Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor.
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'.
Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
Anna
A
Sławińska
Joanna M
JM
Wierońska
Katarzyna
K
Stachowicz
Agnieszka
A
Pałucha-Poniewiera
Michelle A
MA
Uberti
Maria A
MA
Bacolod
Dario
D
Doller
Andrzej
A
Pilc
D000494:Allosteric Regulation / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology
D000813:Anilides; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003509:Cyclohexanecarboxylic Acids; D058787:GABA-A Receptor Antagonists; C581971:N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide; D010879:Piperazines; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D012702:Serotonin Antagonists; D016713:Ritanserin; D012701:Serotonin; D005442:Flumazenil; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C108823:metabotropic glutamate receptor 4