Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d-amphetamine:: modulation by α2-adrenoceptors

被引:24
作者
Wortley, KE
Hughes, ZA
Heal, DJ
Stanford, SC
机构
[1] UCL, Dept Pharmacol, London WC1E 6BT, England
[2] Knoll Pharmaceut Res & Dev, Nottingham NG1 1GF, England
关键词
sibutramine; noradrenaline; d-amphetamine; alpha(2)-adrenoceptors; frontal cortex; in vivo microdialysis;
D O I
10.1038/sj.bjp.0702720
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The effects of sibutramine (0.25-10 mg kg(-1), i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1-3 mg kg(-1) i.p.) using in vivo microdialysis. The role of presynaptic alpha(2)-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha(2)-adrenoceptor antagonist, RX821002. 2 Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg(-1). In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose. 3 Pretreatment with the alpha(2)-adrenoceptor antagonist, RX821002 (dose 3 mg kg(-1), i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg(-1)) and reduced the latency of sibutramine to reach its maximum effect from 144-56 min. 4 RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg(-1)) and had no effect on the latency to reach maximum. 5 These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic alpha(2)-adrenoceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca(2+)-independent release of noradrenaline.
引用
收藏
页码:1860 / 1866
页数:7
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