Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats.
The acute effects of systemic administration of the anti-obesity agent sibutramine on extracellular dopamine (DA) in the nucleus accumbens of freely moving rats were studied using in vivo microdialysis and compared with the actions of phentermine and d-amphetamine at doses 1x and 3x their respective 2 h ED(50) values to reduce food intake in rats. At the lower dose, sibutramine did not elevate extracellular DA concentrations; however, at the higher dose (6.0 mg kg(-1), i.p.) it caused a modest and prolonged increase in extraneuronal DA. A maximal rise was observed at 60 min post-sibutramine treatment (+231% compared to controls) with DA levels remaining elevated for up to 160 min post treatment. In contrast, phentermine and d-amphetamine significantly enhanced DA efflux at both the lower and higher doses. These elevations of DA levels were significantly greater than that seen with the corresponding dose of sibutramine over 0-80 min post treatment. Maximal rises in DA levels resulting from the higher dose of each drug were +733% (phentermine, 3.9 mg kg(-1), i.p.) and +603% (d-amphetamine, 1.5 mg kg(-1), i.p.) compared to controls 40 min post treatment. The highest doses of phentermine and d-amphetamine increased rat locomotor activity up to 100 min and 160 min post treatment, respectively, whereas the equivalent sibutramine dose had no effect. These findings therefore suggest that dopaminergic reward mechanisms are not involved in the reduction of food intake by sibutramine. Furthermore, they are consistent with the view that sibutramine lacks abuse potential.
Rowley
H L
HL
BASF Pharma Research and Development, Nottingham, UK. Helen.Rowley@basf-pharma.co.uk
Butler
S A
SA
Prow
M R
MR
Dykes
S G
SG
Aspley
S
S
Kilpatrick
I C
IC
Heal
D J
DJ
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010645:Phentermine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001067:Appetite Depressants; D000697:Central Nervous System Stimulants; D003503:Cyclobutanes; D010645:Phentermine; D003913:Dextroamphetamine; D004298:Dopamine; C058254:sibutramine