Pharmacological and behavioral characterization of the 5-HT2A receptor in C57BL/6N mice

The serotonin (5-HT) 2A receptor is implicated in numerous psychiatric disorders, making it an important, clinically relevant target. Despite the availability of transgenic mouse lines, the native mouse 5-HT2A receptor is not well-characterized. The goals of the current study were to determine 5-HT2A and 5-HT2C receptor densities in mouse cortex, establish a pharmacological profile of the mouse 5-HT2A receptor, and determine the effects of chronic drug treatment on 5-HT2A receptor density and 5-HT2A receptor-mediated behavior. Receptor densities were determined in cortex and frontal cortex via saturation binding assays using [H-3]ketanserin or [H-3]mesulergine. A pharmacological profile was established by displacing [H-3]ketanserin binding with several ligands. Chronic treatment with 5-HT2A/2C receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), 5-HT2A receptor antagonist, MDL 11939, or vehicle was followed by 5-HT2A receptor density determination. Head twitch responses (HTRs) were counted on select days. Mice had high 5-HT2A, but low 5-HT2C receptor densities. Ligand binding affinities for mouse 5-HT2A receptors correlated with rat, but not rabbit or human, affinities. Chronically DOI-treated mice displayed reduced HTRs and 5-HT2A receptor density compared to saline-treated mice. Receptor density was unchanged following chronic treatment with MDL 11939. The current study provides some basic information about mouse 5-HT2A and 5-HT2C receptors and provides comparisons to rats, rabbits, and humans. The current chronic agonist treatment study demonstrated an important similarity between the 5-HT2A receptor in mice, rats, and rabbits, while antagonist treatment revealed an interesting difference from previous studies in rabbits.