Action of SR46349B suggests new mechanism for head bob behavior in the rabbit

Abstract

Rabbit head bobs are analogous to rodent head twitches as each are behavioral assays of serotonin (5HT)2A receptor activation. In the current study, the 5HT2A antagonist, SR46349B (SR; gift from Sanofi-Synthelabo Recherche), was used to better understand 5HT involvement in the rabbit model. Initially, the antagonist properties of SR were confirmed by demonstrating that SR (0.26μmol/kg, sc) attenuates head bobs elicited by the 5HT2A/2C receptor agonist DOI (0.3μmol/kg, sc). However, administration of SR by itself significantly increased head bobs relative to vehicle. This increase was comparable to the number of head bobs elicited by DOI. To examine whether the behavior was a result of 5HT2A activation, the rabbits were injected with the selective 5HT2A antagonist, ketanserin (3μmol/kg, sc) 1h before either SR or DOI. During the pretreatment period, ketanserin did not significantly alter head bobs relative to vehicle. Ketanserin significantly attenuated DOI elicited head bobs, indicating the behavior was 5HT2A receptor mediated. In contrast, ketanserin had no significant effect on the SR-induced head bobs. These results suggest that while DOI mediates head bobs via the expected 5HT2A receptor mechanism, SR induces the same behavior through a novel mechanism. This result is in keeping with the allosteric nature of SR interaction with 5HT2A receptors.(Grant MH-16841-38; J.A.Harvey)