Article date: August 1999
By: K E Wortley, Z A Hughes, D J Heal, S C Stanford, in Volume 127, Issue 8, pages 1860-1866
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 α2‐adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective α2‐adrenoceptor antagonist, RX821002.
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.
Pretreatment with the α2‐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.
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.
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 α2‐adreno‐ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d‐amphetamine is consistent with this being mainly due to an increase in Ca2+‐independent release of noradrenaline.
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 α2‐adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective α2‐adrenoceptor antagonist, RX821002.
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.
Pretreatment with the α2‐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.
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.
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 α2‐adreno‐ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d‐amphetamine is consistent with this being mainly due to an increase in Ca2+‐independent release of noradrenaline.
British Journal of Pharmacology (1999) 127, 1860–1866; doi:10.1038/sj.bjp.0702720
DOI: 10.1038/sj.bjp.0702720
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