Uxinzelelo kunye nokulutha: igalelo lenkqubo ye-corticotropin ekhuphayo (CRF) kwi-neuroplasticity (2012)

Ngaphambili Mol Neurosci. 2012; 5: 91. Ipapashwe kwi-intanethi ye-2012 ngo-Septemba 6. ikhonkco:  10.3389/fnmol.2012.00091

UCarolina L. Haass-Koffler1,2 kwaye USelena E. Bartlett1,3,*

Abstract

I-Corticotropin releasing factor (CRF) ibonakaliswe ukuba ibangele utshintsho oluhlukeneyo lokuziphatha oluhambelana nokulungelelanisa uxinzelelo. Ukuxhatshazwa kwenkqubo yeCRF nakweyiphi na indawo kunokukhokelela kwiintlobo ezahlukeneyo zokuphazamiseka kwengqondo, kubandakanywa ukuphazamiseka kokusetyenziswa kweziyobisi (SUDs). I-CRF iye yanxulunyaniswa nokuqiniswa kweziyobisi okubangelwa luxinzelelo. Uncwadi olubanzi luchonge iCRF ukuba idlale indima ebalulekileyo kwiindlela zemolekyuli ezikhokelela ekonyukeni kokuchaphazeleka okukhokelela ekubuyeleni kwii-SUDs. Inkqubo yeCRF inendima eyahlukileyo kwii-SUDs. Iphakamisa iziphumo ezibukhali zeziyobisi zokusetyenziswa kakubi kwaye ikwanoxanduva lokwenzeka kwe-neuroplasticity eyenziwe ngamachiza evuswe ngexesha lokurhoxa. Sibonisa kolu phononongo imimandla yobuchopho kunye neesekethe apho iCRF ichazwa khona kwaye inokuthatha inxaxheba kuxinzelelo olubangelwa gwenxa kweziyobisi. Okokugqibela, sizama ukuvavanya indima yokumodareyitha inkqubo yeCRF njengeqhinga lonyango elinokubakho lokunyanga ukungasebenzi kakuhle ngokweemvakalelo okubangelwa kukomelezwa okuqinisekileyo kwezinto zokusetyenziswa gadalala kunye nokomelezwa kakubi okuveliswa kukurhoxa.

Internet: i-neuroplasticity, umlutha, inkqubo ye-corticotropin ekhupha into, i-ethanol, ixhala, uxinzelelo-olubangelwa

intshayelelo

Ukukhotyokiswa ziziyobisi sisimo esingapheliyo esibonakaliswa ngamaxesha okuzila nokuphinda ubuyele. Iimpembelelo zeziyobisi zokusetyenziswa kakubi ekusebenzeni kwengqondo ziye zavavanywa ngokubanzi ngenjongo yokuphuhlisa unyango olunokuthintela ukuphindaphinda kunye nokuququzelela unyango lweengxaki zokusetyenziswa kweziyobisi (SUDs). Uncwadi olubanzi lubonise ukuba iziyobisi ezikhobokisayo zichaphazela iinkqubo ezilawula iindlela zokuvuza (i-mesolimbic dopaminergic pathway), ukufunda kunye neenkqubo zememori (hippocampus), imvakalelo (amygdala), kunye nemisebenzi yokuqonda (i-cortex yangaphambili). Ukomelezwa kweziphumo zokusetyenziswa kakubi kweziyobisi kubalelwa kwizenzo zenkqubo yemilenze nemilenze ethi yona ibe nefuthe kwinkuthazo, iimvakalelo kunye nokuziphatha okuchaphazelayo (Rezayof et al., 2002; UDavide et al., 2008; UMartin et al., 2008; Nielsen et al., 2011; Xue et al., 2012) kunye nophononongo bona (Koob, 1992; UPierce noKumaresan, 2006; Feltenstein kwaye ubone, 2008). Ngokukodwa, ukuguqulwa kokulungiswa komvuzo (Bulumko, 1998, 2005) ichongiwe njengento ebalulekileyo ekhokelela ekwandeni kwamathuba okubuyela kwakhona (uKoob noLe Moal, 1997; Everitt et al., 1999; Koob et al., 2004; Everitt noRobbins, 2005). Ukuphuhliswa kwee-SUDs yinkqubela phambili eqala ngokuvezwa okokuqala kwechiza kwaye iphele ngokuxhomekeka ngokomzimba nangokwengqondo.

Nangona izinto zokusetyenziswa kakubi zineendlela ezahlukeneyo zokwenza, ukuvezwa ngokuphindaphindiweyo kubonakaliswe ukukhokelela kwi-neural adaptations efanayo. Ukukhotyokiswa kulo naluphi na uhlobo lweziyobisi kuchazwe njengenkqubo yokufunda. Abantu bafunda unxulumano phakathi kweziphumo ezinomvuzo zamachiza kunye neempawu zokusingqongileyo eziqikelela ubukho bamachiza. I-Neuroadaptations kwimimandla ehambelana nokufunda kunye nememori (i-hippocampus kunye ne-amygdala) ichaphazeleka emva kwesiganeko esisodwa sayo nayiphi na iziyobisi ngokuchaphazela ukuhanjiswa kwe-synaptic. FUkulandela ukusetyenziswa kweziyobisi ezingapheliyo, ukufuna okunyanzelekileyo kunye nokusetyenziswa okungalawulekiyo kukhokelela kutshintsho oluhlala ixesha elide kwi-synaptic plasticity, njengotshintsho kwi-synaptic strengt.h.

Izifundo zabantu (uGawin noKleber, 1986; Wallace, 1989) kunye novavanyo oluneemodeli zangaphambili (uThatcher-Britton noKoob, 1986; Piazza et al., 1990; UGoeders kunye noGuerin, 1994; Kreibich et al., 2009) baye baqaphela uxinzelelo njengeyona nto ibalulekileyo kwinkqubo yokukhotyokiswa ziziyobisi, kubandakanywa nokuqalisa ukuphinda ubuyele. I-Corticotropin ekhupha into (CRF) iye yabandakanyeka kwi-neuroendocrine kunye neempendulo zokuziphatha kuxinzelelo (uBritton et al., 1982; Koob kunye neBloom, 1985). Kuye kwaboniswa ukuba kusebenze ngexesha lokubuyiselwa kweziyobisi ezibangelwa uxinzelelo, apho lisebenza ukuququzelela ukuphindaphinda kunye nokwandisa ukuxhalaba ngexesha lokurhoxiswa ngokukhawuleza kunye nokungapheliyo. (uShaham et al., 1995; Ambrosio et al., 1997; I-Koob, 1999) kwaye ubone (uSarnyai et al., 2001; UGeorge et al., 2011) kuphononongo olubanzi.

Utshintsho lwe-neuroplastic olwenziwe yiCRF luye lwafundwa zombini kwiisekethe zobuchopho ze-mesolimbic ezibandakanya indawo ye-ventral tegmental (VTA) kunye ne-nucleus accumbens (NAcc) (Ngaphandle kokuba et al., 2003; U-Wang et al., 2007a; Hahn et al., 2009) kunye nakwimimandla yobuchopho ehambelana neemvakalelo, njenge-amygdala (Fudge kunye ne-Emiliano, 2003; UPollandt et al., 2006; UFu et al., 2007; Kash et al., 2008; Francesconi et al., 2009).

Ngaphandle kophando olubanzi oluxhasa indima yeCRF kubukhoboka beziyobisi, uthatho-nxaxheba oluthe ngqo lweCRF kwi-synaptic plasticity eyenziwe ngamachiza ekhokelela ekubuyeleni kwakhona ayikamiselwa.

Olu phononongo luza kuzama ukuphonononga uphando lwakutsha nje ngendima yeCRF kunye nokusebenzisana kwayo neplastiki ye-synaptic plasticity. I-VTA kunye ne-amygdalar nuclei apho i-CRF ichazwe kakhulu iya kuchazwa. Siza kuxoxa ukuba ngaba iCRF iyaququzelela okanye inqanda amandla e-synaptic ukusuka kwimeko yesiseko. Okokugqibela, siya kuzama ukudibanisa utshintsho lwe-neurobiological olubangelwa ukusebenzisana kwezinto zokusetyenziswa gadalala kunye noxinzelelo lokuvavanya ezinye iithagethi zeziyobisi zovavanyo lonyango lokuthintela ukuphinda lubuyele kwaye luququzelele unyango lwe-SUDs.

Ukuphazamiseka kokusetyenziswa kweziyobisi (SUDs) kunye noxinzelelo

Ii-SUDs yimeko engapheliyo kwaye ebuyela umva ebonakaliswa ngumnqweno onzulu wokuthatha iziyobisi ngexesha lokurhoxa. Le nkqubo yokukhanga ikhokelela ekuqhubeleni phambili ukusuka ekusetyenzisweni kokunyanzeliswa kokuqala ukuya ekunyanzelweni okulandelayo kunye nomkhwa wokwenza ukusetyenziswa okukhokelela ekulahlekelweni kolawulo ekunciphiseni ukungenisa kunye nokungakwazi ukuguqula umkhwa owenziwe ngexesha. Omnye wemiceli mngeni ephambili kuphando lwe-preclinical addiction ibe kukucacisa iindlela ezikhokelela ekuphulukaneni nolawulo lokusetyenziswa kweziyobisi kunye ne-predisposition to relaps.e (uKoob kunye noLe Moal, 1997). As ichazwe ngu Imodeli yeNkqubo yoMchasi, ukusetyenziswa okuphindaphindiweyo kwezinto ezikhobokisayo kuguqula imijikelezo yomvuzo ngokunciphisa imeko yolonwabo kunye nokwandisa le meko ilandelayo ingathandekiyo. Emva kokuyeka ukusetyenziswa ngokuphindaphindiweyo kwiziyobisi ezikhobokisayo, kuvela imbuyekezo echasene nemiphumo ephambili yeyeza-iimpawu zokuyeka. Ukuncitshiswa kweempawu zokurhoxisa ngoko kuya kubonisa ukuqiniswa okungalunganga. Ukuncipha kwemeko engathandekiyo yeempawu zokurhoxa kuba yeyona nto iqhubayo ekuqhubekeni nokusetyenziswa kweziyobisi. Kwimbono eyenziwe lula ye ithiyori ye-dopamine (Bulumko, 1978, 2008; IBerridge kunye neRobinson, 1998; Everitt noRobbins, 2005; Diana, 2011), inkqubo ye-acute euphoric efunyenwe ngokunxila imele ukusebenza kwenkqubo ye-dopaminergic, ngelixa icandelo elibi eliphuma kwixesha lokurhoxa liphawulwa kukuncipha komsebenzi we-dopamine (uTomkins kunye nabathengisi, 2001). Intshayelelo ye ubuthi obusebenzayo (UWeiss noKoob, 2001), enxulunyaniswa nemeko yokurhoxa engathandekiyo eqhutywa kukufunwa kwe-neurotransmitter yoxinzelelo, iCRF, yandisa ngakumbi ithiyori ye-dopamine njengoko kusebenza kumlutha.

Inkqubo yokukhupha iCorticotropin (CRF).

I-CRF, ekwabizwa ngokuba yi-corticotropin ekhulula ihomoni (CRH), ibonakaliswe ukuba yenza utshintsho oluhlukeneyo lokuziphatha olunxulumene nokuziqhelanisa noxinzelelo. I-Dysregulation yenkqubo yeCRF nangaliphi na ixesha kunokukhokelela kwiintlobo ezahlukeneyo zeengxaki zengqondo ezifana nokudakumba, ukuphazamiseka okunyanzelekileyo, ukuphazamiseka kwengxaki emva kokuphazamiseka kunye ne-SUD.s (uCole et al., 1990; Sarnyai et al., 1992, 2001; Cador et al., 1993; Koob kunye neKreek, 2007; UKoob kunye noLe Moal, 2008a). Uxinzelelo olubangelwa yi-Footshock lubonakaliswe ukuba luyasebenza ekukhuthazeni ukubuyiselwa kotywala (Le et al., 1998, 2000; Irhasi kunye noMnquma, 2007; Richards et al., 2008), inikotini (Buczek et al., 1999), icocaine (Erb et al., 1996), i-opiate kunye ne-psycostimulants (Lu et al., 2003) kunye neheroin (uShaham et al., 1997) ukufuna. Ngokukodwa iCRF iye yanxulunyaniswa nokubuyiselwa kweziyobisi (Shaham et al., 1997; Makhe et al., 2002; ULiu kunye noWeiss, 2002; UFunk et al., 2006). I-CRF ikwabonakaliswe ukuba ivelisa isimilo esifana nexhala ngexesha lokurhoxa kwi-ethanol engapheliyo (uBaldwin et al., 1991; Overstreet et al., 2004) kwaye unokuba noxanduva lokuzingisa kobuthathaka kunye nokubuyela umva ekugqibeleni.

The Inkqubo yeCRF iqulathe iiligand ezine: CRF, urocortin (UCN) (Vaughan et al., 1995) I-1, i-2, kunye ne-3, i-G-protein-coupled receptors (GPCR), i-CRF-receptor 1 (CRF-R1) kunye ne-CRF-receptor 2 (CRF-R2), kunye ne-CRF eyimfihlo yokubopha iprotheni (CRF- BP); bona iTheyibhile Itheyibhile11 kunye (uBale kunye noVale, 2004) kuphononongo lwenkqubo yeCRF.

Inkqubo yokukhupha iCorticotropin (CRF)..

igamauhloboUkubopha i-receptorInkcazo ye-CNSInkcazo yeperipheralUkubandakanyeka kwimpendulo yoxinzelelo
CRFi-ligandCRF-R1 > CRF-R2idityaniswe kwi-PVN isasazwe ngokubanziamathumbu, ulusu, adrenal glandI-axis ye-HPA: ibangela ukukhutshwa kwe-ACTH ngaphandle kwe-axis ye-HPA: ilawula iimpendulo ezizimeleyo kunye nokuziphatha.
I-CRF-R1i-receptor-CC, CB, MS, HIP, VTA, amygdala, pituitaryβ iiseli pancreasixhala
I-CRF-R2i-receptor-RN, LS, HY, CPintliziyo, i-GI, imiphunga, imisipha yamathambo, i-vasculaturei-anxiogenic/anxiolytic
CRF-BPiprotheni ebophelelayo-CC, HY, amygdala, VTAI-Plasma, i-amniotic fluid, i-placenta, i-pituitary gland, isibindiI-periphery: yenza i-CRF CNS ingasebenzi: ayimiselwanga
UCN 1i-ligandI-CRF-R1/CRF-R2EWI-GI, i-testis, i-myocytes yenhliziyo, i-thymus, ulusu, i-spleenI-periphery: iphakanyiswe kukungaphumeleli kwentliziyo (Wright et al., 2009) I-CNS: lungisa usasazo lwe-glutamatergic synaptic (Liu et al., 2004)
UCN 2i-ligandI-CRF-R2HY, ubuchopho, intambo yomgogodlaintliziyo, iiseli zegazi, i-adrenal glandUlawulo oluphakathi lokuzimela kunye nomnqweno wokutya (Reyes et al., 2001) Umahluko wesini kwindlela yokuziphatha efana noxinzelelo (uChen et al., 2006)
UCN 3i-ligandI-CRF-R2HAYI, amygdalaGI, pancreasi-homeostasis yamandla (Li et al., 2007) iziphumo ezinjenge-anxiolytic (Valdez et al., 2003)

I-CeA, i-nucleus ephakathi ye-amygdala; CB, cerebellum; I-CC, i-cerebral cortex; I-CP, i-plexus ye-choroid; EW, imizimba yeeseli ze-Edinger Westphal nucleus; I-GI, i-gastrointestinal tract; I-HIP, i-hippocampus; HY, i-hypothalamus; I-LS, i-septum esecaleni; MS, i-medial septum; OLF, indawo yokuphunga; I-PVN, i-nucleus ye-paraventricular ye-hypothalamus; RN, raphe iinuclei.

 

Inkqubo yokukhupha iCorticotropin (CRF)..

Ekuqaleni ichongiwe njenge-hypothalamic factor enoxanduva lokuvuselela ihomoni ye-adrenocorticotropic (ACTH) kwi-pituitary yangaphambili (uGuillemin noRosenberg, 1955; Saffran et al., 1955) apho ivuselela i-glucocorticoid synthesis kunye ne-secretion yenza i-adrenal cortex (i-Turnbull kunye ne-Rivier, 1997). Igama layo lasekwa kwiminyaka engamashumi amathathu phambi kokuchongwa kwayo kwi-biochemical 1980's (Vale et al., 1981) ngelixa isazisi saso sofuzo kwiZiko leSizwe loLwazi lwe-Biotechnology (NCBI) yi-CRH. Yi-4.7-kilo-Dalton (kDa) peptide kwaye ineentsalela ze-amino acid ezingama-41. I-Neurosecretory neurons ye-nucleus ye-paraventricular (PVN) ye-hypothalamus synthesize CRF (Meloni et al., 2005). I-CRF ke iye ikhutshelwe kwi-afferent portal blood vessels to the anterior pituitary gland apho ikhuthaza ukukhutshwa kwe-ACTH kumjikelezo wenkqubo. I-hypothalamic-pituitary-adrenal (HPA) i-axis ilawulwa yimpendulo engalunganga evela kwi-glucocorticoids eyenza i-glucocorticoid receptors ngokukodwa kwi-PVN kunye ne-hippocampus. CI-RF iphinda ibonakaliswe ngaphandle kwe-axis ye-HPA ukulawula iimpendulo ezizimeleyo kunye nokuziphatha koxinzelelo (Palkovits et al., 1983; Swanson et al., 1983) kubandakanywa ukubuyiselwa okubangelwa uxinzelelo lokufuna iziyobisi.

I-CRF ilamla iimpendulo zoxinzelelo lomzimba ngokuvula i-CRF-R1 kunye ne-CRF-R2, ezisasazwa kwi-periphery kunye nengqondo. (De Souza, 1995; Bale kunye neVale, 2004). Kukholelwa ukuba ukubophelela kwe-CRF kwi-CRF-Rs yindlela enamanyathelo amabini. I-N-terminus ye-receptor ekuqaleni ibophelela kwi-C-terminus yeCRF, eqalisa ukulungiswa kwakhona kwe-receptor (uGrace et al., 2007). I-CRF N-terminus iqhagamshelana nezinye iisayithi kwi-receptor ukuqalisa umqondiso weselula (Vale et al., 1981; Rivier et al., 1984) kwaye ngenxa yoko uvule i-G-protein (Nielsen et al., 2000; UGrace et al., 2004; Rijkers et al., 2004; Yamada et al., 2004; Ewe, 2005). Inkqubo yeCRF ibandakanya ezinye iipeptides ezine-homology yesakhiwo kwiCRF. I-UCN 1 ibonisa i-45% yolandelelwano lwesazisi kunye neCRF kwaye ibophelela ngokuhambelana okuphezulu kuzo zombini ii-subtypes ze-CRF receptor (Perrin et al., 1995), ngelixa i-CRF ibophelela ngobudlelwane obuphezulu kwi-CRF-R1 (Vaughan et al., 1995; Burnett, 2005). I-UCN 2, eyaziwa ngokuba yi-peptide ehlobene ne-stresscopin, kunye ne-UCN 3, eyaziwa ngokuba yi-stresscopin ibophelela ngokukodwa kwi-CRF-R2 (i-Hsu kunye ne-Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001).

I-CRF-R1 ineentsalela ze-amino acid ezingama-415 kwaye ibonakaliswa kwi-periphery nakwi-CNS (Chang et al., 1993; I-Chen et al., 1993; Vita et al., 1993; Umbumbi et al., 1994; Tsai-Morris et al., 1996; Sanchez et al., 1999; Van Pett et al., 2000). Uxinzelelo olungapheliyo olulamlwa ngokusebenza kwe-CRF-R1 yiCRF iye yanxulunyaniswa nophuhliso lokuphazamiseka kwexhala. (UArborelius et al., 1999); Abachasi be-CRF-R1 baye baboniswa ukunciphisa ukuziphatha okuxhalabisayo (Funk et al., 2007). Iimpuku zeTransgenic ngokucinywa kweCRF-R1 (CRF-R1 knock out (KO) iimpuku) ziye zanciphisa ukusabela kuzo zombini uxinzelelo kunye noxinzelelo, kuphononongo olubanzi bona (iBale kunye neVale, 2004). Esi siphumo se-anxiolytic, nangona kunjalo singabalelwa ekunciphiseni ukujikeleza kweglucocorticoids kwiimodeli zangaphambili (iTronche et al., 1999). Umgca wemouse we-KO onemiqathango wenziwa ukwahlula ukuziphatha kwi-neuroendocrine CRF-mediated CRF-R1 iindlela zokubonisa. Ukungasebenzi okukhethiweyo kwezakhiwo ze-limbic, kodwa kungekhona inkqubo ye-HPA ibonise ukuba i-CRF-R1 imodareyitha ukuziphatha okufana nokuxhalaba kwaye izimeleyo kwi-HPA (Muller et al., 2003). Ngaphaya koko, i-CRF-R1 kucingelwa ukuba yonyusa ukuchaphazeleka kokuziphatha kwakhona kotywala (Hansson et al., 2006; UHeilig noKoob, 2007). Uphononongo lwakutsha nje luvavanye indima yeCRF ngaphakathi nangaphandle kweHPA ibonise ukuba iCRF ngokusebenzisa umqondiso weCRF-R1 inokuba neziphumo ezichaseneyo ekuselweni kotywala okunxulumene noxinzelelo (Molander et al., 2012).

I-CRF-R2 ineendlela ezintathu ezahlukeneyo: α,β, kunye no-γ. I-α iqulethwe ngama-amino acid angama-411 kwaye i-β iqulethwe ngama-amino acid angama-413-418. Zombini zifumaneka kwingqondo kunye ne-periphery; nangona kunjalo, i-CRF-R2β ifumaneka kakhulu entliziyweni kunye ne-vasculature (Lovenberg et al., 1995a,b; Kimura et al., 2002; Burnett, 2005). Ukwahluka kwe-γ yipeptide encinci equlethe kuphela iintsalela ze-amino acid ezingama-397, kwaye ifumaneka kuphela kwingqondo yomntu (Kostich et al., 1998). Indima echanekileyo ye-CRF-R2 kulawulo lwempendulo yoxinzelelo ngumxholo wophando olunzulu. Uphononongo lwemodeli yemouse yemfuza ngokucinywa kwe-CRF-R2 (CRF-R2 KO iimpuku) lubonise ukuba ukusebenza kweCRF yeCRF-R2 kunokukhokelela ekwandeni okanye ekwehleni kwempendulo kwizixinzelelo (Bale et al., 2000, 2002; Iindleko et al., 2000; Kishimoto et al., 2000).

Ukungabikho kwe-antisera ethile exhasa iimvavanyo ze-immunohistochemical kunye nesisombululo esiphantsi seendlela zokubopha i-ligand ziye zanciphisa izifundo zokucacisa ukuhanjiswa kwe-CRF-R kunye nokunciphisa uhlalutyo kwinqanaba le-mRNA. Ukoyisa esi sithintelo, imowusi ye-transgenic echaza ukubonakaliswa kwe-CRF-R1 eneprotein ye-fluorescent eluhlaza (GFP) yenziwe ngempumelelo ibonelela ngesixhobo esinoveli sokuphanda indima ye-CRF-R1 yomqondiso kuhlengahlengiso loxinzelelo (Justice et al., 2008).

I-CRF-BP i-soluble yamanzi, i-37 kD protein kwaye iqulethe iintsalela ze-amino acid ezingama-322 (iBale kunye neVale, 2004). Yi-glycoprotein efihliweyo, egcinwe ngokufanelekileyo kwiigranules ezifihlakeleyo kwaye ikhutshwe kwindawo engaphandle kwe-extracellular ngokusebenzisa i-exocytosis (uBlanco et al., 2011). Iqulethe i-aspargine ye-N-linked-type oligosaccharides ebalulekileyo kwi-CRF-BP ebophelela kwiCRF (Suda et al., 1989). Iinzame zangaphambili zokuchonga i-molecule inhibitors encinci ye-CRF-BP ivelise impumelelo elinganiselweyo ngenxa yenxalenye yobudlelwane obuphezulu (i-picomolar) ye-CRF ebophelela kwi-CRF-BP (Behan et al., 1995a) kwaye nangenxa yokuba i-CRF-BP ubude obupheleleyo (FL) ichaphazeleka kwi-autocatalytic proteolysis (uWoods et al., 1999). Ukucandeka okuzenzekelayo kwe-proteolytic kuvelisa iqhekeza elikhulu le-N-terminal ye-27 kD, CRF-BP (27 kD), egcina isiza esibophelelayo seCRF kunye nencinci, i-9.6 kD C-terminal fragment, CRF-BP (10 kD) (Woods) okqhubekayo., 1999) ngaphandle kwendima ecacileyo yomzimba okanye ye-pathological. Indawo ekhethekileyo yokuqhawula i-CRF-BP (FL) ichongiwe phakathi kweentsalela ze-amino acid i-serine 234 kunye ne-alanine 235. Ukuveliswa kwamaqhekeza amabini kuye kwenza kube nzima kakhulu ukuhlambulula ngempumelelo inani elaneleyo le-CRF-BP (FL) ukufunda i-physiological. iiprotheyini zemveli. I-CRF-BP isasazwa kwi-plasma, i-amniotic kunye ne-synovial fluid, i-placenta, i-pituitary gland, isibindi, kunye nemimandla eyahlukeneyo yobuchopho, kubandakanywa ne-cerebral cortex, i-hippocampus (Behan et al., 1995a), i-amygdala (uHerringa et al., 2004) kunye neVTA (Wang kunye neMorales, 2008). Kwi-periphery, ukujikeleza kwe-CRF-BP kunciphisa izenzo ze-physiological ze-CRF (Kemp et al., 1998). Ngenxa yobudlelwane obuphezulu neCRF, kukholelwa ukuba iCRF-BP idlala indima yesithinteli ngokunciphisa isixa seCRF yasimahla. Engqondweni, nangona kunjalo, i-CRF-BP ibotshwe kakhulu kwi-membrane kwaye ibonakaliswe ngeemali ezahlukeneyo kwi-neurons kunye neeseli ze-neuroglial (Behan et al., 1995b). Ngaphakathi kweeseli ze-neuronal, iziphumo zamva nje zibonise ukuba i-discrete subpopulations ye-VTA dopaminergic kunye ne-γ-aminobutyric acid (GABAergic) neurons echaza iCRF-BP (Wang kunye neMorales, 2008). Indima ye-physiological ye-CRF-BP kwinkqubo ye-nervous central (CNS) ayikacaci. Ukongeza, iithiyori zicebisa ukuba kungenzeka ukuba iCRF-BP inokuncedisa ukucocwa kweCRF emzimbeni kwaye inokukhusela iCRF ekuthotyweni (Seasholtz et al., 2002). Izifundo zemodeli yemouse yemfuza ngokucinywa kwe-CRF-BP (CRF-BP KO iimpuku) zibonise ukuba kukho ukonyuka kokuziphatha okuxhalabileyo (Karolyi et al., 1999). EUphononongo lwe-lectrophysiology lubonise ukuba umqondiso weCRF ngeCRF-R2 ukwenza i-N-Methyl-D-aspartate (NMDA)-mediated excitatory postynaptic currents (EPSCs) kwi-VTA. (Ngaphandle kokuba et al., 2003). Ngaphaya koko, kusetyenziswa iCRF (6–33), i-peptide ekhuphisana neCRF kwindawo yokubophelela kwe-CRF-BP, kodwa ayibopheleli kwi-CRF-R2, kwaboniswa ukuba ithintele ukwenzeka okubangelwa yi-CRF kwee-EPSCs ze-NMDAR-mediated okqhubekayo., 2003). Xa zidibene, ezi ziphumo zibonisa ukuba iCRF-BP inendima eyahluka-hlukeneyo ekumodareyitheni inkqubo yeCRF. Njengoko kuchazwe ngu in vitro kwaye kwi vivo izifundo, ukuhlanjululwa kwe-CRF-BP (FL) yabantu kwimiyinge eyaneleyo yophando ayiphumelelanga ukuza kuthi ga ngoku (Woods et al., 1997). Akukhange kubekho naziphi na izixhobo zophando ezikhoyo ukubonisa indima ye-CRF-BP kwi-CNS ngokubonakalisa i-CRF-BP kwi-cell surface. Ngoko ke, akukhange kwenzeke ukumisela ukuba ngaba iCRF-BP ithatha inxaxheba ngokukodwa kuphawu lweCRF-R2. Isishwankathelo sokubandakanyeka kweCRF ezibophelelayo ekuziphatheni okukhobokisayo sichazwe kwiTheyibhile Itheyibhile22.

Ukubandakanyeka kweCRF ezibophelelayo ekuziphatheni okukhobokisayo.

CRF-R1 abachasiUkunciphisa uxinzelelo-olubangelwa kukubuyela ekufuneni iziyobisi kunye neenguqu zokuziphatha ezinxulumene nokuyeka; iimolekyuli ezincinci kunye neepeptides ziyafumaneka ukuze ziphandwe
CRF-R2 abachasiUkulawulwa kwempendulo yoxinzelelo kunye nokuziphatha komlutha akucaci; iimolekyuli ezincinci kunye neepeptides ziyafumaneka ukuze ziphandwe
Abachasi beCRF-BPUkumodareyithwa komsebenzi we-neuronal kunokuba kujoliswe kuzo zombini iziyobisi zokuxhatshazwa kunye nokuphendula koxinzelelo; kuphela iipeptides ezifumanekayo ukuze ziphandwe

 2 Table

Ukubandakanyeka kweCRF ezibophelelayo ekuziphatheni okukhobokisayo.

Uxinzelelo lweziyobisi olubangelwa luxinzelelo: I-CRF-mediated neurotransmission kunye neplastiki

Ukuqiniswa: indawo ye-ventral tegmental (VTA) kunye ne-nucleus accumbens (NAcc)

Iziyobisi ezikhobokisayo zibonisiwe ukuba zonyusa uxinzelelo lwe-dopamine kwi-NAcc. Ngapha koko, ukonyuka kwe-dopamine kunxulunyaniswa nokwandiswa kwempembelelo ye-hedonic yabaqinisekisi abalungileyo (iFibiger, 1978; Berridge et al., 1989) kunye nophuhliso lweendlela zokuziphatha eziluthayo (iYokel kunye noBulumko, 1975; uBonci kunye noMalenka, 1999; Bulumko, 2008). I-NAcc ifumana igalelo kwi-VTA kwaye kucingelwa ukuba le ndlela inokuba noxanduva kungekuphela nje ngesiphumo esimnandi sokutya ichiza, kodwa kunye nokomelezwa okungalunganga kunye neziphumo zeendlela zokuziphatha zokufuna iziyobisi (uKoob noNestler, 1997).

Ukubandakanyeka kweeseli zeCRF kwi-VTA

I-VTA ifumana uqikelelo lweCRF ikakhulu kwilimbic forebrain kunye nePVN yehypothalamus (Rodaros et al., 2007) eyenza i-glutamatergic synapses kunye ne-symmetric GABAergic synapses (Tagliaferro kunye neMorales, 2008). IPVN yindawo yokudityaniswa kweCRF (UMeloni et al., 2005) kwaye uninzi lwe-asymmetric synapses (glutamatergic) zibonakaliswa kwiCRF- kunye ne-dopaminergic-containing neurons. I-VTA dopaminergic neurons ichaza iCRF-R1 (UVan Pett et al., 2000) kunye nophononongo lwakutsha nje lubonise ukuba tUninzi lwe-VTA neurons ezibonisa iCRF-BP ziyi-dopaminergic (Wang kunye neMorales, 2008).

TInkqubo yeCRF imodareyitha i-dopaminergic neurons ngokuvula iCRF-R1 kunye neCRF-R2; nangona kunjalo, iCRF ayibandakanyekanga kuphela kwi-neuroexcitability yenkqubo ye-dopaminergic. Isenokuba noxanduva lokumodareyitha imincili kunye ne-inhibitory synaptic inputs kuba i-VTA ifumana amagalelo kuzo zombini i-CRF-glutamatergic- kunye ne-CRF-GABAergic-equlathe ii-neurons. (Tagliaferro kunye neMorales, 2008) kunye nokuhlaziywa jonga iBorgland et al. (2010).

I-CRF yonyusa izinga lokudubula kwe-VTA dopaminergic neurons (Korotkova et al., 2006; Wanat et al., 2008) ngeCRF-R1, kwaye ibandakanya i-phospholipase C (PLC)–protein kinase C (PKC) indlela yomqondiso kunye nokuphucula Ih (i-hyperpolarization-activated inward current) (Wanat et al., 2008). I-CRF isenokuphembelela ukwenzeka okuhamba kancinci kancinci kosasazo lwe-synaptic ye-NMDA nge-CRF-R2 kunye nokuvula indlela yomqondiso ye-PLC-PKC. I-CRF-R2-mediated potentiation ibonakaliswe ukuba ifuna ubukho be-CRF-BP (Ungless et al., 2003). Indlela yokusebenza ye-CRF-R2 kunye ne-CRF-BP isaphandwa njengoko izixhobo zophando ezifunekayo ukufunda i-CRF-BP kunye ne-antisera ekujoliswe kuyo ngokukodwa i-CRF-R2 azikafumaneki.

I-CRF ibonakala inezo zombini izenzo ezikhuthazayo kunye nezithintelayo kwi-dopaminergic neurons kwi-VTA. Uphononongo olusebenzisa i-cocaine kunye ne-methamphetamine lubonise oko Isiphumo sochulumanco seCRF kwi-dopaminergic neurons sibandakanya iziganeko ezikhawulezayo, umzekelo inyathelo elinokubakho lokudubula kunye ne-NMDAR-mediated synaptic transmission, ngelixa iziphumo ezithintelayo zeCRF zibandakanya iindlela ezicothayo zokuhanjiswa kwe-synaptic ezinokukhokelela kwiplastiki yexesha elide. (Beckstead et al., 2009). Olo qwalaselo lubonise ukuba iCRF inokuba nezenzo ezahlukeneyo kwizamkeli ezilamla isenzo se-synaptic kwi-dopamine. Lo matshini weselula unokucokisa indima yoxinzelelo ngezenzo zeCRF kukuziphatha kwe-dopamine-mediated (Beckstead et al., 2009).

Njengoko kubonisiwe ukuba amandla e-CRF-R2, kodwa kungekhona i-CRF-R1, ukubonakaliswa kufuna ubukho be-CRF-BP (Ungless et al., 2003), kucetywayo ukuba i-CRF-BP kunye ne-CRF-R2 zidibanise iindlela ezihlala ixesha elide ze-synaptic plasticity (uBonci noMalenka, 1999). BI-oth sensitization yokuziphatha kunye nokubanakho kwexesha elide (LTP) ukwabelana ngeempawu ezininzi ezinjengokubandakanyeka kwe-NMDAR kusebenze ukufakwa kwe-LTP kwi-VTA dopaminergic neurons. (Bonci kunye noMalenka, 1999; Ngaphandle kokuba et al., 2001). ANgenxa yoko, kuye kwacetyiswa ukuba i-synaptic plasticity kwi-synapses evuselelayo kwi-VTA dopaminergic neurons inokudlala indima ephambili ekuqaliseni utshintsho lokuziphatha. Kuba ukusebenza kwe-NMDAR kufunwa ukwenziwa kwe-LTP kwi-VTA dopaminergic neurons, ukusebenza kwe-CRF-Rs kunokulungelelanisa iindlela ezihlala ixesha elide zeplastiki. (Bonci kunye noMalenka, 1999; Ngaphandle kokuba et al., 2001; Bonci kunye neBorgland, 2009).

I-CRF-mediated neurotransmission kunye neplastiki

Uhlengahlengiso lwe-Synaptic olujongwe kuhlengahlengiso lweesekethe ze-neuronal kwizifundo zeziyobisi ezikhobokisayo zibonakaliswe zinefuthe kwindlela yokuziphatha kunye neempawu zememori ezibonisa ii-SUDs. I-neuroplasticity ephantsi kwe-sensitization eyenzelwe iziyobisi ivelise ubungqina obukhulayo obubonisa ukuba inokumela isiphumo semolekyuli ebaluleke kakhulu ekumodareyitheni izimilo zokulutha kwaye iya kuba negalelo ekuziphatheni okunyanzelekileyo okubangelwa luxinzelelo.

Iitheminali zeAxon zeCRF neurons synapse kwiVTA neuronal dendrites (iTagliaferro kunye neMorales, 2008) kwaye kubonakala ngathi uxinzelelo luchaphazela ukukhutshwa kweCRF kulo mmandla (Wang et al., 2006). Uphononongo lwe-Electrophysiological lubonise ukuba iCRF-BP iyadingeka ekuphuhliseni kancinci, okwenzeka okwethutyana kwe-NMDAR-mediated synaptic transmission eyenziwe yiCRF ngeCRF-R2 ngokukodwa (Ungless et al., 2003). Ezi ziphumo ziye zaxhaswa zizifundo zokuziphatha eziye zamisela ukusebenza koxinzelelo ekuqaliseni i-glutamate kunye nokukhululwa kwe-dopamine kwi-cocaine yokufuna iimpuku ezinamava eziyobisi (Wang et al., 2007b). Ucula iimodeli ezingapheliyo ze-cocaine preclinical, uphononongo lubonise ukomelezwa okulungileyo okuhambelana neCRF, ngakumbi iCRF/CRF-R2/CRF-BP ukusebenzisana ne-dopaminergic system.. Ezo ziphumo zixhasa iinzame zophando ezongezelelweyo zokuphuhlisa iindlela ezintsha eziphanda iCRF-BP kumphezulu weseli.

Ukuqukumbela, iCRF yonyusa umsebenzi we-VTA glutamatergic synaptic, onokuthi uququzelele ukudubula kwe-VTA okanye ukufakwa kweplastiki ye-synaptic enokuthi ibangele ukuvezwa okuphindaphindiweyo kwiziyobisi zokuxhatshazwa. Le nkqubo inokuvelisa i-neuroadaptations yexesha elide eguqula iimpendulo zoxinzelelo kunye nokuphucula ukufuna amachiza. Izifundo ze-Electrophysiological ezidityaniswe nezifundo zokuziphatha zicebise ukuba amava angaphambili kunye neziyobisi zokusetyenziswa gadalala angaququzelela amandla oxinzelelo lokuqhuba ukufuna iziyobisi kwaye, ngenxa yoko, ukuphinda ubuyele. Ezi ziphumo zibonisa ukuba iCRF inokubaluleka kwi-synaptic plasticity ekhutshwe ngamachiza kwi-VTA dopaminergic neurons kwaye inokumela i-molecular substrate echaza ixhala kunye nokuphendula koxinzelelo ngexesha lokurhoxa kwizinto ezisetyenziswa kakubi.

Ukubandakanyeka kweselula yeCRF kwi-amygdala

I-amygdala ikholelwa ukuba ngummandla wobuchopho obalulekileyo ekuphenduleni ngokweemvakalelo kwaye ibalulekile ekuboneleleni ngobuchule kulwazi lweemvakalelo (Adolphs et al., 1994; LeDoux, 2003; Phelps kunye neLeDoux, 2005). Iimpendulo ezichaphazelekayo ezichaphazelekayo ziye zafundwa kwi-nuclei ethile ye-amygdala ngokufunda impendulo yokwesaba okusemgangathweni (uDavis, 1992a,b). I-amygdala idityaniswe ngokubanzi kwezinye iingingqi ze-limbic apho ithatha inxaxheba ekudibaniseni ulwazi lwengqondo kunye nokuqonda (LeDoux, 1992, 1993). Ubungqina bovavanyo bucebisa ngamandla isenzo sokusetyenziswa kakubi kweziyobisi kule nkqubo kwaye inokuguqula imicimbi ye-synaptic ngakumbi ngexesha lokurhoxa. Ngelixa i-VTA iye yadityaniswa neziphumo zokuqinisa i-ethanol (uGatto et al., 1994), ukusebenza kwenkqubo ye-GABAergic iye yadibaniswa nefuthe le-alcohol anxiolytic (Frye kunye neBreese, 1982). Ukongeza kwiisekethe ezivuzayo zeqokobhe le-NAcc, kunye nemimandla yobuchopho eyenziwe luxinzelelo lwe-pharmacological, njenge-yohimbine kunye ne-footshock zifunyenwe zithe ngqo kwi-basolateral kunye ne-amygdalar nuclei ephakathi, kunye ne-nucleus yebhedi ye-stria terminalis (BNST) (Funk et al., 2006). Izifundo zangaphambi kweklinikhi zibonise ukuba ukuvezwa kunye nokurhoxa kwi-ethanol kubangela utshintsho olusebenzayo kunye ne-biochemical kwi-amygdala yeegundane, ebonisa ukuba le sekethi ibandakanyeka ekunyukeni kwexesha elide ekuziphatheni okufana nokuxhalaba emva kokuvezwa kwe-ethanol engapheliyo (Christian et al., 2012).

I-amygdala ilamla iimpendulo ezikwimeko kunye nezingenamqathango kwi-aversive stimuli (UDavis kunye neWhalen, 2001) kwaye iphandwe kusetyenziswa imeko yoloyiko lwePavlovian ngokudibanisa isivuseleli esinemeko kunye ne-aversive unconditioned stimulus. Ukuvezwa kwakhona kwe-stimulus engenamiqathango kuvuselela impendulo yoloyiko oluqinisekisiweyo oluvela kumbutho ongenamiqathango (Pitts et al., 2009). Isibonakaliso sombutho senzeka kwi-basolateral amygdala (BLA) kwaye emva koko idluliselwe kwi-nucleus ephakathi ye-amygdala (CeA) (McDonald, 1998; Maren, 1999; UDavis noShi, 2000; Pitkanen et al., 2000; Pare et al., 2004). Le nkqubo yosulelo ibandakanya zombini izinxulumani ezilungileyo nezingalunganga.

Onke amacandelo enkqubo yeCRF, CRF, CRF-Rs kunye neCRF-BP zibonakaliswa kwi-amygdala (Umbumbi et al., 1994). FNgapha koko, i-amygdala ngowona mthombo mkhulu we-extrahypothalamic we-CRF-equlethe i-neurons. (Palkovits et al., 1983; Van Pett et al., 2000). Zombini i-BLA kunye ne-CeA nuclei zidlala indima ekuphenduleni uxinzelelo (Richter et al., 1995; UMerali et al., 1998; Koob kunye noHeinrichs, 1999). Uphononongo olubanzi lubonise ukuba Inkqubo yeCRF ithatha inxaxheba ekuhlanganiseni inkumbulo ebandakanya isekethe ye-BLA-CeA (Roozendaal et al., 2002; Hubbard et al., 2007). Kuye kwaphawulwa ukuba ukukhululwa kweCRF kwi-amygdala yonyuka ngexesha lokuhoxiswa ngokukhawuleza (i-Richter kunye ne-Weiss, 1999); ke ngoko, Kucingelwa ukuba iCRF inokulungelelanisa iplastiki ye-synaptic evuswe ngamachiza (Ngaphandle kokuba et al., 2001, 2003) kunye nophononongo lwakutsha nje, bona (uLuscher noMalenka, 2011). Isiseko se-neuronal sokuqiniswa okungalunganga asiqondwa kakuhle; Nangona kunjalo, uphononongo lwamva nje lokuziphatha lubonise ukuba iCRF iyakwazi ukwenza imisinga ye-synaptic evuselelayo ngeCRF-R1 kwi-CeA iiveki ezimbini emva kokurhoxa kwi-cocaine (Pollandt et al., 2006).

Uphononongo lwakutsha nje lubonise ukuba iCRF-R1 idlala indima ephambili kwixhala (Refojo et al., 2011). Ngelixa ukucinywa kwe-CRF-R1 embindini wengqondo ye-dopaminergic neurons yonyusa ixhala-njengokuziphatha kwaye kunciphisa ukukhutshwa kwe-dopamine kwi-prefrontal cortex, ukucinywa kwe-CRF-R1 kwi-forebrain glutamanergic neuronal network kunciphisa ixhala kwaye kuphazamisa ukuhanjiswa kwi-amygdala kunye ne-hippocampus (Refojo et al., 2011).

Indima yeCRF iye yavavanywa ngokubanzi ekusetyenzisweni kwe-ethanol ngokuzithandela kusetyenziswa ukubonakaliswa kofuzo kunye nokwahluka kofuzo kwiimodeli zangaphambi kweklinikhi bona (Bjork et al., 2010) kuphononongo olubanzi. Kwizilwanyana ezivezwe nge-ethanol, i-ethanol intake yancitshiswa ngokulawulwa komchasi we-CRF-R1, kwaye yavavanywa kusetyenziswa ukungenelela kwe-pharmacological okunciphisa ukuziphatha okuxhalabisayo (Logrip et al., 2011; Zorrilla kunye noKoob, 2012). Ukuncitshiswa kokutya kwe-ethanol kuye kwaphawulwa kwiimpuku ze-transgenic ngokucinywa kwe-CRF-R1 (CRF-R1 KO) (Chu et al., 2007). Abachasi be-CRF-R1 banciphisa ukuxhalaba okunxulumene nokurhoxiswa kweziyobisi kwaye banciphise iziphumo ezibi zokuqinisa i-ethanol ezinxulumene nokuvezwa kwe-ethanol ixesha elide (Ghitza et al., 2006; UMarinelli et al., 2007; U-Li et al., 2007; UKoob kunye noLe Moal, 2008b; Richards et al., 2008). I-CRF-R1 inhibitors ibonise ukuthomalalisa ukuphinda-phinda uxinzelelo kwi-cocaine kunye ne-heroin kwizilwanyana eziqeqeshiweyo (uShaham et al., 1998) kunye nokunciphisa ukubuyiselwa okubangelwa luxinzelelo kunye noxinzelelo-olunyanzeliswayo lokuphinda kusebenze indawo ekhethwayo kwiziyobisi ezininzi eziluthayo (uKoob noZorrilla, 2010).

I-amygdala eyandisiweyo

Phakathi kwezakhiwo ze-extrahypothalamic eziqulethe i-CRF ebonisa ii-neurons kukho "i-amygdala eyandisiweyo." I-amygdala eyandisiweyo iqulethwe yi-BNST, i-central medial amygdala (CeA), i-sublenticular sustantia innominata kunye nommandla wenguqu owenza inxalenye yangasemva ye-NAcc. (UHeimer kunye noAlheid, 1991). Imele isekethe yengqondo ebandakanyekayo ekuqhubeni i-aversive stimuli eveliswa kukurhoxa kwe-ethanol (uKoob noLe Moal, 2001), apho inkqubo ye-GABA iye yatshintshwa kwaye inkqubo ye-CRF kwi-CeA ekufutshane iboniswe ukuba isebenze (uRoberts et al., 1996). Olo qwalaselo lubonisa ukuba umsebenzi we-GABAergic ngaphakathi kwe-interneurons ye-amygdala eyandisiweyo inokudlala indima ebalulekileyo kwimeko yemvakalelo engapheliyo efana nemeko yokubaluleka kokufuna iziyobisi kukuxhomekeka kotywala (uKoob noLe Moal, 2001; I-Koob, 2003, 2009a,b). Ukongeza, i in situ Uphononongo lwe-hybridization lubonise ukuba ukufunwa kwe-CRF-R1 yokubonisa, kumacandelo e-amygdala eyandisiweyo, inokuba noxanduva lokuqhuba utywala ngokugqithisileyo ngokuzithandela kwaye inokudityaniswa nokwandisa umsebenzi woxinzelelo (Hansson et al., 2007).

I-BNST (kunye nemimandla eyahlukeneyo ye-CeA) iye yadibaniswa noxinzelelo kunye nokuxhalaba (uWalker noDavis, 2008) kwaye ibandakanyeka ngokukodwa ngokusayinwa kweCRF (Davis et al., 1997). I-CeA kunye ne-BNST inoqikelelo oluthe ngqo kwiindawo ezininzi zobuchopho eziye zafundiswa ukucacisa iimpawu zoloyiko okanye ixhala (Davis, 1992b). Tyena i-BNST ichongiwe njengomlawuli onokwenzeka wokudubula kwe-VTA dopaminergic neuron (UGeorges kunye noAston-Jones, 2002) kwaye ngenxa yoko babandakanyeka kulawulo lwezenzo ezibukhali zotywala, inikotini, kunye necocaine (Watkins et al., 1999; Carboni et al., 2000; Eiler et al., 2003).

The I-BNST inonxibelelwano olubanzi lwe-dopaminergic fibers (i-Fudge kunye ne-Emiliano, 2003) kwaye iqhagamshelwe kwindlela yomvuzo ngoqikelelo olubanzi kwi-VTA, ngaloo ndlela ibe nefuthe kwigalelo lolonwabo kuzo zombini i-NMDA kunye ne-non-NMDA receptors. (UGeorges kunye noAston-Jones, 2001, 2002). Olu gqithiso lwe-dopaminergic excitatory kwi-VTA lufuna ubukho beCRF (Kash et al., 2008). Ulawulo oluluqilima lwe-cocaine lubonakaliswe ukuba luphembelela ukubonakaliswa kwe-dopamine ngophuculo oluthile oluxhomekeke kwi-CRF-R1 yosasazo oluchulumancisayo lwe-NMDA (Kash et al., 2008). Lo matshini wachazwa njengoluhlobo lweplastiki yexesha elifutshane kwi-BNST, enokuthi ibe noxanduva lweziphumo ezibi zeziyobisi (Kash et al., 2008). Ezi ziphumo zicebise ukuba i-glutamatergic neurotransmission kwi-BNST inokubandakanyeka ngokusebenzayo kunye nokuqiniswa kwezenzo zokusetyenziswa kakubi kweziyobisi (uWalker noDavis, 2008).

I-Basolateral amygdala (BLA)

The I-nucleus ye-basolateral ye-amygdala (BLA) ibandakanyeka kakhulu ekufundeni ngokweemvakalelo (LeDoux, 2000), kwaye emvuzweni (Balleine kunye neKillcross, 2006; Tye et al., 2008). IiNeurons ezivela kwiprojekthi ye-BLA ngqo kwi-CeA kunye nakwi-BNST. I-BLA ubukhulu becala iqulunqwe yi-glutamatergic pyramidal neurons kwaye ibonelela ngegalelo eliphambili le-excitatory kwi-CeA kunye nezinye izakhiwo ze-limbic kunye ne-cortical (Sah et al., 2003); Nangona kunjalo, ukuhanjiswa okuchukumisayo kukholelwa ukuba kumodareyithwe linani elincinci le-GABAergic interneurons efunyenwe apho (i-Washburn kunye ne-Moises, 1992). I-GABAergic interneurons ichongiwe njengabalawuli boxinzelelo kunye noxinzelelo (Silberman et al., 2009).

I-CRF ikhona kakhulu kwi-BLA, ngaphezu kwe-CRF-R1 kunye ne-CRF-BP, (Sakanaka et al., 1986; Umbumbi et al., 1992; Van Pett et al., 2000); nangona kunjalo, iziphumo zeCRF kwi-BLA ziye zafundwa ngaphantsi kwee-nuclei ze-amygdala. I-BLA ibonakaliswe njengeyona nucleus ebalulekileyo yokudibanisa uloyiko kunye nenkumbulo kwaye, ngoko ke, yinto ekujoliswe kuyo ekunciphiseni iinkumbulo zengqondo. Kuye kwaboniswa ukuba i-intra BLA infusions ye-CRF yonyusa ixhala-njengokuziphatha (i-anorexia kunye nokuzilungisa) ezithintelwe lulawulo lomchasi we-CRF-R1 (Jochman et al., 2005). Olunye uphononongo lwe-BLA microinfusion lubonise ukuba iCRF-R1 ivuselela ukuqinisa inkumbulo yoloyiko kwaye esi siphumo sivalwe kulawulo lomnye umchasi weCRF-R1. Inkqubo yokudibanisa inkumbulo yoloyiko ibonakala ilawulwa ngokuthe ngqo kukuvula kwe-CRF-R1 kuba umchasi we-CRF-R2 kwi-BLA ingaphazamisanga imeko yoloyiko lomxholo okanye ukusebenza komkhenkce womxholo kuvavanyo loloyiko olungenawo iziyobisi (Hubbard et al., 2007). Ukusebenza kwe-BLA CRF-R1 kuye kwachazwa njengeplastiki ye-synaptic, kwaye ibonisa ukuba ukusebenza kwe-BLA CRF-R1 kunokuvalelwa ngokwe-pharmacologically ngamamolekyuli amancinci, ukuba nokwenzeka kokunciphisa ukudityaniswa kwememori yoloyiko kubonisa ithuba lonyango elinokubakho lokunciphisa uphuhliso lweemvakalelo ezinzulu. iinkumbulo.

I-nucleus amygdala esembindini (CeA)

I-CeA ichongiwe njengendawo yokomelezwa kokulungileyo kokuzilawula kwe-ethanol kunye nokomelezwa okungalunganga okuhambelana nokurhoxa kwe-ethanol (uBaldwin et al., 1991; Heinrichs et al., 1992, 1995; UKoob kunye noLe Moal, 1997, 2001; Zorrilla et al., 2001). I-CeA ichongwe njengendawo ebalulekileyo yokubuyisela umva uninzi lweziphumo zokuziphatha ezinxulumene nokunxila kwe-ethanol (i-Hyytia kunye ne-Koob, 1995).

Kwi-CeA, uninzi lwe-neurons yi-GABAergic (iLanga kunye neCassell, 1993), kwaye iCRF ibonakaliswe kakhulu kunye ne-GABAergic neurons (Veinante et al., 1997; Usuku et al., 1999). I-CeA ichaza ngokubanzi iCRF, CRF-R1 kunye neCRF-BP (Sakanaka et al., 1986; Umbumbi et al., 1992; Van Pett et al., 2000). Ngaphezu koko, kwi-CeA isenzo seCRF kunye ne-ethanol ibonakaliswe ukwandisa ukukhululwa kwe-GABA (Nie et al., 2004) kunye nesixa sokukhululwa kweCRF sinyusiwe kwiimodeli zangaphambi kweklinikhi zokuxhomekeka kwe-ethanol (Merlo Pich et al., 1995). Iprotein kinase C epsilon (PKCε) ibonakaliswe ukumodareyitha i-CRF-R1 yokubonisa kwi-CeA (Choi et al., 2002) kunye neempuku ze-transgenic ngokucinywa kwe-PKCε (i-PKCε KO iimpuku) zibonise ukuziphatha okuncitshisiweyo okufana nokuxhalaba (uHodge et al., 2002). Izifundo ze-Electrophysiological zibonise ukuba ukukhutshwa kwe-GABA ye-ethanol-induced kwi-amygdala ilawulwa yi-CRF-R1 (Nie et al., 2004) kwaye ukukhutshwa kwe-ethanol-stimulated vesicular GABA kuxhomekeke kwiimodeli zePKCε (Bajo et al., 2008). Indlela yokubonisa i-PKCε kwi-CeA yenziwe isebenze yi-CRF-R1 kwaye imodareyitha i-GABAergic neurotransmission enokuthi ibe negalelo kwimiphumo ye-anxiogenic ye-ethanol (uSmith et al., 1998; Timpl et al., 1998). Olu nxulumaniso lusebenzayo phakathi kwe-ethanol, iCRF kunye ne-PKCε emodareyitha i-GABAergic neurotransmission kwi-CeA inokuba negalelo kulawulo lokuziphatha ngokweemvakalelo olulawula ukomelezwa kokusetyenziswa kwe-ethanol kunye nokomelezwa okungalunganga okuveliswa kukurhoxa kwe-ethanol.

Kuye kwaboniswa ukuba kukho umahluko obalulekileyo phakathi kweziphumo zeCRF kwizilwanyana ezivezwe yi-ethanol ephantsi/ephakathi (ukusetyenziswa kwe-ethanol ngokuzingxamela) kunye nezilwanyana ezixhomekeke kwi-ethanol (i-ethanol ehlala ixesha elide). Ngelixa ukuzinkcinkca-njenge-ethanol (i-Lowery-Gionta et al., 2012) kunokubangela ukuphazamiseka okwethutyana kwenkqubo yeCRF enokuthi ikwazi ukubuyela kuyo imeko ye-homeostatic, ukubonakaliswa okungapheliyo kwe-ethanol (uRoberto et al., 2003, 2004) inokuba noxanduva lweCRF neuroadaptation eya kuba nefuthe kwi imeko yemibono yonke. An imeko yemibono yonke ichazwa njengemeko yokuphambuka okungapheliyo kuthungelwano olulawulayo ukusuka kwinkqubo yabo eqhelekileyo kunye nokusekwa kwendawo eyahlukileyo "yozinzo olubonakalayo" (uKoob noLe Moal, 2001). TUkuphambuka kwakhe okungapheliyo kwinqanaba lokumisela umvuzo litshintshwe kakhulu ngexesha lokurhoxiswa kweziyobisi kwaye linokuba negalelo kwi-neuroadaptation elandelayo evelisa ukuba sesichengeni sokulutha kunye nokubuyela kwakhona (uKoob noLe Moal, 2001). Uxinzelelo olubukhali alunyusi ukubonakaliswa kwe-mRNA yawo nawaphi na amacandelo enkqubo yeCRF kwi-CeA (Herringa et al., 2004), nangona kunjalo, kwi I-CeA yezilwanyana ezivezwe kwi-ethanol, kukho ukonyuka okubonakalayo kweCRF mRNA intetho (Ukunqongophala et al., 2005) kunye nakwizilwanyana ezixhomekeke kwi-ethanol ngexesha lokurhoxa (uSommer et al., 2008).

Ukuqeshwa kweCRF kwi-CeA ngexesha lokusela kwangethuba, ngaphambi kokuxhomekeka, kunokuqalisa utshintsho lwe-neuroplastic kwinkqubo enokuqina ngakumbi ngokuvezwa kwe-ethanol okongeziweyo (Lowery-Gionta et al., 2012). Kuye kwacetywa ukuba olu tshintsho luxhomekeke kwiCRF lube negalelo kwinguqu ukusuka ekuzinkcinkceni ngotywala ukuya ekuxhomekeke kwi-ethanol (Lowery-Gionta et al., 2012). Ababhali bafumanise ukuba i-ethanol yonyusa usasazo lwe-GABAergic kwi-amygdala kuzo zombini iindawo zangaphambili kunye nezasemva kwe-synaptic kwizilwanyana ze-ethanol naïve, ngelixa ukusetyenziswa kwe-ethanol ngokuzinkcinkcayo kuphazamisa usasazo lwe-CRF-mediated GABAergic (Lowery-Gionta et al., 2012). Olu phononongo lubonakalise ukuba ukusela kunciphise ifuthe leCRF enalo kusulelo lwe-GABAergic. Ngokwahlukileyo, abanye baye bafumanisa ukuba izilwanyana ezixhomekeke kwi-ethanol zibonise ukuhanjiswa kwe-GABAergic kwi-CeA (uRoberto et al., 2004).

I-CRF kunye ne-norepinephrine zibonakaliswe ukwandisa umsebenzi we-GABAergic olinganiswa yi-GABAA i-inhibitory postsynaptic potential (IPSCs) ekurekhodweni kweeseli ezipheleleyo kwi-CeA. Esi siphumo sivalwe ngabachasi be-CRF-R1 kwaye savalwa kwiimpuku zeCRF-R1 (Nie et al., 2004; Kash kunye Winder, 2006). Ukukhutshwa kwe-GABA eyongeziweyo eveliswe yi-ethanol kwi-CeA kwizilwanyana ezixhomekeke kuyo yabonwa zombini kwi-electrophysiological and kwi vivo imifuniselo ye-microdialysis (uRoberto et al., 2003). Uphononongo lwakamva kwiimpuku ezixhomekeke kwi-ethanol zangqina ukuba ukusebenzisana kwe-CRF-alcohol ekuhanjisweni kwe-GABAergic kwi-CeA kubonakala ngakumbi ngexesha lokuxhomekeka kotywala (uRoberto et al., 2004).

izigqibo

Olu phononongo lushwankathele iindlela ezininzi ezenza utshintsho oluqhubekayo kwi-synaptic efficacy emva kokulawulwa kweziyobisi ezikhobokisayo. IKuyacaca ukuba inkqubo yeCRF iququzelela kakhulu ukufakwa kunye nokugcinwa kweplastiki kwi-VTA kunye ne-amygdala, kunye nesiphumo sokuphucula i-glutamate-mediated excitation kunye nokunciphisa inhibition ye-GABA-mediated, ngaloo ndlela ibe negalelo kwisiseko semolekyuli sokukhotyokiswa kweziyobisi.

I-Neuroplasticity kumvuzo wokujikeleza kwengqondo emva kwembali yokuxhomekeka kwe-ethanol ibonisiwe (uHansson et al., 2008). Idatha yovavanyo eboniswe kolu hlaziyo ixhasa i-hypothesis yokuba uxinzelelo lubangela iplastiki ngaphakathi kwe-VTA kunye ne-amygdala nuclei kwaye inokuthatha inxaxheba ekuphuhliseni imeko yokukhathazeka okungapheliyo okungakhokelela ekuphuhlisweni kwee-SUDs. Olu tshintsho kwinethiwekhi ye-neuronal ye-limbic inokumela i-trigger engakhokelela ekulahlekelweni kolawulo lokusetyenziswa kweziyobisi. Iziyobisi ezikhobokisayo ziye zaboniswa ukuba ziphembelele uvakalelo lokuziphatha kwaye kukho uncwadi oluninzi oluvavanya indima yoxinzelelo kunye nokuziphatha okukhobokisayo. Uphononongo lwexesha elide lwe-neuroadaptation kubukhoboka botywala lubonise ukuba uxinzelelo lobuchopho kunye neenkqubo zoloyiko ziye zisebenze (UHeilig et al., 2010); hNangona kunjalo, kusekuninzi ekufuneka kucaciswe malunga nezenzo zamachiza kwinkqubo yeCRF, ngokumalunga ne-synaptic plasticity kunye neempendulo zokuziphatha.. Uninzi lwabachasi be-CRF-R1 abathintela igazi ebuchotsheni baphuhlisiwe, nangona ezinye iikhompawundi zibonise ukusebenza kakuhle kwiimodeli zezilwanyana ukunyanga utywala (Gehlert et al., 2007, 2012), abachasi be-CRF-R1 abakaphumeleli kwizilingo zeklinikhi (uKoob noZorrilla, 2012).

Ukuthintela konke ukuchanabeka kwizinto ezixhatshazwayo phantse akunakwenzeka, njengoko izinto ezininzi eziphazamisa ingqondo (utywala, inikotini, icaffeine, kunye namayeza kagqirha) zamkelwa ngokubanzi kuluntu lwethu. Kukho amayeza amaninzi avunyiweyo yi-FDA okanye asetyenzisiweyo ngaphandle kweleyibhile yokuxhomekeka kotywala egxininise kunyango lokunciphisa iimpawu (disulfuram, naltrexone), uncedo ngokuhoxiswa (i-benzodiazepines, i-valporic acid, i-varenicline), kunye nokuthintela ukuphindaphinda (i-acamprosate, i-ondansetron), i-baclofen, i-topiramate, i-varenicline, i-methadone) kunye namanye amayeza avunyiweyo e-FDA kwezinye izibonakaliso kwinqanaba le-preclinical (mifepristone) (Simms et al., 2011), nangona kunjalo, i-recidivism ekusebenziseni kakubi iziyobisi kuseyingxaki enkulu kwii-SUDs. Nangona iindidi ezahlukeneyo zeziyobisi zineendlela ezahlukeneyo zokwenza, ukusetyenziswa kweziyobisi ngokuphindaphindiweyo kukhokelela ekuvuselelweni kwe-HPA axis kunye nokuyeka ngequbuliso ukusetyenziswa kweziyobisi ezingapheliyo kwandisa ukusebenza kweCRF. Amayeza amodareyitha iimpendulo zoxinzelelo anokubonelela ngendlela entsha ye-pharmacotherapeutic yee-SUDs. Ukulawula iziphumo zoxinzelelo ngokusebenza kwinkqubo yeCRF kunokunika ithuba lokuphuhlisa le noveli yonyango ejolise ekunciphiseni ifuthe leCRF kusulelo lwe-synaptic. Ngokwenza lula ukufunwa kwechiza okubangelwa luxinzelelo, kunokwenzeka ukunciphisa ukuphinda ubuyele kwaye uququzelele ukwakheka kweenkumbulo ezineziphumo ezingacimiyo zokuziphatha.

Ukungquzulana kwintetho yomdla

Ababhali bavakalisa ukuba uphando lwenziwe ngokungabikho naluphi na ulwalamano lwezorhwebo okanye lwezezimali olubhekiswa njengengxabano yenzuzo.

Imibulelo

Siyabulela uJ. Simms, S. Srinivasan kunye noL. Daitch ngegalelo labo ekuhlelweni kombhalo-ngqangi. Lo msebenzi uxhaswe ngemali evela kwi-State of California Medical Research ngoTywala kunye nokuSetyenziswa kweZiyobisi ngokusebenzisa i-UCSF ukuya ku-Selena E. Bartlett, amaZiko ezeMpilo eSizwe: 1R21DA029966-01 kunye ne-NIH Fast Track ibhaso lokuhlola iqoqo le-MLSMR ku-Selena E. Bartlett , Isikolo se-UCSF se-Pharmacy (i-Ofisi ye-Dean kunye ne-Clinical Pharmacy) kunye neSikolo sezoNyango (i-Clinical Pharmacology kunye ne-Experimental Therapeutics) ku-Carolina L. Haass-Koffler.

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