Neuropharmacology ea ho qeta ho ja lijo (2018)

(a) Sisteme ea Dopamine

Tsela ea mesocorticolimbic dopaminergic tsela e bapala karolo e kholo ho boits'oaro bo susumetsang, mme ho se sebetse ha eona ho kenyellelitsoe ho kenya letsoho likarolong tsohle tse tharo tsa ho ja ka mokhoa o qobelloang: ho ja ho feta tekano, ho tšela lijo tse ngata ho imolla boemo bo bobe ba maikutlo le ho nona ho feta tekanyo le litlamorao tse mpe. Thutong e matlafatsang ea ho ithuta, ho theha tloaelo ho hloka ho bontšoa ha dopaminergic ho anterior DLS [27]. Dopamine mofuta-1 receptor (D1R) li-neurons, tse etsang tsela e otlolohileng, ea striatonigral, e khannang thabo e ntlafalitsoeng ea dendritic [28], le taolo ea eona e lekanang le dopamine mofuta-2 receptor (D2R) ho supa mokhoa o le mong oa ts'ebetso e potlakileng ea ho theha tloaelo ke lithethefatsi tsa tlhekefetso le lijo tse fumanehang habonolo [29,30]. Liphoofolo tse nang le nalane ea ho kena lijong tse fumanehang nako le nako li bonts'a tloaelo ea ho ja, athe lits'oants'o tse bolokiloeng li boloka lijo tse tataisoang ke sepheo kamora ho li tlola29]. Ka DLS, liphoofolo tse tloaetseng ho ja ho tlatsetsa li ekelitse c-fos ts'ebetsong tse se nang li-neuron tse se nang D2R, e fana ka maikutlo a hore li-neuron tsa D1R li kenelletse tšebetsong e jeoang [29]. Ho feta moo, liente tsa SCH-23390, mohanyetsi oa D1R, ka har'a DLS thibela ntho e tloaetsoeng ea ho ja [29le ho khutlisetsa tlhoko ea ho ikatisa ho liphoofolo tse nang le nalane ea phihlello ea lijo.

Kamora nako, ts'ebetso e fetisisang ea mesocorticolimbic dopaminergic system ho tloha ho pepesetsoa nako e telele ho fihlela ho ho fana ka lijo tse ngatafatsang, tse matlafatsoang li hlahisoa ka sepheo sa ho nyahama / ho theola, ho kenya letsoho ho hlaha ha anhedonia le bofokoli bo susumetsang [16,21]. Ka hona, ho ja ka thata ho tla hlaha e le mokhoa oa ho ikoetlisa ka mokhoa o makatsang ho imolla matšoao ana. Ho na le bopaki bo bong ba ho saena ba dopamine bo tlase ho batho ba batenya, joalo ka ho fumaneha ha li-D2Rs tsa striatal [31-33] le likarabelo tse hlakileng tsa lijo tse matlafatsang [34] ho fumanoe hore li kopantsoe le BMI ka mokhoa o fosahetseng. Ka mokhoa o ts'oanang, likhoto tse fuoeng ho nona haholo-holo li ile tsa fokotsa ts'ebetso ea moputso e neng e sebetsa pele ho [35] le ho latela nts'etsopele ea botena36]. Kamora ho fihlella nako e telele ea ho ja lijo tse nang le mafura a mangata, likhoto tse tona li boetse li bonts'itse mokhoa o phehellang oa ho ja le ho fokotsa li-D2R tsa li-striatal [36]. Ho koala li-D2R ka har'a litšukulu pele ho phihlello ea lijo tse nang le mafura a mangata ho ne ho mpefatsa likotsi tsa moputso mme ho potlakisa ho hlaha ha boits'oaro bo matla ba ho ja [36], ho bonts'a karolo e sebetsang ea li-D2R tse sebetsang ka ho qobella ho ja. Kahoo, ho pepesoa hoa dopamine ho kenyelletsang ho ka baka ho nona ho feta ho lefella khaello e joalo ea moputso. Lisdexamfetamine (LDX), e leng papali ea d-Amphetamine, ke sona feela sethethefatsi sa litlhare se seng se amohetsoe kalafo ea BED, mme se sebetsa ka phetisetso ea phetisetso ea monoamine, ho kenyelletsa le dopamine. LDX e bontšitsoe hore e fokotse ka kotloloho lijo tse qobelloang ho likhoto [37] hammoho le batho, joalo ka tekanyo e qobelloang e amohelang ea Yale-Brown e fetotsoeng bakeng sa ho ja ho itlopa lijo (Y-BOCS-BE) [38]. Tsamaiso ea LDX e hlahisa keketseho e tsitsitseng ea dopamine ea striatal ho likhoto [39], e ka folisang maemo a tlase a dopaminergic e nang le tšobotsi ea ho qhekella ka matla ho imolla boemo bo bobe ba maikutlo.

Bofokoli kapa neuroadaptations ea preronto-cortical dopaminergic signaling ho nahanoa hore ke eona tahlehelo ea taolo e lebisang taelong e sa khaotseng leha ho bile le litlamorao tse mpe [4,40]. Kahare ho PFC, ka kotloloho ho OFC le ACC, ts'ebetso ea dopamine e fokotsehileng e bonoang ho lemalla le botenya e amanang le taolo e fokotsehileng ea thibelo [41]. Li-D2R tsa boemo bo tlase, e leng litholoana tsa botenya, li boetse li amahanngoa le bofokoli bo lumellanang mesebetsing ea pele pele [32,42]. Ho feta moo, mohlomong ka ho eketsa likhathatso tse eketsehileng tsa dopamine ho PFC [39,43], LDX e ntlafalitse li-dysfunctions taolong ea inhibitory ho batho ba nang le BED [38] tse amanang le ho nona ho feta tekano ho sa tsotellehe litlamorao. Kahoo, ka ho eketseha ha maemo a dopamine a extracellular dopamine ka hare ho basal ganglia hammoho le libaka tsa pele, LDX e ka khutlisa ka botlalo dysfunctions tsa dopaminergic tse amanang le likarolo tsa bobeli le tsa boraro tsa ho ja tse qobelloang.

(b) Sistimi ea Opioid

The mu- le kappa-opioid rectyor subtypes li kentsoe ts'ebetsong e qobelloang ea ho ja ka mekhahlelo e fapaneng. Sistimi ea mu-opioid e tsejoa ka moetlo bakeng sa karolo ea eona phepelong ea hedonic, leha ho le joalo haufinyane tjena e fumane tlhokomelo e le molaoli oa tšusumetso ea meputso ea lijo le mekhoa e amanang le eona [44-46], ba kentseng letsoho ka matla phetohong ea ketso-sephetho le khokahano e susumetsoang ke tšebeliso e mpe ea tloaelo [47]. Ho batho ba nang le BED, mokokotlo oa "mu-opioid receptor antagonist" GSK1521498 o fokotse tšebeliso ea lijo tse matlafatsoang hape le leeme le sa tsotelleng lithahasellong tse bonolo tsa lijo [48,49]. Naltrexone, motsoako o kopaneng oa opioid receptor antagonist, o fokotse likarabo tsa neural ho li-cue tsa lijo lithutong tse phetseng hantle, joalo ka ha ho bonts'itsoe ke ts'ebetso e fokotsehileng ea ACC le dorsal striatum [50]. Liteko tse laoloang tse sa sebetsoang tse sebelisang tlhahlobo ea naltrexone li bonts'itse litla-morao tse amanang le ho ja ho itlopa joala [51]. Motsoako oa naltrexone le bupropion, norepinephrine-dopamine reuptake inhibitor, e bile e 'ngoe ea mekhoa e atlehileng haholo [52,53], ho fana ka tlhahiso ea melemo e ka bang teng ea motsoako oa litlhare tse lebisang litselaneng tse ngata tsa methapo ho feta meriana e le 'ngoe e tloaelehileng.

Liphetoho tsamaisong ea li-receptor ea mu-opioid li boetse li etsahala nakong ea ho khaola lijo tse matlafatsang, mme li ka bapala karolo ea ho hlaha ha boemo bo bobe ba maikutlo bo etsang hore boits'oaro bo bobe ba ho ja bo be teng. Likhoto tse fuoang phihlello ea nako e kenang ea tšebetso ea li-mu-opioid receptor e tlamang le ho theosa le tlase ho enkephalin mRNA ho NAc, e fetoleloang ho bonts'a mokhoa o qobelloang oa tokollo ea nako e telele ea ts'ebetso ea morao-rao e latelang ho fetella ho fetang tekano ea lijo [54]. Ka lebaka leo, mmuso oa ho ntša chelete o ka kenngoa ho likhoto tsena ka tsamaiso ea mohanyetsi oa mo-opioid, naloxone, ea fella ka lipontšo tsa boits'oaro bo itseng le boits'oaro bo joalo ba ho tšoenyeha [55]. Phekolo ea Naloxone e ile ea boela ea bontšoa ho baka ho theoha ha extracellular dopamine (−18 ho 27%) le ho eketseha ha acetylcholine ho tsoa (+ 15 ho 34%) litekeng tse tlosoang ka molao tse amanang le litekanyetso tse laoloang ke linaoa [55].

Ho boetse ho na le bopaki ba ho se sebetse hantle ha system ea k- le kappa- opioid ho PFC ka lijo tse qobelloang, tse matlafalitsoeng hore li senyehe maemong a taolo e thibelang tšebeliso e feteletseng ho sa natefeloe le litlamorao tse mpe. Ho hlohlelletsa mo-opioid receptor ka vmPFC ho bontšitsoe ho khothaletsa ho fepa [56] le ho kenya bofokoli taolong ea inhibitory [57], e hlahisitsoeng ke boleng bo eketsehang ba lijo le tlhahiso e senotsoeng ea boitšoaro [58]. Ntle le moo, ka har'a "PFC" (mPFC), taolo ea lethalreo le nang le bokhoni ba ts'ebeliso ea lijo le ts'usumetso e fokotsoang, le khothaletso ea lijo tse matlafatsoang mohlaleng oa phoofolo ea ho ja ka phehello.59,60]. Ka lehlakoreng le leng, naltrexone microinfusion ho NAc e sa hatisetseng lijo le lijo tse matlafatsoang ka mokhoa o ikhethileng [60], e bonts'a mokhoa o fetotsoeng oa ho sebelisa lipilisi pele ho ts'oaetso ea lijo tse matlafatsang. Ntle le moo, liphoofolo tse nang le phihlello ea lijo tse fumanehang habonolo li bonts'a polelo e eketsehileng ea mofuta oa coding bakeng sa opioid peptide pro-dynorphin (PDyn) le polelo e fokotsehileng ea mofuta oa pro-enkephalin (PEnk) mPFC. Liphetho tsena li fana ka maikutlo a hore neuroadaptations ho sistimi ea pele ea opioid e kenya letsoho phepelong ea lijo tse mpe, mohlomong ka lebaka la ho hloka taolo ha lits'ebetso tsa taolo ea thibelo [56].

(c) Corticotropin-releasing factor (CRF) -CRF1 receptor system

Ho na le bopaki bo kholisang ba hore mokhoa o fetelletseng oa hypothalamic corticotropin-releasing factor (CRF) –CRF1 receptor ke lebaka le khannang la ho tlola tekano ka matla ho imolla boemo bo bobe ba maikutlo [20,61]. Nako le nako, nako le nako ha motho a pepesetsoa lijo ebile o li tlohela, o lula a le mothating oa ho hloa tsamaiso ea li-receptor ea CRF-CRF1 butle-butle.20], e bonoang e le keketseho ea CRF karolong e bohareng ea amygdala (CeA) ea liphoofolo nakong ea ho tlohela lijo tse fumanehang habonolo [20,62]. Ho hlophisoa ha sistimi ea CRF-CRF1 ho nahanoa hore qetellong ho hlahisa maikutlo a mabe a maikutlo a hlokometsoeng ha a khaotsa ho bitsoa 'lehlakore le lefifi' la tahi [17,20,61]. Likhoto tse nang le nalane ea lijo tse fumanehang habonolo li bonts'a ho tšoenyeha le boits'oaro bo joalo joalo ka lijo tse fumanehang ha li sa fumaneha (mohlala.20,21,63,64]. Phumano e nchafalitsoeng e ile ea fella ka ho nka lijo tse matlafatsoang le ho felisoa ka botlalo hoa boemo bo sithabetsang ba maikutlo [21]. Ka hona, tsamaiso ea CRF1 receptor antagonist R121919 ho CeA e thibetse boits'oaro bo ts'oaroang ke ho ts'oenyeha le ho ja lijo tse matlafatsang ha phihlello ea lijo li ka khutlisetsoa [20,61].

Sisteme ea CRF-CRF1 e ka har'a bethe ea liteishene tsa stria (BNST) e kanna ea baka ho ja ho tlisoang ke khatello ea methapo e nang le nalane ea thibelo ea lijo [65]. BNST e nka karolo karabong ea khatello ea maikutlo, mme e khothalletsoa ke phihlello ea nako le nako ea lijo tse fumanehang habonolo mofuteng oa phoofolo le ona o sebelisang mekhahlelo ea khatello ea maikutlo [65]. Ho kenella ka R121919 ho BNST ho khonne ho thibela ho ja ka lebaka la khatello ea maikutlo; nts'etsopele ka nalane ea thibelo ea lijo [65]. Mohlaleng o mong oa phoofolo o kotsing ea ho ja ka mokhoa o feteletseng oa khatello ea ho ja, khatello ea maikutlo e eketse polelo ea bongo ea CRF mRNA BNST ea lijo tse jeoang hangata, empa eseng li ja litšoene tse jang -66]. Kahoo, CRF ea BNST e ka fokotsa ho ja ka ho qobelloang ho tsamaisoa ke maemo a sithabetsang mme e ka buisana le CeA ho baka maemo a mabe a maikutlo.

E tataisoa ke bopaki bo ts'episang ba mefuta ea liphoofolo, ho 2016, thuto e laoloang ka mahahapa, e foufalitsoeng habeli, e laoloang ka li-placebo e hlahlobile litlamorao tsa mohanyetsi oa CRF1 pexacerfont mabapi le ho ja ho bakoang ke khatello ea maikutlo ho batho ba baholo ba "thibelang ho ja" ba baholo. Le ha phuputso ena e ile ea emisoa kapele ka mabaka a sa amaneng le litlamorao tse mpe tsa pexacerfont, bafuputsi ba fumane litholoana tse ts'episang phokotso ea litekanyetso tsa mathata a lijo / litabatabelo tse sebelisang YFAS, hammoho le phokotso ea takatso ea lijo le ho ja, leha e ikemetse ka maemo a khatello ea maikutlo [67]. Leha e le sa sampole e theotsoeng, teko ena ea tleleniki e bonts'itse bokhoni bo matla ba bahanyetsi ba CRF1 ba ho fokotsa litakatso tsa lijo lijong tse sa feleng, nako e tiisang ea bokamoso, lithuto tse matla tse felletseng [67]. Barekisi ba CRF1 ba khothalletsoa hore ba atlehe haholo mafu a itseng a kelello bo bonts'ang ho bonts'a ho ata ha CRF haholo; ka hona, liteko tsa tleleniki ea nako e tlang tsa tlhahlobo ea katleho ea bahanyetsi ba CRF1 tse tobileng ho mathata a itseng, maemo, kapa li-subgroups tsa mokuli li bileiloe bakeng sa [68,69].

(d) Sistimi ea Cannabinoid receptor 1

Sistimi ea li-receptor tsa cannabinoid receptor-1 (CB1) ka har'a amygdala e fetola maemo a mabe a maikutlo a amanang le ho ja ka mokhoa o tlamang. Bokhobeng ba lithethefatsi, ho pheta-pheta botahoa le ho hula khafetsa ho baka ho hiroa ha sistimi ea endocannabinoid ka har'a lipotoloho tsa amygdalar, eo ho nahanoang hore e ka sebetsa joalo ka 'buffer system' ho CRF-CRF1 receptor system overactivation [70,71]. Ka mokhoa o ts'oanang, nakong ea ho tlohela lijo tse fumanehang habonolo, endocannabinoid 2-arachidonoylglycerol (2-AG) le mofuta oa cannabinoid mofuta oa 1 (CB1) receptor li fumanoe li eketsoa ho CeA [72]. Ts'ebetso e hlophisitsoeng hantle le ea CeA sebakeng sa CB1 receptor inverse agonist rimonabant e sentse e le boitšoaro bo joalo ba ho tšoenyeha joalo ka ho ja lijo tse tloaelehileng tsa nako ea ho ja nakong ea ho tlohela lijo tse fumanehang habonolo [72,73]. Habohlokoa, rimonabant ha ea ka ea eketsa boits'oaro bo ts'oanang le ho tšoenyeha ho liphoofolo tse laoloang ke linaoa [72,73]. Ka hona, sistimi ea endocannabinoid ea amygdala e khothalletsoa hore e khethoe nakong ea ho khaotsa lijo tse matlafatsoang e le mochine o qobellang ho fokotsa matšoenyeho. Kahoo, li-endocannabinoids li ka thusa ho kokobetsa boemo bo bobe ba maikutlo bo amanang le ho tlohela lijo, 'me rimonabant e ka mpefatsa letšoao le ts'oanang le la ho itlhahisa ha batho ba batenya ba sa jeng lijo tse matlafatsang ha ba leka ho theola boima ba' mele (mohlala ka ho ja). Mokhoa ona o ka 'na oa hlalosa ho hlaha ha litla-morao tse matla tsa mafu a kelello tse latelang kalafo e rimonabant ho bakuli ba batenya haholo [74].

Sisteme ea CB1 e boetse e kenya letsoho ho ho ja ho feta tekano leha e le litlamorao tse mpe. Litekong tse nang le nalane ea ho fihlella lijo tse fumanehang habonolo, rimonabant e fokotse takatso ea lijo tse matlafatsoang ho feta litulong tse matlafatsoang hape e boetse e thibetse ho ja lijo tse matlafatsoang ka teko e bobebe / e lefifi ea ntoa [75]. Leha sebaka sa ts'ebetso ea ho nka karolo phello e sa tsejoe, rimonabant se fumanoe se khetha keketseho ea catecholamine e kang dopamine ho PFC [76], ka hona e khutlisetsa lits'ebetso lits'ebetsong tsa taolo ea inhibitory e amanang le ho saena ka tlase pele ho dopamine ho saena.

(e) Mokhoa oa Glutamatergic

Lihlooho tse peli tse kholo tsa li-glutamatergic receptors (a-amino-3-hyrdoxy-5-methyl-4isoxazolepropionic acid (AMPA), le NLi-receptors tsa -methyl-d aspartate (NMDA) li fumanoe li kentse letsoho ho phehelleng mekhoa ea ho ja, haholo ho ja ho feta tekano le ho ja ho feta tekano le litlamorao tse tlatselletsang. Ho tloaela ho ja lijo tse fumanehang habonolo ho ipapisitse le li-AMPAR ho DLS, e leng e 'ngoe ea likarolo tsa mantlha tsa boko tse kenyelletsang tlhahisong ea tloaelo. Ts'oaetso ea mohanyetsi oa AMPA / kainate receptor antagonist, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) ho kena ka har'a DLS e koaletse ho ja tloaelo, e khutlisetsa tlhoko ea maikutlo ho fokotseha hoa lijo tse fumanehang habonolo [29].

Li-NMDAR li nahanoa hore li amahanngoa le karolo ea ho ja ho feta litlamorao tse mpe ka lebaka la tšebelisano le lits'ebetso tsa taolo ea thibelo. Memantine, mohanyetsi ea sa qothisanang lehlokoa le NMDAR, o fokolitse ho itlopa joala le 'thibelo' ea boits'oaro ba ho ja ka mokhoa o bulehileng, o tla ba nyeoeng le batho [77]. Memantine e boetse e bontšitsoe ho fokotsa khatello ea maikutlo le taolo e ntlafatsang ea kelello ho bareki ba qobelloang [78], mokhoa o khothalletsoang oa ts'ebeliso ea boitšoaro o tšoanang le ho ja ka mokhoa o qobelloang. Ka ho qobella ho ja liphoofolo tse pepesetsoeng monyetla oa ho kena lijong tse matlafatsang letsatsi le leng le le leng, "microinfusion" ea memantine ka har'a khetla ea NAc e fokolitse ho ja joalo ka "23], ho bonts'a hore Sisteme ea NMDAR khetla ea NAc e koetlisoa mesebetsing ea ho ja likhoto. Ts'ebetso kahare ho NAc e fetoloa ke likhakanyo tsa glutamatergic tse tsoang PFC [79-81]. Memantine e boetse e thibetse ho ja lijo tse matlafatsoang le lijo tse matlafatsoang [23].

Kaholo ea mantlha ea NAc, ho ba le mafura a mangata ka lebaka la botenya bo bakileng phetoho ho polasetiki ea glutamatergic synaptic, ho kenyelletsa bokhoni bo eketsehang bo mabapi le glutamatergic synapses, tahlehelo ea bokhoni ba li-synapses tsena tse ka bang teng ho tepella maikutlong a malelele le maqhubu a liehang ho feta a NMDA-Mediated82]. Ho sitisoa ha Synaptic ho ne ho amahanngoa le boitšoaro bo joalo ba bokhoba ba lijo, ho kenyelletsa khothatso e eketsehileng, ho ja haholo le ho eketsa lijo ha lijo li sa fumanehe [82]. Ho tšoaetsoa ho sa bonahaleng lipakeng tsa cortico-accumbens ho kenyellelitsoe ho senya ts'ebetso e tloaelehileng ea polokelo ea tlhaiso-leseling ea tšusumetso le thibelo ea ho arabela [83], mohlomong ho fella ka tahlehelo ea taolo ea tahi le ho ja ho feta tekano le litlamorao.

(f) Sistma-1 sesebelisoa se amohelang

Li-receptor tsa Sigma-1 (Sig-1Rs) li kentsoe ts'ebetsong ea pathophysiology ea mafu a lemallo a kenyelletsang lithethefatsi tse ngata tsa tlhekefetso [84-90], hape ba bonts'itsoe ho fetola ho nona ho feta tekano ntle le litlamorao tse bohloko [59]. Ho liphoofolo tse nang le phihlello ea lijo tsa kamehla, ka linako tsohle kalafo ea mohanyetsi oa Sig-1R BD-1063 e fokotsetse ho ja lijo tse matlafatsoang ka mokhoa o itšetlehileng ka tekanyetso [59]. Ho feta moo, thutong e ts'oanang, BD-1063 e thibetse mokhoa o qobelloang oa ho ja ha o tobane le maemo a mabe [59]. Ho itlama ka likhoto, ho ja likhoto tse qobelloang ho bontšitse keketseho e habeli ea maemo a liprotheine a Sig-1R ho ACC [59]. Kahoo, Sist-1R ea tsamaiso ea mantlha e ka bapala karolo ea phepelo ea ho ja [59], mohlomong ka lebaka la neuromodulation ea dopamine le glutamate signing [91,92].

(g) Tsamaiso ea Cholinergic

Boits'oaro ba ho saena ha acetylcholine (ACh) ho NAc ke mokhoa oa ho khaotsa lithethefatsi tsa tlhekefetso [93], hape e hlokometsoe nakong ea ha e tlosoa lijong tse matlafatsoang [55], ho hlahisa mokhoa ona e le sebapali sa bohlokoa maemong a amanang le maikutlo a mabe. Ka mokhoa o ts'oanang, lithetleng tse nang le phihlello ea ho fumana tharollo ea sucrose le lijo tsa chowon, tse lateloang ke 12 h ntle le monyetla oa ho fumana lijo, ho itlhahisa ka mokhoa o ikhethileng le oa boithatelo bo hlahisang keketseho ea extChacellular ACh ho NAc [55,94]. Keketseho ena ea ACh e ne e boetse e tsamaisana le ho saena ha dopaminergic ho fokotsehileng, hammoho le matšoao a ho khaotsa ka mokhoa o itseng le boitšoaro bo kang ba ho tšoenyeha [55]. Kahare ho NAc, tšebelisano e sebetsang pakeng tsa lits'ebetso tsa dopaminergic le cholinergic li na le phello e matla khothatsong ea ho ja [95,96], ka likhoto tseo tse lapileng li ile tsa emisa ho fepa haeba tekanyo lipakeng tsa tse peli e fetela lebopong la cholinergic [97]. Methati e phahamisitsoeng ea ACh ho NAc le eona e fella ka ho ferekana nakong ea linaha tse tlase tsa dopamine [96], mme ka hona e ka kenya letsoho boemong bo fapaneng ba ho tlohela.

(h) Sistimi e amanang le li-receptor-1 ea trace amine e amanang le eona

Bopaki ba morao-rao bo bonts'a mokhoa oa "trace amine" o amanang le li-receptor-1 (TAAR1) o nka karolo ho matlafatsang ho nona ho sa natefeloe ha ho na le litlamorao tse mpe, mohlomong ka ho nka karolo ha liphathi tsa PFC. TAAR1 ke protheine e kopantsoeng ea G-protein e entsoeng ka li-amine tsa trace le li-neurotransmitters tse ling tse kang dopamine le serotonin [98]. Sistimi ea TAAR1 haufinyane e fihlile tlhokomelong ea bopaki ba karolo ea bona ea ho laola liketso tsa boits'oaro ba psychostimulants [99] empa hape le boitšoaro bo sa susumetsang100]. Phuputso ea morao-rao [101] e fuputse karolo ea sistimi ea TAAR1 ho itlopa lijo le ho e qobella ho ja likhoto tse latelang letsatsi le leng le le leng, ho fihlella lijo tse fumanehang habonolo. Li-injection tsa systemic tsa TAAR1 agonist RO5256390 e ikhethileng ka botlalo le ka mokhoa o ikhethileng oa ho ja lijo tse matlafatsoang, polelo ea sebaka se ratoang bakeng sa lijo tse fumanehang habonolo, hammoho le ho ja ho tlatselletsang joalo ka teko e bobebe / e lefifi [101]. Ho feta moo, liphoofolo tse jang tse jang hangata li fokotsehile tlhahiso ea protheine ea li-receptor tsa TAAR1 ho PFC [101]. Likokoana-hloko tsa sebaka sa RO5256390 ka ho khetheha ho infralimbic, empa eseng prelimbic, cortex e khutlisitse thibelo ea ho itlopa lijo ka likhoto tse qobelloang tsa ho ja [101]. Liphetho tsena li bontša hore TAAR1 e kanna ea ba le karolo ea thibelo ho feta boits'oaro, le hore tahlehelo ea ts'ebetso ena e kanna ea ikarabella bakeng sa ho ja ka thata. Ho khahlisang, li-TAAR1 li boetse li qaptjoa ke amphetamine [98], metabolite e sebetsang ho BED kalafo LDX [102]. Agonism ea LDX le TAAR1 ka hona e ka sebetsa ka mekhoa e ts'oanang ho khutlisa taolo e mpe ea taolo ea boitšoaro ba pelehi.

(i) Sisteme ea Serotonin

Serotonin (5-hydroxytrptamine, 5-HT) neurotransmission e ithutile haholo ka mathata a ho fepa le ho ja, ho kenyelletsa le BED [103], mme e hokahane le boits'oaro bo qobelloang ho OCD le bulimia mothosa [104,105]. Bakuli ba nang le BED show ba fokotse ho lokolloa ha 5-HT ho hypothalamus, 5-HT transporter e tlamang bohareng ba mpa, le 5-HT2a e phahameng le 5-HT5 e tlamang mokokotlong oa NAc [106-108]. Lithethefatsi tsa Serotonergic, joalo ka ho khetha li-serotonin reuptake inhibitors, ho ithutoe ka tsona e le monyetla oa kalafo bakeng sa BED [109,110]. Ho na le karolo e tsebahalang bakeng sa tsamaiso ea serotonin mathateng a nang le matšoenyeho le khatello ea maikutlo; le ts'ebetso ea 5-HT e tlase e fumanoe e le ho bolela esale pele boemo bo bobe pele ho ho ja ho sa feleng [111]. Mokhoa o mong o ka sebelisang lithethefatsi tsa 5-HT bakeng sa ho fokotsa ho ja o fumanoe o le ka 5-HT2c receptor activation ea dopamine neurons sebakeng sa ventral tegmental (VTA) [112]. Moriana oa ho nona oa botenya haholo (agNist ea 5HT-2c) o bontšitsoe hore o fokotsa ho fepa ka lapeng hammoho le boleng ba khothalletso ba lijo ka VTA 5-HT2c activation [113]. d-Amphetamine, e thibelang ho khutlisoa ha monoamine, ho kenyelletsa serotonin, e bontšitsoe ho eketsa mohopolo oa 5-HT ho striatum [114]. Kahoo, LDX e kanna ea khutlisetsa ts'ebetso ea serotonergic e kenyang matla a eona a ho fokotsa boitšoaro bo qobelloang ba ho ja.

(j) Orexin

Karolo ea orexin (hypocretin) e na le karolo e amanang le litloaelo tsa boits'oaro bo bobe [115], ho kenyelletsa ho itlopa lijo tse matlafatsang le tse qobelloang, mohlomong ka ho feto-fetoha hoa matlafatso ea lijo tse matlafatsang le boitšoaro bo fumanehang habonolo [116]. Receptor ea orexin-1 (OX₁R) mohanyetsi o bontšitsoe ho khetha ka mokhoa o ikhethileng oa ho ja lijo tse matlafatsoang [117,118]. Ntle le moo, li-neuron tsa orexin tse ho latela hypothalamus ea morao-rao li qalisoa ke lintlha tsa lijo [119,120], hape o fetole tšebeliso e matla ea cue- e susumetsang ea ho fepa [119] le ho khutlisetsoa ka tlase hoa boits'oaro bo batlang lijo [120]. Kahoo, orexin e supang ka kotloloho e hlophisa karabelo ea lijo tsa cue e tsamaeang le sebopeho sa tloaelo, hape e ka bapala karolo ho tlatseng takatso e kenelletseng, e tloaetseng ho etsoa.

Ho na le litlamorao tse tsebahalang tsa sistimi ea orexin holima khatello ea maikutlo le boits'oaro bo kang ho tšoenyeha [121]; leha hona ho sa ithutoe haholo molemong oa ho tlosoa hoa lijo tse bonolo. Leha ho le joalo, mefuteng ea liphoofolo ea ho itlopa lijo tse kenyelletsang nalane ea thibelo ea caloric le / kapa khatello ea maikutlo e eketseha polelo ea orexin ho hypothalamus ea morao-rao [117,122]. Ho nahanoa hore lithibelo tsa caloric le khatello ea kelello li kenella ho rephula orexigenic pathways le ho khothaletsa ho itlopa lijo. Lisosa tsa OX₁R antagonist e thibela ho itlopa lijo ka mofuta ona oa thibelo e bakoang ke ho itlopa lijo [117]; ho bonts'a karolo e anngoeng ke maikutlo a ho ja ka mokhoa o qobelloang ho imolla letsoalo. Leha ho le joalo, ho lokela ho hlokomeloe hore thibelo ka boeona e ka baka li-neuroadaptations tse khothalletsang ho ja ka mokhoa o phehellang [123,124] Arohane le nalane ea ho pepesehela le ho itlopa lijo tse fumanehang habonolo [23,59,64].