Influence of 5-HT1A receptors on central noradrenergic activity:: microdialysis studies using (+/-)-MDL 73005EF and its enantiomers

被引:41
作者
Hajós-Korcsok, É [1 ]
McQuade, R [1 ]
Sharp, T [1 ]
机构
[1] Univ Oxford, Radcliffe Infirm, Dept Clin Pharmacol, Oxford OX2 6HE, England
基金
英国医学研究理事会;
关键词
5-hydroxytryptamine; serotonin; 5-HT1A receptors; MDL; 73005EF; noradrenaline; microdialysis;
D O I
10.1016/S0028-3908(98)00175-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Recent studies indicate that 5-HT1A receptor agonists stimulate noradrenaline release in the brain. Here we investigate the mechanism underlying the increase in extracellular noradrenaline induced by (+/-)-MDL 73005EF, a weak 5-HT1A receptor agonist. Extracellular noradrenaline was measured in the hippocampus of the awake rat using microdialysis. (+/-)-MDL 73005EF (0.1, 1 and 5 mg/kg s.c.) caused a dose-related increase in noradrenaline. The active S(-)- enantiomer of MDL 73005EF (1 mg/kg s.c.) also increased noradrenaline whereas the inactive R(+)- enantiomer (1 mg/kg s.c.) did not. Measurements of extracellular 5-HT in hippocampus of anaesthetised rats confirmed that the 5-HT1A receptor agonist action of (+)-MDL 73005EF resides in the S(-)- enantiomer. Thus, S(-)-MDL 73005EF (0.3 and 1 mg/kg s.c.) markedly decreased 5-HT, whereas R(+)-MDL 73005EF (1 mg/kg s.c.) did not. The noradrenaline response to (+/-)-MDL 73005EF (1 mg/kg s.c.) was significantly blocked by the selective 5-HT1A receptor antagonist, WAY 100635 (1 but not 0.3 mg/kg s.c). The noradrenaline response to (+/-)-MDL 73005EF (1 mg/kg s.c.) was not modified by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine. Intra-hippocampal application of(+/-)-MDL 73005EF (10 mu M in perfusion medium) did not increase noradrenaline. Although (+/-)-MDL 73005EF has moderate affinity for dopamine D-2 binding sites, the dopamine D-2 receptor antagonist, remoxipride (1 mg/kg s.c.) did not increase noradrenaline. In conclusion, our data suggest that (+/-)-MDL 73005EF increases noradrenaline release in rat hippocampus through activation of 5HT(1A) receptors that appear to be located postsynaptically. These data are discussed in relation to the antidepressant/anxiolytic effects of 5-HT1A agonists. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:299 / 306
页数:8
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