Karolo ea Bokoetliso Tsamaiso ea Tšebeliso ea Matla (2008)

Neuron. Sengoloa se ngotsoeng; e fumaneha ho PMC Sep 22, 2009.

E hatisitsoe ka mokhoa o qetelle o hlophisitsoeng e le:

PMCID: PMC2748830

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Eya ho:

inahaneloang

Ho lemalla lithethefatsi ke bothata bo sa foleng bo hlahang bo qobelloang ke ho qobella ho batla le ho sebelisa lithethefatsi mme ho amana le ho se sebetse hantle ha libaka tsa boko tse oelang moputso le khatello ea maikutlo. Ts'ebetso ea lits'ebetso tsa khatello ea kelello e khothalletsoa hore e be senotlolo sa boemo bo bobe ba maikutlo bo hlahisoang ke ts'ehetso e khannang ho batla lithethefatsi ka mekhoa e mebe ea ho matlafatsa. Tlhahlobo ena e hlahloba karolo ea methapo ea khatello ea kelello (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) le li-system tsa antistress tsa boko (neuropeptide Y, nociceptin [orphanin FQ] ts'ebetsong ea ts'ebeliso ea lithethefatsi, ka ho totobatsa tšebetso ea neuropharmacological ea lits'ebetso tsa extrahypothalamic ho amygdala e atolositsoeng. Ts'ebetso ea khatello ea kelello le lits'ebetso tsa khatello ea kelello li ka bapala karolo ea bohlokoa phetohong ea ho phepelo ea ts'ebeliso ea lithethefatsi hang ha e qaliloe. Ho utloisisa karolo ea khatello ea kelello le lits'ebeletso tsa antistress ho ts'ebelisong ho fana ka lipheo tse ncha tsa kalafo le thibelo ea tšebeliso le temohisiso mokhatlong le ts'ebetso ea mantlha ea maikutlo a boko.

1. Lithethefatsi, Tlatsetso le khatello ea maikutlo: Kenyelletso le Litlhaloso

1.2. Matla a ho Lemalla

Ho lemalla lithethefatsi ke bothata bo sa foleng bo hlahang ka tšebeliso e mpe ea lithethefatsi le tahlehelo ea taolo taolong ea lithethefatsi. Ho lemalla ho na le mehato e meraro: preoccupation / Ho lebella, binge / botaoa, 'me drainare / Ho ama hampe, eo ho eona ho susumetsoa hangata ho busoang mathoasong a pele, mme ho qobelloa ho busa maemong a bolaeang. Ha motho a tloha ho tsubellellang ho ea bohlonong, phetoho e ba ho tloha ho matlafatsong e ntle ea ho khanna boitšoaro bo susumetsoang ho ea ho matlafatso e mpe ea ho khanna boitšoaro bo susumetsoang (Koob, 2004). Mehato ena e meraro e na le khopolo ea ho fepa e mong, ho ba matla le ho feta, 'me qetellong ho lebisa ho boemo ba bophelo bo tsejoang ka hore ke bokhoba (Koob le Le Moal, 1997). The preoccupation / Ho lebella (ho lakatsa) mohato oa kemiso ea bokhoba ba nako e telele e le thuto ea bohlokoa hore e be ntho ea bohlokoa ea ho khutlela ho batho hape e hlalosa tlhekefetso e le bothata bo sa foleng ba ho khutla hape (Lisebelisoa tsa 1 'me Le22).

Lethathamo 1 

Litlhaloso
Lethathamo 2 

Mekhahlelo ea Phallo ea Ho Lemalla

Lithethefatsi tse fapaneng li hlahisa mekhoa e fapaneng ea bokhoba ba ho etsa likarolo tse fapaneng tsa potoloho ea bokhoba, ho latela tekanyetso, bolelele ba tšebeliso, esita le lintlha tsa setso. Ka li-opioids, lithethefatsi tsa khale tsa lithethefatsi, mokhoa oa ho sebelisa lithethefatsi tse kenang kapa tse tsubang tse kenang ka bongata li kenyeletsa ho taha haholo, nts'etsopele ea mamello, ho ata ha ho ja, le dysphoria e tebileng, ho hloka botsitso 'meleng, le matšoao a ho nena le a maikutlo ka nako e itseng. Ho hlaha tloaelo eo ho eona moriana o lokelang ho fumanoa ho qoba letsoalo le tebileng le ho se khotsofale ho etsahalang nakong ea ho khaotsa ho tsuba. Ho lemalla joala kapa bokhoba ba tahi ho ka latela mokhoa o ts'oanang, empa mokhoa oa ho sebelisa lithethefatsi tse fanoang ka molomo hangata o tšoauoa ka ho itlopa joala ho ka ba liketsahalo tsa letsatsi le leng le le leng kapa matsatsi a malelele a ho noha haholo mme o tšoantšoa le lefu le matla la ho khaotsa motho ka mong. Bokhoba ba Nikotine bo fapana le lipaterone tse kaholimo, le matšoao a fokolang a hlakileng a binge / botaoa sethala, mme se na le mokhoa oa ho ja o khetholloang ka ho ja lithethefatsi haholo ntle le nakong ea ho robala le ho ba le maikutlo a mabe ka nako ea ho itima lijo, ho kenyelletsa dysphoria, ho teneha, le takatso e matla. Bokhoba ba tahi ea Marijuana bo latela mokhoa o ts'oanang le opioids le koae, ka sethala sa bohlokoa sa ho tahoa, empa ha ts'ebeliso e sa tsitsang e ntse e tsoela pele, lithuto li qala ho bontša mokhoa oa tšebeliso o nang le tšebeliso e mpe nakong ea ho tsosa e lateloang ke ho khaoha ho kenyelletsa dysphoria, ho teneha le boroko. likhathatso. Phallo ea Psychostimulant (cocaine le amphetamines) e bontša mohlala ka mokhoa o ikhethang binge / botaoa sethala. Ho itlopa hoo ho ka nka lihora kapa matsatsi ha nako e telele 'me hangata ho lateloa ke ho tlosoa ("ho oa") ho tšoauoa ka dysphoria e feteletseng le ho se sebetse. Takatso e matla ea lithethefatsi tsohle e ka lebella ho tlosoa (ke hore, ka li-opioid, joala, nicotine) kapa hangata ho etsahala kamora ho khaotsa ho matla ha ho lakatsa ho susumetsoa ke litekanyetso ka bobeli tsa tikoloho ho bonts'a ho fumaneha ha lithethefatsi le linaha tse ka hare tse amanang le linaha tse mpe tsa maikutlo le khatello ea maikutlo.

Mefuta ea liphoofolo ea matšoao a bokhoba ba lithethefatsi tse kang li-stimulants, opioid, joala, nikotini le Δ9-tetrahydrocannabinol e ka hlalosoa ka mehlala e amanang le mekhahlelo e fapaneng ea potoloho ea bokhoba ba tahi (Shippenberg le Koob, 2002) (Lethathamo 2). Mefuta ea liphoofolo bakeng sa binge / botaoa Boemo ba potoloho ea bokhoba ba lithethefatsi bo ka hlalosoa e le ho lekanya moputso o matla oa lithethefatsi, moo moputso o ka hlalosoang e le se matla se matlafatsang ka boleng bo bong bo eketsehileng ba maikutlo, joalo ka thabo (Lethathamo 1). Mefuta ea liphoofolo ea moputso le matlafatso e atile ebile e netefalitsoe hantle 'me e kenyelletsa ho ikoetlisa ka har'a lithethefatsi, ho rata libaka le ho fokotsa likotsi tsa moputso oa boko. Mefuta ea liphoofolo ea drainare / Ho ama hampe sethala se kenyelletsa ho chechisa sebaka (ho e-na le ho rata) ho tlohella kapa ho itšehla thajana ho tsoa taolong e mpe ea lithethefatsi, ho eketseha ha meputso ea kelello, le keketseho e tlisoang ke ho batla lithethefatsi (Lethathamo 2). Liroto li tla eketsa ts'ebetso ea lithethefatsi tse kenang kahare kapa ka molomo ka mokhoa o pharalletseng oa lithethefatsi le nakong ea ho tlohela puso e lekantsoeng, e lekantsoeng ka bobeli ke taolo e eketsehileng ea lithethefatsi le mosebetsi o eketsehileng oa ho fumana lithethefatsi. Boitšoaro bo eketsehang joalo ba ho iphelisa ka liphoofolo tse itšetlehileng ka bona bo 'nile ba bonoa ka koae, methamphetamine, nicotine, heroin le joala (Ahmed le al., 2000; Ahmed le Koob, 1998; Kitamura et al., 2006; O'Dell le Koob, 2007; Roberts le al., 2000). Moetso ona e tla ba karolo ea mantlha bakeng sa ho lekola karolo ea litsamaiso tsa khatello ea kelello ho ts'ebeliso e boletsoeng ka tlase.

Mefuta ea liphoofolo ea ho lakatsa (preoccupation / Ho lebella sethala) kenyeletsa ho khutlisetsoa hoa lithethefatsi tse latelang kamora ho felisoa hoa lithethefatsi ka bo tsona, ka mekhoa e hokahantsoeng le lithethefatsi, le ho pepeseng khatello ea khatello ea maikutlo (Shaham le al., 2003) (Lethathamo 1). Ho khutlisetsoa ka tlasa lithethefatsi pele ho kenyelletsa ho felisoa ebe ente ea priming ea moriana e felisoa. Boemo ba ho khutlisetsa karabelo kapa boholo ba karabo ho mokoloto o kileng oa tima bo holisoa ho bontša tšusumetso ea boits'oaro ba ho batla lithethefatsi. Ka mokhoa o ts'oanang, tšusumetso e ts'oaroang ke lithethefatsi kapa e amanang le lithethefatsi e ka khutlisetsa boits'oaro ba ho batla lithethefatsi (tlatselletso ea cue-e khothalletsitsoeng). Ho khutlisetsoa ka lebaka la khatello ea maikutlo ho kenyelletsa tšebeliso ea khatello e matla ea maikutlo e ntlafatsang boitšoaro ba ho batla lithethefatsi ho liphoofolo tse felisitsoeng ka lebaka la lithethefatsi. Matšoenyeho ana a ka kenyelletsa khatello ea 'mele e kang footshock, khatello ea kelello joalo ka ho ithiba kapa khatello ea litlhare tse kang yohimbine (Shaham le al., 2003). Litekong tse nang le nalane ea ho its'etleha, ho itšila nako e telele ho ka hlalosoa e le nako kamora ho khaotsa ho ikoetlisa ka matla ho nyamileng moo litheko tse phahameng tsa ethanol holim'a motheo le ts'ebetso ea khatello ea maikutlo e ntseng e tsoela pele (mohlala, libeke tsa 2-8 ka mora beke le morao ho tsoa ho ethanol). Ho itšireletsa ho kopantsoeng ho hokahane le ho eketseha ha meputso ea boko le ho eketseha ha maikutlo le boits'oaro bo joalo ba ho tšoenyeha bo bontšitsoeng ho phehella kamora ho khaoha ka matla ho liphoofolo tse nang le nalane ea ho its'epa. Ho khutlisetsoa ho matla ha khatello ea maikutlo bakeng sa ho batla lithethefatsi le ho khutlisetsoa hoa khatello ea maikutlo joalo ka nako ea ts'ebetso ea ho ila thipa ho tla sebelisoa tlhahlobisong ea morao-rao ho hlahloba karolo ea litsamaiso tsa khatello ea kelello ho ho lebella (craving) mohato oa potoloho ea bokhoba ba tahi (Lethathamo 2).

Mehopolo ea tlhahlobo ena ke hore karolo ea bohlokoa ea ts'ebetsong ea bokhoba ba ts'ebeliso e kenyelletsa tšebelisano e matla le lits'ebetso tsa khatello ea kelello le ts'ebetso ea methapo ea methapo ea khatello ea kelello ho hlahisa boemo bo bobe ba maikutlo boo e bang lebaka le matla la ho batla lithethefatsi tse amanang le ts'ebeliso e qobelloang ho drainare / Ho ama hampe 'me preoccupation / Ho lebella (craving) Mehato ea potoloho ea bokhoba. Tšebeliso e sa feleng ea lithethefatsi tsa tlhekefetso esale e amahanngoa le karabelo e fetelletseng ho bahatelli, 'me likarabo tsena tse fetelletseng li kenya letsoho ho lemeng (Himmelsbach, 1941). Tlhaloso ea likarolo tsa bohlokoa tsa eseng li-hormonal feela empa le li-neurocircuits tsa khatello ea kelello li ralile motheo oa leseli le lecha ho pathophysiology ea ho lemalla.

1.3. Ho susumetsa, Ts'ebetso ea Bohanyetsi le khatello ea maikutlo

Khothatso ke boemo bo tataisang boitšoaro kamanong le liphetoho lipolasing (Hebb, 1949) 'me e arolelana likarolo tsa bohlokoa le likhopolo tsa rona tsa ho hlasimoloha (Pfaff, 2006). Mafapha a susumetsang a fumana matla ka bobeli ho tsoa ho milieu ea ka ntle (li-incentives) kapa bohareng ba bohareng (lipallo tsa sepheo sa mantlha kapa bohare). Kahoo, libaka tse susumetsang kapa tse susumetsang ha li tsoelepele ebile li fapana ha nako e ntse e ea empa li khothalelitsoe nako e telele hore li na le lits'itiso tsa lapeng. Maemong a matla a nakoana, Solomone le Corbit ba hokahanya mohopolo oa tšusumetso le maikutlo a hedonic kapa a maikutlo ha a apareloa ke mohanyetsi mohopolo oa tšusumetso (Solomon le Corbit, 1974) (Lethathamo 1).

Haufinyane tjena, mohopolo oa mohanyetsi o atolositsoe hore o be karolo ea methapo ea kutlo le neurobiology ea ts'ebeliso ea lithethefatsi ho tsoa ponong ea 'mele (Koob le Le Moal, 2008). Lits'ebetso tsa ts'ebetso e ts'oanang le ts'ebetso ea mohanyetsi eo e leng karolo ea ts'oaetso e tloaelehileng ea homeostatic ea mosebetsi oa moputso li kengoa ho hloleha ho khutlela maemong a tloaelehileng a homeostatic mme ka hona e hlahise mefokolo ea moputso e hlahelletseng ho ho lemalla. Lits'ebetso tsena tse hanyetsanang li ne li kopantsoe hore li kopanngoe ke lits'ebetso tse peli: neuroadaptations ea ka hare ho system le neuroadaptations ea lipakeng (system neuroadaptations)Koob le Bloom, 1988) (Lethathamo 1).

Bakeng sa litlhahlobo tsa hona joale, lits'ebetso tse sebetsang joalo ka li-system tsa nuroadaptations li hokahanngoa ho kenyeletsa lits'ebetso tsa khatello ea kelello le lits'ebetso tsa khatello ea kelello. Li-circuits tsena li ka hlalosoa e le mochine o ikatisang oa lapengKoob le Le Moal, 2008). Ka moralo ona, ts'ebeliso ea lithethefatsi e hlalosoa e le mokhoa oa ho potoloha ha moputso oa boko / mekhoa ea boipheliso e ntseng e eketseha butle-butle, e lebisang ts'ebelisong e matla ea lithethefatsi. Morero oa tlhahlobo ena ke ho hlahloba liphetoho tse etsoang kahare ho khatello ea kelello le lits'ebeletso tsa antistress ho ikarabella bakeng sa boemo bo seng bobe ba maikutlo bo fanang ka ts'usumetso ea ho tlama ha bokhoba.

1.4 Hypothalamic-Pituitary-Adrenal Axis

Mokokotlo oa hypothalamic-pituitary-adrenal (HPA) o hlalosoa ke likarolo tse tharo tse kholo: konopo ea "patothricular" ea "hypothalamus" le "" "" "" "" "" "" "" "" "" hypothalamus " Turnbull le Rivier, 1997). Neurosecretory neurons karolong e arohaneng ea methapo ea methapo ea kutlo le ho lokolla CRF ka har'a methapo ea mali ea portal e kenang gland ea anterior. Tlamahano ea CRF ho CRF1 receptor ho pituitary corticotropes e etsa hore ho nkoe ha hormone ea adrenocorticotropic (ACTH) tsamaisong ea kemiso. ACTH eona e thusa ho hlahisa synthetic ea glucocorticoid le secretion ho tloha adrenal cortex. Vasopressin e lokollotsoeng ho li-neurons tsa "parvocellular neurons" e hlahisa li-synergistic litokollong tsa ACTH tse emisitsoeng ke vasopressin V1b li-receptors. Mokokotlo oa HPA o hlophisoa hantle ka ho fana ka likarabo tse mpe tse tsoang ho li-glucorticoid tse sebetsang ho "glucocorticoid receptor" - protheine ea cytosolic e sebetsang ka methapo le methapo ea kutlo, libakeng tse peli tsa mantlha tsa boko: konopo ea potoloho ea mokokotlo le hippocampus. Li-neurology tsa "hypophysiotropic" tsa "moth" ea "hypothalamus" li hlalositsoe ka likhakanyo tse ngata tse amanang, ho kenyeletsoa ho tsoa ho brainstem, li-nuclei tse ling tsa hypothalamic le likarolo tsa methapo ea methapo ea kutlo.

1.5. Amygdala e ekelitsoeng: Khokahano ea khatello ea maikutlo le bokhoba ba tahi

Lipatlisiso tse ncha tse sebetsang li fane ka ts'ehetso bakeng sa tšusumetso ea maikutlo a hore neanoanatomical substrates bakeng sa litlamorao tse ngata tsa ts'usumetso ea merero e amanang le ts'ehetso ea lithethefatsi e ka kenyelletsa "potoloho e tloaelehileng ea neural" e etsang mokhatlo o ikemetseng kahara sebopeho sa basal, se bitsoang "amygdala"Koob le Le Moal, 2001). Amygdala e atolositsoeng e emela sebopeho se nang le likarolo tse 'maloa tsa bokapele ba sefahleho: mokokotlo oa bethe ea stria terminalis, amygdala e bohareng le sebaka sa phetoho karolong e ka morao ea methapo ea methapo ea methapo (ke hore, khetla la morao-rao) (Heimer le Alheid, 1991). Meaho ena e na le ho tšoana ho morphology, immunohistochemistry, le khokahanyo, 'me e amohela likhokahano tse kopanetsoeng ho tsoa ho li-limbic cortices, hippocampus, basolateral amygdala, midbrain, le hypothalamus ea morao-rao. Khokahano e sebetsang ho tsoa mohahong ona e kenyelletsa posterior medial (sublenticular) ventral pallidum, sebaka sa likarolo sa ventral, likhopolo tse fapaneng tsa ts'ebetso ea kelello, mme mohlomong e khahla haholo ho tloha sebakeng sa pono, ts'ebetso e ka nahanoang ho hypothalamus ea morao-rao (Heimer le Alheid, 1991). Lintho tsa bohlokoa tsa amygdala tse atolositsoeng ha li kenyeletse feela li-neurotransmitters tse amanang le litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso empa le likarolo tse kholo tsa tsamaiso ea khatello ea kelello tse amanang le ts'ebetso e mpe ea ts'ehetso (Koob le Le Moal, 2005). Karolo ea mekhoa e ikhethang ea li-neuropharmacological e amanang le litsamaiso tsa khatello ea kelello le li-amygdala tse atolositsoeng e tla hlahlojoa likarolong tse ka tlase.

2. Sisteme ea khatello ea kelello le bokhoba: Corticotropin-Releasing Factor, Norepinephrine, Orexin, Vasopressin, Dynorphin

2.1. Corticotropin-Lokolla Factor

Corticotropin-releasing factor ke 41 amino acid polypeptide e laolang karabelo ea lihormone, kutloelo-bohloko le boitšoaro mabapi le khatello ea maikutlo. Immunantiacustom ea CRF e joalo ka neocortex, amygdala e atolositsoeng, medial septum, hypothalamus, thalamus, cerebellum, le autonomic midbrain le hind-brain nuclei (Swanson et al., 1983) (Setšoantšo sa 1). CRF1 receptor e na le polelo e ngata, e pharalletseng bokong e fetang haholo ka ho ajoa ha CRF le urocortin 1. Ho sibolloa ha li-peptide tse ling tse nang le sebopeho sa Homology, haholo ba lelapa la urocortin (urocortins 1, -2, le -3), e khothalelitse likarolo tse akaretsang tsa li-neurotransmitter bakeng sa lits'ebetso tsa CRF maemong a boitšoaro le a ho ikarabela ho khatello ea maikutlo (Bale le Vale, 2004) (bona Tlhahlobo ea Tlatsetso e fumanehang inthaneteng). Urocortin 1 e tlama ka bobeli ho CRF1 le CRF2 li-receptors 'me li na le phano e fapaneng ea neuroanatomical ho feta CRF. Mofuta oa li-urocortins tsa 2, urocortin 2 (Reyes et al., 2001) le urocortin 3 (Lewis et al., 2001), li fapana le urocortin 1 le CRF ho neuroanatomical, neuropharmacological, le profiles tsa kabo mme ke CRF ea morao-rao e khethang2 agonists.

Setšoantšo sa 1 

Ntlafatso ea libaka le likhakanyo tsa tsamaiso ea khatello ea methapo ea methapo — Corticotropin-Releasing Factor

CRF sebakeng sa "solothicular" ea "hypothalamus" e laola karabelo ea adrenal ho khatello ea maikutlo (Turnbull le Rivier, 1997). Liphetoho tse tsoelang pele mokokotlong oa HPA li bonoa nakong ea phetoho ho tloha taolong e mpe ho isa ho ts'ebetsong ea lithethefatsi tsa tlhekefetso. Ts'ebetso e matla ea lithethefatsi tse ngata tsa tlhekefetso ho liphoofolo e kenya letsoho mokokotlong oa HPA mme e ka qala ts'ebetso ho li-circuits tsa ts'usumetso ea kelello, ho tsamaisa moputso oa lithethefatsi, mme ka lebaka leo e nolofalletsa ho fumana boitšoaro bo batlang lithethefatsi (Piazza et al., 1993; Goeders, 1997; Piazza le Le Moal, 1997; Fahlke et al., 1996). Ha ho etsoa khafetsa koae, opiate, nicotine le joala khafetsa, liphetoho tsena tse mpe li felisitsoe kapa li sa sebetse (Kreek le Koob, 1998; Rasmussen et al., 2000; Goeders, 2002; Koob le Kreek, 2007; Sharp le Matta, 1993; Semba et al., 2004). Khopolo-taba ea pele e ne e le hore karabelo ea atypical ho baetsi ba khatello ea maikutlo e thusa ho phehella le ho khutlela mekhoeng ea ho itšetleha ka opioid, 'me ka mor'a moo khopolo ena e ile ea fetisetsoa ho lithethefatsi tse ling tsa tlhekefetso (Kreek le Koob, 1998).

Habohlokoa bakeng sa thesis ea hona joale, li-glucocorticoids tse phahameng tse potolohang li ka iphepa ho koala li-axis tsa HPA empa li ka "sensitisa" lits'ebetso tsa CRF moqomong o bohareng ba amygdala le norepinephrine ho basolateral amygdala tse tsejoang hore li kenya letsoho likarabo tsa boitšoaro. ho khatello ea maikutlo (Imaki et al., 1991; Makino et al., 1994; Swanson le Simmons, 1989; Schulkin et al., 1994; Shepard et al., 2000). Kahoo, ha ts'ebetso ea axis ea HPA e ka supa tšebeliso ea lithethefatsi tsa pele le binge / botaoa bohato ba ho lemalla, ts'ebetso ea HPA le eona e ka lebisa ho ts'ebetsong e latelang ea lits'ebetso tsa khatello ea kelello tsa extrahypothalamic tse khethollang drainare / Ho ama hampe mohato oa ho lemallaKreek le Koob, 1998; Koob le Le Moal, 2005; Koob le Kreek, 2007) (Setšoantšo sa 2).

Setšoantšo sa 2 

Litlamorao tsa ho tlosoa ha lithethefatsi litekolong tsa CRF ho Amygdala

Bopaki bo boholo hona joale bo fana ka maikutlo a hore lits'ebetso tsa bongo tsa extrahypothalamic CRF li ts'ebetsong nakong ea kholo ea nts'etsopele ea joala, mme ts'ebetso ena e na le bohlokoa bo susumetsang. Nakong ea ho tlosoa ha ethanol, ho lokolloa ha CRF ho eketseha ka har'a khubu ea bohareng ba amygdala le bethe ea "stria terminalis" ea likhoto tse itšetlehileng ka eona (Funk et al., 2006; Merlo-Pich et al., 1995; Olive et al., 2002) (Litšoantšo 1B 'me And2), 2), mme taolo ena ea lits'ebetso tsa CRF ea boko e kentsoe tšebetsong boits'oaro bo ntlafalitsoeng joalo ka boits'oaro le boits'oaro bo ntlafalitsoeng ba ethanol bo amanang le ho tlosoa hoa ethanol. Ho ts'ehetsa hypothesis ena, systemic CRF1 antagonists (Overstreet et al., 2004) kapa subtype nonselective CRF receptor antagonists α-helical CRF9-41 le D-Phe CRF12-41 ha ente intracerebroventricularly (Baldwin et al., 1991) kapa ka kotloloho karolong e bohareng ea amygdala (Rassnick et al., 1993) fokotseha boitšoaro bo kang khatello ea ethanol.

Ho pepesehela khafetsa khafetsa ea phepelo ea ethanol e sa tsitsitseng ea ho etsa hore motho a itšepe haholo ho eketseng litheko, ka nako ea ha a tlohela haholo le nakong ea ha a khaotsa ho tsuba (libeke tsa 2 tsa ho tlohela ho ikhula)O'Dell et al., 2004; Rimondini et al., 2002). Tsamaiso ea Intracerebroventricular le tsamaiso e kenelletseng ea intracerebral kahare ho khubu ea "amygdala" ea CRF1/ CRF2 peptide antagonist ka mokhoa o ikemetseng o thibetse keketseho e khothalletsoang ea ho itlhompha ha ethanol nakong ea ho ikhula ho matla (Valdez et al., 2004). Li-injection tsa systemic tsa molek'hule-CRF e nyane1 antagonists e boetse e thibetse ho ata ha ethanol ho amanang le ho tlosoa hoa ethaneol (Knapp et al., 2004; Funk et al., 2007; Richardson et al., 2008) (Setšoantšo sa 3). CRF2 agonist e kentsoeng ka har'a khubu ea mantlha ea amygdala e bile le phello e ts'oanang ea ho fokotsa keketseho ea boits'oaro ba ethanol bo amanang le ho tlosoa ho matla, ho fana ka maikutlo a karolo bakeng sa CRF2 li-receptors tse khahlano le CRF1 receptors in modulating ethanol ente ho liphoofolo tse its'epileng (Funk le Koob, 2007). Barekisi ba CRF ba kentse intracerebroventricularly kapa ka mokhoa o hlophisehileng ba boetse ba thiba likarabo tse kang tsa ho tšoenyeha joalo ka bahatelli ba hlokometsoeng nakong ea thobalano e sa khaotseng (Breese et al., 2005; Valdez et al., 2003) le taolo e phahameng ea ethanol e amanang le ts'ebetso ea nako e telele ea ho tlohela (Valdez et al., 2004; Funk et al., 2006). Ha ho le ea mong oa bahanyetsi ba CRF ea bileng le litlamorao ho tsamaiso ea boitšoaro ea ethanol literekeng tse sa ts'epahaleng (Valdez et al., 2004). Lintlha tsena li fana ka maikutlo a karolo ea bohlokoa bakeng sa CRF, haholo-holo ka har'a khubu ea amygdala, ho arolelanang taolo e eketsehang ea boits'oaro e amanang le ho its'epa.

Setšoantšo sa 3 

Kameho ea CRF1 Receptor Antagonist on Alcohol and Nicotine Boitšoaro ho litekanyetso tsa Dependent

Polelo e eketsehileng ea CRF1 li-receptors li amahanngoa le tšebeliso ea khatello ea maikutlo e khothalletsoang ke ethanol ho Marchigian Sardinian (msP) likhoto tse khethileng joala (Hansson et al., 2006) hammoho le liphoofolong tse sa khetholloang ka ho fetoloa maemong a morao a latelang (Sommer et al., 2008). Lenaneng la litekanyetso tsa msP tse khethiloeng ka genetically, khetho e phahameng ea ethanol e ne e hokahane le polymorphism ea genetic crhr1 papatso le keketseho ea CRF1 letsoalo ho amygdala hammoho le maikutlo a eketsehang a khatello ea maikutlo le kutloelo-bohloko e eketsehileng ho CRF1 antagonist (Hansson et al., 2006). Likotong tse sa khethiloeng tse senotsoeng mejaraneng e mengata ea ethanol ho tahoa le ho ts'epa, CRF1 mohanyetsi o thibetse ho ja ho eketsehileng ha ethanol ho amanang le ho koala nako e sa lekanyetsoang, phello e tsamaisanang le ho ngolisoa ha CRF1 mofuta le ho fokotseha hoa CRF2 liphatsa tsa lefutso ho amygdala (Sommer et al., 2008). Bacha ba homozygous bakeng sa C allele ea R1876831 e fumanehang ho intron e ka bang le tšusumetso ho hlahisa mongolo oa CRF1 gene ea receptor e noele joala ho feta ka lekhetlo le leng mme e bile le litekanyetso tse phahameng tsa bophelo ba ho nwa haholo ho amanang le liketsahalo tse mpe tsa bophelo ho feta lithuto tse nkileng T allele (Blomeyer et al., 2008). Liphetho tsena li bonts'a monyetla o khahlisang oa hore li-polymorphism tse se nang li-single tsa nucleotide bathong ba motho li ka bolela tlokotsi ho li-subndpes tse ling tsa syndromes tse noang haholo mme, mohlomong tse monate le ho feta, li ka bolela karabelo ts'ebelisong ea bahanyetsi ba CRF receptor kalafong ea bokhoba ba joala.

Litšebelisano tse tšoanang le CRF li hlokometsoe ka ts'ehetso e amanang le cocaine, heroin le nikotine. Tsamaiso e sa foleng ea cocaine e hlahisa karabelo e kang ea ho tšoenyeha e thibetsoeng ke tsamaiso ea intracerebroventricular ea CRF1/ CRF2 antagonist (Sarnyai et al., 1995; Basso et al., 1999). CRF1/ CRF2 peptide antagonist e kentsoe ka har'a khubu ea bohareng ba amygdala le tsamaiso ea tatellano ea CRF1 bahanyetsi ba thibetse sebaka se nyatsehang se amanang le ho tlosoa hoa tlhaho (Heinrichs et al., 1995; Stinus et al., 2005). Ho tlosoa ha Opioid ho boetse ho eketse tokollo ea CRF ho amygdala, e lekantsoeng ke vivo micodialysis (Weiss et al., 2001). CRF1 litoeba tse tsoang mona li ile tsa sitoa ho bonts'a ho hloea ha opioid e maemong a nepahetseng mme tsa sitoa ho bonts'a keketseho e susumetsoang ke "dynorphin mRNA"Contarino le Papaleo, 2005). Mohanyetsi oa CRF o ente intracerebroventricular o thibetse litlamorao tse kang tsa ho ikhula lienjineng tsa bolus tsa nicotine (Tucci et al., 2003). Litlamorao tse kang tsa ho ikhula ho nicotine e sa foleng le tsona li thibetsoe ke CRF1 receptor antagonist (George et al., 2007) (Setšoantšo sa 2). CRF1/ CRF2 Peptide antagonist e boetse e thibetse keketseho e tlisoang ke ho ts'oaroa hoa nicotine lithutong tsa moputso oa boko (Bruijnzeel et al., 2007). Ho fihlella ka mokhoa o tsoelang pele oa ho itšireletsa kahare bakeng sa cocaine ea 12 hr, ho tlosoa hoa opioid ka mokhoa o hlakileng, le ho tlosoa hoa nicotine ho eketsehileng ho eketse tokollo ea CRF ho amygdala nakong ea ho tlohela, e lekantsoeng ke vivo microdialysis (Richter le Weiss, 1999; Weiss et al., 2001; George et al., 2007) (Setšoantšo sa 2). Tsamaiso ea tsamaiso ea CRF1 bahanyetsi ba khutlisitse ts'ebetso e eketsehileng ea ho iphekola ea koae, heroin le nikotine tse amanang le phihlello e atolositsoeng (Specio et al., 2008; George et al., 2007; TN Greenwell, CK Funk, P. Cottone, HN Richardson, SA Chen, K. Rice, MJ Lee, EP Zorrilla, le GFK, tlhaiso-leseling e sa phatlalatsoang.

Karolo ea CRF ho khutlisetsong e bakang khatello ea maikutlo ea lithethefatsi e latela mohlala oa liphetho tse ts'oanang le karolo ea eona litlamong tse kang ho ts'oaroa haholo le keketseho e bakoang ke tšebeliso ea lithethefatsi (bakeng sa litlhahlobo, bona Shaham le al., 2003; Lu et al., 2003) (Setšoantšo sa 1B). CRF e tsoakiloeng1/ CRF2 antagonists inj inj intracerebroventricularly le / kapa CRF1 bahanyetsi ba limolek'hule tse nyane ba thibetse ho khutlisetsoa hoa khatello ea kelello ea koae, opiate, joala le ts'ebetso ea nicotine (Erb et al., 1998; Lu et al., 2001; Shaham le al., 1997, 1998; Shalev et al., 2006; Le et al., 2000; Liu le Weiss, 2002; Gehlert et al., 2007; Hansson et al., 2006; Zislis et al., 2007). Litlamorao tsena li 'nile tsa phetoa ka ente ea intracerebral ea CRF e tsoakiloeng1/ CRF2 antagonist kapa molek'hule-CRF e nyane1 antagonist into the nucleus of the stria terminalis, Median raphe, and ventral tegmental endaweni, empa eseng amygdala kapa nucleus accumbens (Le et al., 2002; Erb et al., 2001; Erb le Stewart, 1999; Wang et al., 2006, 2007), ho fana ka maikutlo a hore libaka tse fapaneng, joalo ka moalo oa bethe ea stria terminalis, median raphe, le sebaka se arohaneng se ka ba bohlokoa bakeng sa ho khutlisetsoa khatello kelellong, ho fapana le karolo ea CRF ho itšebelisong ea lithethefatsi eo e ikemiselitseng e sibolotsoe sebakeng se bohareng ba amygdala (Funk et al., 2006).

Ka bokhutšoanyane, lits'ebetso tsa CRF tsa extrahypothalamic li bapala karolo ea ho loants'a litlamorao tse kang ho tlosoa ho matla, keketseho ea ts'ebeliso ea lithethefatsi e amanang le ts'oaetso, le ho khutlisetsoa ha khatello ea maikutlo bakeng sa lithethefatsi tsohle tse kholo tsa tlhekefetso, ho kenyeletsoa psychostimulants, opioids, ethanol, nicotine, le (ka lithuto tse fokolang) cannabinoids. Bongata ba litlamorao tsena li fumanehile sebakeng sa amygdala se atolositsoeng, 'me ho tlosoa ha lithethefatsi tsohle tse kholo tsa tlhekefetso ho matlafalitse tokollo ea CRF karolong e bohareng ea amygdala, e lekantsoeng ke vivo micodialysis (Litšoantšo 1B 'me Le2) .2). Mokhoa ona oa sephetho o bonts'a karolo e kholo ho CRF ho kenella lipuisanong tse mpe tsa maikutlo tse nang le bohlokoa ba ts'usumetso ho boloka mmuso o ts'epahalang (Koob le Le Moal, 2005; Bruijnzeel le Khauta, 2005).

2.2. Norepinephrine

Norepinephrine ke neurotransmitter e hlophisitsoeng hantle tsamaisong ea methapo ea kutlo e hasaneng hohle bokong (Setšoantšo sa 4) hape e na le ts'ebetso ea hypothesised ho arousal, tlhokomelo, khatello, matšoenyeho le mathata a amanang le ts'ebetso (sheba data ea tlatsetso). 'Mele ea lisele bakeng sa tsamaiso ea norepinephrine ea boko e simoloha liphoofolong le methapong ea methapo. Cousuleus ea "locus" e fumanehang ka har'a dorsal pons ke mohloli oa tsela ea methapo ea methapo ho ea ho cortices le hippocampus, 'me merero ea "brainstem" e kenelle ka mokotleng oa "ventral noradrenergic" ho kenyelletsa letsoalo le ka pele la "basal" le "hypothalamus".

Setšoantšo sa 4 

Localization le Merero ea Tsamaiso ea Khatello ea Brain — Norepinephrine

Norepinephrine e tlamahanya malapa a mararo a ikhethileng a li-receptor — α1, α2, le β-adrenergic — ngoe le e 'ngoe e nang le li-subtypes tse tharo tse amohelang (Rohrer le Kobilka, 1998). The α1 lelapa la receptor le na le α1a, α1b, le α1d. Mong le e mong subtype activates phospholipase C le α2 mme e kopantsoe le sistimi ea inositol phosphate ea bobeli ea len messengerosa ka G protein Gq. Oa sebetsang hantle oa α1 antagonist e sebelisoang ho etsa lipatlisiso tsa ts'ebeliso ea lithethefatsi ke prazosin. The α2 lelapa le na le α2a, α2b, le α2c. Mong le e mong subtype inhibits adenylate cyclase ka coupling ho inhibitory G protheine Gi. Tse peli tse α2 lithethefatsi tse sebelisoang hangata ho etsa lipatlisiso tsa ts'ebeliso ea lithethefatsi ke í2 agonist clonidine le α2 yohimbine antagonist Hobane α2 receptor e hypothesized ho ba presynaptic, lithethefatsi tsena li thibela le ho tsamaisa mosebetsi oa noradrenergic, ka ho latellana. Lelapa la β-adrenergic receptor le na le β1, β2, le β3. Mong le e mong subtype activates adenylate cyclase ka coupling ho G protheine ea Gs. Ke lithethefatsi tse fokolang tsa β-adrenergic tse sibolotsoeng lipatlisisong tse amanang le lithethefatsi, ntle le β-adrenergic antagonist propranolol, mohlomong ka lebaka la bioavailability e sa sebetseng hantle.

Ho tlosoa ha morphine ho reretsoeng ho etsa hore norepinephrine e tsoe ka har'a khubu ea mokokotlo oa "amygdala" le "bed" ea "stria terminalis"Watanabe et al., 2003; Fuentealba et al., 2000). Noradrenergic α2 agonist clonidine, mohanyetsi ea sebetsang oa norepinephrine ea nang le liketso tsa Presynaptic, o thibetse khatello eo ha a araba lijo nakong ea ha ho tloheloa opioid, tekanyo ea karolo e susumetsang ea ho tlosoa ke opioid (Sparber le Meyer, 1978) le litla-morao tse susumetsang tsa khothalletso (ho bea libaka khafetsa) tsa ho tlosoa ke opioid (Schulteis et al., 1998). Boitšoaro bo eketsehileng bo kang ba ho tšoenyeha bo ile ba bonoa nakong ea ho khaotsa koae le morphine ka har'a likhoto mme li thibetsoe ke "ren-adrenergic antagonists propranolol le atenolol (Harris le Aston-Jones, 1993; Khauta et al., 1980). Litlamorao tse ts'oanang li ile tsa bonoa ka liente tse tobileng tsa mohanyetsi oa ad-adrenergic ka ho toba mokokotlong oa "amygdala"Rudoy le van Bockstaele, 2007). Li-antagonists tse sebetsang tsa Norepinephrine (β1 antagonist le α2 agonist) e kentsoe ka har'a mothapo o ka morao oa bethe ea stria terminalis e koetsoeng e hlohlontšitsoeng sebaka se khelosang (Delfs et al., 2000), le bahanyetsi ba β-adrenergic ba hlahisitse litlamorao tse tšoanang ha ba kenngoa ka har'a mothapo o ka hare oa amygdala (Watanabe et al., 2003). Boithuto bo ntlafalitseng litla morao tsa norepinephrine ho khanna ho ts'oaroa ha opioid ho bontsitse hore lesapo la mokokotlo la neradrenergic le fumane ho tlosoa hoa opioid (Delfs et al., 2000), empa haele maqeba a potileng a dorsal noradrenergic ho tsoa sebakeng sa locus coeruleus le neurotoxin 6-hydroxydopamine ha a ka a thibela sebaka sa ho qhekella se hlahisoang ke ho hlohlolla le ho hlohlelletsa sebaka sa ts'usumetso ea opioid (Caille et al., 1999). E lumellana le lithuto tsa litla-morao tsa ho tlosoa hoa opioid, e leng α1 norepinephrine antagonist prazosin e fokotse boitaolo ba hau ho likhoto tse itšetlehileng ka phihlello e atolositsoeng (Greenwell et al., 2008). Prazosin e boetse e thibetse ka mokhoa o ikhethileng oa tšusumetso ea ho sebelisa k'hok'heine ka mokhoa o tsoetseng pele lenaneong la litekanyo ka phihlello e fihletseng ea lithethefatsi (ts'ebetso e hoketsoeng ho hlahisa ts'ebeliso)Wee et al., 2008). Lirata tse atolositsoeng tse fihlellang li bontšitse palo e fokotsehileng ea li-neuron tse nang le α1 adrenergic-like immunoreactivity mokokotlong oa bethe ea stria terminalis, ho fana ka maikutlo a hore α1 tsamaiso ea noradrenergic e ka har'a mookotaba oa bethe ea stria terminalis le eona e ka ameha ho itšetleha ka koae (Wee et al., 2008).

Bopaki bo boholo bo boetse bo bokelletse bo fana ka maikutlo a hore, ho liphoofolo le ho batho, lits'ebetso tse bohareng tsa noradrenergic li kentsoe nakong ea ho tlosoa ka matla ho ethanol mme li ka ba le bohlokoa bo susumetsang. Ho itlopa joala ho batho ho amana le ts'ebetso ea ts'ebetso ea noradrenergic, mme matšoao le matšoao a ho khaotsa joala ho batho a thibetsoe ke postynaptic β-adrenergic blockade (Romach le Barekisi, 1991). Matšoao a ho tlohela joala le 'ona a thibetsoe ho liphoofolo ka tsamaiso ea α1 antagonists le β-adrenergic antagonists le blockade ea khethiloeng ea methapo ea nalane ea norepinephrine (Trzaskowska le Kostowski, 1983). Ho litoeba tse itšetlehileng, α1 antagonist prazosin ka mokhoa o ikhethileng o thibela ho eketseha ha joala ho amanang le ho tlosoa ho matla (Walker et al., 2008). Kahoo, data e fetolang e fana ka maikutlo a hore tšitiso ea ts'ebetso ea noradrenergic e thibela ts'ebetso ea ethanol, hore Noradrenergic neurotransmission e matlafatsoa nakong ea ho tlosoa ha ethanol, le hore litsebi tsa ts'ebetso ea Noradrenergic li ka thibela likarolo tsa ho tlosoa ha ethanol.

Ts'ebetso ea tlhaho ea nicotine e sa laoleheng (phihlello ea 23 hr) e eketsa norepinephrine ho hlahisa li-nucleus tsa "moth" tsa hypothalamus le amygdala, tse lekantsoeng ke vivo micodialysis (Fu et al., 2001, 2003). Leha ho le joalo, nakong ea morao-rao ea ho lokisa 23 hr phihlello ea nicotine, ho lokolloa ha norepinephrine ha hoa ka ha hlola ho phahamisoa amygdala, ho fana ka maikutlo a ho hlaka / ho mamella joalo-joalo (Fu et al., 2003).

Karolo ea norepinephrine ho ho khutlisetsoa khatello ea maikutlo hape e latela mohlala oa liphetho tse ts'oanang le karolo ea eona litlamorao tse kang tsa ho ts'oaroa haholo le keketseho e bakoang ke tšebeliso ea lithethefatsi (bakeng sa litlhahlobo, bona Shaham le al., 2003; Lu et al., 2003). The α2 adrenergic agonist clonidine e fokotse khatello ea maikutlo e bakiloeng ke ho ts'oara koae, opiate, joala le takatso ea nikotine (Le et al., 2005; Erb et al., 2000; Shaham le al., 2000; Zislis et al., 2007). The α2 antagonist yohimbine o batla lithethefatsi (Lee le al., 2004). Lithuto tse lekantsoeng tse nang le ente ea intracerebral le tsona li hlahisitse litla-morao tsa tšebetso ea "systemade" ea norepinephrine mabapi le ho khutlisetsoa ha maikutlo a morphine a nang le maemo a sebaka molemong oa mokokotlo oa bethe ea stria terminalis (Wang et al., 2001). Bahanyetsi ba β-adrenergic ba sebetsang ka mokhoa o hlophisitsoeng ba boetse ba thibetse ho khutlisetsa khatello ea maikutlo ho ferekanyang kelello ea ho batla koae (Leri et al., 2002).

2.3. Dynorphin / κ Opioid System

Dynorphin ke li-peptide tsa opioid tse tsoang mohloling oa prodynorphin ebile li na le leucine (leu) -enkephalin ka tatellano karolong ea N-terminal ea molek'hule mme ke li-ligands tse nkoang e le tsa morao-rao bakeng sa κ opioid receptor (Chavkin et al., 1982). Li-dynorphin li na le kabo e pharaletseng tsamaisong ea methapo ea kutlo (Watson et al., 1982) (Setšoantšo sa 5) hape o bapala karolo ea mefuta e fapaneng ea 'mele ea mmele, ho kenyelletsa molao oa neuroendocrine, taolo ea bohloko, ts'ebetso ea makoloi, ts'ebetso ea pelo, phefumoloho, taolo ea mocheso, boits'oaro ba phepo, le karabelo ea khatello ea maikutlo (Fallon le Leslie, 1986) (bona Tlhahisoleseling ea tlatsetso). Lihlahisoa tse ka bang teng tsa prodynorphin process li kenyelletsa dynorphin A (1-17), dynorphin A (1-8), le dynorphin B (1-29). Kabo ea immunocytochemical ea dynorphin A le -B e bonts'a 'mele ea lisele tsa bohlokoa le lits'oants'o tsa libaka tse amanang le bokhoba tse kang li-nucleus accumbens, khubu ea "amygdala", "nucleus ea" stria terminalis, le hypothalamus (Fallon le Leslie, 1986). Li-Dynorphin li tlama ho li-receptors tsohle tse tharo empa li bontša khetho ea li-receptor tsa κ (Chavkin et al., 1982). Ts'ebetso ea sistor ea dynorphin / κ receptor e hlahisa liketso tse tšoanang le li-opioids tse ling empa hangata liketso tse khahlano le li-μ opioid receptors sebakeng sa khothalletso, moo dynorphin e hlahisang litlamorao tse tšoanang le dysphoric-ho liphoofolo le ho batho (Shippenberg et al., 2007).

Setšoantšo sa 5 

Tsebeliso ea libaka le boithuto ba methapo ea khatello ea kelello Brain-Dynorphin

Dynorphin haesale e le mohopolo oa nako e telele oa ho buella maemo a mabe a maikutlo. Li-agonists tsa κ receptor li hlahisa mefuta e mengoa (Shippenberg et al., 2007) le khatello ea maikutlo le dysphoria ho batho (Pfeiffer et al., 1986). Ts'ebetso ea lits'ebetso tsa dynorphin ho li-nucleus accumbens ke khale e amanang le ts'ebetso ea litsamaiso tsa dopamine ka cocaine le amphetamine. Ts'ebetso ea dopamine D1 li-receptors li tsosa moferefere oa liketsahalo tse qetellang li lebisa ho phokotso ea karolo ea cAMP-elementing binding (CREB) phosphorylation le liphetoho tse latelang ho polelo ea mofuta, haholo ts'ebetso ea polelo ea protachykinin le prodynorphin mRNA. Ts'ebetso e latelang ea lits'ebetso tsa dynorphin e ka kenya letsoho ho dysphoric syndrome e amanang le ts'ebeliso ea koae hape e fana ka maikutlo a ho fokotsa ho lokolloa ha dopamine (Nestler, 2005). Ts'ebetso ea lits'ebetso tsa dynorphin le eona e ka kopanya karolo ea khatello ea maikutlo (dysphoric) ea khatello ea maikutlo (Land et al., 2008; McLaughlin et al., 2003).

Bopaki bakeng sa karolo ea tsamaiso ea dynorphin / κ opioid liketsong tse nuroadaptive tsa lithethefatsi tse ling tsa tlhekefetso li thehiloe lithutong ka bobeli tsa biochemical le antagonist. Bopaki bo tebileng bo fana ka maikutlo a hore dynorphin peptide le polelo ea liphatsa tsa lefutso li kenngoa ts'ebetsong ea striatum, ventral striatum, le amygdala nakong ea tsamaiso e mpe le e sa foleng ea koae le joala (Spangler et al., 1993; Daunais et al., 1993; Lindholm et al., 2000). Mehlala e sa foleng ea taolo ea koae e eketsa μ le κ opioid receptor density bokong ba li-nucleus, cingrate cortex, le basolateral amygdala (Unterwald et al., 1994).

Setsebi se khethiloeng sa κ agonist, ha se fanoa ka mokhoa o fetelletseng ka minipump, se na le tšusumetso ea phello ea tahi ho litoeba tse nang le boiphihlelo ba nako e telele ea ethanol, empa ho kenella ka matla ha motsoako oa κ ha ho na phello, ho fana ka maikutlo a hore monyetla oa hore ho nooa ha ethanol e ka ba teko ea ho hlola litla-morao tsa li-ion agonists (Holter et al., 2000). Ho ts'ehetsa ka kotloloho mohopolo oa hore dynorphin ke karolo ea maikutlo a mabe a fumanoeng a ipapisitse le ts'oaetso ke tlhokomeliso ea hore kapa-binaltorphimine, ha e kenella ka intracerebroventricularly kapa ka tatellano, e thibetse ho itaola ha ethanol ka ho its'episa empa eseng ho liphoofolo tse sa its'epahalleng (Walker le Koob, 2008; BM Walker le GFK, tlhaiso-leseling e sa phatlalatsoang. Litoeba tsa č Knoutout li boetse li noele ethanol tekong ea libotlolo tse peli tse sebelisang litekanyetso tse ntseng li eketseha tsa ethanol (Kovacs et al., 2005).

Ho nts'oa ha Opiate ho bontšitsoe ho eketsa maemo a dynorphin ho amygdala (Rattan et al., 1992)Turchan et al., 1997). Liphoofolo tse nang le nalane ea taolo ea heroin li bonts'itse maemo a eketsehileng a dynorphin A le -B seterekeng ka nako ea nako pele ho seboka se latelang sa taolo ea boits'oaro (Cappendijk et al., 1999). Intracerebroventricular dynorphin kalafo e fokotse ho lokolloa ha dopamine ea heroin le ho eketsa haholo ho itaola ha mananeo a letsatsi le letsatsi a 5 hr, athe mohanyetsi oa κ a bile le litlamorao tse fapaneng (Xi et al., 1998).

Khatello ea maikutlo e eketsa ts'ebetso ea dynorphin, e fana ka maikutlo a tšebelisano e ka bang teng le lits'ebetso tsa CRF. Thibelo ea ts'ebetso ea dynorphin, ekaba ka ho ts'oaroa ha κ receptor antagonism kapa prodynorphin gene, ho khutlisetsa khatello e matlafatsong ea khatello ea kelello ea cocaine e hlahisitsoeng ke litoeba (McLaughlin et al., 2003) le ho thibela ho khutlisetsa khatello ho matlafatsong ea boitšoaro bo batlang koae (cocaine)Beardsley et al., 2005). Ho qobelloa ha khatello ea ho sesa le footshock e ke keng ea qojoa e ile ea hlahisa litheko ho litoeba tse neng li thibetsoe ke mohanyetsi oa kutlo le "dynorphin" mona, CRF e ile ea qhekelloa hore e hlahise pheko ea eona e khathollang ka CRF2 li-receptor-dynorphin tšebelisano (Land et al., 2008). Bopaki bo boetse bo bonts'a hore ho khutlisetsoa morao hoa ts'ebetso ea ho batla lithethefatsi ka ts'ebetso ea li-receptor tsa κ opioid ho kenelletse pakeng tsa CRF, mme ho ts'oaroa ha ts'oaro-ho kenyelletso ea ho ts'oenyeha ha cocaine ho thibetsoe ke CRF1 antagonist (Valdez et al., 2007). Kahoo, dynorphin / κ system e etsisa taolo ea khatello ea liphoofolo ho liphoofolo ho hlahiseng litlamorao tse tlatselletsang le boits'ebetso bo batlang lithethefatsi, mme karabelo ena e khelohileng e ka kenyelletsa ts'ebelisano-kholo ea li-dopamine le li-brain extrahypothalamic CRF system.

2.4. Orexin

Orexin (e tsejoang hape ka hore ke hypocretin) - li-neurons tse fumanehang feela li tsoa ho hypothalamus ea morao-rao mme li sebetsa ka botlalo ho bokong (Peyron et al., 1998), ka bolulo bo boholo ba libaka tsa anatomical tse kenyellelitsoeng ho laola maikutlo a bophelo bo botle, bo susumetsang le khatello ea maikutlo (Baldo et al., 2003) (Setšoantšo sa 6) (bona Tlhahisoleseling ea tlatsetso). Orexin A le orexin B ba na le liketso tse kopantsoeng ke li-receptor tse peli tsa G protein-coupled, OX1 le OX2 (e boetse e bitsoa hypocretin 1 le -2, ka ho latellana, empa orexin A, orexin B, OX1, le OX2 ke nomenclature e amohelehang ea International Union of Pharmacology nomenclature). OX1 e na le tumellano e phahameng ea orexin A, le OX2 e na le kamano e lekanang bakeng sa bobeli ba orexin A le -B (Sakurai et al., 1998). The orexin neuropeptides orexin A le orexin B e sebelisana le noradrenergic, cholinergic, serotonergic, histaminergic, le dopaminergic system, ho tlatselletsa ho HPA axis, ho laola molao oa ho robala, matla a homeostasis, le matla a susumetsang, neuroendocrine, le mesebetsi ea pelo (Sutcliffe le de Lecea, 2002).

Setšoantšo sa 6 

Nts'etsopele ea Libaka tsa Khatello ea Brain Stress System-Orexin (Hypocretin)

Karolo bakeng sa litsamaiso tsa orexin lits'ebetsong tsa neuroadaptive tse hokahaneng le ho ts'ehetsa li hlahisitsoe ka matla ho ipapisitse le tšebetso ea khatello ea kelello bokong. Li-neuron tsa Orexin li kentse letsoho ho batleng lithethefatsi. Li-neuron tsa Orexin tse ho latela hypothalamus ea morao-rao li kenngoa tšebetsong tse amanang le meputso, joalo ka lijo kapa lithethefatsi, le tšusumetso ea ntle ea "neuronalamic orexin neurons" ea boits'oaro e khutlisa boitšoaro bo batlang lithethefatsi litonong (Harris et al., 2005). Ho kenella ha OX1 antagonist ea fokotseha sebaka se ratoang ke morphine (Narita et al., 2006).

U sebelisa mokhoa o ikemetseng oa ho sebelisa k'hok'heine ea k'hok'heine, tsamaiso ea orexin Boitšoaro bo ntlafalitsoeng bo neng bo kile ba tima k'hok'heine, empa ho fapana le moputso o bakang, orexin A kentse sekoloto sa moputso oa nako e telele oa bokoBoutrel et al., 2005). Ho khutlisetsoa hoa boitšoaro ba ho batla koae ka koae hape ho thibetsoe ke bahanyetsi ba Noradrenergic kapa CRF receptor. Khopolo-taba ea OX1 li-receptors li thibetse ho khutlisetsoa ka hare ho boitšoaro ba ho batla koae ka litoeba (Boutrel et al., 2005). Ntle le moo, khatello ea kelello ea "footshock" e matlafalitse ts'ebetso ea ts'ebetso ea methapo ea kutlo ea orexin, e lebisang khopolong ea hore orexin neurons e kenang methapong ea kutlo ea "orexin" nakong ea khatello ea methapo ea kutlo. memori / Memori (Harris le Aston-Jones, 2006). Orexin A, mohlomong e tsoa ho pertifical-dorsomedial hypothalamus, e kenya li-neurons tse hlahisang CRF mokokotlong oa moea oa hypothalamus le khubu ea mantlha ea amygdala (Sakamoto et al., 2004). Li-neuron tsa CRF tsa kahare li-orexin neurons, mohlomong ho tsoa ho amygdala e atolositsoeng (Winsky-Sommerer et al., 2004), e fana ka tlhahiso ea mokhoa oa ho pheta khatello ea maikutlo. Ka kakaretso, liphetho tsena li fana ka maikutlo a kamano e matla lipakeng tsa orexin le moputso / khatello ea maikutlo maemong a taolo ea ho khutlisetsoa hoa boitsoaro bo neng bo felisitsoe ba ho batla lithethefatsi. Boithuto mabapi le karolo ea li-receptor tse khethehileng tsa orexin le libaka tse ikhethang tsa boko ka likarolo tse khothatsang tsa ts'ebeliso ea lithethefatsi li lula li lokela ho hlahlojoa.

2.5. Vasopressin

The neurohypophysial peptide vasopressin e na le liketso tsamaisong ea methapo ea kutlo ho kenyelletsa karolo ea eona ea mantlha e le hormone ea antidiuretic e nkiloeng ho posterior pituitary (bona Tlatsetso ea Tlatsetso). Vasopressin e ajoa ka bongata bokong kantle ho hypothalamus, 'me lintho tse tsepamisitsoeng ka ho fetisisa tsa vasopressin li ka har'a nuclei ea suprachiasmatic le supraoptic, empa maemo a maholo le' ona a bonoe ho septum le locus coeruleus (Setšoantšo sa 7). Vasopressin neurons e ka hare ho amygdala e atolositsoeng hore e hlahisoe ke 'mele ea sele e kahare ho methapo ea methapo ea methapo ea methapo ea methapo ("mesia"de Vries le Miller, 1998). Vasopressin e tlama likarolo tse tharo tse fapaneng tsa "protein" tse nang le "protein" tse ngata tsa "G": V1a, V1b, le V2. The V2 receptor e hlahisoa e batla e le thoteng, moo e arolelanang ketso ea antidiuretic ea vasopressin. The V1a le V1b li-receptor li fumaneha sebakeng sa bokong, 'me ho ajoa ha vasopressin receptor binding ho hlahella ho rat e atolositsoeng ea amygdala, ka ho tsepamisa mohopolo ho "nucleus" ea "stria terminalis", "nucleus" e bohareng ea "amygdala" le "shell" lisa (Veinante le Freund-Mercier, 1997).

Setšoantšo sa 7 

Tsebeliso ea libaka le likhakanyo tsa tsamaiso ea khatello ea kelello-Vasopressin

Bophahamo ba Vasopressin mRNA bo ile ba eketseha ka mokhoa o ikhethileng nakong ea amygdala nakong ea ho iketla ho tloha ho nako hang-hang ho heroin, le V e khethiloeng1b receptor antagonist, SSR149415, e koetsoeng e kenyellelitseng mekhoa ea heroin e batlang, e fana ka maikutlo a hore lits'ebetso tsa vasopressin ho amygdala e ka ba karolo ea bohlokoa liphellong tse sithabetsang tsa maikutlo tse tlisoang ke ho tlohela opioid (Zhou et al., 2008). Ho pepesetsoa ha ethanol nako e telele kapa e sa foleng ho fokotsehile ha vasopressin-like immunoreactivity ho hypothalamus le khutleng ea mohopolo oa "stria terminalis" ho "lateral septum"Gulya et al., 1991). V e khethiloeng1b receptor antagonist dose-ka kotloloho a thibela keketseho ea boits'oaro ba ethanol nakong ea ho khaotsa ho litoeba tse itšetlehileng empa a sena phello ho liphoofolo tse ikemetseng (S. Edward et al., 2008, Soc. Neurosci., abstract). Ho fihla joale, liphuputso tse 'maloa li ithutile ka matla a susumetsang a bahanyetsi ba vasopressin mehlaleng ea liphoofolo le ho ts'oaroa ke khatello ea maikutlo ka lithethefatsi tse ling tsa tlhekefetso. Leha ho le joalo, lingoliloeng li fana ka maikutlo a hore V1b bahanyetsi ba na le li-profiles tse kang tsa mofuta oa bakuli ba khathatsang (bona Supplemental Data) le hore vasopressin le li-receptor tsa eona li hlahisoa haholo ho amygdala e atolositsoeng e fana ka tumellano ea maikutlo a hore lits'ebetso tsa vasopressin ho amygdala tse atolositsoeng li ka ba le karolo ea ho eketsa joala bo amanang le joala.

3. Sistimi ea Brain Antistress le Thibelo ea Tlatsetso: Neuropeptide Y le Nociceptin

3.1. Neuropeptide Y

Neuropeptide Y (NPY) ke 36 amino acid polypeptide e nang le liketso tse matla tsa orexigenic le anxiolytic-like (bona Supplemental Data). NPY e ajoa hohle hara ts'ebetso ea methapo e bohareng empa e tsepamisitse maikutlo ho amygdala e atolositsoeng (Adrian et al., 1983) (Setšoantšo sa 8). Li-subtypes tse ngata tsa NPY tse ngata li fumanoe, le Y1 le Y2 subtypes e ameha haholo ho khatello ea maikutlo le liketso tsa lithethefatsi. Y1 receptor e na le phasalatso e pharalletseng bokong bohle ba rat, moo e fumanehang haholo cortex, tubercle ea olenzi, hippocampus, hypothalamus le thalamus (Parker le Herzog, 1999). Ho ajoa ha Y2 li-receptors li tšoana le Y1 li-receptors, leha Y2 Polelo ea receptor ha e na ngata cortex le thalamus ebile e ngata haholo hippocampus (Parker le Herzog, 1999). Y1 li-receptors li nkoa li le li-postynaptic le Y2 receptors presynaptic (Heilig le Thorsell, 2002).

Setšoantšo sa 8 

Tsebeliso ea libaka le likhakanyo tsa li-System tsa Bist Antistress-Neuropeptide Y

NPY e laetsoeng ho ntšoa ha intanol ka hlokoWoldbye et al., 2002). Boithuto ba morao-rao bo sebelisang meetso ea liphoofolo tse nooang tse ts'epelehileng ka litoeba bo bonts'itse hore NPY e laetsoeng ka mokhoa o batsi oa ho sebelisa joala ho litheko tsa Wistar haeba ba ka ba le nalane ea ts'ebeliso ea joala e hlahisoang ke ho pepesehela phallo ea joala nako e telele (Thorsell et al., 2005). NPY e sebelisoang ka bongata ho intša le eona e hatelletse lino tse tahang ka ho khetheha li fepa likhetho tse phahameng tsa joala empa ha lia ka tsa fetola ho nwa joala ho metsoalle e meng e tlase e tahang joala (Badia-Moholo et al., 2001, 2003). Litlamorao tse tlatselletsang tsa ho nooa ka mokhoa oa intracerebroventricularly NPY mabapi le lino tse tahang ho litekanyetso tsa P li matlafatsoa le ho tšoarella nako e telele kamora nako ea ho itlopa joala.Gilpin et al., 2003). Tsamaiso ea Intracerebroventricular ea NPY ha ea ka ea ama ho kenella ka mokhoa o sa lekanyetsoang oa ho sebelisa joala ka litheko tsa Wistar (Badia-Moholo et al., 2001).

Ha ho fanoa ka bopaki ba hore litlamorao tse khahlano le matšoenyeho a NPY li kopantsoe ke karolo e bohareng kapa ea basolateral amygdala tata (Heilig et al., 1994), sebaka se nang le kelello sa ho hlahloba ho fokotseha ha takatso ea "NPY" ho feteletseng hoa ethanol ke senotlolo se bohareng ba amygdala. Ho ntšoa ha Ethanol ho fokolitse protheine ea NPY kahare le bohloeng ba methapo ea amygdala (Roy le Pandey, 2002). Ts'oaetso ea vaerase e kenang kahare ea "prop-NPY" ea mantlha karolong e bohareng ea amygdala e fokotse ts'ebeliso ea joala e tsoelang pele ke likhoto tsa Long-Evans tse bonts'ang boitšoaro bo kang ba ho tšoenyeha joalo ka mosele o moholo le o mong (Primeaux et al., 2006). Litsing tsa Wistar tse nang le nalane ea ho ts'epahalla le linako tse ngata tsa ho itlopa joala, boteng ba vaerase e hlahisang amygdala NPY oxpxpression boits'oaro bo joalo joalo ka ts'ebetso mme bo hlahisa khatello ea nako e telele ea joala (Thorsell et al., 2007). Litlalehong tsa P tse nang le nalane e telele ea tšebeliso ea joala, infusions ea NPY ka kotloloho mokokotlong oa amygdala e ne e hatella ho nooa ho litheko tsa P tse neng li beoa nako ea ho itlopa joala feela.Gilpin et al., 2008). Likhoto tsa P li bonts'oa li na le maemo a tlase a NPY khubung e bohareng ea amygdala le boits'oaro bo phahameng joalo ka ho tšoenyeha bo tšoanang le litšoene tse senang joala (Suzuki et al., 2004; Pandey et al., 2005). Keketseho ea ts'ebetso ea NPY karolong e bohareng ea amygdala, e hlahisoang ka phetoho mosebetsing oa CREB kapa tsamaiso e tobileng ea NPY, e fokotse tšebeliso ea ethanol le boits'oaro bo ts'oanang le ho ts'oenyeha ho tšoanang le litekong tsa P tse nang le nalane e khutšoanyane ea boits'oaro (Pandey et al. 2005). Exo native NPY e fanoeng ka har'a khubu ea mantlha ea amygdala le eona e fokotse haholo ts'ebeliso ea lino tse tahang ka litoeba tse itšetlehileng ka joala empa eseng ka taolo e e latelang.Gilpin et al., 2008), e netefatsa liphetho tse hlokometsoeng ka tlhahiso ea vaerase e hlahisitsoeng ke vaerase ea ts'ebetso ea NPY (Thorsell et al., 2007).

Ka bobeli Y1 le Y2 li-subtypes tsa receptor li kenella ho noeng e fetelletseng e amanang le ho lemalla joala. Y1 litoeba tse amohelang ka bongata li bonts'a tšebeliso e ngata ea joala (Thiele et al., 2002). Ka lehlakoreng le leng, Y2 Receptor knockout litoeba ho feta haholo joala (Thiele et al., 2004). Boithuto ba thuto ea meriana bo netefalitse hore blockade ea Y1 li-receptors li eketsa ho jella ethanol ho litoeba tse phahameng tsa C57BL / 6 (Sparta et al., 2004) le blockade ea Y2 li-receptor li fokotsa ho kenella hoa ethanol ho liphoofolo tse itšetlehileng ka tsona (Rimondini et al., 2005) le liphoofolong tse arabelang ethanol ka tharollo e monate (Thorsell et al., 2002). Y1 Knice litoeba le Y1 antagonists e bonts'a boemo bo kang ba tšoenyeha, le Y2 Knice litoeba le Y2 bahanyetsi ba bonts'a boemo bo kang ba ho tšoenyeha, ka hona, bo fana ka kamano ea bohlokoa pakeng tsa sistimi ea NPY, likarabo tse kang ho tšoenyeha, le tšebeliso ea joala ho liphoofolo tse its'epileng (Valdez le Koob, 2004). Ha li kopantsoe le mosebetsi o pharaletseng ho liphoofolo tse itšetlehileng ka tsona, lithuto tsena li fana ka maikutlo a hore sistimi ea NPY e ka fetola litlamorao ho ts'ebeliso nakong ea phetoho ho tloha ho se latelang ho ea ho joala bo itšetlehileng.

Lithuto tsena li fana ka maikutlo a hore liphetoho tse bakiloeng ke joala le tse bakiloeng ke joala ts'ebetsong ea NPY ho amygdala li ka nna tsa se amehe feela ho arabiseng likarabo tse kang tsa ho tšoenyeha empa hape le litlamorao tsa ts'epahalo ea ethanol. Khopolo-taba e 'ngoe ke hore ts'ebetso e fokotsehileng ea NPY, e tsamaellanang le ts'ebetso e eketsehileng ea CRF, e ka fana ka mabaka a susumetsang a ho itaola haholo nakong ea ho khaotsa joala kapa ho itlopa joala ho khanna tšebeliso e ngata ea joala (Heilig et al., 1994).

NPY e kentse letsoho ho itšetleha ka lithethefatsi tse ling tsa tlhekefetso, empa lingoliloeng tse fumanehang ha li ngata hakana. Phekolo ea "heroin" e sa foleng e ile ea eketsa tšebetso ea neuron ea NPY e lekantsoeng ke immunohistochemistry ho thalamic paraventricular nucleus le mookoteng oa bethe ea stria terminalis (D'Este et al., 2006). NPY e fanoe intracerebroventricularly e thibetse matšoao a ho khaotsa morphine a hlahisitsoeng ke opioid antagonist naloxone, 'me liphetoho tsena tsa boits'oaro li ne li tsamaea le ho fokotseha ha c-fos expression in locus coeruleus, lateral septal nucleus, periaqueductal grey, cingulate and frontal cortices, le septohippocampal nucleus (Clausen et al., 2001). Li-analog tsa peptide tsa NPY le NPY tse fanoang ka entracerebroventricularly li fokotseha ho tlosoa ha sephethe-phethe ho likhoto (Woldbye et al., 1998).

3.2. Nociceptin (Orphanin FQ)

Nociceptin ke "ligropeptin" ea "testiceptin" ea likhutsana tsa bana (NOP) e amohelang (Mokhatlo oa Machaba o amohetsoeng oa Machaba mabapi le Pharmacology; receptor e boetse e se e bitsoa receptor ea likhutsana kapa opioid receptor-like-1 kapa OrL-1 receptor. ) (Mollereau et al., 1994). Nociceptin ke polypeptide ea 17 amino acid e amanang le sebopeho sa dioorphin A ("io "polypeptide).Reinscheid et al., 1995; Meunier et al., 1995). Nociceptin ha e tlamele ho μ, δ, kapa li-receptors tsa μ, hape ha ho li-opioid tse tsejoang tse tlamang ho NOP receptor. Boithuto ba 'mapa oa likelello li bontšitse hore phepelo ea neuroanatomical ea nociceptin le li-receptor tsa eona li fapane le tse ling tsa li-peptide tse ling tsa opioid mme mohlomong li emela lipotoloho tse haufi tsa projeke ea (Neal et al., 1999) (Setšoantšo sa 9). Boemo bo phahameng ka ho fetisisa ba nociceptin le receptor ea eona e ka fumanoa cortex, amygdala, mookotaba oa "stria terminalis", "medial pre mapemaal cortex"Darland et al., 1998; Neal et al., 1999).

Setšoantšo sa 9 

Tsebeliso ea libaka le likhakanyo tsa li-System tsa Bist Antistress-Nociceptin / Orphanin FQ

Li-agonist tsa NOP receptor, antagonists, le li-knockout li na le litlamorao tse ngata tse sebetsang, ho kenyelletsa ho thibela analgesia e bakang khatello ea maikutlo, litlamorao tse kang tsa ho tšoenyeha, le moputso oa lithethefatsi (bona Tlatsetso ea Tlatsetso). E lumellana le karolo ea nociceptin ho likarabo tse amanang le khatello ea maikutlo, tsamaiso ea nociceptin le eona e ka fetolela ho itšetleha ka liketso ka lits'ebetso tsa maikutlo tsa boko tse amehang karabong ea khatello ea kelello. Phekolo ea Intracerebroventricular ka nociceptin (Ciccocioppo et al., 1999, 2004) kapa peptidic NOP receptor agonists (Economidou et al., 2006) e fokotsehile haholo ts'ebeliso ea ethanol ho litheko tsa msP. Litlamorao tsena li ne li koetsoe ke mohanyetsi oa nociceptin (Ciccocioppo et al., 2003). Leha ho le joalo, litoeba tsa NOP tse ileng tsa khutlisetsoa morao mohloling oa C57BL / 6 le tsona li bontšitse ho fokotseha hoa ts'ebeliso ea ethanol tekong ea likhetho tsa libotlolo tse peli.Sakoori le Murphy, 2008), le mefuta e meng ea tsamaiso ea Non receptor agonist e matlafalitse tšebeliso ea ethanol (Economidou et al., 2006).

Nociceptin e fokotse haholo ho khutlisetsa khatello ea maikutlo phepelong ea ethanol- (empa eseng cocaine-) ho batla boits'oaro ho litoeba tsa Wistar (Martin-Fardon et al., 2000) le ho khutlisetsoa ka matla lithutong tsa msP (Ciccocioppo et al., 2003). Ntle le moo, ts'ebetso ea "Nept receptor inhibited" e kenyellelitsoeng lithethefatsong tsa lithethefatsi tsa ethanol- le morphine.Kuzmin et al., 2003; Shoblock et al., 2005) le ho thibela boitšoaro bo kang ba ho khutlela morao joaloka mokhoa oa ho itlopa joala ho litheko tsa msP (Kuzmin et al., 2007).

Ka hona, ts'ebetso ea ts'ebetso ea nociceptin e fokotsetse litlamorao tse matla tsa lithethefatsi tsa tlhekefetso tse lekantsoeng ke thato ea sebaka, e hlahisitse litlamorao, ts'ebeliso ea ts'ebeliso ea ethanol ka mola o khethiloeng oa genet ka mokhoa o tsejoang ka hore ke hypersensitive ho bahatelli, le ho fokotsa ho khutlisetsoa morao hoa ts'ebeliso ea lithethefatsi. Ho etsa lipatlisiso karolo ea nociceptin ho lino tse tahang tse itšetlehileng ka sebaka le ts'ehetso ea lehae ea sebaka sa ts'ebetso bakeng sa litlamorao tsa eona ho joala e sala mosebetsing oa nakong e tlang.

4. Mechine ea Cellular ea Brain Stress Systems ho Amygdala e Atolositsoeng

Mekhahlelo ea khatello ea kelello le lits'ebetso tsa khatello ea kelello li ka fetisoa hore li sebetse ka tatellano kapa ka ho tšoanang ka mekhoa e tloaelehileng ho amygdala e atileng ho ama maikutlo a maikutlo. Lithuto tsa cellular tse sebelisang mahlale a electrophysiological li na le matla a ho hlakisa mekhoa e tloaelehileng. Ho fihla joale, liphuputso tse ngata li fuputse e le γ-aminobutyric acid (GABA) kapa ketsahalo ea glutamatergic kahare ho amygdala e atolositsoeng, 'me ho tšoana ho itseng ho ka fumanoa sethaleng sa maqhubu se hlahang maemong a tlhahlobo ea methapo ea kutlo.

Amygdala, CRF e fumaneha sebakeng se kahara karolo ea methapo ea methapo ea methapo ea methapo ea kutlo (GABAergic neurons) karolong e ka tlas'a bethe ea "stria terminalis" le "kati" ea "amiagdala" tse fapaneng le tseo colocalized le enkephalin (Letsatsi le al., 1999). Litokisetsong tsa kelello, CRF e ntlafalitse GABAA inhibitory postsynaptic potentials (IPSCs) ho lirekoto tsa seleng ea mantlha ea amygdala, mme phello ena e ne e koetsoe ke CRF1 bahanyetsi le ho CRF1 Knice KniceNie et al., 2004). Nociceptin e bile le litlamorao tse fapaneng mokokotlong o bohareng ba amygdala — e fokotseha GABAergic IPSCs (Roberto le Siggins, 2006). Vasopressin e boetse e butse lisele karolong ea methapo ea methapo e bohareng ea amygdala (Huber et al., 2005). Liphetho tsena li bonts'a hore CRF le vasopressin, tse kang tsoekere, li kenya li-interneuron tsa GABAergic karolong e bohareng ea amygdala.

Bongata ba li-neuron tse bohareng ba li-amygdala ke GABAergic, ebang ke li-inhibitory interneurons tse nang le likhokahanyo tsa nako le nako kapa tsa ho fetisetsa kapa li-neurons tsa "inhibitory" tsa methapo ea kutlo ho li-brainstem kapa libaka tse tlase (mohlala, bethe ea nucleus ea stria terminalis). Khokahano e bohareng ea amygdala e ka tsejoa e le "heke" e laolang phallo ea tlhahisoleseling ka har'a mekoloko ea intra-amygdaloidal, le ho hlophisoa hantle ha GABAergic inhibitory system karolong e bohareng ea amygdala e ka ba mokhoa oa pele oa taolo. li-neuron tsa lehae le tse hlahisoang ho ea tlase mohloling o tlase. Hobane lithethefatsi tsa GABAergic hangata ke li-anxiolytics tse matla, taba ea hore li-neurotransmitters tse tsosang takatso li ka hlahisa tšebetsong ea methapo ea kutlo ea "Gabaergic" le "neurotransmitters" li ka sithabetsa phetiso ea GABAergic sebakeng sa boko se tsejoang ho ameha ka boits'oaro bo amanang le khatello ea maikutlo. Leha ho le joalo, ts'ebetso ea GABAergic ea lehae kahare ho khubung e bohareng ea amygdala e kanna ea susumetsa karabelo ea methapo ea methapo ea kutlo ea inhibitory ea methapo ea methapo ea methapo e laolang tlhaiso-leseling ka har'a potoloho ea "amygdaloidal" (ke hore, ka ho hlakola karolo e bohareng ea "amygdala"). ho eketsa thibelo libakeng tse tlase tse parolang karabelo ea boitšoaro.

Ka mokokotlong oa bethe ea stria terminalis, lirekoto tsa seleng ka botlalo tse tsoang litokisetsong tsa selae li bontšitse hore CRF e ntlafalitse methapo ea methapo ea kutlo ea "GABAergic", 'me phello ea CRF e bonahala e le ka CRF1 receptor e tšoanang le litlamorao ho amygdala, le NPY inhibited GABAergic neurotransication (Kash le Winder, 2006). Sebaka se ka sehloohong sa polokelo ea methapo ea kutlo ea "bedia" se karolong ea moea ea "stria" se karolong ea moea, 'me mona norepinephrine e fokotseha ketsahalo ea glutamatergic e lekantsoeng ka li-electrophysiologic le ka har'a vivo micodialysis (Egli et al., 2005; Forray et al., 1999). Norepinephrine le eona e eketsehile GABAA IPSCs (Dumont le Williams, 2004). Kahoo, haeba motho a kopanya data e tsoang mohutlong o kaholimo oa amygdala le mookotaba oa bethe ea stria terminalis, lintho tse itseng li fetoha (Lethathamo 3). CRF, vasopressin, le norepinephrine li eketsa ts'ebetso ea GABAergic, mme NPY le nociceptin e fokotseha ts'ebetso ea GABAergic, liketso tse maemong a cellular a tsamaellanang le litlamorao tsa boitšoaro bo hlalositsoeng ka holimo le lithuto tsa neuropharmacological (Lethathamo 3).

Lethathamo 3 

Litlamorao tsa Brain Stress Neurotransmitters ketsahalong ea GABAergic ho Amygdala e Atolositsoeng

Bafuputsi ba bang ba pheha khang ea hore thabo e eketsehang mokokotlong oa basygdala e kenya letsoho litlamorao tse kang tsa CRF (Pula ea pula le pula). Ho sebelisa lirekoto tsa lisele tse felletseng tsa lisele tsohle tse tsoang ho basolateral amygdala neurons tsa liphoofolo tse tsamaisitsoeng hantle ho CRF1/ CRF2 agonist, urocortin, o bontšitse N-methyl-D-aspartate (NMDA) li-receptor-mediated receptor tse tsamaeang ka bobeli le li-IPSP tse susumetsang (1)Pula ea pula le pula). Ho tlosoa ha Ethanol, ho tlosoa ha diazepam, le khatello ea maikutlo e sa laoleheng ho hatella le li-IPSC tsa lisele tse amygdala ea basolateral li sebelisa mokhoa o hlophisitsoeng oa seleng ka kakaretsoIsoardi et al., 2007). Liphetho tsena tse kopantsoeng le NMDA ke tse ling tse fapaneng le litlamorao tsa GABA-Mediated tse hlahang khubung e bohareng ea amygdala mme li fana ka maikutlo a hore ho kopantsoe karolo ea karolo ea mantlha le basolateral nuclei ea amygdala ka khatello ea maikutlo le likarabo tsa ts'ehetso.

Ntle le lipatlisiso tsa morao-rao tse itšetlehileng ka ethanol, ha ho na mosebetsi o monyane ka seleng ho amygdala e atolositsoeng mabapi le liphetoho tsa methapo ea kutlo methating ea khatello ea kelello le kholo ea kholo. Liphetoho tse bakoang ke ethanol tse bakang ts'ebetso ea methapo ea methapo ea methapo ea methapo ea methapo ea kutlo ea GABA karolong e bohareng ea amygdala li hokahane le liketso tsa CRF le nociceptin. Tsamaiso e matla ea litekanyetso tsa joala le joala joala bo tahang e eketsehile GabaA li-receptor-mediated IPSCs ka har'a khubu ea methapo ea methapo ea kutlo ea amygdala, 'me sena se hlahisitsoe hore se bakoa ke keketseho ea tokollo ea presynaptic GABA (Roberto et al., 2003; Nie et al., 2004). Ntho e makatsang le ho feta ke hore tokollo ea GABA e matlafalitsoeng e eketseha le ho feta liphoofolong tse its'epileng, tse bontšitsoeng ka bobeli ke methapo ea electrophysiological le ea vivo micodialysis (Roberto et al., 2004). Kholiso ea ethanol e kenyellelitsoeng ho GABAergic IPSCs e koetsoe ke CRF1 antagonists (Nie et al., 2004; Roberto et al., 2004) mme ha ea ka ea bonoa ho CRF1 Knice KniceNie et al., 2004). Nociceptin-induction inhibition ea IPSCs e ile ea eketseha ho liphoofolo tse itšetlehileng ka eona, ho fana ka maikutlo a eketsehang a kutloisiso ea nociceptin (Roberto le Siggins, 2006). Kahoo, ha se feela hore lits'ebetso tsa khatello ea kelello / li-antistress li sebelisana hantle le methapo ea methapo ea methapo ea methapo ea kutlo ea "gabaergic" ea "nucleus" ea "amygdala", empa tebello ea ethanol le eona e hlokomelisa methapo ena ho liketso tsa khatello ea kelello / li-antistress system.

5. Neurocircuitry ea Brain Stress Systems in Dependence

Mekhoa e mehlano e ka bakang arousal-stress neurotransmitter system (CRF, norepinephrine, vasopressin, orexin, dynorphin) le lits'ebetso tse peli tsa antistress neurotransmitter (NPY, nociceptin) li fumanoe tlhahlobisong ea hona joale ho tsoa ponong ea karolo ea karolo ea neuroadaptation e amanang le kholo ea maikutlo a fosahetseng a amanang le ts'ebeliso ea lithethefatsi le bokhoba ba lithethefatsi. Lintlha tse qobellang ka ho fetisisa li ka har'a domain ea CRF, moo, hoo e batlang e le lithethefatsi tsohle tse kholo tsa tlhekefetso, (1) CRF e lokolloa nakong ea ho tlosoa ka mokhoa o matla, (2) bahanyetsi ba CRF ba thibela litlamorao tse kang tsa ho tlosoa ka matla, (3) CRF bahanyetsi ba thibela tšebeliso e feteletseng ea lithethefatsi tse amanang le ho ts'epa, le (4) bahanyetsi ba CRF ba thibela ho khutlisetsoa ha khatello ea maikutlo. Sebaka sa mantlha sa litlamorao tsena ke khubu ea "amygdala" le "nucleus" ea "stria terminalis" ("radius"). Setšoantšo sa 1).

Le ha data e le ngata haholo, e teng ho bahanyetsi ba bang ba Noradrenergic e thibelang litlamorao tse kang tsa ho tlohela opiate, thibela tšebeliso e ngata ea lithethefatsi e amanang le ts'epahalo ea ethanol, cocaine le opioids, 'me li thibela ho khutlisetsoa ha khatello ea kelello bakeng sa koae, opioids, ethanol, le nikotine (bona Setšoantšo sa 4). Hape, ntlha ea mantlha ea litlamorao tsena ke khubu ea bohlokoa ea amygdala le khubu ea boroko ea stria terminalis.

Ho fanoe ka bopaki bo bongata bo bontšang hore dynorphin e eketseha ka har'a li-nucleus tse ngata ka lebaka la ts'ebetso ea dopaminergic, 'me ka lebaka leo, ts'ebetso e mengata ea dynorphin e ka fokotsa ts'ebetso ea dopaminergic. Manane a ho hanyetsa a hlalositsoe ho thibela litlamorao tse tlisoang ke ho tlosoa hoa lithethefatsi le joala bo bongata bo amanang le ts'epahalo ea ethanol le ho khutlisetsoa ha khatello ea maikutlo bakeng sa ho batla lithethefatsi (bona Setšoantšo sa 5). Bopaki bo fana ka maikutlo a hore ts'ebetso ea κ receptor e ka hlahisa tokollo ea CRF (Pina le Takemori, 1992), empa haufinyane ba bang ba phehile khang ea hore litlamorao tsa dynorphin ho hlahisa maemo a mabe a maikutlo li kopantsoe ka ts'ebetso ea litsamaiso tsa CRF (Land et al., 2008).

Bopaki bo fokolang haholo ho fihlela joale bo bontšitse karolo e tobileng ea vasopressin le orexin maemong a mabe a maikutlo a amanang le ts'ebeliso ea lithethefatsi (bona Litšoantšo 6 'me Le7) .7). Mohanyetsi oa vasopressin o thibetse ho khutlisetsa khatello ho khatello ea maikutlo ea heroin le ho itlhatsoa ka moea o khathollang, mme mohanyetsi oa orexin o thibetse ho khutlisetsa khatello ea maikutlo ho bakeng khatello ea koae. Ho tla hlokahala mosebetsi o mongata ho lekola karolo ea litsamaiso tsena le litšebelisano tsa tsona le libapali tse ling tse kholo, tse kang CRF.

Bopaki bo bohlokoa bo fana ka maikutlo a hore ts'ebetso ea NPY karolong e bohareng ea amygdala e ka thibela likarolo tsa ts'usumetso ea ts'epahalo e amanang le taolo ea ethanol e sa foleng. NPY e laetsoeng intracerebroventricularly e ile ea thibela litlamorao tse kang tsa ho tlosoa ho ethanol mme ea thibela tšebeliso e matla ea lithethefatsi tse amanang le ts'epahalo ea ethanol (bona Setšoantšo sa 8). Tsamaiso e tobileng kapa polelo ea ntlafatso ea vaerase ea NPY bokong bo bohareng ba amygdala hape e thibetse ts'ebetso e eketsehileng ea lithethefatsi tse amanang le ts'epahalo ea ethanol. Ke lithuto tse fokolang kapa che tse ileng tsa hlahloba litlamorao tsa NPY lintlheng tse susumetsang tsa ho itšepa le lithethefatsi tse ling tsa tlhekefetso.

Karolo ea nociceptin ho ts'ehetso e fana ka maikutlo a tšebelisano hammoho le litlamorao tse khotsofatsang tsa lithethefatsi tsa tlhekefetso le maemong a susumetsang a ho ts'epa, haholoholo ka ethanol. Nociceptin e thibela litlamorao tse thabisang tsa lithethefatsi tse kholo tsa tlhekefetso tse lekantsoeng ke khetho ea sebaka (bona data ea tlatsetso). Nociceptin e fokotsehile ho itlhompha ha ethanol ho litheko tsa msP tse tsejoang ka hore li na le keketseho e ikhethang ea ketsahalo ea CRF le mofuta oa khatello ea maikutlo. li-rP msP li tsejoa li na le karabelo e phahameng ea basal khatello ea maikutlo, ho bonts'a ho fokotseha ha ethanol ho ts'oanang le likhoto tse itšetlehileng ka tsamaiso ea CRF1 antagonist, le ho ts'oara polymorphism ea liphatsa tsa lefutso ea CRF1 papatso, e lebisang ho CRF e eketsehileng1 letsoalo libakeng tse 'maloa tsa boko (Hansson et al., 2006) (bona Setšoantšo sa 9). Nociceptin le eona e fokotse haholo ho khutlisa khatello ea maikutlo e bakiloeng ke ethanol. Lithuto tsa nako e tlang li lokela ho lekola karolo ea mekhoa ena ka bobeli ea li-antistress (NPY, nociceptin) ho likarabo tse mpe tsa maikutlo tse amanang le ts'ebeliso ea lithethefatsi tse ling tsa tlhekefetso.

Tšebelisano e phatlalalitsoeng e teng lipakeng tsa CRF system le norepinephrine. E hlalosoa e le sistimi ea ho fepa pele maemong a mangata a makhopho le letsoalo la basal, CRF e kenya tšebetsong norepinephrine, le norepinephrine le eona e etsa tšebetso CRF (Koob, 1999; sheba Tlhahisoleseling ea Tlatsetso).

Ketso e tloaelehileng ea li-neurocircuitry ea lithethefatsi tsa tlhekefetso litsamaisong tsa khatello ea kelello le phetoho ea polasetiki ea liserekisi tsena (bona kaholimo) e ka kenyelletsa limolek'hule tsa limolek'hule tse tsamaisang lipotoloho ka tsela e fapaneng kapa tse hlahisoang ke liphetoho tsa tšebetso ea liserekisi kapa ka bobeli. Tšebeliso e pheta-phetoang ea litsela tse kenang kahare ho maqhubu a methapo ea kutlo e ka baka liphetoho ts'ebetsong ea neuronal le / kapa liphetoho ts'ebetsong ea nyutlelie le litekanyetso tse fetotsoeng tsa sengoloa sa mefuta e itseng ea sepheo. Polelo e fetohileng ea liphatsa tsa lefutso tse joalo e ka lebisa tšebetsong ea nako e telele ea liphetoho tsa methapo moo liphetoho tse joalo li etsahalang 'me qetellong li fetoloe ho liphetoho lipakeng tsa methapo ea kutlo eo li-neuron li sebetsang ho eona. Mosebetsi o mongata oa ho lemalla o bonts'itse hore ho pepesetsoa ha opiods le cocaine ka ho sa feleng ho lebisa ho kenngeng ha CREB bokong ba li-nucleus le motsoako o bohareng ba amygdala (Shaw-Lutchman et al., 2002; Edward et al., 2007). Leha taolo e matla ea lithethefatsi tsa tlhekefetso e ka baka ts'ebetso e potlakileng (ka nako ea lihora tse) ea litho tsa lelapa la liprotheine tsa Fos, joalo ka FosB, Fra-1, le Fra-2 ho li-nucleus accumbens, lintlha tse ling tsa ho ngola, isoforms ea ΔFosB, li na le e bontšitsoe hore e bokelle nako e telele ho feta ea matsatsi (matsatsi) ka taolo e pheta-phetoang ea lithethefatsi (Nestler, 2005). Liphoofolo tse nang le ΔFosB e sebetsitsoeng li fetisitse maikutlo ho melemo e tlisoang ke lithethefatsi tsa tlhekefetso, 'me "ΔFosB e ka ba" phetoho "ea limolek'hule e thusang ho qala le ho boloka boemo ba ho lemalla (McClung et al., 2004). Hore na (hona joang) lintlha tse joalo tsa mongolo li ama ts'ebetso ea lits'ebetso tsa khatello ea kelello, joalo ka CRF le tse hlalositsoeng ka holimo, li ntse li tlameha ho ikemisoa.

Tlhahlobo ea tlhahlobo ena e bile khokahanong ea methapo ea khatello ea kelello le maikutlo a holofalitsoeng, haholo-holo mookotaba oa amygdala le khubu ea boroko ea stria terminalis. Lits'ebetso tse tharo ho tse supileng (norepinephrine, orexin, NPY) li ajoa ka bongata bokong empa ka ts'ireletso e boima ea amygdala e atolositsoeng. Lits'ebetso tse 'ne (CRF, vasopressin, nociceptin, dynorphin) li fumaneha haholoanyane makaleng a lehae ho pholletsa le foremrain empa hape le ka pokello e kholo ea amygdala e atolositsoeng (Setšoantšo sa 10). Leha ho le joalo, ho fetoha hoa lits'ebetso tsena tsa neurotransmitter sebakeng sa amygdala e atolositsoeng ho bontša likarolo tsa bohlokoa ts'ebetsong ea maikutlo a susumetsang a ka bang teng ka lebaka la ts'usumetso ea li-neurons tse tsoang ho brainstem (norepinephrine), hypothalamus (nociceptin, NPY), le kahare ho amygdala ka boeona ( CRF, vasopressin, nociceptin, dynorphin). Amygdala e atolositsoeng e amohela lipapatso ho tsoa pele cortex le insula mme e romella lits'ebetso ho "lateroth hypothalamus", "subral tegmental" le "patunculopontine nucleus"Setšoantšo sa 10). Ke likarolo life tsa "neurocircuitry" tse etsang karolo ea bohlokoa maemong a sithabetsang a maikutlo a ts'ebeliso ea lithethefatsi le hore na li sebelisana joang le lits'ebetso tsa khatello ea kelello tse lulang li hlakisoa. Ho tsejoang ke hore boholo ba lisele tse karolong e ka morao ea nko ea mantlha ea amygdala le li-nucleus tsa bethe ea stria terminalis (e atolositsoeng amygdala) ke GABAergic le hore subpopulation e ikhethileng e ikhethileng e ka ba enkephalin kapa CRF, empa ha e e-so ka e e bala hammoho ka seleng e le 'ngoe ea GABAergic (Letsatsi le al., 1999). Ke enkephalin feela, mme eseng CRF, li-neuron tsa colabeled tse ileng tsa qaptjoa ke li-interleukin-1 that, li fana ka maikutlo a hore li-circuits tsa discural neural li teng ka har'a amygdala e atolositsoeng (Letsatsi le al., 1999). Ho feta moo, lithuto tsa electrophysiological anatomical tse hlalositsoeng ka holimo li khothaletsa hore li-neurons tsa GABAergic tse ka har'a mothapo o ka hare oa amygdala li araba li-neurotransmitter tsa khatello ea maikutlo ka ho thunya ho eketsehileng le ho arabela ho li-antistress neurotransmitters ka ho fokotseha ha khatello ea matla. Li-neurons tsena tsa GABAergic tse kenang kahare ho nko e bohareng ea amygdala e kanna ea ba li-interneurons tse thibelang sehokelo se seng sa GABAergic tseleng e atlehang (Letsatsi le al., 1999; Davis et al., 1994).

Setšoantšo sa 10 

Amygdala e Atolositsoeng le likhokahano tsa eona tse fapaneng le tse fapaneng le tse sebetsang ka bongata ka Brain Arousal-Stress Systems

Hypothesis eo karolo e bohareng ea amygdala e thehang ntlha ea ho kopana ea maikutlo a susumetsang ho hlahisa likarabo tsa maikutlo ke khale e thehiloe bakeng sa maemo a tšabo le bohloko. A cortexhamorao amygdalakhubu ea bohareng ba amygdala potoloho e bontšitsoe e le ea bohlokoa bakeng sa polelo ea maemo a tšabo (Phelps le Le Doux, 2005). Khothatso e nang le maemo a acoustic e ile ea kenya tšebetsong mokokotlo oa "amygdala" ea morao-rao ka libaka tse sebetsanang le ho hlahloba likarolo tsa karohano ea methapo ea 'mele ea genial genicrate. Amygdala ea morao-rao, e hlahisa merero ho amygdala e bohareng, e laolang karabelo ea likarabo tsa tšabo ka ho hakanngoa ho tšebetso ea bokoPhelps le Le Doux, 2005).

Bopaki bo tebileng bo ama amygdala maemong a bobeli a ho utloa bohloko le karabelo ea maikutlo maikutlong. Ntle le ho amohela litlatsetso tse hlophisitsoeng hantle le tse hlokolosi, tlhahisoleseling e amanang le bohloko e fetisetsoa ho li-lateral, basolateral, le li-central nuclei tsa amygdala ka mekhoa ea bohloko ea spinothalamic le spinohypothalamic empa hape le ka merero e tsoang ho bohloko ba spino-parabrachial-amygdaloid tsela (lesapo la lesapo la mokokotlo le khutso ea methapo ea kutlo ho ea mokokotlong oa parabrachial le ho ea bokong bo bohareng ba amygdala) (Bernard le Besson, 1990). Litsela tsena ka bobeli li bile le tšusumetso ea ho nka lehlakore la bohloko (Neugebauer et al., 2004). Ho tšoana ho hongata ho ka ba teng lipakeng tsa amygdala maikutlo a khatello ea maikutlo e boletsoeng ka holimo le karolo ea maikutlo e utloisoang bohloko ke amygdala. Tsena tsena li kenyelletsa tšebelisano lipakeng tsa khatello ea maikutlo, khatello ea maikutlo le bohloko (Neugebauer et al., 2004), kamano e pakeng tsa mamello le maikutlo a ho utloa bohloko (Celerier et al., 2001), le mods ea bohloko ba glucocorticoid (Greenwood-Van Meerveld et al., 2001). Tsela eo khatello ea methapo ea kelello e hlalositsoeng ka holimo e bapala karolo ea eona litsamaisong tsena ka bobeli ke phephetso ea lipatlisiso tsa nako e tlang.

6. Hedonic Homeostatic Dysregulation e le Sehopotso sa Khakanyo ea ho hokahanya lits'ebetso tsa khatello le tlhatlhobo

6.1. Hypothalamic-Pituitary-Adrenal Axis joalo ka Morupeli

Joalokaha ho boletsoe kaholimo, lithethefatsi tsohle tsa tlhekefetso li kenya letsoho mokokotlong oa HPA nakong ea ts'ebeliso ea lithethefatsi, 'me ka bobeli CRF le vasopressin maemong a pherese ea hypothalamus li laola likarabo tsena. Leha ho le joalo, ha potoloho ea ts'ebeliso ea lithethefatsi le ho khaotsa e ntse e tsoela pele, karabelo ea axel ea HPA e bonts'a mamello, empa ho pepesetsoa ha kelello khafetsa ho li-glucorticoids tse ngata ho ka tsoela pele ho ba le litlamorao tse kholo ho litsamaiso tsa khatello ea kelello tsa extrahypothalamic. Bopaki bo matla bo fana ka maikutlo a hore li-glucocorticoids li "nyenyefatsa" tsamaiso ea CRF ho amygdala (Imaki et al., 1991; Makino et al., 1994; Swanson le Simmons, 1989). Kahoo, ho ikamahanya le lits'ebetso tsa khatello ea kelello ho ka tlatsetsa boemong bo bobe ba maikutlo bo arohanang le nako kamora ho kenngoa ka letheba la lithethefatsi, empa ka taolo e sa khaotseng ea lithethefatsi e hola ha nako e ntse e feta (kapa e sitoa ho khutlela metheong e tloaelehileng ea homeostatic), ka lehlakoreng le leng ho axis ea HPA, ho hlophisa mochini o matla oa ho matlafatsa (bona le karolo ea "Allostasis and Addiction" ka tlase). Ka hona, li-axis tsa HPA le li-glucocorticoids li hokahane le karabelo e phahameng ho boqhekanyetsi le ho nolofalletsa moputso ts'ebeliso ea lithethefatsi tsa mantlha mme hape li ka nka karolo litokisetsong tse matla likarolong tse ngata tsa neuraxis, haholo-holo lits'ebetsong tse atolositsoeng tsa amygdala moo li kenya letsoho phetoho ho tloha homeostasis ho pathophysiology e amanang le tlhekefetso ea lithethefatsi. Liphetho tsena li fana ka maikutlo a hore ts'ebetso ea karolo ea HPA ea khatello ea maikutlo e ka bapala karolo ea bohlokoa ho tsamaiseng meputso le methapo ea methapo ea kutlo ea kelello e kenelletseng kholisong ea bokhoba ba tahi.

6.2. Ts'ebetso ea Mohanyetsi / Pakeng tsa System-Neuroadaptations

Joalokaha ho hlalositsoe kaholimo, ts'ebetso ea mohanyetsi, mahareng a-neuroadaptations (Lethathamo 1) li filoe hypothesized ho kenyelletsa ts'ebetso ea li-neurotransmitter system tse kopantsoeng hammoho tlhahlobisong ena e le masapo a khatello ea kelello. Kahoo, ho lata tsamaiso ea CRF ho etsahala nakong ea ntlafatso ea ts'ebeliso ea lithethefatsi tsohle tsa tlhekefetso tse nang le bohlokoa bo susumetsang (Setšoantšo sa 1B kaholimo), empa li-neuroadaptations tse eketsehileng pakeng tsa sistimi e amanang le ho tlosoa hoa sepheo li kenyelletsa ts'ebetso ea ts'ebetso ea khatello ea methapo ea dynorphin / κ, norepinephrine khatello ea kelello, tsamaiso ea extrahypothalamic vasopressin, mohlomong le sistimi ea orexin. Ho kenyelletsa moo, ts'ebetso ea ts'ebetso ea khatello ea kelello ea kelello e ka se felle feela ka ts'ehetso e mpe ea boikemisetso bo amanang le ts'oaetso e mpe empa e ka boela ea tlatsetsa bothateng ba khatello ea khatello e bonoang nakong ea ho itima lintho ho batho. Leha ho le joalo, lits'ebetso tsa antistress ea boko, joalo ka NPY le nociceptin, le tsona li ka fokotsoa nakong ea nts'etsopele ea ts'epahalo, ka hona, e tlosa mochine oa ho khutlisa homeostasis (Koob le Le Moal, 2008). Liphetho tsena li fana ka maikutlo a hore tšusumetso ea ho tsoelapele ts'ebeliso ea lithethefatsi nakong ea ts'oaetso ha e kenyeletse feela phetoho mosebetsing oa li-neurotransmitters tse amanang le litlamorao tse matla tsa lithethefatsi tsa tlhekefetso nakong ea kholo ea kholo, joalo ka dopamine, li-peptide tsa opioid, serotonin le GABA, empa ho amoheloa le lits'ebetso tsa khatello ea kelello le / kapa ho sitisoa hoa tsamaiso ea methapo ea kutlo (Koob le Le Moal, 2005).

Sekhahla sa neuroanatomical se kopanyang lits'ebetso tsena tsa khatello ea kelello le lisistress tsa antistress e kanna ea ba li-amygdala tse atolositsoeng. Kahoo, amygdala e atolositsoeng e ka emela suburate ea neuroanatomical bakeng sa litlamorao tse mpe mosebetsing oa moputso o hlahisoang ke khatello ea maikutlo e thusang ho tsamaisa ts'ebetso ea lithethefatsi tse tlamang (Koob le Le Moal, 2008) (Setšoantšo sa 10). Amygdala e atolositsoeng e na le karolo ea ho kopanya maemo a maikutlo joalo ka polelo ea karabelo ea boemo bo tšosang karolong e bohareng ea amygdala (Phelps le Le Doux, 2005) le ho sebetsana le bohloko ba maikutlo (Neugebauer et al., 2004) (Bona ka holimo). Ho kenyelletsoa ha data ho tsoa ho ts'ebeliso ea methapo ea kutlo le ho tloha ho boits'ebetso ba ts'abo le bohloko ho leba substrate e ruileng ea ho hokahana ha maikutlo a amang maikutlo a amanang le tsoelopele ea khatello ea kelello (Pfaff, 2006) hape e fana ka leseli eseng feela mekhoeng ea ho se sebetse maikutlong bokhobeng ba maikutlo empa hape e fana ka mekhoa ea maikutlo ka bo bona.

Nts'etsopele ea boemo bo feto-fetohang ba maikutlo e susumetsang tšusumetso e mpe ea temallo e matlafatsoa ho kenyelletsa tšebetso ea nako e telele, e phehellang ea ts'ebetso ea lits'ebetso tsa mekhahlelo ea methapo e amohelang ho hira lits'ebetso tse ananyang tse tsamaisang linaha tse khelohang. The drainare / Ho ama hampe mohato o hlalositsoeng kaholimo o na le likarolo tsa bohlokoa tsa susumetso, joalo ka ho se ts'oarehe ho sa feleng, bohloko ba maikutlo, malaise, dysphoria, alexithymia, le tahlehelo ea meputso ea tlhaho, mme e tsebahala ka liphoofolo ka ho eketseha ha meputso ea meputso nakong ea ho tlohela lithethefatsi tsohle tse kholo tsa tlhekefetso. Antireward ke mohopolo o thehiloeng khopolong ea hore methapo ea boko e teng sebakeng sa ho fokotsa moputso (Koob le Le Moal, 1997, 2005, 2008). Ha ho its'etleha le ho nts'etsopele, lits'ebetso tsa ho hlapolla bokong joalo ka CRF, norepinephrine, dynorphin, vasopressin, mohlomong le orexin li reretsoe ho hloa molemong oa ho hlahisa maemo a khatello joaloka "Koob le Le Moal, 2001; Nestler, 2005; Aston-Jones et al., 1999) (Setšoantšo sa 10). Litaba tsa hona joale li pheha khang ea hore li-system tsa antistress, joalo ka NPY le orexin eo ho nahanoang hore e senya karabelo ea khatello ea maikutlo, le eona e ka fokotsoa. Ka nako e ts'oanang, ho fokotseha ha ts'ebetso ea moputso ho etsahala ka har'a mekhahlelo e khothalletsoang ea li-amygdala tse matla tsa ventral.Setšoantšo sa 10). Motsoako oa ho fokotseha hoa ts'ebetso ea neurotransmitter ea moputso, ho hira mekhoa ea antirement, le li-system tsa antistresser tse fanang ka tšusumetso e fana ka mohloli o matla oa ntlafatso e mpe e tlatselletsang ts'ebetsong ea ho batla lithethefatsi le ho lemalla.

6.3. Matšoenyeho a Khatello ea Kelello a Fetoha hape

Le ha e thehiloe hanyane ntle le lithutong tsa CRF le norepinephrine, lits'ebetso tsa khatello ea kelello le tsona li ka kenya letsoho bothateng bo matla ba ho lemalla lithethefatsi ka ho khutla hape, moo batho ba lemaletseng lithethefatsi ba khutlang nako e telele ka mor'a ho tlohela ka matla. The preoccupation / Ho lebella (ho lakatsa) sethala e na le litsamaiso tse peli: ho itšila nako e telele le khatello ea maikutlo e khutliselitsoeng morao. Ho liphoofolo, ho itšireletsa nako e telele ho ka kenyelletsa kutloelo-bohloko e eketsehileng ho motho ea sithabetsang kapa ho eketsa lithethefatsi ho latela nako e telele kamora ho tlohela, tseo bobeli ba tsona li hlokometsoeng lithutong tsa joala.Valdez le Koob, 2004). E sebelisa CRF joalo ka mohlala ho tsilatsileng, "CRF" e ts'eletsoa ho kenya letsoho maemong a sithabetsang a maikutlo a fanang ka motheo oa ho batla lithethefatsi (Valdez et al., 2002; Valdez le Koob, 2004).

Khatello ea khatello ea khatello ea maikutlo e matla le ho kenella lipakeng tsa lits'ebetso tse fapaneng tsa khatello ea kelello tse amehang ts'episong ea lithethefatsi, joalo ka ha ho boletsoe ka holimo (bakeng sa tlhahlobo, bona Shaham le al., 2000, 2003). Ha ho khutlisetsoa ka matla khatello ea maikutlo, lits'ebetso tsa CRF tse kahare ho bethe ea stria terminalis lia kenngoa ha khatello ea maikutlo e hlohlelletsa ho oela hape (Shaham le al., 2003). Boholo ba CRF bo thibela ho khutlisetsoa ha koae, joala le ho itaola ka lebaka la khatello ea maikutloErb et al., 1998; Liu le Weiss, 2002; Shaham le al., 1998; Zislis et al., 2007). Leha ho le joalo, ho khutlisetsoa ka khatello ea maikutlo ho etsahala ntle le ts'usumetso e susumetsang ea khatello ea kelello ea HPA (Erb et al., 1998; Le et al., 2000; Shaham le al., 1997). Lisebelisoa tse ling tsa khatello ea kelello tse kenelletseng ho khutlisetsoeng khatello ea maikutlo li kenyelletsa norepinephrine, orexin, vasopressin le nociceptin (bona ka holimo). Kahoo, lits'ebetso tsa khatello ea kelello li ka ama bobeli drainare / Ho ama hampe mohato le preoccupation / Ho lebella mohato oa potoloho ea ts'ebeliso ea lithethefatsi, leha e le ho etsa likarolo tse fapaneng tsa maikutlo a amygdala a atamelaneng (khubu ea mantlha ea amygdala le moeli oa bethe ea stria terminalis; bona ka holimo), le methapo e amanang le boemo bo bobe ba maikutlo ba ts'ebeliso ea lithethefatsi e ntse e tsoela pele nakong ea nako e telele Ho se be teng molemong oa ho beha motho kotsing ea "ho lakatsa" ts'ebetso ea lithethefatsi, cue-, le khatello ea maikutlo tse khutlisetsang khatello ea kelello tse tsamaisoang ke ts'ebetso ea methapo, le mohlomong ho hlophisoa bocha, sistimi ea pele (Volkow le Fowler, 2000).

6.4. Allostasis le Ho lemalla

Moralo o akaretsang oa khopolo nakong eohle ea tlhahlobo ena ke hore ts'ebeliso ea lithethefatsi e emela phomolo e nang le lits'ebetso tsa taolo ea homeostatic tse laolang boemo ba maikutlo ba phoofolo. Leha ho le joalo, mofuta oa ho kenella ho khatello ea kelello le lits'ebetso tsa antistress tse hlahisoang ke ho itaola hangata ka lithethefatsi tsa tlhekefetso o re maikutlo a tlhekefetso ea lithethefatsi a emelang khefu e bonolo le homeostasis ha a lekana ho hlalosa likarolo tse ngata tsa bohlokoa tsa ho lemalla. Bokhoba ba lithethefatsi, bo tšoanang le mafu a mang a sa foleng a 'mele, a joalo ka khatello e phahameng ea mali, a mpefala ha nako e ntse e ea, a ba le tšusumetso e kholo ea tikoloho (mohlala, khatello ea maikutlo),' me e siea moelelo o setseng oa tlhaho o lumellang "ho bala" kapele esita le likhoeli le lilemo ka mor'a detoxation le thibelo. Litšobotsi tsena tsa bokhoba ba lithethefatsi li lebisitse ho ho lekantsoeng ha bokhoba ba lithethefatsi e le ho fetang feela khatello ea maikutlo ea lapeng empa e le karohano e matla le homeostasis ea lits'ebetso tsena, e bitsoang allostasis.

Allostasis e hlalosoa e le "botsitso ka phetoho" mme e fapane le homeostasis hobane phepelo pele, ho fapana le karabelo e mpe, mekhoa e hanoa hore e lebelletsoe (Sterling le Eyer, 1988). Le ha ho le joalo, bokhoni bona ba ho bokella lisebelisoa ka potlako le ho sebelisa mekhoa ea ho li fepa li lebisa boemong bo tšosang haeba litsamaiso li se na nako e lekaneng ea ho qala homeostasis. An naha e mameloang e ka hlalosoa e le boemo ba ho kheloha ho sa feleng ha tsamaiso ea taolo ho tsoa maemong a eona a tloaelehileng (homeostatic).

Lisebelisoa tsa khatello ea kelello li arabela ka potlako ho mathata a lebelletsoeng ho homeostasis empa li lieha ho lula kapa ho se koale hang ha o se o kopane (Koob, 1999). Kahoo, mochine oa 'mele o lumellang karabelo e potlakileng le e tsitsitseng ea phephetso ea tikoloho o fetoha mohloli oa thuto ea bophelo haeba nako e lekaneng kapa lisebelisoa li sa fumanehe ho koala karabelo. Kahoo, tšebelisano lipakeng tsa CRF le norepinephrine bokong ba kelello le basal phatsa, tšebelisano lipakeng tsa orexin le CRF ho hypothalamus le basal forebrain, le tšebelisano lipakeng tsa CRF le vasopressin le / kapa orexin li ka lebisa maemong a sa foleng a maikutlo (Koob, 1999). Mehato e ts'oanang ea allostatic e ka kopuoa hore e amehe ho tsamaiseng ts'ebetso ea methapo e amanang le khatello ea kelello le lits'ebetso tsa antistress tsa ho lemalla.Koob le Le Moal, 2001). Liphephetso tse phetoang (mohlala, ka lithethefatsi tsa tlhekefetso) li lebisa boitekong ba kelello ka liphetoho tsa lisele, tsa cellular le tsa neurocircuit ho boloka botsitso, empa ka litšenyehelo. Bakeng sa sebopeho sa bokhoba ba lithethefatsi se hlalositsoeng mona, ho kheloha masala ho tsoa mokhoeng o tloaelehileng oa moputso oa boko ho rehiloe lebitso naha e mameloang. Mmuso ona o bonts'a ho kopanya ho sa feleng hoa meputso e behiloeng ke liphetoho tse ngata tse amanang le phetoho, ho kenyelletsa mosebetsi o fokotsehileng oa mekotla ea meputso, tahlehelo ea taolo e kholo, le ho tsamaisa mekhatlo ea ts'usumetso ea ts'usumetso, empa hape le ho hloa lits'ebetso tsa khatello ea kelello le boits'ireletso ho lits'ebetso tsa khatello ea kelello. Liphetho tsena kaofela li etsa hore ho be thata ho batla lithethefatsi le ho ts'oara lithethefatsi tse tsejoang ka hore ke ho lemalla.Koob le Le Moal, 2008).

lumela hore baa fokola

Mosebetsi ona o tšehelitsoe ke lichelete tsa Setsi sa Naha sa Bophelo ho tsoa ho Setsi sa Naha sa Tlhekefetso ea Lithethefatsi, Setsi sa Naha sa Ts'ebeliso e Mpe ea Joala le Tahi, le Setsi sa Naha sa Lefu la Ts'oaetso ea Lefu la Ts'oaetso ea Lefu la Ts'oaetso ea Kelello le Liphio, le chelete ea poraefete e tsoang Setsing sa Pearson sa Alcoholism le Bokhoba ba Tahi. Patlisiso. Sengoli se rata ho leboha Michael Arends le Mellany Santos ka thuso ea bona mabapi le ho hlophisoa ka letsoho, Janet Hightower ka thuso ea hae e kholo le lipalo, Dr. Charles Neal ka mosebetsi oa hae oa ho tsamaisa neuroanatomical ea nociceptin (Neal et al., 1999) le bakeng sa thuso ea hae ka Setšoantšo sa 9, le Ngaka Michel Le Moal bakeng sa lipuisano le moralo oa 'nete. Sengoli se boetse se rata ho leboha batho ba latelang bakeng sa litlhaloso tse tebileng le lipuisano mabapi le buka e ngotsoeng ka letsoho: Dr. Heather Richardson, Dr. Scott Edward, Dr. Dong Ji, Dr. Kaushik Misra, Dr. Laura Orio, Dr. Nick Gilpin, Dr. . Olivier George, Dr. Marisa Roberto, Dr. Sunmee Wee, le Dr. Benjamin Boutrel. Ena ke nomoro ea phatlalatso 19397 e tsoang ho TheHTMLps Research Institute.

Mongolo o botlaaseng ba leqephe

TLHOKOMELISO TLALI

Tlhahisoleseling ea tlatsetso e ka fumaneha ka sengoloa sena inthaneteng ho http://www.neuron.org/cgi/content/full/59/1/11/DC1/.

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