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, β1,β2, 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(125I)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. © 1992 Wiley‐Liss, Inc.
Drug Development Research – Wiley
Published: Jan 1, 1992
Keywords: serotonin; anxiety; 5‐HT 1C ; receptors; autoradiography
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