Research progress on the pathogenesis of attention deficit hyperactivity disorder based on the theory of Dopamine deficits / 中华实用儿科临床杂志

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, which seriously affects physical and mental health in children.Its etiology and pathogenesis are complex and have not been fully elucidated.Currently, the theory of Dopamine (DA) deficits has been widely recognized and studied in the international academic community.The DA system is considered as the key to the pathogenesis of ADHD.The causes of DA deficits are complex.In addition to the well-established reuptake disorder caused by abnormal DA transporter function, DA deficits are also associated with the activation of DA vesicle cycle enzymatic inactivation, vesicle transport dysfunction, and receptor dysfunction, which are of great significance in analyzing disease pathogenesis and drug development.This article reviews the research on the causes of DA deficits proposed in recent years based on the theory of DA deficits, aiming to provide ideas and references for the research on the pathogenesis of ADHD in China.

Neurobiological mechanisms in the regulation of conditioned fear memory by the retrieval-extinction paradigm / 中华行为医学与脑科学杂志

Fear memories are temporarily suppressed after repeated retrieval, a phenomenon known as memory extinction.How to reduce or even eliminate fear memory is the key to the treatment of fear related diseases such as post-traumatic stress disorder(PTSD). A single extinction training based on Pavlov's fear regulation task could only inhibit the expression of conditioned fear memory traces, but it could not eliminate the acquired conditioned fear memory. However, according to the reconsolidation theory based on memory, the retrieval-extinction paradigm has a more lasting effect on the erasure and rewriting of fear memory, and can effectively prevent the return of fear memory. Studies have shown that extraction-regression is closely related to a variety of neurotransmitter receptors such as glutamate receptor(GluR), dopamine receptor(DAR), L-type voltage-gated calcium channels(LVGCs) and cannabinoid. Moreover, its effect is closely related with factors such as retrieval-extinction memory stage. At present, most of the researches on extracted boundary conditions only stay at the level of behavior, with little understanding and exploration on the level of molecular mechanism. From the perspective of molecular neurobiology, with different stages of memory and different types of receptors and molecular mechanisms, this research reviewed the mechanisms of retrieval-extinction in recent years.It provided valuable signaling pathways, molecular targets and research directions for the treatment of fear-related diseases such as PTSD.

Blood pressure and its association with antiparkinsonian medications in patients with Parkinson′s disease / 中华神经科杂志

Parkinson′s disease (PD) is the second most common neurodegenerative disease following Alzheimer′s disease. The non-motor symptoms of PD have attracted increasing attention. The occurrence of abnormal blood pressure is related to many factors, including aging, PD related autonomic nerve dysfunction, and drugs for PD treatment,including levodopa, dopamine receptor agonists. Abnormal blood pressure severely limits the clinical use of anti-PD drugs. In order to better understand the relationship between anti-PD drugs and blood pressure in patients with PD. This article summarizes the manifestations of abnormal blood pressure, and analyzes the correlation between anti-PD drugs and blood pressure, summarizes the possible mechanisms of how anti-PD drugs affects the blood pressure in PD.

Mechanism of Suoquanwan on Enuresis Based on Network Pharmacology and Experimental Verification / 中国实验方剂学杂志

Objective:To explore the targets and relevant signaling pathways of Suoquanwan in the treatment of enuresis using network pharmacology，and animal expriments are applied to further define its mechanism of action. Method:Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP） database was used to screen out active chemical components of Suoquanwan，varieties of systematic biological databases were integrated to construct the "active component-disease-target" network relationship，and the common protein protein interaction network（PPI） network genes were functionally enriched. Quantitative real time polymerase chain reaction（Real-time PCR） and Western blot were used to verify the effect of Suoquanwan on AVPR2 and DRD2 gene. Result:A total of 32 active ingredients were screened from Suoquanwan. These active ingredients were interacted with 131 potential targets relating to Enuresis，which contained 14 core target genes，namely arginine vasopressin receptor 2 （AVPR2）， neurotrophic receptor tyrosine kinase 1（NTRK1）， dopamine receptor D2（DRD2）， opioid receptor mu 1（OPRM1）， 5-hydroxytryptamine receptor 1A（HTR1A）， 5-hydroxytryptamine receptor 1B（HTR1B），solute carrier family 6 member 4（SLC6A4），Adrenoceptor Alpha 2A（ADRA2A）， prostaglandin-endoperoxide synthase 2（PTGS2）， cholinergic receptor muscarinic 2（CHRM2）， solute carrier family 6 member 3 （SLC6A3）， 5-hydroxytryptamine receptor 6（HTR6）， solute carrier family 6 member 2（SLC6A2）， cytochrome P450 family 2 subfamily C member 19（CYP2C19）. Gene enrichments mainly involved to G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and neuroactive ligand-receptor interaction. Real-time PCR and Western blot results showed that Suoquanwan could enhance the expression of AVPR2 in rat kidney，and weaken the expression of DRD2 in rat adrenal. Conclusion:The main chemical constituents in Suoquanwan may alleviate enuresis by regulating AVPR2 and DRD2 and then participating in the G protein-coupled receptor signaling pathway，regulation of trans-synaptic signaling，regulation of neurotransmitter transport and other biological processes.

DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo

Objective: Studies to reduce the heterogeneity of attention-deficit/hyperactivity disorder (ADHD) have increased interest in the concept of sluggish cognitive tempo (SCT). The aim of this study was to investigate if the prevalence of two variable-number tandem repeats (VNTRs) located within the 3′-untranslated region of the DAT1 gene and in exon 3 of the dopamine D4 receptor (DRD4) gene differ among four groups (31 subjects with SCT but no ADHD, 146 individuals with ADHD but no SCT, 67 subjects with SCT + ADHD, and 92 healthy controls). Methods: We compared the sociodemographic profiles, neurocognitive domains, and prevalence of two VNTRs in SCT and ADHD subjects versus typically developing (TD) controls. Results: The SCT without ADHD group had a higher proportion of females and lower parental educational attainment. Subjects in this group performed worse on neuropsychological tests, except for psychomotor speed and commission errors, compared to controls. However, the ADHD without SCT group performed significantly worse on all neuropsychological domains than controls. We found that 4R homozygosity for the DRD4 gene was most prevalent in the ADHD without SCT group. The SCT without ADHD group had the highest 7R allele frequency, differing significantly from the ADHD without SCT group. Conclusion: The 7R allele of DRD4 gene was found to be significantly more prevalent in SCT cases than in ADHD cases. No substantial neuropsychological differences were found between SCT and ADHD subjects.

Relationship between aggressive behavior in patients with bipolar disorder and DRD4 gene polymorphism and personality characteristics / 上海交通大学学报（医学版）

Objective: To explore the relationship between aggressive behavior, dopamine receptor D4 (DRD4) exon III 48 bp variable number tandem repeat (VNTR) and personality characteristics in patients with bipolar disorder. Methods: From January 2015 to December 2018, 173 patients with bipolar disorder were selected from Shanghai Changning Mental Health Center, Shanghai Jing'an Mental Health Center, Shanghai Xuhui Mental Health Center, and Shanghai Jiading Central Hospital. According to the score of Modified Overt Aggression scale (MOAS), 173 patients were divided into aggressive behavior group (research group) and non-aggressive behavior group (control group). General survey and the temperament and personality questionnaire (Temperature and Character Inventory, TCI) were carried out, respectively. The polymorphism of DRD4 gene were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Genetic equilibrium test of genotype Hardy-Weinberg and the difference of genotype frequency between the two groups were analyzed by using SHEsis software. The relationship between aggression behavior and DRD4 gene polymorphism and personality traits in bipolar disorder patients was analyzed by χ2 test and t test. Results: There was no significant difference in the general data between research group and control group (P>0.05). Six alleles and nine genotypes of DRD4 exon III 48 bp VNTR were detected. The most common alleles in the two groups were four repeat alleles. There were statistical differences in the frequency distribution of genotypes and alleles of DRD4 exon III 48 bp VNTR between the two groups (P=0.040, P=0.018). The scores of novelty seeking and harm avoidance in the research group were higher than those in the control group (P=0.026, P=0.000), while the scores of cooperativeness and self-directedness were lower than those in the control group (both P=0.000). Patients with long repeat alleles had significantly higher scores in novelty seeking and harm avoidance, and lower scores in cooperativeness, compared with patients with short repeat alleles (P=0.000, P=0.006, P=0.038). Conclusion: Aggressive behavior in patients with bipolar disorder may be associated with DRD4 exon III 48 bp VNTR. In bipolar disorder, patients with aggressive behavior have unique personality characteristics in impulsiving, novelty-seeking, exploring, being afraid of uncertainty, revengeful, behaving himself and so on. Patients with long repeat alleles have more significant personality abnormalities.

Effect of Gastrodia elata on improving sleep in mice and its mechanism / 中草药

Objective: To investigate the sleep promoting effect of Gastrodia elata on mice and its effect on the central dopamine (DA) system, and study the mechanisms of gastrodin, the active constituent of G. elata. Methods: Five groups of mice were treated by gavage with saline, gastrodia, olive oil, gastrodia mixed with olive oil and positive control Estazolam, respectively, for 20 d (10 mice per group). Hypnosis induced by suprathreshold and subthreshold doses of Pentobarbital sodium were used to evaluate the effect of G. elata on sleep in mice. Sleep latency, occurrence rate and duration were recorded at the 7th and 20th day. The DA content in the brain tested by ELISA and the expression of DA receptor subtypes detected by qRT-PCR were used to determine the effect of G. elata on central DA system. Western blotting was further used to detect the expression levels of ERK pathway related protein. Results: After 20 d of gavage, the sleep latency of mice was significantly shortened, the sleep occurrence rate was increased, the sleep duration was prolonged, and the content of brain DA was significantly increased. At the same time, the expression levels of all the dopamine receptor subtypes were significantly up-regulated. Furthermore, the gastrodin, the active constituent of G. elata, could activate the dopamine receptor D2 rather than the D1-mediated signaling pathway. Conclusion: G. elata might regulate sleep by up-regulating the activity of central DA system. Gastrodin, the active constituent of G. elata, could play a regulating role through D2-mediated signaling pathway.

Expression of dopamine receptors in rat olfactory bulb and its role in hyposmia of Parkinson' s disease rat model / 解剖学报

Objective: To observe the localization and expression of dopamine receptors in olfactory bulb (OB) of rats and explore the effect of L-levodopa (L-DOPA) treatment on hyposmia in Parkinson' s disease (PD) rat model. Methods: Western blotting, immunohistochemistry and immunofluorescence were used to observe the expression and localization of dopamine receptors in the OB. PD rat model was established by bilateral 6-hydroxy dropamine(6-OHDA) injection to detect the effect of L-DOPA treatment on the hyposmia and the expression of glutamic decarboxylase (GAD) and brain derived neurotrophic factor (BNDF) of PD rats. Results Dl and D2 receptors were the major subtypes in the OB.D1 and D2 receptors were expressed by GAD positive Î3-aminobutyric acid (GABA) ergic neurons in the granule cell layer(GCL) which surrounded by tyrosine hydroxylase (TH) positive nerve fibers. The expression of TH in the GCL layer of PD rats decreased significantly (0. 05±0. 01 vs 0. 01±0. 00,P<0. 001). After L-DOPA treatment, the time of finding food balls in PD rats was significantly reduced [(624. 4±113.4)s vs (312. 4±79. 35) s, P<0.05]and the expression of BDNF in the OB was increased (0. 02±0. 01 vs 0. 07±0. 01, P<0. 01). Conclusion Dl and D2 are expressed in the GABAergic neurons in the GCL layer of OB. L-DOPA treatment alleviates the hyposmia of PD rats, which may be related to the D1-D2 receptor heteromeractivation and its downstream BDNF expression of GABAergic neurons.

Role of Helix 8 in Dopamine Receptor Signaling

G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished β-arrestin-mediated desensitization, resulting in increased Gs signaling.

Limonene Inhibits Methamphetamine-Induced Sensitizations via the Regulation of Dopamine Receptor Supersensitivity

Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine-induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. The development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine-induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonene-pretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity.

Dopamine receptor D2 polymorphism is associated with alleviation of obesity after 8-year follow-up: a retrospective cohort study in obese Chinese children and adolescents / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

OBJECTIVE@#The aim of this study was to explore the association of dopamine receptor D2 (DRD2) polymorphism and alleviation of obesity in children and adolescents after 8-year follow-up.@*METHODS@#This retrospective cohort study included obese children and adolescents with a follow-up period of 8 years. Baseline clinical characteristics and DRD2 polymorphisms (including rs1076562, rs2075654, and rs4586205) were extracted from medical records. A follow-up visit was performed in May 2017 to collect related data including height, weight, diet compliance, and exercise compliance.@*RESULTS@#One hundred and nine obese children and adolescents were included in the current study. Among three DRD2 single nucleotide polymorphisms, only rs2075654 had a statistically significant association with alleviation of obesity, as the alleviation rate for minor allele carriers (68.6% for TC+TT) was higher compared to the major allele homozygote (43.3% for CC). After adjusting for all related factors, the hazard ratio of rs2075654 minor allele carriers for the alleviation of obesity was 3.34 (95% confidence interval (CI): 1.30‒8.58).@*CONCLUSIONS@#The rs2075654 polymorphism of DRD2 is related to long-term obesity alleviation in obese Chinese children and adolescents.

Effect of Electroacupuncture on Central Dopamine Receptor in Morphine-dependent Rats / 上海针灸杂志

Objective To observe the change of dopamine receptor in ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC) in morphine-dependent rats, and the regulation effect of electroacupuncture (EA). Method Thirty male SD rats were randomized into a control group, a model group and an EA group, 10 rats each. Morphine-dependent rat models were induced by morphine self-administration. In the EA group, bilateral Jiaji points (EX-B2) of T5 and L2 were selected, and the EA intervention lasted 4 d. Western blotting method was adopted to observe the change of the contents of dopamine receptor D1 and D2 in VTA, NAc and PFC of the rats. Result After the intervention, compared to the model group, the morphine intake was reduced significantly in the EA group (P<0.05); the level of D2 declined significantly in VTA of rats in the model group (P<0.05); the level of D1 increased significantly and D2 declined significantly in NAc of rats in the model group (P<0.05); the level of D1 declined significantly and D2 increased significantly in PFC of rats in the model group (P<0.05); EA produced regulation effect on the altered contents of D1 and D2 in the cerebral areas mentioned above, approaching the normal level. Conclusion EA can inhibit the hunger of addiction rats for morphine to some extent; the contents of dopamine receptors in dopamine projection pathway will take adaptive changes after morphine addiction, while EA can regulate the abnormal expressions of dopamine receptors, producing a protective effect on dopamine receptors of morphine-dependent rats.

Association between methylation status of CpG island in DAT1 and DRD4 genes and clinical symptoms of ADHD / 中国神经精神疾病杂志

Objective To investigate the correlation of methylation status in DA T1 and DRD4 genes and severity of clinical manifestations in ADHD patients.Methods One hundrd eleven DSM-Ⅳ defined ADHD patients were enrolled in this study and the demographic data were collected.Clinical symptoms were also assessed by Attention Deficit Hyperactivity Disorder Rating Scale-Ⅳ Home Version (ADHD-RS-Ⅳ) and self-developed Oppositional Defiant Disorder (ODD) rating scale.Bisulfite genomic sequencing (BGS) was used to detect the methylation status of every CpG site in DA T1 and DRD4 promoter CpG island in peripheral venous blood.Results The DNA methylation level in total CpG island for DA T1 was higher in individuals without depression,anxiety or ADHD family history compared to individuals with above family histories (P＜0.05).The differences on methylation levels for DA T1 and DRD4 were not significant between high and low ADHD-RS-Ⅳ total score (≤30 vs.＞30),ADHD-RS-Ⅳ inattention score (≤ 17 vs.＞17),and ADHD-RS-Ⅳ hyperactivity/impulsivity score (≤13 vs.＞13) subgroups (all P＜0.05).The methylation levels in total CpG island in DA T1 was higher in individuals whose ODD score were ＜9 compared to those whose ODD score were ≥9 (P＜0.05).Conclusions Methylation status of CpG island in DAT1 may influence the severity of oppositional defiant symptom in ADHD patients,which is correlated with depression,anxiety and ADHD family histories.

Association between smoking and dopamine receptor D2 polymorphisms in male patients with schizophrenia / 中国心理卫生杂志

Objective:To investigate the association between dopamine receptor D2(DRD2) polymorphisms and smoking in male patients with schizophrenia.Methods:Totally 773 patients with schizophrenia (567 smokers and 206 non-smokers) and 302 normal controls (168 smokers and 134 non-smokers) were recruited.The two single nucleotide polymorphisms (SNPs) (rs1800497 and rs1079597) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP).SHEsis genetic analysis platform was used to calculate linkage disequilibrium index and infer allele distribution and haplotype frequency.Results:There was no significant difference in two SNPs genotype and allele distributions between the patients and normal controls or between smokers and non-smokers in either patients or normal controls alone (Ps ＞ 0.05);the frequency estimations of haplotype C-A and T-G in patients with schizophrenia were higher than in normal controls (8.0％ vs.5.2％,10.2％ vs.4.1％,Ps ＜0.05),T-A (34.6％ vs.40.2％,P ＜0.05),whereas the frequency estimation of haplotype T-A in patients with schizophrenia was lower than in normal controls,and all the differences were statistically significant (34.6％ vs.40.2％,P ＜ 0.05).It was also observed that the frequency estimation of haplotype T-A in normal smokers was significantly lower than in normal non-smokers (2.5％ vs.6.1％,P ＜0.05).Conclusion:There may be a correlation between DRD2 polymorphisms and the susceptibility to schizophrenia,but not between DRD2 polymorphisms and smoking neither in patients with schizophrenia nor in normal controls.

Correlation study between the expression of dopamine receptor in brain and the pancreatic encephalopa-thy / 实用医学杂志

Objective To investigate the expression of dopamine receptor in brain of rats with pancreatic encephalopathy and provide a theoretical basis to reveal pathogenesis of pancreatic encephalopathy. Methods A rat model of experimental pancreatic encephalopathy was induced by retrograde injection of 5％sodium taurocholate into the pancreatic duct. The pathological changes of pancreas and brain were detected. The water content in brain tissue was determined. The superoxide dismutase activity and malondialdehyde content in brain tissue homogenate were detected by the chemical colorimetry. Levels of TNF-α,IL-1β,tyrosine hydroxylase and dopamine receptor-2 were detected by immunohistochemistry(SP method). Results Cerebral sulcus was shallow,ventricle was small-er and the superficial veins were dilated and congested. The inflammatory cell infiltration and pancreatic acinar cell necrosis in the pancreas and neuron edema ,inflammatory cell infiltration ,microvessel adherent leukocytes in brain were observed by light microscope in model groups at 3,6,12 hours. Compared with the control group. The activities of superoxide dismutase in brain tissue in model groups at 3,6,12 hours were significantly decreased (P < 0.01). The level of malondialdehyde and the water content of brain tissue were significantly increased (P <0.01 ,respectively). Compared with the control group ,levels of brain TNF-α,IL-1β,tyrosine hydroxylase and dopamine receptor-2 in model groups at 3,6,12 hours were significantly increased(P < 0.01,respectively).Conclusions The incidence of pancreatic encephalopathy may be related to the influx of oxygen free radical and inflammatory factors,invading nerve center by blood-brain barrier and inducing the increased production of dopa-mine and the upregulation of dopamine receptor in brain.

Correlation study between the expression of dopamine receptor in brain and the pancreatic encephalopa-thy / 实用医学杂志

Objective To investigate the expression of dopamine receptor in brain of rats with pancreatic encephalopathy and provide a theoretical basis to reveal pathogenesis of pancreatic encephalopathy. Methods A rat model of experimental pancreatic encephalopathy was induced by retrograde injection of 5％sodium taurocholate into the pancreatic duct. The pathological changes of pancreas and brain were detected. The water content in brain tissue was determined. The superoxide dismutase activity and malondialdehyde content in brain tissue homogenate were detected by the chemical colorimetry. Levels of TNF-α,IL-1β,tyrosine hydroxylase and dopamine receptor-2 were detected by immunohistochemistry(SP method). Results Cerebral sulcus was shallow,ventricle was small-er and the superficial veins were dilated and congested. The inflammatory cell infiltration and pancreatic acinar cell necrosis in the pancreas and neuron edema ,inflammatory cell infiltration ,microvessel adherent leukocytes in brain were observed by light microscope in model groups at 3,6,12 hours. Compared with the control group. The activities of superoxide dismutase in brain tissue in model groups at 3,6,12 hours were significantly decreased (P < 0.01). The level of malondialdehyde and the water content of brain tissue were significantly increased (P <0.01 ,respectively). Compared with the control group ,levels of brain TNF-α,IL-1β,tyrosine hydroxylase and dopamine receptor-2 in model groups at 3,6,12 hours were significantly increased(P < 0.01,respectively).Conclusions The incidence of pancreatic encephalopathy may be related to the influx of oxygen free radical and inflammatory factors,invading nerve center by blood-brain barrier and inducing the increased production of dopa-mine and the upregulation of dopamine receptor in brain.

Association of methylation status of CpG islands in DAT1 and DRD4 genes with attention deficit hyperactivity disorder / 中华行为医学与脑科学杂志

Objective To explore the difference of methylation status of CpG island in promoter re?gion of DAT1 and DRD4 genes between children with attention deficit hyperactivity disorder ( ADHD) and normal controls,and further understand the pathogenesis of ADHD from a epigenetics point of view. Methods 111 ADHD patients and 118 normal controls were enrolled in the present study. The demographic data and peripheral venous blood were collected from both groups. Bisulfite genomic sequencing ( BGS) was used to confirm the methylation status of every CpG site in promoter region of DAT1 and DRD4 genes. Results No significant differences were found between ADHD patients and normal controls on percentage of methylated CpG sites in total CpG islands for both DAT1 and DRD4 (P>0.05) . However,the percentage of methylation in No. 17 CpG site for DAT1 and No. 8 CpG site for DRD4 was higher in ADHD patients ( 23. 42% and 64.86% respectively)compared with that in normal controls(11.86% and 47.46% respectively)(P<0.05).In all samples,the percentage of methylated CpG site in total CpG island for DAT1 was higher in males com?pared with that in females(P<0.05),whereas that for DRD4 was higher in females compared with that in males (P<0.05);the same gender difference on methylation level for DAT1 was also found in ADHD patients and for DRD4 in normal controls(P<0.05) . In all samples and in ADHD patients,percentage of methylated CpG site in total CpG island for DAT1 was higher in individuals over 7 years old compared with that in indi?viduals younger than or equal to 7 years old(P<0.05). Conclusions Methylation status of CpG island in DAT1 and DRD4 genes promoter region might correlate with ADHD susceptibility.Methylation status of CpG island in DAT1 and DRD4 genes show differences in different age span and sex.

Identification and optimization of a potent and highly selective D3 dopamine receptor agonist / 中国药理学与毒理学杂志

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 RxPathHunter? 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 SHSY5Y 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 SHSY5Y 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.

Cell-type specific examination of central amygdala dopamine receptor 2 expressing neurons as a translational target for pharmacological enhancement of extinction / 中国药理学与毒理学杂志

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 (CeA) 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 mRNAs that are differentially regulated following fear learning including Npy5r, Rxrg, Sst5r, Fgf3, ErbB4, 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.

Research Progress in Drug Interactions of Haloperidol / 中国药师

Objective:To summarize the drug interactions of haloperidol used in combination with the other drugs to provide refer-ence for safe, reasonable and effective use of haloperidol in clinics. Methods:By retrieving Micromedex? , Pubmed, CNKI and so on, the interactions between haloperidol and the other drugs were summarized and analyzed. Results:The effect of haloperidol was on do-pamine receptors, and haloperidol was mainly metabolized by hepatic cytochrome P450 ( CYP) enzymes. When haloperidol was com-bined with the other drugs, significant interactions of pharmacokinetics and pharmacodynamics were induced by affecting CYP enzymes or dopamine receptor. Conclusion:In clinical practice, the other drugs combined with haloperidol should be reasonable and careful to ensure safe, effective and rational drug use.