Inverse Agonism at [alpha]2A Adrenoceptors Augments the Hypophagic Effect of Sibutramine in Rats

Because the use of monoamine reuptake inhibitors as weight-reducing agents is limited by adverse effects, novel antiobesity drugs are needed. We studied acute effects of the noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor sibutramine (SIB), alone and after pretreatment with 1- and 2-adrenoceptor (AR), and 5-HT1/2/7, 5-HT1B and 5-HT2C receptor antagonists in order to determine which ARs and 5-HT receptors act downstream of SIB on feeding and locomotion. Acute effects on caloric and water intake, meal microstructure and locomotion were assessed, using an automated weighing system and telemetry in male rats with restricted 18-h access to Western style diet. SIB 3 mg/kg reduced meal size and frequency, which suggests enhanced within- and postmeal satiety. Imiloxan (2B-AR), WB4101 (1-AR), SB-224289 (5-HT1B), and modestly BRL 44408 (2A/D-AR) attenuated SIBs effect on meal size, suggesting that 2B- and 1-ARs and 5-HT1B receptors mediate within-meal satiety, with a modest role for 2A/D-ARs. Only prazosin (1/2B/2C-AR) counteracted SIBs effect on meal frequency. At 3 mg/kg, SIB modestly increased locomotion. This effect was blocked by metergoline (5-HT1/2/7), WB4101 (1-AR), and RX821002 (2-AR). Interestingly, the 2-AR antagonists atipamezole and RX821002 enhanced SIBs effect on caloric intake, probably due to inverse agonistic actions at 2A-autoreceptors that further enhanced release of NA that regulates caloric intake. Thus, an inverse agonist of presynaptic 2A-ARs might beneficially enhance SIBs weight-reducing effect and offer novel treatment for obesity. All in all, the present data supports the ARs and 5-HT receptors involved in the effects of SIB on different aspects of caloric intake and locomotion. [PUBLICATION ABSTRACT]