Investigation of serotonergic regulation of acerylcholine release in the cortex

用在体微透析法测定自由活动大鼠额叶皮质细胞外ACh浓度，研究了5-羟色胺受体和5-羟色胺受体在皮质投射胆碱能神经元5-羟色胺能调节中的作用。无法影响皮质ACh输出。在中缝背核局部应用选择性5-羟色胺摄取抑制剂氟西汀(1um/60min)可显著减少基础ACh输出。相反，在额叶皮质局部应用8-OH-DPAT(100 nM，10微米，60min)，对基础ACh的输出没有任何影响。注射芬氟拉明(10 mg/kg，ip)40min后，额叶皮质注射8-OH-DPAT(10um/60min)，可显著增强芬氟拉明增加皮层ACh释放的能力。…大鼠腹腔注射5-甲氧基-O-二甲基甲基四氢叶酸(2.5 mg/kg)大脑皮层ACh输出增加30min。这些结果暗示了两种可能性。首先，中缝背核和大脑皮层的5-羟色胺受体可能分别在5-羟色胺能调节额叶皮质ACh释放中起抑制和刺激作用。第二，5-羟色胺的功能可能随着5-羟色胺的活性增加而增强，从而通过5-羟色胺受体增加ACh的释放。NOR局部注射选择性5-HT3受体拮抗剂ICS-205、930(0.1、10µm/60min)影响ACh的输出。此外，额叶皮质局部应用选择性5-HT3激动剂2-甲基-5-羟色胺(10,000微米，作用60分钟)对ACh的输出没有影响。均为全身性(2.5 mg/kg，ip)局部给予5-羟色胺受体激动剂DOI(1,100微米，60分钟)可显著增加皮层ACh水平。注射DOI(2.5 mg/kg)后60min，局部应用ICS-205,930(1uM，60min)或2-甲基-5-羟色胺(10um，60min)均不影响ACh产量。此外，在5-羟色胺拮抗剂酮色林(5 mg/kg，ip)后，这些化合物以同样的方式应用于额叶皮质，但未能影响额叶皮质的ACh浓度。这些结果提示，5-HT3受体在5-羟色胺能调节额叶皮质ACh释放中可能不起重要作用。较少

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