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.2010 Jun;35(7):1464-76.
doi: 10.1038/npp.2010.16. Epub 2010 Mar 3.

Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

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Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

Anne Marie D Axel et al. Neuropsychopharmacology.2010 Jun.

Abstract

Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED(50) of 1.3 mg/kg. The hypophagic response of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, alpha(1) adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D(1) receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, alpha(2) adrenoceptor antagonist), haloperidol (0.03 mg/kg, D(2) receptor antagonist), NGB2904 (0.1 mg/kg, D(3) receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT(2A/C) receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate alpha(1) adrenoceptor and DA D(1) receptor function.

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Figures

Figure 1
Figure 1
High-fat diet (Research Diets #D12492, 60% fat kcal., energy density 5.24 kcal/g) induces a significantly higher body weight gain over 10 weeks, as compared with rats receiving standard chow (Altromin 1324, 10% fat kcal, energy density 2.85 kcal/g). Data are shown as mean±SEM*p<0.05;**p<0.01;***p<0.001.
Figure 2
Figure 2
Tesofensine induces hypophagia in the DIO rat. (a) Dose–response effect of tesofensine (0.1–3.0 mg/kg, s.c.,n⩾6 per group) on total food intake in the DIO rat during a 12 h nocturnal period. Total food intake over the entire observation period is shown in gram (lefty-axis) as well as relative to vehicle-treated DIO rats (righty-axis). (b) Time–response effect of incrementing doses of tesofensine (0.1–3.0 mg/kg, s.c.) on cumulated nocturnal food intake (2 h intervals). Data are shown as mean±SEM**p<0.01;***p<0.001.
Figure 3
Figure 3
Temoral pharmacodynamics of acute tesofensine treatment in the DIO rat. Time–response effect of tesofensine (1.5 mg/kg, s.c.,n=6) or saline vehicle (n=6) on food intake during a 72 h monitoration period. Upper panel, 12 h interval data points. Lower panel, 2 h interval data points with dark and white horizontal bars below thex-axis indicating dark and light phases, respectively. The arrow denotes when tesofensine or vehicle was administered. Data are shown as mean±SEM***p<0.001 (compared with vehicle controls).
Figure 4
Figure 4
Feeding kinetics of tesofensine-induced hypophagia in the DIO rat. (0.1–3.0 mg/kg, s.c.,n⩾6 per group, overall dose–response effects on food intake in the same animals are shown in Figure 1). (a) total number of meals, (b) average meal size, (c) average meal duration, (d) latency to first meal, and (e) first meal size during a 12 h nocturnal period. Data are shown as mean±SEM*p<0.05,**p<0.01,***p<0.001 (compared with vehicle controls).
Figure 5
Figure 5
Tesofensine-induced hypophagia is dependent on stimulatedα1 adrenoceptor function. Effect of prazosin (1.0 mg/kg, s.c.) on tesofensine-induced (1.5 mg/kg, s.c.) hypophagia in the DIO rat. (a) Total food intake (gram, lefty-axis; relative to vehicle controls, righty-axis) and (b) cumulated food intake (gram) during 12 h nocturnal period. Data are shown as mean±SEM*p<0.05,**p<0.01,***p<0.001 (compared with vehicle controls);###p<0.001 (compared with vehicle+tesofensine).
Figure 6
Figure 6
Tesofensine-induced hypophagia is dependent on stimulated DA D1 receptor function. Effect of SCH23390 (0.03 mg/kg, s.c.) on tesofensine-induced (1.5 mg/kg, s.c.) hypophagia in the DIO rat. (a) Total food intake (gram, lefty-axis; relative to vehicle controls, righty-axis) and (b) cumulated food intake (gram) during 12 h nocturnal period. Data are shown as mean±SEM*p<0.05,**p<0.01,***p<0.001 (compared with vehicle controls);#p<0.05,##p<0.01 (compared with vehicle+tesofensine).
Figure 7
Figure 7
Tesofensine-induced hypophagia does not involveα2 adrenoceptor, DA D2, DA D3, or 5-HT2A/C receptor function. Effect of (a) RX821002 (0.3 mg/kg, s.c.), (b) haloperidol (0.03 mg/kg, s.c.), (c) NGB2904 (0.1 mg/kg, s.c.), or (d) ritanserin (0.03 mg/kg, s.c.) on tesofensine-induced (1.5 mg/kg, s.c.) hypophagia in the DIO rat. Data are shown total nocturnal food intake (gram) as mean±SEM**p<0.01,***p<0.001 (compared with vehicle controls).
Figure 8
Figure 8
Chronic tesofensine treatment causes a sustained body weight reduction with a temporal suppressive effect on food intake. Effect of a daily dose of tesofensine (2.0 mg/kg, s.c.) on body weight gain (a) and food intake (b) over a 16-day treatment period. Data are shown as mean±SEM*p<0.05,**p<0.01,***p<0.001 (compared with vehicle controls).
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