Sibutramine induces potential-dependent exocytotic release but not carrier-mediated release of dopamine and 5-hydroxytryptamine.
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.
Ukai
Kiyoharu
K
Central Research Institute, Kaken Pharmaceutical Co. Ltd., 14 Shinomiya Minamikawara-cho, Yamashinaku, 607 Kyoto, Japan. ukai_kiyoharu@kaken.co.jp
Nakagawa
Terutake
T
Ohyama
Tadashi
T
Nakanishi
Hiroshi
H
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003503:Cyclobutanes / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004308:Dothiepin / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects* / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D017551:Microdialysis / Q000379:methods; D010477:Perfusion; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
D003503:Cyclobutanes; D012701:Serotonin; D013779:Tetrodotoxin; D004298:Dopamine; D004308:Dothiepin; C058254:sibutramine; D011224:Prazosin