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

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.