Curr Opin Pharmacol. 2009 Feb; 9 (1): 53-8. Epub 2009 Jan 8.
De Mei C, Ramos M, Iitaka C, Borrelli E.
mohloli o moholo
Univesithi ea California Irvine, Lefapha la Microbiology le Molekolo oa Lijalo, 3113 Gillespie NRF, Irvine, CA 92617 USA.
inahaneloang
Dopamine (DA) e tšoaeang e laola mesebetsi e mengata ea 'mele ho tloha ho locomotion ho fihlela secretion ea hormone,' me e bapala karolo ea bohlokoa ho lemeng. DA ea phahameng, mohlala, ho araba lithethefatsi tsa tlhekefetso, ka nako e tšoanang o kenya li-neuron tse hlahisang li-receptor tse fapaneng tsa DA; Likarabo tsa li-neurons / li-receptor tse fapaneng li hlophisoa joang molatong oa liphetho le liphetho tsa seleng, li ntse li sa hlalosoe ka botlalo. Ho supa ho tloha li-receptor tsa D2 (D2Rs) ke mohlala o motle oa ho bontša bothata bona. Li-D2R li na le tsamaiso ea lehae ea Presynaptic le postynaptic le mesebetsi, e arolelanoang ke isoforms tse peli ho vivo. Liphetho tsa morao-rao tse tsoang ho litoeba tsa "Knoutout" li hlakisa karolo ea sebaka le litlamorao tse ikhethileng tsa D2 ka hona li eketsa kutloisiso ea rona ea hore na DA e fetola joang 'mele ea neuronal.
Selelekela
Likarabo tsa meputso ea tlhaho (ke hore lijo) le lithethefatsi tse lemalloang li arolelana likarolo tsa hedonic le ho phahamisa maemo a dopamine (DA) tsamaisong ea mesolimbic, libakeng tse kang NAcc, e bonts'itsoeng e le karoloana e ikhethang ea sebopeho sa moputso [1-3] . Lithethefatsi tsa tlhekefetso li sebelisa sisteme ea dopaminergic ho lata litlamorao tsa boits'oaro ba bona le ho ntlafatsa likarabo tsa DA ho nolofalletsa thuto ea sistimi.
Litlamorao tsa DA li hlahella ka ho sebelisana le li-membrane receptor tsa lelapa la G-protein coupept receptor [4]. Kahoo, ho tšebeliso ea lithethefatsi DA ho saena, e laoloang ke efe kapa efe ea li-receptor tse hlano tsa DA, e matlafalitsoe ka matla e lebisang ho tsitsinyehong kapa ho thibelo ea litsela tse laoloang ke D1-like (D1 le D5) le lelapa la D2-like receptor (D2, D3 le D4 ), e fetolelang ts'ebetsong ea ts'ebetso / ts'oaetso ea li-neuron le li-circuits tse khethehileng. Sehloohong sena re tla shebana le li-pre-and postynaptic DA D2 receptor (D2R) ho saena le ho sebetsa ho vivo.
Li-D2R, tse hlahisoang ka bongata bokong, li fumaneha sebakeng ka bobeli ho li-neurone tsa presynaptic dopaminergic neurons, empa hape le ka li-neurons tse lebisitsoeng ke litumellano tsa dopaminergic (Fig.1). Ntle le ho ba le tikoloho e habeli, li-receptors tsa D2 ke sechaba se nang le matla a mangata a thehiloeng ke li-isoforms tse peli tse ikhethang, tse bitsoang D2S (S = khutšoane) le D2L (L = nako e telele) e hlahisoang ke ho qaptjoa ha mofuta o le mong [4]. Litoeba tse fetotsoeng ka liphatsa tsa lefutso tse fetotsoeng kapa tse fetotsoeng [5-9] polelo ea D2Rs li bile bohlokoa haholo ho khethollleng mesebetsi e amanang le D2R ho vivo [10]. Re tla bua ka tlatsetso e lekanang ea mekhoa ea boipheliso ea post-synaptic D2R e arabelang ho arabela bophahamo ba DA bo hlahisoang ke lithethefatsi tsa tlhekefetso kapa ke litsebi tsa DA ka ho bapisa sephetho sa litoeba tse hlaha.
Setšoantšo sa 1
Pele le ka li-postynaptic signaling e kopantsoe ke D2L le D2S
Phetisetso ea Signal ka D2L le D2S ka tsela e fapaneng e ama likarabo tsa postynaptic
Tšusumetso e ntle ea intracellular ea DA ke ts'ebetso ea tsela ea cAMP [4]. Mmila ona o kenngwa tšebetsong ka li-receptors tse kang D1 mme o thibetsoe ke li-receptors tse kang D2. Ho "striatal medium spiny neurons" (MSNs), ho phahama ha boemo ba cAMP ho lebisa ts'ebetsong ea protheine Kinase A (PKA) [11] mme ka lebaka leo phosphorylation ea letoto le leholo la sepheo sa cellular mme ka bohlokoa ho DA- le cAMP-regated phosphoprotein ea 32 kDa (DARPP-32), [12] (Fig.1). Blockade ea D2R e tsosa phosphorylation e itšetlehileng ka PKA ea DARPP-32. Phello ena e ka khoneha e kopantsoe haholo ka ho hatella thibelo e hlahisitsoeng ke D2R sethaleng sa adenylyl. Phosphorylation e thathamisitsoeng ke PKA ho Thr34 e fetola DARPP-32 hore e be inhibitor e matla ea PP-1, ka tsela eo e holisa likarabo tse hlahisoang ke ts'ebetso ea ts'ebetso ea cAMP / PKA. Habohlokoa le ho feta, blockade of D2R-Mediated signaling e hlahisa phello ea khatello ea maikutlo, e fumanehang ho DARPP-32 null-mice [13]. Ts'ebetso ea li-D1R e eketsa phosphorylation ea Thr34 ka ts'usumetso ea Golf-Mediated [14]. Ka lehlakoreng le leng, ts'ebetso ea li-D2Rs e fokotsehile phosphorylation ea DARPP-32 ho Thr34 ka ho thibela tlhahiso ea CAMP [11] ka Gi-mediated. Ntle le moo, li-agonists tsa D2Rs li hlohlelletsa tšebetso ea protheine ea phosphatase-2B, ka hona e eketsa dephosphorylation ea DARPP-32 ho Thr34 [11].
Ho khahlisang ke hore SKF81297, agonist ea D1R, e hlahisa keketseho e menang makhetlo a leshome setulong sa phosphorylation ea DARPP-32 ho Thr34, ka litoeba tsa WT, D2R - / - le D2L - / - litoeba [15]. Quinpirole, agonist e ikhethileng ea D2, e sebetsana le keketseho ea phosphorylation ea DARPP-32 ho Thr34 e hlahisoang ke dopamine D1 agonist, ho WT, empa eseng ho D2R - / - kapa D2L - / - tishu [15]. Sena se fana ka maikutlo a hore isoform ea D2L e ikarabella bakeng sa molao oa tsamaiso ea li-receptor-mediated joaloka D2-DNPX-32 ho li-MSNs, ka tsela eo, e bonts'a ho kenya letsoho ka ho khetheha ha li-receptor isoform ho signynaptic D2R-Mediated signaling.
Ka lehlakoreng le ka dopaminergic methapo ea kutlo ea substantia nigra (sn) le ventral tegmental sebakeng (VTA), phokotsong ea phosphorylation tsa tyrosine hydroxylase (TH) on Ser40, hlohlelletsoa ke dopamine D2 agonists itseng, o lahlehile ka D2R - / - litoeba, empa a sireletsa ho D2L - / - joalo ka li-tishu tsa WT [15]. E bonts'a phello e kholo ea D2S e ikhethang ea presynaptic.
Ho tsebahala ha tšebetso ea "isoform-mediated presynaptic" le "postynaptic" ho ka etsahala haholo ka lebaka la bokhoni ba D2L le D2S ea ho sebelisana le liproteine tse fapaneng tsa G le lipalo tsa li-signature [16,17] kapa ka ho ikamahanya le liprotheine le protheine.
Haufinyane tjena, moelelo oa serine / threonine kinase AKT ho saena e tšoaeang qeto ke DA ka li-receptors tse kang D2 [18]. Ts'ebetso ea tsela ena e ikemetse ka mokhoa oa cAMP ebile e kenelletse ka popo ea mochini o nang le liprotheine tse tharo, protheine ea protheine β-bindin 2, AKT le phosphatase PP-2A [18]. Ho khahlisang, ketsahalo ea li-psychostimulants ho striatum e etsa hore ho fokotsehe kapele ha "phosphorylation ea AKT le ts'ebetso, ka ts'ebetso ea D2-like receptor [18]. Habohlokoa, phosphorylation ea AKT ha e laoloe kamora kalafo ea psychostimulants ho D2R - / - le D2L - / - striata [19], e bonts'a phello e ikhethileng ea D2R-Mediated mohlomong e itšetlehileng ka ts'ebetso ea D2L.
Bohlahlobisisi ba nako e tlang bo lokela ho lekola hore na litlamorao tse tlalehiloeng tsa D2R-mediated signaling ho AKT le PKA pathways lia tšoana, le hore na li hlahisitsoe ka li-neuron tse tšoanang.
D2R e pakeng tsa mesebetsi ea pele ho li-synaptic ho li-neuron tsa postynaptic
Litumellano tsa Nigrostriatal le mesolimbic, ka ho latellana ho tsoa ho SN le VTA, sensory ea heke, motor le tlhahiso ea tlhahisoleseling ho striatum. Ha re arabela liketsahalong tse bohlasoa, matšoao a moputso a tsoang ho orbitofrontal cortex le amygdala ea basolateral ba fihla seterekeng moo DA e leng molebeli oa likhakanyo tsena. Ka mokhoa o ts'oanang, DA modulates e kenyelletsa lintho tse tsoang ho dorsal striatum ho tloha libakeng tsa sensory le motor cortical [1], moo e ts'oarellang lerata le eketsang phello ea susumetso e kholo ka mochine oa D2R-mediated [20].
Ntle le li-MSN, li-D2R li boetse li hlahisoa ke li-interneuron tsa li-striatal [21] tse nang le litlamorao tsa bohlokoa tsa 'mele [22,23]. Lisele tsena li emela 5% feela ea li-striatal neurons, leha ho le joalo karolo ea tsona e bohlokoa ts'ebetsong ea 'mele ea tlhahisoleseling e tsoang ho likopanong tsa cortical, thalamic le mesencephalic. Ho nka karolo ha li-interinurons tsa cholinergic mabapi le phetisetso ea tšebetso ea li-MSNs, ka ho saena ho itšetlehileng ka D2R ho bontšitsoe ka mokhoa o hlakileng [22,23]. Mechini ea Presynaptic D2R-mediated le eona e bile le tšusumetso ho lokolloeng ha GABA le glutamate [20,24,25] ho tsoa ho li-striatal and cortical neurons. Ka hona, ntle le ts'ebetso ea ho fetolela ea DA ho li-dopaminergic neurons, li-D2R li sebetsa joaloka heteroreceptors, li fetole tokollo ea neurotransmitter ho tsoa ho li-neurons tsa postynaptic. Ha re etsa joalo, karolo ea presynaptic ea tokollo ea li-D2Rs ha e ame feela karabelo ea li-neurop tsa dopaminergic, empa hape e fetoloa haholo ka mokhoa oa lisele tse leng ho tsona.
Ts'ebetso ea Presynaptic D2R-Mediated ho dopaminergic neurons
Boithuto ho D2R - / - litoeba li fumane hore li-receptor tsa D2 ke "ore fide "autoreceptors e laolang synthesis ea DA le ho lokolla [26-29]. Ho khahlisang ke hore, ha moelelo oa motheo oa DA maemong a thelehileng o tšoana le WT le D2R - / - banab'abo, tokollo ea DA e ts'oeroeng ka ente ea koae e phahame haholo D2R - / - mutants ha e bapisoa le liphoofolo tsa WT mme e le kaholimo ho mokokotlo ea keketseho ea DA e bonoang hangata liphoofolong tsa WT [27]. Liphetho tse ts'oanang le tsona li fumanoe ho arabela morphine [27].
Tlhokomeliso ea hore D2R-Mediated auto-inhibition e bapala karolo e kholo ho laoleng ho lokolloa ha DA maemong a maemo a phahameng a kantle ho DA e kanna ea hlalosa tšusumetso e kholo ea D2R mabapi le liphetoho tse hlahisoang ke lithethefatsi tsa tlhekefetso mme haholo-holo ka cocaine ka blockade ea DA transporter ( DAT). Kahoo, maemong a tloaelehileng D2R autoreceptors, e thibelang ho thunya le ho lokolloa ha DA, ke eona feela ntho e setseng e ka felisang phello ea koae.
Habohlokoa, ho tlosoa hoa mokokotlo oa D2L isoform ho D2L - / - litoeba, tse ntseng li hlahisa li-receptors tsa D2S, ha e nyenyefatse mesebetsi ea D2R-Mediated autoreceptor, ho ts'ehetsa karolo e ikhethileng ea li-isynormic ea D2S isoform ho vivo [8].
Ka hona, ho qhaloa ha ts'ebetso ea D2R autoreceptor, e kopantsoeng le D2S, e ka bapala karolo ea bohlokoa ho pathophysiology ea ts'ebeliso e mpe ea lithethefatsi le ho loants'eng kotsi ea lithethefatsi. Motsoako ona o tšehetsoa ka mokhoa o sa tobang ke lipono tsa liphoofolo tse kotsing ea ho hlekefetsoa ka lithethefatsi. Liphoofolo tsena li tšoauoa ka tokollo e ntlafalitsoeng ea DA mabapi le lithethefatsi tse lemalloang [30] le ka palo e tlase ea libaka tsa tlama tsa D2R [31] le thibelo e tlase ea ts'ebetso ea ho hlatsuoa ha DA e bakoang ke ho fokotseha hoa somatodendritic autoreceptor sensitivity [32].
Hape, ts'ebetso ea D2Rs e tlalehiloe ho laola ho ts'oaroa ha DAT ho membrane ea plasma, ka ts'ebetso ea tsela ea MAPK [33], le hore D2Rs e sebelisana 'moho le DAT modulating tšebetso ea eona [34]. Kahoo, li-D2R, 'me mohlomong le D2S isoform, ho kenyelletsa taolo ea DA, li nka karolo ka matla taolong ea tokollo ea eona ka mekhoa e fapaneng har'a ona eo tšebelisano le DAT e leng ea bohlokoa haholo.
Matla a susumetsang a koae a koae a kenella ka lebaka la ho ba sieo ha D2S
E hlekefetsoa haholo ke batho, cocaine e phaellisa psychomotor ea eona le litlamorao tsa cellular ka ho thibela ts'ebetso ea DAT ho dopaminergic neurons [35]. Li-glutamate le dopaminergic antagonists li felisa ts'ebetso ea ho kenya liprotheine tsa liphatsa tsa lefutso tsa pele (IEGs) tse hlahisoang ke cocaine [36,37]. Mabapi le hona, ts'ebetso ea D1Rs ke tlhokahalo e felletseng ea ho kenella karabelong ea cellular le boits'oaro ho koae, joalokaha ho bontšitsoe ke lithuto tse entsoeng ho D1R - / - litoeba [38]. Boithuto ba morao-rao, bo sebelisang litoeba tsa transgenic tseo ho tsona lisele tse D1R le D2R li bonts'itsoeng ke polelo ea liprotheine tsa fluorescent, li ntlafalitse le ho tšehetsa liphumano tsena ka ho supa hore karabelo e matla ea cellular ho koaeine e kenella haholo D1R-, empa eseng li-neurons tse hlahisang D2R [ 39].
Boemong bona ho ka lebelloa hore tlhekefetso ea liphatsa tsa lefutso ea D2Rs, haeba ho na le letho, e eketseng litlamorao tsa koae ka vivo, ka lebaka la karolo e tlalehiloeng ea D2R e thehiloeng ho ts'ireletso ho tsebiso ea DA. Leha ho le joalo, sena ha se seo se se bonoeng.
Phello ea cocaine ho D2R - / - litoeba joale li se li lekiloe kamora kalafo e matla le e sa foleng le lithutong tsa ho itlhompha ka liphetho tsa hore D2R - / - litoeba li sitisitse likarabo ho lithethefatsi. Habohlokoa, sena ha se hlahe ho leseli le nang le phoso la D1R-mediated e le karabelo ea cellular le boits'oaro ba D2R - / - litoeba ho tsamaisa DI1Rs tse fumanehang [40,41]. Tumellanong le polelo e sa amaneng le D1R-Mediated in D2R - / - litoeba, ts'ebetso ea IEG c-fos ke li-agonists tse ikhethileng tsa D1R tse sa sebetseng ho susumetsa mofuta oa gene ea WT, e hlahisitse ts'ebetso ea mofuta ona. ka striatum ea D1R - / - litoeba [2].
Leha ho le joalo, ts'usumetso ea ts'ebetso ea makoloi ka koae e kenngoa haholo ho D2R - / - litoeba mabapi le taolo ea WT mme ha e eketsehe ka mokhoa o itšetlehileng ka lethal dose [40,42]. Ho makatsang ke hore Tsamaiso ea koae ho D2R - / - litoeba li hloleha ho hohela c-fos (Fig.2). Sena se lebisa ho hypothesize ea hore ha ho se na D2Rs potoloho ea inhibitory, hangata e laoloang ke D2R, e senoloa e lebisa ho hatelloeng ho tlalehiloeng ha c-fos induction ho li-MSN. GABA le acetylcholine li emela likhetho tse ntle moelelong ona moo tahlehelo ea taolo e kopanetsoeng ea D2R ea tokollo ea bona e ka bakang ho phatloha ha neurotransmitters e le 'ngoe kapa bobeli ba tsona (25] ho li-MSNs tse thibelang c-fos induction (Fig.2). Ntle le moo, tahlehelo ea li-D2R e sitisa sebopeho sa li-macromolecular complexes pakeng tsa D2R le liprotheine tse ling, tseo ka tloaelo li laolang karabelo ea cellular le boits'oaro ho cocaine [43].
Setšoantšo sa 2
Litholoana tsa cellular tsa cocaine ho li-neuron tsa striatal.
Ho putsa le ho matlafatsa thepa ea lithethefatsi tse lemalloang ha ho se na D2R
Melemo e khahlisang ea koae ho D2R - / - litoeba, joalo ka ha li hlahlojoa ke li ratang sebaka (CPP), li fumaneha [40]. Leha ho le joalo, lithuto tsa boits'oaro li bonts'itse hore D2R - / - litoeba li ikatisa cocaine e ngata ho feta litoeba tsa WT [44]. Tlatsetso ea li-neuromodulators tse ling (ke hore noradrenalin, serotonin) [45] ha e bua ka CPP le boits'oaro ho cocaine ho D2R - / - e ke ke ea qheleloa ka thoko 'me e emetse tlhahlobo e ngoe. Ntlha ena e bohlokoa haholo ha ho shejoa lintlha tse ngata tse bonts'ang litlamorao tsa lithethefatsi tse ling tse 'maloa tsa tlhekefetso ho D2R - / - litoeba. Ka ho khetheha, li-D2R - / - liphetoho ha li arabele thepa e atlehang le e matlafatsang ea morphine [46-48] le joala [49,50]. Ka hona ho bonts'a hore ho saena ka mokhoa o tiileng oa D2R ho hlokahala ho hlahisa sephetho se atlehang le se matlafatsang sa lithethefatsi tse ngata.
Habohlokoa, D2L - / - litoeba, tse ntseng li hlahisa D2S le ho boloka mesebetsi ea D2R-Mediated autoreceptor [8,9,27], li na le likarabo tse fumanehang le tse khotsofatsang tsa koae e tšoanang le ea liphoofolo tsa WT [40]. Kahoo ho hlahisa karolo e atileng ea D2S ho boitšoaro le cellular ho lithethefatsi tsa tlhekefetso.
Sena se fana ka maikutlo a hore litlamorao tsa presynaptic D2R tse sebelisang eseng feela tokollong ea DA, empa hape le GABA [25,51,52], glutamate [20] le acetylcholine [22] li ka bapala karolo ea karabo ea lithethefatsi tsa tlhekefetso.
Qetellong, ho kenella ka kotloloho ho D2S le D2L ka ho latellana mesebetsing ea pele le ea postynaptic e siea potso e le karolo ea isoform e ngoe sebakeng se seng le se seng, hobane li-isoform ka bobeli li hlahisoa ho D2R e hlalosang li-neurons. Phephetso e 'ngoe e phephetsang ke hore ho ts'oaroa ha isoform ka bobeli ho membrane ho ka se laoloe ka ho lekana [53]. Ntlafatso ea mahlale a litoeba le ho hlahisa mefuta e mecha ea liphoofolo le lisebelisoa li lokela ho thusa ho hlakisa ntlha ena.
Nahanisisa
Liphetho tse fumanoeng tlhahlobisong ea liphetoho tsa D2R li fane ka bopaki ba ho kenya letsoho ho fapaneng ha D2L le D2S ho D2R-Mediated signaling e ts'oeroeng ke lithethefatsi tsa tlhekefetso le li-agonists tse tobileng. Ho ba siea ha li-signature tsa D2L-mediated ho sitisa tsamaiso ea litsela tsa PKA le AKT ka D2R, empa ha e ame karabelo ea koloi le moputso ho koaeine. Ka lehlakoreng le leng, ho saena lipakeng tsa D2S ho bonahala e le tlhoko e phethahetseng bakeng sa sephetho sa koloi le litlamorao tsa koae hape e ka ba lithethefatsi tse ling. Litlhatlhobo tsa nako e tlang le mehlala li hlokahala ho ntšetsa pele litsoantso tse amehang likarolong tsena, ebang li teng ho dopaminergic kapa ho li-neurons tsa postynaptic.
Liteboho
Ho sebetsa ka laboratoring ea E Borrelli e amanang le tlhahlobo ena ho tšehelitsoe ke chelete e tsoang NIDA (DA024689) le European Community (EC LSHM-CT-2004-005166).
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