The 5-HT_(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin(8-OH-DPAT) promotes ejaculation of male rats, whereas dapoxetine delays this process. However, the gene expression profile of the brain at ejacula...The 5-HT_(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin(8-OH-DPAT) promotes ejaculation of male rats, whereas dapoxetine delays this process. However, the gene expression profile of the brain at ejaculation following administrationof these two compounds has not been fully elucidated. In the present study, a transcriptomic Body Map was generated by conducting mRNA-Seq on brain samples of male Sprague–Dawley rats. The study included four groups: pre-copulatory control(CK) group,ejaculation(EJ) group, 0.5 mg/kg 8-OH-DPAT-ejaculation group(DPAT), and 60 mg/kg dapoxetineejaculation(DAP) group. The resulting analysis generated an average of approximately 47 million sequence reads. Significant differences in the gene expression profiles of the aforementioned groups were observed in the EJ(257 genes), DPAT(349 genes) and the DAP(207 genes) compared with the control rats. The results indicate that the expression of Drd1 and Slc6a3 was significantly different after treatment with 8-OH-DPAT, whereas the expression of Drd4 was significantly different after treatment with dapoxetine. Other genes, such as Wnt9b, Cdkn1 a and Fosb, exhibited significant differences in expression after the two treatments and are related to bladder cancer, renal cell carcinoma and sexual addiction. The present study reveals the basic pattern of gene expression that was activated at ejaculation in the presence of 8-OH-DPAT or dapoxetine, providing preliminary gene expression information during rat ejaculation.展开更多
This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential h...This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to the anticholinesterase, diisopropylfluorophosphate (DFP). FSL rats are more sensitive to the hypothermic effects of cholinergic, serotonergic, and dopaminergic agonists but less sensitive to the locomotor or stereotypic effects of dopamine agonists. FSL rats exhibit greater immobility in the forced swim test and reduced social interaction compared with FRL rats, but do not differ in saccharin intake, behavior in the elevated plus maze, or responses for rewarding brain self-stimulation. The exaggerated immobility and reduced social interaction are counteracted by chronic treatment with antidepressants. Because FSL rats were more sensitive to 5-HT1A receptor agonists, high (HDS) and low (LDS) 8-OH-DPATsensitive lines were selectively bred for differential hypothermic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). HDS rats were also more sensitive to the hypothermic effects of oxotremorine, a cholinergic agonist, but selection for this response did not diverge with later selection. HDS rats exhibited greater immobility in the forced swim test than LDS rats and this correlated response could be seen early in selection (generation 3). HDS rats also showed reduced social interaction compared to LDS rats, but did not differ in behavior in the elevated plus maze. These findings confirm that selection for hypothermic responses to pharmacological agents do have behavioral consequences, notably the production of depressive-like phenotypes, which can be counteracted by chronic antidepressant treatment. Because increased 5-HT1A receptor sensitivity was common to both selected lines (FSL and HDS), neurobiological processes dependent on this receptor could contribute to the abnormal behaviors that manifest in these rat lines and thus suggesting a mechanism underlying depressive behaviors in humans. However, available human data are inconsistent with this hypothesis and suggest that other mechanisms underlie these behavioral abnormalities in HDS and FSL rats. These mechanisms as well as additional behavioral testing in these rat lines will be discussed.展开更多
目的本研究欲探讨阻断淀粉样前体蛋白-C端片段(Amyloid Precursor Protein C Terminal Fragments,APP-CTFs)毒性通路对Cofilin磷酸化的影响方法大鼠胚鼠大脑皮层神经元细胞培养,采取3种方法阻断APPCTFs毒性通路。1APP-695转染后γ-内切...目的本研究欲探讨阻断淀粉样前体蛋白-C端片段(Amyloid Precursor Protein C Terminal Fragments,APP-CTFs)毒性通路对Cofilin磷酸化的影响方法大鼠胚鼠大脑皮层神经元细胞培养,采取3种方法阻断APPCTFs毒性通路。1APP-695转染后γ-内切酶抑制剂DAPT处理2利用YENPTY段删除的pEGFP-APP C99,C57转染至大鼠神经元细胞3GSK-3β抑制剂LiCl处理,3种方法阻断后,均采用蛋白印迹方法检测Ph-cofilin蛋白水平。结果 DAPT处理组与未处理组比较Ph-cofilin蛋白表达水平降低(P<0.05)。转染YENPTY段删除的pEGFPAPP CTFs组未能明显增强磷酸化Cofilin的蛋白表达水平(P>0.05),虽然转染APP-CT99,57-pEGFP组与空载体对照组相比较,Ph-Cofilin蛋白表达水平明显增加(P<0.05)。LiCl处理组与非处理组相比,Ph-Cofilin蛋白表达无明显改变(P>0.05)。结论提示APP-CTFs诱导的Cofilin磷酸化过程与APP-CTFs核转移毒性通路有关,但与其诱导的GSK-3β-Tau毒性通路无关。展开更多
The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation...The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation of presynaptic 5-HT1A receptors with a low dose of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) or the blockade of postsynaptic 5-HT1A receptors with the antagonist WAY-100635 (1.0 mg/kg) did not affect the numbers of IgM-antibody forming cells (IgM-AFC) in the spleen of highly aggressive rats, which were characterized by higher immune responsiveness compared to nonaggressive line. On the other hand, the same doses of 8-OH-DPAT and WAY-100635, as well as a higher dose of 8-OH-DPAT (1.0 mg/kg), which is known to activate postsynaptic 5-HT1A receptors, produce immunostimulation in nonaggressive rats. However, only the highest dose of 8-OH-DPAT (5.0 mg/kg) was able to cause immunosuppression in nonaggressive rats that was mainly dependent on stimulation of postsynaptic 5-HT1A receptors. In contrast to nonaggressive rats, the dose of 1.0 mg/kg 8-OH-DPAT was sufficient to produce a decrease in the numbers of IgM-AFC in highly aggressive rats. Thus, pharmacological activation of pre- and postsynaptic 5-HT1A receptors, as well as the blockade of postsynaptic 5-HT1A receptors, produced different effects on the immune response in two lines of rats selected for high level of aggression or its absence. These data may have implications for more efficient treatments of a number of mental disorders associated with abnormal aggression.展开更多
Status epilepticus （SE） is a life-threatening neurological emergency associated with a high mortality rate. The serotonin 1A （5-HTIA） receptor is a possible target for the treatment of SE, but its role in animal m...Status epilepticus （SE） is a life-threatening neurological emergency associated with a high mortality rate. The serotonin 1A （5-HTIA） receptor is a possible target for the treatment of SE, but its role in animal models and the precise area of brain involved remain controversial. The hippocampus is a candidate site due to its key role in the development of SE and the existence of a high density of 5-HT1A receptors. Therefore, we investigated the effects of subcutaneous and intrahippocampal activation of 5-HT1A receptors in lithium-pilocarpine-induced SE, and tested whether the hippocampus is a true effector site. We developed SE in male Sprague-Dawley rats by giving lithium chloride （LiCI; 3 meq/kg, i.p.） 22-24 h prior to pilocarpine （25 mg/kg, i.p.）, and found that 8-OH-DPAT, a 5-HT1A receptor agonist administered subcutaneously （s.c.） at 0.5 or 1.0 mg/kg 1 h before pilocarpine injection increased the latency to the first epileptiform spikes, the electrographic SE, and the behavioral generalized seizures （GS）, while reducing the total EEG seizure time （P 〈0.01）. The duration of GS was shortened only by 1.0 mg/kg 8-OH-DPAT s.c. （P 〈0.05）. All these effects were inhibited by combined administration of WAY-100635 （1.0 mg/kg, s.c.） （P 〈0.05）, an antagonist of the 5-HT1A receptor, but WAY-100635 alone and low doses of 8-OH- DPAT （0.01 and 0.1 mg/kg） did not alter seizure activity. Furthermore, intrahippocampal 8-OH-DPAT only shortened the GS duration （P 〈0.05）. These findings imply that the 5-HT1A receptor is a promising therapeutic target against the generation and propagation of SE, and hippocampal receptors are involved in reducing the seizure severity.展开更多
文摘The 5-HT_(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin(8-OH-DPAT) promotes ejaculation of male rats, whereas dapoxetine delays this process. However, the gene expression profile of the brain at ejaculation following administrationof these two compounds has not been fully elucidated. In the present study, a transcriptomic Body Map was generated by conducting mRNA-Seq on brain samples of male Sprague–Dawley rats. The study included four groups: pre-copulatory control(CK) group,ejaculation(EJ) group, 0.5 mg/kg 8-OH-DPAT-ejaculation group(DPAT), and 60 mg/kg dapoxetineejaculation(DAP) group. The resulting analysis generated an average of approximately 47 million sequence reads. Significant differences in the gene expression profiles of the aforementioned groups were observed in the EJ(257 genes), DPAT(349 genes) and the DAP(207 genes) compared with the control rats. The results indicate that the expression of Drd1 and Slc6a3 was significantly different after treatment with 8-OH-DPAT, whereas the expression of Drd4 was significantly different after treatment with dapoxetine. Other genes, such as Wnt9b, Cdkn1 a and Fosb, exhibited significant differences in expression after the two treatments and are related to bladder cancer, renal cell carcinoma and sexual addiction. The present study reveals the basic pattern of gene expression that was activated at ejaculation in the presence of 8-OH-DPAT or dapoxetine, providing preliminary gene expression information during rat ejaculation.
文摘This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to the anticholinesterase, diisopropylfluorophosphate (DFP). FSL rats are more sensitive to the hypothermic effects of cholinergic, serotonergic, and dopaminergic agonists but less sensitive to the locomotor or stereotypic effects of dopamine agonists. FSL rats exhibit greater immobility in the forced swim test and reduced social interaction compared with FRL rats, but do not differ in saccharin intake, behavior in the elevated plus maze, or responses for rewarding brain self-stimulation. The exaggerated immobility and reduced social interaction are counteracted by chronic treatment with antidepressants. Because FSL rats were more sensitive to 5-HT1A receptor agonists, high (HDS) and low (LDS) 8-OH-DPATsensitive lines were selectively bred for differential hypothermic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). HDS rats were also more sensitive to the hypothermic effects of oxotremorine, a cholinergic agonist, but selection for this response did not diverge with later selection. HDS rats exhibited greater immobility in the forced swim test than LDS rats and this correlated response could be seen early in selection (generation 3). HDS rats also showed reduced social interaction compared to LDS rats, but did not differ in behavior in the elevated plus maze. These findings confirm that selection for hypothermic responses to pharmacological agents do have behavioral consequences, notably the production of depressive-like phenotypes, which can be counteracted by chronic antidepressant treatment. Because increased 5-HT1A receptor sensitivity was common to both selected lines (FSL and HDS), neurobiological processes dependent on this receptor could contribute to the abnormal behaviors that manifest in these rat lines and thus suggesting a mechanism underlying depressive behaviors in humans. However, available human data are inconsistent with this hypothesis and suggest that other mechanisms underlie these behavioral abnormalities in HDS and FSL rats. These mechanisms as well as additional behavioral testing in these rat lines will be discussed.
文摘目的本研究欲探讨阻断淀粉样前体蛋白-C端片段(Amyloid Precursor Protein C Terminal Fragments,APP-CTFs)毒性通路对Cofilin磷酸化的影响方法大鼠胚鼠大脑皮层神经元细胞培养,采取3种方法阻断APPCTFs毒性通路。1APP-695转染后γ-内切酶抑制剂DAPT处理2利用YENPTY段删除的pEGFP-APP C99,C57转染至大鼠神经元细胞3GSK-3β抑制剂LiCl处理,3种方法阻断后,均采用蛋白印迹方法检测Ph-cofilin蛋白水平。结果 DAPT处理组与未处理组比较Ph-cofilin蛋白表达水平降低(P<0.05)。转染YENPTY段删除的pEGFPAPP CTFs组未能明显增强磷酸化Cofilin的蛋白表达水平(P>0.05),虽然转染APP-CT99,57-pEGFP组与空载体对照组相比较,Ph-Cofilin蛋白表达水平明显增加(P<0.05)。LiCl处理组与非处理组相比,Ph-Cofilin蛋白表达无明显改变(P>0.05)。结论提示APP-CTFs诱导的Cofilin磷酸化过程与APP-CTFs核转移毒性通路有关,但与其诱导的GSK-3β-Tau毒性通路无关。
文摘The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation of presynaptic 5-HT1A receptors with a low dose of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) or the blockade of postsynaptic 5-HT1A receptors with the antagonist WAY-100635 (1.0 mg/kg) did not affect the numbers of IgM-antibody forming cells (IgM-AFC) in the spleen of highly aggressive rats, which were characterized by higher immune responsiveness compared to nonaggressive line. On the other hand, the same doses of 8-OH-DPAT and WAY-100635, as well as a higher dose of 8-OH-DPAT (1.0 mg/kg), which is known to activate postsynaptic 5-HT1A receptors, produce immunostimulation in nonaggressive rats. However, only the highest dose of 8-OH-DPAT (5.0 mg/kg) was able to cause immunosuppression in nonaggressive rats that was mainly dependent on stimulation of postsynaptic 5-HT1A receptors. In contrast to nonaggressive rats, the dose of 1.0 mg/kg 8-OH-DPAT was sufficient to produce a decrease in the numbers of IgM-AFC in highly aggressive rats. Thus, pharmacological activation of pre- and postsynaptic 5-HT1A receptors, as well as the blockade of postsynaptic 5-HT1A receptors, produced different effects on the immune response in two lines of rats selected for high level of aggression or its absence. These data may have implications for more efficient treatments of a number of mental disorders associated with abnormal aggression.
基金supported by grants from the National Natural Science Foundation of China (81000556, 81100968, 81171227)the Traditional Chinese Medicine Scientific Research Fund of Zhejiang Province, China (2010ZA069)
文摘Status epilepticus （SE） is a life-threatening neurological emergency associated with a high mortality rate. The serotonin 1A （5-HTIA） receptor is a possible target for the treatment of SE, but its role in animal models and the precise area of brain involved remain controversial. The hippocampus is a candidate site due to its key role in the development of SE and the existence of a high density of 5-HT1A receptors. Therefore, we investigated the effects of subcutaneous and intrahippocampal activation of 5-HT1A receptors in lithium-pilocarpine-induced SE, and tested whether the hippocampus is a true effector site. We developed SE in male Sprague-Dawley rats by giving lithium chloride （LiCI; 3 meq/kg, i.p.） 22-24 h prior to pilocarpine （25 mg/kg, i.p.）, and found that 8-OH-DPAT, a 5-HT1A receptor agonist administered subcutaneously （s.c.） at 0.5 or 1.0 mg/kg 1 h before pilocarpine injection increased the latency to the first epileptiform spikes, the electrographic SE, and the behavioral generalized seizures （GS）, while reducing the total EEG seizure time （P 〈0.01）. The duration of GS was shortened only by 1.0 mg/kg 8-OH-DPAT s.c. （P 〈0.05）. All these effects were inhibited by combined administration of WAY-100635 （1.0 mg/kg, s.c.） （P 〈0.05）, an antagonist of the 5-HT1A receptor, but WAY-100635 alone and low doses of 8-OH- DPAT （0.01 and 0.1 mg/kg） did not alter seizure activity. Furthermore, intrahippocampal 8-OH-DPAT only shortened the GS duration （P 〈0.05）. These findings imply that the 5-HT1A receptor is a promising therapeutic target against the generation and propagation of SE, and hippocampal receptors are involved in reducing the seizure severity.
