Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats

Rowley, Helen L.; Butler, Sarah A.; Prow, M. R.; Dykes, Steve; Aspley, Susan; Kilpatrick, I.C.; Heal, David J.

doi:10.1002/1098-2396(200011)38:2<167::aid-syn8>3.0.co;2-w

Cited by 38 publications

(26 citation statements)

References 30 publications

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“…This effect was seen at dose of 5 and 1 Omglkg but not at 2.0mglkg. Another similar study conducted by Rowley et al (2000) found that sibutramine, at a dose of 6.0mglkg, injected into the nucleus accumbens resulted in a mode st and prolonged increase in extraneuronal DA. This effect, however, was not equivalent to the greater effects caused by d-amphetamine and phentermine, both indirect NA and DA agonists at lower doses (0.5 and 1.3mglkg, respectively).…”

Section: 123-dopamine Food Intake and Macronutrient Selectionmentioning

confidence: 99%

“…Sibutramine has aiso been shown to block the re-uptake of dopamine (DA) but at about a 3-fold lower potency when compared to 5-HT and NA (Luseombe et al, 1989). More reeent studies suggest that sibutramine increases extracellular DA concentrations at similar levels to 5-HT in an animal model (Balcioglu & Wurtman, 2000;Rowley et al, 2000). Serotonin, an indole amine and neurotransmitter, is recognised to have an influence on food intake and macronutrient selection (reviewed by Alexander, 1998 andBooth, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Effect of sibutramine on macronutrient selection in male and female rats

Leblanc

Thibault

2003

Physiology & Behavior

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Section: 123-dopamine Food Intake and Macronutrient Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of sibutramine on macronutrient selection in male and female rats

Leblanc

Thibault

2003

Physiology & Behavior

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“…Whilst the pathobiology of both events remains uncertain, a link with elevated plasma serotonin (5HT) has been proposed on more than one occasion 3 -6 and for valvulopathy, 5HT receptor mechanisms on valve tissue are also postulated to be relevant. 7 Aside from the known ability of phentermine to promote dopamine release in the brain, 8,9 recent discussion on its mode of action has centred on a proposal that phentermine may inhibit monoamine oxidase (MAO). 10 Within this proposal, the authors not only inferred that such an action could boost free 5HT concentrations in plasma beyond those evoked by 5HT-releasing agents such as fenfluramine and S( þ )-fenfluramine, but for the same reason they also warned against the possible combined use of phentermine with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine.…”

Section: Introductionmentioning

confidence: 99%

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

Kilpatrick

Traut²,

Heal

2001

Int J Obes

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OBJECTIVE AND DESIGN:It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO A and MAO B in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO A and MAO B , their respective target enzymes, with IC 50 values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO A and MAO B with IC 50 values for each enzyme in the moderate to high micromolar range. For MAO A , the IC 50 for phentermine was estimated to be 143 mM, that for S( þ )-fenfluramine, 265 mM and that for sertraline, 31 mM. For MAO B , example IC 50 s were as follows: phentermine (285 mM), S( þ )-fenfluramine (800 mM) and paroxetine (16 mM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S( þ )-fenfluramine, S( þ )-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.

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“…As an example, sibutramine reduces food intake through NE and 5-HT reuptake inhibition, and the ED 50 values obtained at 2 h are identical when this drug is given orally [ED 50 ϭ 2.8 mg/kg (95% confidence interval, 1.6 -5.0); Jackson et al, 1997] or i.p. [ED 50 ϭ 2.0 mg/kg (95% confidence interval, 1.0 -4.1); Rowley et al, 2000]. Thus, to avoid handling the animals during drug administration, sibutramine was given via chronically implanted i.p.…”

mentioning

confidence: 99%

Acute Cardiovascular Effects of Sibutramine in Conscious Rats

Woolard

Bennett²,

Dunn³

et al. 2003

J Pharmacol Exp Ther

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Sibutramine is a serotonin and norepinephrine reuptake inhibitor, used in the treatment of obesity. In this study, cardiovascular effects of sibutramine (0.9, 3, or 9 mg kg Ϫ1 i.p.) were measured in conscious Sprague-Dawley rats, in the absence and presence of ␤-and/or ␣-adrenoceptor antagonism (with propranolol and/or phentolamine, respectively). Sibutramine caused pressor and tachycardic effects, with celiac and mesenteric vasoconstrictions, and hyperemic hindquarters vasodilatation. Pretreatment with propranolol inhibited the tachycardic and hindquarters vasodilator effect of sibutramine, whereas phentolamine inhibited the pressor and vasoconstrictor effects of sibutramine. In the presence of phentolamine, sibutramine caused hyperemic mese nteric vasodilatation. In preconstricted, isolated, mesenteric vessels, sibutramine and its metabolites BTS 54 505 (N-desmethylsibutramine) and BTS 54 354 (N-didesmethylsibutramine) (10 M) produced significant vasodilatations. Neither sibutramine nor BTS 54 505 enhanced vessel sensitivity to norepinephrine, whereas BTS 54 354 produced a significant leftward shift in the concentration-response curve to norepinephrine. Collectively, the results indicate that the overt cardiovascular effects of sibutramine involve ␣-adrenoceptor-mediated celiac and mesenteric vasoconstrictions, and ␤-adrenoceptor-mediated hindquarters vasodilatation and tachycardia. The mesenteric vasodilator response to sibutramine, seen in the presence of phentolamine, may be a direct effect of the drug and/or its metabolites, on vessel tone. The cardiovascular effects of sibutramine in vivo may be secondary to inhibition of peripheral and/or central reuptake of monoamines by the metabolites BTS 54 354 and/or BTS 54 505. It remains to explain why BTS 54 354, but not BTS 54 505, enhanced norepinephrine sensitivity in vitro, because both metabolites are potent inhibitors of the norepinephrine transporter.

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Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats

Cited by 38 publications

References 30 publications

Effect of sibutramine on macronutrient selection in male and female rats

Effect of sibutramine on macronutrient selection in male and female rats

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

Acute Cardiovascular Effects of Sibutramine in Conscious Rats

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