Male Wistar rats were housed in cages linked to running wheels and fed on a schedule designed to reduce their body weight by 20-30%. During this period of semi-starvation the rats increased their daily running wheel activity (RWA) by up to 30 km/day. RWA could be kept at this level provided that body weight was kept constant. Different serotonin receptor (5-HT) agonists and antagonists were tested for their effects on RWA and it was found that RWA could be suppressed only by agonists with high affinity for the 5-HT1C receptor (TFMPP, mCPP, DOI and quipazine). Serotonin receptor agonists, which do not pass the blood-brain barrier, and 5-HT itself had no effect on RWA. The inhibitory effect of the agonists on RWA was prevented by pretreatment with antagonists that also had high affinity for 5-HT1C receptors (mianserin, metergoline and mesulergine). From these results we conclude that semi-starvation-induced hyperactivity can be blocked by 5-HT1C agonists. Furthermore we suggest that the animal model presented in this study might be a useful tool for in vivo studies on selective 5-HT1C receptor activation.