The
noradrenaline (NA) and
serotonin reuptake inhibitor,
sibutramine, gives effective
weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and
serotonin transporters to
sibutramine's hypophagic and cardiovascular effects, and whether selective
5-hydroxytryptamine (5-HT(1A)) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy.
Sibutramine (1-10 mg/kg p.o.) dose-dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate.
Sibutramine gave greater occupancy of NA than
serotonin reuptake sites. Coadministration of the selective 5-HT(1A) agonist
F-11440 (2.5 mg/kg p.o.) attenuated
sibutramine-induced
hypertension and
tachycardia without altering its food intake effects. The selective NA reuptake inhibitors,
nisoxetine or
reboxetine, did not alter food intake alone, but each reduced food intake when combined with
F-11440. These results suggest that
sibutramine-induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5-HT(1A) activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5-HT(1A) activation. Hence increased synaptic
serotonin, via
serotonin reuptake inhibition or 5-HT(1A) activation, together with increased NA, would appear to produce hypophagia. Thus
weight loss with minimal cardiovascular risk could be achieved by 5-HT(1A) activation combined with NA transporter blockade.