Acute and chronic effects of serotonin (5HT) antagonists on serotonin binding sites.

The administration of 14 daily doses of cyproheptadine, BC-105, metergoline and methysergide induced a marked decrease in the number (Bmax) of 3H-spiroperidol binding sites (5HT2 sites) in frontal cortex, when assayed 48 h after the last dose; the apparent affinity (KD) of 3H-spiroperidol was not changed. The same treatment schedules failed to modify the KD and Bmax values for 3H-5HT binding to the 5HT1 site in the hippocampus. Cyproheptadine, BC-105 and methysergide, but not metergoline, decreased the density of 5HT2 sites in frontal cortex 48 h after a single dose. Additional studies of the decrease in 3H-spiroperidol binding after in vivo treatment with cyproheptadine showed that the extent of binding loss was unaltered by repeated washing. Furthermore, cyproheptadine added in vitro to membranes isolated from frontal cortex inhibited the binding of 3H-spiroperidol in a competitive manner; Scatchard plots were linear with the same maximum binding (Bmax) and different slopes. Therefore, these preliminary studies suggest that the loss of 5HT2 binding sites after in vivo treatment with cyproheptadine and with other 5HT antagonists may reflect an adaptive response. This apparent paradoxical effect suggests that the action of these drugs at the 5HT2 binding sites should be reevaluated.