Abstract
The effects of sibutramine on central dopaminergic system in rats and mice were examined by neurochemical and behavioral pharmacological methods. Dopamine reuptake inhibition by sibutramine in brain synaptosomes was only 4-5 times stronger than those of amitriptyline and dosulepin, which do not exhibit dopamine uptake inhibition in vivo. Single treatment with sibutramine did not alter the brain content of dopamine and DOPAC. However, similar to methamphetamine and pargyline, sibutramine antagonized methyl-4-pheny-1,2,3,6-tetrahydro-pyridine (MPTP) induced dopamine depletion in mouse brain. In forced swimming tests of reserpinized mice, sibutramine shortened the immobilized time, similar to dopaminergic drugs including nomifensine, bupropion (dopamine-reuptake inhibitor), methamphetamine, SKF 38393 (dopamine D1 agonist), quinpirole (dopamine D2 agonist) and apomorphine (dopamine D1/D2 agonist). In addition, sibutramine caused rotational behavior toward the lesioned side in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine. These results suggest that sibutramine exhibits neurochemical and behavioral dopaminomimetic activity in vivo, which is mediated by dopamine reuptake inhibition by the active metabolites of sibutramine.
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