea ethanol e boetse e bonoe ho litoeba tsa transgenic ka ho tlosoa ha CRF-R1 (CRF-R1 KO) (Chu et al., 2007). Barekisi ba CRF-R1 ba fokotsa ho tšoenyeha ho amanang le tlhekefetso ea lithethefatsi mme ba fumana litlamorao tse mpe tsa ethanol tse amanang le ho pepeseha hoa ethanol nako e telele (Ghitza et al., 2006; Marinelli et al., 2007; Li et al., 2007; Koob le Le Moal, 2008b; Richards et al., 2008). Li-inhibitors tsa CRF-R1 li bonts'itse ho khutlisa khatello ea maikutlo e bakiloeng ke khatello ea koae le heroin liphoofolong tse koetlisitsoeng (Shaham et al., 1998) le ho fokotsa ho khutlisetsoa ha khatello ea maikutlo le ts'usumetso ea khatello ea maikutlo ka lebaka la lithethefatsi tse ngata tse lemalloang (Koob le Zorrilla, 2010).

Amygdala e atolositsoeng

Har'a likarolo tsa extrahypothalamic tse nang le CRF e hlalosang li-neurons ho na le "amygdala e atolositsoeng." Amygdala e atolositsoeng e na le BNST, medie amygdala (CeA), karolo e bohareng ea femantia voominata le sebaka sa phetoho se etsang karolo e ka morao ea NAcc. (Heimer le Alheid, 1991). E emetse potoloho ea boko e kenyang letsoho ho sebetsanang le maikutlo a susumetsang a hlahisoang ke ho tlosoa hoa ethanol (Koob le Le Moal, 2001), eo ho eona sistimi ea GABA e fetotsoeng 'me sistimi ea CRF e haufi le CeA e bonts'itsoe e sebetsa (Roberts et al., 1996). Seo ba se boneng se bonts'a hore ts'ebetso ea GABAergic kahare ho li-amygdala tse atolositsoeng e ka bapala karolo ea bohlokoa maemong a sa thabiseng a maikutlo a kang a ts'ebetso ea ho batla lithethefatsi ho itšetleha ka joala (Koob le Le Moal, 2001; Koob, 2003, 2009a,b). Ntle le moo, a in situ Phuputso e entsoeng mabapi le ho nyalanya e bontšitse hore ho hira matšoao a CRF-R1, likarolong tsa amygdala tse atolositsoeng, ho ka ba le boikarabello ba ho khanna joala bo bongata ba boithaopo mme bo ka hokahanngoa le ho eketsa ts'ebetso ea khatello ea maikutlo (Hansson et al., 2007).

BNST (hammoho le libaka tse ikhethang tsa CeA) e amahanngoa le khatello ea maikutlo le matšoenyeho (Walker le Davis, 2008) hape e kenelletse ka kotloloho ho lets'oao la CRF (Davis et al., 1997). CeA le BNST li na le lipalo tse tobileng libakeng tse ngata tsa boko tse ithutoang ho hlakisa matšoao a ts'abo kapa matšoenyeho (Davis, 1992b). The BNST e fumanoe e le molaoli ea ka khonehang oa ho fokotseha ha neuron ea VTA dopaminergic (Georges le Aston-Jones, 2002) hape ka lebaka la ho kenya letsoho taolong ea liketso tse mpe tsa joala, nicotine, le koae (Watkins et al., 1999; Carboni et al., 2000;; Eiler et al., 2003).

The BNST e na le khokahano e pharaletseng ea li-dopaminergic fibers (Fudge le Emiliano, 2003) hape e hokahane le tsela ea moputso ka likhakanyo tse pharalletseng ho VTA, ka hona e susumetsa kenyelletso e khahlisang ka bobeli NMDA le li-receptors tse seng tsa NMDA (Georges le Aston-Jones, 2001, 2002). Ts'oaetso ena e thabisang ea dopaminergic ho VTA e hloka boteng ba CRF (Kash et al., 2008). Ts'ebetso ea Acoca cocaine e bontšitsoe ho kenya letsoho ho dopamine ho supa ka ts'ebetso e ikhethileng ea CRF-R1 e ntlafalitsoeng ea phetisetso ea thabo ea NMDA (Kash et al., 2008). Mochine ona o ile oa hlalosoa e le mofuta oa nakoana oa polasetiki ho BNST, e kanna ea ikarabella ho litlamorao tse mpe tsa lithethefatsi tse lemalloang (Kash et al., 2008). Liphumano tsena li khothalelitse hore glutamatergic neurotransication ho BNST e kanna ea ameha ka tšebetso e matla ea ho matlafatsa liketso tsa tlhekefetso ea lithethefatsi (Walker le Davis, 2008).

Basolateral amygdala (BLA)

The basolateral nucleus ea amygdala (BLA) e kenella ka matla ho ithuteng maikutlo (LeDoux, 2000), le moputsong (Balleine le Killcross, 2006; Tye et al., 2008). Li-Neurons tse tsoang ho projeke ea BLA ka kotloloho ho CeA le BNST. BLA e kopantsoe haholo ke "glutamatergic pyramidal neurons" 'me e fana ka sephetho sa mantlha sa thabo ho CeA le likarolo tse ling tsa limbic le cortical (Sah et al., 2003); leha ho le joalo, phetisetso e khahlisang e lumeloa hore e fetoloa ke palo e nyane ea li-interneuron tsa GABAergic tse fumanoang moo (Washburn le Moises, 1992). Li-interneurons tsa GABAergic li fumanoe e le batsamaisi ba khatello ea maikutlo le matšoenyeho (Silberman et al., 2009).

CRF e teng ka bongata ho BLA, ho ekelletsa ho CRF-R1 le CRF-BP, (Sakanaka et al., 1986; Potter et al., 1992; Van Pett et al., 2000); leha ho le joalo, litlamorao tsa CRF ho BLA li ithutile hanyane haholo ho feta li-nuclei tse ling tsa amygdala. BLA e bontšitsoe e le motheo oa bohlokoa bakeng sa ho kopanya tšabo le ho hopola mme, ka hona, ke sepheo se ka fokotsang mehopolo ea maikutlo. Ho bontšitsoe hore infra BLA infusions ea CRF e eketsa boits'oaro bo ts'oanang le boits'oaro (anorexia le boikoetliso) bo thibetsoeng ke tsamaiso ea mohanyetsi oa CRF-R1 (Jochman et al., 2005). Phuputso e 'ngoe ea BLA microinfusion e bontšitse hore CRF-R1 e kenya ts'ebetso ea ts'ebeliso ea memori le hore phello ena e thibetsoe ke tsamaiso ea mohanyetsi e mong oa CRF-R1. Ts'ebetso ea ho kopanya mohopolo oa tšabo e bonahala e laoloa ka kotloloho ke ts'ebetso ea CRF-R1 kaha CRF-R2 mohanyetsi ho BLA ha ea ka ea sitisa boemo ba tšabo bo amanang le maemo kapa ts'ebetso ea ho kobeha ha maemo ho latela litekong tse se nang lithibelo tse se nang lithethefatsi (Hubbard et al., 2007). BLA CRF-R1 ts'ebetso e hlalositsoe e le ts'ebetso ea polasetiki ea synaptic, mme e bonts'a hore ts'ebetso ea BLA CRF-R1 e ka koaloa ka pharmacologically ka limolek'hule tse nyane, monyetla oa ho senya ts'ebetso ea kopanyo ea memori ea tšabo e fana ka monyetla oa phekolo o ka fokotsang kholo ea maikutlo a tebileng mehopolo.

Nucleus amygdala (CeA)

CeA e khethiloe e le sebaka sa ho matlafatsa ka mokhoa o nepahetseng oa taolo ea ethanol le bakeng sa ntlafatso e mpe e amanang le ho tlosoa hoa ethanol (Baldwin et al., 1991; Heinrichs et al., 1992, 1995; Koob le Le Moal, 1997, 2001; Zorrilla et al., 2001). CeA e boetse e khethiloe e le sebaka sa bohlokoa sa ho khutlisetsa litla-morao tse ngata tse amanang le tahi ea ethanol (Hyytia le Koob, 1995).

Ho CeA, li-neuron tse ngata ke GABAergic (Letsatsi le Cassell, 1993), mme CRF e sebelisana haholo le Gabaergic neurons (Veinante et al., 1997; Letsatsi et al., 1999). CeA e bua haholo ka CRF, CRF-R1 le CRF-BP (Sakanaka et al., 1986; Potter et al., 1992; Van Pett et al., 2000). Ho feta moo, ho CeA ketso ea CRF le ethanol e bontšitsoe ho eketsa tokollo ea GABA (Nie et al., 2004) le palo ea ho lokolloa ha CRF e eketsoa ka mehlala ea boikemelo ba ethanol (Merlo Pich et al., 1995). Protein kinase C epsilon (PKC bec) e bonts'itsoe ho fetolela lets'oao la CRF-R1 ho CeA (Choi et al., 2002) le litoeba tsa transgenic ka ho tlosoa ha litoeba tsa PKC bec (PKC bec KO) li bonts'itse boitšoaro bo fokotsehileng bo kang boits'oaro (Hodge et al., 2002). Boithuto ba electrophysiological bo bontšitse hore ho lokolloa ha ethaneol-indued GABA ho amygdala ho laoloa ke CRF-R1 (Nie et al., 2004) le hore ethanol-e susumetsoang ea vesicular GABA ho lokolloa ho latela mehlala ea PKCchas (Bajo et al., 2008). PKCchas e bontšang tsela ho CeA e sebetsoa ke ts'ebetso ea CRF-R1 mme e hlophisa li-neurotransication tsa GABAergic tse ka bakang litlamorao tsa ho tšoenyeha ha ethanol (Smith et al., 1998; Timpl et al., 1998). Khokahano ena e sebetsang pakeng tsa ethanol, CRF le PKC bec e hlophisang methapo ea methapo ea kutlo ea GABAergic ho CeA e ka kenya letsoho ho phahameng ha boitšoaro ba maikutlo bo laolang ho matlafatsoa ho matla ha ts'ebeliso ea ethanol le matlafatso a mpe a hlahisoang ke ho tlosoa hoa ethanol.

Ho bonts'itsoe hore ho na le phapang e kholo lipakeng tsa litlamorao tsa CRF ho liphoofolo tse pepesitsoeng / tse itekanetseng tsa ethanol (tšebeliso ea binge-like ethanol) le liphoofolo tse its'epileng ka ethanol (ho pepeseha joaloka ethanol). Ha e ntse e itlopa lijo tse kang ethanol (Lowery-Gionta et al., 2012) e kanna ea baka tšenyo ea nakoana ea sistimi ea CRF e ka tsebang ho khutlela ho eona homeostatic state, expon-like ethanol (Roberto et al., 2003, 2004) e kanna ea ikarabella bakeng sa CRF neuroadaptation e ka susumetsang naha e mameloang. e naha e mameloang e hlalosoa e le boemo ba ho kheloha ho sa feleng hoa marang-rang a taolo ho tsoa ts'ebetsong ea bona e tloaelehileng le ho theha sebaka se fapaneng sa "botsitso bo hlakileng" (Koob le Le Moal, 2001). Tho kheloha ho sa fetoheng ha mokhahlelo oa moputso ho fetoloa haholo nakong ea ho khaotsa lithethefatsi 'me ho ka kenya letsoho ho etseng morao nko ho hlahisa kotsi ea ho lemalla le ho oela hape (Koob le Le Moal, 2001). Khatello ea kelello e matla ha e eketse polelo ea mRNA ea likarolo tsohle tsa sistimi ea CRF ho CeA (Herringa et al., 2004), leha ho le joalo, ho CeA ea liphoofolo tse pepesitsoeng ke ethanol, ho bile le keketseho e kholo ho CRF mRNA expression (Ha a fane ka al., 2005) hammoho le ho liphoofolo tse itšetlehileng ka ethanol nakong ea ho tlohela (Sommer et al., 2008).

Ho bokelloa ha CRF ho CeA nakong ea liketsahalo tsa ho noha pele ho nako, pele ho ts'ehetso, ho ka qala liphetoho tsa neuroplastic tsamaisong e ka bang matla le litlatsetso tse eketsehileng tsa ethanol (Lowery-Gionta et al., 2012). Ho reriloe hore phetoho ena e itšetlehileng ka CRF e kenya letsoho phetohong ea ho tloha ho noang ho itlopa joala ho ea ho ts'epahalo ea ethanol (Lowery-Gionta et al., 2012). Bangoli ba boetse ba fumane hore ethanol e ntlafatsa phetiso ea GABAergic sebakeng sa amygdala libakeng tse ka pele le tsa post-synaptic maemong a liphoofolo a ethanol naïve, ha tšebeliso ea binge ea ethanol e koala CRF-Mediated GABAergic transmission (Lowery-Gionta et al., 2012). Phuputso ena e senotse hore ho nwa ho fokotsitse phello eo CRF e bang le eona phetisong ea GABAergic. Ho fapana le seo, ba bang ba fumane hore liphoofolo tse itšetlehileng ka ethanol li bontšitse phetisetso e ntlafalitsoeng ea GABAergic ho CeA (Roberto et al., 2004).

CRF le norepinephrine li bontšitsoe ho eketsa ts'ebetso ea GABAergic e lekantsoeng ke GABAA inhibitory postsynaptic uwezo (IPSCs) ho ho rekota lisele ka botlalo ho tsoa ho CeA. Phello ena e ne e koetsoe ke bahanyetsi ba CRF-R1 mme e koetsoe ho litoeba tsa CRF-R1 Knoutout (Nie et al., 2004; Kash le Winder, 2006). Ho lokolloa ha GABA ho ntseng ho hlaha ho hlahisoang ke ethanol ho CeA ho liphoofolo tse its'epileng ho ile ha bonoa ka bobeli ho elektroloji le Ka vivo Liteko tsa maiketsetso (Roberto et al., 2003). Boithuto ba morao-rao mabapi le likhoto tse itšetlehileng ka ethanol bo ile ba tiisa hore tšebelisano ea CRF-joala phetisong ea GABAergic ho CeA e phatlalatsoa haholo nakong ea ts'ehetso ea joala (Roberto et al., 2004).

Nahanisisa

Tlhahlobo ena e akaretse mekhoa e mengata e sebetsang e fetolang ts'ebeliso ea litlhare tse latelang tsa ts'ebeliso ea lithethefatsi tse tlatsetsang. It ho totobetse hore Sisteme ea CRF e thusa haholo ho kenella le ho bolokoa hoa polasetiki ho VTA le amygdala, ka ntlafatso e hlahisang pherekano le boits'ireletso ba GABA, ka hona e kenya letsoho molek'huleng oa ts'ebeliso ea lithethefatsi.

Neuroplasticity ho li-circry tsa moputso oa boko kamora ho latela nalane ea ts'epahalo ea ethanol e bontšitsoe (Hansson et al., 2008). Lintlha tsa boithuto tse bontšitsoeng tlhahlobisong ena li ts'ehetsa maikutlo a reng khatello ea kelello e kenella ka har'a VTA le amygdala nuclei mme e ka nka karolo ho nts'etsopele ea boemo bo sa foleng ba ho tšoenyeha bo ka lebisang ho nts'etsopele ea li-SUDs. Liphetoho tsena khokahanong ea methapo ea methapo li ka emela sesosa se ka lebisang tahlehelong ea tšebeliso ea lithethefatsi. Lithethefatsi tse tlatsetsang li bonts'itsoe ho susumetsa maikutlo a boitšoaro mme ho na le sehlopha se seholo sa lingoliloeng tse hlahlobang karolo ea khatello ea maikutlo le boits'oaro bo lematsang. Boithuto ba neuroadaptation ea nako e telele tšebelisong ea joala bo bontšitse hore khatello ea kelello le lits'ebetso tsa ts'abo li fetoha ts'ebetso (Heilig et al., 2010); hLeha ho le joalo, ho ntse ho na le ho hongata ho lokelang ho hlakisoa mabapi le liketso tsa lithethefatsi tsamaisong ea CRF, mabapi le polasetiki ea synaptic le likarabo tsa boits'oaro.. Lira tse 'maloa tsa likokoana-hloko tse kenang mali le likokoana-hloko tsa CRF-R1 li se li hlahisitsoe, leha ho le joalo likhakanyo tse ling li bonts'itse katleho ea mehlala ea liphoofolo ho phekola bokhoba ba tahi (Gehlert et al., 2007, 2012), Bahanyetsi ba CRF-R1 ha ba so ka ba atleha litekong tsa bongaka (Koob le Zorrilla, 2012).

Ho thibela ho pepesetsoa lintho tsohle tsa tlhekefetso ho batla ho sa khonehe, kaha lintho tse ngata tsa kelello (joala, nicotine, caffeine le meriana e fanoang) ka kakaretso li amoheloa sechabeng sa rona. Ho na le meriana e mengata e lumelloang ke FDA kapa e sebelisitsoeng kantle ho lengolo la ts'oaetso ea joala e shebaneng le kalafo ea phokotso ea matšoao (disulfuram, naltrexone), thuso ka ho tlosa (benzodiazepines, valporic acid, varenicline), le thibelo ea ho khutlela morao (acamprosate, ondansetron, baclofen, topiramate, varenicline, methadone) le ba bang ba fumaneng meriana ea tumello ea FDA bakeng sa matšoao a mang ke sethaleng sa preclinical (mifepristone) (Simms et al., 2011), leha ho le joalo, recidivism ea ts'ebeliso e mpe ea lithethefatsi e ntse e le bothata bo boholo ho li-SUD. Leha mekhahlelo e fapaneng ea lintho tse sebelisang tlhekefetso e le mekhoa e fapaneng ea ts'ebetso, ts'ebeliso e mpe ea lithethefatsi e lebisa ho tsitsipeng ea axel ea HPA le ho khaotsa ho tšebeliso e mpe ea lithethefatsi ho sa feleng ho eketsa ts'ebetso ea CRF. Mithethefatsi e fetolang likarabo tsa khatello ea maikutlo e ka fana ka mokhoa o mocha oa pharmacotherapeutic bakeng sa SUDs. Ho laola sephetho sa khatello ea maikutlo ka ho etsa ts'ebetsong ea CRF ho ka fana ka monyetla oa ho nts'etsapele phekolo ea nalane e tataisitsoeng ho fokotsa phello ea CRF lipuisanong tsa synaptic. Ka ho nolofalletsa takatso ea lithethefatsi e bakang khatello ea maikutlo, ho ka etsahala ho fokotsa ho khutla le ho nolofatsa sebopeho sa mehopolo ka litlamorao tse bobebe tsa boitshwaro.

Khohlano ea polelo ea thahasello

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

lumela hore baa fokola

Re leboha J. Simms, S. Srinivasan le L. Daitch ka tlatsetso eo ba e entseng ho hlophiseng buka e ngotsoeng ka letsoho. Mosebetsi ona o ne o tšehelitsoe ke chelete e tsoang ho State of California Medical Research on Alcohol & Substance Abuse through UCSF to Selena E. Bartlett, the National Institutes of Health: 1R21DA029966-01 and NIH Fast Track award ho hlahloba pokello ea MLSMR ho Selena E. Bartlett , UCSF School of Pharmacy (Ofisi ea Dean le Clinical Pharmacy) le Sekolo sa Bongaka (Clinical Pharmacology and Experimental Therapeutics) ho ea ho Carolina L. Haass-Koffler.

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