In order to clarify the mechanism underlying the anti-obesity effects of sibutramine, we examined the effects of sibutramine on extracellular levels of dopamine and 5-hydroxytryptamine (5-HT) through microdialysis in the striatum in unanesthetized and freely moving rats. Sibutramine (5 mg/kg, oral administration (p.o.)) increased extracellular dopamine and 5-HT levels in rat striatum. The tricyclic antidepressant dosulepin (80 mg/kg, p.o. or 1 microM perfusion through the striatal probe) increased 5-HT levels only. Sibutramine-induced dopamine release was antagonized by perfusion of tetrodotoxin (1 microM) through the microdialysis probe in the striatum. However, sibutramine-induced dopamine release was not inhibited by prazosin (1 mg/kg, intraperitoneal injection (i.p.)), a suppressor of serotonergic activity in the striatum via blockade of alpha(1)-adrenoceptors, or perfusion with nomifensine (1 microM), an inhibitor of dopamine re-uptake. These results suggest that sibutramine increases dopamine levels in the striatum by exocytotic release and not by a carrier-mediated mechanism.
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