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I-Stepholidine increases the frequency of sEPSC via the activation of D1 dopamine signaling pathway in rat prelimbic cortical neurons

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Acta Pharmacologica Sinica 2007年第5期 627-633页

作者： Ming GAO Chang-liang LIU Shen yang Xue-chu ZHEN guo-zhang jin Department of Pharmacology,state key laboratory of drug research,institute of materia medica,shanghai institutes for biological sciences,chinese academy of sciences,shanghai 201203,china

Aim:To investigate the effect of l-stepholidine (SPD) on the frequency of spon-taneous excitatory postsynaptic currents (sEPSC) in the pyramidal cells betweenlayers Ⅴ and Ⅵ in the prelimbic cortex (PL).Methods:A whole-cell patch clamp inrat brain slices was ***:SPD significantly increased the frequency ofsEPSC in a concentration-dependent manner.A selective D1dopamine receptorantagonist SCH23390 blocked SPD-mediated effects,whereas the D1agonistSKF38393,but not the D2/3antagonist sulpiride,mimicked SPD-mediated increasein the frequency of ***,both protein kinase A (PKA) inhibitor N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide hydrochloride andprotein kinase C (PKC) inhibitor chelerythrine attenuated the effect of SPD ***:SPD elicits its effect on the frequency of sEPSC on the PLpyramidal cells via presynaptic D1receptors,and is dependent on PKA and PKCsignaling pathways.

关键词： l-stepholidine prelimbic cortex whole-cell patch clamp spontaneous excitatory postsynaptic currents dopamine receptor

Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes

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Acta Pharmacologica Sinica 2004年第12期25卷 31-39页

作者： yu FU2,3,4, Zi-tao ZHU2,5, xing-zu ZHU2, guo-zhang jin2,6 2state keylaboratory of drug research,shanghai institute ofmateria medica, shanghai institutes for biologicalsciences, chineseacademy of sciences, Graduate Schoolof the chinese academy of sciences, shanghai 201203, chinaNow in Department of Pharmacology and Toxicology, Univer-sity of Texas medical Branch, USA.Now in Department of Physiology & Pharmacology, OregonHealth sciences University, USA,5Now in Department of Physiology & Pharmacology, OregonHealth sciences University, USA, state key laboratory of drug research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antago- nist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was re- corded in the nucleus accumbens (NAc) neurons of na?ve and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by the change of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB-18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which was reversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited by iontophoretically applied THPB-18 in 90 % of 6-OHDA-lesioned rats, while THPB-18 caused variable effects on the firing of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked by iontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to l-stepholidine, THPB-18 also possesses the “D1 agonistic-D2 antagonistic” dual action on the VTA-NAc DA system.4Now in Department of Pharmacology and Toxicology, Univer-sity of Texas medical Branch, USA.5Now in Department of Physiology & Pharmacology, OregonHealth sciences University, USA,4Now in Department of Pharmacology and Toxicology, Univer-sity of Texas medical Branch, USA.5Now in Department of Physiology & Pharmacology, OregonHealth sciences University, USA,5Now in Department of Physiology & Pharmacology, OregonHealth sciences University, USA,

关键词： berberine dopamine D1 receptors dopamine D2 receptors nucleus accumbens

PFC control VTA DA neurons activity

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PFC control VTA DA neurons activity

第十二届全国神经精神药理学学术交流会

作者： Gao Ming Liu Chang - Liang Chu Hong - yuan yang Shen shi wei - xing jin guo - zhang state key laboratory of drug research, shanghai institute of materia medica, shanghai institutes for biological sciences, chinese academy of sciences, shanghai 201203

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Effects of (-)-stepholidine on NMDA receptors:comparison with haloperidol and clozapine

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Acta Pharmacologica Sinica 2007年第7期28卷 953-958页

作者： wei-hua GU~2,Shen yang~2,wei-xing shi~3,Xue-chu ZHEN~2,guo-zhang jin~(2,4)~2 Department of Pharmacology,state key laboratory of drug research,shanghai institute of materia medica,shanghai institutes ofbiological sciences,Graduate School of the chinese academy of sciences,chinese academy of sciences,shanghai 201203,china ~3 Neuropsychopharmacological research Unit,Department of Psychiatry,Yale University School of Medicine,New Haven,Connecticut06511,USA Department of Pharmacology State Key Laboratory of Drug Research ShanghaiInstitute of Materia Medica Shanghai Institutes of Biological Sciences Graduate School of theChinese Academy of Sciences Chinese Academy of Sciences Shanghai 201203 Chi

Aim:To examine whether （-）-stepholidine （SPD） has a direct effect on the N-methyl-D-aspartic acid receptors （NMDAR） containing the NMDA receptor sub-units NR2A or NR2B and to compare its effect with those of haloperidol （Hal） andclozapine （Cloz）.Methods:NMDAR was transiently expressed in human embry-onic kidney 293 （HEK293） *** in intracellular calcium concentration([Ca2+]i) induced by NMDAR activation were monitored with Fura-2 ratio ***:SPD had no significant effects on either subunit of NMDARat a concentration of less than 100 μmol/*** selectively inhibited NMDARcontaining the NR2B subunit,whereas Cloz inhibited both subunits of *** both Hal and Cloz inhibited NR1a/NR2B receptor-mediated Ca2+influx,their effects were *** was more potent and had a faster peak effect ***:Both Hal and Cloz inhibit NMDAR-mediated function,whereasSPD produced only a little inhibition at a high *** on our otherstudies,the modulation of SPD on NMDAR function may be via D1receptoraction underlying an indirect mechanism.

关键词： (-)-stepholidine haloperidol clozapine NMDA receptor calcium imaging neuroleptics

Activation of dendritic NMDA receptor induces an oscillatory firing of pyramidal neurons in the prefrontal cortex

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Activation of dendritic NMDA receptor induces an oscillatory...

中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Chang-Liang LIU,Hui-Kun WANG,guo-yuan HU,guo-zhang jin,Xue-Chu ZHEN~* Department of Pharmacology,state key laboratory of drug research,institute of materia medica,shanghai institute for biological sciences,chinese academy of sciences,shanghai,china

Oscillation is an important process in neural system for presenting,integrating and synchronizing neuronal *** only the neuronal networks but also a single neuron can oscillate at a broad band,whereas the mechanisms underlying oscillation are *** depolarized by current injection,most pyramidal neurons in layer V-VI of rat prefrontal cortex(PFC) fire regularly or in single burst at the very ***,when glutamate applied to the apical dendrite,all neurons showed an oscillatory firing,with a frequency of *** oscillation disappeared in the presence of NMDA receptor(NMDAR) antagonist APV,suggesting the dependence of NMDAR *** is further supported by the fact that pressure ejection of NMDA to the apical dendrite evoked a similar oscillation,whereas AMPA or high concentrations of KC1 failed to produce such *** of synaptic transmission by tetrodotoxin (TTX) did not disrupt the oscillatory firing,indicating that the firing is not due to network activities but to the intrinsic properties of individual *** voltage dependence of the NMDA conductance in Mg free solution or preventing Ca influx in Ca free solution completely blocked the ***,we detected parallel changes between intracellular Ca oscillation and oscillating membrane potential in response to dendritic NMDA *** observations demonstrate mat the voltage dependence of the NMDAR and Ca influx play a key role in the generation of the ***,block of SK channels and conductances underlying sAHP resulted in a depolarization plateau,which is the same as when the extracellular Ca is ***,block of either SK channels or sAHP currents respectively failed to prevent the *** results indicate that the repolarization of the membrane potential relies on both SK and sAHP currents and that the intracellular Ca takes effect mainly through these two *** conclusion,our data provide evidenc

关键词： apical dendnte pyramidal neuron prefrontal cortex burst oscillation NMDA receptor SK channel

SKF83959-inhibited excitatory neurotransmission in hippocampus is independent of phosphatidylinositol-coupled dopamine D1 receptor but is mediated by inhibiting voltage-gated sodium channels

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SKF83959-inhibited excitatory neurotransmission in hippocamp...

中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Hong-yuan CHU~1 Xue-Qin CHEN~1 Ao zhang~2 guo-zhang jin~1 guo-yuan HU~1 Xue-Chu ZHEN~(1 *) 1 state key laboratory of drug research Department of Neuropharmacology shanghai institute of materia medica chinese academy of sciences shanghai china 2 Department of Medicinal chemistry shanghai institute of materia medica chinese academy of sciences shanghai china

＜正＞Objective The central dopamine system exerts a profound influence on excitatory neurotransmission in hippocampal CA1 ***83959,a phenylbenzazepines derivative,produced a potent anti-Parkinsonian effect via selective activation of a putative phosphatidylinositol-coupled dopamine D1 ***,how the atypical D1 receptor agonist SKF83959 regulates the neurotransmission remains *** present study was designed to explore the effects of SKF83959 to glutamate release in hippocampal CA1 *** The influence of SKF83959 to excitatory neurotransmission was studied by recording of extracellular field potentials by whole-cell patch-clamp technique. Results（1） SKF83959 inhibited the excitatory neurotransmission of hippocampal CA1 region in a concentration-dependent manner.（2） SKF83959-induced inhibitory effect was not mediated by dopamine receptors and other related receptors.（3） SKF83959 induced a robust membrane depolarization and a significant reduction of neuronal excitability.（4） SKF83959-induced reduction of neuronal excitability was mediated by inhibition of voltage-gated sodium channels. Conclusion The present study demonstrated that SKF83959-induced inhibition of glutamate release is independent of dopamine *** regulatory effect on excitatory neurotransmission is mediated via inhibition of presynaptic sodium channels.

关键词： SKF83959 dopamine hippocampus PPF sodium channel depolarization Parkinson’s disease

Requirement of PSD-95 for dopamine D1 receptor modulating glutamate NR1a/NR2B receptor function

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Acta Pharmacologica Sinica 2007年第6期28卷 756-762页

作者： wei-hua GU~2,Shen yang~2,wei-xing shi~(2,3,4),guo-zhang jin~2,Xue-chu ZHEN~(2,4)~2 Department of Pharmacology,state key laboratory of drug research,shanghai institute of materia medica,shanghai institutes ofbiological sciences,chinese academy of sciences,shanghai 201203,china ~3 Neuropsychopharmacological research Unit,Department ofPsychiatry,Yale University School of Medicine,New Haven CT 06511,USA DepartmentofPharmacology StateKeyLaboratoryofDrugResearchShanghaiInstituteofMateriaMedicaShanghaiInstitutesoJBiologicalSciencesChineseAcademyofSciencesShanghai201203China

Aim:To elucidate the role of scaffold protein postsynaptic density （PSD）-95 inthe dopamine D1receptor （D1R）-modulated NR1a/NR2B receptor ***:The human embryonic kidney 293 cells expressing D1R （tagged with theenhanced yellow fluorescent protein） and NR1a/NR2B with or without co-expres-sion of PSD-95 were used in the *** Ca2+influx measured by imagingtechnique was employed to monitor N-methyl-D-aspartic acid receptors （NMDAR）***:The application of dopamine （DA,100 μmol/L） did not alterglutamate/glycine （Glu/Gly）-induced NMDAR-mediated Ca2+influx in cells onlyexpressing the D1R/NR1a/NR2B ***,DA increased Glu/Gly-induced Ca2+influx in a concentration-dependent manner while the cells wereco-expressed with PSD-95.D1R-stimulated Ca2+influx was inhibited by a selectiveD1R antagonist ***,pre-incubation with either the proteinkinase A （PKA） inhibitor H89,or the protein kinase C （PKC） inhibitor chelerythrineattenuated D1R-enhanced Ca2+influx induced by the N-methyl-D-aspartic acid（NMDA） *** results clearly indicate that D1R-modulated NR1a/NR2Breceptor function depends on PSD-95 and is subjected to the regulation of PKAand ***:The present study provides the first evidence that PSD-95is essential in D1R-regulated NR1a/NR2B receptor function.

关键词： D1 dopamine receptor NMDA PSD-95 signal transduction calcium

Towards Better Antipsychotic drugs： an Update on 1 -Stepholidine

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中国药理通讯 2005年第4期22卷 8-9页

作者： wei - xing shi guo - zhang jin state key laboratory of drug research Department of PharmacologyShanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

PFC control VTA DA neurons activity

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中国药理通讯 2006年第4期23卷 23-24页

作者： Gao Ming Liu Chang- Liang Chu Hong- yuan yang Shen shi wei -xing jin guo- zhang state key laboratory of drug research Shanghai Institute of Materia MedicaShanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203

Aim: To investigate the functional correlation between medial prefrontal cortex (mPFC) and ventral tegmental area (VTA). Methods : VTA DA neurons firing and PFC local field potential (LFPs) were simultaneously recorded with multisites recording in chloral hydrate - anesthetized rats. Results: Based on the relative amplitude of the slow oscillation ( SO), we divided VTA DA neurons into two groups : high SO (HS) and low SO (LS). Nearly half of 232 (47%) VTA DA neurons were HS cells because the mean power between 0. 5 - 1.5Hz (P0. 5-1. 5Hz ) in their autospectra was significantly higher than that between 0 -3Hz (P0-3Hz). In most VTA DA cells (67%), the SO was significantly coherent with mPFC LFPs with a high coherence. We refer to these DA neurons as PFC - coupled (PC) cells, which included both high SO (HS) and low SO (LS) cells, mPFC inactivation induced by TTX local infusion significantly decreased the SO in most cells tested (27/29), and had no significant effect on firing rate and bursting. Compared to non - lesioned rats, mPFC transection markedly decreased both the number of HS cells and the amplitude of the SO. Phase analysis between VTA DA neuron firing and mPFC LFPs suggests that the SO in most DA neurons has a nearly anti - phase relation with PFC oscilla- tions and the phase lag between the SO and PFC was greater than 40% of a cycle period. In most PFC pyramidal neurons,

关键词：中枢神经中脑腹侧被盖区前额叶皮质 DA神经活性功能相关性细胞周期