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dopamine d1 receptor-mediated upregulation of BKCa channels in retinal Mller cell in a rat chronic ocular hypertension model

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Dopamine D1 receptor-mediated upregulation of BKCa channels ...

中国神经科学学会第十届全国学术会议

作者： Hang-Jing WU Yan-Ying MIAO Min JI Wei YANG Xiong-Li YANG Zhong-Feng WANG Institutes of Brain Science Institute of Neurobiology and State Key Laboratory of Medical NeurobiologyFudan University

Miiller cell gliosis is a universal response in many retinal pathological conditions.Our previous work demonstrated that downregulation of Kir K channels contributes to the Miiller cells gliosis in a rat chronic ocular hypertension(COH) model.However,if and how outward K currents are involved in Miiller cell gliosis in glaucoma are largely unknown.Here,we investigated the changes of TEA-sensitive large-conductance Ca-activated K(BK)channels in Miiller cells in rat COH model reproduced by ligating three episcleral veins.We found that outward Kcurrent densities in Miiller cells isolated from the COH rats were significantly increased.Further experiments showed that the increased outward K currents were mainly mediated by BK channels.The peak current densities of BKchannels were remarkably increased in Miiller cells isolated from the COH rats during 1-4 weeks after the operation.Afterward,the current densities gradually declined to control level.We hypothesized that increased extracellular dopamine(dA) in glaucoma activates dA dl receptors and then increases BK currents in Miiller cells.In agreement with our hypothesis,SKF81297,a selective dA dl receptor agonist,remarkably enhanced BK currents in Miiller cells obtained from normal rats,and the effects were reversed by a dl receptor antagonist SCH23390.Pretreatment with either Rp-cAMP,a competitive inhibitor of cAMP,or H-89,a PKA inhibitor,blocked SKF81297-induced effect on the BK while extracellular application of forskolin,an adenylate cyclase activator,mimicked the SKF81297 effect,suggesting an involvement of cAMP-PKA signaling pathway.Since increased BK currents may hyperpolarize the membrane potential of Miiller cells,dA dl receptor-mediated effect on BK of Miiller cell in COH rats seems to oppose the Kir channel inhibition-induced depolarization of the cells,thereby attenuating Miiller cell gliosis.

关键词： Müller cell BKCa channel dopamine d1 receptor glaucoma

Roles of dopamine d1 receptor-expressing Neurons in the Nucleus Accumbens in the Regulation of Wakefulness in Mice

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Roles of Dopamine D1 Receptor-expressing Neurons in the Nucl...

中国睡眠研究会第九届学术年会

作者： LUO Yan-Jia WANG Lu LI Ya-dong YUAN Xiang-Shan QU Wei-Min HUANG Zhi-Li department of Pharmacology Fudan University State Key Laboratory of Medical Neurobiology Fudan University The Institutes of Brain Science and Collaborative Innovation Center for Brain Science Fudan University

OBJECTIVE The nucleus accumbens(NAc),a part of basal ganglia,has been reported to play a role in motivation and reward.dysfunction of NAc causes numerous neurological disorders associated with sleep-wake disturbances.There are two different subpopulations of principle projection neurons in the NAc,dopamine d receptor(R)-expressing medium spiny neurons(dR-MSNs)and dR-MSNS,both of which are GABAergic MSNs.However,whether NAc dR-MSNs are involved in

关键词： dopamine d1 receptor nucleus accumbens optogenetics chemogenetics sleep-wake cycle

Effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization in high myopia mice

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International Journal of Ophthalmology(English edition) 2023年第7期16卷 1034-1040页

作者： Yan-Yan Ji Shi-Xi Zhang Ye Kang Song Chen Clinical College of Ophthalmology Tianjin Medical UniversityTianjin 300020China Tianjin Eye Hospital Tianjin 300020China Liaocheng Aier Eye Hospital Liaocheng 252100Shandong ProvinceChina dezhou Aier Eye Hospital Dezhou 253000Shandong ProvinceChina YanTai Aier Eye Hospital Yantai 264000Shandong ProvinceChina

AIM:To evaluate effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization(CNV)in high myopia mice.METHOdS:The C57BL/6J mice were deprived of the right eye for 4wk,and the high myopia was diagnosed by optometry,the diopter was less than-6.00 d,and CNV was induced by 532 nm laser.The changes of dopamine d1 receptor(dRd1),dopamine d2 receptor(dRd2),and vascular endothelial growth factor A(VEGFA)were detected by Western blot technology at 0.5,1,2h,and 7d after 0.01%,0.05%,and 0.1%atropine eye drops,respectively,the area of CNV was measured.RESULTS:Significant increases were observed on the expression of dRd2 in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(Pdecreases were observed on the expression of dRd1 and VEGFA in mouse high myopia model at 0.5,1,2h,7d with 0.05%and 0.1%atropine eye drops(Pduced by laser in the drug-treated group was significantly smaller than that in the control group,and the higher the concentration,the more significant the inhibitory effect(Pdrops can decrease the level of VEGFA and inhibit high myopia CNV indirectly by up-regulating the level of dRd2 and down-regulating the level of dRd1,and the effect of 0.05%and 0.1%atropine eye drops is more significant.

关键词： high myopia choroidal neovascularization low concentration atropine eye drops dopamine d1 receptor dopamine d2 receptor

New therapeutic strategies targeting d1-type dopamine receptors for neuropsychiatric disease

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Frontiers in Biology 2015年第3期10卷 230-238页

作者： Young-Cho Kim Stephanie L. Alberico Eric Emmons Nandakumar S. Narayanan department of Neurology University of Iowa Iowa City IA 52242 USA Aging Mind and Brain Initiative Carver College of Medicine University of Iowa Iowa City IA 52242 USA

The neurotransmitter dopamine acts via two major classes of receptors, dl-type and d2-type. d1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of d1 dopamine signaling in two major domains： L-dOPA-induced dyskinesias in Parkinson＇s disease and cognition in neuropsychiatric disorders. While there are many drugs targeting d2-type receptors, there are no drugs that specifically target d1 receptors. It has been difficult to use selective dl-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate d1 dopamine signaling by targeting second messengers downstream of d1 receptors, aUosteric modulators, or by making targeted modifications to dl-receptor machinery. The development of therapies specific to dl-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.

关键词： d1dR dopamine d1 receptor dyskinesia cognition

Effects of(-)stepholidine in animal models for schizophrenia

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Acta Pharmacologica Sinica 2006年第9期27卷 1111-1118页

作者： Bart A ELLENBROEK 6500 HB Nijmegen department of Cognitive Neurosciences Section Molecular Neurobiology The Netherlands University of Nijmegen

Aim:(-)Stepholidine(SPd)is an active ingredient of the Chinese herb Stephaniaintermedia,which binds to the dopamine d1and d2like receptors.Biochemical,electrophysiological and behavioural experiments have provided strong evidencethat SPd is both a d1and a d2antagonist,which could make SPd a uniqueantipsychotic drug.The present study aimed to investigate the antipsychoticproperties of SPd in two animal models for schizophrenia.Methods:The effectsof SPd,clozapine and haloperidol in increasing forelimb and hindlimb retractiontime in the paw test and in reversing the apomorphine and MK801-induced dis-ruption of prepulse inhibition was investigated.Results:In the paw test,clozapineand SPd increased the hindlimb retraction time,with only a marginal effect on theforelimb retraction time,whereas haloperidol potently increased both.In theprepulse inhibition paradigm,all three drugs reverse the apomorphine-induceddisruption in prepulse inhibition,while none of the drugs could reverse the MK801-induced disruption.SPd even slightly,but significantly,potentiated the effectsof MK801.Conclusion:The data show that SPd showed antipsychotic-like ef-fects in both the prepulse inhibition paradigm and in the paw test.Moreover,theresults of the paw test suggest that SPd has an atypical character with a relativelysmall potency to induce extrapyramidal side effects.

关键词： acoustic startle response antipsyehotics apomorphine dopamine d1 receptor dopamine d2 receptor MK801 paw test prepulse inhibition clozapine haloperidol

M4 Muscarinic Acetylcholine receptor Modulates dopamine-dependent Behaviors and Its Therapeutic Potential in Parkinson's disease

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神经药理学报 2019年第Z1期 60-61页

作者： LI Xing ZHOU Hu HUANG Yu-qi WANG Li-yun State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Zhongyuan Hengkang Biotechnology Co. Ltd.

Acetylcholine(ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic Ach receptors(M1-M5 mAChRs). In addition,mAChRs are densely expressed in the striatum and are vigorously involved in the regulation of striatal neuronal activity. Interestingly,M4 are coexpressed with d1 dopamine receptors in a specific subset of striatal projection neurons. It is generally viewed that the M4-mediated cholinergic transmission interacts with other local transmitters to maintain striatum neuronal homeostasis and synaptic plasticity. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors,we used viral expression and strategy to delete the M4 mAChR gene in vivo and in vitro within the mouse dorsal striatum. In vitro studies,both genetic knockdown and pharmacologic inhibition of M4 receptors decreased the OXo-M induced dARPP-32-Thr75 phosphorylation in MSNs. More important the newly generated mutant mice displayed several striking behavioral phenotypes,including enhanced in d1 dopamine receptor dependent behaviors. Additionnally,we developed and characterized a novel compound,R-dm8021 [R(-)-desmethyl-phencynonate hydrochloride(3-azabicyclo(3,3,1) nonanyl-9-yl-cyclopentyl-phenylglycolate],that was highly selective for M4 receptor subtype(Wang et al.,2005 a,2005 b;2009).We evaluated the pharmacological potential of R-dm8021 on improvement of Parkinson’s severe motor deficit. Compared with THP(currently the most commonly used anticholinergic drugs in patients with Pd),R-dm8021 possesses much more potential modulated effects on dA-dependent behaviors,which may be attributed to its selective antagonism to M4 receptor. Our results provide novel data to support the therapeutic potential of M4 receptor antagonists for the treatment of Parkinson’s disease;our findings have substantial clinical relevance.

关键词： acetylcholine M4 receptor dopamine d1 receptor Parkinson’s disease

Localization of dopamine dl receptor in carp retina

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Localization of dopamine Dl receptor in carp retina

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Xiao-Min ZHANG,Yong-Mei ZHONG,Xiong-Li YANG Institute of Neurobiology,Institutes of Brain Science and State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200032,China

＜正＞dopamine,as an important neuromodulator in the vertebrate retina,exerts its actions through two classes of receptors,known as the d1 and d2 receptors.In this work,localization of d1 receptors in carp retina was studied using immunofluorescence double labeling and confocal laser scanning microscopy.d1-immunoreactivity（-IR） was observed in a lot of cells in the inner nuclear layer（INL） and some cells in the ganglion cell layer（GCL）.Anti-protein kinase C（PKC）, tyrosine hydroxylase（TH） and choline acetyltransferase（ChAT） antibodies were used to label rod-ON bipolar cells, dopaminergic amacrine cells（ACs） and cholinergic ACs,respectively.double labeling experiments showed that d1 was strongly expressed in the somata of rod-ON bipolar cells,whereas the dendrites in the outer plexiform layer（OPL） and the terminals in the inner plexiform（IPL） of these cells were weakly labeled.TH-labeled dopaminergic ACs were located in the inner part of the INL and sent processes mainly into the outer sublayer of the IPL.d1 -IR was clearly observed in the somata but not seen in the processes of dopaminergic ACs.In addition,d1 was also expressed in the somata of two types of cholinergic ACs（ACh-a,ACh-b）,with their cell bodies located in INL and GCL,respectively,but not in their processes in the IPL.Furthermore,labeling for d1 was also observed in the ganglion cells which were retrogradely labelled by fluorogold. The wide expression profile of d1 suggests that the retinal dopaminergic system is organized in a way that favors its working through both wiring and volume transmission.

关键词： dopamine d1 receptor immunofluorescence double labeling bipolar cell amacrine cell ganglion cell

The essential role of dopaminergic system in the food-anticipatory activity in mice

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The essential role of dopaminergic system in the food-antici...

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yuan-Yuan LIU~1,Tian-Ya LIU~2,Zong-Yuan HONG~2,Wei-Min QU~1,Zhi-Li HUANG~(1,*) 1 department of Pharmacology,State Key Laboratory of Medical Neurobiology,Shanghai Medical College,Institute of Brain Science,Fudan University,Shanghai 200032,China 2 Institute of Quantitative Pharmacology,department of Pharmacology,Wannan Medical College,Wuhu 241001, China

Objective When food is available during a restricted and predictable time of the day,mammals exhibit food-anticipatory activity(FAA),a daily increase in locomotor activity preceding the presentation of food.Although many studies attempted to locate the food-entrainable circadian oscillator in the central nervous system,the mechanisms for FAA are a matter of controversy.The present study was designed to clarify the role of dopaminergic and histaminergic systems in FAA.Methods The mice were given access to food for 2 h(CT19-CT21) in ICR mice and for 4 h(CT 17-CT21) in gene-manipulated mice.FAA was monitored by infrared locomotor activity sensors and defined as the locomotor activity occurred 2 h before the availability of food.dopamine d,receptor(R),d2R,and histamine H,R-specific antagonists,and dR- and HR-knockout(KO) mice were used to clarify the role of dopamine and histamine receptors in FAA induced by food restriction(FR).In addition,brain monoamine concentrations on the 14 day of FR were determined by HPLC-ECd.Results Pretreatment with dR antagonist SCH23390 at 1,3,or 10μg/kg significantly decreased FAA by 19%,26%or 19%,respectively,and dR antagonist raclopride at 22,67,or 200μg/kg significantly decreased FAA by 16%,36%or 41%,respectively,as compared with vehicle control.Moreover,co-administration of SCH23390 and raclopride synergistically inhibited FAA by 57%.Consistently,the levels of dopamine and its metabolites in the striatum and midbrain were significantly increased during FR-induced FAA,even in the mice pretreated with dR and dR antagonists.Similarly,dR KO mice exhibited attenuated FAA.However,pretreatment with pyrilamine at 2.5,5,or 10 mg/kg did not significantly decrease FAA,although it decreased the locomotor activity during the dark period in ad libitum mice,and H,R KO did not affect FAA.Conclusion These results strongly indicate that dopaminergic system plays an essential role in the food-anticipatory activity in mice.

关键词： antagonist dopamine d1 receptor d2 receptor food restriction histamine H1 receptor food-anticipatory activity