Caffeine e eketsa ho hlaseloa ha dopamine ea D2 / D3 ho fumanoa ha boko ba motho (2015)

Tlhaloso: Phetolelo ea Psychiatry (2015) 5, e549; Doi: 10.1038 / tp.2015.46

E phatlalalitsoe marang-rang ka la 14 Mmesa 2015

ND Volkow1, GJ Wang1, J Logan2, D Alexoff2, JS Fowler2, PK Thanos2, C Wong1, V Casado3, S Ferre4 le D Tomasi1

  1. 1Lenaneo la Patlisiso la Intramural, Setsi sa Naha sa Ts'ebeliso e Mpe ea Joala le Tahi, Bethesda, MD, USA
  2. 2Brookhaven National Laboratory, Upton, NY, USA
  3. 3Lefapha la Biochemistry le Molek'hule ea Biology, Univesithi ea Barcelona, ​​Barcelona, ​​Spain
  4. 4Lenaneo la Patlisiso la Intramural, Setsi sa Naha sa Tlhekefetso ea Lithethefatsi, Baltimore, MD, USA

Sengoloa: Ngaka ND Volkow, Lenaneo la Lipatlisiso la Intramural, Setsi sa Naha sa Tlhekefetso ea Lithethefatsi, 6001 Executive Boulevard, Kamore ea 5274, Bethesda, MD 20892, USA. Lengolo-tsoibila: [imeile e sirelelitsoe]

E amohetse 29 December 2014; E amohetse 10 Hlakola 2015

Ka holimo ho leqephe

inahaneloang

Caffeine, e leng ntho e rekisoang ka ho fetisisa lefatšeng e sebelisang kelello, e sebelisetsoa ho khothaletsa ho falimeha le ho ntlafatsa tlhokomeliso. Joalo ka lithethefatsi tse ling tse khothatsang (li-stimulants le modafinil), koae e ntlafatsa ho supa ha dopamine (DA) bokong, eo e e etsang haholo-holo ka ho hanyetsa adenosine A2A li-receptors (A2AR). Leha ho le joalo, ha ho hlake hore na caffeine, ho litekanyetso tse jeoang ke batho, e eketsa tokollo ea DA kapa hore na e fetola mesebetsi ea li-receptors tsa DA tsa postynaptic ka tšebelisano ea eona le li-adenosine receptors, tse li fetolang. Re sebelisitse positron emission tomography le [11C] raclopride (DA D2/D3 receptor radioligand sensative to endo native DA) ho lekola hore na caffeine e eketse tlhahiso ea DA ho striatum taolong e phetseng hantle ea 20. Caffeine (300 mg po) e atolositse haholo ho fumaneha ha D2/D3 li-receptors ka putamen le ventral striatum, empa eseng ho caudate, ha li bapisoa le placebo. Ntle le moo, keketseho e bakiloeng ke caffeine ho D2/D3 ho fumaneha ha li-receptor ka har'a ventral striatum ho ne ho amahanngoa le keketseho e bakiloeng ke caffeine. Seo re se fumaneng se bontša hore bokong ba motho, caffeine, ka tekanyetso e tloaelehileng e nooang, e eketsa phumaneho ea DA D2/D3 li-receptors, tse bonts'ang hore caffeine ha e eketse DA ho striatum bakeng sa sena e kanna ea fokotseha D2/D3 ho fumaneha ha receptor. Sebakeng seo, re toloka liphetho tsa rona ho bonts'a keketseho ea D2/D3 maemo a receptor ho striatum le caffeine (kapa liphetoho ho tumellanong). Kamano lipakeng tsa keketseho ho D2/D3 ho fumaneha ha "receptor" kahare ho ts'ebetso ea bohlasoa le ho falimeha ho fana ka maikutlo a hore caffeine e ka ntlafatsa tsoekere, ka karolo e 'ngoe, ka ho emisa D.2/D3 li-receptors.

Ka holimo ho leqephe

Selelekela

Caffeine ke ntho e sebelisoang ka ho fetisisa kelellong e sebelisoang ka ho fetisisa kelellong.1 Litlamorao tsa eona tse tsosang takatso ea litlhare li tšoana le tsa lithethefatsi tse susumetsang (amphetamine le methylphenidate) le modafinil, e leng lithethefatsi tse eketsang dopamine (DA) ho supa ka ho thibela batsamaisi ba DA le / kapa ho ntlafatsa tokollo ea DA litsing.2, 3, 4 Litlamorao tse matlafatsang tsa DA tsa lithethefatsi tsena lia hlohlelletsa5, 6 le litlamorao tsa ho matlafatsa.7, 8, 9, 10 Ho fapana le hoo, lithuto tsa preclinical li bonts'a hore litlamorao tsa k'hemik'hale ea caffeine li kopantsoe le ho hanyetsoa ha eona ke li-receptors tsa adenosine (A1 Le A2A likaroloana).11 Ka ho khetheha, mohanyetsi oa eona oa A2A li-receptors (A2AR) ho striatum e bile le tšusumetso ho litlamorao tsa eona tsa dopaminergic.12 Ka mokhoa o ts'oanang, keketseho e bakoang ke caffeine e eketseha mesebetsing ea locomotor13 hape o tsosa14 hlaha ekare e qhekelloa ke A2AR joalo ka ha ba le sieo ho A2ARice Knoutout, le khutsisa polelo ea A2AR ka RNA e nang le moriri o mokhuts'oane oa "nucleus" e bokellaneng e kena-kenana le litlamorao tsa koae ka ho tsoha ha hae.15

Striatum e bontša maemo a phahameng a A2AR moo ba kopanngoeng teng le postynaptic D2 li-receptors (D2R) ba etsa A2ARD2R li-heteromers.16, 17, 18 Ka tšebelisano le litumellano tsa adenosine inhibits D2R ho saena. Ka hona, ho li-neuron tsa striatal, A2AR agonists fokotseha D2R agonist e tlamang.19 Caffeine, ka ho thibela A2AR, e ka ntlafatsa DA ho supa ka D2R.20 Le ha e ne e qala ho phatlalatsoa hore monahano oa kofi ea adenosine A1 li-receptors li hlahisitse keketseho ea DA ho li-nucleus tse bokellaneng,21 tlhahiso ena e fumanoe feela ka mor'a tekanyetso e phahameng haholo ea koae 'me ha ea ka ea khahlisoa ke ba bang.22, 23 Ho feta moo, thuto ea ho nahana ka bokong le [11C] raclopride, e leng radioligand e qothisanang lehlokoa le DA bakeng sa ho tlama ho D2 le D3 li-receptors (D2/D3R), e bonts'itse hore caffeine ea molomo (200 mg) e ekelitse ho tlama ha eona ho striatum,24 e sa tsamaellaneng le keketseho ea DA. Leha ho le joalo, sampole e nyane ho tsoa thutong (n= 8) e thibela kakaretso ea eona. Kahoo, taba ea hore na "caffeine" e eketsa striatal DA le hore na ketso ea ts'ebetso efe bakeng sa litlamorao tsa k'hafeine bokong ba motho e lula e sa hlaka.

Ho lekola hore na k'hafeine e eketsa DA joang bokong ba motho, re sebelisitse positron emission tomography (PET) le [11C] raclopride25 mme a leka ho laola li-20 tse laolang bophelo bo botle hang ka placebo le hang ka kofi ea molomo. Tekanyetso ea kofi ea 300-mg ea caffeine e ile ea khethoa ho bontša tekanyo e tloaelehileng ea kofi ea likhabinete tsa 2-3 tsa kofi. Re ile ra kholoa hore caffeine e ke ke ea eketsa DA maemong, empa ho e-na le hoo e ne e tla ntlafatsa mats'oao a DA ka ho eketsa D2R.

Ka holimo ho leqephe

Lisebelisoa le mekhoa

Lihlooho

Phuputso ena e kenyelletsa taolo ea banna ba phetseng hantle ba 20 (38 ± 8 ea lilemo, index ea mmele 26 ± 3; lilemo tsa thuto 14 ± 2) e hapuoe ka lipapatso likoranteng tsa lehae. Mekhoa ea ho lelekoa e ne e kenyelletsa tšebeliso ea lino tse fetang tse peli tsa caffeine ka letsatsi, bokuli ba hona joale kapa bo fetileng ba kelello ka DSM IV ho kenyeletsoa bothata bofe kapa bofe ba tšebeliso ea lithethefatsi (batho ba tsubang); nalane ea nakong e fetileng kapa ea hona joale ea lefu la methapo, ea pelo kapa ea endocrinological; nalane ea ho sithabela hlooho ka lebaka la ho lahleheloa ke kelello ho feta 30 min; le bokuli ba hona joale ba bongaka. Ba 12 ba neng ba nkile karolo ba ile ba tlaleha hore ha ba noe kofi (kapa lino tse tahang), e mong o tlaleha senoelo se le seng ka letsatsi mme ba babeli ba tlaleha linoelo tse peli ka letsatsi. Ho ile ha fumanoa tumello e ngotsoeng ho tsoa lithutong tsohle mme lithuto li ile tsa hlahlojoa tsa ba tsa amoheloa ke Boto ea Institutional Review Board e Stony Brook University Medical Center.

Litlaleho tsa boithatelo le likala le methapo ea pelo

Ho ithuta ka litlamorao tsa boitšoaro ba kofi, re ile ra itlhahloba ka litekanyetso tse mabapi le 'tlhokomeliso', 'mokhathala', 'ho robala' le 'maikutlo' re sebelisa likala tsa analog (tse thathamisitsoeng ho tloha 1 ho 10 le tse fumanoeng pele le ka 30 le 120 min kamora ho tsamaisoa ha placebo kapa caffeine, joalo ka ha ho hlalositsoe pele.26 Ts'ebeliso ea likala tsa analog ho lekola litlaleho tsa litla-morao tsa lithethefatsi li bontšitsoe hore li ka hlahisa bana le ho bolela esale pele likarabo tsa lithethefatsi.27 Bakeng sa tlhahlobo ea khokahano, re sebelisitse mehato e fumanoeng metsotso ea 120 kamora taolo ea kofi (qetellong ea [11C] raclopride scan), e ka hare ho nako ea litlamorao tse phahameng tsa kofi (60-120 min).28

Sekhahla sa pelo le khatello ea mali li ile tsa tlalehoa makhetlo a mararo nako le nako ka nako ea metsotso e mehlano pele ho tsamaiso ea placebo kapa caffeine 'me nako le nako ka mor'a moo ho fihlela 120 min post postbo kapa post caffeine. Mehato e nkuoeng pele ho placebo kapa caffeine e ne e le karolelano (mehato ea pele ho lithethefatsi) mme tse nkuoeng 60-120 min post management li nkuoe e le mehato ea kamora ts'ebeliso ea lithethefatsi. Litholoana tsa lithethefatsi li ile tsa hlahlojoa joalo ka lipara t- Papiso e haufi haholo lipakeng tsa pele le likhato tsa kamora lithethefatsi.

Mehato ea caffeine ho plasma

Mali a Venous a ile a huleloa pele le ho 30, 60 le 120 min kamora ho tsamaisoa ha koae. Caffeine e plasma e ile ea emisoa ho sebelisa chydatography e sebelisang metsi haholo.29

PET scan ninemanga.com

Re sebelisitse HR + tomografia (qeto 4.5 × 4.5 × 4.5 mm ka bophara bo felletseng ka halofo e phahameng, lisepa tsa 63) ka [11C] raclopride 4-8 mCi (tšebetso e khethehileng 0.5-1.5 Ci μM-1 qetellong ea bomo). Mekhoa ea ho nahanisisa e ne e hlalositsoe pele.30 Ka bokhutšoanyane, li-scans tsa emission tse matla tsa 20 li ile tsa fumanoa hang kamora ho entoa bakeng sa kakaretso ea 54 min. Barupeluoa ba ile ba hlahlojoa le [11C] raclopride habeli, hanngoe ka placebo le hanngoe ka caffeine; scans ea placebo e entsoe 2 h pele ho tlhahlobo ea kofi. Caffeine (300 mg) le placebo (tsoekere ea tsoekere) li ne li tsamaisoa ka molomo ka 60 min pele ho [11C] ente ea raclopride. Re khethile 60 min e le litlamorao tse phahameng tsa kofi e tsoang ka molomo ho ~ 60 min ha e tsamaisoa e le letlapa.28 Bophelo ba halofo ea caffeine ho plasma ke ~ 3-5 h,31 kahoo nako ena ea nako e netefalitse maemo a phahameng a caffeine ea plasma nakong ea litekanyo tsa PET (60-120 min post caffeine).

Tlhahlobo ea setšoantšo sa PET

Re ile ra sekaseka bokhoni bo tlamang ba tlamang (BP)ND) litšoantšo tse sebelisang Statistical Parametric Mephu (SPM8; Setsi sa Wellcome Trust sa Neuroimaging, London, UK), se ileng sa re nolofalletsa ho etsa papiso ho latela pixel-pi-pixel.32 Ka ho khetheha, re hakantse bakeng sa voxel e 'ngoe le e' ngoe ea boholo ba kabo ea boholo ba eona, e lekanang le tekanyo ea tekanyo ea mahlaseli a mahlaseli a radiotracer ka har'a striatum ho ea ka cerebellum, e sebelisoang e le sebaka sa ho buuoa.33 Litšoantšo tsena li ile tsa etsoa ka mokhoa o tloaelehileng sebakeng sa stereotactic sa Montreal Neurological Institute se sebelisang 12-paramente affine change and 2-mm isotropic voxels. Template ea Montreal Neurological Institute ea setso, eo pele e neng e nts'etsitsoe ho sebelisoa litšoantšo tse tsoang lithutong tse phetseng hantle tsa 34 tse fumanoeng ka [11C] raclopride le tatellano e tšoanang ea PET,34 e sebelisitsoe bakeng sa boholo ba sebaka sa tlhaho ea litšoantšo tsa karolelano ea palo. Lits'oants'o tsa setšoantšo sa karolelano ea tekanyetso li tsamaisana le BPND + 1.

Tlhahlobo e ikemetseng ea "interest" (ROI) e ile ea etsoa ho sebelisoa li-ROI tse khethiloeng pele ho li-caudate, putamen le ventral striatum (VS) joalo ka ha ho hlalositsoe pele25 ho lokisa liphetho tsa SPM. Mehato ea ROI e sebelisitsoe bakeng sa tlhahlobo ea khokahano le litekanyetso tsa boits'oaro tse anngoeng haholo ke caffeine le ho lekola kamano le maemo a caffeine ho plasma.

Lipatlisiso tsa sethathamo

Limmapa tsa boko (BPND) li ile tsa ntlafatsoa ka nepo ho SPM8 li sebelisa kernel ea 8-mm isotropic Gaussian ho fokotsa litlamorao tse amanang le phapang ea methapo ea kelello ho lithuto. Masy striatal (dorsal striatum le VS) e thehiloe ho sebelisoa li-atlase tsa boko tsa dijithale tse fanoang ke software ea MRIcro (www.cabiatl.com/mricro/). Ka ho khetheha, li-voxels tse tsamaeang le striatum (caudate, putamen le VS) li ne li hlalositsoe sebakeng sa Montreal Neurological Institute stereotactic space sebelisa atlas e bitsoang automated Anatomical Labeling atlas.35 Ts'ebetso e le 'ngoe (ka hare ho lithuto) e sebelisitsoeng ho hlahloba litlamorao tsa lithethefatsi (placebo vs caffeine) ho BPND ka SPM8. Bohlokoa ba Statist bo thehiloe ke mokhoa o thata PFWE<0.05, e lokisitsoe bakeng sa lipapiso tse ngata maemong a voxel (ka har'a mask ea striatal) ho sebelisoa mohopolo oa tšimo o sa reroang ka khalemelo e fosahetseng ea lelapa. Bakeng sa pono ea pono mabapi le sebaka sa MRI sa libaka tse fapaneng haholo pakeng tsa placebo le caffeine, re sebelisitse moeli o sa nepahalang oa P

Bakeng sa tlhahlobo e ikemetseng ea ROI, bohlokoa ba lipalo bo thehiloe ho P<0.05, haeba e tiisa liphetho tsa SPM.

Bakeng sa mehato ea boits'oaro le ea pelo, re bapisitse ntlha e 'ngoe le e' ngoe pakeng tsa lintlha tsa placebo le caffeine re sebelisa tlhahlobo e phetoang ea phapang. Litlhahlobo tsa crelation li ile tsa etsoa ho lekola kamano lipakeng tsa libaka tseo caffeine e fetotseng BPND le mekhoa ea boits'oaro e ileng ea angoa haholo ke caffeine. Bohlokoa bo thehiloe ho P

Ka holimo ho leqephe

Results

Litlamorao tsa caffeine litlalehong tsa boits'oaro le litekanyetsong tsa pelo

Ho bapisoa pakeng tsa kofi le placebo bakeng sa mehato e lumellanang ho bontšitse litlaleho tse phahameng haholo tsa 'tlhokomeliso' ka bobeli ho 30 '(P= 0.05) le ho 120 '(P= 0.01) le lintlha tse tlase ho 'boroko' ho 120 '(P= 0.04) ho feta placebo. Phapang lipakeng tsa caffeine le placebo bakeng sa lintlha tse mabapi le ho feto-fetoha ha maikutlo le mokhathala li fihletse litlamorao feela (P> 0.06 <0.09; Setšoantšo sa 1).

Setšoantšo sa 1.

Setšoantšo sa 1 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

Litlamorao tsa boitšoaro tsa placebo le caffeine pele le 30 le 120 min kamora taolo ea bona. Bohlokoa bo tsamaisana le ho bapisoa pakeng tsa placebo (matšoao a bohlooho) le caffeine (matšoao a batsho) le boleng bo lumellanang le liphoso tse tloaelehileng.

Sebopeho se felletseng le litšomo (54K)

 

Mehato e tloaelehileng ea pelo le methapo ea pelo ha ea ka ea angoa haholo ke caffeine (pre vs post). Ka ho khetheha, bakeng sa tekanyo ea pelo, pre pre postbobo (70 ± 10 vs 64 ± 9) kapa pre vs post caffeine (66 ± 9 vs 65 ± 11); bakeng sa khatello ea systolic, pre vs post placebo (124 ± 6 vs 122 ± 7) kapa pre vs post caffeine (128 ± 11 vs 129 ± 9); kapa ka khatello ea diastolic, pre vs postbobo (67 ± 10 vs 65 ± 9) kapa pre vs post caffeine mehato (71 ± 12 vs 69 ± 11); ha ho na e 'ngoe e fapaneng ka ho felletseng.

Mehato ea caffeine ho plasma

Ho ne ho se na litekanyetso tsa cafeine tse fumanehang mefuteng ea plasma e nkuoeng pele ho tsamaiso ea kofi. Mehato ea mahloriso a koae ka plasma e ne e le 4.7 ± 2 μg ml-1 ho 30 min, 5.2 ± 1 μg ml-1 ho 60 min le 4.8 ± 0.6 μg ml-1 motsotso oa 120. Sena se tiisa hore re ne re ena le maemo a phahameng a koae ka plasma ka nako ea [11C] injlopride ente (60 min post caffeine) le litekanyetso tse phahameng ka nako ea mekhoa ea boits'oaro (30 le 120 min post caffeine).

Litlamorao tsa caffeine ho D2/D3Ho fumaneha

SPM e senotse hore caffeine e eketsehile D2/D3Phumaneho ea R (e bonoe ha e eketseha ho BPND) ka ho le letona le ka ho le letšehali striatum (ho kenyeletsoa dorsal putamen le VS) joalo ka ha ho bonts'itsoe ka limmapa tse akaretsang tsa lipalo le boleng ba motho ka mong bo nkuoeng bohareng ba lihlopha tse kholo (Setšoantšo sa 2, Lethathamo 1).

Setšoantšo sa 2.

Setšoantšo sa 2 - Ka bomalimabe ha re khone ho fana ka mokhoa o mong o fumanehang bakeng sa sena. Haeba o hloka thuso ho fumana setšoantšo sena, ka kopo ikopanye le help@nature.com kapa mongoli

(a) Limmapa tsa Brain tse fumanoeng ka Statistical Parametric Mapping (SPM) li bonts'a phapang e kholo ho D2/D3Phumaneho ea R, e ileng ea hlalosoa e le bokhoni bo tlamang ba ho tlama (BP)ND), lipakeng tsa placebo le caffeine bakeng sa caffeine e fapaneng> placebo. Moeli oa bohlokoa o lumellana le Pu<0.01, lihlopha> li-voxels tse 100. (b) Melao ea motho ka mong ea BPND mehato e ntšitsoeng ho dorsal putamen le ka hare ho terriatum ka mor'a placebo le ka mor'a kofi.

Sebopeho se felletseng le litšomo (133K)

 

Tafole ea 1 - Bohlokoa ba lipalo-palo bakeng sa liphetoho tsa BPND bakeng sa phapang ea kofi e kholo ho feta placebo.

Lethathamo la 1 - Bohlokoa ba lipalo bakeng sa liphetoho ho BPND bakeng sa caffeine e fapaneng le e kholo ho feta placebo - Ka bomalimabe ha re khone ho fana ka sengoloa se fumanehang bakeng sa sena. Haeba u hloka thuso ea ho fihlela setšoantšo sena, ka kopo ikopanye le thuso@nature.com kapa sengoliTafole e feletseng

 

ROI e ikemetseng ea sekaseka, e hlophisitse kofi eo ha e bapisoa le keketseho e nyane empa e bohlokoa ho BPND, ho putamen (placebo: 2.84 ± 0.37 vs caffeine: 2.97 ± 0.35; P= 0.05) le ho VS (placebo: 2.69 ± 0.31 vs caffeine: 2.84 ± 0.39, P= 0.05) empa eseng ho caudate.

Likhohlano lipakeng tsa phetoho e bakiloeng ke caffeine ho D2/D3Ho fumaneha le boitšoaro le maemo a plasma

Tlhahlobo ea khokahano le ROI ea striatal le litloaelo tsa boits'oaro li bonts'itse khokahano e ntle pakeng tsa VS le ho falimeha (r= 0.56, P= 0.01) e joalo e eketseha ho D2/D3Ho fumaneha ha caffeine ho ne ho amana le ho eketseha ha tlhokomeliso.

Tlhahlobo ea khokahano lipakeng tsa liphetoho tse susumetsoang ke koae ho D2/D3Ho fumaneha ha striatum le maemo a caffeine ho plasma a ne a se bohlokoa.

Ka holimo ho leqephe

Puisano

Mona re bontša hore caffeine e eketsa D2/D3Ho fumaneha ka har'a striatum (ho pakahatsoa ke keketseho ea BPND ho dorsal putamen le VS) sehlopheng sa taolo e phetseng hantle e nang le litekanyetso tse tlase tsa kofi ea letsatsi le letsatsi ea kofi. Liphumano tsena li tsamaellana le liphetho tsa PET ea pele [11C] Patlopride boithuto bo entsoeng sehlopheng se senyenyane sa lithuto (ba noang kofi ea tloaelo) bao le bona ba tlalehileng ba eketseha ho D2/D3Ho fumaneha ka har'a striatum ka caffeine (200 mg).24 Se fumanoeng liphuputsong tsena tse peli se fana ka maikutlo a hore caffeine e ho tekanyetso e tloaeloang ho ja batho e ka ntlafatsa letšoao la DA ka ho eketsa D2/D3Maemo a R kapa tumellano ea bona ho fapana le ho eketsa ho lokolloa ha DA ho striatum.

Mona re toloka liphetho tsa rona tsa keketseho ho BPND (ho BPND phumaneho) e nang le koae ho bontša hore li bonts'a keketseho ho D2/D3Maemo a R ho fapana le ho bonts'a a fokotseha ho endo native DA, e leng tsela eo ka tloaelo e eketsehang ho BPND lia fetoleloa (tlholisano e fokotsoe ho tsoa ho DA ho tlama ho D2/D3R). Mabaka a tlhaloso ena a latela. Taba ea pele, ho amoheloa hore lithethefatsi tse lemosang (amphetamine, methylphenidate le modafinil) li eketsa tokollo ea DA ho striatum.3, 25, 36 Taba ea bobeli, lithuto tsa tleliniki li bontšitse hore keketseho ea DA ho striatum e hlahisoang ke lithethefatsi tse matlafatsang e amahanngoa le ho eketseha ha tlhokomeliso.5 Kamora nako, lithuto tsa pele li bonts'itse hore keketseho ea boikoetliso ba DA e susumetsoang ke li-susumetso le modafinil li hlokahala bakeng sa liketso tsa bona tse khothatsang.6 Kahoo, haeba caffeine e ne e fokolitse DA ho striatum, sena se ka be se bakile keketseho ea mokhathala le boroko ho e-na le keketseho ea tlhokomeliso e bonoang ka mor'a taolo ea kofi. Tlhaloso ea rona ea hore keketseho ea litekanyetso tsa D2/D3Ho fumaneha ha VS ka caffeine ho bontša keketseho ea D2/D3Maemo a R a boetse a tsamaisana le liphumano tsa rona tsa hore ho fokotseha ha D2 / D3R ho VS kamora ho nyahlatsoa ke boroko ho amana le ho falimeha ho fokolang.5

Striato-pallidal neuron e fetola thabo ea eona ka ho fetola D2Maemo a R kahara membrane.37 Kahoo, D2Fokotsa fatše ka ho hlohlelletsa DA38 le ho nyala hape ka ho saena lipalo tsa DA.39, 40 DA e hlohlelletsa D2E tsosa bohloeki ba bona,38 ebe e ka qhekelloa kapa ea thetsoa.38, 41 Internalization ea D2R e laoloa ke A2AR,42 agonists e nolofalletsa bohare ba eona ka ho tlangoa ha β-bindin 2 ho A2ARD2Li-receptor heteromers43 athe A2AR bahanyetsi ba kena-kenana le D2R kahare ho li-neuron tsa striatal.44 Kahoo, caffeine e ka kena-kenana le tonic A2AHo its'etleha kahare ho D2E kopantsoe ke endo native adenosine, e ka tlatsetsang ho litlamorao tsa eona tsa psychostimulant.14, 19, 45, 46 Ka sebele, seo re se fumaneng hammoho le se tlalehiloeng pele se bonts'a hore kofi e eketsa D2Ho fumaneha ka har'a striatum,24 ts'ehetsa toloko ena. Joalo ka ha k'hafeine e etsa liphetoho tse tsoang ho DA, ka karolo e 'ngoe, e khahlanong le eona ke A2AR,47 Kaffeine-induction D2R keketseho ea striatum e ka tsamaellana le lehloeo la caffeine la A.2A-medioe D2R kahare. Ka sebele, A2A receptor Knoutout litoeba bontša eketsehile D2Maemo a R ho striatum;48 leha re ke ke ra lekana boemo bo sa foleng ba ho kokota le litlamorao tsa ho pepesetsoa ke kofi e mpe.

Leha ho le joalo, ho sa tsotelehe mochine o ikarabellang bakeng sa keketseho ea striatal D2/D3Ho fumaneha ha R, liphetho tsa rona li bonts'a hore ho batho, caffeine ka tekanyetso e sebelisoang hangata, ha e eketse DA ho striatum. Sena se lumellana le se fumanoeng ho tsoa liphuputsong tse mabapi le Microphalalicent ho bontša hore koae (0.25-5 mg kg-1 kahare kapa 1.5 ho 30 mg kg-1 inraperitoneally) ha a ka a phahamisa DA maemong a bokellaneng ba nyutlelie,22, 23 leha thuto e tlalehiloe e eketseha ka kholo (10 mg kg-1 intraperitoneally) empa eseng tekanyetso e tlase ea caffeine (3 mg kg-1 kahare).21 Kahoo, motheong oa liphetho tsa hajoale le tsa pele24 'me sephetho sa preclinical, caffeine ho litekanyetso tse amanang le ts'ebeliso ea batho ha e bonahale e eketsa DA ho li-nucleus accumbens. Ha bokhoni ba lithethefatsi tsa tlhekefetso ho eketsa DA bo hlokahala bakeng sa litlamorao tsa bona tse ntle le bakeng sa neuroadaptations e amanang le tšebeliso ea lithethefatsi,49 hona ho ka hlalosa hore na hobaneng caffeine e sa hlahise tsamaiso e qobelloang le tahlehelo ea taolo e khethollang ho lemalla.50

Keketseho e bakoang ke caffeine ho D2/D3R ho VS li ne li amahanngoa le ho eketseha ha tlhokomeliso. Kopano ena lipakeng tsa ho ba seli le D2/D3E pheta liphumano tsa rona tsa pejana ka ho hloka boroko empa e le ka lehlakoreng le fapaneng, leo re bonts'itseng hore litheko li fokotseha ho D2/D3Ho fumaneha ha VS ka lebaka la ho hloka boroko ho ne ho amahanngoa le phokotso ea tlhokomeliso.5 Phuputsong e fetileng ea PET, keketseho ea caffeine e bakoang ke striatal D2/D3Ho fumaneha ka R ho ne ho amana le mokhathala o fokotsehileng.24 Kahoo sena se fana ka bopaki bo ntlafalitseng ho supa ka D2/D3R libakeng tse phetseng hantle li ka ntlafatsa tlhokomeliso kapa ho fokotsa mokhathala, athe ho supa ho fokotsehile ho ka fokotsa tlhokomeliso kapa ho eketsa mokhathala.

Meeli ea ho ithuta

Ka setso, keketseho ho D2/D3Ho fumaneha ka [11C] raclopride, joalokaha ho bonoe mona, e se e fetoletsoe ho bontša ho fokotseha ha tokollo ea DA. Sebakeng seo, mohlala oa rona o re lebisa ho li fetolela e le keketseho ho D2/D3Maemo a R le / kapa ho eketseha ha tumellano. Leha ho le joalo, mohlala oa rona o ke ke oa hlakisa pherekano e ka bang teng e fetang e le 'ngoe e ka amang tlamo ea [11C] lebala la lipapali. Ntlheng ena, liteko tsa pele tse sebelisang metsoako e meng e khethiloeng li lokela ho etsoa ho etsa lipatlisiso tsa hore na litlamorao tsa koae li ho [11C] raclopride e tlamang e bonts'a liphetoho lipuong kapa tumelong ea D2/D3R le hore na litla-morao tsena li bontša likhang tsa koae ho A2AR. Hape hobane [11C] raclopride e tlama ho D2R le D3R,51 re ke ke ra khetholla hore na keketseho ea kofi ea caffeine e bakiloe ke BPND e bonts'a keketseho feela ho D2R kapa hape ho D3R. Leha ho le joalo, ho putamen moo letsoalo la D3R e tlase haholo ho feta ea D2R,52 litlamorao tsa caffeine li kanna tsa bonts'a D2R. Ntho e 'ngoe e ka re ferekanyang thutong ea rona ke hore, "caffeine" haholo e fokotsa phallo ea mali a letsoele.53 e ka sitisang BPND mehato e le litlamorao tsa phallo ea mali a khubung e fapana lipakeng tsa cerebellum le striatum.54 Leha ho le joalo, hobane caffeine e fokotsa phallo ea mali a likhoerekhoere ka mokhoa o moholo ho feta ho "cerebellum",54 sena se ka lebisa ho fokotseha ha BP ea striatalND, athe re bontšitse se fapaneng; ke keketseho ea BP ea striatalND le caffeine, e bontšang hore seo re se fumaneng ha se ka lebaka la liphetoho tse tlisoang ke caffeine phallo ea mali a likhoerekhoere. Leha mokhoa oa raclopride PET o ke ke oa khetholla pakeng tsa presynaptic le postynaptic D2 / D3R, taba ea hore caffeine ke mohanyetsi ho li-receptors tsa A2A, tse hlahisoang ka li-neuron tsa spiny tse mahareng tse hlahisang D2R empa eseng li-neurons tsa DA li re lebisa ho nka hore litlamorao ke tsa postynaptic. Ntho e 'ngoe e ferekanyang lithutong tsa rona ke phello ea tatellano kaha placebo e ne e lula e fuoa 2 h pele ho kofi. Leha ho le joalo, lithuto tse hlahlobisitseng tlhahlobo ea test-repet ea mofuta oa raclopride binding (ho kenyeletsoa le ea rona)55, 56 ha baa tlaleha phapang e kholo lipakeng tsa mehato le ha mehato e phetoang e ne e etsoa ka letsatsi le le leng57 joalo ka thuto e hajoale, e bonts'ang hore sephetho sa tatellano ea monyetla ha se khone ho ikarabella bakeng sa liphetho tsa rona. Ha re khone ho lekola hore na barupeluoa ba ile ba khona ho tseba hore na ba fumana caffeine kapa placebo kaha ha rea ​​ka ra ba botsa qetellong ea thuto. Kamora nako, ha rea ​​ka ra bokella disampole tsa mali bakeng sa epinephrine le norepinephrine, tse eketsoang ke caffeine.58 Kahoo, re ke ke ra fana ka tlhahiso ea litlamorao tsa litlamorao tsa k'hafeine tsamaisong ea boitšoaro mabapi le litlamorao tsa boitšoaro ba kofi. Leha ho le joalo, kamano e bohlokoa lipakeng tsa keketseho ea ho fumaneha ha D2R ho VS le tlhokomeliso e bonts'a hore litlamorao tsa caffeine ho lets'oao la D2R li kenya letsoho ho lematseng ha eona.

Ka holimo ho leqephe

fihlela qeto e

Re bontša keketseho e kholo ho D2/D3Ho fumaneha ha striatum le tsamaiso ea kofi, e leng se bonts'ang hore caffeine ho litekanyetso tse nooang ke batho ha e eketse DA ho striatum. Sebakeng seo re tolokela liphumano tsa rona ho bonts'a hore litlamorao tse ntlafatsang tsa DA tsa caffeine bokong ba motho ha li tsamaisane ka kotloloho le lipakeng tsa keketseho ea D2/D3Maemo a R le / kapa liphetoho ho D2/D3R amanang.

Ka holimo ho leqephe

Khohlano ea thahasello

Bangoli ba phatlalatsa hore ha ho na likhohlano tsa thahasello.

Ka holimo ho leqephe

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Ka holimo ho leqephe

Liteboho

Re leboha Colleen Shea, Pauline Carter, Karen Apelskog le Ruben Baler ka menehelo ea bona. Patlisiso ena e ne e tšehelitsoe ke Lenaneo la Patlisiso la Intramural Intramural (NIAAA).