The Time-Course for Up- and Down-Regulation of the Cortical 5-Hydroxytryptamine (5-HT)_2A Receptor Density Predicts 5-HT_2A Receptor-Mediated Behavior in the Rabbit

Abstract

5-Hydroxytryptamine (serotonin; 5-HT)₂ receptor agonists such as (±)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) injected systemically or directly into frontal cortex, elicit stereotyped head movements that are mediated by 5-HT_2A receptors. Chronic administration of 5-HT_2A receptor antagonists can produce either a down-regulation, e.g., d-2-bromolysergic acid diethylamide (BOL) or an up-regulation, e.g., α-phenyl-10(2-phenylethyl)-4-piperidinemethanol (MDL11,939) of cortical 5-HT_2A receptors in the rabbit with no change in the density of the 5-HT_2C receptor. We examined the degree to which the time course for the onset and offset of changes in cortical 5-HT_2A receptor density was correlated with functional changes as measured by the magnitude of DOI elicited, 5-HT_2A receptor-mediated head movements (head bobs). First, the magnitude of DOI-elicited head bobs was measured over 1 to 8 days after chronic BOL (5.8 μmol/kg), MDL11,939 (10 μmol/kg), or vehicle administration. Second, rabbits were injected with BOL, MDL11,939, or vehicle once daily for 8 days, and then, 1 to 8 days after the cessation of drug or vehicle, DOI-elicited head bobs were determined. Samples of frontal cortex were obtained for each animal immediately following behavioral testing, and 5-HT_2A receptor density was measured using [³H]ketanserin. Thus, each animal provided a value for receptor density and number of head bobs, and these two measures showed a high degree of correlation between 0.94 for BOL and 0.95 for MDL11,939. This study establishes that the density of 5-HT_2A receptors in cortex reflects their functional status.