Study summary · research use only
Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in diet-induced obese (DIO) rats examined tesofensine, a triple monoamine reuptake inhibitor that inhibits noradrenaline, 5-HT, and dopamine reuptake, assessing appetite, weight, and forebrain dopamine levels via microdialysis in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), compared with age-matched chow-fed rats. Tesofensine treatment (2.0 mg/kg/day for 14 days) caused an anorexigenic and weight-reducing response in DIO rats, which also showed reduced baseline extracellular dopamine levels in the NAcc and PFC versus chow-fed rats. Acute tesofensine (2.0 mg/kg) normalized accumbal dopamine levels in DIO rats but not chow-fed rats, evoked a stronger stimulatory response on NAcc/PFC dopamine in DIO rats, and altered striatal dopamine D2 receptor expression and transporter binding. The authors suggest tesofensine's anti-obesity effects are, at least in part, associated with modulation of central dopaminergic activity.
Abstract
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, but whether 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 together with 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.
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