MIANSERIN-INDUCED 5-HT(2) RECEPTOR DOWN-REGULATION RESULTS IN ANXIOLYTIC EFFECTS IN THE ELEVATED PLUS-MAZE TEST

Several agents that downregulate 5-HT2 receptors produce anxiolytic effects in humans, but the role of 5-HT2 receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5-HT2 receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5-HT2 receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus-maze. Following testing in the elevated maze, the head-shake response to 4-iodo-R-(-)-2,5-dimethoxyphenylisopropylamine (DOI), a selective 5-HT2/5-HT1C agonist was assessed, and in a separate group of animals 5-HT1A, 5-HT1B, 5-HT1C, beta-1,beta-2, and 5-HT2 agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose-related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head-shakes induced by DOI were also dose-dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5-HT2 receptor antagonist, 7-amino-8 [I-125]ketanserin was decreased by 50%. Binding of DOI to 5-HT2 receptors was decreased by 46%, and to 5-HT1C receptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5-HT2 receptor plays at least a permissive role in anxiety-like behaviors, since an intact 5-HT2 system is necessary for the full expression of the anxiety-like response, but the role of 5-HT1C receptor downregulation in the effects of mianserin cannot be ruled out at this time.