A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine.
Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1-3 mg/kg PO) and methamphetamine (0.3-30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED50 values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10-100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [3H]-dopamine from preloaded rat striatal slices was not altered by 10(-7)-10(-5) M concentrations of sibutramine, BTS 54,354, BTS 54,505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10(-8)-10(-4) M) caused a significant concentration-dependent increase in [3H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 30 mg/kg PO) did not alter 3-methoxytyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3-10 mg/kg IP or 0.42-4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10-100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Heal
D J
DJ
Boots Pharmaceuticals Research Department, Nottingham, UK.
Frankland
A T
AT
Gosden
J
J
Hutchins
L J
LJ
Prow
M R
MR
Luscombe
G P
GP
Buckett
W R
WR
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001763:Blepharoptosis / Q000139:chemically induced / Q000517:prevention & control; D001923:Brain Chemistry / Q000187:drug effects; D016642:Bupropion / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology; D003503:Cyclobutanes / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000502:physiology*; D005793:Generalization, Psychological; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051381:Rats; D012110:Reserpine; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000502:physiology
D000928:Antidepressive Agents; D003503:Cyclobutanes; D016642:Bupropion; D008694:Methamphetamine; D012110:Reserpine; C001746:3-methoxytyramine; D004298:Dopamine; C058254:sibutramine