Abstract
Since 5-HT6 receptors play role in controlling feeding and satiety and dopamine is essential for normal feeding behavior, we evaluated the ability of EMD 386088—5-HT6 receptor partial agonist and dopamine transporter inhibitor—to reduce body weight in obese rats, as well as its anorectic properties (calorie intake reduction) in rat model of excessive eating and the influence on metabolism (plasma glucose and glycerol levels). We also determined the effect of the studied compound on pica behavior in rats and its influence on blood pressure after single administration. EMD 386088 reduced body weight in obese rats fed high-fat diet and decreased calorie intake in both models applied (rat model of obesity and of excessive eating). In both models EMD 386088 regulated plasma glucose and increased plasma glycerol levels. The latter proves that the compound reduced body fat. We think that it might have increased lipolysis, but this requires further studies. The reduction in glucose levels is the first symptom of metabolic disorders compensation. EMD 386088 did not cause pica behavior in rats but increased blood pressure after single administration. We think that partial 5-HT6 agonists might have potential in the treatment of obesity. Thus, EMD 386088 requires extended studies.
Highlights
The distribution of serotonergic 5-HT6 receptors within the central nervous system includes hypothalamic regions, which play important role in appetite, food intake, and body weight control (Heal et al, 2008)
EMD 386088 administered intraperitoneally at a dose of 5 mg/kg b.w. to rats fed high-fat diet caused a significant decrease in body weight gain compared with the obese rats
We found that EMD 386088—a partial 5-HT6 agonist and dopamine transporter inhibitor—reduced body weight and decreased calorie intake in obese rats and in the rat model of excessive eating
Summary
The distribution of serotonergic 5-HT6 receptors within the central nervous system includes hypothalamic regions, which play important role in appetite, food intake, and body weight control (Heal et al, 2008). Studies indicated that 5-HT6 receptor ligands might have anti-obesity activity (Woolley et al, 2001; Heal et al, 2008; Karila et al, 2015). The 5-HT6 receptor antagonists (i.e., PRX-07034, Ro 04-6790, BVT 5182, SB 271046) decreased food intake by enhancing satiety and caused profound weight-loss in various rodent models of obesity (Heal et al, 2008; Karila et al, 2015). The compound caused significant hypophagia in non-obese and diet-induced obese rats (Fisas et al, 2006; Heal et al, 2008).
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