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ObjectiveVentrolateral periaqueductal gray (vlPAG) locates in ascending reticular activating system, which plays a key role in the sleep-wake circle. However, the role of vlPAG in general anesthesia has not been identified. To investigate the effect of the dopamine receptor in vlPAG neurons on propofol anesthesia, we used real-time in vivo fiber photometry, microinjection and EEG.MethodsTo observe the alteration of neuronal activity in the vlPAG throughout propofol anesthesia, 10 Sprague-Dawley rats were used for calcium fiber photometry recording. 50 vlPAG bilateral microinjection models were established and assigned into five groups randomly, including D1R agonist group, D1R antagonist group, D2R agonist group, D2R antagonist group, and control group (n=10). Under propofol anesthesia, 1 μL of D1R agonist, D1R antagonist, D2R agonist, D2R antagonist, and isotonic saline were microinjected into the vlPAG of animals in the corresponding groups, respectively. The induction time, recovery time and the changes in electroencephalogram (EEG) before and after microinjection were recorded and analyzed.ResultsThe neuronal activity in the vlPAG was significantly inhibited during the induction period and markedly recovered during the recovery period from propofol anesthesia (P<0.05). Subsequently, the microinjection of D1R agonist into the vlPAG notably prolonged the induction time and reduced the emergence time of propofol anesthesia with a decrease of δ-band ratio. While the microinjection of D1R antagonist accelerated the induction time and prolonged the emergence time of propofol anesthesia with an increase of δ-band ratio and a decrease in β-band ratio in cortical EEG (P<0.05). The induction and recovery time of D2R agonist /antagonist group did not differ with those of control group. As well, EEG before and after microinjection in D2R agonist /antagonist group did not different.ConclusionThese results indicate that vlPAG modulates the process of propofol anesthesia via D1R.
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Objective: To observe the changes of dopamine (DA) levels in the hippocampal dentate gyrus (DG) region of the rats during the establishment and extinction process of active avoidance conditioned reflex, and to investigate the effect of D1 receptor in the active avoidance learning of the rats and its mechanism. Methods: A total of 24 male SD rats were randomly divided into non-training group, training group, control group and SCH group (n= 6). The rats in training group were trained for active avoidance whereas the rats in non-training group were only put into the shuttle box without training, and then the DA levels in extracellular fluid in DG region of the rats in two groups were measured. In control and SCH groups, the saline or SCH-23390 was injected into the DG region of the rats before the active avoidance training, and then the glutamate (Glu) levels and the field excitatory postsynaptic potential (fEPSP) amplitudes in extracellular fluid in DG region of the rats in two groups were examined. The rates of active avoidance of the rats were recorded by behavioral analysis system of the shuttle box. The levels of DA and Glu in DG region of the rats were measured by microdialysis and HPLC techniques, and the amplitude of fEPSP in DG region of the rats was examined by electrophysiological recording. Results: The DA level in DG region of the rats in training group was gradually increased during the establishment process and was gradually decreased during the extinction process of conditioned reflex; compared with the 1st day, the DA level in DG region of the rats on the 5th day was markedly increased (P0. 05). In control group, the rats reached the establishment criterion on the 5th day (active avoidance rate > 65%) and reached the criterion of extinction on the 7th day (active avoidance rate 0. 05). Compared with control group, the Glu level and fEPSP amplitude of the rats in SCH group on the 5th day were markedly decreased (P<0. 05). Conclusion: DA in hippocampal DG region of the rats can facilitate the active avoidance learning via activation of D1 receptors, and its mechanism is associated with the enhancement of Glu level and synaptic transmission efficiency.
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Objective To explore the effects of chronic sleep deprivation (CSD) on the ultrastructure and downstream signaling pathway of dopamine D1 receptor of the hippocampus in rats. Methods Thirty-five male SD rats were selected in this experiment, of which 11 with the lightest weight, shortest weight-bearing swimming time or no finding the platform within 90 s in Morris water maze experiment were excluded. The other 24 rats were randomly divided into tank control (TC) group, CSD group and CSD+dopamine D1 receptor agonist SKF38393 (SKF) group. The CSD rat model was established by modified multi-platform water environment, and then the rats in the SKF group were intraperitoneally injected with SKF38393 (1 mg/kg) at 15-21 d of CSD. At 21 d after CSD, the ultrastructure of hippocampus was observed by transmission electron microscopy, and the expression of key factors in dopamine D1 receptor-related signal pathway in the hippocampus was detected by Western blotting and qPCR. Results The mitochondrial swelling, degeneration and destruction of membrane structure of the hippocampus neurons induced by CSD were improved by SKF38393. Compared with the TC group, the mRNA expression levels of adenylate cyclase 5 (Adcy5), protein kinase cAMP-dependent catalytic α (Prkacα), dopamine and cAMP-regulated phosphoprotein (Darpp32), Ras-related protein (Rap) 1a, extracellular signal regulated kinase 1 and 2 (ERK1/2), phospholipase C β1 (PLCβ1), calcium/calmodulin-dependent protein kinase IIa and IV (CaMKIIa, CaMKIV) in the CSD group were significantly decreased (P<0.05), and the protein levels of total and phosphorylatied protein kinase A catalyzes subunit α (PKAcα), phosphorylated ERK1/2, phosphorylated PLCβ1, and phosphorylated CaMKIV were significantly decreased (P<0.05). Compared with the CSD group, the mRNA expressions of Prkacα, Darpp32, Rap1a, Rap1b, ERK1 and CaMKIV in the SKF group were significantly increased (P<0.05), and the protein levels of total and phosphorylated PKAcα and phosphorylated CaMKIV were significantly increased (P<0.05), while the expression of PLCβ1 and total CaMKIV was similar in the two groups. Conclusion CSD damages the ultrastructure of the hippocampus neurons in rats, which can be effectively improved by dopamine D1 receptor agonist SKF38393, and the protective mechanism may be related to the PKA pathway and phosphoinositol pathway.
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ObjectiveTo investigate the effects of dopamine D1 receptor (D1R) tool drugs and combined acupuncture and medicine on striatal expressions of D1R and dopamine transporters (DAT) in middle cerebral artery occlusion (MCAO)-reperfusion rats.MethodForty-seven male SD rats were randomly grouped, used to make a model and given corresponding interventions. The materials were taken and fixed six hrs later. Striatal D1R and DAT expressions were detectedby an immunohistochemical method in different groups.ResultThe neurological deficit score was significantly higher in the model group than in the blank group. Electroacupuncture treatment decreased the score significantly (P0.05). DAT expression was significantly down-regulated in the other groups compared with the model group (P0.05).ConclusionCerebral ischemia-reperfusion can result in high D1R and DAT expressions in rat striatum on the ischemic side. Electroacupuncture, D1R antagonists and a combination of the two can significantly down-regulate D1R expression and have a protective effect on the brain. The effects of electroacupuncture and D1R antagonists can not be added to each other. D1R signaling pathway may be one of ways by which electroacupuncture produces a protective effecton the brain.
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Objective:To investigate the relationship between dopamine D1 receptor ( DRD1 ) gene polymorphisms and clozapine efficacy in male schizophrenic patients. Methods:Totally 46 male schizophrenic patients were treated by clozapine for 6-8 weeks. The clinical response was determined by the Positive and Negative Symptom Scale (PANSS). DRD1 gene rs265981, rs5326, rs4532, rs1799914, rs686 and rs4867798 polymorphisms were detected by the gene sequencing, while plasma clozapine levels were monitored during the treatment. Results:The total clinical efficacy of clozapine response group and the non-response group was compared, the distribution of rs265981 genotype TT, TC and CC and allele T and C had statistically significant differences (P=0. 025;P=0. 005), and the distribution of rs686 genotype CC, CT and TC and allele C and T had statistically significant differences ( P=0. 044;P=0. 010). The negative symptom of the response group was compared with that of the non-response group, the distribution of rs4532 gen-otype GG, GA and AA and allele G and A had statistically significant differences (P=0. 034; P=0. 013). Conclusion: The poly-morphisms of DRD1 gene rs265981 and rs686 may have influence on the clinical efficacy of clozapine, and rs4532 may have influence on the negative symptom.
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ObjectiveTo evaluate whether post-traumatic stress disorder(PTSD)-like rats more easily to acquire the alcohol induced conditioned place preference(CPP),and its relationship with dopamine D1 receptor.Methods40 SD rats were randomly divided into four groups:PTSD + ethanol group ( PE.),control + ethanol group (CE),PTSD + saline group(PS),and control + saline group(CS).All rats of each group were trained for CPP with alternate injections of alcohol ( 2 mg/kg,i.p.) and saline ( 10 ml/kg,i.p.).PE and PS group were subjected to single prolonged stress (SPS) for PTSD model.Four groups were evaluated the performances of freezing behavior and plus maze test after SPS 24 hours and 7 days.And on SPS 7 days four groups were respectively detected D1 dopamine receptor-positive cells number in amygdale by immunohistochemistry.ResultsCompared with control group,freezing time of PTSD group was remarkable longer on 7 days after SPS not 24 hours( (89.13 ±8.60) s vs(22.25± 5.85) s,q =8.77,P ＜ 0.01 ),and number of entry into the open arms and time spent in the open arms of PTSD group were both less than control group on 7 days after SPS not 24 hours( (4.25 ± 1.26) vs ( 14.38 ± 2.18),( 12.38 ± 3.30) s vs (40.38 ± 7.29 ) s,q =4.74 and 4.08,P ＜ 0.01 ).In CPP,the CPP value of post-conditioning only in PE group was obviously higher than that of pre-conditioning ( q=31.81,P＜ 0.01 ).The CPP value of postconditioning in PE group was higher than that of CS group,CE group and PS group( q=-38.32,-22.21,-33.38,P＜0.05).There were no significant differences in the number of D1 dopamine receptor-positive cells in the amygdale region among four groups (F =0.07,P ＞0.05 ).ConclusionThe PTSD-like rats are easier to acquire the alcohol CPP,which maybe not relate to the changes of the number of D1 dopamine receptor-positive cells in amygdala.
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Objective To investigate the relationship between cognitive function of first-episode schizophrenic patients and dopamine D1 receptor gene. Methods A total of 112 first-episode schizophrenic patients and 60 healthy controls were evaluated with Wechsler adult intelligence scale ( WAIS-R), Wechsler memory scale (WMS) and Wisconsin card sort test (WCST) ,and genotyped one polymorphism (rs4532) within DRD1 gene using TaqMan SNP genotyping assay. Results There were no significant differences on the frequencies of the genotypes and alleles of rs4532 polymorphism between patients with schizophrenia and normal controls ( x2 =2.90, P=0.35; x2 = 0.01, P= 0. 93 ). There were significant differences in all index of WCST between two groups (P ＜0.01 ). Patients with rs4532G allele had worse WCST performance than those without G allele ((60.9 ± 13.2)%vs (44.9 ±21.3)%, t=4.79, P=0.00002). Conclusion Rs4532 polymorphism of DRD1 gene may be associated with executive function impairment in schizophrenic patients.
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Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5~8 Hz) and alpha (8~13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.
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Animals , Rats , Apomorphine , Benzazepines , Dopamine , Electroencephalography , Haloperidol , Receptors, Dopamine , Receptors, Dopamine D1 , Receptors, Dopamine D2ABSTRACT
OBJECTIVE: Dopamine plays a key role in the proliferation regulation of the smooth muscle cells. The purpose of this study was to observe the degree of expression of dopamine D1 and D2 receptors and dopamine transporter (DAT) and to evaluate the influence of methylation about control of expression of DAT in uterine leiomyoma and normal myometrial tissue. METHODS: In 20 patients who underwent hysterectomy due to uterine leiomyoma, normal myometrial and leiomyoma specimens were obtained. The expression of dopamine D1 and D2 receptors and DAT was demonstrated by using RT-PCR and immunohistochemistry in each normal myometrium and leiomyoma. Analysis of the DNA methylation status of DAT was conducted using HpaII digestion and the methylation-sensitive PCR. RESULTS: The mRNA level of dopamine D1 receptor was relatively higher in normal myometrium than D2 receptor and it was also unchanged in leiomyomas. However, the mRNA levels of dopamine D2 receptor and DAT in leiomyomas were much higher than normal myometrium. Consistent with elevated mRNA levels, high levels of dopamine receptors protein expression were detected by immunohistochemistry in leiomyomas. The degree of methylation at CpG sites of the area intron 1 of DAT (genomic position, +377 - +888) was decreased in leiomyomas. CONCLUSION: These results suggest that overexpressed dopamine D2 receptor and DAT would be associated with proliferation of human uterine leiomyomas and the methylation status of the CpG island of DAT determines its expression.
Subject(s)
Animals , Female , Humans , Mice , CpG Islands , Digestion , DNA Methylation , Dopamine Plasma Membrane Transport Proteins , Dopamine , Hysterectomy , Immunohistochemistry , Introns , Leiomyoma , Methylation , Myocytes, Smooth Muscle , Myometrium , Polymerase Chain Reaction , Receptors, Dopamine D1 , Receptors, Dopamine D2 , Receptors, Dopamine , RNA, MessengerABSTRACT
BACKGROUND: Dopamine receptors have been regarded as a strong candidate involved in etiology of schizophrenia and a target for various antipsychotic drugs. The purpose of our study was to investigate whether dopamine D1 receptor(DRD1) gene polymorphisms would predict the treatment response to antipsychotics in schizophrenia. METHOD: One hundred thirty-four schizophrenic patients, who met DSM-IV criteria for schizophrenia were entered into a 48-week study. The psychopathology of the patients was assessed at baseline, 12th, 24th, 48th weeks of treatment by PANSS. Responders were defined by a 20% of the reduction in total PAnSS score at end point. The genomic DNA fragment corresponding to nucleotides of dopamine D1 receptor gene was amplified by polymerase chain reaction(PCR). RESULT: Neither allelic frequencies nor genotypes for dopamine D1 receptor differed significantly between responders and non-responders. Also, there was no difference of changes of PANSS scores among three genotype groups of the dopamine D1 receptor. CONCLUSION: Allelic variation in the dopamine D1 gene is not associated with individual differences in antipsychotic response.
Subject(s)
Humans , Antipsychotic Agents , Diagnostic and Statistical Manual of Mental Disorders , DNA , Dopamine , Genotype , Individuality , Nucleotides , Psychopathology , Receptors, Dopamine , Receptors, Dopamine D1 , SchizophreniaABSTRACT
Objective To study the effects of chronic ouabain treatment on Na+-K+-ATPase activity and the expression of dopamine D1 receptor in rat kidney cortex. Methods A total of 28 male Sprague-Dawley (SD) rats were randomly divided into ouabain group and control group,which were treated with ouabain or saline for 5 weeks; rat tail systolic blood pressure (SBP) was recorded weekly. Rats were sacrificed after 3 and 5 weeks,respectively. Then Na+-K+-ATPase activity and the expression of dopamine D1 receptor in rat kidney cortex were measured by colorimetric assay and real-time PCR,respectively. Results After 3 weeks of ouabain treatment,the mean SBP did not change significantly,but the Na+-K+-ATPase activity increased (P