Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d-amphetamine: modulation by alpha2-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 alpha2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha2-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 alpha2-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 alpha2-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.
Wortley
K E
KE
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT.
Hughes
Z A
ZA
Heal
D J
DJ
Stanford
S C
SC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003503:Cyclobutanes / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D001067:Appetite Depressants; D003503:Cyclobutanes; D018341:Receptors, Adrenergic, alpha-2; C058525:2-methoxyidazoxan; D003913:Dextroamphetamine; C058254:sibutramine; D009638:Norepinephrine; D019329:Idazoxan