LIPOTSO: Ke pampiri e entsoeng hantle feela e sebelisang mekhoa e meng ea ho lemalla.
Boithuto bo Felletseng: Mekhoa ea Neurobiologic ho Moputso oa lithethefatsi le ho lemalla
Harv Rev Psychiki. 2004; 12 (6): 305-320.
doi: 10.1080 / 10673220490910844.
inahaneloang
Mekhoa ea Neurophysiologic e tlasa boitšoaro bo sa laoleheng, bo khothalletsang bo hlalosang mmuso o lemaletseng. Liphetoho tsena tse “thata-thata” bokong li nkuoa e le tsa bohlokoa bakeng sa phetoho ea ho tloha ts'ebelisong e mpe ea lithethefatsi. Tlhahlobo ena ea lithuto tsa preclinical le tsa tliliniki (haholo-holourouro) e tla hlalosa kamoo khopolo-taba pakeng tsa thabo, moputso, le bokhoba li hlahisitsoeng ka teng ha kutloisiso ea rona ea mekhoa ea biologic e tlasa lits'ebetso tsena e hatetse pele. Le ha mesolimbic dopaminergic efflux e amanang le moputso oa lithethefatsi e ne e nkuoa e lekana le biologic ea monyaka, ts'ebetso ea dopaminergic e etsahala boteng ba tšusumetso e sa lebelloang le e nooang (e ka ba e khahlisang kapa e tsosang takatso) mme e bonahala e supa boemo bo susumetsang ba ho batla kapa tebello. Ho ntšoa ha dopamine nakong ea ts'ebeliso ea lithethefatsi tse sa foleng ho lula ho bokella likarolo tsa bokong le "preortalal cortex", ho kenya litheko tsa lithethefatsi ho amygdala (ka mekhoa ea glutaminergic) le ho kenyelletsa cortex ea amygdala, cterate ea orterofortal le cortex ea dorsolateral pele. lithethefatsi. Boko bo sa tsotelleng, bo lemalloang bo hlohlelletsoa morao ho khutlela ts'ebelisong ea lithethefatsi ha bo baka ts'ebeliso e le 'ngoe ea lithethefatsi, lithahasello tsa lithethefatsi, ho lakatsa, kapa khatello ea kelello, le ts'ebetso e' ngoe le e 'ngoe e hlalosoang ke sebaka se fapaneng sa boko kapa tsela ea methapo. Tsela e qobelloang ea ts'ebeliso ea lithethefatsi e tlatselletsoa ke bofokoli ba taolo le tšusumetso ea liqeto, tseo hape li kopantsoeng ke orbitofrontal cortex le anterior cingulate. Ka har'a moralo ona, ho fanoa ka lipheo tsa nakong e tlang tsa kalafo ea meriana
Meputso e monate. Ho lemalla ho lematsa. Meputso e fumanoa ha e arajoa, e fana ka thabo le thabo. Bokhoba ba boitšoaro bo kenyelletsa boitšoaro bo sa khaotseng, bo qobelloang, le bo sa laoleheng bo ka sebetsanang le ho senya. Leha ho bile le phapang ena e totobetseng, moputso le bokhoba ba nakong e fetileng bo ne bo nahanoa hore bo arolelana li-underpinnings tse tloaelehileng tsa neurobiologic. Moetso ona o kopaneng o entse ntlafatso e makatsang, 'me moputso le bokhoba bo se bo nkiloe e le mekhahlelo e fapaneng ea methapo e amanang le mekhahlelo e fapaneng, empa e le e mengata, mekhahlelo ea neuroanatomical. Thutong ena, ke tla qala ka pono ea nalane ea mesolimbic dopamine le moputso, e lateloe ke likhopolo tse peli tsa bokhoba (ke hore, dopamine depletion le sensitization) tse tataisang nts'etsopele ea meriana ka lilemo tse 'maloa. Litlhaloso tse ncha tsa karolo ea dopamine moputsong le bokhobeng li hlahisoa, li bonts'a kutloisiso ea rona ea hajoale ea dopamine e le mokena-lipakeng oa tebello, ho batla, le bocha. Mekhoa e 'meli e akaretsang e amanang le ho khutla hape hoa lithethefatsi e tla tšohloa: melao e qobelloang, e nkuoang e le likarolo tse' ne tsa kelello, e mong le e mong a kenyelletsa sepheo sa ho khutla (ke ho re, ho roka, lithahasello tsa lithethefatsi, ho lakatsa, le khatello ea maikutlo); le dyscontrol ea inhibitory e ka eketsang ts'ebetso ea lithethefatsi e tlamang. Karolo ea mesocorticolimbic dopaminergic le glutaminergic pathways, intracellular mechanisms, le likarolo tse nepahetseng tsa boko maemong a qobelloang a ts'ebeliso ea lithethefatsi le dyscontrol ea inhibitory e tla ba sepheo sa likarolo tsena mabapi le ho khutla ha lithethefatsi.
Li-caate tse 'maloa li lokiselitsoe. Taba ea pele, khafetsa ke tla sebelisa lentsoe “bokhoba”1 (o sebelisa mantsoe a khothaletsoang ke American Academy of Pain Medicine, American Pain Society, le American Society of Addiction Medicine) ho fapana le "ho itšetleha"2 ho bua ka ho rarahana ha boits'oaro bo kenyelletsang ho tlohela, ho mamella, tahlehelo ea taolo, ts'ebeliso e qobelloang, le ts'ebeliso e tsoelang pele ho sa tsotellehe litlamorao tse mpe. Taba ea bobeli, bokhoba ba lithethefatsi bo tla tšohloa ka ho khetheha mabapi le lintho tse sebelisoang tlhekefetso, haholo-holo koae. Le ha ho le joalo, ts'ebetso ea methapo ea kutlo, sebopeho sa boko, le ts'ebetso ea boits'oaro le ts'ebeliso ea kelello e kenyelletsang ts'ebelisong ea lintho tse lemalloang hangata li amana le bokhoba ba ho se mamele, bo kang ba ho kenyelletsa thobalano le papali ea chelete. Taba ea boraro, tlhahlobo efe kapa efe ea ts'ebetso ea methapo ea kutlo molemong oa ho lemalla e tlameha, ka ho tlameha, ho ikhetholla tseleng ea eona mme ka boomo o tlohele tsoelo-pele ea bohlokoa tšimong. Qetellong, tlhahlobo ena e tla shebisisa lits'ebetso tsa biologic tse kenyelletsang ho khutlisetsong ea lithethefatsi kamora nako ea ho itlopa joala-li-process tseo ke lumelang hore ke lipotso tse khahlang le tse tsietsang ho utloisisa mofuta oa bokhoba. Kahoo, likhopolo tsa bokhoba ba ho kenyelletsa "mohanyetsi" kapa mekhoa ea ho tlohela e ke ke ea tšohloa.3-5
TLHOKOMELISO LE MESOLIMBIC DOPAMINE
Ba baholo le Milner6 e qalile kutlwisiso ea rona ea sejoale-joale ea mekhoa ea moputso oa boko ho 1954. Mosebetsing ona oa seminal, litoeba li ile tsa fuoa monyetla oa ho tsamaisa motlakase libakeng tse fapaneng tsa boko. Libaka tse ikhethileng tsa boko li fumanoe li etsa hore motho a ikitlaetse, hangata e le ho khetholla boitšoaro bo bong. Ho netefatsa ho batho liphetho tsa Olds le Milner, Heath7,8 e bonts'itse hore lithuto ka mokhoa o ts'oanang li tla fana ka ts'usumetso ea motlakase libakeng tse itseng tsa "menyaka" ea boko (bakeng sa litlhaloso tsa boitšoaro, bona sehlooho sa Baumeister sa 2000).9 Lilemong tse mashome tse latelang, methapo ea boko, methapo ea methapo ea kutlo, le li-neurotransmitters tse amehang boiphihlelo ba moputso le matlafatso li ile tsa ntlafatsoa le ho feta (bona tlhahlobo ea Gardner).10 Tsela ea mesolimbic, haholoholo, e ile ea tsebahala e le karolo ea bohlokoa ho litlhahlobo tsa moputso. Tsela ena e simoloha ho tsoa ho libopeho tsa sele ea dopaminergic sebakeng se potolohileng (VTA), e leng selefo se nang le "dopamine" se fumanehang karolong ea moea (kapa tegmentum, e bolelang "sekoaelo") sa mpa ea bohareng. Morero ona oa li-axon tsa dopaminergic mme o emisa ka ho khetheha ka mokokotlong oa mokokotlo (NAc) empa o boetse o kenella sebakeng sa amygdala, bethe ea "stria terminalis" (BNST), sebaka se ts'oanang le septal, le hypothalamus ea morao. VTA e haufi, le haufi haholo le nigra e 'ngoe, e' ngoe e nang le matla a dopamine. Le ha merero eaantiantia nigra e qala haholo ho dorsal striatum (ka tsela ea mesostriatal) le lits'ebetso tse tsamaeang le makoloi, mesolimbic pathway mediates moputso.11
Boiphihlelo ba moputso bo tsamaisana le ts'ebetso ea mesolimbic dopaminergic tsela. Meputso ea tlhaho, e kang lijo kapa thobalano — hammoho le lintho tse ngata tse hlekefelitsoeng ke batho, ho kenyeletsa joala, amphetamine, koae, koae, matekoane, nikotini, opiates le phencyclidine10,12-17-Increase extracellular e tsepamisitsoeng ea mesolimbic dopamine (DA). Li-cocaine tse matlafatsang le li-amphetamine li holisa ka kotloloho lets'oao la mesolimbic dopaminergic ho li-postynaptic DA receptor ka mekhoa e fapaneng ea synaptic. Cocaine e eketsa likhakanyo tsa dopaminergic ka ho thibela phepelo ea "presynaptic dopamine transporter" (DAT).18 DAT e na le boikarabello ba ho kopanya bothateng bo kopaneng ba DA ho khutlela ho "neuron" ea kutlo, 'me ho lula ha DAT ka koae ho thibela ho ts'oaroa hape ha DA. Amphetamines e eketsa synaptic DA haholo-holo ka ho eketsa ho lokolloa ha DA ho li-synicic vesicles.19 Ka bobeli k'hok'heine le "amphetamine" li eketsa khatello ea mantlha ea DA maemong a latellanang le nako ea hore DA e lule sebakeng sa postynaptic receptor. Ka lebaka la ts'usumetso ea tsona e tobileng ts'ebetsong ea dopaminergic, li-stimulants (haholo-holo cocaine) li nkuoa e le lithethefatsi tsa prototypic tsa moputso mme kahoo li fetohile mohopolo oa lithuto tsa bioloji le tsa kalafo (bona likarolo tse latelang). Le ha lithethefatsi tse sa sebetseng li kenella ka kotloloho tseleng ea mesolimbic ka lits'ebetso tse fapaneng tsa li-receptor, lisebelisoa tsena li arolelana thepa e tloaelehileng ea pharmacologic ea micolimbic DA-haholo-holo ho NAc.10 Lithethefatsi tsena tse se nang thuso li tlama ka liprotheine tsa G protein-coupled kapa ligand-gated ion. Lithethefatsi tse kopanyang le li-receptor tsa G protein-coupled (le sebaka sa tsona se tlamang), li kenyelletsa tetrahydrocannabinol (THC) (agonist ho li-cannabinoid receptors); opiates, joalo ka heroin kapa morphine (agonists ho li-opioid receptors, activating dopamine ka VTA GABAergic disinhibition);20 le caffeine (antagonist ho striatal adenosine A2 receptors). Lithethefatsi tse tlamang ka ligand-gated ion checeptors li kenyelletsa joala (mothetsi oa allostatic ho GABAergic receptors le inhibitor ea N-methyl-D-aspartate [NMDA] glutamate receptors); phencyclidine (PCP) (e thibela li-receptor tsa NMDA tsa NMDA); le lihlahisoa tsa nikotine, joalo ka lisakerete (li-agonists ho li-nicotinic cholinergic receptors).
Phapano ea anatomical e entsoeng lipakeng tsa moputso oa lithethefatsi le ho tlosoa hoa lithethefatsi e boetse e tiisa bohlokoa ba tsela ea mesolimbic ho tsamaiso ea lithethefatsi. Thutong ea khale e entsoeng ke Bozarth le Wise,21 morphine e ile ea tsamaisoa sebakeng sa VTA kapa periventricular grey (PVG) ea likhoto bakeng sa lihora tsa 72 (PVG ke sebaka sa "stemors" sa boko se nang le pokello e kholo ea li-receptor tsa opioid). Kamora ho tsamaisoa ha opioid antagonist naloxone, litoeba tse kenyellelitsoeng ke moruti tse nang le morphine li bontšitse matšoao a ho ikhula, athe likhoto tse tlatselitsoeng ke VTA ha li a ka tsa etsa joalo. Ntle le moo, litoeba li ka koetlisetsoa ho ikoalla morphine ho VTA empa eseng PVG. Phuputso ena e bontšitse karohano e hlakileng pakeng tsa ts'ebetso ea bioloe e amehang ho khahlaneng le moputso, e ts'ehetsa karolo ea VTA moputsong oa lithethefatsi.
Leruo le lengata la lithuto tsa preclinical le hlahlobisitse ka kotloloho litlamorao tsa ho eketseha kapa ho fokotseha ha DA ho NAc holim'a taolo ea lithethefatsi.22-24 Re sebelisa mokhoa oa "vodiodialysis" oa vivo, liphetoho tse ka fetohang motsotsong oa li-neurotransmitter li ka hlahlojoa ka nako ea nnete nakong ea tlhahlobo. Ka mokhoa ona, Pettit le Toka25 o fumane khokahano lipakeng tsa palo ea koae e ipehileng ka litoeba le DA ea kantle ho naha e lokollotsoeng NAc. Ka lehlakoreng le leng, boitlamo ba ho itaola ha lintho tse matlafatsang bo latela ho tsamaisoa ha bahanyetsi ba DA (mohlala, haloperidol)26,27 kapa lesapo la mokokotlo la lisele tsa dopaminergic ho NAc.28 Lithuto tse sebetsang tsa neuroimaging li boetse li netefalitse bohlokoa ba tsela ea mesolimbic le ho lokolloa ha DA ho ea holimo cocaine. U sebelisa imagingance resonance imaging e sebetsang hantle (fMRI), Breiter le basebetsi mmoho29 ba fuoa cocaine ho batho ba lemaletseng koae ha likelello tsa bona li ntse li hlahlojoa. Metsotsong e 'maloa e latelang, lithuto li ile tsa khona ho khetholla "ho potlaka" hoo ba ho tlalehileng ka motsotso oa pele kapa tse peli tse latelang tsa tšebeliso ea koae ho tsoa ho "ho lakatsa" ho latela ho felisoa ha ho potlaka. Kaha mekhoa ea fMRI e lumella mehato ea ts'ebetso ea ts'ebetso ea boko ho hlahlojoa metsotsoana e meng le e meng, litšoantšo tse ikhethang tsa ts'ebetso ea boko li fumanoe nakong ea liphihlelo tsa "ho potlaka" le "ho lakatsa". Nakong ea ho potlaka, empa eseng ho lakatsa, ts'ebetso ea ts'ebetso e eketsehileng ea ts'ebetso e ile ea bonoa VTA, e lumellana le ts'ebetso ea tsela ea mesolimbic. Phuputsong e sebelisang positron emission tomography (PET), Volkow le basebetsi mmoho30 e tsamaisitsoeng ka koae ho lithuto nakong ea ho nahanisisa, mme a tlaleha hore boemo ba ho lula ha DAT kapa DAT blockade bo ne bo amahanngoa haholo le boholo ba ho itlaleha bo phahameng. Lithuto tse ling tsa Volkow le basebetsi mmoho31 fana ka maikutlo a hore ho lokolloa ha DA (joalo ka ha ho hlahlojoa ke mosebetsi oa D2 receptor occupation) e ne e le ponelo-pele ea bokhoni bo phahameng ho feta kamoo ho neng ho le thibelo ea selemo ka teng. Khopolo e akaretsang e tataisang lipatlisiso tsa bokhoba ba taolo bakeng sa boholo ba lilemo tse mashome a mabeli tse fetileng e bile hore litlamorao tsa lintho tsa mantlha tsa tlhekefetso li ne li itšetleha ka ts'ebetso ea dopaminergic ea tsela ea mesolimbic.
Phetoho e tlohang phetong ya hae ho ya tlhahisong: TLHOKOMELISO DOPAMINE
The Dopamine Depletion Hypothesis ea Ho Lemalla
E phahameng kapa e potlakileng e amanang le ts'ebetso ea mesolimbic e bontšitse hore neurotransmitter DA ka boeona e ikarabella bakeng sa maikutlo a monate a amanang le meputso. Ts'ebetso ea ho tsamaisa lithethefatsi e tsoelang pele (ke hore, litloaelo tsa boits'ebetso) e nkuoe e le sephetho sa tlhokahalo e tsoelang pele ea ho phahamisa likhahla tsa DA-le thabo e felletseng - tseleng ea mesolimbic le libaka tse amanang le boko. Khopolo-taba ena e ile ea bolela esale pele hore ho itlopa joala ha koae ho ka etsa hore e be le bofokoli ba DA,3,32,33 e bakang ho oa ha k'hok'heine ea koae (ke hore, anhedonia, khatello ea maikutlo) le tlhoko ea biologic (ke hore, ho lakatsa) k'hok'heine e eketsehileng ho tlatsa mabenkele a DA a felileng. Ho nyahamisoa ke DA ka lebaka la lithethefatsi ho 'nile ha bitsoa ka mokhoa o fapaneng e le "dopamine depletion hypothesis"32 kapa "modumo o akaretsang oa anhedonia."34 Bopaki ba li-receptor tse matla tsa DAT35 (ho fana ka tlhahiso ea hore ho phahamisoe karabo ea ho lula setulong sa DAT ka cocaine) le ho fokotsa li-receptor tsa DA D236,37 (e fana ka maikutlo a ho theoha ha karabelo molemong oa likhatiso tsa DA tse lulang li le teng sebakeng sa postynaptic) ke lithuto tsa PET tse tšehetsang ts'ebetso ea ts'ebetso ea dopaminergic hape. Likhatiso tse tsitsitseng tsa D2 li ile tsa qaptjoa bakeng sa ho nyenyefatsa litšepiso tse matlafatsang tsa meputso ea tlhaho le ho phahamisa tlhoko ea litheko tse matlafalitsoeng ke linthla tsa dopaminergic efflux. Mohlala, keketseho ea li-receptor tsa D2 e fokotsa ho itaola ha joala literemeng,38 athe li-primates tse nang le li-receptor tse tlase tsa D2 li bonts'a litheko tse phahameng tsa boiketsetso ba koae.39 Lithuto tse itšetlehileng ka cocoaine le tsona li bonts'itse mesebetsi ea sele ea dopaminergic haholo (joalo ka ha ho bonahatsoa ke liphetoho tse etsahalang [11C] raclopride binding hape ho tlalehiloe hore e amana hantle le ho itaola ka mokhoa oa koae ho likhoto, hoo litekanyetso tse tlase tsa DA li hlahisang litekanyetso tse phahameng tsa taolo e phahameng, mme maemo a phahameng a DA a hlahisa litekanyetso tse tlase le tse tlase tsa tsamaiso ea maemo.40
Ho tla fihlela joale, liteko tsa ho phekola bokhoba ba koae ka ho kenya tšebetsong li-dopaminergic receptors —'me ka tsela eo lentsoe la dopaminergic le ntse le eketseha — ha lia atleha. Li-agonists tse 'maloa tsa dopaminergic (mohlala, pergolide,41 amantadine,42,43 bromocriptine,42,44,45 methylphenidate,46 le mazindol)47 ha ea ka ea fokotsa litheko tsa ho khutla lithutong tse lemaletseng koae. Haholo-holo ho makatsa e ne e le thuto ea boithuto ea sephetho sa tlhahlobo ea DA le ho itšireletsa ha koae ka litoeba tse haelloang ke li-cocaine. Rocha le basebetsi mmoho48 ithutile liphatsa tsa lefutso tse fetotsoeng moo litheko tsa DAT li sa hlahisoeng (DAT - / - - litoeba tsa ho kokota). Kaha litoeba tsena li ne li sena li-receptor tsa DAT ho tlama koae, tsamaiso ea koae ha ea ka ea etsa hore ho be le keketseho e kantle ho naha ea DA ea ventral. Leha ho le joalo, ka tšohanyetso, ka nako ea - - - - litoeba tse ipatileng ka bongata bo tšoanang le litoeba tsa mofuta oa litoeba (litoeba tse nang le li-receptor tse setseng tsa DAT). Phuputso ena e senotse hore DAT kapa keketseho ea synaptic DA e ne e le bohlokoa bakeng sa ho itaola k'hok'heine. Lithuto tse ling tsa Rocha le basebetsi mmoho48 (e tlalehiloe sengoliloeng se le seng) e bonts'a hore thepa ea ntlafatso ea koae e kanna ea ba e kopantsoe le ho lula ha cocaine ho transporter ea serotonergic. Patlisiso tse ling, joalo ka ha li hlahlojoa ke Spanagel le Weiss,49 o boetse o khothalelitse hore, ntle le lintho tse khothatsang, mesolimbic DA neurotransication ha e nke karolo ea bohlokoa ho matlafatsong e bolokiloeng ke lithethefatsi tsa tlhekefetso.
Boikutlo le bokhoba
Hypotization hypothesis e hlahisitse pono e fapaneng le ea bohlokoa ba dopamine ts'ebetsong ea bokhoba. Khopolo-taba ena e boletse esale pele hore taolo e pheta-phetoang ea lithethefatsi e tla "nyenyefatsa" tsamaiso ea DA ho lithethefatsi le lithahasello tse amanang le eona tsa lithethefatsi.50-52 Ketsahalo ena e ile ea boleloa esale pele ha ho elelloa hore ts'ebeliso ea nako le nako, ea tšusumetso ea motlakase libakeng tsa boko ba methapo e etsa hore ho be le tsusumetso e matla ea "neuronal" e tsoelang pele. Sesebelisoa sa sensus se bonts'itsoeng se bonts'a maikutlo a phehellang, a phahamisitsoeng molemong oa ts'ebeliso e latelang ea ts'usumetso ea mantlha kapa litheko tse amanang le eona.53,54 Kameho e susumetsang ea Cocaine e qalile ho bonoa ke Grode ho 1912,55 e ileng ea lateloa ke lithuto tsa pele ho tleleniki tse bonts'ang nts'etsopele e tsoelang pele ea monyetla oa ho ts'oaroa ka kakaretso ho latela taolo ea koae ea letsatsi le letsatsi51 le botebo bo matla ba li-receptor tsa dopaminergic ho li-stimulants tsa psychomotor.56-58 Cocaine e kenyellelitseng maikutlo le lithohisele tsa setho sa cocaine li ile tsa khothaletsoa e le khokahano ea mabaka lipakeng tsa tšebeliso e mpe ea koae le ho ts'oaroa ke koae,59 ho tšoha,60,61 Psychology,62 le ho lakatsa.50 The sensitization hypothesis of addiction (haholo-holo mabapi le cocaine) ka hona e boletse esale pele hore ts'ebeliso ea ts'ebeliso ea lithethefatsi e tla fokotseha ka karabelo ho lithethefatsi tse sebelisoang ho hatella methapo ea methapo ea kutlo (mohlala, carbamazepine bakeng sa lefu la sethoathoa sa nakoana) kapa dopaminergic antagonists e hanyetsang karabelo ea hypersensitive dopaminergic . Phuputso e entsoeng ke Carbamazepine e sa boneng mahlo habeli e bontšitse katleho e lekantsoeng ea kalafo ea ts'ebeliso ea koae,63-65 le ha ho le joalo, le bahanyetsi ba dopaminergic (mohlala, flupenthixol, risperidone, le ecopipam) ba ne ba sa sebetse ho fokotsa ts'ebeliso ea ts'ebeliso ea koae hape.66
Ts'ebetso ea pharmacologic e tataisoang ke DA-depletion kapa -sensitization hypotheses ha e hlahise meriana e thusang bakeng sa kalafo ea ho lemalla koae. Liteko tsena tsa tleleniki li khothalelitse hore ho sitisoa ha phetisetso ea dopaminergic e ne e le ntho e poteletseng ho feta keketseho kapa ho fokotseha ha kantle ho tumello kapa kutlo ea dopaminergic. Tlhatlhobo bocha ea karolo ea dopamine ho mafu a lemallo e bile ho lokiselitsoe.
TLHALOSO EA BOTSOALLE, HO ITHUTA LE HO FIHLELA: TLHOKOMELISO EA PUSO EA MESOLIMBIC
Ntle le karabelo e nyahamisang ea bakuli ho dopaminergic agonists le antagonists, phetoho ea paradigm boemong ba DA ts'ebetsong ea bokhoba e etsahetse ka kamohelo ea hore (1) DA ha e etse, 'me ka boyena, e etsa "thabo," (2) mesolimbic DA efflux ha e eketsehe eseng karabong ea moputso feela, empa hape le tebello ea moputso o ka bang teng le nakong ea linaha tse khelohelang, ho kenyelletsa le ho sisinyeha ha maoto, khatello ea maikutlo le ts'ebetso ea lithethefatsi tse tšoenyang mahlo,17,24,34 (3) keketseho ea kantle ho likhahla tsa DA e iponahatsa ka litoeba tse iketsang k'hok'heine ea "cokine" e litonnyaneng (litoeba tse amohelang tekanyo e tšoanang le ea koae e tšoanang le eo litoeba tse ling li ka ipehelang eona),67 ho senola hore boitlhokomelo ba koae e phahamisa mesolimbic DA efflux ha e bapisoa le tsamaiso ea cocaine, le (4) DA e bapala ka mokhoa o makatsang, le ho feta, likarolo tsa ho toloka mohopolo le ho fumana boits'oaro bo matlafatsoang ke meputso ea tlhaho le tlhoko ea lithethefatsi. .
Kahoo, menahano ea pele mabapi le karolo ea ho susumetsa ha kelello ea motlakase ho hlalosa "meputso" tseleng e ne e bonahala e le bonolo haholo. Berridge68 o hlokometse hantle hore mosebetsi oa Heath oa pele7,8 (Bona kaholimo) o tlaleha hore bakuli ba tsamaisang motlakase ka mokhoa o qobelloang. Ho fapana le ho khothaletsa "thabo" ho tsoa phihlelong eo, bakuli bana ba hlalositse takatso ea ho ba le maikutlo a eketsehileng le lintho tse ling tse nyarosang. Ho ile ha bonahala hore tsela ea "monate", e khetholloang haholo ho tsoa liphuputsong tsa liphoofolo (tse tsebahalang ka ho tšaba ho arolelana maikutlo le maemo a tsona a nnete), e kanna eaba e ne e sa tsamaisoa hantle. Sebakeng seo, Berridge le basebetsi mmoho23 le ba bang69 ba khothalelitse hore tsela ea mesolimbic e khetholle ts'usumetso, or batla, ea moputso o lebelletsoeng — eseng ketsahalo e thabisang ea moputso ka boeona. Ho hlohlelletsa tsela ena ka hona ho ka baka maemo a susumetsang a "ho hloka" (an tebello ea monate) empa e ne e hana ho ba mokena-lipakeng oa moputso oa hae oa ho hlonepha, oa ho hlonepha kapa ho “rata.”70 Phapang pakeng tsa "ho rata" le "ho batla" e ne e le bohlokoa, hobane e ne e khetholla matla a khomphutha ea ntho le matla a eona a ho lemalla. Ebile, liphuputso tse fetileng li senotse hore boits'ireletso ba lithethefatsi bo ka bolokoa nthong e lemaletseng ntle le boithabiso bo sa reng letho - ke hore, ho rata lithethefatsi e ne e se mokhoa oa pele bakeng sa boits'oaro ba ho batla lithethefatsi le ho sebelisa lithethefatsi.71 Di Chiara15 theorised e batlang e tšoana le leha e le karohano, karolo ea NAc, e tiisa hore ts'ebetso ea mesolimbic dopaminergic activation thuto e susumetsang, eseng ho hloka kelello (sheba karolo e latelang). Schulz le basebetsi mmoho72 e bonts'itse hore li-neurons tsa DA li tuka mollo feela ha li arabela moputsong oa lipale tse ncha, ho sa tsotelehe boleng ba tlhasimollo ea hedonic; ts'ebetso ea ts'ebetso ea lets'oao e ne e itšetlehile ka ho tsebahala ha moputso. Ka hona, buka e sa lebelloang, e sa reroang, e iketsahallang le e tsosang maikutlo e tsosa letšoao le matla la dopaminergic, ho sa tsotellehe boikemisetso bo matla ba tšusumetso.73 Ka polelo e 'ngoe le e' ngoe e pheta-phetoang ea tšusumetso, ho ts'oaroa ha DA ho fokotseha ho fihlela ts'usumetso e se e sa hlahise karabelo ea neuronal. Karolo ena ea DA e lumellana le lithuto tsa PET tse bonts'ang hore ho lokolloa ha DA ka lebaka la methylphenidate ho fumaneha lithutong tse lemaletseng koae ka koae.74 Mohlomong khothalletso ea koae ke ntho e nchafatsang haholoanyane lithutong tse sa hlokeng ho bapisoa le baithaopi ba lemaletseng koae. Boitekong ba ho koala likarolo tse fapaneng tsa karabelo ea mesolimbic DA, Salamone le basebetsi mmoho34 ba khothalelitse hore NAc DA ke "sebopeho sa sensorimotor" "e kentseng tšebetsong tšebetso e phahameng ea sephethephethe sa motor le sensorimotor tse bohlokoa bakeng sa ts'ebetso ea ts'usumetso, kabo ea karabelo, le karabelo ho maemo a susumetsoang" - bangoli ba lumela hore, hula leleme hantle feela joalo ka lentsoe 'moputso.' ”
Karolo ea tsela ea mesolimbic, mme haholo NAc, ka hona e rarahane ho feta (hape e rata likhang) ho feta kamoo ho neng ho lumeloa pele. Leha ho le joalo, tšobotsi e tloaelehileng ea mabitso a holimo a ka nkuoa ho fana ka maikutlo a hore mesolimbic dopamine system e kenella phetolelong kapa ho ithuteng ha bathusi ba khothatsang ba nepahetseng le ba seng mpe, le hore ho supa ha DA ho bonahala ho khothaletsa boitšoaro bo lebisitsoeng ho sepheo ho sa tsotelehe mofuta oa ho tiisa. Ka ho hlakileng, sisteme ea mesolimbic e lekola boteng, kapa boleng, ba matlafatso a ka bang teng. Ho etsa tlhahlobo ena, likarolo tse ling tsa boko le tsa maoto li tlameha ho sebetsa ka tsela e tšoanang le moputso oa boko. Kutloisiso ea karolo ea ts'ebetso ea bokhoba kahoo e boetse e hloka ho kenyelletsoa ha libaka tsa boko tse amanang le VTA le NAc. Joalokaha ho boletsoe pejana, VTA e fana ka dopaminergic innervation eseng feela ho NAc, empa le amygdala le BNST. Ntle le moo, VTA e hlophisa DA ho tsoa tseleng ea boraro ea dopaminergic, tsela ea mesocortical, e khethollang libaka tsa pele tsa cortical tse kenyelletsang orbitofrontal cortex (OFC) le cingulate ea ka ntle.11 E kopantsoe le glutaminergic le likhokahanyo tse ling tsa phepelo ea neurotransmitter, NAc e kopantsoe le OFC, cterxe ea ka ntle, cortex ea insular, cortex ea insular, le hippocampus. Ka lebaka la bohlokoa ba libaka tsena ho utloisisa lits'ebetso tse tlatselletsang tse boletsoeng ka tlase, tlhaloso e khutšoane le setšoantšo sa libaka tsena tsa boko li fanoa lebokoseng la mongolo le Setšoantšo sa 1.
Joale, kutloisiso ee e ncha ea mesolimbic dopamine tsela, le ho kenyelletsoa ha likarolo tse ling tsa maoto le li-preortal tsa cortical, li ka re tataisa joang kutloisisong ea rona ea ts'ebetso ea bokhoba? Keketseho ho tloha ts'ebelisong ea lithethefatsi ho isa ho lemalloang ho lithethefatsi e ka fetoha ha ts'ebetso e phetoang ea ts'ebetso ea mesolimbic e amanang le ts'ebeliso e mpe ea lithethefatsi e eketsa boleng ba ts'usumetso, kapa ho se sebetse hantle ha moriana. Ha mekhoa ea maemo a bophelo e hokahana le ho matlafatsoa ka taolo e pheta-phetoang ea lithethefatsi, ts'ebetso e tlasa ts'ebetso ea ts'ebetso ea mesolimbic DA butle-butle e kenyelletsa li-neurocircuitry tse amehang mohopolong oa maikutlo, menahano e totobetseng, karabelo ea khatello ea maikutlo, ho etsa liqeto, le boitšoaro bo sitisang boiphihlelo ba ts'ebeliso ea lithethefatsi. Likarabo tsena tsa neuroadaptive li lula li ntse li tšoarehile leha ho sa sebelisoe lithethefatsi ka mokhoa o tsoelang pele mme ho nahanoa hore ke sesosa sa mantlha sa ho khutla ha lithethefatsi. Likarolo tse peli tse latelang li tla bua ka ts'ebetso ea boko e kenyelletsang ho khutla ts'ebelisong ea lithethefatsi, ho kenyelletsa le ts'ebetso e qobelloang ea lithethefatsi le dyscontrol ea inhibitory e fumanoang lithutong tse lemaletseng lithethefatsi, hammoho le kamano ea drive ea lithethefatsi le dyscontrol ea inhibitory ho dopaminergic dysregulation.
TLHOKOMELISO E ETSANG LELAPA
Ts'ebeliso ea lithethefatsi e qobelloang e ka nahanoa (e fetotsoe ho tloha Koob & Moal)3 e hlahile libakeng tse 'ne tsa bokong tse fetang ka nqa tsohle, e' ngoe le e 'ngoe e renang molemong oa tšebeliso ea lithethefatsi. Libaka tse 'ne / marangrang a hokahana le lits'usumetso tse tloaelehileng tsa ho khutla: (1) priming (ke hore, seno se le seng se tlisang ho itlopa joala),79 (2) litakatso tsa lithethefatsi, (3) litakatso, le (4) khatello ea maikutlo. Likarolo tse mabapi le litheko tsa pelehi le lithethefatsi li boetse li hlalosa mekhoa e kenelletseng mekhoeng ea ho lemalla.
Priming: The Nucleus Accumbens and Dopamine
Boithuto ba pelehi ba ho poma bo tiisa lipatlisiso tsa bongaka-hore taolo e le 'ngoe ea lithethefatsi ke eona e khothalletsang tšebeliso ea lithethefatsi haholo. Dopamine e bonahala e bapala karolo ea bohlokoa ho priming, hobane ho khutlisetsoa hoa boits'oaro bo khahlisang le bo tsosang takatso ho khothaletsoa ke botsamaisi ba ts'ebetso ea dopaminergic agonists ka kotloloho, le litlamorao tsa heroin, amphetamine, le cocaine li thibetsoe ke bahanyetsi ba DA.58 (Reinstatement e bua ka ho nchafatsoa ha ho batla lithethefatsi mefuteng ea phoofolo kamora ho felisoa hoa taolo ea lithethefatsi tse fetileng. Bona tlhahlobo ea Shaham le basebetsi mmoho).80 Kameho ea kantle ho kantle ho DA ho NAc holim'a ts'ebeliso ea lithethefatsi, leha ho le joalo e thatafatsoa ke likarabo tse makatsang tsa li-receptor subtypes tsa DA. Li-receptor tsa Dopaminergic li na le malapa a mabeli a pharaletseng (D1 le D2) le li-subtypes tse hlano (D1-joalo: D1, D5; D2-joalo: D2, D3, D4).81 Le ha li-agonists ka bobeli tsa D1 le D2 li na le thepa e matlafatsang, li-receptor tse peli li na le litlamorao tse hlakileng pusetsong ea lithethefatsi. Khothatso ea li-receptor tsa D2 ho NAc e baka ho khutlela morao ho bakoang ke lithethefatsi, athe lithethefatsi tse matlafatsang li-receptor tsa D1 li thibela ho khutlela mokhoeng o bakoang ke lithethefatsi (bona Self & Nestler58 bakeng sa tlhahlobo). Phapang pakeng tsa li-receptors tsa D1- le D2 e ka utloisisoa hamolemohali ka kananelo ea lits'oants'o tsa postreceptor tse hlahisitsoeng ke tokollo ea lithethefatsi tse hlahisitsoeng ke lithethefatsi ho tsoa tseleng ea len messengerosa la bobeli. D2 receptors inhibit intracellular adenylyl cyclase ka ho kopanya le liprotheine tsa inhibitory G tse fokotsang tlhahiso ea cAMP, athe li-receptor tsa D1 li hlohlelletsa sebopeho sa cAMP ka ho kenya liprotheine tsa membrane G tse hlasimollang cymbase ea adenylyl. Ho pepeseha ho sa feleng ha k'hok'heine, heroin, morphine, le ethanol kaofela ho etsa hore ho fokotsehe tseleng ea bobeli ea NAc cAMP, 'me ho be le keketseho e kholo ea "cymbase" ea adenylyl,' me ka lehlakoreng le leng, protein kinase. Ka hona, ho bonahala eka phokotso e phehellang ea D2 e kenyelletsang ho intracellular cAMP e latelang ts'ebetso ea lithethefatsi e sa foleng e ka baka ho eketseha ha taolo ea lithethefatsi, athe litlamorao tsena li ka hanyetsoa ke ho hlohlelletsa li-receptor tsa D1.
Li-ligands tsa D2 li-receptor ha lia ka tsa ipaka li le molemo kalafong ea ts'ebeliso ea ts'oaetso e matlafatsang; Li-agonists tsa D2 li-receptor li matlafatsa mefuteng ea liphoofolo, mme bahanyetsi ba li-receptor ba D2 ha ba atlehe lithutong tsa batho. Leha ho le joalo, kaha D2-agonists e bonahala e sebetsa haholo ts'ebetsong ea priming, meriana e lebisitseng D2-e kang D3 le D4 receptors e fumanoe. Ntle le moo, athe li-receptor tsa D1 le D2 li kenelletse hantle bokong bohle, li-receptors tsa D3 li hlahisoa ka mokhoa o ikhethileng tsamaisong ea mesolimbic, haholo-holo ho NAc, le li-receptor tsa D4 li na le methapo e phahameng ho li-preortal cortex (PFC) le li-suprachiasmatic nucleus. .11 Boithuto ba preclinical bo senola hore bahanyetsi ba li-receptor ba D3 ba thibela liketso tse matlafatsang tsa koae le ho ts'oara ho ts'oaroa hoa boitšoaro bo batlang cocaine;82,83 tlhahlobo e lekanyang ea li-receptor ligin ea D3 e seng e ntse e lekoa le liteko tsa batho.84 Phuputsong e khahlisang ea motho e lekolang tšebelisano lipakeng tsa liphatsa tsa lefutso le tšebeliso ea lithethefatsi, lithuto tse phetseng hantle tse nang le li-polymorphisms tse fapaneng tsa D4-n-tandem-repats (VNTR) li ile tsa fuoa lethalinyana la joala la ho chesa ebe le hlahlojoa bakeng sa ho lakatsa. Lihlopha tse nang le li-polymorphisms tsa D4 VNTR tse fapaneng li bontšitse karabelo e fapaneng ho mohanyetsi oa D4,85 ho hlahisa bohlokoa bo ntseng bo eketseha ba meriana ea machaba ho tsebisa ts'ebeliso ea meriana e lebisitsoeng ho mofuta oa motho ka mong.
Litaba tsa Lithethefatsi: The Nuklea Accumbens le Amygdala
Matla a likotsi tse amanang le lithethefatsi ho etsa hore a khutlele tšebeliso ea lithethefatsi a bonoa khafetsa tikolohong ea bongaka, a etsa hore ho be le temoso ho bakuli ba lemaletseng ho qoba "batho, libaka le lintho" tse amanang le ts'ebeliso ea bona ea lithethefatsi. (Leha lits'oants'o tse joalo li ka etsa hore motho a lakatse, taba ena e tšohloa karolong e latelang). Di Chiara15 e fana ka maikutlo a hore tšebeliso e sa khaotseng ea lithethefatsi e matlafatsa mekhatlo e khothatsang le e khothalletsang meputso, ka hona, e tiisa tsela ea mesolimbic le kahare ho khokahano pakeng tsa ntho le litheko tse amanang le eona tsa lithethefatsi. Ho sithabela ha boiphihlelo ba tšebeliso ea lithethefatsi tumellanong le moemeli ea nang le maemo a tikoloho ho hlahisa "memori ea ho lemalla"86 kapa "neural ghost" (Glenn Horwitz, puisano ea motho ka mong). Moea ona oa neural o lula o kenelletse ka har'a mesolimbic circry, haholo-holo amygdala87-O thehiloe kantle ho temohisiso. Ha o hlohlelletsa tsela ea mesolimbic, ebang ke likhakanyo tsa lithethefatsi tse boemo bo tlase88 kapa ka priming lithethefatsi, potoloho e activated, ho kenya takatso, kapa ho batla, bakeng sa lithethefatsi tse ling.
Amygdala e ts'oaneleha ho hapa, ho boloka, le ho hlahisa mehopolo ea maikutlo. PET le fMRI neuroimaging lithuto tsa cocaine-89-92 le lithuto tse lemaletseng lithethefatsi93 bonts'a ho pepesetsoa hoa cue ho susumetsoa ke lithethefatsi ho susumetsa ts'ebetso ea sebaka sa amygdalar. Ha liphoofolo li koetlisetsoa ho tloaelana le "sebaka" se itseng le taolo ea lithethefatsi (ke hore, khetho ea sebaka se itseng), li khutlela tikolohong e amanang le ho amohela moriana. Kamora ho koetela hoa amygdala, liphoofolo li "lebala" mokhatlo ona.94-95 Matla a matlafatsang a lithethefatsi a ntse a le teng, leha ho le joalo, ha boitaolo ba lithethefatsi bo ntse bo phehella ho lateloa ke thobalano ea amygdalar. Sebopeho sa mekhatlo lipakeng tsa liketsahalo tse khothatsang le tse khotsofatsang ka hare (kapa tse tlohelang) liketsahalo li tsamaisoa ke ho hlohlelletsa li-neuron tsa dopaminergic.49 Leha ho le joalo, glutamate e boetse e bonahala e le mokena-lipakeng oa polasetiki ea cue-e susumetsang ea boitšoaro ka likhokelo tsa glutamatergic tse projeke ho tloha amygdala ho ea ho NAc.96 Keketseho ea tokollo ea glutamate kamora ho phetoa khafetsa ha koae le eona e buisana, bonyane karolo ea eona, e susumetsang tlhaselo ea cocaine.97,98
Sebaka se secha sa lipatlisiso se hlahloba mekhoa e makatsang e tsamaeang le ts'ebeliso ea lithethefatsi khafetsa e bontšang hore likhokahanyo tsa mnenomic tse khutlisetsang mohopolo oa morao-rao li kenelletsoa ke liphetoho tsa nako e telele tsa lisele le tsa limolek'hule. Ho ntšoa ha li-neurotransmitters tse tsoang kantle ho nako ho ka susumetsa liphetoho tsena maemong a makatsang ka ho eketsa kapa ho fokotseha ha protheine, ho kenyelletsa liprotheine tse fetoletsoeng (kapa tsa sebopeho). Liprotheine tsa Messenger (mohlala, G) li ile tsa tšohloa karolong e fetileng. Lintho tse hatisang li laola tlhahiso ea liphatsa tsa lefutso tsa mRNA ka ho tlama likarolo tsa taolo ea liphatsa tsa lefutso tse ikhethileng. Lintlha tse peli tse hatisitsoeng tse amanang haholo le taolo ea lithethefatsi tse sa feleng ke ΔFosB le CREB (protein ea karabo ea cAMP) (bona Nestler99 le Chao & Nestler100 bakeng sa litlhahlobo). ΔFosB ke setho sa lelapa la Fos la lintlha tsa bongaka tsa pelehi. Boholo ebile ho ka etsahala hore ebe litho tsohle tsa lelapa lena li kenella ka potlako kamora ho pepesetsoa ka matla ho amphetamine cocaine, ethanol, nicotine, opiates le PCP. ΔFosB e ikhethile har'a liprotheine tsena ka hore e tsitsitse ebile e phehella ka nako ea libeke kapa likhoeli tse 'maloa.101 Ts'ebetso e pheta-phetoang ea lithethefatsi ka hona e baka ho bokellana ha ΔFosB, haholo-holo ka li-neuron tsa giriergic tsa kati spiny neurons tse nang le dynorphin le ntho P.102,103 ΔFosB e fokotsa polelo ea "dynorphin" ho li-neuron tsa "striatal proion" neurons. Ho bokelloa ha drugFoxB ke lithethefatsi ho ntlafatsa boleng ba kutlo litlamorao tse khahlisang tsa koae le morphine,103,104 mohlomong ka lebaka la sephetho sa maikutlo a dynorphin ea striatal holim'a li-receptor tsa kappa-opioid ho li-neurons tsa VTA dopaminergic. Kaha "ΔFosB e tsitsitseng e ikhethile ho amygdala le PFC, ho fanoe ka maikutlo a hore" ΔFosB e kanna ea fetoha "molek'hule" e bolokang kamano lipakeng tsa boiphihlelo ba moputso oa lithethefatsi le litheko tse amanang le lithethefatsi khale kamora ts'ebeliso ea lithethefatsi li felile 105
Leqhubu le Tebileng la Lithethefatsi: Potoloho ea Striato-Thalamo-Orbitofrontal
Mmila o kenyelletsang khannareng e qobelloang ea lintho ke potoloho ea striato-thalamo-orbitofrontal. Potoloho ena e hokahane ka thata le libaka tse ling tsa pele le tsa maoto, ho kenyeletsa le anterior cingrate, insula, dorsolateral prefrontal cortex (DLPFC), le amygdala. Lits'ebetso tse kenyelletsang thepa li kenyelletsa 'mesocortical dopaminergic tsela, e ts'ebetsang libaka tsa PFC tse kenyeletsang OFC le cingulate ea ka ntle,11 le li-neuron tsa glutamate tse projeke eo khafetsa lipakeng tsa PFC le amygdala, hape le ho tloha ho PFC ho ea ho NAc le VTA.96 Potoloho ena ea striato-thalamo-orbitofrontal e bile le tšusumetso ho ramatiki e nang le ts'usumetso e matla (OCD), lefu le arolelanang likarolo tse tloaelehileng le mafu a lemalloang; ka mantsoe a mang, ts'ebetso ea lithethefatsi le joala e kenyelletsa ho hloka taolo holim'a menahano e makatsang le boits'oaro bo qobelloang bo lebisitsoeng ho fumana le ho tsamaisa lintho.106,107
Tloaelo e tloahelehileng ea tšebeliso ea lithethefatsi e ka hlahlojoa ka mokhoa o matla le sekala se sa hlokofatsang sa ho noesa,106 tekanyo e rerang esale pele ea sephetho sa kalafo.108 Patlisiso e le 'ngoe ea photon emission computerized tomography (SPECT) le lithuto tsa ho nka litšoantšo tsa PET li bonts'a ts'ebetso e eketsehileng ea OFC, cingulate ea anterior, le striatum ho OCD, mme ts'ebetso ena ea boko e tloaela ho latela kalafo e atlehileng ea pharmacologic kapa psychosocial.109-111 Ts'ebetso e phahameng ea OFC e bonoa ka mokhoa o ts'oanang lithutong tse lemaletseng koae ka nako ea takatso ea koae112 'me ka bobeli ba ho emisa113 le methylphenidate114 Tsamaiso, e fana ka maikutlo a hore OFC e fana ka maikutlo a tebileng bakeng sa liphephetso tse fapaneng tsa kelello le tsa meriana. Ntle le moo, PET e 'ngoe90-92,114 le fMRI112,115,116 lithuto nakong ea litakatso tsa koae, methylphenidate, le joala li bonts'itse ts'ebetso ea cingrate ea ka ntle, DLPFC, insula, le amygdala. Garavan le basebetsi mmoho,117 leha ho le joalo, ho bapisa ts'ebetso ea ts'ebetso ea ts'ebetso ea boko le fMRI lithutong tse lemaletseng koae le tse sa thibeloeng ha ba ntse ba shebelletse lifilimi tse bontšang batho ba tsubang koae kapa ba etsa liketso tsa thobalano. Likarolo tsa cocaine li hlahisa likarolo tse tšoanang tsa tlhaho tsa tlhaho tse ts'oanang le lithethefatsi tsa cocaine, li fana ka maikutlo a hore ts'ebetso ea libaka tsena tse thata le tse thata ha e amane le potoloho e ikhethileng e amanang le lithethefatsi tsa lithethefatsi. Ho khahlisang le ho feta ke ho fumana hore, athe batho ba lemaletseng koae ba ile ba arabela ka mokhoa o matla ho lithahasello tsa koae ho feta taolo (joalo ka ha ho ne ho lebeletsoe), sehlopha se lemaletseng koae se bontšitse lets'oao la mokokotlo ka lebaka la ts'usumetso ea thobalano le setho sa thobalano. sehlopha se sa lemalleng. Tumellanong le tlhahlobo ea bongaka, thuto ena e fana ka maikutlo a hore tšebeliso e mpe ea lithethefatsi e etsa hore motho a "batle" ha a araba likamano tse amanang le lithethefatsi, eseng karabong ea maikutlo a tlhaho. Ts'ebeliso e mpe ea lithethefatsi ka lebaka leo e bonahala e kopanya li-circonal tsa "neuronal" hantle, e le hore tšebetso e sebetsang e arabela haholo ho tsusumetso e amanang le lithethefatsi le hore ho rala, ho etsa liqeto, le ho shebisisa mekhoa eohle ho tšehetsa ho ts'oaroa ha lithethefatsi le ho kenella.
Ho Khatelloa ke Khatello ea Kelello le Kelello: The Limbic-Hypothalamic-Pituitary-Adrenal Axis
Khatello ea maikutlo ke sesosa se tloaelehileng sa ho khutlela ho bakuli ba lemaletseng joala,118 khatello ea maikutlo le nako ke tšusumetso e matla bakeng sa ho khutlisetsa tšebeliso ea lithethefatsi mehlaleng ea liphoofolo.58,119 Liphuputso tse entsoeng pele ho lipatlisiso tse mabapi le taba ena li senotse hore khatello ea maikutlo (ho kenyelletsa khatello ea maikutlo, tšohanyetso ea nako e telele, karohano ea bo-mme, khatello ea bokhachane, ho itšehla thajana, ho hloka taolo, tikoloho e sa tsitsang ea sechaba, le ho se be le lijo kapa thibelo) kaofela ke li-modulators tsa boits'oaro ba ho batla lithethefatsi, leha ho le joalo litlamorao ho khatello ea maikutlo efe kapa efe e ikhethang, ke khatello ea maikutlo le ts'ebetso ea lithethefatsi. Ho tsitsipana ha leoto le sa tsitsinyeheng, leha ho le joalo, ho ba khatello ea maikutlo e ts'oanang ka ho fetesisa ea ho khutlisetsoa hoa lithethefatsi (bona Lu et al.119 bakeng sa tlhahlobo). Potoloho ea khatello ea maikutlo e kenyeletsa hypothalamic-pituitary-adrenal (HPA) le lits'ebetso tsa khatello ea maikutlo tsa extortypothalamic corticotropin-releasing factor (CRF), ho kenyelletsa amygdala le BNST.3 Matšoenyeho a kantle a hlohlelletsa ho khutlela ts'ebelisong ea lithethefatsi ka BNST77 le Amygdala,58 libaka tse amehang ka ho khetheha ka litlamorao tsa neuropeptide CRF. Ho khutlisetsa ts'ebeliso ea lithethefatsi kamora ho ts'oaroa ha maoto ho thibetsoe ke tsamaiso ea bahanyetsi ba CRF,120 ho senola hore CRF ke mokena-lipakeng ts'ebetsong ena e boelang hape. Norepinephrine (o qala ho tsoa ho locus coeruleus)121,122 le glutamate (ho qala ho tsoa ho amygdala)123 hape ba kenelletse ho khutlisetsong ha khatello ea tšebeliso ea lithethefatsi. Joalokaha ho hlalositsoe ka litakatso tse amanang le lithethefatsi le litakatso, ho khutlisetsoa ho ts'oaroang ke tšabo ea maoto ka tsela e tšoanang ho kenyelletsa likhakanyo tsa glutaminergic tse tsoang ho PFC le amygdala ho ea NAc.123
Khatello ea kelello e sebetsana le mesolimbic DA ka ho kenyelletsa ho pepeseha ha glucocorticoids. Ka mor'a ts'ebetso e bakiloeng ke khatello ea maqhubu a HPA, li-glucocorticoids li tšela mokoallo oa mali le ts'ebetsong ea methapo ea methapo ebe li tlama le VTA (le tse ling) li-glucocorticoid receptors.124,125 Glucocorticoids e na le phello e lumellang ho mesolimbic DA,126,127 le khatello ea maikutlo le lintho tse sebelisang tlhekefetso (mohlala, amphetamine, cocaine, ethanol, morphine, le nicotine) li baka ho ts'oaroa hoa lisele tsa midbrain dopaminergic.128 Ka hona, tokollo e bakiloeng ke khatello ea maikutlo ea bobeli ba extrahypothalamic CRF le glucocorticoids e hlohlelletsa mekhoa ea methapo e sebetsanang le ts'ebetso e qobelloang ea ts'ebeliso ea lithethefatsi. Ka lehlakoreng le leng, motho ea lemaletseng joala o tahi. lithuto li bontša. karabelo e kopantsoeng ea maqhubu a HPA ha a sebetsana le khatello ea maikutlo le kelello le maikutlo.129-131 Mokhoa ona oa "inverse U", oo ho oona ho ka bang thata ka ho feteletseng le ho ba le glucocorticoids ka bongata, o bonahala mesebetsing e mengata ea 'mele.132 Kaha liphuputso tsa pele li bontša hore ho kenella hoa tšebetso ea HPA-axis ho bolela esale pele ho khutlela kalafong e latelang.133,134 litlhare tse eketsang molumo oa HPA li ka ba molemo kalafong ea liithuti tse lemaletseng joala. Mohlala, bahanyetsi ba opioid naltrexone le nalmefene ba thibela phello ea inhibitory ea li-endorphin tsa endo native ho paraventricular corticotropin-releasing hormone (CRH),135,136 ka ho etsa joalo e eketseha corticotropin le cortisol. Bohanyetsi ba Opioid bo ka fokotsa ho khutla hape ka ho fokotsa khatello e amanang le joala e amanang le joala ea HPA, 'me ea baka khaello ea karabelo ea HPA-axis khatello ea maikutlo.
Ka kakaretso, likhakanyo tse 'ne tse akaretsang tsa dopaminergic le glutaminergic li hokahanya libaka tsa boko tse tsamaisang mohopolo oa maikutlo, takatso ea lithethefatsi, le karabelo ea khatello ea maikutlo le semelo sa mantlha sa ts'ebeliso ea lithethefatsi - ke hore VTA le NAc. Liketsahalo tsa extracellular synaptic li baka liphetoho tse kenelletseng tse ka bakang ho phehella ha lithahasello tse amanang le lithethefatsi nako e telele kamora ts'ebeliso ea lithethefatsi li felile. Lisosa tsa ho khutla ha lithethefatsi hape le litloaelo tse amanang le tsona tse eketsehileng le tse amanang le tsona li fana ka maikutlo a hore ho kenella ha lithethefatsi bakeng sa phallo ea lithethefatsi ho tlameha ho kena lipakeng tsa mekhahlelo e mengata ea neuronal, mohlomong ho lebisa lits'ebetsong tse ikhethang tsa linaha tse tsamaeang ka bomong.
DITLHAKISO TSA BOTSOALLE TSA BOPHELO BONOLO
Khokahano e qobelloang ea lithethefatsi e ke ke ea ikarabella ka botlalo bakeng sa ho khutlela hape. Leha ho na le takatso e sa feleng ea joala kapa lithethefatsi, karolo e kholo ea bakuli ba lemaletseng lithethefatsi e lula e le batsi bophelo bohle ba bona. Ho oela hape hape, litakatso tse entsoeng ke 'nete, menahano e shebelletseng, le ho khutlela ts'ebeliso ea lithethefatsi kamora liketsahalo tse bohloko li ka ts'oaroa ke taolo e matla ea taolo holim a mmuso o qobelloang ho khanna. Khaello ea thibelo ea thibelo (ke hore, ho qobella), leha ho le joalo, e ka fana ka fensetere eo ho eona lithethefatsi li ka itlhalosang. Le ha ho se na drive e qobelloang ea lithethefatsi, ho ba sieo ha taolo ea thibelo ho ka lebisa tšebeliso e mpe ea lithethefatsi (bona. Setšoantšo sa 2). Ho ba sieo ha thibelo ea thibelo lithutong tse lemaletseng ho bonoa mehatong e lekantsoeng le ea liteko tsa ts'ebetso ea maikutlo le ho nka liqeto,137-142 ho senola bofokoli ba bokhoni ba lithuto tse lemalloang ka bobeli ho thibela likarabo pele (kapa ka mokhoa o hlophisitsoeng ka matla)137 le ho khetha meputso e liehang ho feta e potlana ho feta e potlakileng.138,141,142
OFC e nka karolo ka botebo ho lekola boteng ba meputso le likotlo tse ka bang teng (ka mantsoe a phahameng, moputso o tlase oa chelete, phaello e potlakileng ea ho lieha, lintho tse ts'oanang kapa tse sa lumellaneng) 'me e nka karolo ho susumetseng le ho etseng liqeto. Bakuli ba nang le marapo a OFC, ka mohlala, ba etsa liqeto tse sa tsotelleng le tse sa potlakeloang, leha ho le joalo, bokhoni ba bona ba kelello — bo kang ho hopola, ho ithuta, puo le tlhokomelo — bo lula bo bolokiloe. Ka kakaretso, ho bonahala eka ho na le tiisetso ea boitšoaro, e tsoelang pele ho araba maikutlo a seng a sa putse; phetoho ea maemo a tšebeliso ea matlafatso ha e fetole likarabo tsa boits'oaro.143 Mohlala, lithuto tse nang le mabala a OFC li sebetsa hampe mosebetsing oa Papali ea Chelete,144 e etsisang liphihlelo tsa sebele tsa bophelo tse kenyelletsang ho hloka botsitso, moputso le kotlo. Bafuputsi ba 'maloa ba bontšitse hore batho ba lemaletseng lithethefatsi le lithethefatsi ha ba sebetse hantle mosebetsing ona.142,145,146 Karolo e 'ngoe ea bohlokoa e kenyang thibelo ea thibelo ea bokhoni ke cingrate e ka ntle, e lekang ts'ebetso, e ts'oanang likhohlano le ho lekola boitšoaro. Ts'ebetso ho mosebetsi oa papali ea papali ea chelete e hokahane haholo le ho phomola rCBF ea cingulate ea kantle.147
U sebelisa mekhoa ea ho nahana ka PET, Volkow le basebetsi-'moho ba bontšitse khokahano e matla lipakeng tsa nomoro ea li-receptor ea DriNUMX ea strior le tšebeliso ea matla ea OFC le cingrate ea anterior ho cocaine-36 le lithethefatsi tsa methamphetamine148 bakuli. Ha e theoha palo ea li-receptor tsa D2, e fokotsa mosebetsi oa OFC le cingulate ea anterior. Ho fokotseha ha basal OFC sebakeng sa phallo ea mali a khubung ea mali (rCBF) lithutong tse lemalloang ke koae, ho amanang le taolo, ho netefalitsoe laboratoring ea rona ho sebelisa mekhoa ea ho nahana ea SPECT (bona Setšoantšo sa 3).113 Khokahano lipakeng tsa nomoro ea li-receptor ea D2 le OFC le mesebetsi ea nakoana ea cingrate e tlalehiloeng ke Volkow le basebetsi mmoho36,148 e ka fana ka maikutlo a khokahano ea neurobiologic lipakeng tsa mmuso o qobellehang oa ho khanna le bofokoli ba inhibitory bo amanang le bokhoba ba lithethefatsi. Kahoo, phetoho e ts'oanang tseleng ea mesocortical e kanna ea hlahisa taolo ea thibelo e sa senyeheng (ka lebaka la phokotso ea mesocortical ho PFC) ka takatso e matla ea ts'usumetso e bakoang ke lithethefatsi (ka lebaka la karabelo e tlatselletsang ho litlatsetso tsa tlhaho tse amanang le phokotso ea striatal Li-receptor tsa D2).
Libaka tsa boko tse kenyang ts'ebetsong ea thibelo, haholo-holo OFC le cingulate ea ka ntle, e bile tsona mohopolo oa lithuto tse 'maloa tse nang le mathata a ts'ebeliso ea lithethefatsi. Joalokaha ho boletsoe kaholimo, lithuto tsa PET le SPECT li bonts'itse koae eo,36,113 joala-,149 le lithethefatsi tsa methamphetamine150 lithuto li bonts'a mosebetsi oa basal o fokotsehileng oa OFC. Nakong ea mosebetsi oa ho kenella oa Stroop, e lekolang bokhoni ba ho thibela karabo ea pele (ke hore, inhibition reaction), kamano lipakeng tsa ts'ebetso ea mosebetsi le ts'ebetso ea OFC e sitisoa lithutong tse lemaletseng joala.161 Activation ea OFC, joalo ka ha e lekantsoe ke fMRI, e boetse e chenchiloe mosebetsing oa ho etsa liqeto lithutong tse lemaletseng lithethefatsi tsa methamphetamine.152 Cingrate ea ka ntle e bonts'a ts'ebetso e fokotsehile ts'ebetsong lithutong tse lemaletseng nakong ea mosebetsi oa ho itšireletsa,153 Tsamaiso ea thepa113,154 le tlhahiso ea khatello ea kelello e tataisoang ke mongolo.155 Ts'ebetso e fosahetseng ea OFC156,157 le mokokotlo oa ka ntle, haholoholo ka ho arabela mesebetsing ea kelello e kenyang ts'ebetso ea ts'ebetso kapa ho etsa liqeto, e fana ka maikutlo a hore likarolo tsena tsa boko li ka nka karolo ho se khone ho lemalla ha motho ea lemaletseng ho thibela ts'ebetso hape hore e se ke ea khutla.
THECC le cingulate ea ka ntle le eona e bapala karolo e hlahelletseng menahanong e bohlasoa le litakatsong tse hlalositsoeng pejana. Leha ho le joalo, athe libaka tsena tsa boko li bonts'a ts'ebetso e eketsehileng ea ts'ebetso ea boko (ho amana le taolo) nakong ea takatso ea ho kenella, ka kakaretso li bonts'a ts'ebetso e fokotsehileng (e amanang le taolo) nakong ea mesebetsi e meng e sebetsang (bona ka holimo). Liphumano tsena li fana ka maikutlo a hore tsela ea mesocorticolimbic ha e sebetse ka nepo litabatabelo tse amanang le lithethefatsi kapa maikutlo, empa e na le boikemelo ho lithahasello tse amanang le lithethefatsi.
LITLHAKISO TSA HO FIHLA: TLHOKOMELISO EA BOPHELO
Tlhahlobo ena e hlalositse ts'ebetso e tsoelang pele ea ts'ebeliso ea lithethefatsi tsa neurobiologic tlas'a ts'ebetso e sa laoleheng ea lithethefatsi, e shebile karolo e ikhethileng eo dopamine e e phethang moputsong le bokhobeng. Morero oa mantlha oa boiteko bona ke ho tataisa nts'etsopele ea meriana bakeng sa mafu a lemallo. Ho boletsoe liphofu tse 'maloa tsa morero,' me ho bile le ts'ebetso e tsepamisitsoeng holim'a li-receptor tsa dopaminergic. Tlhahlobo e bonts'a bohlokoa ba tsela ea mesolimbic ho nts'etsopele ea temallo-eo ka hona e ka ba sebaka se nepahetseng sa ho kenella pele ts'ebetsong ea bokhoba. Bathong ba kotsing e kholo (ke hore, ba nang le mabaka a matla a liphatsa tsa lefutso kapa tikoloho bakeng sa nts'etsopele ea bothata ba tšebeliso ea lithethefatsi), meriana e sebelisanang le tsela ea mesolimbic ea ho fokotsa ts'ebetso ea litheko tsa lithethefatsi e kanna ea ipaka e le thuso joalo ka mohato oa thibelo. Ka lehlakoreng le leng, tabeng ea tšebeliso ea lithethefatsi tse pheta-phetoang tse nkang libaka tsa pele-tsela ea mesocortical e kanna ea ba sepheo se nepahetseng bakeng sa kalafo. Tlhahlobo e hlokomela bohlokoa bo lekanang ba mefuta e fapaneng ea lisosa, 'me e le mekhoa e ntlafalitsoeng ho arola mokhoa o ikhethileng oa ho khutlela morao oa mokuli ka mong, ho kenella ho kenelletseng ho (psychosocial and pharmacologic) ho ka lebisa ho ts'ebetso ea "neurotransmitter" e amanang le "neurotransmitter" le potoloho ea methapo ea methapo. Mohlala, bakuli ba lemaletseng lithethefatsi tse tlalehang karabelo e matla litabeng tse ikhethang ba ka arabela hantle litsing tsa khokahano ea amygdalar-mesolimbic, athe mokuli ea tšoailoeng e le mofetoheli ea sa tsubeng158 e ka hloka ts'ebetso e ntlafalitsoeng ea tšebetso ea orbitof Pambal kapa anterior cingrate - mohlomong ka ho matlafatsa tlhahiso ea dopaminergic. Ho qhekella genotypes ho lokela ho lebisa ho mokhoa oa thekiso ea meriana ho nts'etsopele ea lithethefatsi, ho fana ka kalafo e khethehileng ea lithethefatsi ho polymorphism e khethiloeng. Kamora nako, liphetoho tse fetotsoeng ke lithethefatsi ka poso,159 moromuwa, le liprotheine tse hatisang li fana ka mohopolo o khahlisang bakeng sa lipheo tsa meriana tsa nakong e tlang. Ntle le meriana e boletsoeng esale pele, li-dopaminergic agents tse ntseng li hlahlojoa hona joale li kenyelletsa vanoxerine,160,161 inhibitor ea nako e telele, e sa sebetsaneng le ea presynaptic DAT, le disulfiram, e thibelang dopamine-B-hydroxylase.162
Lisebelisoa tse ling tsa li-receptor li ikama ka kotloloho ho li-neurop tsa dopaminergic mme li fana ka menyetla e metle ea ho kenella ha pharmacologic. Joalokaha ho hlokometsoe pejana ho tlhahlobo, lithethefatsi tse ngata tsa tlhekefetso li na le kamano e phahameng le G protein-mediated kapa li-ion-receptor tse etsang hore ho lokolloe dopaminergic. Mekhoa e meng ea litlolo ea lithethefatsi ea lits'ebetso tsa li-receptor tsena li netefalitse ts'ebeliso e itseng kalafong ea lithethefatsi, 'me mekhoa e mecha e ntse e tsoela pele. Ka mohlala, Naltrexone e bonahala e fokotseha takatso ea joala163,164 ka ho thibela li-mu-opioid receptors tse hatellang li-neurons tsa GABAergic. Li-neuron tsena, ka lehlakoreng le leng, li thibela li-neurons tsa VTA dopaminergic.165 Ho ferekanya ha li-mu-opioid receptors ka hona ho fella ka ho thibeloa ha li-neurons tsa GABAergic, ho bakang ho fokotseha ho hoholo ha tokollo ea VTA DA. Barekisi ba opioid ba bonahala ba sena thuso e ngata, leha ho le joalo, ho lakatseng lintho tse ling, ho kenyeletsa le heroin. Baclofen, GABAB agonist ea morao-rao e thibelang ho lokolloa ha dopamine, e fokotsa boikemelo ba ho itaola lithutong tsa preclinical166 hape o bontšitse tšepiso ea pejana ea ho fokotsa tšebeliso ea koae lithutong tsa batho.167 Litlhahiso tsa pele tsa boiphihlelo ba bongaka bo sebetsang lithutong tse itšetlehileng ka koae li boetse li tlalehiloe ka vigabatrin, e leng khetho e sa fetoheng le e sa fetoheng ea GABA transaminase.168 Enadoline, e kopanyang li-receptor tsa kappa-opioid le e thibelang ho lokolloa ha DA, e bona litla-morao tsa boitšoaro le boitšoaro ba koaeine lithutong tsa pele le ho hlahlojoa bakeng sa liteko tsa batho.169 Topiramate ka bobeli e nolofalletsa ts'ebetso ea GABA ho sebelisa sebaka se seng sa benzodiazepine ho GABAA receptor le antagonizing mesebetsi ea glutamate ho alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) le li-receptor tsa kianate. Seteishene sena se bonts'itse katleho ho joala-170 le koae- koae171 lithuto. Glucocorticoid antagonists kapa agonists e ka ipaka e le thuso ka ho fetola litlamorao tse lumellang ho lokolloa ha mesolimbic DA, haholoholo nakong ea khatello ea maikutlo. Metyrapone, e thibelang motsoako oa cortisol, hajoale e ntse e hlahlojoa bakeng sa ho lemalla koae ka sethala sa liteko tsa kliniki I, leha khatello ea ts'ebetso ea HPA-axis ka ketoconazole e sa sebetse ho fokotsa tšebeliso ea koae.172 Joalokaha ho hlalositsoe pejana, leha ho le joalo, meriana e sebetsang, eseng e thibelang, ts'ebetso ea HPA-axis e ka ba molemo ho feta. Li-receptor tsa 5HT3 li ngata libakeng tse lipakeng tsa terminal tsa DA, joalo ka NAc le striatum, 'me li bonahala li loants'a phello ea thabo ea likhomphutha tse sebetsang ho nyoloha ho tsoa li-neuron tsa DA.173 Ho fetola phetisetso ea 5HT3 le 5HT3 antagonist ondansetron inhibits sensitization cocaine-induction,174 e fokotse tšebeliso ea joala lithutong tse itšetlehileng ka joala pele ho nako.175 mme e ntse e hlahlojoa mohatong oa liteko tsa bongaka tsa karolo ea II bakeng sa ts'ebeliso ea koae.176 Cannabinoids activate mesolimbic DA ka li-receptor tsa CB1, 'me rimonabant ea CB1 receptor antagonist rimonabant e fokotsa ho khutlisoa ha koae.177 Le ha DA e eketsa takatso ea takatso ea lijo, boikoetliso ba limela tsa cholinergic bo thibela boitšoaro ba takatso le ho eketsa boits'oaro.178 Matlafatso ea Boitšoaro ka hona e 'nile ea bonoa e le tekano lipakeng tsa NAc DA le tsamaiso ea cholinergic179-O fetotsoe, bonyane ka karolo, ke li-interneurons tsa cholinergic tse ka hare ho NAc. Boithuto ba preclinical bo bonts'itse phello e thibelang baetsi ba likoloto tsa cholinergic mabapi le ho itaola.180,181 Ibogaine, e leng indole alkaloid ka tlhaho, e tlama ho kappa-opioid, NMDA glutamate, le li-nicotinic receptors, mme e thibela polelo ea NAc DA liphoofolong tse lemosang koae.182 Ibogaine e bontšitsoe hore e fokotsa cocaine, ethanol, morphine, le boithamollo ba nicotine mefuteng ea liphoofolo,183 le bopaki bo bongata ba anecdotal bo bonts'a hore lithethefatsi tsena li na le katleho ea kalafo kalafong ea koae le ho lemeng ha heroine.184 Tse 'maloa tsa mekhoa ena e mecha li ntse li shebane le Setsi sa Naha sa Teko ea Tlhabollo ea Dithethefatsi.176
Phihlelo ea mafu a mang a sa foleng a bongaka le a kelello, a joalo ka khatello ea maikutlo, lefu la sethoathoa, khatello ea maikutlo le lefu la kelello, le fana ka maikutlo a hore ho tla hlokahala liphekolo tse ngata tsa kalafo bakeng sa kalafo e atlehileng ea batho ba bangata ba lemaletseng. Litlhare tse lebisang lits'ebetso tse ngata tsa receptor 'me li etselitsoe litšobotsi tse ikhethileng tsa motho ea khutlang, genotype le ho lemalla tlatsetso e ka ba tšebeliso e nepahetseng ha nts'etsopele ea meriana e ntse e tsoela pele.
Mongolo o botlaaseng ba leqephe
Litokisetso tsa buka ena e ngotsoeng ka letsoho li ile tsa tšehetsoa ke Setsi sa Naha mabapi le Thibelo ea Ts'ebeliso e Mpe ea Lithethefatsi. DA11434 le Setsi sa Naha sa Ts'ebeliso e Mpe ea Joala le Tahi ha se fe. AA1570.
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