The role of serotonin-2 (5-HT2) and dopamine receptors in the behavioral actions of the 5-HT2A/2C agonist, DOI, and putative 5-HT2C inverse agonist, SR46349B

Rationale

Atypical antipsychotic efficacy is often attributed to actions at serotonin-2 (5-HT₂) and dopamine receptors, indicating a potential benefit of understanding the interplay between these systems. Currently, it is known that 5-HT₂ receptors modulate dopamine release, although the role of specific dopamine receptors in 5-HT₂-mediated behavior is not well understood.

Objectives

We examined the role of 5-HT_2A, 5-HT_2C, and dopamine (D1 and D2) receptors in the behavioral response to a 5-HT_2A/2C agonist (DOI) and 5-HT_2A/2C antagonist (SR46349B).

Materials and methods

Effects were assessed by measuring rabbit head bobs (previously characterized as 5-HT_2A receptor-mediated) and body shakes (5-HT_2C-mediated).

Results

As expected, DOI produced head bobs and body shakes, and these DOI-elicited behaviors were attenuated by the SR46349B pretreatment. Unexpectedly, SR46349B also induced head bobs when administered alone. However, SR46349B-elicited head bobs are distinguishable from those produced by DOI since the 5-HT_2A antagonist, ketanserin, only attenuated DOI-elicited head bobs. Conversely, 5-HT_2C ligands (SB242084 and SB206553) inhibited SR46349B but not DOI-induced head bobs. Furthermore, when administered alone, SB206553 (a 5-HT_2C inverse agonist) produced head bobs, indicating the behavior can be either 5-HT_2A or 5-HT_2C mediated. Next, it was revealed that D1 and D2 receptors play a role in DOI-elicited head bobs, but only D1 receptors are required for SR46349B-elicited head bobs.

Conclusions

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.