(The FASEB Journal. 2008;22:lb612)
© 2008 FASEB
Serotonin2A (5-HT2A) receptor antagonists can be distinguished by their ability to elicit head bob behavior in the rabbit.
Vincent Aloyo,
Kuldip Dave,
Laura Scarlota and
John Harvey
Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA
ABSTRACT
Head twitches in rodents and head bobs in rabbits are behavioral assays of 5-HT2A receptor activation. We have previously demonstrated that in the rabbit head bobs are dose dependently elicited by the 5-HT2A/2C receptor agonist DOI and this behavior is inhibited by the 5-HT2A receptor antagonist ketanserin. In the current study we explored the behavioral properties of several 5-HT2A receptor antagonists (BOL, ketanserin, M100907, MDL 11939 and spiperone) in adult male New Zealand rabbits. Initially, the antagonist properties of all 5 drugs was confirmed by demonstrating that following sc administration they each attenuated head bobs elicited by the 5HT2A/2C receptor agonist DOI (0.3µmol/kg, sc). Systematic examination of the behavioral effects revealed that several of these drugs elicit head bobs by themselves in the absence of agonist. Both ketanserin (3 umol/kg) and BOL (5.8 umol/kg) did not display head bob behavior. In marked contrast, MDL 11939 (3 and 10 umol/kg), M100907 (2.5 umol/kg) and spiperone (0.75 umol/kg) all elicited head bobs, suggesting that these compounds are partial agonists at the 5-HT2A receptor. To test this hypothesis, rabbits were pretreated with ketanserin 60 min before administering the second drug. Although ketanserin robustly attenuated DOI elicited head bobs it failed to reduce head bobs elicited by MDL 11939, M100907 and spiperone. Thus, we conclude that these three antagonists are eliciting head bobs by a 5-HT2A receptor independent mechanism(s). Currently, experiments are underway to test this hypothesis.
