A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine

Abstract

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)

Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study

“…In both animals and humans, it potently inhibits the reuptake of serotonin (5-HT) and noradrenaline, 6,7 but not dopamine. 7,8 Sibutramine represents a new class of agent for the treatment of obesity that differs from drugs such as fen¯uramine and d-fen¯uramine, which exclusively activate 5-HT systems, and from drugs such as d-amphetamine, mazindol and the b 3 -adrenoreceptor agonists, which exclusively activate catecholamine systems. 9±12 In healthy volunteers, sibutramine appears to be free from anticholinergic effects.…”

“…9±12 In healthy volunteers, sibutramine appears to be free from anticholinergic effects. 13 It has no amphetamine-like abuse potential in either animals 8 or recreational drug users. 14 In rats, sibutramine causes a dose-dependent decrease in food intake and bodyweight.…”

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by β-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial

“…8,14 Additionally, sibutramine has been shown to increase energy utilisation. 19,20 The increased energy utilisation activity of sibutramine may be indirectly generated by central stimulation of efferent sympathetic output to the ␤ 3 -adrenoceptors in brown adipose tissue.…”

“…12,13 Both preclinical and clinical studies strongly suggest that dopamine is not a target for sibutramine at pharmacologically relevant concentrations. 8,10,11,14 Consistent with its enhancement of noradrenergic activity relative to placebo, normotensive obese patients on sibutramine treatment have experienced small mean increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Increases of 1 to 3 mm Hg and increases in pulse rate (PR) of 4 to 5 beats per minute (bpm) at doses up to 20 mg have been reported.…”

Effects of Chronic Administration of Sibutramine on Body Weight, Food Intake and Motor Activity in Neonatally Monosodium Glutamate-Treated Obese Female Rats: Relationship of Antiobesity Effect with Monoamines

“…In this regard, we have reported that sibutramine increased rat motor activity due to activation of the dopaminergic system in the nigro-striatum [28]. Otherwise, there is also a report that sibutramine does not have dopaminergic effects [18]. It is still unclear whether continued administration of sibutramine maintains the increase in spontaneous motor activity, as observed after acute administration, which contributes to the anti-obesity effect of sibutramine by energy expenditure.…”