Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor

Neuropharmacology. 2013 Mar;66:225-35. doi: 10.1016/j.neuropharm.2012.05.001. Epub 2012 May 23.


Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / physiology*
  • Anilides / pharmacology*
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Flumazenil / pharmacology
  • GABA-A Receptor Antagonists / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / physiology*
  • Ritanserin / pharmacology
  • Serotonin / metabolism
  • Serotonin Antagonists / pharmacology


  • Anilides
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Cyclohexanecarboxylic Acids
  • GABA-A Receptor Antagonists
  • N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide
  • Piperazines
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Serotonin Antagonists
  • Ritanserin
  • Serotonin
  • Flumazenil
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • metabotropic glutamate receptor 4