Mianserin‐induced 5‐HT₂ receptor downregulation results in anxiolytic effects in the elevated plus‐maze test

Abstract

Benjamin, D., E.I. Saiff, T. Nevins, and H. Lal: Mianserin-induced 5-HT2 receptor downregulation results in anxiolytic effects in the elevated plus-maze test. Drug Dev. Res. 26~287-297, 1992. Several agents that downregulate 5-Hl-2 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-HT,/5-HTlc agonist was assessed, and in a separate group of animals 5-HTlA, 5-HT1,, 5-HTl ,, p1,p2, 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 DO1 were also dose-dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5-HT, receptor antagonist, 7-amino-8 ['251]ketanserin was decreased by 50%. Binding of DO1 to 5-HT, receptors was decreased by 46%, and to 5-HT,c 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-HT, system is necessary for the full expression of the anxiety-like response, but the role of

Animal models of the anxiogenic effects of ethanol withdrawal

“…A potential mechanism for the delayed onset of effect is provided by the report that binding of selective ligands to 5-HT 2A and 5-HT 2C receptors were significantly reduced 48 h after pretreatment with mianserin [Benjamin et al, 1992]. Binding to 5-HT 1A , 5-HT 1B , and β-adrenergic receptors were not effected.…”

“…5-HT 2 antagonists have been found to reverse anxiety-like behaviors in the EPM during EW. Single doses of mianserin, a 5-HT 2 antagonist, given either 2 or 7 days before cessation of ethanol, blocked the development of anxiogenic signs in the EPM during EW [Benjamin et al, 1992;Lal et al, 1993;Prather et al, 1991b]. Little effect was seen at 15 min after administration of mianserin.…”

(�)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2), a novel putative anxiolytic agent lacking affinity for benzodiazepine sites and serotonin-1A receptors

“…Also, the anxiolytic effects of 5-HT2 antagonists can be overcome by agonists of these receptors. In addition, it has been suggested that 5-HT2 receptors may play an inhibitory role on plus-maze behavior and that a down-regulation of these receptors may be responsible for the anxiolytic profile observed 48 h after mianserin administration (Benjamin et al 1992). Thus, a different explanation for the mechanism of action could be offered.…”