A novel behavioral model that discriminates between 5-HT2A and 5-HT2C receptor activation

2,5-Dimethoxy-4-iodoamphetamine (DOI), a serotonin (5-HT)2A/2C receptor agonist, elicits shaking behaviors in rodents, which have been reliably quantified as behavioral correlates of 5-HT2A receptor activation. Such studies are lacking in the rabbit. As part of our research examining the role of the 5-HT2 receptor in rabbits, we analyzed the behavioral effects of systemically administered DOI in rabbits. DOI (0.01-3 micromol/kg) or vehicle was injected, and two distinct behaviors, head bobs (vertical head movements) and body shakes (wet dog shakes), were counted for 90 min following the injection. DOI dose-dependently increased the number of head bobs and body shakes. The selective 5-HT2A receptor antagonist ketanserin (1-3 micromol/kg), 1 h before DOI (0.3 micromol/kg) challenge, significantly attenuated head bobs, but not body shakes. In contrast, the selective 5-HT2C receptor antagonists SDZ SER 082 (1-3 micromol/kg) and SB 206553 (1 micromol/kg) 30 min before challenge, significantly reduced body shakes but not head bobs produced by the same dose of DOI. This study establishes that, in rabbits, DOI mediates head bobs via 5-HT2A receptors and body shakes via 5-HT2C receptors. Thus, the rabbit provides a novel behavioral assay that discriminates between 5-HT2A and 5-HT2C receptor activation.