TY - JOUR
T1 - Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat
AU - Hansen, Henrik H
AU - Jensen, Majbrit M
AU - Overgaard, Agnete
AU - Weikop, Pia
AU - Mikkelsen, Jens D
PY - 2013
Y1 - 2013
N2 - Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, butwhether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss togetherwith reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.
AB - Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, butwhether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss togetherwith reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.
U2 - 10.1016/j.pbb.2013.07.018
DO - 10.1016/j.pbb.2013.07.018
M3 - Journal article
SN - 0091-3057
VL - 110
SP - 265
EP - 271
JO - Pharmacology, Biochemistry and Behavior
JF - Pharmacology, Biochemistry and Behavior
ER -
