Qhov cuam tshuam ntawm DPTQ, A Novel Positive Allosteric Modulator Ntawm Dopamine D1 Receptor, On Spontaneous Eye Blink Rate Thiab Spatial Working Memory hauv Nonhuman Primate Part 2

Cov teebmeem ntawm DPTQ spatial ua haujlwm nco kev ua tau zoo ntawm qhov xav tau koob tshuaj zoo

Ib koob tshuaj DPTQ yog thawj zaug kuaj ntawm 2.5 mg / kg piv rau lub tsheb. Sib cais tab sis sib tshooj hauv paus tau siv rau ob qho xwm txheej. Cov ntaub ntawv tsheb tau qhia hauv daim duab 4a rau ib pawg ntawm 10 tus tsiaj. Pab pawg kev hloov pauv hauv kev ua tau zoo sib txawv me ntsis los ntawm cov hauv paus hauv qab 2 lub lis piam tom ntej nrog qhov sib txawv loj tshaj plaws rau cov pab pawg nruab nrab tsuas yog nce mus txog 5% (p=0.51, ua ke t-test nyob rau hauv cov ntsiab lus piv rau hauv paus). Nco ntsoov, tsis muaj kev cuam tshuam rau kev ua tau zoo rau hnub 1. DPTQ (2.5 mg/kg, IM) cov ntaub ntawv tau qhia hauv daim duab 4b rau ib pawg ntawm 9 tus tsiaj.

Lub hauv paus yog hais txog cov yam ntxwv ntawm kev puas siab puas ntsws ruaj khov thiab kev coj tus cwj pwm uas tsim los ntawm txoj kev loj hlob. Kev nco yog hais txog lub peev xwm ntawm tib neeg lub hlwb kom tau txais, txheej txheem, thiab khaws cov ntaub ntawv. Muaj kev sib raug zoo ntawm cov hauv paus ntsiab lus thiab kev nco, thiab rau qee qhov, cov hauv paus ntsiab lus tuaj yeem cuam tshuam rau tus neeg lub cim xeeb.

Ua ntej, muaj lub hauv paus ruaj khov tuaj yeem pab tus neeg muaj tus cwj pwm zoo thiab lub siab zoo, uas tuaj yeem pab txhim kho kev nco. Piv txwv li, lub sijhawm pw tsaug zog tsis tu ncua, kev tawm dag zog ib txwm, noj zaub mov kom zoo, thiab tus cwj pwm zoo rau lub neej tuaj yeem txhim kho kev nco. Qhov no yog vim tias cov kev ua neej nyob zoo no tuaj yeem ua rau tib neeg lub cev thiab lub hlwb noj qab haus huv, yog li txhim kho kev ua haujlwm ntawm lub hlwb thiab kev nco.

Qhov thib ob, lub hauv paus ruaj khov kuj tseem tuaj yeem pab tib neeg kom nyob twj ywm thiab tsom mus. Qhov no tseem ceeb heev rau kev txais tos thiab ua cov ntaub ntawv. Kev ua neej tsis zoo thiab tsis sib haum xeeb tuaj yeem cuam tshuam rau tus neeg lub peev xwm ua kom pom tseeb thiab mloog zoo, uas tuaj yeem cuam tshuam kev nco. Kev ua neej nyob tsis tu ncua tuaj yeem pab tus neeg kom muaj kev sib haum xeeb thiab kev xav, yog li txhim kho kev nco.

Thaum kawg, lub hauv paus zoo tuaj yeem ua rau tib neeg muaj kev cia siab thiab ntseeg siab, uas tuaj yeem pab txhim kho kev nco. Lub hauv paus zoo tsim kev ntseeg siab rau koj tus kheej thiab koj lub neej yav tom ntej, thiab kev ntseeg siab no ua rau koj lub cim xeeb ntse dua, hloov tau yooj yim, thiab ua haujlwm zoo dua.

Hauv cov ntsiab lus, muaj qee qhov kev sib raug zoo ntawm lub hauv paus thiab kev nco. Lub hauv paus ruaj khov, noj qab nyob zoo, koom ua ke, thiab muaj txiaj ntsig zoo tuaj yeem pab tib neeg kom muaj kev noj qab haus huv thiab kev xav zoo, yog li txhim kho kev nco. Yog li ntawd, peb yuav tsum siv zog los tsim peb lub hauv paus los txhim kho peb lub peev xwm nco. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche deserticola tuaj yeem pab peb txhim kho peb lub cim xeeb vim Cistanche deserticola yog cov khoom siv tshuaj suav tshuaj uas muaj ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm cov nqaij minced los ntawm ntau yam khoom xyaw uas nws muaj, nrog rau cov kua qaub, polysaccharides, flavonoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub ntxiv los txhim kho kev nco

1- txoj kev ANOVA tau qhia tias tag nrho cov ntaub ntawv teev tseg rau txhua tus tsiaj rau txhua hnub txawv ntawm cov ntaub ntawv hauv paus rau txhua tus tsiaj (F[10,69]=6.48, p<0.0001). No immediate acute effect was seen on day 1 but, a slight (10%) diminution of performance was evident by day 2 which became more robust by day 3, more than 48 h post-injection (mean = 61.1; post hoc comparison with baseline, p=0.025). Note that in this first data set those tests on the days following day 1 were originally purely exploratory and therefore have low N values in some cases.

Kev soj ntsuam kev coj cwj pwm qhia tau hais tias cov tsiaj thawj zaug nyob rau hnub 2 thiab 3 tau ua haujlwm me ntsis los ntawm qhov koob tshuaj no suav nrog kev ceev faj / kev saib xyuas, tab sis tsis yog kev ua kom lub cev muaj zog, uas tuaj yeem cuam tshuam rau lawv cov lus teb. Qhov kev puas siab puas ntsws hauv kev paub tam sim ntawd tau ua raws li qhov kev txhim kho loj heev pom nyob rau hnub tom qab (txhais tau tias=84.3) uas tau mob siab rau ob peb hnub (hnub 4, 5, thiab 6, p.<0.01).

Cov teebmeem ntawm kev rov ua dua ntawm kev ua haujlwm ntawm qhov chaw nco

Txhawm rau tshuaj xyuas seb qhov koob tshuaj rov ua dua yuav ua rau muaj kev ua siab ntev, kev ua tiav, lossis kev nkag siab ntawm cov teebmeem no, ib koob tshuaj 2.5 mg / kg tau muab tshuaj hnyav rau hnub 1 (1 teev ua ntej kuaj, thiab tom qab ntawd lub tsheb (Fig. 5a) lossis ib qho ntxiv. koob tshuaj 2.5 mg/kg (Fig. 5b) tau muab rau hnub 5 (tam sim tom qab kuaj). Tsiaj txhu raug muab tso rau hauv DPTQ hnub 1 thiab lub tsheb hnub 5 ( pab pawg tsheb) lossis DPTQ ob hnub (DPTQ pawg ), tom qab ntawd hla mus rau lwm pab pawg kho mob tom qab lub sijhawm ntxuav kom tsim nyog Cov txiaj ntsig ntawm kev tswj hwm lub tsheb raws li koob thib ob tuaj yeem pom hauv daim duab 5a (n=10). ib qho kev sim zoo ib yam rau txoj kev tshawb fawb ib zaug rau DPTQ tau piav qhia saum toj no, raws li qhia hauv daim duab 4. Cov txiaj ntsig tshwm sim zoo ib yam li cov uas tau pom rau yav dhau los kev kawm ib koob tshuaj (F[10, 94]=5.23, p<0.0001), except that the deficit on day 3 was small and did not achieve significance (p=0.278 vs baseline) after which an enhancement appeared over the next few days (days 4 and 8, p < 0.001; day 5, p < 0.0001; days 10 and 12, p<0.05 vs baseline). 

Ib pawg ntawm cov tsiaj tib yam (n=6) tom qab ntawd tau raug xa mus rau DPTQ pawg, tau txais koob tshuaj dua 2.5 mg / kg DPTQ rau hnub 5 (tag nrho cov ntsiab lus tseem ceeb F[10, 54]=5 .41, ib<0.0001). Following the acute dose of 2.5 mg/kg IM on day 1, a non-significant dip in performance was seen on day 3 which was followed by a rebound enhancement on days 4 and 5 (p<0.01). However, following the repeat of the dose on day 5, there is a reduction in performance to baseline on day 6, followed by enhancement for the subsequent week (days 8 and 12, p<0.05; days 10 and 14, p<0.01). Notably, performance was now significantly improved on the last day.

Cov teebmeem ntawm cov koob tshuaj tsawg ntawm DPTQ ntawm {{0}}.1 thiab 1.0 mg/kg

Raws li cov ntaub ntawv saum toj no peb tau sim qhov kev xav tias qhov koob tshuaj ntawm 2.5 mg / kg yuav yog qhov zoo tshaj plaws rau cov txiaj ntsig zoo ntawm kev paub txog thiab qhov koob tshuaj qis dua tuaj yeem ua tiav qhov tseem ceeb, ua kom muaj txiaj ntsig zoo hauv kev ua haujlwm nco thaum tseem zam qhov kev cuam tshuam ntawm qhov ntxov. kev tsis txaus ib ntus. Raws li kev xav, cov koob tshuaj qis dua (1.0 thiab 0.1 mg/kg, IM) ntawm DPTQ tau tshwm sim los qhia kev txhim kho yam tsis muaj kev puas tsuaj thaum ntxov ntawm kev nco (daim duab 6).

Ntawm qhov koob tshuaj ntawm {{0}}.1 mg/kg (Fig. 6a), DPTQ tshwm sim los ua tsis muaj qhov txo qis ntawm kev ua tau zoo nyob rau hnub 3 tab sis tseem, kev txhim kho me me ntawm kev ua haujlwm nco tau ntev txog 2 lub lis piam hauv pawg no ntawm 10 tsiaj (F[10, 98]=2.39; p {{10}}.014). Ib qho kev txhim kho tseem ceeb hauv kev paub tau pom nyob rau hnub 3 (p < 0.01) tom qab ze rau qhov kev ua tau zoo ntxiv rau hnub 2 (p=0.053). Thaum qhov kev ua tau zoo nyob rau hnub 4 tau nce mus txog qhov tseem ceeb (p=0.053), cov hnub tom qab tau pom kev txhim kho kom pom tseeb (hnub 5 thiab 10, p < 0.05; hnub 6, 8, thiab 12, p < 0.01) mus txog hnub 14. Rau 8 ntawm cov tsiaj no ces sim ntawm koob tshuaj 1.0 mg/kg, peb rov pom qhov kev txhim kho tseem ceeb hauv kev ua haujlwm nco nyob rau ob lub lis piam (Fig. 6b; F[10, 74]=2.75, p=0.006).

Txaus siab rau qhov kev txhim kho kom pom tseeb tuaj yeem pom txij hnub 2 (p<0.01) and although performance on day 3 was still elevated (p<0.05) there was a noticeable reduction in score that day before the strong improvement seen on day 4 (p < 0.0001). This enhancement continued for the next 3 days (day 5, p<0.05; days 6 and 8, p<0.05) and then faded until day 14 (p<0.05). To make a direct comparison between doses we performed an ANOVA across the 3 doses for days 3, 4, and 5. When we compared the effects of each on day 3, where we saw the initial reduction in performance at the high dose, we found a critical effect of dose (F[2,23]=10.18, p<0.001). Both doses of 0.1 and 1.0 mg/kg yielded a significantly higher score than that at 2.5 mg/kg (p < 0.01, p<0.05, respectively). Conversely, by day 4, a significant proportion of the variance in the data was also attributable to dose (F[2,22]=4.547, p<0.05) but this effect was inverted with the score at 2.5 mg/kg now becoming significantly greater than that at 0.1 mg/kg. No difference in scores could be attributed to the difference in dose on day 5.

Dose-dependent teebmeem ntawm ncua sij hawm

Tib cov ntaub ntawv tau raug tshuaj xyuas los tshuaj xyuas qhov cuam tshuam ntawm koob tshuaj ntawm D1PAM kev kho mob ntawm kev ncua sijhawm ua haujlwm tsis raug thiab yuav ua li cas qhov no txawv ntawm lub sijhawm cuam tshuam rau kev tswj hwm ntawm txhua koob tshuaj DPTQ. Rau lub hom phiaj no, peb tau xaiv los sib piv lub sij hawm taw tes ntawm hnub 5 los sib piv nrog cov kev ua yuam kev uas pom tom qab mob hnyav thiab cov hauv paus ntsiab lus raws li cov teebmeem ntawm DPTQ tau tshwm sim zoo tshaj plaws nyob rau hauv tag nrho cov koob tshuaj hnub ntawd. Tsis muaj qhov cuam tshuam tseem ceeb ntawm ib qho xwm txheej ntawm hnub 1 tau tshwm sim siv 2- txoj kev ANOVA. Raws li pom hauv daim duab 7, DPTQ ntawm qhov koob tshuaj tsawg ntawm 0.1 mg/kg ua rau me ntsis nce qhov yuam kev ntawm ob qho tib si luv (0, 1) N thiab ntev (3, 4) N ncua sijhawm ntawm txoj haujlwm thaum kuaj xyuas nws cov teebmeem hnyav rau hnub 1. Txawm li cas los xij, 96 teev tom qab hnub 5, qhov koob tshuaj ntawm D1 PAM no tau ua rau me me tab sis tsis tseem ceeb hauv kev ua yuam kev, tshwj xeeb tshaj yog thaum lub sijhawm ua haujlwm qeeb. Ob txoj kev RMANOVA pom tias tsis muaj qhov cuam tshuam tseem ceeb ntawm koob tshuaj thiab tsis muaj kev cuam tshuam nrog kev ncua rau hnub 5. Ntawm qhov koob tshuaj 1.0 mg/kg, DPTQ ua rau tsis muaj qhov txo qis ntawm qhov yuam kev luv luv rau hnub 1 tab sis tau tsim kev txo qis rau hnub 5. Txawm hais tias muaj qee qhov pov thawj ntawm kev txo qis ntawm qhov kev ncua sij hawm ntev rau hnub 5, qhov no tau pom tias tsis muaj qhov tseem ceeb yog vim muaj qhov sib txawv loj ntawm kev ua yuam kev los ntawm kev ncua sijhawm hauv txoj haujlwm.

Kev sib tham

Qhov zoo allosteric modulators ntawm dopamine D1 receptor tuaj yeem tso cai rau kev txhawb nqa tshuaj ntawm D1 teeb liab uas tsis muaj qhov tsis zoo xws li cov lus teb rov qab-U, kev ua siab ntev, thiab tachyphylaxis cuam tshuam nrog qee qhov kev kho D1 agonist. Hauv cov nas transgenic hD1, D1PAMs tshiab tshaj tawm xws li DETQ thiab medaled twb tau pom tias ua raws li cov lus cog tseg no hauv cov qauv xws li locomotor kev ua haujlwm thiab kev paub txog cov khoom tshiab (Svensson et al. 2017; Bruns et al. 2018; Hao et al. 2019, thiab Meltzer li al. 2019).

Txawm li cas los xij, qhov muaj peev xwm paub txog tus nqi ntawm D1PAMs mus dhau qhov kev ywj pheej los ntawm cov kev txwv no. Tsis zoo li tag nrho thiab ib nrab agonists, D1PAMs tsis tuaj yeem ua haujlwm ntawm tus kheej ntawm dopamine kis. Rau lawv qhov kev ua ntawm D1R, dopamine yuav tsum raug tso tawm ntawm cov chaw tshwj xeeb thiab qib ntawm kev hloov kho zoo yuav tsum nyob ntawm qib ntawm dopaminergic stimulation ntawm cov chaw, xws li ntawm cov leeg ntawm pyramidal neurons (Smiley li al. 1994) lossis cov dendrites ntawm inhibitory interneurons (Muly li al. 1998) nyob rau hauv cov cheeb tsam xws li PFC. Qhov no txhais tau hais tias D1PAMs tuaj yeem muab kev txhawb nqa ua haujlwm rau D1 teeb liab txuas ntxiv yam tsis muaj kev cuam tshuam spatiotemporal teeb meem hauv kev faib tawm ntawm qhov kev taw qhia, ua yeeb yam nrog lub sijhawm tiag tiag ntawm dopaminergic stimulation ntawm qhov chaw orthosteric.

Qhov kev ua kom tsim nyog lom neeg zoo li no tuaj yeem muab cov txiaj ntsig zoo rau kev kho mob ntawm cov kab mob tsis txaus hauv D1 signaling, xws li hnub nyoog txog kev paub txog kev poob qis. Ntxiv mus, qhov muaj D1PAMs xws li DETQ, DPTQ, thiab medaled tuaj yeem muab cov cuab yeej los daws cov kev sib txuam ntawm cov txheej txheem cuam tshuam nrog kev hloov pauv ntawm qhov tsis txaus, qhov zoo, thiab ntau dhau D1R stimulation thiab nws cuam tshuam rau neuroplasticity thiab kev paub (Williams thiab Castner 2006). Qhov kev tshawb pom ntawm txoj kev tshawb fawb tam sim no qhia tau hais tias qhov tseem ceeb ntawm D1PAMs, tsis yog rau kev kho mob ntawm neuropsychiatric mob xwb, tab sis kuj yog cov cuab yeej tshuaj rau kev txiav tawm ntawm cov tshuab neuronal hauv qab ob qho tib si muaj txiaj ntsig thiab cuam tshuam rau kev paub txog kev ua haujlwm zoo (Goldman-Rakic ​​li al. 2004; Roberts et al., 2010; Svensson et al., 2019).

DPTQ together with the closely related structural analogs DETQ and mevidalen belong to the tetrahydroisoquinoline series of D1PAMs (Svensson et al., 2017 Hao et al., 2019). These molecules show high potency and specificity for the human D1 receptor vs. other targets including the dopamine D2 receptor. The lack of affinity of DPTQ for the D2 receptor was confirmed in a broad screening study using 3 [H]-raclopride as a ligand where the D2 was found to be Ki>5.6 µM (cov kev tshawb pom tsis tau tshaj tawm). Qhov no yog nyob rau hauv txoj kab nrog yav dhau los cov ntaub ntawv luam tawm rau Mevidalen thiab DETQ uas tsis pom muaj kev ua haujlwm ntawm 10 µM hauv kev ua haujlwm thiab kev sib khi rau D2 receptor. DPTQ muaj qhov txo qis zog thiab ua tau zoo ntawm cov nas ib txwm muaj D1 receptor.

Qhov no muaj feem xyuam rau kev hloov pauv tshwj xeeb ntawm nas nyob rau hauv lub voj thib ob uas cov molecules khi (Wang li al., 2018). Raws li tau pom yav dhau los, cov D1PAMs no muaj peev xwm zoo sib xws thiab muaj txiaj ntsig zoo hauv cov tsiaj tsis muaj nas xws li tib neeg, dev, thiab rhesus liab (Svensson li al., 2017, Wang et al., 2018, Hao et al. 2019). Rau DPTQ, muaj kwv yees li ntawm 40-fold ntau dua potency rau tib neeg thiab liab vs. nas D1 receptor (saib Table 1). Raws li tag nrho cov pib hauv vivo tus cwj pwm ntawm D1PAMs tau ua tiav hauv tib neeg D1 khob-hauv nas, peb suav tias tus liab yog ib hom zoo dua tsim nyog rau kev soj ntsuam tshuaj ntxiv ntawm cov txheej txheem tshiab no.

DPTQ ua koob tshuaj-nyob ntawm ib txwm primate D1R los hloov qhov muag ntsais qhov muag

Cov kev sim thawj zaug tau lees paub tias DPTQ tuaj yeem cuam tshuam rau lub hlwb kev ua haujlwm hauv cov tsiaj tsis yog tib neeg los ntawm kev ua ncaj qha ntawm haiv neeg D1R los ntawm kev soj ntsuam nws cov teebmeem ntawm qhov muag ntsais qhov muag thiab txiav txim siab txog kev sib raug zoo ntawm cov tshuaj pharmacodynamic teb thiab cov tshuaj pharmacokinetics ntawm plasma raug tom qab IM tswj. Txij li qhov no yog thawj qhov kev tshawb fawb D1 PAM hauv NHP, peb tau siv cov tshuaj pharmacokinetic (PK) kev tshawb fawb thiab hauv vitro projections ntawm lub hlwb tsis muaj zog rau kev xaiv koob tshuaj (5 mg / kg, IM).

Qhov kev npaj ua rau lub hlwb tsis muaj zog ntawm DPTQ tom qab 5 mg / kg, IM DPTQ ranged ntawm 202 nM mus rau 38 nM dhau 2 h tom qab noj. Qhov no muaj feem cuam tshuam nrog yim npaug mus rau ib feem ntawm DPTQ EC50 hauv hD1 thiab liab D1 cAMP kev soj ntsuam. Raws li qhov no, koob tshuaj 5 thiab 10 mg / kg yuav tsum txaus rau kev kawm hauv vivo. Qhov no kuj tau lees paub nyob rau hauv txoj kev tshawb fawb qhov muag blink. Tsis tas li ntawd, cov ntaub ntawv no cuam tshuam los ntawm kev tshawb pom hauv tib neeg D1 nas (Svensson li al. 2017; Hao et al. 2019) thiab cov neeg ua haujlwm noj qab haus huv (Wilbraham li al. 2021) qhov twg peb tau pom tias koob tshuaj D1PAM uas ua rau lub hlwb tsis muaj zog / CSF concentrations ntawm, los yog ntau dua, EC50 hauv tib neeg D1cAMP kev soj ntsuam kuj ua rau muaj kev coj cwj pwm tseem ceeb xws li locomotor stimulation thiab wake-promotion.

Hauv cov tsiaj txhu, suav nrog tib neeg, qhov muag ntsais qhov muag cuam tshuam nrog kev mloog, kev paub txog kev sib koom tes, thiab kev ua haujlwm ntawm tus cwj pwm nyuaj (Jongkees thiab Colzato 2016; Ranti li al. 2020; Andreu-Sánchez li al. 2021; Dave et al. 2021). Central dopaminergic inputs rau lub frontal cortex thiab basal ganglia modulate yeem thiab spontaneous eyeblink mechanisms thaum lub sij hawm kev txawj ntse (Maffei thiab Angrilli 2018; Pajkossy li al. 2018; Imburgio li al. 2021). Ntau cov kev tshawb fawb tau pom tias tib neeg thiab liab qhov muag ntsais qhov muag yog nce los ntawm kev xaiv ncaj qha D1 receptor stimulation, thaum lub luag hauj lwm ntawm ib tug D2 receptor mechanism nyob rau hauv liab qhov muag blink yog tsis tshua meej (Kleven thiab Koek 1996; Czoty li al. 2004; Jutkiewicz thiab Bergman 2004; Desai et al. 2007; Dang et al. 2017).

Kotani et al. (2016) tau pom tias dopamine ua tshwj xeeb los ntawm D1 receptor los cuam tshuam qhov muag ntsais qhov muag, tsis yog D2 receptor tsev neeg. Nyob rau hauv txoj kev tshawb no, nonhuman primates pom ib tug ntshiab nce nyob rau hauv spontaneous qhov muag ntsais qhov muag tom qab cumulative dosing ntawm DPTQ, raws li zoo raws li ib tug zoo xws li cov nyhuv qhia ua ntej nrog ib tug D1 agonist SKF82958 thiab D1PAM DETQ (Bruns li al. 2018). Qhov nce ntawm qhov muag ntsais qhov muag los ntawm D1 PAM liab yog li qhia tias muaj peev xwm D1 mechanism hauv kev txhim kho cov txheej txheem kev txawj ntse (saib "Spatial ua haujlwm nco" ntu tom ntej).

Peb tau pom tias kev tswj lub tsheb liab tau tsaug zog ntawm lub rooj zaum liab thaum lub qhov muag ntsais txoj kev kawm, thaum cov liab tau txais DPTQ tau ceev faj, tshwj xeeb tshaj yog nyob rau hauv cov lus teb rau cov koob tshuaj ntau dua. Kev ntsuas EEG hauv cov nas transgenic hD1 yav dhau los tau qhia tias lub hauv paus dopamine D1 receptors muaj lub luag haujlwm tseem ceeb hauv kev coj cwj pwm thiab kev ceev faj (Qu li al. 2008; Herrera-Solis li al. 2017; Bruns li al. 2018). D1-Lub xeev kev ceev faj nyob ntawm no yog qhov yuav tsum tau ua ua ntej rau cov txheej txheem kev paub zoo uas koom nrog kev kawm thiab kev ua haujlwm nco (Dai li al. 2020; Kozak li al. 2020; Zhang et al. 2019). Qhov no yog ua raws li qhov kev xav tias kev paub txog kev txawj ntse, tshwj xeeb tshaj yog tias muaj cov tshuaj dopamine thiab D1 receptors, tuaj yeem txuas mus rau kev paub txog kev xav, kev txhawb siab rau (Carli li al. 1989), thiab kev coj cwj pwm. Ib qho piv txwv tseem ceeb ntawm qhov kev txhais lus no los ntawm kev paub txog kev ua haujlwm tau tshwm sim nyob rau hauv cov neeg mob Parkinson tus kab mob uas qhia tau hais tias muaj kev nkag siab ntau dua, ua rau muaj kev coj cwj pwm ntau ntxiv hauv "ON" uas tsis yog "OFF" xeev (McGuigan li al. 2019).

Cov koob tshuaj ntau ntawm kev xaiv D1 receptor stimulation tau tshaj tawm tias ua rau tus nplaig protrusion hauv cov liab (Bédard thiab Boucher 1989; Koshikawa li al. 1991; Tomiyama li al. 2012). Ntawm qhov siab tshaj plaws IM koob tshuaj ntawm DPTQ, qhov ncauj txav nrog tus nplaig protrusion tau pom hauv qee cov liab hauv txoj kev tshawb no. Txawm li cas los xij, qhov kev txav ntawm qhov ncauj nrog tus nplaig protrusion tsis tau tshaj tawm nrog D1PAM zoo sib xws hauv cov kev tshawb fawb soj ntsuam tsis ntev los no ntawm cov neeg laus cov neeg ua haujlwm pab dawb (Wilbraham li al. 2021) qhia tias cov teebmeem zoo li no yuav tsis cuam tshuam rau tib neeg.

Cov ntshav plasma siab rau DPTQ tom qab 5 mg / kg, IM koob tshuaj qhia txog lub hlwb muaj peev xwm ua tau raws li lossis ntau dua EC50 tus nqi rau tib neeg lossis liab D1 receptor nyob rau hauv cAMP kev soj ntsuam rau potentiation ntawm dopamine. Qhov nce hauv qhov muag ntsais teb ntawm qhov koob tshuaj no yog cov pov thawj tseeb ntawm lub hauv paus D1 receptor activation uas kuj tau txais kev txhawb nqa los ntawm kev soj ntsuam ntawm kev ceeb toom ntxiv piv rau cov tsiaj kho tsheb. Zuag qhia tag nrho, cov kev tshawb pom no yog nyob rau hauv txoj kab nrog cov txiaj ntsig los ntawm hD1 nas, uas D1PAMs tau qhia kev coj cwj pwm tsis tu ncua nrog locomotor stimulation ntawm koob tshuaj uas ua rau lub hlwb tsis muaj zog ntawm lossis siab dua hauv vitro hD1 EC50 qib hauv cAMP kev soj ntsuam (Svensson li al. 2017 thiab Hao et al. 2019).

Raws li pom ntawm no tau pom tias lub hlwb tsis muaj zog ntau dua li liab EC5 0 rau cAMP tau ua tiav tom qab koob tshuaj 5 mg / kg, IM tab sis tsis yog qhov qis tshaj ntawm 0.1 mg / kg, IM. Raws li tau tham hauv qab no, qhov no qhia tias kev paub txog kev txawj ntse tshwm sim ntawm koob tshuaj (lub hlwb concentrations) uas qis dua qhov yuav tsum tau ua rau lub cev muaj zog stimulation thiab, qhov tseeb rau stimulation ntawm cAMP ntau lawm. Muaj ntau yam piv txwv ntawm cov tshuaj tiv thaiv qis qis ntawm D1 agonists hauv cov ntaub ntawv (Cai thiab Arnsten 1994; Castner li al. 2000; Roberts li al. 2010) thiab nicotinic Alpha7 agonists (Castner li al. 2011). Cov teebmeem no yog qhia txog cov txheej txheem rhiab heev uas ua ncaj qha rau ntawm qee qhov chaw synaptic uas tom qab ntawd mus rau cuam tshuam synaptic plasticity uas yuav cuam tshuam txog cov noob caj noob ces tam sim ntawd.

Dose-dependent teebmeem ntawm DPTQ ntawm kev ua haujlwm nco hauv cov primate

Cov txiaj ntsig tau pom tias muaj qhov tsis zoo tag nrho ntawm DTPQ ntawm kev ua haujlwm ntawm lub cim xeeb 1 h tom qab txhaj tshuaj, tsis hais txog kev siv tshuaj npaum li cas. Qhov no yog txawm tias peb tuaj yeem suav tau tias qee qhov kev cuam tshuam neuronal tau tshwm sim ntawm 1 teev tom qab kev tswj hwm los ntawm kev pom zoo ntawm qhov muag ntsais qhov muag. Cov tshuaj pharmacokinetics qhia tau hais tias tsis muaj qhov tshwm sim ntawm cov ntshav plasma ntxiv dhau thawj hnub. Txawm li cas los xij, ntau tus neeg ua haujlwm neuro-active muaj cov teebmeem uas hnub kawg lossis lub limtiam tom qab kis tau (piv txwv li, cov tshuaj tiv thaiv kev ntxhov siab ntawm ketamine). Txoj kev tshawb fawb tam sim no pom tias DPTQ tiag tiag muaj qhov tseem ceeb ntawm kev ua haujlwm nco - kev ua haujlwm tsis zoo ntawm kev nco tau pom 49 teev tom qab IM tswj hwm ntawm koob tshuaj tsuas yog 2.5 mg / kg. Qhov koob tshuaj no yuav raug txiav txim siab tias yuav ua rau muaj qhov nce siab ntawm qhov muag ntsais tab sis tsis ua rau kev paub tsis meej rau lwm 48 teev. Tseeb, muaj ib txoj kev tshawb fawb qhia tias qhov muag blinks yuav muaj kev cuam tshuam rau kev ua haujlwm nco (Irwin 2014), txawm hais tias cov koob tshuaj siv ntawm no yuav tsis xav tias yuav muaj kev cuam tshuam rau qhov muag ntsais qhov muag, yeej tsis yog 49 teev tom qab.

Ntxiv mus, ib txoj kev tshawb fawb tsis ntev los no tau qhia tias tib neeg cov kev kawm 'spontaneous eyeblinks thaum lub sij hawm ncua sij hawm ntawm kev ua hauj lwm nco tau muaj kev cuam tshuam nrog lawv spatial ua hauj lwm nco kev ua tau zoo (Ortega li al. 2022). Tsis tas li ntawd, lawv pom muaj kev sib koom ua ke ntawm qhov muag muag ntxiv thaum lub sij hawm ob qho kev txhawb nqa encoding thiab rov qab tau thaum lub sijhawm ua haujlwm, muaj peev xwm ua rau muaj kev xav pom qhov muag siab. Yog li ntawd, nws muaj peev xwm xav tau tias qee lub sij hawm ntev ntawm cov txheej txheem ntawm neuroplasticity yuav tsum tau koom nrog hauv kev paub txog kev puas hlwb. Qhov cuam tshuam ntawm neuroplasticity nyob rau hauv cov teebmeem ntawm DPTQ ntawm qhov koob tshuaj no yog tom qab ntawd ua rau txhua qhov tseeb los ntawm qhov tseeb tias tsuas yog ib hnub tom qab kev ua haujlwm ntawm kev ua haujlwm tau zoo dua qub thiab qhov kev txawj ntse no tau tshwm sim rau lub lim tiam tom ntej. Peb tau soj ntsuam ntxiv cov teebmeem neuroplastic ntawm DPTQ ntawm kev paub txog kev ua haujlwm los ntawm kev tswj hwm cov koob tshuaj rov qab rau hnub 1 thiab hnub 5. Ntawm kev tshuaj xyuas cov txiaj ntsig ntawm kev rov ua dua, nws tau pom tseeb tias qhov txo qis hauv kev ua tau zoo rau hnub 3 tom qab thawj koob tshuaj hauv cov tshuaj. Kev sim ua ntej tsis tseem ceeb ntxiv lawm uas yuav qhia tau qee qhov cuam tshuam rau hauv cov txheej txheem ntawm kev koom tes. Txawm hais tias qhov tshwm sim no, nws tau pom tias qhov thib ob, rov ua dua koob tshuaj DPTQ ntawm 2.5 mg / kg nyob rau hnub 5 tau ua rau muaj kev cuam tshuam tsis zoo rau hnub tom ntej uas tau txiav txim siab hauv ob hnub tom ntej kom tau txais kev txhim kho tseem ceeb hauv kev ua tau zoo tag nrho cov chav kawm ntawm lub lim tiam tom ntej. Yog li, txawm tias qhov cuam tshuam ntxiv rau hnub 3, kev rov ua dua ntawm qhov koob tshuaj no rau hnub 5 tuaj yeem ua rau qee qhov kev suav ntawm nws cov txiaj ntsig zoo.

Tom qab ntawd peb sim rov ua qhov kev paub txog kev txawj ntse yam tsis tau ua rau muaj kev paub tsis meej ua ntej siv txawm tias qis dua ntawm {{0}}.1 thiab 1.0 mg/kg. Qhov peb tau pom yog tias peb tsis tsuas yog ua tiav qib tseem ceeb ntawm kev paub txog kev txawj ntse tab sis tam sim no tshwm sim tsuas yog 1 lossis 2 hnub tom qab DPTQ kev tswj hwm yam tsis muaj kev cuam tshuam tsis zoo hauv kev ua haujlwm hauv txoj haujlwm. Txawm hais tias qhov kev txhim kho no tsis yog qhov ua tau zoo li qhov pom ntawm koob tshuaj 2.5 mg / kg, nws tseem tshwm sim nyob rau ob peb hnub tom ntej. Qhov tseem ceeb, peb rov pom cov tsos mob ntawm kev txo qis hauv kev ua haujlwm hnub 3 ntawm qhov nruab nrab koob ntawm 1.0 mg / kg.

Cov kev tshawb pom no thoob plaws txhua qhov kev siv tshuaj noj tau hais tias muaj kev cuam tshuam rau lub sijhawm ntev neuroplasticity thiab txawm hais tias qhov no yuav tau nthuav dav los ntawm cov txheej txheem uas ua rau muaj qhov tsis xws luag, nws tsis yog nyob ntawm nws.

Muaj ob peb lub neuronal mechanisms thiab teeb liab transduction txoj kev uas tej zaum yuav muaj kev koom tes nyob rau hauv cov teebmeem no. Txawm hais tias plasma concentrations ntawm DPTQ yog qhov tsis txaus ntseeg tom qab 12 lossis 24 teev, nws muaj peev xwm hais tias qee qhov kev khi rau hauv qhov chaw intracellular allosteric tuaj yeem ua rau muaj kev cuam tshuam ntev dua thiab qhov no yuav ua rau nws thiaj li ua rau desensitization thiab / lossis internalization ntawm D1 receptors thiab lub sijhawm tshwm sim ntawm Defcient D1 signaling. Txawm li cas los xij, tsis muaj pov thawj ntawm qhov no thiab nws tsis zoo li, muab lub zog nruab nrab ntawm DPTQ rau qhov chaw sib txuas ua ke (Hao li al. 2019). Txawm hais tias muaj qee qhov pov thawj tias qee tus D1 agonists tuaj yeem cuam tshuam rau PKC kev taw qhia ntawm cov koob tshuaj ntau dua (Lee li al. 2014; Glovaci thiab Chapman 2015), ib qho kev taw qhia ntau dua pom ntawm cov koob tshuaj tsawg uas tau sim ntawm no yuav yog los ntawm ERK1 teeb liab tshwm sim los ntawm D{ {9}} tau yooj yim nrhiav neeg ua haujlwm ntawm beta-arrestin (saib Yang 2021 rau kev tshuaj xyuas). Nws tau raug pom tias, nyob rau hauv tej yam kev mob ntawm dopamine depletion, muaj ib qho tseem ceeb hloov nyob rau hauv D1R signaling rau ib txoj kev uas tshwm sim los ntawm extracellular teeb liab tswj kinase / mitogen-activated protein kinase (ERK1/2 / MAP kinase; Gerfen li al. 2002. ; Haberny et al. 2004; Papadeas et al. 2004).

Hauv kev tshawb fawb ntawm nas PFC, raug rau cov khoom tshiab ua rau muaj kev nce ntxiv ntawm phosphorylated ERK1/2. Inhibition of ERK kinase impaired long-term memory rau cov khoom 24 h tom qab tab sis tsis yog lub sij hawm "luv" nco 1 h tom qab pib raug (Nagai li al. 2007). ERK1/2 phosphorylation hauv vivo thiab hauv vitro tau nce los ntawm kev tswj hwm ntawm SKF38393 thiab kev nco mus ntev tau raug cuam tshuam los ntawm kev txhaj tshuaj ncaj qha ntawm SCH23390 tab sis tsis yog raclopride ncaj qha rau hauv PFC. Hauv unilateral 6-OHDA lesioned nas hlais, antagonists ntawm PLC, PKC, thiab IP3 receptors ua rau txo qis lub peev xwm ntawm SKF38393 los txhawb kev ua kom ERK1/2 (Fieblinger li al. 2014). Cov kev tshawb pom no muab cov lus qhia muaj zog tias, nyob rau hauv cov xwm txheej ntawm dopamine deficiency, D1R stimulation tej zaum yuav muaj peev xwm ntau dua ntawm kev taw qhia los ntawm ERK1/2 txoj kev thiab muaj lub zog ntau dua ntawm cov protein synthesis, synaptic plasticity, thiab kev nco mus ntev, ntawm hom. uas yuav piav qhia txog qhov cuam tshuam qeeb ntawm DPTQ ntawm kev ua haujlwm nco elucidated hauv txoj kev tshawb no tshwm sim los ntawm kev txhais lus hauv zos hauv dendrites ntawm prefrontal neurons (Sutton thiab Schuman 2005).

Tej zaum yuav muaj ntau yam kev cuam tshuam los ntawm kev cuam tshuam ntawm DPTQ ntawm koob tshuaj 2.5 mg / kg. Ib qho uas yog lub luag haujlwm rau kev txo qis thaum ntxov hauv kev ua haujlwm nco ua haujlwm thiab lwm qhov uas suav nrog kev txhim kho hauv qab no. Yog li, nws yog qhov pom tau tias lub zog ntawm qhov txiaj ntsig zoo ntawm neuronal plasticity tej zaum yuav yog nyob ntawm lub zog ntawm qhov qub potentiation ntawm D1 signaling tab sis tseem tuaj yeem tshwm sim txawm tias qhov potentiation tsis muaj zog li ua rau muaj kev puas tsuaj ntawm kev paub. Yog li ntawd, tshwj xeeb tshaj yog hais txog qhov tshwm sim thawj zaug nrog rau qhov koob tshuaj no, muaj peev xwm tshwm sim tias qhov kev xav ntawm inverted-U ntawm D1R-dependent dopamine signaling yuav tsis yog qhov tshwm sim zoo li qub tab sis kuj tseem muaj cov khoom tseem ceeb ntawm lub cev. Tseeb tiag, cov khoom hauv lub cev no yuav yog qhov tseem ceeb heev rau kev kho mob ntawm lub cev muaj zog vs. Tsis tas li ntawd, peb cov ntaub ntawv qhia tau hais tias qhov hloov pauv U-zoo li qhov tshwm sim ntawm cov koob tshuaj siab yuav tsis yog qhov tsis zoo nrog cov txheej txheem no vim tias muaj kev cuam tshuam ua ntej tau pom ntau qhov ntau npaum li cas (tsawg kawg 25-fold). Qhov no kuj tseem siv tau rau D1 agonists raws li tau tham hauv qab no.

Ib qho tseem ceeb ntawm qhov kev pab cuam ntawm D1R qhia txog cov txheej txheem ntawm plasticity koom nrog hauv kev paub yog zoo ib yam nrog peb cov kev tshawb fawb yav dhau los hauv cov neeg tsis yog tib neeg primates. Yog li, peb tau pom tias kev rov ua dua ntawm qhov koob tshuaj ultralow ntawm tag nrho D1 agonist ABT-431 tuaj yeem ua rau lub sijhawm ntev rov ua haujlwm ntawm kev nco ua haujlwm hauv cov tsiaj raug kho nrog haloperidol ntev los tsim cov kev cai qis ntawm D1R (Castner et al. 2000). Tib txoj kev tswj hwm tau tsim kev txhim kho hauv kev ua haujlwm nco hauv cov laus rhesus liab uas kav ntev txog ib xyoos thiab tuaj yeem rov kho dua tom qab los ntawm kev rov ua dua ntawm tib txoj cai (Castner thiab Goldman-Rakic ​​2004). Cov txheej txheem ntawm neuroplasticity koom nrog yuav tsum muaj kev ua haujlwm tshwj xeeb, muaj feem cuam tshuam txog kev txhim kho ntawm dendritic spines thiab kev nrhiav neeg ua haujlwm ntawm AMPA thiab NMDA receptors rau postsynaptic membrane ntawm cov pob txha (Buonarati li al. 2019; Delint-Ramírez li al. 2008; Mahan etal. 1990; Neeb et al. 2004). Peb tsis ntev los no tau qhia tias D1PAM DETQ txhim kho lub hlwb ntawm ob qho tib si pCREB thiab AMPA receptor pGluR1 hauv hD1 nas, zoo ib yam li qhov tau pom rau D1 agonist SKF82958 (Bruns li al. 2018), muab cov pov thawj ntxiv neurochemical ntxiv rau kev txhim kho synaptic plasticity. . Kev tshawb fawb ntxiv yog xav tau los tshawb xyuas lub luag haujlwm ntawm cov txheej txheem no nyob rau lub sijhawm ntev ntawm kev paub txog kev txawj ntse los ntawm D1PAMs xws li DPTQ.

Thaum peb tshuaj xyuas qhov kev ncua sij hawm ntawm qhov qis thiab nruab nrab ntawm cov koob tshuaj DPTQ peb pom tias qhov kev paub txog kev txawj ntse tau siv rau ob qho tib si luv luv thiab ntev qeeb uas ib tus tsiaj tau ntsib hauv txoj haujlwm los ntawm hnub 4. Qhov kev tshawb pom no zoo ib yam nrog cov pov thawj uas D1 signaling. muaj kev koom tes hauv ob qho tib si kev ua haujlwm tsis tu ncua hauv cov hlwb prefrontal pyramidal uas tuaj yeem sawv cev rau kev ua haujlwm nco buffers koom nrog (Durstewitz li al. 2000). Txawm li cas los xij, qhov no tsuas yog mus txog qhov tseem ceeb rau qhov tshwm sim ntawm 1.0 mg / kg koob tshuaj ntawm qhov ncua sij hawm luv luv uas ua rau cov lus nug ntawm qhov deb npaum li cas ntawm kev ceev faj thiab kev saib xyuas kom pom ntau dua ntawm cov koob tshuaj ntau dua tuaj yeem ua rau muaj kev paub zoo dua. Txawm hais tias qhov tseeb mechanisms koom nrog, nws yuav tshwm sim tias kev sib xyaw ua ke txo qis ntawm kev ua yuam kev ntawm ob qho tib si luv luv thiab ntev ncua kev txhawb nqa kev txhim kho hauv kev ua haujlwm nco.

Txoj kev tshawb fawb tam sim no tsim kom pom tias D1PAM DPTQ muaj cov kev ua yeeb yam tseem ceeb uas tshwm sim los ntawm kev txhawb nqa ntawm haiv neeg D1 receptors hauv cov tsis yog tib neeg primate. Cov kev tshawb pom no yog ib kauj ruam tseem ceeb rau pem hauv ntej kom nkag siab ntxiv txog D1PAM mechanism thiab muaj peev xwm raws li lawv muab lub hauv paus rau kev tshawb nrhiav kev txhais lus tsis tau yav tas los, dhau ntawm kev ua haujlwm ntawm tib neeg D1 khob-hauv nas. Thaum pom cov teebmeem ntawm lub cev muaj zog tshwm sim ntawm koob tshuaj 5–10 mg / kg IM, hauv kev sim qhov muag ntsais muag, ob qho tib si rau lub sijhawm ntev thiab lub sijhawm luv luv tshem tawm cov teebmeem ntawm DPTQ ntawm kev ua haujlwm qeeb qeeb tau pom hauv qhov koob tshuaj qis dua, txuas mus rau tsuas yog 0.1 mg/kg. Cov qib ntshav plasma qis ntawm DPTQ ntawm 0.1 mg / kg koob tshuaj nrog qhov tsis txaus ntseeg ntawm lub hlwb raug txhawb nqa qhov tsis pom lub cev muaj zog ntawm qhov koob tshuaj no uas tuaj yeem ua rau tsis zoo ntawm kev paub.

Muab qhov tseeb tias qhov kis tau ntawm qhov koob tshuaj no yuav poob qis dua EC50 rau kev sib sau ntawm cAMP, nws zoo nkaus li tias lwm txoj hauv kev hloov pauv cov teeb liab yuav muaj feem cuam tshuam rau kev paub txog ntawm qhov koob tshuaj no. Qhov kev tshawb pom no zoo ib yam nrog cov ntaub ntawv qhia tias cov koob tshuaj qis qis ntawm D1 agonists yuav zoo rau kev txhim kho kev ua haujlwm nco thiab taw qhia rau cov txiaj ntsig kho mob ntawm D1PAM tshaj tag nrho thiab ib nrab D1 agonists (Cai thiab Arnsten 1997; Castner li al. 2 000; Castner thiab Goldman-Rakic ​​2004; Kozak li al. 2020). Cov txiaj ntsig no qhia tau hais tias kev paub txog kev txawj ntse nrog D1PAM no tuaj yeem ua tiav yam tsis muaj kev cuam tshuam ntawm qhov tsis txaus ntseeg thaum siv tshuaj tsawg ntawm DPTQ. Nws tseem yuav pom tias qhov rov ua dua ntawm D1 PAM ntawm 0.1 lossis 1.0 mg / kg tuaj yeem ua rau muaj kev nce qib ntawm kev txawj ntse uas muaj peev xwm ua tau zoo ntawm kev kho mob rau cov txheej txheem no. Ua ke, cov ntsiab lus ntawm kev coj tus cwj pwm qhia tau hais tias muaj ntau yam zoo ntawm D1PAM (DETQ), suav nrog tsis muaj qhov hloov pauv U-zoo li koob tshuaj- teb thiab kev tsim kho sai. Cov kev tshawb pom no kuj tau lees paub nrog cov qauv zoo sib xws uas tau txais txiaj ntsig / LY3154207 (Hao li al. 2019) thiab LY314885 (Hao li al. 2022). Peb xaus lus tias DPTQ thiab cov qauv zoo sib xws tuaj yeem muaj txiaj ntsig zoo rau kev kho mob ntawm kev paub tsis meej hauv ntau yam kab mob neuropsychiatric suav nrog kev paub tsis meej vim kev laus lossis neurodegeneration.

Kev lees paub

Peb ua tsaug rau Xin Zhou ntawm Eli Lilly rau kev txhawb nqa nrog PK kev tshuaj ntsuam thiab Maria Shanabrough hauv Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv ntawm Yale Tsev Kawm Ntawv Tshuaj rau kev txhawb nqa nrog PK cov qauv.

Cov lus tshaj tawm

Kev tsis sib haum xeeb

Txoj haujlwm no tau txais nyiaj los ntawm kev tshawb fawb daim ntawv cog lus los ntawm Eli Lilly & Co. rau Drs. Stacy Castner thiab Graham Williams. Tag nrho lwm tus kws sau ntawv tau ua haujlwm lossis cog lus los ntawm Eli Lilly & Co. thaum lub sijhawm lossis tseem muaj feem hauv tuam txhab.

Qhib Access

Kab lus no tau tso cai raws li Creative Commons Attribution 4.0 Daim ntawv tso cai thoob ntiaj teb, uas tso cai siv, sib koom, hloov kho, faib, thiab luam tawm hauv ib qho nruab nrab lossis hom ntawv, tsuav yog koj muab credit rau tus thawj sau ) thiab qhov chaw, muab qhov txuas mus rau Creative Commons daim ntawv tso cai, thiab qhia seb puas tau hloov pauv. Cov duab lossis lwm yam khoom siv thib peb hauv tsab xov xwm no suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai tshwj tsis yog tau qhia lwm yam hauv kab qiv nyiaj rau cov khoom siv. Yog tias cov ntaub ntawv tsis suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai thiab koj qhov kev npaj siv tsis raug tso cai los ntawm txoj cai lij choj lossis tshaj qhov kev tso cai siv, koj yuav tsum tau txais kev tso cai ncaj qha los ntawm tus tuav ntaub ntawv.

Cov ntaub ntawv

1. Andreu-Sánchez C, Martín-Pascual MÁ, Gruart A, Delgado-García JM (2021) Cov neeg saib hloov qhov muag-blink tus nqi los ntawm kev kwv yees cov ntsiab lus piav qhia. Lub hlwb Sci 11(4): 422. https://doi.org/10.3390/brainsci{11}}

2. Asin K, Wirtshafter D (1993) Cov teebmeem ntawm rov ua dua dopamine D1 receptor stimulation ntawm kev sib hloov thiab c-fos qhia. Eur J Pharmacol 235:167–168.https://doi.org/10.1016/0014-2999(93)90840-e

3. Balice-Gordon R, Honey GD, Chatham C, Arce E, Duvvuri S, Naylor MG, Liu W, Xie Z, DeMartinis N, Harel BT, Braley GH, Kozak R, Park L, Grey DL (2020) A neurofunctional domains mus rau kev ntsuam xyuas D1 / D5 dopamine receptor ib nrab agonism ntawm kev paub thiab kev txhawb siab hauv cov neeg ua haujlwm noj qab haus huv uas muaj peev xwm ua haujlwm tsawg. Int J Neuropsychopharmacol 23(5): 287–299.

4.Bédard PJ, Boucher R (1989) Efect of D1 receptor stimulation in normal and MPTP liab. Neuroscience Lett 104(1–2): 223–228.

5. Benjamini Y, Krieger AM, Yekutieli D (2006) Adaptive linear step-up txheej txheem uas tswj qhov kev tshawb pom tsis tseeb. Biometrika 93: 491–507.

6. Biglan K, Munsie L, Svensson KA, Ardayfo P, Pugh M, Sims J, Brys M (2022) Kev nyab xeeb thiab kev ua tau zoo ntawm kev sib tw hauv Lewy lub cev dementia: theem 2, randomized, placebo-tswj sim. Mov Disord 37(3): 513–524.

7. Blanchet PJ, Grondin R, Bédard PJ, Shiosaki K, Britton DR (1996) Dopamine D1 receptor desensitization profile hauv MPTP-lesioned primates. Eur J Pharmacol 309(1): 13–20.

8. Bodnar M, Malla A, Joober R, Lepage M (2008) Cognitive markers of short-term Clinical results in first-episode psychosis. Br J Psychiatry 193(4): 297–304.

9. Bruns RF, Mitchell SN, Watford KA, Harper AJ, Shanks EA, Carter G, O'Neill MJ, Murray TK, Eastwood BJ, Schaus JM, Beck JP, Hao J, Witkin JM, Li X, Chernet E, Katner JS, Wang H, Ryder JW, Masquelin ME, Thompson LK, Hlub PL, Maren DL, Falcone JF, Menezes MM, Zhang L, Yang CR, Svensson KA (2018) Preclinical profile of a dopamine D1 potentiator qhia kev kho cov khoom siv hauv paj hlwb thiab kev puas siab puas ntsws. Neuropharmacology 128: 351–365.

10. Buonarati LOSSIS, Hammes EA, Watson JF, Greger IH, Hell JW (2019) Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation. Sci Signal 12(562): eaar6889.
11. Cai JX, Arnsten AF (1994) Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 283(1): 183–9
12. Cai JX, Arnsten AF (1997) Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 283(1): 183–189

13. Carli M, Jones GH, Robbins TW (1989) Kev cuam tshuam ntawm unilateral dorsal thiab ventral striatal dopamine depletion ntawm qhov muag tsis pom kev hauv nas: kev tsom xam neural thiab kev coj cwj pwm.

14. Castner SA, Goldman-Rakic ​​PS (2004) Txhim kho kev ua haujlwm nco hauv cov laus liab los ntawm kev ua kom muaj zog ntawm dopamine D1 receptor stimulation. J Neurosci 24(6): 1446–1450.

15. Castner SA, Williams GV (2007) Los ntawm kev tsim txiaj rau kev tsim txiaj: kev nkag siab los ntawm kev nkag siab ntawm cov neeg tsis yog tib neeg primate. Prog Neuropsychopharmacol Biol Psychiatry 31(8): 1572–1592.

For more information:195077648nn@gmail.com