5-HT(2A) receptor agonism and 5-HT(2C) inverse agonism produce the same behavior, likely due to similar downstream actions at D1 receptors. Consequently, 5-HT(2C) agonism or D1 agonism may be effective therapies for disorders, such as schizophrenia, currently being treated with 5-HT(2A) antagonists.

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Rabbit head bobs are analogous to rodent head twitches and are behavioral assays of serotonin (5HT)2A receptor activation. Both are elicited by the 5HT2A/2C receptor agonist DOI and this effect is attenuated by the 5HT2A antagonist ketanserin. We have demonstrated that the 5HT2A antagonist, SR46349B (SR; Sanofi‐Synthelabo Recherche) induces rabbit head bobs which are not blocked by ketanserin thus SR does not elicit head bobs as a partial agonist at 5HT2A receptors. The current study was designed to determine if SR elicits head bobs via interaction with dopamine D1 receptors. The D1 antagonist SCH 23390 (0.05μmol/kg) was administered to New Zealand rabbits 30 min prior to DOI (0.3μmol/kg) or SR (0.26μmol/kg). In confirmation to the results obtained in rats, SCH23390 significantly attenuated DOI elicited head bobs. Similarly, SCH23390 also significantly attenuated SR elicited head bobs. SCH23390 exhibits high affinity for the D1 receptor and 25 fold lower affinity for the 5HT2A receptor. Thus, it may act as a competitive antagonist to inhibit DOI elicited head bobs. However, since ketanserin does not attenuate SR elicited head bobs, the ability of SCH23390 to interact with 5HT2A receptors cannot account for the inhibition. These results suggest DOI mediates head bobs via the expected 5HT2A receptor mechanism, but SR induces the same behavior by increasing extracellular dopamine. (MH‐16841‐39; J. A. Harvey)

Rabbit head bobs and rodent head twitches are behavioral assays of serotonin (5‐HT)2A receptor activation; each behavior can be elicited by DOI (a 5‐HT2A/2C agonist) and attenuated by ketanserin (a 5‐HT2A antagonist). 5‐HT2A receptor antagonists M100907 (M100) and MDL11939 (MDL) also elicit head bobs; however, these effects are distinguishable from DOI‐elicited responses as they are not blocked by ketanserin, suggesting a mechanism other than 5‐HT2A receptor activation. The current study examined the potential role of 5‐HT2C and dopamine (DA) receptors in inducing head bobs. Pre‐administration of the 5‐HT2C antagonist, SB242084 (1umol/kg, sc, 30 min) reduced head bobs elicited by both M100 (2.5umol/kg) and MDL (3umol/kg). Pretreatment of rabbits with the D1 antagonist SCH23390 (0.05umol/kg) also blocked M100 and MDL elicited head bobs. Moreover, administration of a D1 agonist, SKF38393 (9umol/kg) increased head bobs. To further characterize the role of 5‐HT2C receptors, we tested the response to a 5‐HT2C inverse agonist, SB206553. At a dose of 1umol/kg, we found no effect; however, a higher dose (3umol/kg) significantly increased head bobs. Consequently, head bobs may be considered an in vivo measure of 5‐HT2C inverse agonism. Finally, given the role of 5‐HT in DA release, we conclude that SB206553, M100, and MDL all induce the same behavior through 5‐HT2C inverse agonist‐mediated activation of D1 receptors.

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