PMID- 23932919
OWN - NLM
STAT- MEDLINE
DCOM- 20140715
LR  - 20161125
IS  - 1873-5177 (Electronic)
IS  - 0091-3057 (Linking)
VI  - 110
DP  - 2013 Sep
TI  - Tesofensine induces appetite suppression and weight loss with reversal of low 
      forebrain dopamine levels in the diet-induced obese rat.
PG  - 265-71
LID - S0091-3057(13)00186-X [pii]
LID - 10.1016/j.pbb.2013.07.018 [doi]
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, 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.
CI  - (c) 2013 Elsevier Inc. All rights reserved.
FAU - Hansen, Henrik H
AU  - Hansen HH
AD  - Department of Pharmacology, Neurosearch A/S, Pederstrupvej 93, DK-2750 Ballerup, 
      Denmark. Electronic address: hbh@gubra.dk.
FAU - Jensen, Majbrit M
AU  - Jensen MM
FAU - Overgaard, Agnete
AU  - Overgaard A
FAU - Weikop, Pia
AU  - Weikop P
FAU - Mikkelsen, Jens D
AU  - Mikkelsen JD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130807
PL  - United States
TA  - Pharmacol Biochem Behav
JT  - Pharmacology, biochemistry, and behavior
JID - 0367050
RN  - 0 (Appetite Depressants)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - BLH9UKX9V1 (Tesofensine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Appetite/*drug effects
MH  - Appetite Depressants/*pharmacology
MH  - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology
MH  - *Diet
MH  - Dopamine/*metabolism
MH  - In Situ Hybridization
MH  - Male
MH  - Obesity/*metabolism
MH  - Prosencephalon/*drug effects/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Weight Loss/*drug effects
OTO - NOTNLM
OT  - Dopamine
OT  - Obesity
OT  - Prefrontal cortex
OT  - Striatum
OT  - Tesofensine
OT  - Weight loss
EDAT- 2013/08/13 06:00
MHDA- 2014/07/16 06:00
CRDT- 2013/08/13 06:00
PHST- 2013/03/26 00:00 [received]
PHST- 2013/07/15 00:00 [revised]
PHST- 2013/07/26 00:00 [accepted]
PHST- 2013/08/13 06:00 [entrez]
PHST- 2013/08/13 06:00 [pubmed]
PHST- 2014/07/16 06:00 [medline]
AID - S0091-3057(13)00186-X [pii]
AID - 10.1016/j.pbb.2013.07.018 [doi]
PST - ppublish
SO  - Pharmacol Biochem Behav. 2013 Sep;110:265-71. doi: 10.1016/j.pbb.2013.07.018. 
      Epub 2013 Aug 7.