Ukulinganisa indima yeDopamine ekusebenziseni iziyobisi gwenxa kunye neziyobisi (2009)

Izimvo: Olunye lophononongo lwamva nje nolona lubalaseleyo lwendima ye-dopamine kwikhoboka leziyobisi. IVolkow yenye yeengcali zokuqala kumlutha, kunye nentloko yangoku ye-NIDA.

I-Neuropharmacology. I-2009; I-56 (iSuppl 1): 3-8.

Ipapashwe kwi-intanethi ye-2008 Jun 3. doi:  10.1016 / j.neuropharm.2008.05.022

ND Volkow,* UJS Fowler, GJ Wang, R. Umthengisi, yaye F. Telang

Ulwazi loMbhali ► Ulwazi lobunikazi kunye neelayisensi ►

Inguqulelo yokugqibela yomhleli yeli nqaku iyafumaneka apha Neuropharmacology

Bona amanye amanqaku ku-PMC Wisdom nqaku epapashwe.

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Abstract

I-Dopamine ibandakanyeka ekuqiniseni iziyobisi kodwa indima yayo kwikhobokisa alicacanga. Apha sichaza izifundo zokucinga nge-PET eziphanda ukubandakanyeka kwe-dopamine ekusebenziseni gwenxa iziyobisi kwingqondo yomntu. Emntwini iimpembelelo zokunyanga zamachiza zinxulunyaniswa nokunyuka okukhulu kunye nokukhawuleza kwi-dopamine yangaphandle, ehambelana nezo zibangelwa kukudubula kweseli yomzimba kodwa zixinekile kwaye zirhwebesheka. Ukusukela iiseli zedopamine umlilo xa uphendulwa kwisistimenti esishukumisayo, ukwenziwa kwento yokunyanga ngamandla ngamachiza kufunyanwa njengobuso obukhulu (ukujonga ingqalelo, ukuvusa inkanuko, imeko yokufunda kunye nokhuthazo) kunye nokusetyenziswa okuphindaphindiweyo kweziyobisi kunokuphakamisa imilinganiselo efunekayo ukuze kusebenze iiseli ezenziwa dopamine kunye nokusayina. Ewe, izifundo ezinemifanekiso zibonisa ukuba abo baxhaphaza iziyobisi banophawu lokuhla kwe-dopamine D2 receptors nakukhutshwa kwe-dopamine. Oku kwehla komsebenzi we-dopamine kunxulunyaniswa nomsebenzi wengingqi otshitshisiweyo kwi-cortex ye-orbitofrontal (ebandakanyeka kwi-salience factor; ukuphazamiseka kwayo kukhokelela ekuziphatheni okunyanzelekileyo), i-cingate gyrus (ebandakanyeka kulawulo lwe-inhibitory; ukuphazamiseka kwayo kubangela ukungxamiseki) kunye ne-dorsolateral preortal cortex (ebandakanyeka kwisigqeba sokulawula. umsebenzi; ukuphazamiseka kwayo kukhokelela kulawulo oluphosakeleyo lwezenzo). Ngokudibeneyo, imeko ebangelwa zezi ziyobisi zikhokelela ekuqiniseni uphawu lwe-dopamine xa ityhilwe kwimigangatho ebekiweyo, ethi ke iqhube inkuthazo yokufumana ichiza ngokuyinxalenye ngokuvula imimandla yangaphambili kunye ne-striatal. Ezi zinto zifunyanisiweyo zibeka intsilelo kwimisebenzi ye-dopamine-eyenziwe nge-pre-prealal and drigulation-ekulahlekelweni kolawulo kunye nokunyanzelwa kokungena kweziyobisi okukhokelela xa umntu olikhoboka lotywala esebenzisa amachiza okanye efumana imeko efanelekileyo. Umsebenzi ophungulweyo we-dopamine kubantu abanomlutha kwakhona unciphisa ubuntununtunu babo bokuqiniswa kwendalo. Ungenelelo lonyango olujolise ekubuyiseleni ithoni ye-dopaminergic yobuchopho kunye nomsebenzi weengingqi zecortical cortical kunokuphucula ukusebenza kwangaphambili, ukuphucula ulawulo lwe-inhibitory kunye nokuphazamisa ukungahambelani kunye nokulawulwa okunyanzelekileyo kweziyobisi ngelixa kunceda ukukhuthaza umntu olikhoboka lokuzibandakanya ekuziphatheni okungahambelani neziyobisi.

Internet: I-Positron emission tomography, Orbitofadal cortex, Cingrate gyrus, Dorsolateral preortal cortex, Dopamine D2 receptors, Umvuzo, iPredisposition, Salience, Raclopride, Fluoro-deoxyglucose

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1. intshayelelo

Iziyobisi zokuxhatshazwa zibangela ukunyuka okukhulu kwi-dopamine ye-extracellular (DA) kwimimandla ye-limbic (kubandakanya i-nucleus accumbens; NAc) (I-Di Chiara kunye ne-Imperato, i-1988; I-Koob kunye neBhloko, 1988), ezinxulunyaniswa nefuthe lazo lokuqinisa. Ezi ziphumo ziyafanaSchultz et al., 2000). Nangona ezinye izifundo zezilwanyana zibuze ukuba ingaba ukunyuka kweDA kwi-NAc kudibana njani nomvuzo (Drevets et al., 2001; Imini et al., 2007), izifundo zokucinga ngomntu zibonise ukuba ukunyuka okunyanzeliswa ziyobisi kwi-DA kwisistriatum (kubandakanya ne-ventral striatum, apho ikhoyo i-NAc) kudityaniswa neenkcazo zembuyekezo (ephezulu, euphoria) ( Volkow et al., 1996a; Drevets et al., 2001). Nangona kunjalo, kuyabonakala kwakhona ukuba inqanaba lokudubula leeseli ze-DA alingomvuzo nje (UTobler et al., 2007kunye nokulindeleka komvuzo (Volkow et al., 2003b) kodwa kunye ukungasebenzi kakuhle Umsitho othileIiroll et al., 1984; Williams et al., 1993; Horvitz, 2000; UZink et al., 2003). Ubungqindilili bomsitho buqhutywa kukungalindeleki kwayo, ngokungeyonyani, ngokulindelwe komgangatho okanye ngeziphumo zayo zokomelela (ezintle kunye nezingalunganga) (Volkow et al., 2003, 2006b). Ukudutyulwa kweeseli ze-DA, kungqinelana nokusetyenziswa kwechiza kuyakwenza lula ukudityaniswa kwememori yokulandelela exhunyiwe kwichiza. Ezi zinto, ziya kuthi zibangele ukuba iiseli ze-DA zidubule ngokuchatshazelwa kwixesha elizayo kwisiphumo esayanyaniswa nesiyobisi (silindele umvuzo)I-Waelti et al., 2001). Ngenxa yendima ye-DA yenkuthazo, i-DA inyusa inxulunyaniswa neziyobisi okanye ichiza ngokwalo kunokwenzeka ukuba litshintshe inkuthazo yokufumana umvuzo (McClure et al., 2003).

Ukwanda kolwazi ngokubhekisele kwindima ye-DA kwiinkqubo zokuqinisisa kukhokelele kwiimodeli ezintsonkothileyo zeziyobisi ezinobungozi. Kukholelwa ngoku ukuba iziyobisi ziyaqinisa kungekuphela nje ukuba ziyonwabisa kodwa ngenxa yokwanda kwe-DA, zenziwa njengezimvo ezizezinye eziya kuthi zikhuthaze ukuthengwa kwesiyobisi ngakumbi (nokuba kuthini na ukuba ichiza liboniwe oko. ).

Iindlela zokucinga ngobuchopho zibe negalelo elikhulu koku kuqonda okutsha. Basivumele ukuba silinganise iinkqubo ze-neurochemical kunye ne-metabolic kwingqondo yomntu ephilayo (Volkow et al., 1997a), ukuphanda ubume beenguqu kwi-DA ebangelwa ziyobisi zokuxhatshazwa kunye nokuziphatha kwabo, kunye nokufunda utshintsho lweplastikhi kwimisebenzi ye-DA yeengqondo kunye neziphumo zoko kwizifundo ezichaphazela iziyobisi. Eli phepha linika uphononongo oluhlaziyiweyo lweziphumo ezifanelekileyo.

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2. I-dopamine ebangelwa ziziyobisi iyanda kwingqondo yomntu kunye nasekuqinisweni

Ukusetyenziswa kwe-positron emission tomography (PET) kunye ne-D2 DA receptor radioligands (umzekelo, [11C] ubuhlanga, [18F]N-methylspiroperidol) ibonakalise into ebaluleke kakhulu kwisifundo sobudlelwane obuphakathi kwendlela yesiyobisi sokuguqula i-DA kunye nokuqiniswa kwayo (okt. Indlela isetyenziswe kakuhle ukuvavanya iziphumo zamachiza anyusa amandla (okt. Methylphenidate, amphetamine, cocaine) kunye nezo ze-nicotine (U-Barrett et al., 2004; Brody et al., 2004; I-Montgomery et al., 2007; UTakahashi et al., 2007). Zombini ulawulo olungena ngaphakathi lwe-methylphenidate (0.5 mg / kg), efana necocaine, yonyusa iDA ngokuvimba izithuthi ze-DA (i-DAT) kunye nezo ze-amphetamine (0.3 mg / kg), ezifana ne-methamphetamine, yandisa i-DA ngokuyikhulula kwi Isiphelo sendlela edlula nge-DAT, ukunyusa ingxinano yangaphandle ye-DA kwi-striatum kunye nokunyuka okunxulunyaniswa neengxelo zokuzikhupha "eziphakamileyo" kunye ne "euphoria" (Hemby et al., 1997; UVillemagne et al., 1999). Okubangela umdla kukuba, i-methylphenidate ehlelwe ngomlomo (i-0.75-1 mg / kg) yonyusa i-DA kodwa ayibonwa njengento yokuqinisa (I-Chait, 1994; Volkow et al., 2001b). Ukusukela ulawulo olungena ngaphakathi lukhokelela kutshintsho olukhawulezileyo lwe-DA ngelixa ulawulo ngomlomo luyonyusa kancinci i-DA, ukusilela ukugcina "phezulu" nge-methylphenidate yomlomo-okanye i-amphetamine (I-Stoops et al., 2007) -Inokubonakala kancinci kancinci kwi-pharmacokinetics (I-Parasrampuria et al., 2007). Ewe, isantya sokungena kweziyobisi gadalala kwingqondo sele samkelwe njengenxalenye ephambili yempembelelo yokuqinisa (I-Balster kunye ne-Schuster, i-1973; Volkow et al., 1995, 2000). Akumangalisi ukuba i-DA inyuka kwi -ralral striatum eyenziweyo emva kokutshaya, enesantya esifanayo sokuthathwa kwengqondo, zidibene nemiphumela yokuqinisa (Brody et al., 2004).

Olu nxibelelwano phakathi kokuthatha ngokukhawuleza kwengqondo (olukhokelela kutshintsho olukhawulezileyo lwe-DA) kunye neepropathi zokomeleza iziyobisi ezinikiweyo zibonisa ukubandakanyeka kokudubula kwe-phasic ye-DA. Ukuqhuma okukhawulezayo (> i-30 Hz) eveliswe kukukhutshwa kwe-phasic kukhokelela kukutshintsha okungalunganga kwamanqanaba e-DA anegalelo ekuqaqambiseni ubunyani bento evuselelayo (Ubabalo, 2000). Oomatshini abema ngokuchaseneyo nokudubula kweseli ye-tonic (ngokuhamba kancinci kwe-5 Hz), enoxanduva lokugcina amanqanaba e-DA asisiseko asemgangathweni wokubeka inkqubo yokuphendula kwi-DA. Ke ngoko, sicebise ukuba iziyobisi zokuphathwa gadalala zilawula ukuguqula utshintsho kuxinzelelo lwe-DA olulingisayo, kodwa olugqithisileyo, olo luveliswa kukudutyulwa kweseli ye-physiologic phasic. Kwelinye icala ukuphathwa ngomlomo kwamachiza okunyusa amandla, eyindlela esetyenziselwa iinjongo zonyango kunokwenzeka ukuba kubangele utshintsho olucothayo lwe-DA olufana nezo zinxulumene nokudubula kweseli ye-tonic (IVolkow neSwanson, 2003). Kungenxa yokuba iziyobisi ezivuselelayo ziyayivimba iDS, eyona ndlela iphambili yokukhupha i-DA (Williams no Galli, 2006), banako-nokuba banikwe ngomlomo-bonyusa ixabiso lokuqiniswa kwezinye izinto zokuqinisa (imbuyekezo yendalo okanye iziyobisi) (Volkow et al., 2001b). Ngokufanayo, i-nicotine, eyenza ukuba i-DA idubule esiseleni, ikwanyusa ixabiso lokuqiniswa leshukumisa sayo. Kwimeko yokugqibela ukudityaniswa kwe-nicotine kunye nomvuzo wendalo kunxulunyaniswa ngokungalinganiyo kwiziphumo zokomeleza.

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3. Indima ye-dopamine kwiziphumo zexesha elide leziyobisi zokuxhatshazwa kwi-DA kwingqondo yomntu: ukubandakanyeka kugqirha

Ukonyuka kwe-Synaptic kwi-DA kwenzeka ngexesha lotywala iziyobisi kuzo zombini iziyobisi nakwizifundo ezingezozamakhoboka (I-Di Chiara kunye ne-Imperato, i-1988; I-Koob kunye neBhloko, 1988). Nangona kunjalo, ligcuntswana nje lezifundo ezivelweyo-owona msebenzi ungohlobo lodidi olusetyenzisiweyo-oluhlala luqhuba unyanzeliso lokuqhubeka nokuthatha iyeza (Schuh et al., 1996). Oku kubonisa ukuba ukonyuka okunyanzelekileyo kweziyobisi kwi-DA kukodwa akunakuchaza ukuphucuka okulandelayo kotywala. Ngenxa yokuba iziyobisi zifuna ukuphathwa gwenxa kweziyobisi, kunokwenzeka ukuba zibezinxalenye-kubantu abasesichengeni-ekubekweni okuphindaphindiweyo kwenkqubo ye-DA, kushukumisela uqhelaniso lwe-neuro emvuzweni / isisiququ, ukuqhubela phambili / ukuqhuba, ulawulo lwe-inhibitory / umsebenzi olawulayo kunye nememori / imeko imijikelezo, zonke eziguqulwe zangumgaqo wedopaminergic (Volkow et al., 2003a).

Ngokuhambelana nalo mgca wengcinga, kukho ubungqina obandayo bokuba ukuvezwa kwezinto ezivuselelayo, i-nicotine, okanye i-opiates kuvelisa utshintsho oluguqukayo kulwakhiwo lwe-dendrites kunye ne-dendritic spines kwiiseli kwiindawo eziphambili zobuchopho kunye nendima yokuqhubela phambili, umvuzo, ukugweba kunye ulawulo lwezinto ezingalawulekiyo (URobinson noKolb, i-2004). Umzekelo, uhlengahlengiso olungapheliyo kwisibonakaliso se-receptor ye-DA kunokubangela iimpendulo ze-glutamate receptor ezinamandla okuchaphazela ukuqina kwe-plastiki ye-synaptic (UWolf et al., 2003). Inyani yokuba yi-DA (UWolf et al., 2003; Liu et al., 2005), kodwa kunye ne-glutamate, i-GABA, kunye nezinye ii-neurotransmitters, zonke ziimodyuli ezinobuchule obuninzi beplastiki ye-synaptic, isondeza indlela eqondile edibanisa iziphumo zeziyobisi zokuxhatshazwa kunye notshintsho oluguqulwayo, hayi kwiziko lembuyekezo kodwa nakwiminye imijikelezo emininzi, ngokuqinisa, ukubumba, kunye nokucima ii-synapses.

Kusetyenziswa iiradio radiator ezininzi ekufumaneni nasekulinganiseni ezi ntlobo zotshintsho kwiithagethi zenethiwekhi ye-DA kwingqondo yomntu (1 Table). Sebenzisa [18F]N-methylspiroperidol okanye [11C] ubuhlanga buhle thina nabanye (UMartinez et al., 2004, 2005, 2007) bonise ukuba izifundo zilikhoboka leziyobisi ezahlukileyo (i-cocaine, i-heroin, utywala, kunye ne-methamphetamine), zibonise ukuncipha okukhulu kwi-D2 DA receptor ekhoyo kwi-striatum (kubandakanya i-ventral striatum) eqhubekayo kwiinyanga emva kokukhutshwa kwesidenge (Volkow et al., 2007a). Iziphumo ezifanayo ziye zaxelwa kutshanje kwizifundo ezixhomekeke kwisicotine (Fehr et al., 2008).

1 Table

1 Table

Isishwankathelo seziphumo ze-PET ngokuthelekisa iithagethi ezahlukileyo ezibandakanyeke kwi-arhente yokuhlaselwa kwe-DA phakathi kwabaxhaphazi beziyobisi kunye nezifundo zolawulo apho kuchongwe khona umahluko obalulekileyo phakathi kwamaqela

Kubalulekile ukwalatha kule meko ukuba ukunyuka kwestrato kwi-DA kubangelwa yi-methylphenidate ye-intravenous okanye amphetamine ye-intravenous (ihlolwe ngo [11C] i-raclopride) kubaxhaphazi be-cocaine kunye nabanxilisayo ubuncinci i-50% isezantsi kunezifundo zokulawula (Volkow et al., 1997b; UMartinez et al., 2007). Ukusukela kukonyuka kwe-DA okubangelwa yi-methylphenidate kuxhomekeke kukhutshelo lwe-DA-umsebenzi wokudubula iseli ye-DA-kuvakala ngokucacileyo ukuba umahluko unokubonakalisa ukuncipha kweseli le-DA kwabaxhaphazi iziyobisi.

Kubalulekile ukukhumbula ukuba iziphumo zezifundo ze-PET ezenziwe [11C] ubuhlanga, obuthathelwa ingqalelo kukhuphiswano kunye ne-DA yezangaphandle, luphawu nje olwamkelekileyo lwe-D2 DA receptors ekhoyo ukubopha isikram. Ke ngoko, naluphi na ukuncitshiswa kwe-D2 DA receptor ekhoyo njengoko ilinganiswe ne- [11C] umdyarho webala unokubonakalisa ukuncipha kwamanqanaba e-D2 DA receptors kunye / okanye ukwanda kokukhutshwa kwe-DA (ukukhuphisana ngokubopha ne [11C] i-raclopride ye-receptors ye-D2) kwi-striatum (kubandakanya i-NAc). Nangona kunjalo inyani yokuba abo baphathe gadalala i-cocaine xa inikezwe i-iv MP ibonise ukunciphisa okucekeceke ngokubopha okungafaniyo (isibonakaliso sokunciphisa ukukhutshwa kwe-DA) kubonisa ukuba kubaxhaphazi be-cocaine bobabini bancitshisiwe kumanqanaba okwamkela i-D2 receptors kunye nokwehla kokukhutshwa kwe-DA kwi-striatum. Umntu ngamnye uya kuba negalelo ekunciphiseni ubuntununtunu kwizifundo ezinoburheletyo kwizincedisi zendalo (Volkow et al., 2002b). Kuba iziyobisi zinamandla kakhulu ekuvuseleleni imijikelezo yomvuzo elawulwa yi-DA kunezixhaso zendalo, iziyobisi ziya kuba nakho ukwenza isebenze imijikelezo yomvuzo odakileyo. Oku kuncipha kokuziva, kwelinye icala kungabangela inzala encitshisiweyo yenkuthazo yendalo esingqongileyo, mhlawumbi okunokubeka phambili izinto eziza kukhokelela ekufuneni iziyobisi njengendlela yokwenza ixeshana ngokujikelezayo komvuzo. Njengoko ixesha lihamba, imeko engapheliyo yokuziphatha oku inokuthi ichaze utshintsho ukusuka ekuthatheni iziyobisi ukuze uzive "uphakame" uye ekuzithatheni ukuze uzive uqhelekileyo.

Zeziphi izinto ezihambelana nemetabolism kunye nokusebenza kokuphambuka okungapheliyo okuchaphazela iziyobisi kwimpilo ye-dopaminergic? Sebenzisa i-radiatorracer ye-PET [18F] i-fluoro-deoxyglucose (FDG) yokulinganisa umxholo we-glucose metabolism, thina kunye nabanye siye sabonisa ukunciphisa umsebenzi kwi-orbitofrontal cortex (OFC), i-cingulate gyrus (CG) kunye ne-dorsolateral pre kwangaphambilial cortex (DLPFC) kwizifundo eziluthayo (iziyobisi, abasebenzisa kakubi i-cocaine, abaxhaphazi abaxhaphaza abantwana)ELondon et al., 1990; UGalynker et al., 2000; U-Ersche et al., 2006; Volkow et al., 2007a). Ukongeza, kwi-cocaine (I-Volkow neFowler, i-2000kunye ne-methamphetamine (IVolkowet al., 2001aiziyobisiVolkow et al., 2007d), sibonise ukuba umsebenzi ophungulweyo kwi-OFC, CG kunye ne-DLPFC unxulunyaniswa nokuncipha kokufumaneka kwe-D2 DA receptors kwi-striatum (bona Ikhiwane. 1 kwiziphumo ze-cocaine kunye ne-methamphetamine). Kuba i-OFC, i-CG kunye ne-DLPFC bayabandakanyeka kulawulo lwe-inhibitory (I-Goldstein neVolkow, i-2002) kunye nokulungiswa kwemvakalelo (Phan et al., 2002), besikhuphe into yokuba ulawulo lwabo olungaqhelekanga olwenziwe yi-DA kwizifundo ezikhobokisayo lunokunciphisa ukuphulukana kwabo nolawulo lokusebenzisa iziyobisi kunye nokuzilawula kwabo ngokweemvakalelo. Ewe, kwiziselo ezinxilisayo, ukuncitshiswa kwe-D2 DA receptor receptor kwi-ventral striatum kubonisiwe ukuba kunxulunyaniswa nobunxila obunxilisayo kunye nokunyanzeliswa okukhulu kwe-cue kunye ne-CG yokunyanzeliswa kwangaphambili, njengoko kuvavanywa nge-FMRI (UHeinz et al., 2004). Ukongeza, kuba ukonakaliswa kwe-OFC kukhokelela kuhambo lokunyamezelana (Imiqulu, i2000) -Kwaye ukungonakali kwabantu kwi-OFC kunye ne-CG zinxulunyaniswa nokuziphatha okunyanzelekileyo kokuziphatha (Saxena et al., 2002) -Sikhuphe nengxelo yokuba ukunganyanzelwa yi-DA kwezi ngingqi kungasenza ukuba singanyanzelwa ziyobisi.Volkow et al., 2005).

Ikhiwane. 1

Ikhiwane. 1

(A) Ukuhambisa ivolumu eqhelekileyo11C] umdyarho we-raclopride obophelela kwi-striatum ye-cocaine kunye ne-methamphetamine abaxhaphazi kunye nezifundo zokuthelekisa ezingekho gwenxa iziyobisi. (B) Ukulungelelaniswa kokufumaneka kwe-DA receptor (Bmax/Kd) kwi-striatum enemilinganiselo ye-metabolic ...

Nangona kunjalo, umbutho unokutolikwa ubonakalisa ukuba ukungasebenzi kakuhle kwimimandla yaphambi kwexesha kungabeka abantu emngciphekweni wokusetyenziswa gwenxa kweziyobisi kwaye kuphela apho ukusebenzisa iziyobisi okuphindaphindiweyo kungakhokelela ekuthotyelweni kwe-receptors ze-D2 DA.

I-DA ikwamisa kwakhona imisebenzi ye-hippocampus, i-amygdala kunye ne-dorsal striatum, imimandla ebekwe kwimemori, imeko kunye nokudalwa komkhwa (Volkow et al., 2002a). Ngaphaya koko, uhlengahlengiso kwezi ndawo lubhalwe kwiimodeli zokusetyenziswa gwenxa kweziyobisi (IKauer kunye neMalenka, i-2007). Ewe kunjalo, ukwanda kokuqonda ukubaluleka kokubandakanyeka kwimemori kunye neendlela zokufunda kwikhoboka leziyobisi (UVanderschuren no-Everitt, i-2005). Iziphumo zeziyobisi zokuxhatshazwa kwiinkqubo zeememori zicebisa ngeendlela ezinokuthi zithathe inxaxheba kwisimo sokukhuthala-oko kukuthi, ngokufunda okulungiselelwe imeko-yenkuthazo. Kuphando lokuphinda ubuye, kubaluleke kakhulu ukuqonda ukuba kutheni iziyobisi ezinamakhoboka eziyobisi zinomnqweno onamandla wesiyobisi xa zichaziwe kwindawo apho ziye zaluthatha khona iyeza, kubantu ebezenzakalisile ngaphambili ekusebenziseni iziyobisi, kunye nokusetyenziswa kweziyobisi. ichiza. Oku kufanelekile kwiklinikhi ngokokuvezwa kwezinto ezinesimo esivumayo (inkuthazo eyayinxulunyaniswe ngamandla namava amachiza) oloncedo oluphambili lokuphinda ubuye. Kuba iDA iyabandakanyeka kuqikelelo lomvuzo (Schultz, 2002), I-DA kuqikelelwe ukuba ibenike iimpendulo eziphantsi komnqweno wakhe. Izifundo zaphambi kokuba kuxhaswe le ntelekelelo: xa ukungathathi hlangothi kubhangqwe ngechiza, izilwanyana ziya kuthi kunye nemibutho ephindaphindeneyo-zifumane amandla okunyusa i-DA kwi-NAc nakwi-dorsal striatum xa zivelisiwe kwindawo ekhoyo ngoku. Ngokwembonakalo, ezi mpendulo ze-neurochemical zifunyenwe zinxulunyaniswa neendlela zokufuna iziyobisi (UVanderschuren no-Everitt, i-2005).

Kubantu, izifundo ze-PET kunye [11C] ubuhlanga buhlanga buqinisekisile le hypothesis ngokubonisa ukuba kwi-cocaine abahlukumezi iziyobisi ii-cocaine-cue ividiyo yeziganeko zezifundo ezithatha i-cocaine) yandise kakhulu iDA kwi-dorsal striatum, kwaye olu nyuko lwalunxulunyaniswa nokunqwenela i-cocaine (Volkow et al., 2006c; Wong et al., 2006) ngendlela exhomekeke kwi-cue (Volkow et al., 2008). Ngenxa yokuba dorsal striatum ibaluleke kakhulu kwimikhwa yokufunda, lo mbutho unokubonakalisa ukomelela kwemikhwa njengoko kusenzeka okungapheliyo kotywala. Oku kuphakamisa ukuba iimpendulo ezimiselweyo ze-DA zibangela ukuba kwenzeke, imikhwa yokuqala kwaye emva koko ukusetyenziswa kweziyobisi okunyanzelekileyo, kunokubonakalisa ubuntlola bokuqala be-neurobiological. Kusenokwenzeka ukuba ezi mpendulo zibekiweyo zibandakanya ulungelelwaniso kwiindlela zecortico-striatal glutamatergic ezilawula ukukhutshwa kwe-DA (UVanderschuren no-Everitt, i-2005).

Ukuvavanya ukuba ukunyuka kwe-cue eyenziwe yi-DA kubonisa impendulo esisiseko okanye impendulo yesibini kumlo osele ucinga ngokufunda kwizifundo ezixekisayo ze-cocaine kuvavanye iziphumo zokunyusa i-DA (iphunyezwe ngolawulo ngomlomo lwe-methylphenidate), ngaphandle nangaphandle kwendawo, kumzamo ukufumanisa ukuba ingaba i-DA inyuka yodwa ingabanqwenela na. Iziphumo zophononongo ziveze ukungahambelani okucacileyo phakathi komlomo we-methylphenidate-induction ye-DA ukwanda kunye neminqweno ehambelana ne-cuevings (Volkow et al., 2008) Ukucebisa ukuba ukonyuka kwe-cue okubangelwa kukonyuka kwe-DA ayisiyi mpembelelo eziphambili kodwa kunoko kubonakalisa ukwehla kweeseli ze-DA (ii-cortico-striatal glutamatergic iindlela ezilawula ukukhutshwa kwe-DA; IKalivas neVolkow, i-2005). Oku kuqaphela kukhokelela ngakumbi kwiziphumo ezicekeceke ze-DA zokudubula kumjikelezo wokulutha, kuba ukusilela kwe-methylphenidate-eyanyiswe i-DA inyusa ukuba nomnqweno kule paradigm kungacaciswa kukucothisa kwe-DA. Kwelinye icala, utshintsho olukhawulezileyo lwe-DA luye lwabangelwa kukudubula kweseli ye-phasic-njengempendulo yesibini ekusebenzeni kweendlela zeendlela-inokubangela impumelelo kumnqweno wokufumana ulwazi kwi-cue. Kufanelekile ukuqaqambisa, ukuba uMartinez et al. uxele ukungqinelani okungalunganga phakathi kwe-DA inyuselezelwa yi-amphetamine ye-intravenous kubaxhaphazi becocaine kunye nokukhetha kwabo icocaine ngaphezulu kwemali xa kuvavanywa kwiparadigm eyahlukileyo (UMartinez et al., 2007). Oko kukuthi, izifundo ezibonise ukwanda kwe-DA esezantsi xa zinikwa i-amphetamine zezona zinokukhetha i-cocaine ngaphezulu kokuqiniswa kwemali. Kungenxa yokuba kwizifundo zabo baye baxela ukunyuka kwe-DA kubaxhaphazi becocaine xa kuthelekiswa nolawulo oku kungabonisa ukuba abaxhaphazi becocaine ngokuncipha okukhulu ekusebenzeni kwengqondo dopaminergic zezabo banokukhetha i-cocaine ngaphezulu kwezinye izixhasi.

Yiya e:

4. I-DA kunye nokuba semngciphekweni wokusetyenziswa gwenxa kweziyobisi

Ukuqonda ukuba kutheni abanye abantu besengozini enkulu yokuba likhoboka leziyobisi kunabanye kuhlala kungoyena mbuzo ucela umngeni kuphando lokusebenzisa iziyobisi. Kwizilawuli ezisempilweni zokungasebenzisi gwenxa iziyobisi sabonisa ukuba ukubakho kwe-D2 DA receptor kwisistriatum kulungisiwe iimpendulo zabo zecala lokunyusa iziyobisi i-methylphenidate. Izihloko ezichaza amava njengento emnandi zazinamanqanaba asezantsi ama-receptors xa kuthelekiswa nalawo achaza i-methylphenidate njengengathandekiyo (Volkow et al., 1999, 2002c). Oku kuphakamisa ukuba ubudlelwane phakathi kwamanqanaba e-DA kunye nokuphendula okuqinisayo kulandela ijika elinombhalo o-U: mncinci kakhulu kunento yokwenza nokuqinisa ngelixa kakhulu linokuphazamiseka. Ke, amanqanaba aphezulu e-D2 DA receptor anokukhusela ngokuchasene nolawulo lweziyobisi. Inkxaso yoku ibonelelwa ngezifundo ezizodwa, ezibonisa ukuba amanqanaba aphezulu e-D2 DA receptors e-NAc anciphisa kakhulu isiselo esinxilisayo kwizilwanyana ebeziqeqeshelwe ukuzenzela utywala ngaphambili (Thanos et al., 2001) utyekelo lwee-cynomolgus macaque ezihlala iqela ukuzilawula ngokwazo icocaine (Morgan et al., 2002), kunye nezifundo zeklinikhi ezibonisa ukuba izifundo ezazinganxiliswa butywala ezazingezizo iintsapho ezinxilisayo zazinokuphakama (D2 DA receptors) kwi-striatum kunabantu abangenazo iimbali zosapho (Volkow et al., 2006a). Ukunyuka okuphezulu kwe-D2 DA receptors kwezi zifundo, kuphakama imetabolism yabo kwi-OFC nakwi-CG. Yiyo loo nto sinokuthi sigqithisele ukuba amanqanaba aphezulu e-D2 DA receptors anokuzikhusela ngokuchasene notywala ngokuguqula imijikelezo yangaphambili ebandakanyeka kulwazi lwe-salience kunye nolawulo lwe-inhibitory.

Kwelinye icala lesiphelo, sifumene ubungqina bokwenza uxinzelelo lwe-dopamine kwimimandla ethile yobuchopho kubantu abadala abane-ADHD xa kuthelekiswa nolawulo. Ukusilela kubonwe kwinqanaba le-receptors ye-D2 ye-DA kunye nokukhululwa kwe-DA kwi-caudate (Volkow et al., 2007b) nakwi-ventral striatum (Volkow et al., 2007c). Kwaye, ngokuhambelana nemodeli yangoku, i-phenotype ye-DA edandathekileyo inxulunyaniswa namanqaku aphezulu kwizxelo zokuzazisa ze-methylphenidate ukuthanda ukuthanda (Volkow et al., 2007b). Into ebangela umdla kukuba, ukuba ishiywe ingalungiswa, abantu abane-ADHD banomngcipheko omkhulu wokuphazamiseka ekusetyenzisweni gwenxa kweziyobisi (U-Elkins et al., 2007).

Okokugqibela, umahluko wokwabelana ngesondo kweziphazamiso zomlutha uye waphononongwa uphinda-phindwayo, kwaye kuya kuba sengqiqweni ukubuza ukuba ngaba izifundo ezizezamabali zinokuxhasa ubungqina bobuchwephesha obucacisa ukuba umahluko ubangelwa yinxalenye yokwahluka kwenkqubo ye-DA kunye / okanye ukuba zibangelwa ngumahluko kwizinto ezenziwayo. imimandla ephambili (Koch et al., 2007). Ewe, uphononongo lwakutsha nje lubhale iipateni zesidocphic zesini zokukhutshwa kwe-amphetamine-induction striatal DA ((UMunro et al., 2006; URic Cardi et al., 2006) enokuchaphazela ukusetyenziswa gwenxa kweziyobisi ngokwahlukileyo kumadoda nabafazi; nangona idatha ingavumeli okwangoku ukupheliswa okucacileyo malunga nokuba amadoda okanye abafazi babonisa iimpendulo ezinkulu ze-DA. Kukwanokwenzeka ukuba iipateni ziya kuthathela ingqalelo iimeko zokuvavanya, ezinje ngemeko, iminyaka kunye nenqanaba lomjikelo wokuya esikhathini.

Xa zidityanisiwe, ezi zinto ziqwalaselyo zibonelela ngengqondo ebalulekileyo kwinkqubo yenkxaso ye-DA kwinto yokuba sesichengeni, ekuveleni kweziphephiso zengqondo ezixhaphakileyo zengqondo, kunye neepateni zokuziphatha ezihamba gwenxa ngokwesini.

Yiya e:

5. Impembelelo zonyango

Izifundo zokulinganisa zilungelelanise indima ye-DA kwiziphumo zokuqiniswa kweziyobisi zokuphathwa gadalala ebantwini kwaye yandise umbono wesiko lokubandakanyeka kwe-DA kwikhoboka leziyobisi. Ezi ziphumo zicebisa ngeendlela ngeendlela zokunyanga iziyobisi ezithi zizame ukuba (a) zinciphise ixabiso lomvuzo wesiyobisi esikhethwayo kunye nokonyusa ixabiso lomvuzo wabantu abangaxhasi iziyobisi; (b) yenze buthathaka iimeko zokuziphatha zeziyobisi, kunye nogqozi lokuthatha iyeza; kunye (c) nokomeleza inhibitory yangaphakathi nolawulo oluphezulu. Akuxoxwanga kolu hlaziyo kukuzibandakanya okubalulekileyo kwimijikelezo elawula iimvakalelo kunye nokuphendula koxinzelelo (UKoob noLe Moal, i-1997) ngokunjalo nabo banembono yokuqonda okukuko kwiimfuno neminqweno (Grey kunye neCritchley, 2007), ekwajolise ekujoliseni ungenelelo ngoncedo lwezonyango.

Yiya e:

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