Iinkqubo zoxinzelelo lwengqondo kwi-amygdala kunye nokulutha (2009)

Res Resin. 2009 ngo-Oktobha 13; 1293: 61-75. Pu: 10.1016 / j.brainres.2009.03.038

UGeorge F. Koob^*

Abstract

Ukungalawuleki kwiinkqubo zeemvakalelo zobuchopho ezilamla ukuvuswa kunye noxinzelelo yinxalenye ephambili ye-pathophysiology yokukhotyokiswa ziziyobisi. Ukukhotyokiswa kweziyobisi kukuphazamiseka okungapheliyo okubonakaliswa kukunyanzelwa ukuba ufune kwaye uthathe iziyobisi kunye nophuhliso lokuxhomekeka kunye nokubonakaliswa kwemeko yeemvakalelo ezimbi xa ichiza lisusiwe. Ukusebenza kweenkqubo zoxinzelelo lobuchopho kucingelwa ukuba yeyona nto iphambili kwimeko yeemvakalelo engalunganga eveliswa kukuxhomekeka okuqhuba ukufuna iziyobisi ngeendlela zokuqinisa ezingalunganga. Ingqwalasela yophononongo lwangoku kwindima yeenkqubo ezimbini eziphambili zokuvuselela ingqondo / uxinzelelo ekuphuhliseni ukuxhomekeka. Ugxininiso lubekwe kwizenzo ze-neuropharmacological ze-corticotropin-releasing factor (CRF) kunye ne-norepinephrine kwiinkqubo ze-extrahypothalamic kwi-amygdala eyandisiweyo, kubandakanywa ne-nucleus ephakathi ye-amygdala, i-nucleus yebhedi ye-stria terminalis, kunye nommandla wenguqu kwigobolondo le-nucleus. iqokelela. Ubungqina obubambekayo bubonisa ukuba ezi nkqubo zoxinizelelo lobuchopho, ngaphambili zingahoywanga njengenxalenye yokuxhomekeka nokuba likhoboka, zidlala indima ephambili ekubandakanyeni inguqu yokuxhomekeka nokugcina ukuxhomekeka xa sele iqalisiwe. Ukuqonda indima yoxinzelelo lwengqondo kunye neenkqubo zokulwa noxinzelelo kwiziyobisi akunikezeli nje ukuqonda kwi-neurobiology "yecala elimnyama" lokulutha kodwa ikwabonelela ngokuqonda kumbutho kunye nomsebenzi wesiseko sesekethe yengqondo ekhokela isimilo esikhuthazayo.

Internet: Umlutha, I-Neurobiology, Uxinzelelo, i-Corticotropin-releasing factor, i-Norepinephrine, i-amygdala eyandisiweyo

1. Isakhelo sombono: umlutha, uxinzelelo, ukurhoxa okukhuthazayo, kunye nokuqiniswa okungalunganga

Ukukhotyokiswa ziziyobisi sisifo esihlala sibuyela umva esibonakala kukunyanzelwa ukuba ufune kwaye uthabathe ichiza kunye nokulahlekelwa kulawulo ekunciphiseni ukusela. Inqaku lesithathu eliphambili elibandakanywe ngabanye kwaye libaluleke kakhulu kuphononongo lwangoku kukuvela kwimeko yeemvakalelo engalunganga (umzekelo, i-dysphoria, ixhala, ukucaphuka) xa ukufikelela kwechiza kuthintelwe (kuchazwa apha njengokuxhomekeka)UKoob noLe Moal, i-1997, 2008). likhoboka isetyenziswe ngokutshintshanayo kwisivumelwano esikhoyo kunye negama Ukuxhomekeka kwiziyobisi (ngoku ichazwe yi I-Diagnostic and Statistical Manual of Disabilities, uhlelo lwesi-4; Umbutho we-Psychiatric Association, i-1994), kodwa "ukuxhomekeka" ngemeko ephantsi "d" kuya kusetyenziswa ukuchaza ukubonakaliswa kwesifo sokurhoxisa xa ukulawulwa kweziyobisi ezingapheliyo kumisiwe (UKoob noLe Moal, i-2006). Ukusetyenziswa ngamathuba athile kodwa okulinganiselweyo kwechiza kunye ne Ezinokwenzeka ukuxhatshazwa okanye ukuxhomekeka kwahlukile ekuveleni kwesimo esingapheliyo sokuxhomekeka kweziyobisi.

istres inokuchazwa njengeempendulo kwiimfuno (ngokuqhelekileyo ziyingozi) emzimbeni (I-Selye, 1936) eziye zachazwa ngokwembali zinguqu ezahlukeneyo zomzimba ezibandakanya ukusebenza kwe-hypothalamic-pituitary-adrenal (HPA) axis. Oku kusebenze kubonakaliswe ngokukhululwa kwe-adrenal steroids ebangelwa ukukhululwa kwehomoni ye-adrenocorticotropic (ACTH) kwi-pituitary. Ukukhutshwa kwehomoni ye-Adrenocorticotropic kulawulwa, ngokuphindaphindiweyo, ngokukhulula i-hypothalamic corticotropin-releasing factor (CRF) kwi-pituitary portal system ye-median eminence. Inkcazo yoxinzelelo oluhambelana ngakumbi kunye nokubonakaliswa kwayo okuninzi kumzimba yilo naluphi na utshintsho kwiinkqubo zengqondo ze-homeostatic (Burchfield, ngo-1979). Ukwakhiwa koxinzelelo emva koko kuye kwadibaniswa nokwakhiwa kokuvusa kwaye ngenxa yoko kunokubonisa ukuqhubeka okugqithisileyo kwe-pathological ye-activation ye-activation yesiqhelo yomzimba okanye yeemvakalelo iinkqubo (UHennessy noLevine, ngo-1979; I-Pfaff, i-2006).

Ukukhotyokiswa ziziyobisi kuye kwajongwa njengengxaki ebandakanya izinto zokungangxami kunye nokunyanzeliswa (Ikhiwane. 1). Impulsivity Inokuchazwa njengomntu ozibandakanya ngokukhawuleza, ukusabela okungacwangciswanga kwizivuseleli zangaphakathi nangaphandle ngaphandle kokujonga iziphumo ezibi zezi mpendulo kumntu okanye kwabanye. Ukunyanzeliswa inokuchazwa njengokunyamezela ekuphenduleni kwimiphumo emibi okanye ukunyamezela phambi kweempendulo ezingalunganga kwiimeko ezikhethiweyo. Zombini ezi zinto zibonakalisa inkuthazo eyongeziweyo yokufuna iziyobisi kwaye zibe nokungqinwa kobuso kunye neempawu zokuXhomekeka kweSiyobisi njengoko kuchazwe nguMbutho weNgqondo waseMelika.

Isicwangciso sokuqhubela phambili kokuxhomekeka etywaleni ngokuhamba kwexesha, ebonisa utshintsho kwiindlela ezisisiseko zenkuthazo. Ukususela ekuqaleni, ukuqinisa ngokuqinisekileyo, iziphumo zeziyobisi ezonwabisayo, inkqubo yokulutha iqhubela phambili ngokuhamba kwexesha ukuze igcinwe. ...

Ukuthoba imijikelo yokunyanzeliswa kunye nokunyanzeliswa kuvelisa umjikelo odibeneyo wokulutha oquka izigaba ezithathu-ukuzixakekisa/ukulangazelela, ukuzinkcinkca/ukunxila, yaye ukurhoxiswa / kuchaphazeleka kakubi-apho ukungxamiseka kudla kongamela kumanqanaba okuqala kwaye ukunyanzeliswa kulawula kwinqanaba lesiphelo. Njengoko umntu esuka ekunyanzelweni ukuya ekunyanzelweni, utshintsho lwenzeka lusuka kuqinisekiso olulungileyo oluqhuba indlela yokuziphatha ekhuthazayo ukuya kuqinisekiso olubi oluqhuba isimilo esikhuthazayo (I-Koob, i-2004). Ukomelezwa okungalunganga kunokuchazwa njengenkqubo apho ukususwa kwe-stimulus ephazamisayo (umzekelo, isimo sengqondo esibi sokuyeka iziyobisi) kwandisa amathuba okuphendula (umzekelo, ukuxhomekeka-ukuthathwa kweziyobisi). Ezi zigaba zintathu zicingwa njengokunxibelelana omnye komnye, ziba namandla ngakumbi, kwaye ekugqibeleni zikhokelela kwimeko ye-pathological eyaziwa ngokuba likhoboka (addiction).UKoob noLe Moal, i-1997).

Ithisisi yolu phononongo yeyokuba eyona nto iphambili kwinkqubo yokulutha ibandakanya ukwenziwa kusebenze okunzulu kweenkqubo zoxinzelelo kwingqondo esebenzisanayo kodwa ezimeleyo kwiinkqubo zoxinzelelo lwehomoni. Ezo nkqubo zoxinzelelo lobuchopho ziphinda zicingelwe ukuba zenziwe zasekhaya kwi-nucleus esembindini ye-amygdala kunye nokuvelisa imeko yeemvakalelo engalunganga eba yintshukumisa enamandla yokufuna iziyobisi ehambelana nokusetyenziswa okunyanzelekileyo. Ingqwalasela yeli phepha iya kuba kwindima ye-CRF kunye ne-norepinephrine kumlutha njengento ephambili yenkqubo enzima egcina i-homeostasis yeemvakalelo.

2. Iinkqubo zoxinzelelo lweHormonal: i-hypothalamic-pituitary-adrenal axis

I-axis ye-HPA yenziwe ngezakhiwo ezintathu eziphambili: i-nucleus ye-paraventricular ye-hypothalamus, i-lobe yangaphambili ye-pituitary gland, kunye ne-adrenal gland (ukuhlaziywa, bona USmith noVale, ngo-2006). I-Neurosecretory neurons kwi-medial parvocellular subsaivation of the patriacular nucleus synthesize kwaye ikhulule i-CRF kwimithambo yegazi esecaleni engena kwi-gland yangaphakathi ye-pituitary. Ukuhlanganiswa kweCRF kwiCRF₁ i-receptor kwi-pituitary corticotropes yenza ukukhululwa kwe-ACTH kwi-systemic circulation. Ihomoni ye-Adrenocorticotropic yona ivuselela i-glucocorticoid synthesis kunye nokuphuma kwi-adrenal cortex. I-axis ye-HPA ilungiswe kakuhle ngempendulo engalunganga evela kwi-glucocorticoids ejikelezayo esebenza kwii-receptors ze-glucocorticoid kwiindawo ezimbini eziphambili zobuchopho: i-nucleus ye-paraventricular kunye ne-hippocampus. I-hypophysiotropic neurons ye-nucleus ye-paraventricular ye-hypothalamus ayigcinwanga ngamagqabantshintshi amaninzi ahlukeneyo, kubandakanywa kwi-brainstem, enye i-hypothalamic nuclei, kunye ne-forebrain limbic structures.

3. Iinkqubo zoxinzelelo lwengqondo: i-corticotropin-releasing factor kunye ne-norepinephrine

I-Corticotropin-releasing factor yi-41 amino acid polypeptide elawula i-hormonal, uvelwano, kunye neempendulo zokuziphatha kwiingcinezelo. Ukufunyanwa kwezinye iipeptide ezine-homology yolwakhiwo, ngakumbi usapho lwe-urocortin (urocortins 1, 2, kunye ne-3), lucebise ngeendima ezibanzi ze-neurotransmitter kwiinkqubo zeCRF kwindlela yokuziphatha kunye neempendulo ezizimeleyo kuxinzelelo.I-Bale kunye neVale, i-2004; Hauger et al., 2003). I-CRF enkulu efana ne-immunoreactivity ikhona kwi-neocortex, i-amygdala eyandisiweyo, i-medial septum, i-hypothalamus, i-thalamus, i-cerebellum, kunye ne-autonomic midbrain kunye ne-hindbrain nuclei (UCharlton et al., ngo-1987; I-Swanson et al., 1983). Ukusasazwa koqikelelo lwe-urocortin 1 lugqithelana neCRF kodwa lukwanokusasazwa okwahlukileyo, kubandakanywa okubonakalayo, i-somatosensory, ukuva, i-vestibular, i-motor, i-tegmental, i-parabrachial, i-pontine, i-median raphe, kunye ne-cerebellar nuclei (Zorrilla kunye noKoob, ngo-2005). ICRF₁ I-receptor inobuninzi, ibonakaliso ebanzi kwingqondo edlula kakhulu ngokusasazwa kweCRF kunye ne-urocortin 1.

I endogenous ekhethiweyo CRF₂ iiagonists-uhlobo 2 urocortins urocortin 2 (Reyes et al., 2001kunye ne-urocortin 3 (Lewis et al., 2001)-yahluke kwi-urocortin 1 kunye ne-CRF kwiiprofayili zabo ze-neuropharmacological. I-Urocortins 2 kunye ne-3 ibonisa ukukhetha okuphezulu okusebenzayo kwiCRF₂ receptor kwaye babe nosasazo lwe-neuroanatomical olwahlukileyo kwezo zeCRF kunye ne-urocortin 1. I-Urocortins 2 kunye ne-3 zibaluleke kakhulu kwi-hypothalamic nuclei echaza iCRF₂ i-receptor, kubandakanywa i-nucleus ye-supraoptic, i-neurons ye-magnocellular ye-nucleus ye-paraventricular, kunye ne-forebrain, kubandakanywa ne-hypothalamus ye-ventromedial, i-septum esecaleni, i-nucleus yebhedi ye-stria terminalis, kunye ne-medial kunye ne-cortical amygdala (Li et al., 2002). ICRF_{2 (a)} I-isoform ye-receptor ifumaneka nge-neuronal kwiindawo zobuchopho ezahlukileyo kwezo zeCRF/urocortin 1/CRF.₁ inkqubo ye-receptor, efana ne-ventromedial hypothalamic nucleus, i-nucleus ye-paraventricular ye-hypothalamus, i-nucleus ye-supraoptic, i-nucleus tractus solitarius, i-postrema yendawo, i-lateral septum, kunye ne-nucleus yebhedi ye-stria terminalis.

I-Norepinephrine ibophelela kwiintsapho ezintathu ezihlukeneyo ze-receptors, i-α₁, α₂, kunye ne-β-adrenergic, nganye ineentlobo ezintathu ze-receptor (URohrer noKobilka, 1998). I-α₁ usapho lwe-receptor luquka α_1a, α_1b, kunye ne-α_1d. Uhlobo ngalunye olusezantsi lusebenzisa i-phospholipase C kwaye ludityaniswe nenkqubo yesithunywa se-inositol phosphate yesibini nge-G-protein G._q. Indawo yokusebenza e-cy₁ I-receptor antagonist esetyenziswe kuphando lokuxhomekeka kweziyobisi yi-prazosin. I-α₂ usapho luquka α_2a, α_2b, kunye ne-α_2c. Uhlobo ngalunye olusezantsi luthintela i-adenylate cyclase ngokudityaniswa ne-G-protein G ethintelayo_i. Zimbini α₂ amachiza aqhele ukusetyenziswa kuphando lokuxhomekeka kwiziyobisi zi-α₂ I-agonist clonidine kunye ne-α₂ umchasi yohimbine. Usapho lwe-β-adrenergic receptor lubandakanya i-β₁, β₂, kunye β₃. Uhlobo ngalunye olusezantsi lusebenzisa i-adenylate cyclase ngokudityaniswa ne-G-protein G_s. Ambalwa amachiza e-β-adrenergic athe ajongwa kuphando lokuxhomekeka kumachiza, ngaphandle kwe-β-adrenergic antagonist propranolol, mhlawumbi ngenxa yokungafumaneki kakuhle kobuchopho.

Mhlawumbi eyona nto ibangela umdla kukunxibelelana okuxeliweyo kwenkqubo ye-nervous central CRF kunye ne-central nervous system norepinephrine systems. Icingelwa njengenkqubo yokutya phambili kumanqanaba amaninzi e-pons kunye ne-basal forebrain, i-CRF yenza i-norepinephrine, kunye ne-norepinephrine yona isebenze i-CRF (I-Koob, i-1999). Ubungqina obuninzi be-pharmacologic, physiologic, kunye ne-anatomic buxhasa indima ebalulekileyo kwintsebenziswano ye-CRF-norepinephrine kummandla we-locus coeruleus ekuphenduleni uxinzelelo (UValentino et al., ngo-1991, 1993; Van Bockstaele et al., 1998). Nangona kunjalo, i-norepinephrine ikwakhuthaza ukukhululwa kwe-CRF kwi-nucleus ye-paraventricular ye-hypothalamus.UAlonso et al., ngo-1986), i-nucleus yebhedi ye-stria terminalis, kunye ne-nucleus ephakathi ye-amygdala. Ezo nkqubo zonikezelo lwangaphambili ziye zacingelwa ukuba zinentsingiselo enamandla yokusebenza ekuhlanganiseni into ephilayo kumngeni wokusingqongileyo, kodwa loo ndlela inokuba sesichengeni ngakumbi kwi-pathology (I-Koob, i-1999).

4. I-amygdala eyandisiweyo: ujongano loxinzelelo kunye nokulutha

Idatha yamva nje ye-neuroanatomical kunye nemigqaliselo emitsha esebenzayo ibonelele ngenkxaso ye-hypothesis yokuba i-neuroanatomical substrates yeziphumo ezininzi ezikhuthazayo zokulutha kweziyobisi zinokubandakanya i-neural circuitry eyenza iqumrhu elahlukileyo kwi-basal forebrain, ebizwa ngokuba "yi-amygdala eyandisiweyo" (UAlheid noHeimer, ngo-1988). I-amygdala eyandisiweyo imele i-macro-structure eyakhiwe ngezakhiwo ezininzi ze-basal forebrain: i-nucleus yebhedi ye-stria terminalis, i-central medial amygdala, kunye nommandla wenguqu kwi-posterior ye-nucleus accumbens ephakathi (oko kukuthi, igobolondo elingasemva) (UJohnston, 1923; Heimer kunye neAlheid, 1991). Ezi zakhiwo zineemfaniso kwi-morphology, i-immunohistochemistry, kunye noqhagamshelwano (UAlheid noHeimer, ngo-1988), kwaye bafumana unxibelelwano oluhlukeneyo oluvela kwi-limbic cortices, i-hippocampus, i-basolateral amygdala, i-midbrain, kunye ne-lateral hypothalamus. Uqhagamshelo oluvela kule ngxaki lubandakanya i-posterior medial (sublenticular) ventral pallidum, indawo ye-ventral tegmental, iingqikelelo ezahlukeneyo ze-brainstem, kwaye mhlawumbi inomdla kakhulu kwimbono yokusebenza, uqikelelo olubonakalayo kwi-hypothalamus esecaleni.Heimer kunye neAlheid, 1991). Izinto eziphambili ze-amygdala eyandisiweyo ayibandakanyi kuphela i-neurotransmitters ehambelana nemiphumo emihle yokuqinisa iziyobisi zokusetyenziswa kakubi, kodwa kunye namacandelo amakhulu eenkqubo zoxinzelelo lwengqondo ezinxulumene nokomelezwa kakubi kokuxhomekeka (UKoob noLe Moal, i-2005).

5. Ubungqina be-Pharmacological ngendima yeCRF kunye ne-norepinephrine kwiimeko ezimbi zeemvakalelo ezinxulumene nokuyeka iziyobisi.

Impendulo eqhelekileyo ekurhoxisweni ngokukhawuleza kunye nokuyeka ixesha elide kuzo zonke iziyobisi ezinkulu zokusetyenziswa kakubi kukubonakaliswa kweempendulo ezinjengexhala okanye eziphazamisayo. Iimodeli zezilwanyana ziveze iimpendulo ezinjengokukhathazeka kuzo zonke iziyobisi ezinkulu zokusetyenziswa kakubi ngexesha lokurhoxa kakhulu (Ikhiwane. 2). Umahluko oxhomekeke kuye udla ngokuba yimpendulo yokwenziwa kwinoveli kunye/okanye uvuselelo olujikayo, olufana nebala elivulekileyo okanye eliphakamileyo elidibanisa imaze, okanye impendulo esebenzayo kwisivuseleli esichasayo, esifana nokungcwatywa kokhuselo lwesinyithi esinombane. Ukurhoxa kulawulo oluphindaphindiweyo lwe-cocaine kuvelisa impendulo efana ne-anxiogenic kwi-maze ephakanyisiweyo kunye novavanyo olukhuselayo lokungcwaba, zombini zitshintshwa lulawulo lwabachasi be-CRF (USarnyai et al., 1995; I-Basso et al., 1999). Ukurhoxiswa okukhawulezileyo ekuxhomekeke kwi-opioid nako kuvelisa iziphumo ezifana nexhala (Schulteis et al., 1998; UHarris no-Aston-Jones, i-1993). Ukurhoxiswa okukhawulezileyo kwi-opioids nako kuvelisa indawo engathandekiyo (Stinus et al., 1990). Apha, ngokungafaniyo nendawo ekhethwayo, iimpuku ezivezwe kwindawo ethile ngelixa zihamba ngokukhawuleza ukurhoxa kwi-opioids zichitha ixesha elincinci kwindawo yokurhoxa-xa zinikezelwe ngokhetho phakathi kwaloo ndawo kunye nemekobume engadityaniswanga. Ulawulo olucwangcisiweyo lweCRF₁ i-receptor antagonist kunye nolawulo oluthe ngqo lwe-intracerebral ye-peptide CRF₁/ CRF₂ umchasi naye wehlise i-opioid ebangela ukurhoxa kwendawo (Stinus et al., 2005; U-Heinrichs et al., 1995). Abachasi abasebenzayo be-noradrenergic (okt, β₁ Umchasi kunye ne-α₂ I-agonist) ithintele indawo ye-opioid yokurhoxisa-eyenzelwe ukuzonda (Delfs et al., 2000).

Iziphumo zomchasi weCRF kwi-ethanol, nicotine, icocaine, kunye nokurhoxa kwe-opioid ekhuthazayo. (A) Isiphumo solawulo lwe-intracerebroventricular yeCRF peptide antagonist α-helical CRF_9-41 kwiimpuku ezivavanyiweyo kwindawo ephakamileyo yokudibanisa ...

Ukurhoxiswa kwe-Ethanol kuvelisa isimilo esifana nexhala esitshintshwa lulawulo lwe-intracerebroventricular yeCRF.₁/ CRF₂ abachasi be-peptidergic (UBaldwin et al., 1991), ukulawulwa kwe-intracerebral ye-CRF ye-peptidergic₁/ CRF₂ umchasi kwi-amygdala (URassnick et al., 1993), kunye ne-systemic injections ye-molecule encinci ye-CRF₁ abachasiI-Knapp et al., 2004; Ngaphezulu kwe-et al., 2004; I-Funk et al., 2007). Abachasi beCRF batofelwe nge-intracerebroventricularly okanye ngokwenkqubo kwakhona bathintele iimpendulo ezinokuthi zibe nexhala kuxinzelelo olubonwa ngexesha lokuyeka ixesha elide kwi-ethanol engapheliyo.UBreese et al., 2005; UValdez et al., 2003). Ukurhoxa okukhawulezileyo kwi-nicotine kuvelisa iimpendulo ezifana nexhala ezithi zijikwe kwakhona ngabachasi beCRF (UTucci et al., 2003; UGeorge et al., 2007). Ezi ziphumo zabachasi be-CRF ziye zafakwa kwi-nucleus ephakathi ye-amygdala (URassnick et al., 1993).

6. Ubungqina be-Neurochemical ngendima yeCRF kunye ne-norepinephrine kwiziphumo ezikhuthazayo zokurhoxiswa kweziyobisi.

Ulawulo olungapheliyo lweziyobisi zokusetyenziswa kakubi nokuba ngokuzilawula okanye ngokuzilawula kwandisa iCRF engaphandle kwe-extracellular ukusuka kwi-amygdala eyandisiweyo elinganiswa kwi vivo microdialysis (Ikhiwane. 3). Ukufikelela ngokuqhubekayo kwi-intravenous self-control ye-cocaine ye-12 h yokwandisa i-CRF ye-extracellular kwi-dialysates ye-nucleus ephakathi ye-amygdala (I-Richter kunye ne-Weiss, i-1999). Ukurhoxiswa kwe-opioid okubangelwa emva kokufakelwa kwe-morphine pellet engapheliyo kwiimpuku kwandisa i-CRF ye-extracellular kumbindi we-amygdala (Weiss et al., 2001). Ulawulo lwe-nicotine olubukhali kunye nokurhoxiswa kwi-nicotine engapheliyo inyuse iCRF ngaphandle kwe-hypothalamic kwi-basal forebrain (Matta et al., 1997). Ukonyuka kwe-CRF-njenge-immunoreactivity kuye kwabonwa kwiimpuku zabantu abadala ezivezwe kwi-nicotine ngexesha lokufikisa kwaye inyanyaniswe ne-phenotype efana nexhala.Slawecki et al., 2005). I-CRF ye-Extracellular ibonakaliswe ukuba yonyuswe kwi-nucleus ephakathi ye-amygdala ngexesha lokuhoxiswa ngokukhawuleza kwi-nicotine engapheliyo elawulwa nge-minipump (UGeorge et al., 2007). Ngexesha lokurhoxiswa kwe-ethanol, iinkqubo ze-CRF ze-extrahypothalamic ziye zisebenze ngokugqithisileyo, ngokunyuka kwe-CRF engaphandle kwe-extracellular ngaphakathi kwe-nucleus ephakathi ye-amygdala kunye ne-nucleus yebhedi ye-stria terminalis yeempuku ezixhomekeke kwixesha lokurhoxiswa ngokukhawuleza (2-12 h) (I-Funk et al., 2006; Merlo-Pich et al., 1995; I-Olive et al., 2002). Ukuhoxiswa okukhawulezileyo ekuvezweni okungapheliyo kwe-cannabinoid kwandisa iCRF kwi-nucleus ephakathi ye-amygdala (Rodriguez de Fonseca et al., 1997). Zizonke ezi ziphumo zibonisa ukuba onke amachiza aphambili okusetyenziswa gwenxa avelisa ukonyuka okumangalisayo kumanqanaba e-CRF angaphandle kwi vivo i-microdialysis ngexesha lokuhoxiswa ngokukhawuleza emva kokulawulwa kweziyobisi ezingapheliyo.

(A) Iimpembelelo zokuhoxiswa kwe-ethanol kwi-CRF-efana ne-immunoreactivity (CRF-L-IR) kwi-rat amygdala enqunywe yi-microdialysis. I-Dialysate yaqokelelwa kwiiyure ezine ze-2 h rhoqo zitshintshwa kunye ne-nonsampling 2 amaxesha. Amaxesha amane esampula ayehambelana ...

I-Norepinephrine kudala icingelwa ukuba isebenze ngexesha lokurhoxa kwiziyobisi zokuxhatshazwa. I-opioids yehla ukudubula kwe-noradrenergic neurons kwi-locus coeruleus, kwaye i-locus coeruleus yasebenza ngexesha lokurhoxiswa kwe-opioid (Nestler et al., 1994). Iziphumo ezingapheliyo ze-opioid kwinkqubo ye-locus coeruleus noradrenergic zibonakaliswe kuluhlu olubanzi lwezifundo ezibandakanya ukulawulwa kwe-cyclic adenosine monophosphate (cAMP) indlela yokubonisa kunye nokwandisa ukubonakaliswa kwe-tyrosine hydroxylase (Nestler et al., 1994). Uphononongo lwakutsha nje lubonisa ukuba imiba ye-neurotrophic (umz., i-brain-derived neurotrophic factor and neurotrophin-3 evela kwi-non-noradrenergic neurons) inokubaluleka kwi-opiate-induced molecular neuroadaptations kwindlela ye-locus coeruleus noradrenergic.Akbarian et al., 2001, 2002). Ubungqina obuninzi bubonisa ukuba kwizilwanyana nakubantu, iinkqubo ze-noradrenergic ezisembindini zisebenza ngexesha lokuhoxiswa ngokukhawuleza kwi-ethanol kwaye zinokuba nokubaluleka kokukhuthaza. Ukurhoxiswa kotywala ebantwini kuhambelana nokusebenza kwe-noradrenergic kwi-cerebrospinal fluid (Borg et al., ngo-1981, 1985; Fujimoto et al., 1983). Ukuzilawula okungapheliyo kwe-nicotine (ukufikelela kwe-23 h) ukwandisa ukukhululwa kwe-norepinephrine kwi-nucleus ye-paraventricular ye-hypothalamus (Ubukhali kunye neMatta, 1993; UFu et al., 2001) kunye ne-amygdala (UFu et al., 2003). Nangona kunjalo, ngexesha lokugcinwa kwexesha elide le-23 h yokufikelela kwi-nicotine, amanqanaba e-norepinephrine ayengaphakanyiselwanga kwi-amygdala, ebonisa ukuba i-desensitization / ukunyamezela-impembelelo (UFu et al., 2003).

7. Ubungqina be-Pharmacological yendima yeCRF kunye ne-norepinephrine ekunyuseni inkuthazo yokufuna iziyobisi ekurhoxisweni.

Ukukwazi kweearhente ze-neuropharmacological ukuvimba i-anxiogenic-efana ne-aversive-efana ne-aversive-efana nempembelelo yempembelelo yokurhoxiswa kweziyobisi kunokuqikelela iziphumo ezikhuthazayo zezi arhente kwiimodeli zezilwanyana zokufikelela okwandisiweyo kumachiza. Imifuziselo yezilwanyana yokufikelela okwandisiweyo ibandakanya ukuvezwa kwezilwanyana kwiiseshini ezongeziweyo zokuzilawula ngokwazo kwimithambo yeziyobisi (i-cocaine, i-6 h; i-heroin, i-12 h; inikotini, i-23 h) kunye nokuvezwa komphunga (14 h on/12 h off) i-ethanol. Izilwanyana ke zivavanyelwa ukuzilawula ngokwazo ngamaxesha ahlukeneyo ukuya ekurhoxisweni, ukusuka kwi-2-6 h ye-ethanol ukuya kwiintsuku ezine-nicotine. Abachasi beCRF bathintele ngokukhethayo ukonyuka kokuzilawula kweziyobisi ezinxulumene nokufikelela okwandisiweyo kulawulo lwe-cocaine (I-Specio et al., 2008, i-nicotine (UGeorge et al., 2007kunye ne heroin (Greenwell et al., 2009a). Abachasi beCRF bathintele ukwanda kokuzilawula kwe-ethanol kwiimpuku ezixhomekeke kuwe (I-Funk et al., 2007) (1 Table, Ikhiwane. 4).

Indima yeCRF kukuxhomekeka

Iziphumo ze-molecule encinci yeCRF₁ abachasi be-receptor ekuzilawuleni kweziyobisi kwiimpuku ezixhomekeke (A) Isiphumo semolekyuli encinci yeCRF₁ i-receptor antagonist MPZP ekuzilawuleni okusebenzayo kotywala (g/kg) kwiimpuku ezixhomekeke nezingaxhomekekanga. Uvavanyo lwaba ...

Ubungqina beendawo ezithile ebuchotsheni zilamla ezi zenzo zichasayo zeCRF zigxile kumbindi we-amygdala. Izitofu zabachasi beCRF ezifakwe ngqo kwinucleus ephakathi ye-amygdala zithintele iziphumo ezichaseneyo zokurhoxa kwe-opioid (U-Heinrichs et al., 1995) kwaye ithintele iziphumo ze-anxiogenic-ezifana nokurhoxiswa kwe-ethanol (URassnick et al., 1993). Ulawulo lwe-Intracerebroventricular yeCRF₁/ CRF₂ umchasi D-Phe CRF_12-41 ithintele ukonyuka okunyanzeliswa kokuxhomekeka ekuzilawuleni kwe-ethanol ngexesha lokurhoxa ngokungxamisekileyo kunye nokuziyeka ixesha elide (UValdez et al., 2004; URimondini et al., 2002). Xa ilawulwa ngokuthe ngqo kwi-nucleus ephakathi ye-amygdala, amanani aphantsi e-D-Phe CRF_12-41 uthintele ukuzilawula kwe-ethanol kwiimpuku ezixhomekeke kwi-ethanol (I-Funk et al., 2006). I-CRF₂ I-agonist, i-urocortin 3, ifakwe kwi-nucleus ephakathi ye-amygdala iphinde ivimbele ukuzilawula kwe-ethanol kwiigundane ezixhomekeke kwi-ethanol (I-Funk et al., 2007), icebisa iCRF ehambelanayo₁/ CRF₂ isenzo kwi-nucleus ephakathi ye-amygdala enegalelo kulamlo lokusela-okubangelwa ukusela kwi-rat (I-Bale kunye neVale, i-2004).

Ezi datha zibonisa indima ebalulekileyo ye-CRF, ngokukodwa ngaphakathi kwi-nucleus ephakathi ye-amygdala, ekulayini ukwanda kokuzilawula okuhambelana nokuxhomekeka kwaye iphakamisa ukuba i-CRF kwi-basal forebrain inokuba nendima ebalulekileyo ekuphuhliseni iziphumo ezikhuthazayo. eziqhuba ukwanda kokufunwa kweziyobisi okunxulunyaniswa necocaine, iheroin, kunye nokuxhomekeka kwinikotini.

Inkxaso ikhona indima yeenkqubo ze-norepinephrine kwi-ethanol self-administration kunye nokunyuka kokuzilawula okuhambelana nokuxhomekeka. Ubungqina obubalulekileyo buxhasa intsebenziswano phakathi kwenkqubo ye-nervous central norepinephrine kunye nokuqiniswa kwe-ethanol kunye nokuxhomekeka. Kuluhlu lwezifundo zokuqala, u-Amit kunye noogxa babonise ukuba ukusetyenziswa kwe-ethanol ngokuzithandela kuye kwehliswa kokubini okukhethiweyo kwe-pharmacological kunye ne-neurotoxin-specific disruption of noradrenergic function.UAmit et al., ngo-1977; UBrown no-Amit, ngo-1977). Ulawulo lwe-dopamine β-hydroxylase inhibitors ekhethiweyo ivelise ukuthotywa okuphawulweyo kokusela utywala kwiigundane ezikhetha utywala ngaphambili (UAmit et al., ngo-1977). Ulawulo oluphakathi lwe-neurotoxin 6-hydroxydopamine kwiidosi eziye zaphelelwa kakhulu i-norepinephrine neurons zikwathintele ukusetyenziswa kwe-ethanol kwiimpuku (UBrown no-Amit, ngo-1977; Imason et al., 1979). Ulawulo lwe-Intragastric self-ethanol nalo luvalwe yi-dopamine β-hydroxylase inhibition.Davis et al., 1979). Ukuchithwa okukhethiweyo kwe-norepinephrine kwi-cortex ye-prefrontal ye-ethanol ephezulu ye-C57BL / 6J iigundane ezinciphisa ukusetyenziswa kwe-ethanol (UVentura et al., 2006). Iimpuku ngokunkqonkqozwa kwengqondo ye-norepinephrine ngokunkqonkqoza kwe-dopamine β-hydroxylase gene inokhetho oluncitshisiweyo lwe-ethanol (Weinshenker et al., 2000).

Kwizifundo zamva nje, i-α₁ I-noradrenergic receptor antagonist prazosin ithintele ukwanda kweziyobisi ezinxulumene nokuxhomekeka kwe-ethanol (Walker et al., 2008), ukufikelela okwandisiweyo kwicocaine (Wee et al., 2008), kunye nokufikelela okwandisiweyo kwii-opioids (Greenwell et al., 2009b) (2 Table, Ikhiwane. 5). Ke ngoko, ukuguqulwa kwedatha kucebisa ukuba ukuphazamiseka komsebenzi we-noradrenergic kuthintela ukuqiniswa kwe-ethanol, ukuba i-noradrenergic neurotransmission iphuculwe ngexesha lokurhoxiswa kweziyobisi, kwaye abachasi abasebenzayo be-noradrenergic banokukuthintela ukonyuka kokuzilawula kwechiza okuhambelana nokurhoxa.

Indima ye-norepinephrine ekuxhomekekeni

Iziphumo ze-α₁ I-adrenergic receptor antagonist prazosin kwi-self-administration yeziyobisi kwiigundane ezixhomekeke. (A) Iimpendulo ezichanekileyo (± SEM) ze-ethanol ngexesha leeseshoni zemizuzu engama-30 kwizilwanyana ezingaxhomekekanga kunye ne-ethanol ezilandela i-0.0 kunye ne-1.5 ...

8. Isiseko seselula kwi-nucleus ephakathi ye-amygdala yeziphumo ezikhuthazayo zeCRF kunye nokusebenzisana kwe-norepinephrine ekuxhomekekeni.

Uphononongo lwesellula olusebenzisa ubuchule be-electrophysiological lubonise ukuba umsebenzi we-γ-aminobutyric acid (GABA) ngaphakathi kwe-interneurons ye-amygdala eyandisiweyo inokubonisa imeko yeemvakalelo engalunganga yokubaluleka kwenkuthazo ekufuneni iziyobisi ekuxhomekekeni.I-Koob, i-2008). ICRF ngokwayo iyayiphucula iGABA_A I-inhibitory postsynaptic potentials (IPSCs) kushicilelo lweseli epheleleyo yenucleus esembindini we-amygdala kunye ne-nucleus yebhedi ye-stria terminalis kulungiselelo lwesilayi sobuchopho, kwaye esi siphumo sivalwe yiCRF.₁ abachasi kwaye ivaliwe kwiCRF₁ knockout (NguNie et al., 2004; I-Kash kunye ne-Winder, i-2006). Kwi-amygdala, i-CRF ibekwe ngaphakathi kwi-subpopulation ye-GABAergic neurons kwi-nucleus yebhedi ye-stria terminalis kunye ne-nucleus ephakathi ye-amygdala eyahlukileyo kwezo zidibanisa i-enkephalin.Imini et al., 1999).

Kwi-norepinephrine, ubungqina bucebisa indlela efanayo kwinucleus yebhedi ye-stria terminalis apho ukurekhodwa kweeseli ezipheleleyo ukusuka kumalungiselelo esilayi kubonise ukuba i-norepinephrine yokuphucula i-GABAergic neurotransmission. Isiphumo se-noradrenergic sabonakala sihamba nge-α₁ i-receptor (UDumont noW Williams, 2004). Ukuba idatha evela kwi-nucleus ephakathi ye-amygdala kunye ne-nucleus yebhedi ye-stria terminalis idityanisiwe, ngoko ke ukuhambelana okuthile kubonakala: i-CRF kunye ne-norepinephrine yokwandisa umsebenzi we-GABAergic, izenzo kwinqanaba leselula elihambelana nemiphumo yokuziphatha echazwe ngasentla nge-neuropharmacological. izifundo.

Ngenxa yokuba amachiza e-GABAergic aqhelekile ukuba yi-anxiolytics eyomeleleyo, into yokuba ii-neurotransmitters ezinjenge-anxiogenic-ezifana ne-neurotransmitters zinokuvula i-GABAergic neurotransmitters kunye ne-anxiolytic-like neurotransmitters zinokucinezela usulelo lwe-GABAergic kwingingqi yobuchopho eyaziwa ngokuba ibandakanyeka kukuziphatha okunxulumene noxinzelelo inokubonakala ixakile. Nangona kunjalo, umsebenzi we-GABAergic wendawo ngaphakathi kwi-nucleus ephakathi ye-amygdala unokuchaphazela ngokusebenzayo ukuphendula kwe-neuronal ye-inhibitory central nucleus ye-amygdala gating elawula ukuhamba kolwazi kwiisekethe ze-intra-amygdaloidal zasekhaya (okt, ngokunqanda i-nucleus ephakathi ye-amygdala), ekhokelela. ukwandisa uthintelo kwimimandla esezantsi elamla impendulo yokuziphatha (Ikhiwane. 6).

I-Neurocircuitry kwi-nucleus ephakathi ye-amygdala enxulumene ne-CRF kunye ne-norepinephrine ekuhoxisweni kokukhuthaza. I-CRF ayicingelwanga kuphela ukuqhuba i-GABAergic interneurons ebandakanya iinkqubo zeemvakalelo ze-hypothalamic kunye ne-midbrain, kodwa kunye ngqo. ...

Utshintsho kwi-neurotransmission kwiinkqubo zoxinzelelo lwengqondo kunye nophuhliso lokuxhomekeka kunokubonakalisa i-GABAergic neuron sensitization kwizenzo zoxinzelelo lwengqondo / iinkqubo zokulwa noxinzelelo. Ukukhutshwa kwe-GABA eyongeziweyo eveliswe yi-ethanol kwi-nucleus ephakathi ye-amygdala inyuke ngakumbi kwizilwanyana ezixhomekeke kuyo, ibonakaliswe zombini nge-electrophysiological and kwi vivo amanyathelo e-microdialysis (URoberto et al., 2004). Ukuphuculwa okukhuthazisiweyo kwe-ethanol ye-GABAergic IPSC kwavalwa yiCRF₁ abachasiNguNie et al., 2004; URoberto et al., 2004) khange ibonwe kwiCRF₁ knockout (NguNie et al., 2004). Ngaloo ndlela, utshintsho olungapheliyo lwe-ethanol olubangelwa yi-neuronal ye-GABA interneurons kwi-nucleus ephakathi ye-amygdala inokudityaniswa kwinqanaba leselula kunye nezenzo ze-CRF ezibonisa iziphumo zokuziphatha kwiimodeli zezilwanyana zokusela ngokugqithiseleyo.

Ngenxa yokuba uninzi lwe-neurons kwi-nucleus ephakathi ye-amygdala yi-GABAergic (USun kunye noCassell, ngo-1993), indlela yokulamla ekujoliswe kuyo ezantsi okunxulunyaniswa nemeko yeemvakalelo inokubonakalisa nokuba zii-neuron ezithintelayo kunye noqhagamshelo oluqhubekayo okanye lokuphakela phambili okanye i-neuron ethintelayo yokujonga kwi-brainstem okanye kwimimandla esezantsi (umzekelo, i-nucleus yebhedi ye-stria terminalis). Ngaloo ndlela, i-nucleus ephakathi ye-amygdala inokucingelwa ukuba "isango" elilawula ukuhamba kolwazi ngeesekethe ze-intra-amygdaloidal. Ngaphezu koko, ukulungiswa kakuhle kwenkqubo ye-GABAergic inhibitory kumbindi we-amygdala kunokuba yimfuneko yokulawula zombini i-neurons yasekhaya kunye nemveliso ukuya kwi-nuclei esezantsi.Ikhiwane. 6).

9. Iinkqubo zoxinzelelo lwengqondo kunye nokulutha

Ukukhotyokiswa ziziyobisi, okufana nolunye ukuphazamiseka kwengqondo okungapheliyo kunye nokuphazamiseka kwengqondo okufana noxinzelelo lwegazi oluphezulu, luba mandundu ngokuhamba kwexesha, luxhomekeke kwimpembelelo enkulu yendalo esingqongileyo (umzekelo, uxinzelelo lwangaphandle), kwaye lushiya umkhondo we-neural oshiyekileyo ovumela "ukuphinda uphinde ube likhoboka" kwaneenyanga. kunye neminyaka emva kokukhutshwa kunye nokuyeka. Ezi mpawu zokukhotyokiswa ziziyobisi zikhokelele ekubeni kuqwalaselwe kwakhona ukukhotyokiswa ziziyobisi njengokungaphezulu nje kwe-homeostatic dysregulation yokusebenza ngokweemvakalelo, kodwa njengekhefu eliguquguqukayo kunye ne-homeostasis yezi nkqubo ezibizwa ngokuba yi-allostasis.UKoob noLe Moal, i-2001; UKoob noLe Moal, i-2008). Ingqikelelo echazwe apha yeyokuba ukukhotyokiswa ziziyobisi kubonisa ikhefu kunye neendlela zokulawula ingqondo ye-homeostatic elawula imeko yeemvakalelo yesilwanyana. I-Allostasis ichazwa njengozinzo ngotshintsho kunye nenqaku elitshintshiweyo (I-Sterling kunye ne-Eyer, 1988) kwaye ibandakanya indlela yokudlulisela phambili kuneendlela zokuphendula ezingalunganga ze-homeostasis. Isixhobo sokudlulisa ukutya sineengenelo ezininzi zokuhlangabezana neemfuno zokusingqongileyo. Ngokomzekelo, kwi-homeostasis, xa imfuno eyongeziweyo ivelisa umqondiso, impendulo engalunganga ingalungisa imfuno, kodwa ixesha elifunekayo lingaba lide kwaye izibonelelo azikho. Uphononongo oluqhubekayo lwemfuno kunye nohlengahlengiso oluqhubekayo lwazo zonke iiparamitha ezibhekiselele kwiindawo ezintsha zokuseta kucingelwa ukuba zenzeke kwi-allostasis. Esi sixhobo sokuhlanganisa izixhobo ngokukhawuleza kunye nokusebenzisa iindlela zokuthumela phambili kunokukhokelela kwimeko ye-allostatic ukuba iinkqubo azinalo ixesha elaneleyo lokumisela kwakhona i-homeostasis. An imeko yemibono yonke inokuchazwa njengombandela wokuphambuka okungapheliyo kwenkqubo yolawulo yenqanaba layo eliqhelekileyo (lasekhaya).

I-hypothesis echazwe apha kukuba iinkqubo zoxinzelelo lwengqondo ziphendula ngokukhawuleza kwimiceli mngeni elindelekileyo kwi-homeostasis (ukuthatha iziyobisi ngokugqithisileyo) kodwa ziyacotha ukuhlala okanye azivale ngokukhawuleza xa sele zibandakanyekile.I-Koob, i-1999). Ke, eyona ndlela isebenzayo yezendalo evumela impendulo ekhawulezileyo nezinzileyo kumngeni wokusingqongileyo iba yinjini ye-pathology ukuba ixesha elaneleyo okanye izixhobo azifumaneki ukuvala impendulo. Ukusebenzisana phakathi kweCRF kunye ne-norepinephrine kwi-brainstem kunye ne-basal forebrain, kunye negalelo elivela kwezinye iinkqubo zoxinzelelo lwengqondo, kunokukhokelela kwiimeko ezingapheliyo ezifana neemvakalelo ezinxulumene nokulutha.UKoob noLe Moal, i-2001).

Ezo meko zingathandekiyo ngokweemvakalelo zibandakanyeka kakhulu ngexesha lokurhoxa ngokungxamisekileyo kwiziyobisi ezingapheliyo zokusetyenziswa kakubi kodwa zikwahlala "zivuselelwa" kwiindawo ezimbini ezinxulumene nokubuyela ekufuneni iziyobisi. Ummandla wokuqala kukwakhiwa kokuzila ixesha elide. Iimpawu ezininzi eziphawulwa ziimeko zeemvakalelo ezingathandekiyo ziqhubeka ixesha elide emva kokurhoxa kwiziyobisi zokuxhatshazwa. Ukuyeka ukusela utywala ixesha elide, umzekelo, kuye kwaphawulwa kakhulu ebantwini, apho ukudinwa, ukuxinana, kunye nokuxhalaba kuye kwaxelwa ukuba kuqhubeke ukusuka kwiiveki ezi-5 emva kokurhoxa ukuya kwiinyanga ezili-9.Roelofs, ngo-1985; Alling et al., ngo-1982). Ezi zimpawu, ukurhoxa emva kokukhawuleza, zithande ukuba nomdla kwindalo kunye ne-subacute kwaye zihlala zikhokelela ekubuyeleni kwakhona (Hershon, ngo-1977; uAnnis et al., ngo-1998). Eyona nto iphambili yokuphinda ubuyele kukuchaphazeleka kakubi (Zywiak et al., 1996; U-Lowman et al., ngo-1996). Kuhlalutyo lwesibini lwezigulane kwiiveki ezili-12 zolingo lweklinikhi kunye nokuxhomekeka kotywala kunye nokungafikeleli kwiikhrayitheriya zayo nayiphi na enye i-DSM-IV yokuphazamiseka kwemizwelo, umbutho kunye nokuphindaphinda kunye ne-subclinical negative state affective state yomelele ngakumbi.Imason et al., 1994). Umsebenzi wezilwanyana ubonise ukuba ukuxhomekeka kwangaphambili kunciphisa "umda wokuxhomekeka" ukuze izilwanyana ezixhomekeke ngaphambili zenziwe zixhomekeke kwakhona zibonise iimpawu ezinzulu zokuyeka umzimba kunamaqela afumana utywala okokuqala (Branchey et al., ngo-1971; Baker kunye noCannon, ngo-1979; Becker kunye noHale, ngo-1989; Becker, 1994). Imbali yokuxhomekeka kwiigundane ze-Wistar zamadoda inokuvelisa ukuphakama kwexesha elide kwi-ethanol self-administration emva kokurhoxiswa ngokukrakra kunye nokukhupha i-detoxification (URoberts et al., 2000; URimondini et al., 2002, 2008; Sommer et al., 2008). Ukonyuka kokuzilawula kwakho kukhatshwa kukusabela okwandisiweyo kokuziphatha kuxinzelelo kunye nokuphendula okwandisiweyo kubachasi benkqubo yeCRF yobuchopho (UValdez et al., 2003, 2004; UGehlert et al., 2007; Sommer et al., 2008).

I-domain yesibini kukunyuka kovakalelo ekubuyiselweni kwakhona kwindlela yokuziphatha yokufuna iziyobisi ebonakaliswe ekubuyiseleni uxinzelelo. Iindidi ezahlukeneyo zoxinzelelo, ebantwini nakwizilwanyana, ziya kubuyisela ukufuna iziyobisi. Kwizilwanyana, ngokuqhelekileyo ukufuna iziyobisi kucinywa kukuvezwa ngokuphindaphindiweyo kwindawo yokufuna iziyobisi ngaphandle kwechiza kwaye kwiimeko zokusebenza ukuvezwa okuphindaphindiweyo kwimpendulo yomsebenzisi ngaphandle kwechiza. I-stressor, efana ne-footshock, uxinzelelo lwentlalo, okanye uxinzelelo lwe-pharmacological (umzekelo, i-yohimbine), ibuyisela ukuziphatha kokufuna iziyobisi. I-neural circuitry yokubuyisela uxinzelelo-i-induced overlap kunye neyokurhoxisa okukhuthazwayo okuchazwe ngasentla (Shaham et al., 2003). Imbali yokuxhomekeka ikwandisa ukubuyisela okubangelwa uxinzelelo (I-Liu kunye ne-Weiss, i-2002).

Imingeni ephindaphindiweyo (umzekelo, ukusetyenziswa ngokugqithiseleyo kweziyobisi zokuxhatshazwa) kukhokelela kwiinzame zengqondo nge-molecular, cellular, kunye neenguqu ze-neurocircuitry ukugcina uzinzo kodwa ngexabiso. Kwisakhelo sokukhotyokiswa kweziyobisi esicaciswe apha, ukutenxa okushiyekileyo kulawulo lweemvakalelo zobuchopho (okt. imeko yemibono yonke) ikhuthazwe lutshintsho oluninzi lwe-neurobiological, kubandakanya ukuncipha komsebenzi wemijikelezo yomvuzo, ukulahleka kolawulo olulawulayo, ukuququzelelwa kwemibutho ye-stimulus-response, kunye nokufunwa kweenkqubo zoxinzelelo lwengqondo ezichazwe ngasentla. Iinkqubo zoxinzelelo lwengqondo ezisengozini ziphinda zicingelwe ukuba zibe negalelo ekunyanzelweni kokufuna iziyobisi kunye nokusetyenziswa kweziyobisi kunye nokubuyela ekufuneni iziyobisi nasekuthatheni iziyobisi okubizwa ngokuba likhoboka (addiction).I-Koob, i-2009).

10. Isishwankathelo kunye neziphetho

Ukurhoxa ngokungxamisekileyo kuzo zonke iziyobisi ezinkulu zoxhatshazo kwandisa imida yokuvuza, iimpendulo ezifana nexhala, kunye neCRF kwi-amygdala, nganye inentsingiselo ekhuthazayo. Ukusetyenziswa kweziyobisi okunyanzelekileyo okunxulunyaniswa nokuxhomekeka kulamlwa kungekuphela nje kokuphulukana nomsebenzi weenkqubo zomvuzo kodwa kunye nokufunwa kweenkqubo zoxinzelelo lwengqondo ezifana neCRF kunye ne-norepinephrine kwi-amygdala eyandisiweyo. Iinkqubo zokuvuselela ingqondo / uxinzelelo kwi-amygdala eyandisiweyo inokuba ngamacandelo aphambili eemeko zeemvakalelo ezimbi eziqhuba ukuxhomekeka kwiziyobisi zokusetyenziswa gwenxa kwaye zinokugqithana kunye nezinto ezingalunganga zeemvakalelo zezinye iipsychopathologies.

Imibulelo

Le yinombolo yopapasho 19930 evela kwiScripps Research Institute. Uphando luxhaswe yiPearson Centre for Alcoholism and Addiction Research and National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 and DA04398 from the National Institute on Drug Abuse, kunye neDK26741 yeSizwe yeDiabetes. kunye neZifo zokuSiga kunye nezintso. Umbhali ungathanda ukubulela uMike Arends ngoncedo lwakhe ngokulungiselela umbhalo.

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