Investigation of serotonergic regulation of acerylcholine release in the cortex

采用体内微透析法测定自由活动大鼠额叶皮层胞外乙酰胆碱能浓度，研究了5-HT_<1A>和5-HT_3受体在皮层投射胆碱能神经元的5-羟色胺能调控中的作用。[1]系统给予选择性5-HT_<1A>受体激动剂8-OH-DPAT （0.1 mg/kg, s.c）不能影响皮质乙酰胆碱分泌。在中隔背核局部应用选择性5-羟色胺摄取抑制剂氟西汀（1毫微克60分钟）可显著降低基础乙酰胆碱输出。相反，通过反透析在额叶皮层局部应用8-OH-DPAT（分别为100 nM，10 muM, 60 min）不会产生基础乙酰胆碱输出的任何变化。然而，在注射芬氟拉明（10 mg/kg, i.p） 40分钟后，8-OH-DPAT （10 muM, 60 min）应用于额叶皮层，显著增强了芬氟拉明增加皮质乙酰胆碱释放的能力。腹腔注射5-甲氧基- o - dmt （2.5 mg/kg）显著增加皮质乙酰胆碱分泌30分钟。这些结果暗示了两种可能性。首先，中隔背核和皮层中的5-HT_<1A>受体可能分别在额叶皮层中发挥抑制和刺激乙酰胆碱释放的5-羟色胺能调节作用。其次，5-HT_<1A>的功能可能随着5-HT_<2A>活性的增加而增强，从而导致通过5-HT_<1A>受体释放ACh的增加。-2]系统（0.02,0.6 mg/kg, s.c）和局部（0.1,10 muM, 60 min）给予选择性5-HT_3受体拮抗剂ICS-205,930均不影响乙酰胆碱分泌。此外，在额叶皮质局部应用选择性5-HT_3激动剂2-甲基-5- ht （10,000 muM, 60 min）对ACh输出无影响。5-HT_<2A>受体激动剂DOI全身（2.5 mg/kg, i.p）和局部（1100 muM, 60 min）给药均显著提高皮质乙酰胆碱水平。注射DOI (2.5 mg/kg) 60分钟后，局部应用ICS-205,930 （1muM持续60分钟）和2-甲基-5- ht （10 muM持续60分钟）均不影响乙酰氨基酚的输出。此外，在5- ht_ <2A>拮抗剂酮色林（5mg /kg, i.p）后，这些化合物以相同的方式施用，未能影响额叶皮层的乙酰胆碱浓度。这些结果提示，5-HT_3受体可能在脑额叶皮层对乙酰胆碱释放的5-羟色胺能调节中不起重要作用。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