Dopamine Tlhekefetsong ea lithethefatsi le ho lemalla lithethefatsi: Litholoana tsa Lithuto tsa ho Nahana le Tlhahlobo ea Phekolo (2007)

Dopamine (DA) ke neurotransmitter e 'nileng ea amahanngoa le litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso mme e kanna ea ba le karolo ea bohlokoa ho bakang liphetoho tsa neurobiological tse amanang le bokhoba. Khopolo ena e bonts'a 'nete ea hore lithethefatsi tsohle tsa tlhekefetso li eketsa khatello ea kholo ea DA ho li-nucleus accumbens. Keketseho mecheng ea DA e na le karolo ea bohlokoa ho bokeng moputso le ponelopele ea moputso, ts'ebetsong ea sepheo sa ho fumana moputso, le ho thusa ho ithuta.¹ Ho boetse ho lumeloa hore likhoutu tsa DA eseng feela bakeng sa moputso empa bakeng sa boselamose, boo, ntle le moputso, bo kenyelletsang maikutlo, pale, le sepheo se sa lebelloang. Phapang ea litlamorao tsa DA e kanna ea fetoleloa ke likarolo tse ikhethileng tsa boko (limbic, cortical, and striatal) eo li e fetolang.

Mona, re akaretsa lintlha tse fumanoeng ho tsoa lipatlisisong tsa monahano tse sebelisang positron emission tomography (PET) ho lekola karolo ea DA litlamorao tse matlafatsang tsa lithethefatsi, liphetoho tsa bongoana tsa nako e telele lithutong tse lemaletseng lithethefatsi, le ho ba tsietsing ea ho lemalla. Leha lithuto tse ngata tsa PET tsa bokhoba ba tahi li tsepamisitse maikutlo ho DA, ho hlakile hore litheko tsa lithethefatsi tse tsoang ho li-neurotransmitters tse ling (ke hore, glutamate, γ-aminobutyric acid, opioids, le cannabinoids) le tsona li kentse letsoho, empa ho haella ha li-radioligands ho lekane. lipatlisiso tsa bona.

Litlamorao tsa ho pepesetsoa ha lithethefatsi ka nako e khuts'oane likelellong tsa DA bokong ba motho li ka ithutoa ho sebelisoa PET le D2 DA receptor radioactive ligands tse ts'oarellang tlholisano le endo native DA, joalo ka raclopride e ngotsoeng le carbon 11 (¹¹C). Kamano lipakeng tsa litlamorao tsa lithethefatsi ho DA le thepa ea tsona e matlafatsang bokong ba motho (e lekotsoe ke litlaleho tsa "high" le "euphoria") e ithutile bakeng sa lithethefatsi tse matlafatsang methylphenidate le amphetamine. Methylphenidate, joalo ka koae, e eketsa DA ka ho thibela batsamaisi ba DA, athe amphetamine, joalo ka methamphetamine, e phahamisa DA ka ho e lokolla ho terminal ka batsamaisi ba DA. Intravenous methylphenidate (0.5 mg / kg) le amphetamine (0.3 mg / kg) e ekelitse khatello ea kantle ea DA le DA ka har'a striatum, mme keketseho ena e ne e amana le keketseho ea litlaleho tsa boits'oaro tse phahameng le tse kholo.² Ka lehlakoreng le leng, ha e fanoa ka molomo, methylphenidate (0.75-1 mg / kg) le eona e ile ea eketseha DA empa e ne e sa nkuoe e le e matlafatsang.³ Hobane tsamaiso ea methapo e lebisa ho liphetoho tse potlakileng ho DA, athe tsamaiso ea molomo e eketsa DA butle, ho sitoa ho boloka tse phahameng ka methylphenidate ea molomo e kanna ea bonts'a pharmacokinetics ea eona e liehang. Ka sebele lebelo leo lithethefatsi tsa tlhekefetso li kenang bokong li amoheloa e le tse amang litlamorao tsa tsona.⁴ Mokhatlo ona o boetse o bontšitsoe lithutong tsa PET tse ileng tsa lekola pharmacokinetics of cocaine (ba sebelisa [¹¹C] cocaine) le MP (ba sebelisa [¹¹C] methylphenidate) bokong ba motho, e tlaleha hore ke ho ts'oaroa ha lithethefatsi kapele ho bokong empa eseng khatello ea kelello ka karolo e 'ngoe e neng e amana le ho phahama.⁵ Ho itšetleha ka litlamorao tse matlafatsang tsa lithethefatsi mokhoeng oa meriana ea bok'hemik'hale ho fana ka maikutlo a kamano e ka bang teng le phasic DA cell (ho thunya ka potlako masimong> 30 Hz), e lebisang liphetohong tse potlakileng mahlorisong a DA mme mosebetsi oa ona ke ho totobatsa botsitso ea tšusumetso.⁶ Sena se fapane le ho thunngoa ha sele ka selefounu (ho thunya butle ha 5 Hz), e bolokang maemo a DA a tsitsitseng mme ts'ebetso ea ona e le ho beha karabelo ea tsamaiso ea DA ka kakaretso. Sena se re lebisitse ho nahana hore lithethefatsi tsa tlhekefetso li baka liphetoho mokhoeng oa DA tse etsisang empa li fetisa tse hlahisoang ke ho hlaseloa ha sele ea DA ka phasic.

Keketseho ea Synaptic mokhatlong oa DA e ba teng nakong ea taolo ea lithethefatsi lithutong tse lemalloang le tse seng litlamong. Leha ho le joalo, ho khanna ka thata ho tsoelapele ho sebelisa lithethefatsi ha o pepesehetse lithethefatsi ha ho qobelloe lithutong tsohle. Le ha e le tahlehelo ea taolo le tšebeliso e mpe ea lithethefatsi tse supang bokhoba, keketseho ea nako e khuts'oane ea lithethefatsi ea nakoana ea DA e ke ke ea hlalosa boemo bona. Hobane tšebeliso ea lithethefatsi e hloka taolo ea lithethefatsi ea nako e telele, re fana ka maikutlo a hore ho batho ba tlokotsing (ka lebaka la liphatsa tsa lefutso, nts'etsopele, kapa maemo a tikoloho), ts'ebeliso ea lithethefatsi e amana le tšitiso e pheta-phetoang ea li-circuits tsa boko tse laoloang ke DA tse amehang ka moputso / boits'oaro, ho susumetsa / ho khanna. , inhibitory control / Ts'ebetso ea botsamaisi, le mohopolo / maemo. Mona, re tšohla liphumano tse tsoang lipatlisisong tsa ho nahana ka mofuta oa liphetoho tsena.

Matšoao a mangata a radio radio a sebelisitsoe ho lekola liphetoho lipakaneng tse amehang ho tšebetso ea methapo ea methapo ea DA (Lethathamo 1). U sebelisa 18-N-methylspiroperidol kapa [¹¹C] raclopride, rona le ba bang re bonts'itse hore lithuto tse nang le lithethefatsi tse ngata tse fapaneng tsa koae (cocaine, heroin, joala le methamphetamine) li na le phokotso e kholo ho fumaneheng ha D2 DA receptor ho striatum (ho kenyelletsa le ventral striatum) e phehellang likhoeli kamora hore e fete phetisetso (e hlahlobetsoe ho Volkow et al²). Re boetse re senotse bopaki ba tšebetso e fokotsehileng ea lisele tsa DA ho batho ba hlekefetsang koae. Ka ho khetheha, re bonts'itse hore keketseho e kholo ea boemo ba DA e hlahisoang ke methylphenidate e kenelletseng (e lekantsoeng le [¹¹C] raclopride) ho batho ba hlekefetsang koae ba ile ba hlakoloa haholo ha ba bapisoa le keketseho ea boemo ba DA lithutong tsa taolo (50% tlase).⁷ Hobane khatello ea DA e eketsoa ke methylphenidate e its'epahalla ho lokolloa ha DA, e leng ts'ebetso ea ho ts'oaroa ha lisele tsa DA, re re mohlomong phapang ena e ka fokolisa ts'ebetso ea sele ea DA ho bahleketsi ba koae. Ho fumanoe liphihlelo tse tšoanang ho ba sebelisang joala hampe.⁸

Lithuto tsena tse nahanang ka kelello li fana ka maikutlo a tlhekefetso ea 2 lithutong tse lemalloang tse ka lebisang ho fokotseheng ha liphetho tsa lipotoloho tsa DA tse amanang le moputso; ke hore, e fokotseha ho li-receptors tsa D2 tsa DA mme e fokotseha ho lokolloe ha DA ho striatum (ho kenyelletsa le li-nucleus accumbens). E mong le e mong o ne a tla kenya letsoho ho fokotseng kutloelo-bohloko lithutong tse lemaletseng ho ba matlafatsang ba tlhaho. Hobane lithethefatsi li na le tšusumetso e matla ho susumetsang liteishene tsa meputso tse laoloang ke DA ho feta li-feminse tsa tlhaho, re phatlalalitse hore lithethefatsi li ntse li khona ho kenya tšebetsong likhakanyo tsa moputso tse laoloang ka tlase. Boikutlo bo fokotsehileng ba liserekisi tsa meputso li ka lebisa ho fokotseha hoa thahasello ea tikoloho ea letsatsi le letsatsi, mohlomong li ka etsa hore lithuto li fuoe ka mokhoa oa nakoana bakeng sa li-circuits tsa meputso tse tlasa phetoho ea ho sebelisa lithethefatsi ho ikutloa li le holimo ho li nka hore li utloe. tloaelehileng.

Boithuto ba preclinical bo bonts'itse karolo e hlahelletseng ea DA molemong oa ho khothaletsa ho bonahala e le karolo pakeng ka potoloho e laoloang ke DA e amanang le orbitofrontal cortex (OFC) le anterior cingulate gyrus (CG).⁹ Boithutong ba lipono lithutong tsa batho ba sebelisang radioactive tracer fludeoxyglucose F 18, rona le ba bang re bontšitse tšebetso e fokotsehileng ho OFC le CG litlelaseng tse fapaneng tsa lithuto tse lemaletseng (ho hlahlojoa Volkow et al²). Ho feta moo, lithutong tse lemaletseng lithethefatsi tsa cocaine- le methamphetamine, re bonts'itse hore ts'ebetso e fokotsehileng ho OFC le CG e amana le ho fokotseha hoa fumaneha ha li-receptor tsa D2 DA ho striatum (e hlahlojoa Volkow et al⁷) (Figure). Hobane OFC le CG ba nka karolo kabelong ea boleng ba matlafatso e le ts'ebetso ea maemo, tšitiso ea bona ho motho ea hlekefetsang e ka kena-kenana le bokhoni ba bona ba ho fetola boleng ba sethethefatsi e le ts'ebetso ea litlatsetso tse ling, e ba mokhoa o ka sehloohong o susumetsang boitšoaro . Ho fapana le sebopeho sa tšebetso e fokotsehileng ea OFC le CG ha e sa sebelisoe ke lithethefatsi, lithuto tse lemalloang li bonts'a ts'ebetso e eketsehang libakeng tsena ha e hlahisoa le tšusumetso e amanang le lithethefatsi, e lumellanang le litekanyetso tse ntlafalitsoeng tsa lithethefatsi kapa litlatsetso tsa lithethefatsi lithutong tsena. Ho feta moo, ts'ebetso e ntlafalitsoeng ea OFC le CG e ne e amana le botebo ba takatso ea lithethefatsi. Sena se re lebisitse ho hakanya hore hypermetabolism ho OFC le CG e bakoa ke lithethefatsi kapa litheko tsa lithethefatsi tse tlatsetsang ts'ebetsong ea lithethefatsi tse tlatselletsang, joalo ka ha e baka boitšoaro bo qobelloang ho bakuli ba nang le mathata a ho shebahala habonolo.¹⁰ Matla ana a mabeli a ho sitisoa ha ts'ebetso ea boko ba OFC-CG a tsamaisana le boitšoaro ba motho ea lemaletseng lithethefatsi, eo ho qobelloa ha hae ho sebelisa lithethefatsi ho tlisoang ke litekanyetso tsa tlhalohanyo tse thehiloeng ho kelello tsa ho se sebelise lithethefatsi; feela joalo ka ho bakuli ba nang le mathata a ho sheba lintho habonolo, ho qobelloa ho phehella le ha ba leka ho emisa boitšoaro.

CG le OFC li ameha le taolo ea thibelo, e ileng ea re lebisa ho phatlalatso e ileng ea sitisa modumo ea DA ea OFC le CG hape e kenya letsoho tahlehelong ea taolo ea tahi ea lithethefatsi ke lithuto tse lemaletseng lithethefatsi.¹⁰ Taolo ea inhibitory e boetse e itšetlehile ka cortex ea dorsolateral prefrontal, e amehang hape le ts'ebelisong (e hlahlojoa Volkow et al²). Ts'ebetso e sa tloaelehang kahare ho dorsolateral preortal cortex e lebelletsoe ho ama lits'ebetso tse amehang taolong e kholo ho kenyelletsa ho senyeha ha boits'oaro le taolo ea boits'oaro, e nang le karolo ea bohlokoa phetohong ea kelello e ntlafatsang tsamaiso ea lithethefatsi.¹⁰

Li-circuits tse tlasa mohopolo le ho ithuta, ho kenyelletsa ho ithuta ka tšusumetso, ho ithuta ka tloaelo, le mohopolo o fokolisang (o hlahlobetsoe Vanderschuren le Everitt¹¹), ho entsoe tlhahiso ea ho ba le karolo tšebelisong ea lithethefatsi. Litlamorao tsa lithethefatsi tsamaisong ea memori li fana ka maikutlo a hore mekhoa e sa nke lehlakore e ka fumanang thepa e matlafatsang le litšusumetso tse matla, ke hore, ka ho ithuta ka mokhoa o khothalletsoang. Ha ho etsoa lipatlisiso mabapi le ho oela hape, ho bile bohlokoa ho utloisisa hore na hobaneng batho ba lemaletseng lithethefatsi ba nang le lithethefatsi ba ba le takatso e matla ea lithethefatsi ha ba pepesetsoa libaka tseo ba nkileng lithethefatsi ho tsona, ho batho bao tšebeliso ea lithethefatsi li etsahetseng ho bona le tse ling tse sebelisitsoeng ho tsamaisa lithethefatsi. lithethefatsi. Sena se bohlokoa molemong oa ho pepesehela litheko tse nang le maemo (tšusumetso e amanang le moriana ona) ke ona o kenyang letsoho hore motho a boele a oele hape. Hobane DA e kenelletse ho phatlalatseng moputso (e shebiloe ho Schultz⁹), re fane ka maikutlo a hore DA e kanna ea fana ka likarabo tse etsang hore motho a lakatsoe. Boithuto liphoofolong tsa liphoofolo tse sebelisang maiketsetso bo ts'ehetsa maikutlo ana: ha maikutlo a ho se nke lehlakore a kopantsoe le lithethefatsi, ba tla fumana bokhoni ba ho eketsa DA maemong a bokellaneng a methapo le dorsal striatum, e be maemo a loketseng. Ho feta moo, likarabo tsena tsa methapo ea kutlo li amahanngoa le boitšoaro ba ho batla lithethefatsi (bo hlahlobetsoe Vanderschuren le Everitt¹¹). Bathong ba batho, lithuto tsa PET le [¹¹C] raclopride haufinyane e netefalitse khopolo ena ka ho bonts'a hore, ho batho ba hlekefetsang koae, koae ea lithethefatsi (video ea cocaine-cue ea litšoantšo tsa lithuto tse nkang cocaine) e ile ea eketsa haholo DA ho dorsal striatum le hore keketseho ena e ne e amana le ho lakatsa koae.^12- 13 Hobane dorsal striatum e bohlokoa mokhoeng oa ho ithuta tloaelo, tloaelo ena e ka bonts'a ntlafatso ea litloaelo ha bokhoba ba ho lemalla bo ntse bo tsoela pele. Sena se fana ka maikutlo a hore tšitiso ea mantlha ea ts'ebeliso ea lithethefatsi ho tsoa bokhobeng e ka ba karabelo ea maemo a DA e hlahisang litloaelo tse lebisang ho ts'ebeliso e mpe ea lithethefatsi. Ho kanna ha likarabo tsena tse maemong a matle li bonts'a liphetoho lipakeng tsa litsela tsa corticostriatal glutamatergic tse laoloang ho lokolloa ha DA (ho hlahlojoa Vanderschuren le Everitt¹¹).

Potso e phephetsang ho neurobiology ea ts'ebeliso e mpe ea lithethefatsi ke hore na hobaneng batho ba bang ba hlaseleha habonolo ho feta ba bang ho lemalla lithethefatsi. Liphuputso tse entsoeng li bontša hore phapang e atileng haholo makaleng a DA e ka ba mochini o le mong o tlatsetsang ho fapana hoa karabelo litabeng tsa lithethefatsi tsa tlhekefetso. Ka ho khetheha, mehato ea motheo ea li-striatal tsa D2 tsa DA lithutong tse sa hlokeng molao li bontšitsoe ho bolela likarabo tse tlatselletsang liphellong tse matlafatsang tsa kalafo ea methylphenidate ea methapo; batho ba hlalosang boiphihlelo bona e le bo khahlisang ba ne ba le maemo a tlase haholo a li-receptor tsa D2 DA ha li bapisoa le tse hlalosang methylphenidate e le tse sa thabiseng (e hlahlojoe Volkow et al⁷). Sena se fana ka maikutlo a hore kamano lipakeng tsa mekha ea DA le likarabo tse matlafatsang li latela tsela e potiloeng e nang le sebopeho sa U: e nyane haholo ha e na matla a ho matlafatsa empa e ngata haholo e ka fokolisang. Kahoo, maemo a phahameng a li-receptor tsa D2 DA a ka itšireletsa khahlanong le ts'ebetso ea lithethefatsi. Ts'ehetso ea sena e fanoe ke lithuto tsa pele ho tsa morao-rao tse bonts'ang hore melaoana ea li-receptor tsa D2 DA ka har'a nucleus e fokotsa haholo tšebeliso ea joala ho liphoofolo tse neng li koetliselitsoe ho itlopa joala.¹⁴ le ka lithuto tsa tliliniki tse bonts'ang hore lithuto bao, leha ba ne ba na le nalane e matla ea lelapa ea joala, e ne e se lino tse tahang ba ne ba e-na le li-receptor tse phahameng tsa D2 DA striatum ha li bapisoa le batho ba se nang nalane ea malapa a joalo.¹⁵ Lithutong tsena, li-receptor tse phahameng tsa D2 DA li phahamela metabolism ho OFC le CG. Kahoo, re tiisa hore maemo a phahameng a li-receptor tsa D2 DA a ka itšireletsa khahlanong le joala ka ho feto-fetola lipotoloho tse ka pele tse kenyellelitsoeng ho sesiti sifa le taolo ea thibelo.

Lithuto tse entsoeng ka ho qhekella li ntlafalitse karolo ea DA litlamorao tse matlafatsang tsa lithethefatsi tsa tlhekefetso bathong mme li atolositse maikutlo a setso a ho nka karolo ha DA ho lemalleng lithethefatsi. Liphumano tsena li bonts'a maano a multicomponent bakeng sa kalafo ea ho lemalla lithethefatsi tse kenyeletsang maano a (1) ho fokotsa boleng ba moputso oa lithethefatsi tsa khetho le ho eketsa boleng ba moputso oa litlatsetso tsa nondrug, (2) e fokolisa boits'oaro ba lithethefatsi, (3) e fokolisa tšusumetso khanna ho nka sethethefatsi sena, mme (4) matlafatsa matlafatsa inhibitory le taolo e phahameng (Lethathamo 2).

Lengolo: Nora D. Volkow, MD, Setsi sa Naha sa Tlhekefetso ea Lithethefatsi, 6001 Executive Blvd, Kamore ea 5274-MSC 9581, Bethesda, MD 20892 ([imeile e sirelelitsoe]).

E amoheloa bakeng sa phatlalatso: January 17, 2007.

Menehelo ea Mongoli:Mohopolo oa ho ithuta le moralo: Volkow. Ho fumana data: Volkow, Wang, Swanson, le Telang. Tlhahlobo le tlhaiso-leseling: Volkow, Fowler, Wang le Telang. Moralo oa buka e ngotsoeng ka letsoho: Volkow le Swanson. Phetoho e matla ea buka e ngotsoeng ka letsoho bakeng sa litaba tsa bohlokoa tsa mahlale: Volkow, Fowler, Wang, Swanson le Telang. Tlhahlobo ea statistical: Volkow. Fumana chelete: Volkow, Fowler, le Wang. Ts'ehetso ho tsa tsamaiso, botekgeniki le thekeng: Volkow, Fowler, Wang le Telang. Tsamaiso ea ho ithuta: Volkow, Wang le Telang.

Phatlalatso ea Lichelete: Ha ho tlaleho.

Lithuso / Tšehetso: Boithuto bona bo tšehelitsoe karolo e 'ngoe ke lenaneo la Intramural la National Institute on Alcohol Abuse and Alcoholism; lithuso tsa DA 06891, DA 09490, DA 06278, le AA 09481 ho tsoa ho Likolo tsa Naha tsa Bophelo; le Lefapha la Matla la Amerika, Ofisi ea Patlisiso ea Tlhaho le Tikoloho.