5‐HT1A Activation Counteracts Cardiovascular But Not Hypophagic Effects of Sibutramine in Rats

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.