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Investigation of serotonergic regulation of acerylcholine release in the cortex

皮质中乙酰胆碱释放的血清素调节研究

基本信息

批准号：
08671090
负责人：
HIRANO Hitoshi
金额：
$ 1.47万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

The role of 5-HT_<1A> and 5-HT_3 receptors in the serotonergic regulation of cortically projecting cholinergic neurons was studied using in vivo microdialysis to measure extracellular ACh concentrations in the frontal cortex of freely moving rats.[Exp.-1] Systemically administered selective 5-HT_<1A> receptor agonist 8-OH-DPAT (0.1 mg/kg, s.c.) failed to affect cortical ACh output. Local application of the selective 5-HT uptake inhibitor fluoxetine (1 muM for 60 min) in the dorsal raphe nucleus significantly decreased basal ACh output. In contrast, locally applied 8-OH-DPAT (100 nM,10 muM for 60 min, respectively) in the frontal cortex via reverse dialysis did not produce any change in basal ACh output. 8-OH-DPAT (10 muM for 60 min) applied in the frontal cortex 40 min after the injection of fenfluramine (10 mg/kg, i.p.), however, significantly potentiated fen fluramine's ability to increase cortical ACh release. Intraperitoneal injection of 5-Methoxy-O-DMT (2.5 mg/kg) significantly in … More creased cortical ACh output for 30 min. These results suggest two possibilities. First, the 5-HT_<1A> receptors in the dorsal raphe nucleus and in the cortex may plan an inhibitory and stimulatory role, respectively, in the serotonergic regultion of ACh release in the frontal cortex. Second, the function of 5-HT_<1A> may increase with increasing activity of 5-HT_<2A>, resulting in the increase in ACh release via 5-HT_<1A> receptors.[Exp.-2] Neither systemically (0.02,0.6 mg/kg, s.c.) nor locally (0.1,10 muM for 60 min) administered selective 5-HT_3 receptor antagonist ICS-205,930 influenced the ACh output. In addition, local application of the selective 5-HT_3 agonist 2-Methyl-5-HT (10,000 muM for 60 min) in the frontal cortex had no effect on the ACh output. Both systemic (2.5 mg/kg, i.p.) and local (1,100 muM for 60 min) administration of the 5-HT_<2A> receptor agonist DOI significantly increased corti cal ACh levels. Neither locally applied ICS-205,930 (1muM for 60 min) nor 2-Methyl-5-HT (10 muM for 60 min) 60 min after injection of DOI (2.5 mg/kg) affected the ACh output. Furthermore, these compounds applied in the same manner after ketanserin (5 mg/kg, i.p.), a 5-HT_<2A> antagonist, failed to impact the ACh concentrations in the frontal cortex. These results suggest that the 5-HT_3 receptors may not play an important role in the serotonergic regulation of ACh release in the frontal cortex. Less

用<1A>在体微透析法测定自由活动大鼠额叶皮层细胞外ACh浓度，研究了5-HT_3和5-HT_3受体在皮质投射胆碱能神经元ACh能调节中的作用。[实验：1]全身施用选择性5-HT_<1A>受体激动剂8-OH-DPAT（0. lmg/kg，s.c.）未能影响皮质ACh输出。选择性5-HT摄取抑制剂氟西汀（1 μ M，60分钟）在中缝背核的局部应用显着降低基础ACh输出。相反，局部应用8-OH-DPAT（100 nM，10 μ M，60分钟，分别）在额叶皮层通过反向透析没有产生任何变化，基础ACh输出。在注射芬氟拉明（10 mg/kg，i. p.）后40分钟，在额叶皮层中应用8-OH-DPAT（10 μ M，60分钟），然而，显着增强芬氟拉明增加皮质ACh释放能力。腹腔注射5-甲氧基-O-DMT（2.5 mg/kg）， ...更多信息增加皮质ACh输出30分钟。这些结果表明两种可能性。第一，中缝背核和皮层5-HT_2<1A>受体可能分别对额叶皮层ACh释放的胆碱能调节起抑制和兴奋作用。第二，随着5-HT_2<1A>活性的增强，5-HT_2的功能增强，从而<2A>导致通过5-HT_2受体释放ACh的增加<1A>。[实验：2]全身（0.02、0.6 mg/kg，s.c.）局部应用选择性5-HT_3受体拮抗剂ICS-205，930（0.1，10 μ M，60 min）也不影响ACh的分泌。此外，在额叶皮层局部应用选择性5-HT_3激动剂2-Methyl-5-HT（10，000 μ M，60分钟）对ACh输出没有影响。全身（2.5 mg/kg，i. p.）局部（1,100 μ M，60分钟）给予5-HT_<2A>2受体激动剂DOI可显著增加皮质ACh水平。注射DOI（2.5mg/kg）后60 min局部应用ICS-205，930（1 μ M，60 min）和2-甲基-5-HT（10 μ M，60 min）均不影响ACh的分泌。此外，这些化合物在酮色林（5 mg/kg，i. p.）之后以相同的方式施用，5-HT_2<2A>拮抗剂对额叶皮质ACh浓度无明显影响。结果提示，5-HT_3受体在额叶皮质ACh释放的多巴胺能调节中可能不起重要作用。少