Investigation of serotonergic regulation of acerylcholine release in the cortex

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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