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

• Published in: Psychopharmacology 2011-02, Vol.213 (2-3), p.393-401
• Main Authors: Scarlota, Laura C., Harvey, John A., Aloyo, Vincent J.
• Format: Article
• Language: English
• Subjects: Amphetamines - pharmacology; Animals; Antipsychotic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Fluorobenzenes - pharmacology; Head Movements - drug effects; Male; Neurosciences; Original Investigation; Pharmacology/Toxicology; Phenols - pharmacology; Psychiatry; Rabbits; Receptor, Serotonin, 5-HT2A - drug effects; Receptor, Serotonin, 5-HT2A - metabolism; Receptor, Serotonin, 5-HT2C - drug effects; Receptor, Serotonin, 5-HT2C - metabolism; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Receptors, Dopamine D1 - drug effects; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - metabolism; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-1928-2

Rationale Atypical antipsychotic efficacy is often attributed to actions at serotonin-2 (5-HT 2 ) and dopamine receptors, indicating a potential benefit of understanding the interplay between these systems. Currently, it is known that 5-HT 2 receptors modulate dopamine release, although the role of specific dopamine receptors in 5-HT 2 -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.