Vol. 299, Issue 3, 1066-1072, December 2001

Selective and Divergent Regulation of Cortical 5-HT_2A Receptors in Rabbit

Vincent J. Aloyo, Kuldip D. Dave, Tariq Rahman and John A. Harvey

Department of Pharmacology and Physiology, MCP-Hahnemann University, Philadelphia, Pennsylvania

It is well established that repeated administration of both 5-hydroxytryptamine₂ (5-HT₂) receptor agonists and antagonists decreases the density of 5-HT_2A and 5-HT_2C receptors. However, the regulation of these two receptors has not been studied in the same tissue. Therefore, we examined the effects of repeated daily injections of the 5-HT₂ receptor agonists (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and D-lysergic acid diethylamide (LSD) and the antagonists d-2-bromolysergic acid diethylamide hydrogen tartrate (BOL) and -phenyl-2-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939) on rabbit cortical 5-HT_2A and 5-HT_2C receptors. Repeated administration of DOI, LSD, or BOL decreased cortical 5-HT_2A receptor density but had no effect on the density of cortical 5-HT_2C receptors. Repeated administration of the selective 5-HT_2A receptor antagonist MDL 11,939 significantly increased 5-HT_2A receptor density. This unexpected outcome also occurred without any change in cortical 5-HT_2C receptor density. The down-regulation of 5-HT_2A receptors produced by chronic administration of BOL was associated with a decrease in DOI-elicited head bobs, whereas 5-HT_2A receptor up-regulation produced by MDL 11,939 was associated with an increase in DOI-elicited head bobs compared with controls. These studies demonstrate that 5-HT_2A receptor antagonists can both down- and up-regulate the density of cortical 5-HT_2A receptors and these changes in receptor density have functional consequences for 5-HT_2A receptor-mediated behaviors. Furthermore, because DOI, LSD, and BOL have approximately equal affinities for the 5-HT_2A and 5-HT_2C receptors, these results suggest that different mechanisms regulate 5-HT_2A and 5-HT_2C receptor density, in that chronic occupation of 5-HT_2C receptors does not modulate their density in rabbit frontal cortex.