OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric disorders.Currently available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncerta...OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric disorders.Currently available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays physiologically.Our lab employed high throughput screening paradigms to discover highly selective modulators for the DRD3.METHODS The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the DRD2.Confirmation and counter-screens assessed selectivity and mechanisms of action.We identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining selectivity.The lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK assays.Potential neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell model.RESULTS ML417 displays potent,DRD3-selective agonist activity in multiple functional assays.Binding and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other GPCRs.ML417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell model.CONCLUSION We have discovered and characterized ML417,a potent and highly selective DRD3 agonist.This compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.展开更多
Behavioral and molecular characterization of cell-type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorde...Behavioral and molecular characterization of cell-type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorders.Identification of cell-type specific changes in neuronal translation following fear learning allows for targeted pharmacological intervention during fear extinction learning,mirroring possible treatment strategies in humans.Here we identify the central amygdala(Ce A)Drd2-expressing population as a fear-supporting population that is molecularly distinct from other,previously identified fear-supporting CeA populations.Sequencing of actively translating transcripts of Drd2 neurons identifies m RNAs that are differentially regulated following fear learning including Npy5r,Rxrg,Sst5r,Fgf3,Erb B4,Fkbp14,Dlk1,Ssh3 and Adora2a.Direct pharmacological manipulation of NPY5R,RXR,and ADORA2A confirms their importance in fear behavior and validates the present approach of identifying pharmacological targets for the modulation of emotional learning.展开更多
To study the effect of PD Ⅰ administration on dopamine receptors (DR, , DRz ) mRNAs expression in the lesioned striatum of the PD rat model and confirm if PDⅠ has the effect of dopamine receptor agonist. The PD ra...To study the effect of PD Ⅰ administration on dopamine receptors (DR, , DRz ) mRNAs expression in the lesioned striatum of the PD rat model and confirm if PDⅠ has the effect of dopamine receptor agonist. The PD rats with unilateral 6-hydroxydopamine lesioned were administrated with PD Ⅰ , L-dopa methyl/benserazide, L-dopa methyl/benserazide/ PD Ⅰ , normal saline respectively for 4 weeks and their behavioral changes were observed. Then the rats were sacrificed and RT-PCR technique was used to detect changes of dopamine receptors (DR1, DR2) mRNAs expression in the ipsilateral striatum 1 day after the last treatment. The results showed that treatment with PD Ⅰ plus L-dopa resulted in a stable contralateral rotation behavior; treatment with L-dopa resulted in a progressively increased contralateral rotation behavior. Rotation behavior induced by anhydromorphine decreased with PD Ⅰ or PD Ⅰ plus L-dopa treatment. Treatment With L-dopa or PD Ⅰ plus L-dopa, up-regulation of DR, mRNA and down-regulation of DR2 mRNA were observed in the ipsilateral striatum which were more obvious than that treated with PD Ⅰ or vehicle (P〈0. 05). It was concluded that long-term treatment with PD Ⅰ could alleviate the behavior of PD rats. PD Ⅰ had no apparent effect on the dopamine receptors (DRI , DRz ) mRNAs expression in the ipsilateral striatum and the PD Ⅰ has no agonist effect on dopamine receptors.展开更多
Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than −6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in v...Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than −6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in visual input affect the balance between ocular growth and refractive power development. If a mismatch occurs during eye development, the severity of this error affects the degree of myopia. In different animal models of this disease, we found that spatial visual stimuli are essential for maintaining a stable refractive status and normal vision. This is evident because the effects of changes in temporal visual stimuli (e.g., flickering light) on this process depend on whether spatial information is present or absent in the visual environment. Furthermore, the frequency, wavelength and intensity of light are involved in controlling refraction development. However, the molecular mechanisms underlying light-induced refraction changes are still unclear. There is definitive evidence that dopamine (DA) is one of the regulators of this process. This retinal neurotransmitter released by dopaminergic amacrine cells appears to play an important role in vision-guided eye growth because its synthesis and release are positively associated with the light intensity and spatial stimuli impinging on the retina. We found that bright light enhances retinal DA synthesis, and attenuates form deprivation myopia (FDM) development via activation of the dopamine receptor 1 (D1R). A nonselective DA receptor agonist apomorphine (APO) inhibited FDM in dopamine receptor 2 (D2R) knockout mice. These individual similar effects of DA and APO in wildtype and D2R knockout mice suggest that D1R activation has a protective effect against myopia development. On the other hand, D2R activation instead appears to promote myopia development because either genetic D2R ablation or pharmacological inactivation of D2R also attenuates myopia development. Based on these results, we hypothesize that the visual environment regulates the retinal DA levels, which in turn affects the relative balance between D1R and D2R activation. When D1R is relatively hyperactivated, the ocular refractive status shifts towards hyperopia. In contrast, such an effect on D2Rpromotes the refractive status to shift in the opposite direction towards myopia.展开更多
The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary ...The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary artery vascular remodeling.Forty Arbor Acres(AA)broilers were randomly divided into four groups(n=10):a control group(deionized water,Og/L NaCl),a freshwater group(FW,deionized water+1 g/L NaCl),highly salinized freshwater group 1(H-SFW-1,deionized water+2.5 g/L NaCl)and highly salinized freshwater group 2(H-SFW-2,deionized water+5 g/L NaCl).The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water(H-SFW-1&H-SFW-2),which significantly increased the content of angiotensin II(Ang II)and the expression of angiotensin II type 1(AT1)receptor protein.Meanwhile,it significantly decreased the expression of dopamine receptor D4(DRD4)protein.The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers,which could be significantly inhibited by DRD4 agonists(D4A,HY-101384A)and enhanced by DRD4 inhibitors(D4I;HY-B0965).In addition,the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers,either at the transcriptional or translational level.At the same time,the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A.The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner.These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers,accompanied by varying degrees of proliferation of pulmonary artery smooth muscle.This mechanism may involve response of its receptor being induced by increased Ang II,while DRD4 can negatively regulate it.展开更多
Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Cu...Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.展开更多
Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive ...Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.展开更多
Patients infected with coronavirus disease 2019(COVID-19)have high serum levels of proinflammatory cytokines.The"cytokine storm"has become one of the major causes of death for critically ill patients infecte...Patients infected with coronavirus disease 2019(COVID-19)have high serum levels of proinflammatory cytokines.The"cytokine storm"has become one of the major causes of death for critically ill patients infected by COVID-19.Glucocorticoids,plasma from convalescent patients,blood purification,and tocilizumab are currently recommended for use when the body’s inflammatory response is overactivated.However,there are limitations in terms of medicinal effects,equipment reserves,and treatment expense.These challenges prompted us to assess classical agents with good safety and mature production technology.A recent study showed that nucleotide-binding oligomerization domain(NOD)-,leucine-rich repeat(LRR)-,and pyrin domain-containing protein 3(NLRP3)inflammasomes drive COVID-19 pathology.We speculate that suppression of NLRP3 inflammasome-derived cytokine production may be beneficial in COVID-19-infected patients.Dopamine receptors are present in almost all immune cells and can modulate their activation,proliferation,and cytokine production of immune cells.Previous studies have shown that dopamine receptor agonists can control systemic inflammation through inhibition of the NLRP3 inflammasome.This suggests that dopamine receptor agonists may be a new strategy for the treatment of overactive immune responses in COVID-19 patients.This is worthy of further investigation in clinical practice.展开更多
Background:Dopamine and dopamine receptor D1(DRD1),a member of the dopamine receptor family,have been indicated to play important roles in cancer progression,but dopamine secretion in hepatocellular carcinoma(HCC)and ...Background:Dopamine and dopamine receptor D1(DRD1),a member of the dopamine receptor family,have been indicated to play important roles in cancer progression,but dopamine secretion in hepatocellular carcinoma(HCC)and the effects of DRD1 on HCC remain unclear.This study was designed to explore the contribution of the dopaminergic system to HCC and determine the relationship between DRD1 and prognosis in HCC patients.Methods:The dopamine metabolic system was monitored using enzyme-linked immunosorbent assays(ELISAs).The expression of DRD1 was detected by microarray analysis,immunohistochemistry(IHC),and quantitative real-time PCR(qRT-PCR).Stable DRD1 knockout and overexpression cell lines were established for investigation.Transwell,colony formation,and Cell Counting Kit 8(CCK8)assays were performed to assess the malignant behaviors of cancer cells.The cAMP/PI3K/AKT/cAMP response element-binding(CREB)signaling pathway was evaluated by Western blot.This pathway,which is agitated by DRD1 in striatal neurons,had been proven to participate in tumor progression.Xenograft HCC tumors were generated for in vivo experiments.Results:Dopamine secretion increased locally in HCC due to an imbalance in dopamine metabolism,including the upregulation of dopa decarboxylase(DDC)and the downregulation of monoamine oxidase A(MAOA).Dopamine promoted the proliferation and metastasis of HCC.DRD1 was highly expressed in HCC tissues and positive DRD1 expression was related to a poor prognosis in HCC patients.The upregulation of DRD1 agitated malignant activities,including proliferation and metastasis in HCC by regulating the cAMP/PI3K/AKT/CREB pathway,and the downregulation of DRD1 had opposing effects.The effects of dopamine on HCC was reversed by depleting DRD1.SCH23390,a selective DRD1 antagonist,inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo.Conclusion:Dopamine secretion was locally increased in HCC and promoted HCC cell proliferation and metastasis.DRD1 was found to exert positive effects on HCC progression and play a vital role in the dopamine system,and could be a potential therapeutic target and prognostic biomarker for HCC.展开更多
Parkinson’s disease is the second most common neurodegenerative disease in the world.Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization,which is essential to...Parkinson’s disease is the second most common neurodegenerative disease in the world.Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization,which is essential to Parkinson’s disease.Moreover,the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson’s disease has recently been shown.We studied the interaction between D2 dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis.The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D2 dopamine receptor interaction among them.These compounds are promising therapies for Parkinson’s disease,and the method used in this study has great potential for application in large-scale drug screening and evaluation.展开更多
OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in s...OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in stria⁃tal neurotransmission that affect glutamatergic transmission to control the etiology of neuropsy⁃chiatric disorders.METHODS To study dorsal striatum(DS)region-specific neuronal and behav⁃ioral responses modulated by M4 receptors,we used clustered regularly interspaced short palin⁃dromic repeats-associated protein 9 technology to generate mice lacking M4 in the dorsal stria⁃tum(DS-M4-KD).The M4 positive allosteric modu⁃lator,VU0467154,were used to study the phar⁃macologically profiles with M4 receptor stimula⁃tion in WT mice.Oxotremorine M(Oxo-M),a no subtype-selective muscarinic agonist,was used to show that mAchRs activation,in order to dissect the particular function of M4,in DS-M4-KD mice.Open filed test and forced swim test were used to assess the change of psychiatric-like behav⁃iors.Western blotting and immunohistochemistry were used to detect protein levels of phosphory⁃lation site of dopamine-and cAMP-regulated phosphoprotein of 32 ku(DARPP-32).Whole-cell patch-clamp recording was used to assess M4-mediated cholinergic inhibition of glutamater⁃gic synaptic input transmission.RESULTS West⁃ern blotting and immunohistochemistry assay showed VU0467154(5 mg·kg-1,ip)promoted phosphorylation of DARPP-32 at Thr75,and atten⁃uated D1-dependent phosphorylation of DARPP-32 at Thr34 within the mouse DS.Consistently,the Oxo-M(4μg,icv)also increased DARPP-32 phosphorylation at site Thr75 to reversed phos⁃phorylation at site Thr34 in WT mice,but not in DS-M4-KD mice.In parallel with altered DARPP-32 responses,VU0467154 or Oxo-M evoked a psychological stress response and reversed D1-induced hyperlocomotion in mice in open field test and force swim tests.However,Oxo-M sup⁃pression of D1-depengdeng behavioral respons⁃es was impaired in DS-M4-KD mice.Whole-cell patch recording showed that VU0467154 or Oxo-M mediated endogenous cholinergic inhibition of miniature excitatory postsynaptic currents through M4 receptors,which in turn suppressed D1-depen⁃dent glutamatergic synaptic transmission in the DS.CONCLUSION This study provides evidence for the role of M4 receptors in regulation of dopa⁃mine/DARPP-32 signaling and glutamate respons⁃es in the DS,and therefore modulation of psychi⁃atric behaviors associated with D1 signaling.This results indicate the mechanisms of treatments targeting M4 in psychiatric disorders.展开更多
OBJECTIVE:To observe the effect of herb-partitioned moxibustion at the Tianshu (ST 25) and Qihai (CV 6) acupoints in rats with Crohn's disease,and explore the underlying mechanism from dopamine (DA) and dopamine r...OBJECTIVE:To observe the effect of herb-partitioned moxibustion at the Tianshu (ST 25) and Qihai (CV 6) acupoints in rats with Crohn's disease,and explore the underlying mechanism from dopamine (DA) and dopamine receptor 1 (D1 R) in the colon,spinal dorsal horn and hypothalamus.METHODS:The rats were randomly divided into the normal,model (CD),herb-partitioned moxibustion (Mox) and mesalazine (Mesa) groups.Damage in the colons was scored and observed by hematoxylin and eosin staining.DA and D1R protein expression in the colonic mucosa were detected by immunohistochemistry.The concentrations of DA and D1R in the spinal dorsal horn and hypothalamus were measured by enzyme-linked immunosorbent assay,and D1R mRNA expression was evaluated by quantitative real-time polymerase chain reaction.RESULTS:In the colon,compared with the normal group,DA,D1 R protein expressions and D1 R mRNA expression were significantly higher in the model group,while decreased in the Mox group and the Mesa group.In the spinal dorsal horn and hypothalamus,compared with the normal group,the concentrations of DA and D1 R,and the D1R mRNA expressions were significantly higher in the model group,and decreased in the Mox group and the Mesa group.CONCLUSION:Herb-partitioned moxibustion at the Tianshu (ST 25) and Qihai (CV 6) acupoints relieved ulceration in CD rats,the underlying mechanism maybe relative with the regulation of DA and D1R in the colon,spinal dorsal horn and hypothalamus by moxibustion.展开更多
The correlation between -94 G/A polymorphism in the dopamine D1 receptor gone and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies ...The correlation between -94 G/A polymorphism in the dopamine D1 receptor gone and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies of the -94 G/A polymorphism in the dopamine D1 receptor gone by real-time PCR using TaqMan fluorescent probes. One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated. Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls. The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls. Thus, the -94 G/A polymorphism in the dopamine D1 receptor gone was found to be associated with schizophrenia in a Chinese Han population from Shandong province.展开更多
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,a...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(P<0.05).Significant decreases 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(P<0.05).The area of CNV induced 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(P<0.05).CONCLUSION:The 0.01%,0.05%,0.1%atropine eye drops 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.展开更多
BACKGROUND: It has been demonstrated that the septal nucleus is involved in the pathogenesis of schizophrenia. Based on autopsies of schizophrenia patients, studies have shown a reduced number of septal nucleus neuro...BACKGROUND: It has been demonstrated that the septal nucleus is involved in the pathogenesis of schizophrenia. Based on autopsies of schizophrenia patients, studies have shown a reduced number of septal nucleus neurons and glia. In addition, experimental rat models of schizophrenia have shown increased dopamine receptor D2 binding sites in the basal ganglia, septal nuclei, and substantia nigra. Previous studies have demonstrated that the septal nucleus modulates dopamine metabolic disorder and dopamine D2 receptor balance. OBJECTIVE: Dopamine D2 receptor expression in a rat model of schizophrenia, combined with antipsychotic drugs, was analyzed in the prefrontal lobe, striatum, and brainstem. In situ hybridization was used to observe the effects of stereotactic septal nucleus lesions on dopamine D2 receptor expression in the brains of methylamphetamine-treated rats. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed in the Laboratory of General Institute of Psychosurgery, Third Hospital of Chinese PLA from November 2005 to June 2006. MATERIALS: A total of 120 healthy, adult Sprague Dawley rats, weighing approximately 200 g, were included. Methylamphetamine (Sigma, USA) and an in situ hybridization detection kit for dopamine D2 receptor (Boster, China) were also used for this study. METHODS: All rats were randomly allocated to the following 4 groups, with 30 rats in each group: normal control, simple administration, septal nucleus lesion, and sham-operated groups. In the normal control group, rats were not administered or lesioned. In the remaining 3 groups, rats were intraperitoneally administered 10 mg/kg methylamphetamine, once per day, for 15 successive days to establish a schizophrenia model. Following successful model establishment, rats from the septal nucleus lesion group were subjected to stereotactic septal nucleus lesions. The cranial bone was exposed in rats from the sham-operated group, and the septal nucleus was not lesioned. MAIN OUTCOME MEASURES: At 7 days post-surgery, dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem were detected by in situ hybridization. RESULTS: Dopamine D2 receptor expression in the rat prefrontal lobe, striatum, and brainstem was significantly higher in the simple administration group and sham-operated group, compared with the normal control group (P 〈 0.01). In the septal nucleus lesion group, dopamine D2 receptor expression was significantly less than the simple administration and sham-operated groups, (P 〈 0.01). There was no significant difference in dopamine D2 receptor expression between the simple administration and sham-operated groups (P 〉 0.05). CONCLUSION: Septal nucleus lesions reduce dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem in a rat model of schizophrenia, indicating that the septal nucleus modulates dopamine D2 receptor expression.展开更多
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...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.展开更多
The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesi...The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.展开更多
BACKGROUND Burning mouth syndrome(BMS)is characterized by burning sensation of the oral mucosa.There is a lack of effective treatment.In recent years,a special subtype of BMS has been reported,in which oral burning se...BACKGROUND Burning mouth syndrome(BMS)is characterized by burning sensation of the oral mucosa.There is a lack of effective treatment.In recent years,a special subtype of BMS has been reported,in which oral burning sensation is alleviated after chewing,speaking,or dopaminergic drug delivery.Currently,there are few reports about the subtype of BMS in China.This study was a retrospective analysis of the clinical data of BMS patients sensitive to dopamine agonist at our hospital,aiming to improve the recognition on this disease.CASE SUMMARY Eight patients diagnosed with dopamine agonist responsive BMS at the Liaocheng People's Hospital from January 1,2017 to June 30,2020 were recruited.The clinical manifestations,treatment,and prognosis were retrospectively analyzed.There were three male and five females in the eight patients.The median age was 56 years(range,46-65 years).All the eight patients showed burning pain in the mouth.The symptoms were mild in the morning and severe in the evening,and alleviated after chewing,talking,and other oral activities.Four patients were accompanied by restless legs syndrome(RLS).Family history of RLS was positive in two patients.All patients were treated with pramipexol,and symptoms were basically relieved after 2-8 wk.CONCLUSION Dopamine agonist responsive BMS is a special subtype of BMS,which is alleviated after oral activities.Dopamine receptor agonist is an effective treatment.展开更多
Hemocyte counts and phenoloxidase(PO)activity were examined after hemolymph being incubated in dopamine(DA),noradrenaline(NE)and serotonin(5-HT).Results showed that all the three biogenic amines(BAs)had a significant ...Hemocyte counts and phenoloxidase(PO)activity were examined after hemolymph being incubated in dopamine(DA),noradrenaline(NE)and serotonin(5-HT).Results showed that all the three biogenic amines(BAs)had a significant impact on total hemocyte count(THC),differential hemocyte count(DHC),and intracelluar and extracelluar phenoloxidase(PO)activity.Among these Bas,DA had the strongest effect on the above parameters,whereas 5-HT had the least effect.Preincubation with D1 receptor antagonist SCH23390,D2 receptor antagonist Sulpiride and 1:1 admixture of the two could significantly inhibit the effect of DA on these parameters.SCH23390 showed a stronger inhibitory effect than Sulpiride,and the admixture exhibited the strongest effect.These results suggested that the change of hemocyte count and activation of prophenoloxidase(proPO)system in Litopenaeusvan-namei hemocyte can be regulated by BAs,and DA modulates the two parameters via its receptors.展开更多
BACKGROUND: Dopamine receptors are divided into D1 and D2 subgroups. It has been reported that D2 receptors resist neural toxicity induced by excitatory amino acids and muscarine, and also alleviate epilepsy attacks ...BACKGROUND: Dopamine receptors are divided into D1 and D2 subgroups. It has been reported that D2 receptors resist neural toxicity induced by excitatory amino acids and muscarine, and also alleviate epilepsy attacks following pilocarpine treatment. However, it has not yet been established whether D2 receptors regulate temporal epilepsy. OBJECTIVE: To observe the effects of the D2 antagonist haloperidol on hippocampal neuronal apoptosis and electrical brain activity in a rat model of kainic acid-induced temporal epilepsy. DESIGN, TIME AND SETTING: Randomized grouping and histopathological study were performed at the Neurology Medicine Institute of Zhujiang Hospital, Southern Medical University from August to December 2004. MATERIALS: Twenty-five adult, male, Sprague Dawley rats were selected for the present study. Kainic acid (Sigma, USA) was injected into the right lateral ventricle to establish models of temporal epilepsy. A PowerLah multiplying channel eleetrophysiolograph was provided by AD Instruments, Australia. METHODS: The rats were randomly divided into 5 groups (n = 5): control, model, haloperidol hippocampus, haloperidol striatum, and haloperidol substantia nigra. Temporal epilepsy was established in all rats except the control group. Haloperidol was slowly injected into the hippocampus, striatum and substantia nigra, respectively, in three different injection groups. Normal saline was injected into the right lateral ventricle of the control rats. MAIN OUTCOME MEASURES: Hippocampal apoptosis was observed on the day 3 of treatment using TUNEL staining. Changes in electroencephalogram at 0, 0.5, 2, 6, and 12 hours following treatment onset were observed using a PowerLab multiplying channel electrophysiolograph. Animal behaviors were classified according to the Racine criteria. RESULTS: Twenty-five rats were included in the final analysis. Seizures did not occur in the control group. In the model group, 10 minutes after kainic acid injection to the lateral cerebral ventricle, epilepsy seizures occurred and reached a peak within one hour. Hippocampal neuronal apoptosis occurred following epilepsy, in particular on day 3. Following haloperidol injection, hippocampal neuronal apoptosis increased, in particular in the haloperidol hippocampus group, and was significantly greater than the model group (P 〈 0.05). CONCLUSION: Results suggested that D2 receptors inhibited temporal epilepsy. The hippocampal D2 receptors exhibited the strongest influence on temporal epilepsy in the hippocampus, followed by the suhstantia nigra and the striatum.展开更多
基金supported by National Institute of Neurological Disorders and Stroke Intramural Research Program
文摘OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric disorders.Currently available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays physiologically.Our lab employed high throughput screening paradigms to discover highly selective modulators for the DRD3.METHODS The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the DRD2.Confirmation and counter-screens assessed selectivity and mechanisms of action.We identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining selectivity.The lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK assays.Potential neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell model.RESULTS ML417 displays potent,DRD3-selective agonist activity in multiple functional assays.Binding and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other GPCRs.ML417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell model.CONCLUSION We have discovered and characterized ML417,a potent and highly selective DRD3 agonist.This compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.
文摘Behavioral and molecular characterization of cell-type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorders.Identification of cell-type specific changes in neuronal translation following fear learning allows for targeted pharmacological intervention during fear extinction learning,mirroring possible treatment strategies in humans.Here we identify the central amygdala(Ce A)Drd2-expressing population as a fear-supporting population that is molecularly distinct from other,previously identified fear-supporting CeA populations.Sequencing of actively translating transcripts of Drd2 neurons identifies m RNAs that are differentially regulated following fear learning including Npy5r,Rxrg,Sst5r,Fgf3,Erb B4,Fkbp14,Dlk1,Ssh3 and Adora2a.Direct pharmacological manipulation of NPY5R,RXR,and ADORA2A confirms their importance in fear behavior and validates the present approach of identifying pharmacological targets for the modulation of emotional learning.
文摘To study the effect of PD Ⅰ administration on dopamine receptors (DR, , DRz ) mRNAs expression in the lesioned striatum of the PD rat model and confirm if PDⅠ has the effect of dopamine receptor agonist. The PD rats with unilateral 6-hydroxydopamine lesioned were administrated with PD Ⅰ , L-dopa methyl/benserazide, L-dopa methyl/benserazide/ PD Ⅰ , normal saline respectively for 4 weeks and their behavioral changes were observed. Then the rats were sacrificed and RT-PCR technique was used to detect changes of dopamine receptors (DR1, DR2) mRNAs expression in the ipsilateral striatum 1 day after the last treatment. The results showed that treatment with PD Ⅰ plus L-dopa resulted in a stable contralateral rotation behavior; treatment with L-dopa resulted in a progressively increased contralateral rotation behavior. Rotation behavior induced by anhydromorphine decreased with PD Ⅰ or PD Ⅰ plus L-dopa treatment. Treatment With L-dopa or PD Ⅰ plus L-dopa, up-regulation of DR, mRNA and down-regulation of DR2 mRNA were observed in the ipsilateral striatum which were more obvious than that treated with PD Ⅰ or vehicle (P〈0. 05). It was concluded that long-term treatment with PD Ⅰ could alleviate the behavior of PD rats. PD Ⅰ had no apparent effect on the dopamine receptors (DRI , DRz ) mRNAs expression in the ipsilateral striatum and the PD Ⅰ has no agonist effect on dopamine receptors.
文摘Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than −6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in visual input affect the balance between ocular growth and refractive power development. If a mismatch occurs during eye development, the severity of this error affects the degree of myopia. In different animal models of this disease, we found that spatial visual stimuli are essential for maintaining a stable refractive status and normal vision. This is evident because the effects of changes in temporal visual stimuli (e.g., flickering light) on this process depend on whether spatial information is present or absent in the visual environment. Furthermore, the frequency, wavelength and intensity of light are involved in controlling refraction development. However, the molecular mechanisms underlying light-induced refraction changes are still unclear. There is definitive evidence that dopamine (DA) is one of the regulators of this process. This retinal neurotransmitter released by dopaminergic amacrine cells appears to play an important role in vision-guided eye growth because its synthesis and release are positively associated with the light intensity and spatial stimuli impinging on the retina. We found that bright light enhances retinal DA synthesis, and attenuates form deprivation myopia (FDM) development via activation of the dopamine receptor 1 (D1R). A nonselective DA receptor agonist apomorphine (APO) inhibited FDM in dopamine receptor 2 (D2R) knockout mice. These individual similar effects of DA and APO in wildtype and D2R knockout mice suggest that D1R activation has a protective effect against myopia development. On the other hand, D2R activation instead appears to promote myopia development because either genetic D2R ablation or pharmacological inactivation of D2R also attenuates myopia development. Based on these results, we hypothesize that the visual environment regulates the retinal DA levels, which in turn affects the relative balance between D1R and D2R activation. When D1R is relatively hyperactivated, the ocular refractive status shifts towards hyperopia. In contrast, such an effect on D2Rpromotes the refractive status to shift in the opposite direction towards myopia.
基金This research was funded by the Fundamental Research Funds for the Central Universities(Grant No.2662020DKPY013)the National Natural Science Foundation of China(Grant No.31972748)the Huazhong Agricultural University 2020 College Student Science and Technology Innovation Fund(SRF).
文摘The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary artery vascular remodeling.Forty Arbor Acres(AA)broilers were randomly divided into four groups(n=10):a control group(deionized water,Og/L NaCl),a freshwater group(FW,deionized water+1 g/L NaCl),highly salinized freshwater group 1(H-SFW-1,deionized water+2.5 g/L NaCl)and highly salinized freshwater group 2(H-SFW-2,deionized water+5 g/L NaCl).The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water(H-SFW-1&H-SFW-2),which significantly increased the content of angiotensin II(Ang II)and the expression of angiotensin II type 1(AT1)receptor protein.Meanwhile,it significantly decreased the expression of dopamine receptor D4(DRD4)protein.The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers,which could be significantly inhibited by DRD4 agonists(D4A,HY-101384A)and enhanced by DRD4 inhibitors(D4I;HY-B0965).In addition,the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers,either at the transcriptional or translational level.At the same time,the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A.The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner.These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers,accompanied by varying degrees of proliferation of pulmonary artery smooth muscle.This mechanism may involve response of its receptor being induced by increased Ang II,while DRD4 can negatively regulate it.
基金supported by the National Natural Science Foundation of China,No.82071254(to WZ).
文摘Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.
基金supported by the National Natural Science Foundation of China,No.82101263Jiangsu Province Science Foundation for Youths,No.BK20210903Research Foundation for Talented Scholars of Xuzhou Medical University,No.RC20552114(all to CT)。
文摘Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.
基金National Natural Science Foundation of China(82104148)Shanghai Sailing Program(21YF1403600)+1 种基金Shanghai"Rising Stars of Medical Talent"Youth Development Program(076478684Q/2022-00033)project of China Pharmaceutical Association(CMEI2022KPYJ00545)
文摘Patients infected with coronavirus disease 2019(COVID-19)have high serum levels of proinflammatory cytokines.The"cytokine storm"has become one of the major causes of death for critically ill patients infected by COVID-19.Glucocorticoids,plasma from convalescent patients,blood purification,and tocilizumab are currently recommended for use when the body’s inflammatory response is overactivated.However,there are limitations in terms of medicinal effects,equipment reserves,and treatment expense.These challenges prompted us to assess classical agents with good safety and mature production technology.A recent study showed that nucleotide-binding oligomerization domain(NOD)-,leucine-rich repeat(LRR)-,and pyrin domain-containing protein 3(NLRP3)inflammasomes drive COVID-19 pathology.We speculate that suppression of NLRP3 inflammasome-derived cytokine production may be beneficial in COVID-19-infected patients.Dopamine receptors are present in almost all immune cells and can modulate their activation,proliferation,and cytokine production of immune cells.Previous studies have shown that dopamine receptor agonists can control systemic inflammation through inhibition of the NLRP3 inflammasome.This suggests that dopamine receptor agonists may be a new strategy for the treatment of overactive immune responses in COVID-19 patients.This is worthy of further investigation in clinical practice.
基金This work was supported by grants from the National Natural Science Foundation of China(grant 81971057 to WAZ and grant 81902490 to DTC).
文摘Background:Dopamine and dopamine receptor D1(DRD1),a member of the dopamine receptor family,have been indicated to play important roles in cancer progression,but dopamine secretion in hepatocellular carcinoma(HCC)and the effects of DRD1 on HCC remain unclear.This study was designed to explore the contribution of the dopaminergic system to HCC and determine the relationship between DRD1 and prognosis in HCC patients.Methods:The dopamine metabolic system was monitored using enzyme-linked immunosorbent assays(ELISAs).The expression of DRD1 was detected by microarray analysis,immunohistochemistry(IHC),and quantitative real-time PCR(qRT-PCR).Stable DRD1 knockout and overexpression cell lines were established for investigation.Transwell,colony formation,and Cell Counting Kit 8(CCK8)assays were performed to assess the malignant behaviors of cancer cells.The cAMP/PI3K/AKT/cAMP response element-binding(CREB)signaling pathway was evaluated by Western blot.This pathway,which is agitated by DRD1 in striatal neurons,had been proven to participate in tumor progression.Xenograft HCC tumors were generated for in vivo experiments.Results:Dopamine secretion increased locally in HCC due to an imbalance in dopamine metabolism,including the upregulation of dopa decarboxylase(DDC)and the downregulation of monoamine oxidase A(MAOA).Dopamine promoted the proliferation and metastasis of HCC.DRD1 was highly expressed in HCC tissues and positive DRD1 expression was related to a poor prognosis in HCC patients.The upregulation of DRD1 agitated malignant activities,including proliferation and metastasis in HCC by regulating the cAMP/PI3K/AKT/CREB pathway,and the downregulation of DRD1 had opposing effects.The effects of dopamine on HCC was reversed by depleting DRD1.SCH23390,a selective DRD1 antagonist,inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo.Conclusion:Dopamine secretion was locally increased in HCC and promoted HCC cell proliferation and metastasis.DRD1 was found to exert positive effects on HCC progression and play a vital role in the dopamine system,and could be a potential therapeutic target and prognostic biomarker for HCC.
基金by the National Key Basic Research Foundation of China(Grant No.2006CB910301)the National Programs for High Technology Research and Development Program(863 Program)(No.2004AA404260)+1 种基金the National Natural Science Foundation of China(Grant Nos.30970599 and 30770421)the Fundamental Research Funds for the Central Universities of China(Grant No.1104006).
文摘Parkinson’s disease is the second most common neurodegenerative disease in the world.Beta-arrestin-2 has been reported to be an important protein involved in D2 dopamine receptor desensitization,which is essential to Parkinson’s disease.Moreover,the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson’s disease has recently been shown.We studied the interaction between D2 dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis.The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D2 dopamine receptor interaction among them.These compounds are promising therapies for Parkinson’s disease,and the method used in this study has great potential for application in large-scale drug screening and evaluation.
文摘OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in stria⁃tal neurotransmission that affect glutamatergic transmission to control the etiology of neuropsy⁃chiatric disorders.METHODS To study dorsal striatum(DS)region-specific neuronal and behav⁃ioral responses modulated by M4 receptors,we used clustered regularly interspaced short palin⁃dromic repeats-associated protein 9 technology to generate mice lacking M4 in the dorsal stria⁃tum(DS-M4-KD).The M4 positive allosteric modu⁃lator,VU0467154,were used to study the phar⁃macologically profiles with M4 receptor stimula⁃tion in WT mice.Oxotremorine M(Oxo-M),a no subtype-selective muscarinic agonist,was used to show that mAchRs activation,in order to dissect the particular function of M4,in DS-M4-KD mice.Open filed test and forced swim test were used to assess the change of psychiatric-like behav⁃iors.Western blotting and immunohistochemistry were used to detect protein levels of phosphory⁃lation site of dopamine-and cAMP-regulated phosphoprotein of 32 ku(DARPP-32).Whole-cell patch-clamp recording was used to assess M4-mediated cholinergic inhibition of glutamater⁃gic synaptic input transmission.RESULTS West⁃ern blotting and immunohistochemistry assay showed VU0467154(5 mg·kg-1,ip)promoted phosphorylation of DARPP-32 at Thr75,and atten⁃uated D1-dependent phosphorylation of DARPP-32 at Thr34 within the mouse DS.Consistently,the Oxo-M(4μg,icv)also increased DARPP-32 phosphorylation at site Thr75 to reversed phos⁃phorylation at site Thr34 in WT mice,but not in DS-M4-KD mice.In parallel with altered DARPP-32 responses,VU0467154 or Oxo-M evoked a psychological stress response and reversed D1-induced hyperlocomotion in mice in open field test and force swim tests.However,Oxo-M sup⁃pression of D1-depengdeng behavioral respons⁃es was impaired in DS-M4-KD mice.Whole-cell patch recording showed that VU0467154 or Oxo-M mediated endogenous cholinergic inhibition of miniature excitatory postsynaptic currents through M4 receptors,which in turn suppressed D1-depen⁃dent glutamatergic synaptic transmission in the DS.CONCLUSION This study provides evidence for the role of M4 receptors in regulation of dopa⁃mine/DARPP-32 signaling and glutamate respons⁃es in the DS,and therefore modulation of psychi⁃atric behaviors associated with D1 signaling.This results indicate the mechanisms of treatments targeting M4 in psychiatric disorders.
基金Supported by the National Basic Research Program of China(973 Program,No.2015CB554501)Program of National Natural Science Foundation of China(No.81574079)+2 种基金Program for outstanding medical academic leader(2015,No.80)Shuguang Program of Shanghai Education Commission(No.14SG39)Shanghai Rising-Star Program(No.16QA1403400)
文摘OBJECTIVE:To observe the effect of herb-partitioned moxibustion at the Tianshu (ST 25) and Qihai (CV 6) acupoints in rats with Crohn's disease,and explore the underlying mechanism from dopamine (DA) and dopamine receptor 1 (D1 R) in the colon,spinal dorsal horn and hypothalamus.METHODS:The rats were randomly divided into the normal,model (CD),herb-partitioned moxibustion (Mox) and mesalazine (Mesa) groups.Damage in the colons was scored and observed by hematoxylin and eosin staining.DA and D1R protein expression in the colonic mucosa were detected by immunohistochemistry.The concentrations of DA and D1R in the spinal dorsal horn and hypothalamus were measured by enzyme-linked immunosorbent assay,and D1R mRNA expression was evaluated by quantitative real-time polymerase chain reaction.RESULTS:In the colon,compared with the normal group,DA,D1 R protein expressions and D1 R mRNA expression were significantly higher in the model group,while decreased in the Mox group and the Mesa group.In the spinal dorsal horn and hypothalamus,compared with the normal group,the concentrations of DA and D1 R,and the D1R mRNA expressions were significantly higher in the model group,and decreased in the Mox group and the Mesa group.CONCLUSION:Herb-partitioned moxibustion at the Tianshu (ST 25) and Qihai (CV 6) acupoints relieved ulceration in CD rats,the underlying mechanism maybe relative with the regulation of DA and D1R in the colon,spinal dorsal horn and hypothalamus by moxibustion.
基金the Scientific Foundation of Shandong Population and Family Planning, No. 2006-7
文摘The correlation between -94 G/A polymorphism in the dopamine D1 receptor gone and schizophrenia remains poorly understood despite extensive research. This study sought to evaluate the genotypes and allele frequencies of the -94 G/A polymorphism in the dopamine D1 receptor gone by real-time PCR using TaqMan fluorescent probes. One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated. Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls. The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls. Thus, the -94 G/A polymorphism in the dopamine D1 receptor gone was found to be associated with schizophrenia in a Chinese Han population from Shandong province.
文摘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(P<0.05).Significant decreases 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(P<0.05).The area of CNV induced 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(P<0.05).CONCLUSION:The 0.01%,0.05%,0.1%atropine eye drops 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.
文摘BACKGROUND: It has been demonstrated that the septal nucleus is involved in the pathogenesis of schizophrenia. Based on autopsies of schizophrenia patients, studies have shown a reduced number of septal nucleus neurons and glia. In addition, experimental rat models of schizophrenia have shown increased dopamine receptor D2 binding sites in the basal ganglia, septal nuclei, and substantia nigra. Previous studies have demonstrated that the septal nucleus modulates dopamine metabolic disorder and dopamine D2 receptor balance. OBJECTIVE: Dopamine D2 receptor expression in a rat model of schizophrenia, combined with antipsychotic drugs, was analyzed in the prefrontal lobe, striatum, and brainstem. In situ hybridization was used to observe the effects of stereotactic septal nucleus lesions on dopamine D2 receptor expression in the brains of methylamphetamine-treated rats. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed in the Laboratory of General Institute of Psychosurgery, Third Hospital of Chinese PLA from November 2005 to June 2006. MATERIALS: A total of 120 healthy, adult Sprague Dawley rats, weighing approximately 200 g, were included. Methylamphetamine (Sigma, USA) and an in situ hybridization detection kit for dopamine D2 receptor (Boster, China) were also used for this study. METHODS: All rats were randomly allocated to the following 4 groups, with 30 rats in each group: normal control, simple administration, septal nucleus lesion, and sham-operated groups. In the normal control group, rats were not administered or lesioned. In the remaining 3 groups, rats were intraperitoneally administered 10 mg/kg methylamphetamine, once per day, for 15 successive days to establish a schizophrenia model. Following successful model establishment, rats from the septal nucleus lesion group were subjected to stereotactic septal nucleus lesions. The cranial bone was exposed in rats from the sham-operated group, and the septal nucleus was not lesioned. MAIN OUTCOME MEASURES: At 7 days post-surgery, dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem were detected by in situ hybridization. RESULTS: Dopamine D2 receptor expression in the rat prefrontal lobe, striatum, and brainstem was significantly higher in the simple administration group and sham-operated group, compared with the normal control group (P 〈 0.01). In the septal nucleus lesion group, dopamine D2 receptor expression was significantly less than the simple administration and sham-operated groups, (P 〈 0.01). There was no significant difference in dopamine D2 receptor expression between the simple administration and sham-operated groups (P 〉 0.05). CONCLUSION: Septal nucleus lesions reduce dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem in a rat model of schizophrenia, indicating that the septal nucleus modulates dopamine D2 receptor expression.
文摘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.
基金supported by a Research Development Fund(UTS Start-Up Grant 2018)from the University of Technology Sydney to AC。
文摘The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.
文摘BACKGROUND Burning mouth syndrome(BMS)is characterized by burning sensation of the oral mucosa.There is a lack of effective treatment.In recent years,a special subtype of BMS has been reported,in which oral burning sensation is alleviated after chewing,speaking,or dopaminergic drug delivery.Currently,there are few reports about the subtype of BMS in China.This study was a retrospective analysis of the clinical data of BMS patients sensitive to dopamine agonist at our hospital,aiming to improve the recognition on this disease.CASE SUMMARY Eight patients diagnosed with dopamine agonist responsive BMS at the Liaocheng People's Hospital from January 1,2017 to June 30,2020 were recruited.The clinical manifestations,treatment,and prognosis were retrospectively analyzed.There were three male and five females in the eight patients.The median age was 56 years(range,46-65 years).All the eight patients showed burning pain in the mouth.The symptoms were mild in the morning and severe in the evening,and alleviated after chewing,talking,and other oral activities.Four patients were accompanied by restless legs syndrome(RLS).Family history of RLS was positive in two patients.All patients were treated with pramipexol,and symptoms were basically relieved after 2-8 wk.CONCLUSION Dopamine agonist responsive BMS is a special subtype of BMS,which is alleviated after oral activities.Dopamine receptor agonist is an effective treatment.
基金supported by the Program for New Century Excellent Talents in University (No. NCET-06-0597)Ministry of Education 111 Project (No. B08049)
文摘Hemocyte counts and phenoloxidase(PO)activity were examined after hemolymph being incubated in dopamine(DA),noradrenaline(NE)and serotonin(5-HT).Results showed that all the three biogenic amines(BAs)had a significant impact on total hemocyte count(THC),differential hemocyte count(DHC),and intracelluar and extracelluar phenoloxidase(PO)activity.Among these Bas,DA had the strongest effect on the above parameters,whereas 5-HT had the least effect.Preincubation with D1 receptor antagonist SCH23390,D2 receptor antagonist Sulpiride and 1:1 admixture of the two could significantly inhibit the effect of DA on these parameters.SCH23390 showed a stronger inhibitory effect than Sulpiride,and the admixture exhibited the strongest effect.These results suggested that the change of hemocyte count and activation of prophenoloxidase(proPO)system in Litopenaeusvan-namei hemocyte can be regulated by BAs,and DA modulates the two parameters via its receptors.
基金Supported by: a grant from Military High-Technological Key Project, No. 2002 (Health Medicine) 18-16
文摘BACKGROUND: Dopamine receptors are divided into D1 and D2 subgroups. It has been reported that D2 receptors resist neural toxicity induced by excitatory amino acids and muscarine, and also alleviate epilepsy attacks following pilocarpine treatment. However, it has not yet been established whether D2 receptors regulate temporal epilepsy. OBJECTIVE: To observe the effects of the D2 antagonist haloperidol on hippocampal neuronal apoptosis and electrical brain activity in a rat model of kainic acid-induced temporal epilepsy. DESIGN, TIME AND SETTING: Randomized grouping and histopathological study were performed at the Neurology Medicine Institute of Zhujiang Hospital, Southern Medical University from August to December 2004. MATERIALS: Twenty-five adult, male, Sprague Dawley rats were selected for the present study. Kainic acid (Sigma, USA) was injected into the right lateral ventricle to establish models of temporal epilepsy. A PowerLah multiplying channel eleetrophysiolograph was provided by AD Instruments, Australia. METHODS: The rats were randomly divided into 5 groups (n = 5): control, model, haloperidol hippocampus, haloperidol striatum, and haloperidol substantia nigra. Temporal epilepsy was established in all rats except the control group. Haloperidol was slowly injected into the hippocampus, striatum and substantia nigra, respectively, in three different injection groups. Normal saline was injected into the right lateral ventricle of the control rats. MAIN OUTCOME MEASURES: Hippocampal apoptosis was observed on the day 3 of treatment using TUNEL staining. Changes in electroencephalogram at 0, 0.5, 2, 6, and 12 hours following treatment onset were observed using a PowerLab multiplying channel electrophysiolograph. Animal behaviors were classified according to the Racine criteria. RESULTS: Twenty-five rats were included in the final analysis. Seizures did not occur in the control group. In the model group, 10 minutes after kainic acid injection to the lateral cerebral ventricle, epilepsy seizures occurred and reached a peak within one hour. Hippocampal neuronal apoptosis occurred following epilepsy, in particular on day 3. Following haloperidol injection, hippocampal neuronal apoptosis increased, in particular in the haloperidol hippocampus group, and was significantly greater than the model group (P 〈 0.05). CONCLUSION: Results suggested that D2 receptors inhibited temporal epilepsy. The hippocampal D2 receptors exhibited the strongest influence on temporal epilepsy in the hippocampus, followed by the suhstantia nigra and the striatum.