Mokokotlo oa thalamus o sebelisoa ke meputso ea tlhaho le lithethefatsi tsa tlhekefetso: bopaki ba morao-rao ba karolo ea bohlokoa bakeng sa pontšo ea orexin / hypocretin mokokotlong ona oa thalamic moetlo oa ho batla lithethefatsi (2014)

Front Behav Neurosci. 2014; 8: 117.

E hatisitsoe Inthaneteng 2014 Apr 3. doi:  10.3389 / fnbeh.2014.00117

PMCID: PMC3982054

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

Eya ho:

inahaneloang

Phephetso e kholo bakeng sa kalafo e atlehileng ea ho lemalla lithethefatsi ke tšitiso ea nako e telele ea ho ikhula hape le mekhoa e mengata e kentsoeng ts'usumetsong ea ho qala ts'ebeliso ea lithethefatsi nakong ea ho khaotsa ho tsuba. Haufinyane, tsamaiso ea orexin / hypocretin (Orx / Hcrt) e bontšitsoe e bapala karolo ea boits'oaro ba ho batla lithethefatsi. Sisteme ea Orx / Hcrt e laola mefuta e fapaneng ea ts'ebetso ea 'mele, ho kenyelletsa ho fepa, metabolism ea matla le ho tsosa. E boetse e bontšitsoe hore e hapiloe ke lithethefatsi tsa tlhekefetso. Li-neuron tsa Orx / Hcrt li fumaneha ka ho khetheha ho hypothalamus ea morao-rao e sebetsang sebakeng sa "patala" (PVT), sebaka se khethiloeng e le "setsi sa" se tsamaisang tlhahisoleseling ebe se fetola moputso oa mesolimbic le li-system tsa khatello ea extrahypothalamic. . Le ha ho sa nahanoe hore ke karolo ea "lithethefatsi tsa bokhoba ba lithethefatsi", bopaki ba morao-rao bo bonts'a hore PVT e kentse letsoho phetolong ea ts'ebetso ea moputso ka kakaretso le boits'oaro bo lebisitsoeng ke lithethefatsi ka ho khetheha. Bopaki bo bontša karolo ea phetisetso ea Orx / Hcrt ho PVT ts'ebetsong ea ts'ebetso ea moputso ka kakaretso le boits'oaro bo lebisitsoeng ke lithethefatsi ka ho khetheha. Khopolo-taba e 'ngoe ke hore, kamora ho pepesetsoa lithethefatsi khafetsa, mokhoa oa Orx / Hcrt o nka karolo ea ho khetha litlamorao tsa litlamorao tsa lithethefatsi vs. meputso ea tlhaho. Tlhahlobo ea hona joale e tšohla liphumano tsa morao-rao tse bonts'ang ho haroa hampe ha PVT ka lithethefatsi tsa tlhekefetso, haholo-holo Orx / Hcrt-PVT neurotransmission.

Keywords: "nucleus" ea thalamus, orexin / hypocretin, ts'ebeliso ea lithethefatsi, boitšoaro bo batlang lithethefatsi, moputso oa tlhaho

Selelekela

Bokhoba ba lithethefatsi ke bokuli bo sa feleng bo hlahang ka boitšoaro bo tsoelang pele ba ho batla lithethefatsi le ho sebelisa lithethefatsi (O'Brien le McLellan, 1996; Leshner, 1997; O'Brien et al., 1998; McLellan et al., 2000). Tlhahiso-leseling ea mekhoa ea methapo ea kutlo e tlatselletsang bothateng bo sa tsitsitseng ba ho lemalla le ho tsebahatsa lipheo tsa kalafo ea pharmacological bakeng sa thibelo ea ho khutla e hlahile e le bothata bo boholo lipatlisisong tsa bokhoba ba taolo.

Boithuto bo 'maloa bo batlile ho hlakisa likarolo tsa neuronal tse laolang litšobotsi tsa boitšoaro bo khothalletsoang ba ho lemalla. Libaka tsa bongo tse fumanoeng li ameha ho khutla hape (boits'oaro ba lithethefatsi) -e kenyelletsa "cortex" ea makhopho pele ho nako, sebaka sa bohareng ba "amygdala", "nucleus" ea "stria terminalis", "hippocampus" et al., 2001; McFarland le Kalivas, 2001; Mok'hadinale et al., 2002; Goldstein le Volkow, 2002; Ito et al., 2002; Bona, 2002; Kalivas le Volkow, 2005; Weiss, 2005; Belin le Everitt, 2008; Steketee le Kalivas, 2011). Haufinyane tjena, bopaki bo hlahang bo hlahisitse hore thalamus e kanna ea kenyelletsoa mesebetsing ea methapo ea kutlo. Ho joalo, e nkuoa e le senotlolo sa bohlokoa lipakeng tsa ventral striatopallidum le dorsal striatum mme e ka kenya letsoho kholisong ea boitšoaro bo hatelletseng ba ho batla lithethefatsi (Pierce le Vanderschuren, 2010).

Har'a li-nuclei tsa thalamus, "patventricular nucleus" ea thalamus (PVT) e na le boemo ba pivotal neuroanatomical mme ka hona e susumetsa likarolo tse ileng tsa kenelletse ts'ebetsong ea ho batla lithethefatsi (Moga et al., 1995; Sekhahla le Seterata, 1998; Van der Werf et al., 2002). Taba ea bohlokoa mabapi le tlhahlobo ena ke tšireletso ea maikutlo ea hypothalamic orexin / hypocretin (Orx / Hcrt). Li-peptide tsa Orx / Hcrt li fumanoa mefuteng e fumanehang libakeng tsohle tsa nucleus ena ea thalamic, athe botenya ba fiber bo fokolang bo fumaneha sebakeng se haufi sa methapo le intralaminar thalamic nuclei (Kirouac et al., 2005). Leha bopaki bo qobellang bo bonts'a karolo ea Orx / Hcrt ho tsosa le ho boloka boemo ba ho tsosa (de Lecea, 2012), bopaki bo tsoelang pele bo tšehetsa karolo ea bohlokoa le e ikhethang ts'ebetsong ea moputso ka kakaretso le tšebeliso e mpe ea lithethefatsi (ho lekola, bona Mahler et al., 2012).

Bohlokoa ba bohlokoa ha u bua ka ts'ebetso ea moputso ka kakaretso ke eona e khethollang matšoao a neural a amanang le boits'oaro bo “tloaelehileng” vs. boitšoaro bo laoloang ke lithethefatsi. Monyetla o mong ke oa hore li-circonal tsa methapo tse tsamaisang taolo ea litabatabelo tsa lithethefatsi le lithethefatsi ke litekanyetso tse tloaelehileng tsa ts'usumetso ea maikutlo tse hlahisoang ka mokhoa o matla ke lithethefatsi 'me ha li khethehe lits'ebetsong tse amanang le bokhoba. Ts'ebetso e hlahisitsoeng ke lithethefatsi e hlahisoang ke lithethefatsi "ka tloaelo" e laolang moputso oa tlhaho e ka baka maemo a macha a ts'usumetso kapa ho tataisa ka mokhoa o hlakileng o laolang likarabo tsa moputso oa tlhaho ho boits'oaro bo laoloang ke lithethefatsi (Kelley le Berridge, 2002). Morero oa tlhahlobo ena ke ho akaretsa lintlha tse fumanoeng tsa morao-rao tse supang ho hira PVT hampe ka lithethefatsi tsa tlhekefetso, ka kotloloho phetisetso ea Orx / Hcrt-PVT, e le sistimi e ncha ea methapo ho etiology ea ho ts'oara lithethefatsi.

PVT

PVT e lutse haufi le karolo ea dorsal ea ventricle ea boraro. PVT ke karolo ea dorsal midline thalamic nuclei mme e bapala karolo ea bohlokoa mesebetsing e amanang le arousal, tlhokomelo, le tlhokomeliso (Bentivoglio et al., 1991; Groenewegen le Berendse, 1994; Van der Werf et al., 2002). Le ha methapo ea methapo ea methapo ea methapo ea methapo le intralaminar li ile tsa qaptjoa pele ho nka karolo ho etseng phepelo ea litlatsetso tse sa khetholleng (Berendse le Groenewegen, 1991), joale ho tsebahala hore setho se seng le se seng sa li-nuclei tsena se ka hare ho libaka tse ikhethang tsa cortex le striatum (Groenewegen le Berendse, 1994; Van der Werf et al., 2002; Smith et al., 2004).

Lithuto tsa Neuroanatomical li bonts'itse hore PVT e amohela likhakanyo tse tsoang libakeng tsa brainstem tse amanang le tšebetso ea methapo ea kutlo le tsamaiso ea methapo ea kutlo (Cornwall le Phillipson, 1988b; Chen le Su, 1990; Ruggiero et al., 1998; Krout le Loewy, 2000; Krout et al., 2002; Hsu le Theko, 2009). Ntle le moo, PVT, ka ho hakanngoa ha eona ho cortex ea pele le li-bokellase tsa nucleus (Berendse le Groenewegen, 1990; Su le Bentivoglio, 1990; Brog et al., 1993; Freeman & Cassell, 1994; Moga et al., 1995; Sekhahla le Seterata, 1998; Otake le Nakamura, 1998; Parsons et al., 2007; Li le Kirouac, 2008; Li-Vertes le Hoover, 2008; Hsu le Theko, 2009), e beha sebopeho sena sa thalamic maemong a ikhethileng a amang mekhoa ea cortico-striatal e kenyelletsang moputsong le khothatsong (Pennartz et al., 1994; Mok'hadinale et al., 2002; Walker et al., 2003).

PVT e fumana litlatsetso tse kholo le tse ikhethang tse tsoang libakeng tse 'maloa tsa hypothalamus, ho kenyelletsa le suprachiasmatic, arcuate, dorsomedial, le ventromedial nuclei, le libaka tsa hypothalamic tsa morao-rao le tsa morao-rao (Cornwall le Phillipson, 1988a; Chen le Su, 1990; Novak et al., 2000a; Peng le Bentivoglio, 2004; Kirouac et al., 2005, 2006; Otake, 2005; Hsu le Theko, 2009), meaho ea bohlokoa bakeng sa polelo ea boitšoaro bo susumetsoang (Swanson, 2000). Ho makatsang ke hore, PVT ke sepheo sa Orx / Hcrt hypothalamic neurons (Kirouac et al., 2005) mme e bontšitsoe hore e sebetsa e le khokahano lipakeng tsa hypothalamus le cortical-striatal projeke tse bohlokoa bakeng sa ho kopanya tekatekano ea matla, ho tsosa, le moputso oa lijo (mohlala, Kelley et al., 2005).

Liteko tse batlisisang ts'ebetso ea "neuronal activation" ea PVT li bonts'itse khafetsa hore sebaka sena sa boko se boetse se hapuoa nakong ea ho tsosa kapa ka khatello ea maikutlo (Peng et al., 1995; Bhatnagar le Dallman, 1998; Novak le Nunez, 1998; Sekhahla le Seterata, 1999; Novak et al., 2000b; Otake et al., 2002). PVT e boetse e kentse letsoho taolong ea khafetsa ea lijo le ts'ebetso ea hypothalamic-pituitary-adrenal ho arabela khatello ea maikutlo e sa feleng, ts'ebeliso ea lijo, le tekanyo ea matla (Bhatnagar le Dallman, 1998, 1999; Jaferi et al., 2003). Le ha li sa kenyelletsoa ka har'a methapo ea methapo ea kutlo, bopaki ba morao-rao bo beha PVT phetohong ea boitšoaro bo lebisitsoeng ke lithethefatsi. Ha e le hantle, merero ea PVT e lebisa libakeng tsa boko tse amehang taolong ea boits'oaro ba lithethefatsi, tse kang li-nucleus accumbens, amygdala, khubu ea boroko ea stria terminalis, le preortal cortex (Moga et al., 1995; Sekhahla le Seterata, 1998; Van der Werf et al., 2002). Bohlokoa, liphuputso tsa pejana li bonts'itse ts'ebetso ea PVT ha e ntse e batla ethanol (Dayas et al., 2008; Hamlin et al., 2009), mme bopaki ba morao-rao bo bonts'itse ts'ebetso e matla le e khethang ea PVT nakong ea ho ts'oara koae e sa hlaheng nakong ea moputso oa tlhaho (mohlala, motho ea matlafatsang ea tloaelehileng ea matlafatsang) (Martin-Fardon et al., 2013). Har'a mesebetsi e 'maloa e boletsoeng ka holimo, tlhahlobo ena e bua ka ho nka karolo ha PVT lithethefatsing. vs. tloaelo ea ho batla moputso oa tlhaho (taolo e sa tsubang). Tlhahlobo ena e sebelisa mantsoe "tloaelo e matlafatsang" kapa "moputso oa tlhaho" ho hlalosa boemo bo sa tsotelleng (hangata tharollo e monate haholo) e tla sebetsa e le taolo ea papiso bakeng sa moriana.

Sisteme ea Orx / Hcrt

Orx / Hcrt peptides, orexin A le B (Orx-A le Orx-B), eo hape a tsejoang ka hore ke li-hypocretins (Hcrt-1 le Hcrt-2), ke li-neuropeptides tse hlahisoang ka ho khetheha ka li-neurons tsa dorsal tuberal hypothalamic nuclei: lateral hypothalamus, perfukical nucleus , le dorsomedial hypothalamus (de Lecea et al., 1998; Sakurai et al., 1998b). Orx-A / Hcrt-1 le Orx-B / Hcrt-2 ke lihlahisoa tsa polypeptide e le 'ngoe e tloaelehileng ea pele, prepro-orexin, ka ts'ebetso e tloaelehileng ea proteinolytic (de Lecea et al., 1998). Li-peptide tsena li arolelana lintho ka tatellano 'me ke li-ligands tsa li-receptor tse peli: Hcrt-r1 le Hcrt-r2. Hcrt-r1 e kopanya Orx-A e amanang le 20-30 nM empa e na le tumellano e tlase haholo (10- to 1000-fold tlaase) bakeng sa Orx-B, athe Hcrt-r2 e tlama li-peptide ka bobeli ba tumellano e tšoanang (moleng oa 40 nM; Sakurai et al., 1998a; Ammoun et al., 2003; Scammell le Winrow, 2011). Liphuputso tse ngata li bontšitse hore li-receptors tsa Orx / Hcrt li kopantsoe le liprotheine tsa G-protein. Leha ho le joalo, G-coupling ea li-receptor tsena e hole le ho hlaka empa e ipapisitse le liphetho tse 'maloa Hcrt-r1 le Hcrt-r2 li ka nyarosang G.i / o, Gs le Gq liprotheine tsa lelapa (Gotter et al., 2012; Kukkonen, 2013).

Orx / Hcrt neurons e amohela lintho tse tsoang libakeng tse ngata tsa boko 'me li ea bokong kaofela, ka hona e ba le li-circonal tse ngata tsa methapo (Peyron et al., 1998; Letsatsi et al., 1999; Nambu et al., 1999). Dense Orx / Hcrt li-terminals li ka fumanoa ka cortex ea "cerebral", "bulb", "hothocampus", amygdala, basal forebrain, hypothalamus, tuberomammillary nucleus, PVT, arcuate nucleus ea hypothalamus, le brainstem (Peyron et al., 1998; Letsatsi et al., 1999; Nambu et al., 1999). Orx / Hcrt neurons e fumana likhakanyo tse tsoang ho "methapo ea methapo ea methapo" ea methapo, "li-nucleus" tsa "" "" "" "methapo ea methapo" "" "" "" "" "" "methapo ea methapo," "" "hypothalamus" le "hypothalamus" le "sebaka" sa "hypothalamus". 2005). Mabapi le Hcrt-rs, ho bontšitsoe likhaolo tse lekanyelitsoeng tsa Hcrt-r1 le Hcrt-r2 mRNA, ka phapang e sebetsang pakeng tsa Hcrt-r1 le Hcrt-r2 (Tretri et al., 1998; Lu et al., 2000; Marcus et al., 2001; bakeng sa tlhahlobo, bona Aston-Jones et al., 2010), ho fana ka maikutlo a likarolo tse fapaneng tsa 'mele bakeng sa karolo e' ngoe le e 'ngoe ea li-receptor.

Ka lebaka la likhokahano tsa eona, tsamaiso ea Orx / Hcrt e kenella mesebetsing e mengata ea 'mele. Sisteme ea Orx / Hcrt e kenella ka matla taolong ea ho fepa, ho tsosa, ho robala / ho tsosa linaha, karabelo ea khatello ea maikutlo, matla a homeostasis, le moputso (bakeng sa tlhahlobo, bona Tsujino le Sakurai, 2013). Haholo-holo bohlokoa bakeng sa tlhahlobo ena, bopaki bo tšehetsa karolo ea bohlokoa le e ikhethang bakeng sa tsamaiso ea Orx / Hcrt tšebelisong ea lithethefatsi (bakeng sa ho lekola, bona Mahler et al., 2012), ka ho khetheha Orx / Hcrt neurons e fumanehang ka morao ho hypothalamus (Harris et al., 2005). Haholo-holo, merero ena ea li-neurons ho PVT, li-nucleus accumbens shells, ventral pallidum, sebaka se kenang ka mokokotlo oa mokokotlo, mokokotlo oa "amygdala" le "nucleus ea" stria terminalis (Peyron et al., 1998;; Baldo et al., 2003; Winsky-Sommerer et al., 2004). Qalong e kentse letsoho taolong ea boitšoaro ba ho fepa (Sakurai et al., 1998a; Edward et al., 1999; Haynes et al., 2000, 2002), li-neurons tsena li bapala karolo ea modulatory mosebetsing oa moputso, ka tlatsetso e itseng boits'ebetsong bo amanang le lithethefatsi (Harris et al., 2005).

Sistimi ea Orx / Hcrt e lumellana le litlamorao tsa boitšoaro ba lithethefatsi tsa tlhekefetso

Orx / Hcrt e tlalehiloe ho ntlafatsa litlamorao tsa tšusumetso ea maemo a susumetsoang ke ho fumaneha ha lithethefatsi, ho eketsa tšusumetso ea ho batla lithethefatsi, le ho eketsa liketso tse matlafatsang tsa lithethefatsi tsa tlhekefetso.

Ebile, intra-ventral tegmental area microinjection ea Orx-A e hlahisa ntlafatso ea boikhethelo ba sebaka sa morphine-ikiwa se thehiloeng maemong (CPP), athe tsamaiso ea mohanyetsi oa Hcrt-r1 N- (2-methyl-6-benzoxazolyl) -N′ -1,5-n-aphthyridin-4-yl urea (SB334867) e lumellana le polelo ea CPP e susumetsoang ke morphine (Harris et al., 2005). E lumellana le karolo ea Orx / Hcrt polelong ea CPP, ha e kenngoa ka mokhoa o hlophisehileng, bahanyetsi ba Hcrt-r1 SB334867 le 5-bromo-N- [(2S,5S) -1- (3-fluoro-2-methoxybenzoyl) -5-methylpiperidin-2-yl] methyl-pyridin-2-amine (GSK1059865) e fokotsa tlhahiso ea "cocaine-" le amphetamine-indedu CPP (Gozzi et alzizi. 2011; Hutcheson et al., 2011; Sartor le Aston-Jones, 2012), ho fana ka maikutlo a karolo e hlahelletseng ea Hcrt-r1 liphellong tse khotsofatsang tsa koae le amphetamine. Ho khahlisang, ho nka karolo ha Hcrt-r2 ho sa tsoa hlalosoa ka mekhoa e meng ea boitšoaro ba ethanol. Blockade of Hcrt-r2 sebelisa (2,4-dibromo-phenyl) -3 - ([4S,5S] -2,2-dimethyl-4-phenyl- [1,3] dioxan-5-yl) -urea (JNJ-10397049) ho tlalehiloe hore e theotse ho fumaneha, polelo, le ho khutlisetsoa ha CPP e thehiloeng ke ethanol (Shoblock et al., 2011), ho fana ka maikutlo a hore Hcrt-r2 e kanna ea ameha haholo phelisong e thabisang ea ethanol.

Orx / Hcrt e boetse e hlalositsoe e bapala karolo ea maikutlo a psychostimulant-induction locomotor sensitization. SB334867 e kenella ka kotloloho kapa kahare ho sekhahla sa likarolo tse khubung e thibetse ho fumaneha ha maikutlo a koae, e ts'oarelletsa ts'ebetso ea maqhubu a thabo a susumetsoang ke cocaine ho dopaminergic neurons ea sebaka sa ventral tegmental (Borgland et al., 2006), hape e thibe polelo ea amphetamine sensitization (Quarta et al., 2010). Ho feta moo habeli Hcrt-r1 / Hcrt-r-2 antagonist N-biphenyl-2-yl-1 - [[1-methyl-1H-benzimidazol-2-yl) acetyl] -l-prolinamide ea sensorization ea amphetamine le polelo ea liphatsa tsa lefutso tse amanang le polasetiki sebakeng sa kotloloho ea mocheso ka mor'a amphetamine ea nako e telele (Winrow et al., 2010).

Orx / Hcrt e boetse e tlalehiloe hore e nka karolo ho laola tšusumetso ea ho sebelisa lithethefatsi. Ha e kenella sebakeng sa "ventral tegmental tegmental", Orx-A / Hcrt-1 e eketsa monyetla oa ho itšeha ha k'hok'heine ea k'habeche lenaneong la ts'ebetso ea tsoelo-pele (España et al., 2011). Antagonizing Hcrt-r1 e nang le SB334867 e fokotsa ts'usumetso ea ho itaola k'hok'heine hape e fumana ntlafatso e khothalletsoang ea cocaine e tsoang ho dopaminergic signaling in the nucleus accumbens ha e kenngoa sebakeng sa ventral tegmental (España et al., 2010). Ho feta moo, blockade ea Hcrt-r1 e fokotsa nicotine (Hollander et al., 2008) le heroin (Smith le Aston-Jones, 2012) ho itaola, 'me ho hanyetsana ka bobeli ke Hcrt-r1 kapa Hcrt-r2 ho fokotsa boitšoaro ba hau ntle le ho kena-kenana le tsamaiso ea boithati (Lawrence et al., 2006; Shoblock et al., 2011;; Brown et al., 2013). Qetellong, liphumano tsa morao-rao li bontšitse hore mohanyetsi oa Hcrt-r2 o fokotsa khatello ea khatello ea heroin (Schmeichel et al., 2013).

Orx / Hcrt e bapala karolo ea bohlokoa mekhoeng ea ho batla lithethefatsi e bakoang ke khatello ea maikutlo kapa tšusumetso e amanang le lithethefatsi. Intracerebroventricular (ICV) ente ea Orx-A / Hcrt-1 e eketsa meroalo ea intracranial ea ho itšunya-tšunya (ICSS) mme e khutlisetsa ho ts'oana ha koae le ho ts'oara koae (Boutrel et al., 2005; Plaza-Zabala et al., 2010). Ho feta moo, blockade ea Hcrt-r1 e thibela ho khutlisetsoa hoa cueine le ethanol le khatello ea heroin (Boutrel et al., 2005; Lawrence et al., 2006; Richards et al., 2008; Smith et al., 2010; Jupp et al., 2011b; Smith le Aston-Jones, 2012; Martin-Fardon le Weiss, 2014a,b).

Sisteme ea Orx / Hcrt e boetse e bontšitsoe e bapala karolo ho feliseng lithethefatsi. SB334867 e bonts'a matšoao a somatic a ho tlosoa ha nicotine le morphine (Sharf et al., 2008; Plaza-Zabala et al., 2012), le li-neuron tsa Orx / Hcrt li kenngoa ts'ebetsong ho latela taolo ea nicotine e mpe le nakong ea nicotine (Pasumarthi et al., 2006; Plaza-Zabala et al., 2012) le morphine (Georgescu et al., 2003) ho tlosa. Boithuto bo bong bo supa ho ba teng ha khokahano lipakeng tsa methapo ea mali ea Orx / Hcrt le matšoao a ho tlohela joala ho batho (Bayerlein et al., 2011; von der Goltz et al., 2011), e ts'ehetsa ts'oaetso ea hore tsamaiso ea Orx / Hcrt e bohlokoa bakeng sa liphetoho tsa boitšoaro tse amanang le ts'ebeliso ea lithethefatsi le ho tlosoa hoa liphoofolo le batho.

Karolo ea mantlha ea li-neurons tsa Orx / Hcrt ho hypothalamus ea morao-rao litabeng tsa bokhoba ba lithethefatsi e teng (Harris et al., 2005). Orx / Hcrt neurons ho latela hypothalamus ea morao-rao e fetoha ts'usumetso e amanang le cocaine, ethanol, morphine, le lijo (Harris et al., 2005; Dayas et al., 2008; Martin-Fardon et al., 2010; Jupp et al., 2011b), le Orx / Hcrt microinjection ho hypothalamus ea morao-rao e eketsa ho kenella ha ethanol ka boithaopo (Schneider et al., 2007). Polelo ea CPP e khothalletsoang ke lijo, morphine, le cocaine e amana le ts'ebetso ea methapo ea methapo ea methapo ea kutlo (Harris et al., 2005). Ho khahlisang, CPP e kentsoeng ke koae e ne e amahanngoa le ho fokotseha ha polelo ea Orx / Hcrt mRNA ho hypothalamus ea morao-rao, ho fana ka maikutlo a mofuta o mong oa karabelo e latelang ts'ebetso e matla ea neuronal e khothalletsoang ke cocaine (Zhou et al., 2008).

Bopaki ba boitšoaro bo botle le bo sebetsang bo bontša karolo ea Orx / Hcrt ho tšoaea litlamorao tsa neurobehahlangual le tse susumetsang tsa ethanol le lithethefatsi tse ling tsa tlhekefetso (Borgland et al., 2006; Bonci le Borgland, 2009; Thompson le Borgland, 2011). Habohlokoa, Orx / Hcrt ke li-hypothalamic neuropeptides tseo ho neng ho tlalehiloe hore li laola ho fepa (Sakurai et al., 1998a). The blockade ea Hcrt-r1 ka SB334867 e fokotsa ho ja haholo (Haynes et al., 2000; Rodgers et al., 2001; Ishii et al., 2005), le sistimi ea Orx / Hcrt e bonahala e hloa leihlo ho laola phepelo ea lijo tse matlafatsoang haholo (Nair et al., 2008; Borgland et al., 2009; Choi et al., 2010).

Le ha tsamaiso ea Orx / Hcrt e tsebahala ka ho laola (tlhaho) mosebetsi oa moputso, liphumano tse boletsoeng ka holimo li bonts'a hore Sisteme ea Orx / Hcrt e bapala karolo ea bohlokoa litlamorao tsa ts'usumetso ea lithethefatsi tsa tlhekefetso. Boithuto ba morao-rao bo bonts'itse hore tsamaiso ea Orx / Hcrt, ehlile e kenelletse ka matla ho lithethefatsi tsa tlhekefetso ho feta ke batho bao e seng lithethefatsi bao e seng lithethefatsi. Mohlala, Hcrt-r1 kapa Hcrt-r2 blockade e sebetsa haholoanyane ho fokotsa tsamaiso ea ethanol ho feta ho ja ka mokhoa oa sucrose (Shoblock et al., 2011; Jupp et al., 2011a;; Brown et al., 2013). Ntle le moo, ho sebelisa mofuta o khutlisetsoang oa phoofolo ea mofuta oa ho khutla, oo ho oona ho neng ho khothaletsoa cococaine, ethanol, le li-supporcist tse tloaelehileng li phahamisa maemo a lekanang a ho khutlisetsoa, ​​litheko-kholo tsa litlatse tsa Hcrt-r1 ka mokhoa o ikhethileng o khutliselitsoeng maemong o tlisoang ke ts'usumetso e amanang le cocaine- kapa ethanol. ha e na litlamorao ho khothatso e tšoanang e etselitsoeng khothatso e tloaelehileng (Martin-Fardon le Weiss, 2009, 2014a,b; Martin-Fardon et al., 2010).

PVT e kenya letsoho ts'ebetsong ea ho batla lithethefatsi

PVT e hlahisitsoe ho ba mohokahanyi oa bohlokoa oo likhoro tsa Orx / Hcrt-coded tse amanang le moputso pakeng tsa hypothalamus tsa morao-rao le li-ventral le dorsal striatum (Kelley et al., 2005). Ts'ebetso ena ea methapo ea methapo ea kutlo (hypothalamic-thalamic-striatal neurocircuitry) e kanna ea fetoha hore e lelefatse libaka tsa boiketlo le ho khothaletsa ho fepa ka ntle le phethahatso ea litlhoko tsa pele tsa matla, ka ho etsa joalo ho theha mehloli ea matla bakeng sa khaello ea lijo ea nako e tlang (Kelley et al., 2005). Ho nahanoa hore ts'ebetso e mpe ea ho hira sistimi ena ka lithethefatsi tsa tlhekefetso e ka "senyeha" ts'ebetso ea eona ho ea boits'oarong bo feteletseng bo lebisitsoeng ke lithethefatsi, bo ka hlalosang kutloisiso e eketsehang ea ts'ebetso ea Orx / Hcrt ho hokahanya ho kenella ha boitšoaro le boits'oaro ba ho batla lithethefatsi ho fapana le boitšoaro e lebisitsoeng moputsong oa tlhaho.

Bopaki bo bongata bo ts'ehetsa ho kenya letsoho ha PVT ho khutlisetsong hoa ts'ebeliso ea lithethefatsi ka ho khetheha e hlohlelletsoang ke tšusumetso e fumanehang ho fumaneha ha moriana ka boona. Mohlala, ho khutlisetsoa hoa litekanyetso tsa mantlha kapa tse khothalelitsoeng tsa ho ts'oasa joala ho amana le ho hira ea PVT ea bohlokoa (Wedzony et al., 2003; Dayas et al., 2008; Perry le McNally, 2013). Ntle le moo, ts'ebetso ea PVT e thibela ho khutlisetsoa hoa litlamorao ho phepelo ea taba ea semolao (Hamlin et al., 2009; Hlatse et al., 2010), ho khutlisetsa cocaine pele e hlohlellelitsoeng (James et al., 2010), sensacization ea cocaine (Bacha le Deutch, 1998), le polelo ea CPP e susumetsoang ke koae (Browning et al., 2014). Ho feta moo, li-neurons tsa PVT li hlahisoa ka ho ikhetholla hape ho koae ka koae (Brown et al., 1992; Franklin le Druhan, 2000), methamphetamine-paired (Rhodes et al., 2005), le ethanol-paired (Wedzony et al., 2003; Dayas et al., 2008) takatso ea maemo, athe ho pepesetsoa ts'usumetso e amanang le sucrose ha ho khothalletse ts'ebetso ea PVT (Wedzony et al., 2003).

Ntle le lithuto tse ngata tse bonts'itseng tlatsetso ea PVT likarolong tse fapaneng tsa bokhoba ba lithethefatsi, monehelo o tobileng oa ho saena ha Orx / Hcrt ho senotlolo sena sa thalamic o sa tsoa hapa tlhokomelo e ngata. PVT e kenelletse ka bongata ke likhoele tsa Orx / Hcrt (Kirouac et al., 2005; Parsons et al., 2006) mme ke mohloli o moholo oa liphatlalatso tsa glutamatergic ho li-nucleus accumbens, li-nucleus tsa "stria terminalis", nucleus e bohareng ea amygdala, le medial prefrontal cortex (Parsons et al., 2007; Li le Kirouac, 2008; Li-Vertes le Hoover, 2008; Hsu le Theko, 2009). Libaka tsena tsa boko ke karolo ea methapo ea kutlo. Liphuputso tsa pejana li bontšitse hore blockade ea li-receptor tsa Hcrt-r1 ho PVT ha ea ka ea hlahisa phokotso ea ho khutlisetsoa hoa cueine e bakiloeng ke ho batla koae (James et al., 2011) e fana ka tlhahiso ea hore ho hanyetsa Hcrt-r2 kahara sebaka sena sa boko ho ka sebetsa haholoanyane ho thibela lithethefatsi tsa litlamorao tsa tlhekefetso. Ka tumellano le hypotheses ena, lithuto tse ling li bontšitse hore microinjection ea Hcrt-r2 antagonist (2S)-1-(3,4-dihydro-6,7-dimethoxy-2(1H) -isoquinolinyl) -3,3-dimethyl-2 - [(4-pyridinylmethyl) amino] -1-butanone hydrochloride (TCSOX229) empa eseng SB334867 ho PVT haholo e fumane polelo ea lexxone-e hlahisoang ke AlPA ., 2011), e bolelang karolo e ikhethileng ea PVT Hcrt-r2 ho arolelanang ho tlosoa ha morphine. Ho feta moo, nicotine e hlobaetsang e eketse polelo ea Fos ho li-neuron tsa Orx / Hcrt tse tsoang ho hypothalamus ea morao-rao ho ea ho PVT (Pasumarthi le Fadel, 2008), e fana ka maikutlo a ho nka karolo ha tsela ena ho nicotine arousal. Karolo ea merero ea Orx / Hcrt ho tloha ho hypothalamus ea morao-rao ho PVT mabapi le ethanol ho ts'ehetsa ho fumanoe ho bontšitseng hore litloaelo tse amanang le joala tse amanang le joala li kenya tšebetsong li-neurons tsena (Dayas et al., 2008). Ka ho khetheha, li-neuron tsa Fos-positive hypothalamic Orx / Hcrt li ile tsa bonoa litoebeng tse senotsoeng molemong oa maemo a fetileng a amanang le ho fumaneha hoa ethanol vs. likhoto tse senotsoeng ke tšusumetso e tšoanang e neng e entsoe pele ka moputso o sa lefelloeng, 'me tšusumetso e amanang le ethanol e ile ea eketsa palo ea li-neurons tsa FV-PVT tse amanang haufi le Orx / Hcrt fibers (Dayas et al., 2008).

Taba ea bohlokoa ke hore, PVT e tlalehiloe hore e kenya letsoho taolong ea phepelo. Mohlala, mabala a PVT (Bhatnagar le Dallman, 1999) kapa thibelo ea li-neurons tsa PVT tse nang le GABAA antagonist muscimol (Stratford le Wirtshafter, 2013) li bontšitsoe ho eketsa phepo. Ka mokhoa o ts'oanang, lesion ea electrolytic ea PVT e kenyellelitse ho eketseha ha litekanyetso le litekanyetso tsa mali tsa corticosterone hangata tse hlahisoang ke tebello ea ho fumana lijo (Nakahara et al., 2004). Mona ke mehlala e 'maloa feela ea karolo ea khubu ena ea taolo ea lijo tse boletsoeng mona, mme ho tšohla taba ena ho feta tekano mabapi le tlhahlobo ea hona joale. Likarolo tse latelang li bua ka liphumano tsa moraorao laboratoring ena tse hlalosang ho kenella ha PVT (le ho fetisoa hoa Orx / Hcrt) vs. boitšoaro bo tloaelehileng bo susumetsoang bo lebisang ho tloaelo e tloaelehileng.

PVT e hiroa ka mokhoa o fapaneng ke cocaine vs. moputso oa tlhaho: ho ikamahanya le ho batla koae

Bopaki bo bong bo tsoang laboratoring ena (Martin-Fardon et al., 2013) e bontšitse mokhoa o fapaneng oa ho hira PVT ka lebaka la tšusumetso e amanang le koae vs. stimuli e popetsoeng ka se matlafatso se tloaelehileng se matlafalitsoeng sa lebese, se lomisitsoeng hantle sa lebese (SCM). Morero oa thuto ena e ne e le ho theha mokhoa oa ho hira oa PVT o hlahisitsoeng ke tlhahiso ea khothalletso ea khethollo (SD) e tloaetseng ho sebelisoa ke k'hok'heine kapa ea SCM e sebelisang mofuta oa phoofolo o khutlang hape o hlalositsoeng pele (mohlala, Baptista et al., 2004; Martin-Fardon et al., 2007, 2009). Ka bokhutšoanyane, likhoto tsa Wistar tsa banna li ile tsa koetlisetsoa ho hokahanya le SD ka ho fumaneha ha koae kapa CM (S+) vs. saline kapa moputso (S-). Kamora ho felisoa ha koae- le karabelo e matlafalitsoeng ea SCM, likhoto li hlahisitsoe le S+ kapa S- a le mong. Tlhahiso ea koae S+ kapa SCM S+ (empa eseng S eo e seng moputso S-) kamora ho felisoa hoa maemo a ts'oanang a ho khutlisetsoa morao joalo ka ha ho hlalositsoe lithutong tsa pejana (Baptista et al., 2004; Martin-Fardon et al., 2007, 2009). Mekokotlo e ile ea ngolloa bakeng sa Fos ho PVT, 'me li-neurons tsa Fos-positive tsa baloa ka mor'a cocaine S+ kapa SCM S+ tlhahiso le ho bapisoa le lipalo tse fumanoeng kamora S- tlhahiso. Tlhahiso ea koae S+ empa eseng saline S- c-fos e sebetsang. Ka lehlakoreng le leng, tlhahiso ea bobeli ea SCM S+ le moputso o sa lefelloeng S- hlahisa tlhahiso e tšoanang ea neural. Morero oa khokahano pakeng tsa likarabo tse khutliselitsoeng le palo ea lisele tse nang le Fos tse ntle ho PVT li senotse khokahano ea bohlokoa sehlopheng sa koae empa eseng sehlopheng sa SCM (Martin-Fardon et al., 2013). Lintlha tsena li fana ka maikutlo a hore PVT e nkuoa ka kotloloho nakong ea ha ho ts'oaroa koae empa e sa ts'oaroe ke SCM, 'me e ts'ehetsa maikutlo a hore sebopeho sena sa thalamic se kenya letsoho ts'ebetsong ea ts'ebeliso ea lithethefatsi.

Orx / Hcrt ho pvt mediates boits'oaro ba koae ka litoeba

Khopolo-taba ea bohlokoa sehlopheng sa koae empa eseng sehlopheng sa SCM e fana ka maikutlo a hore koae e etsa hore ho se sebetsane ha methapo ea kutlo ho PVT. Morero oa thuto e latelang e ne e le ho fuputsa karolo e ikhethang ea phetiso ea PVT Orx / Hcrt ho batleng koae vs. boits'oaro bo khothalletsoang ho batla SCM. Likhoto tsa Male Wistar li ile tsa koetlisetsoa ho ipeha k'hok'heine ea nako e khutšoane (ShA; 2 h / ka letsatsi), cocaine e fihlellang nako e telele (LgA; 6 h / day; ke hore, mohlala oa phoofolo e itšetlehileng ka koae), kapa SCM (30 min / letsatsi) bakeng sa kakaretso ea matsatsi a 21 ebe o fuoa koetliso ea ho timela letsatsi ka leng bakeng sa matsatsi a 14. Letsatsing le hlahlamang, likhoto li ile tsa amohela li-microinjections tsa Orx-A / Hcrt-1 (0, 0.25, 0.5, 1, le 2 μg) ebe li kenngoa likamoreng tse sebetsang tlas'a maemo a ho timela ka 2 h. Orx-A / Hcrt-1 e khutlisitse ShA le LgA cocaine e batlang le ea SCM e batlang empa e na le lintlha tse fapaneng tse fapaneng tsa karabo. Litlamorao tsa ho khutlisetsoa ha Orx-A / Hcrt-1-ho kopitsa ho ts'oara ha cocaine sehlopheng sa ShA ho bontšitsoe ke ts'ebetso ea phello ea ente ea U, e nang le litekanyetso tse tlase empa eseng litekanyetso tse phahameng tsa ho khutlisa (Matzeu et al., 2013). Ka lehlakoreng le leng, Orx-A / Hcrt-1 e kentse tšebetsong ea sehlopha sa SCM maemong a phahameng empa eseng a tlase. Phetoho ea letsoho la Orx-A / Hcrt-1 e sebelisitsoeng ka letsohong e ile ea bonoa bakeng sa ho khutlisoa ha ho batla ha koae ea ShA ha ho bapisoa le ho batla ha SCM. Ho ekelletsa moo, ho khutlisetsoa ha Orx-A / Hcrt-1-sehlopheng sa LgA ho hlahisitse phetoho e ka letsohong le letšehali la ts'ebetso ea ho arabela ha lipilisi ha e bapisoa le sehlopha sa SCM le phetoho e ka holimo ha e bapisoa le sehlopha sa ShA. Liphumano tsena li fana ka maikutlo a hore nalane ea ho ts'epa koae e lebisa phetohong ea PVT, e lebisang ho "sensitization" ea phetiso ea LH-PVT-Orx / Hcrt, e bonts'itsoeng ke kutloelo-pele e eketsehang (ke hore, ho tloha ka letsohong le letšehali) le likarabo tse matla tsa boitšoaro. (ke hore, phetoho e nyolohang) ho litlamorao tsa Orx-A / Hcrt-1, e fetisang phetisetso ea Orx / Hcrt-PVT ka mokhoa o batlang boitšoaro ba cocaine le ho kenya letsoho ho khethehileng ha PVT ho li-neurocircuitry tse amanang le ho batla koae. Ho tseba hore Orx / Hcrt e kenya letsoho taolong ea tšebetso ea 'mele e mengata, motho a ka pheha khang ea hore tsamaiso ea kantle ea Orx / Hcrt ho PVT e ka hlahisa litlamorao tse sa utloahaleng. Haufinyane tjena, ho tlalehiloe hore tsamaiso ea intra-PVT ea Orx-A ka tekanyo ea 1.5- ho ea 4.5-makhetlo a phahametseng tekanyo e phahameng e sebelisitsoeng mona e eketsehile haholo molemong oa boits'oaro le boitlhopho, bo ka sitisang (ho re, fokotsa) mosebeletsi ea arabelang (Li et al., 2010). Leha ho le joalo, thutong ea hona joale, tsamaiso ea Orx-A e khutlisitse (e eketsehileng) boitšoaro bo batlang meputso; ka hona, hodima lethathamo la lethal dose le khethiloeng, Orx-A ha ea tlameha ho hlahisa liphetoho tse sa hlakileng ka boits'oaro ba "maikutlo" bo ka ikarabellang bakeng sa mesebetsi e fapaneng ea karabo ea tekanyetso e hlahisitsoeng ka lihlopha tse fapaneng.

fihlela qeto e

Kutloisiso e kholo ea ts'ebetso ea methapo e khothalletsang boits'oaro bo tlatselletsang bo tla fana ka mekhoa e shebiloeng haholo le e sebetsang ea ho qala le ho lelefatsa lithethefatsi le joala. Lintlha tse tsoang laboratoring ena le lingoliloeng li bonts'a hore phetisetso ea Orx / Hcrt-PVT e bapala karolo e ikhethang ea boitšoaro bo susumetsoang ke tšusumetso ea lithethefatsi vs. meputso ea tlhaho le hore nalane ea ho ts'epa koae e fetola kutloisiso ea PVT ho sephetho sa prxing sa Orx-A. Sena se fana ka maikutlo a hore lithethefatsi tsa tlhekefetso ka kakaretso dysregrate neurotransication ho PVT le hore ka tšebeliso e telele ea lithethefatsi kapa joala, Sisteme ea Orx / Hcrt e nka karolo e khethollang ho loants'a lithethefatsi tsa tlhekefetso e batlang vs. ho batla moputso oa tlhaho. Ho sa ntseng ho lokela ho hlakisoa ke li-neuromechanisms tse kenyelletsang karohano ena e pharalletseng ea phetisetso ea Orx / Hcrt-PVT. Khopolo-taba e 'ngoe ke hore nalane ea ts'ebeliso e mpe ea lithethefatsi e etsa hore motho a se ke a hlola a e-ba le tšusumetso ea khatello ea methapo ea methapo, e bonahatsoang ke phetoho ea polelo ea Orx / Hcrt ho PVT kapa phetoho ea tlhahiso ea Orx / Hcrt ho hypothalamus ea morao. ho fetoha ho bonahatsoa ke kamano pakeng tsa ts'ebetso ea PVT le ts'ebetso ea ho ts'oara koae. Nalane ea ho itaola lithethefatsi e ka boetse ea baka li-neuroadaptations (mohlala, matlafatso a matla a synaptic) ho PVT le eona e phethela tšebetso ea eona e "tloaelehileng" ho latela boits'oaro bo fetisisang bo lebisitsoeng ke lithethefatsi.

Ha re nahana ka bohlokoa ba thibelo ea ho khutla ho batho ba kamora ts'ehetso, ho ka ba bohlokoa ho tseba hore na litlamorao tsa lithulusi tsa meriana (mohlala, li-antagonists tsa Hcrt-r) li fetoha ho batho ba latelang, joalo ka ha ho hlalositsoe pejana bakeng sa li-receptor tsa metabotropic glutamate (Aujla et al., 2008; Hao et al., 2010; Sidhpura et al., 2010; Kufahl et al., 2011) le sistimi ea nociceptin (mohlala, Economidou et al., 2008; Martin-Fardon et al., 2010; Aujla et al., 2013) le hore na litlamorao li tsamaisoa ke PVT. Lingoliloeng le tlhaiso-leseling e hlahisoang ke laboratori ea rona e ts'ehetsa ka matla mokhoa o neng o sa tsejoe, e leng phapang ea phetisetso ea Orx / Hcrt-PVT, ho etiology ea ts'ebeliso ea lithethefatsi, e ka thusang ho tseba sepheo sa nalane sa kalafo bakeng sa ts'ebeliso ea lithethefatsi.

Khohlano ea polelo ea thahasello

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

lumela hore baa fokola

Ena ke nomoro ea phatlalatso 25036 e tsoang ho TheHTMLps Research Institute. Patlisiso ena e ne e tšehelitsoe ke NIH / NIDA Aid DA033344 (Remi Martin-Fardon). Bangoli ba leboha M. Arends ka thuso ea ho hlophisa buka e ngotsoeng ka letsoho.

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