Investigation of the mechanisms underlying the hypophagic effects of the 5‐HT and noradrenaline reuptake inhibitor, sibutramine, in the rat

Abstract

1 Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotoninnoradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramineinduced hypophagia. 2 Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3 Sibutramine (10 mg kg 71 , p.o.) produced a signi®cant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the a 1 -adrenoceptor antagonist, prazosin (0.3 and 1 mg kg 71 , i.p.), and partially antagonized by the b 1 -adrenoceptor antagonist, metoprolol (3 and 10 mg kg 71 , i.p.) and the 5-HT receptor antagonists, metergoline (nonselective; 0.3 mg kg 71 , i.p.); ritanserin (5-HT 2A/2C ; 0.1 and 0.5 mg kg 71 , i.p.) and SB200646 (5-HT 2B/2C ; 20 and 40 mg kg 71 , p.o.). 4 By contrast, the a 2 -adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg 71 , i.p.) and the b 2 -adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg 71 , i.p.) did not reduce the decrease in food intake induced by sibutramine. 5 These results demonstrate that b 1 -adrenoceptors, 5-HT 2A/2C -receptors and particularly a 1 -adrenoceptors, are involved in the e ects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…Notably, the PVN is among the brain regions expressing the highest NE transporter (NET) binding level (Kung et al, 2004), which argues for tesofensine produced a blockade of NET function within the PVN, resulting in efficient accummulation of PVN synaptic NE favoring anorexic a 1 adrenoceptorinduced signaling. Specificity for a 1 adrenoceptor effects in the PVN after NET inhibition is further supported by the finding that sibutramine elevates synaptic NE levels in the PVN of lean rats, which is thought to be linked to its a 1 adrenoceptor antagonist-sensitive hypophagic effect (Jackson et al, 1997;Wortley et al, 1999).…”

“…For sibutramine, suppression of food intake could be partially reversed by simultaneous ritanserin or SB206553 administration, thus implicating 5-HT 2A/C or 5-HT 2B/C receptor activation (Jackson et al, 1997;Grignaschi et al, 1999;Balcioglu and Wurtman, 2000). It is suggested that the serotonergic effects of sibutramine on feeding and body weight may likely be ascribed to its primary and secondary amine metabolites, which are triple MRIs, rather than sibutramine per se (Heal et al, 1998;Glick et al, 2000;Nelson and Gehlert, 2006).…”

“…Correspondingly, prazosin also prevented the acute hypophagic effect of sibutramine (Jackson et al, 1997). In addition, selective NE reuptake inhibitors, such as nisoxetine, desmethylimipramine, and LY368975, produce anorexic effects in the rat (Durcan et al, 1988;Gehlert et al, 1998;Billes and Cowley, 2007).…”

Serotonin controlling feeding and satiety

“…The potential cardiovascular risk of this compound is probably largely related to its adrenergic properties. The anti-obesity effects of sibutramine, however, are due to its effect on the serotonergic system, but alphaand beta-adrenoreceptors are also involved [341,342]. Assuming that only a modest weight loss will be achieved in many patients following a long period of taking the drug, safety becomes the most important issue for anti-obesity drugs.…”

Sibutramine, a serotonin–norepinephrine reuptake inhibitor, causes fibrosis in rats

“…In such a model, using Sprague-Dawley rats, Jackson et al, (1997) described the hypophagic effects of Sibutramine and identified the key adrenoreceptors and serotonergic receptors involved in its pharmacological mechanism. In a study to determine the safety of Sibutramine it was observed that, following Sibutramine 3 administration, ultrastructural changes in morphology associated with fibrosis in liver tissue in Sprague-Dawley rats fed a high energy diet that did not result in weight gain, could be observed by Oberholzer et al (2013).…”