Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models

PLoS One. 2015 Nov 10;10(11):e0142499. doi: 10.1371/journal.pone.0142499. eCollection 2015.

Abstract

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / drug therapy*
  • Depression / drug therapy*
  • Locomotion / drug effects
  • Male
  • Mice
  • Models, Animal*
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology
  • Serotonin Antagonists / therapeutic use*

Substances

  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A

Grants and funding

This study was supported by Jagiellonian University grant number K/DSC/001955 and Silesian University of Technology grant number BK 227/RAu1/2015/1. The research was partially performed on the infrastructure supported by POIG.02.03.01-24-099/13 grant: “GeCONiI–Upper Silesian Center for Computational Science and Engineering”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.